A-1 APPENDIX 1: LITERATURE SEARCH STRATEGY $ Truncation symbol adj Adjacent (i.e., terms are near/next to one another, any order) adj# Adjacent within # of words ti Title ab Abstract kw Keyword sh Subject heading/descriptor exp Explode subject heading fs Floating subject heading pt Publication type tn Trade name rn Registry number (i.e., CAS) tw Text word hw Heading word DATABASES LIMITS KEYWORDS/DESCRIPTORS Ovid - Medline - Medline In-Process & Other Non- Indexed Citations - EMBASE - BIOSIS Previews Human Systematic Reviews/Meta-Analyses Medline In-Process & Other Non-Indexed Citations 1. Octreotid$.ti,ab. 2. Longastatin$.ti,ab. 3. DRG-0115.ti,ab. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab. 8. 83150-76-9.rn. 9. or/1-8 10. ((meta adj analy$) or metaanaly$ or (met adj analy$) or metanaly$ or (health adj technology adj assessment$) or hta$1).ti,ab. 11. (technology adj assessment$ adj2 biomedical).ti,ab. 12. (technology adj assessment$ adj2 bio-medical).ti,ab. 13. ((systematic$ adj ((literature adj review$) or review$ or overview$)) or (methodologic$ adj ((literature adj review$) or review$ or overview$))).ti,ab. 14. ((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ or overview$))).ti,ab. 15. ((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or overview$)) or (pool$ adj analy$)).ti,ab. 16. or/10-15 17. 9 and 16 Medline 1. Octreotid$.ti,ab. 2. Longastatin$.ti,ab. 3. DRG-0115.ti,ab. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab.
Transcript
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APPENDIX 1: LITERATURE SEARCH STRATEGY $ Truncation symbol adj Adjacent (i.e., terms are near/next to one another, any order) adj# Adjacent within # of words ti Title ab Abstract kw Keyword sh Subject heading/descriptor exp Explode subject heading fs Floating subject heading pt Publication type tn Trade name rn Registry number (i.e., CAS) tw Text word hw Heading word DATABASES LIMITS KEYWORDS/DESCRIPTORS Ovid - Medline - Medline In-Process & Other Non-Indexed Citations - EMBASE
- BIOSIS Previews
Human
Systematic Reviews/Meta-Analyses Medline In-Process & Other Non-Indexed Citations 1. Octreotid$.ti,ab. 2. Longastatin$.ti,ab. 3. DRG-0115.ti,ab. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab. 8. 83150-76-9.rn. 9. or/1-8 10. ((meta adj analy$) or metaanaly$ or (met adj analy$) or metanaly$ or (health adj technology adj assessment$) or hta$1).ti,ab. 11. (technology adj assessment$ adj2 biomedical).ti,ab. 12. (technology adj assessment$ adj2 bio-medical).ti,ab. 13. ((systematic$ adj ((literature adj review$) or review$ or overview$)) or (methodologic$ adj ((literature adj review$) or review$ or overview$))).ti,ab. 14. ((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ or overview$))).ti,ab. 15. ((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or overview$)) or (pool$ adj analy$)).ti,ab. 16. or/10-15 17. 9 and 16 Medline 1. Octreotid$.ti,ab. 2. Longastatin$.ti,ab. 3. DRG-0115.ti,ab. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab.
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DATABASES LIMITS KEYWORDS/DESCRIPTORS 8. 83150-76-9.rn. 9. or/1-8 10. ((meta adj analy$) or metaanaly$ or (met adj analy$) or metanaly$ or (health adj technology adj assessment$) or hta$1).ti,ab. 11. (technology adj assessment$ adj2 biomedical).ti,ab. 12. (technology adj assessment$ adj2 bio-medical).ti,ab. 13. ((systematic$ adj ((literature adj review$) or review$ or overview$)) or (methodologic$ adj ((literature adj review$) or review$ or overview$))).ti,ab. 14. ((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ or overview$))).ti,ab. 15. ((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or overview$)) or (pool$ adj analy$)).ti,ab. 16. Meta-Analysis.pt. 17. Meta-Analysis.sh. 18. exp Technology Assessment, Biomedical/ 19. or/10-18 20. 9 and 19 EMBASE 1. *Octreotide/ 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. Sandostatin.tn. 10. Sandostatin LAR.tn. 11. Omega.tn. 12. Octreotide.tn. 13. Longastatin.tn. 14. or/1-13 15. Meta-Analysis.sh. 16. Systematic review.sh. 17. Biomedical Technology Assessment.sh. 18. ((meta adj analy$) or metaanaly$ or (met adj analy$) or metanaly$ or (health adj technology adj assessment$) or hta$1).ti,ab. 19. (technology adj assessment$ adj2 biomedical).ti,ab. 20. (technology adj assessment$ adj2 bio-medical).ti,ab. 21. ((systematic$ adj ((literature adj review$) or review$ or overview$)) or (methodologic$ adj ((literature adj review$) or review$ or overview$))).ti,ab. 22. ((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ or overview$))).ti,ab. 23. ((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or overview$)) or (pool$ adj analy$)).ti,ab. 24. or/15-23 25. 14 and 24 BIOSIS 1. Octreotid$.hw,ti,ab.
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DATABASES LIMITS KEYWORDS/DESCRIPTORS 2. Longastatin$.hw,ti,ab. 3. DRG-0115.hw,ti,ab. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).hw,ti,ab. 5. Sandostatin$.hw,ti,ab. 6. SMS-LAR.hw,ti,ab. 7. Sandoz 201-995.hw,ti,ab. 8. 83150-76-9.rn. 9. or/1-8 10. ((meta adj analy$) or metaanaly$ or (met adj analy$) or metanaly$ or (health adj technology adj assessment$) or hta$1).ti,ab. 11. (technology adj assessment$ adj2 (biomedical or bio-medical)).ti,ab. 12. ((systematic$ adj ((literature adj review$) or review$ or overview$)) or (methodologic$ adj ((literature adj review$) or review$ or overview$))).ti,ab. 13. ((quantitative adj (review$ or overview$ or synthes$)) or (research adj (integration$ or overview$))).ti,ab. 14. ((integrative adj2 (review$ or overview$)) or (collaborative adj (review$ or overview$)) or (pool$ adj analy$)).ti,ab. 15. or/10-14 16. 9 and 15 Performed 16 May 2006 99 unique records after de-duping in Reference Manager Medline In-Process & Other Non-Indexed Citations - 1 Medline – 42 EMBASE - 44 BIOSIS – 12
Economic Studies Medline In-Process & Other Non-Indexed Citations 1. Octreotid$.ti,ab. 2. Longastatin$.ti,ab. 3. DRG-0115.ti,ab. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab. 8. 83150-76-9.rn. 9. or/1-8 10. (cost or costs or costing or cost-effective$).ti,ab. 11. (sensitivity analysis or sensitivity analyses).ti,ab. 12. (economic$ or pharmacoeconomic$ or pharmaco-economic$).ti,ab. 13. budget$.ti,ab. 14. (QOL or QOLY or QOLYs or HRQOL or QALY or QALYs or QALE or QALEs).ti,ab. 15. (Quality adj1 (life or (willingness adj2 pay))).ti,ab. 16. (Quality adj1 adjusted life year$).ti,ab. 17. (Quality adj1 adjusted life expectanc$).ti,ab. 18. or/10-17 19. 9 and 18
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DATABASES LIMITS KEYWORDS/DESCRIPTORS Medline 1. Octreotide.sh. 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. 83150-76-9.rn. 10. or/1-9 11. Economics.sh. 12. Economics, medical.sh. 13. Economics, pharmaceutical.sh. 14. exp "Costs and Cost Analysis"/ 15. exp health care costs/ 16. exp decision support techniques/ 17. economics.fs. 18. (cost or costs or costing or cost-effective$).ti,ab. 19. (sensitivity analysis or sensitivity analyses).ti,ab. 20. (economic$ or pharmacoeconomic$ or pharmaco-economic$).ti,ab. 21. budget$.ti,ab. 22. value of life.sh. 23. quality of life.sh. 24. quality-adjusted life years.sh. 25. (QOL or QOLY or QOLYs or HRQOL or QALY or QALYs or QALE or QALEs).ti,ab. 26. (Quality adj1 (life or (willingness adj2 pay))).ti,ab. 27. (Quality adj1 adjusted life year$).ti,ab. 28. (Quality adj1 adjusted life expectanc$).ti,ab. 29. or/11-28 30. 10 and 29 EMBASE 1. *Octreotide/ 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. Sandostatin.tn. 10. Sandostatin LAR.tn. 11. Omega.tn. 12. Octreotide.tn. 13. Longastatin.tn. 14. or/1-13 15. exp health economics/ 16. exp economic evaluation/ 17. exp pharmacoeconomics/ 18. exp economic aspect/ 19. (cost or costs or costing or cost-effective$).ti,ab.
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DATABASES LIMITS KEYWORDS/DESCRIPTORS 20. (sensitivity analysis or sensitivity analyses).ti,ab. 21. (economic$ or pharmacoeconomic$ or pharmaco-economic$).ti,ab. 22. budget$.ti,ab. 23. quality adjusted life year.sh. 24. exp quality of life/ 25. (QOL or QOLY or QOLYs or HRQOL or QALY or QALYs or QALE or QALEs).ti,ab. 26. (Quality adj1 (life or (willingness adj2 pay))).ti,ab. 27. (Quality adj1 adjusted life year$).ti,ab. 28. (Quality adj1 adjusted life expectanc$).ti,ab. 29. pe.fs. 30. or/15-29 31. 14 and 30 BIOSIS 1. Octreotid$.hw,ti,ab. 2. Longastatin$.tw. 3. DRG-0115.tw. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).tw. 5. Sandostatin$.tw. 6. SMS-LAR.tw. 7. Sandoz 201-995.tw. 8. 83150-76-9.rn. 9. or/1-8 10. Economic$.hw. 11. Pharmacoeconomic$.hw. 12. (cost or costs or costing or cost-effective$).ti,ab. 13. (sensitivity analysis or sensitivity analyses).ti,ab. 14. (economic$ or pharmacoeconomic$ or pharmaco-economic$).ti,ab. 15. budget$.ti,ab. 16. (QOL or QOLY or QOLYs or HRQOL or QALY or QALYs or QALE or QALEs).ti,ab. 17. (Quality adj1 (life or (willingness adj2 pay))).ti,ab. 18. (Quality adj1 adjusted life year$).ti,ab. 19. (Quality adj1 adjusted life expectanc$).ti,ab. 20. or/10-19 21. 9 and 20 Search Performed 30 May 2006
362 unique records after de-duping Reference Manager Medline In-Process & Other Non-Indexed Citations – 4 Medline – 141 EMBASE - 203 BIOSIS – 14
Ovid - Medline - Medline In-Process & Other Non-Indexed Citations
3. DRG-0115.ti,ab. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 5. Sandostatin$.ti,ab. 6. SMS-LAR.ti,ab. 7. Sandoz 201-995.ti,ab. 8. 83150-76-9.rn. 9. or/1-8 10. (random$ or sham$ or placebo$ or (singl$ adj (blind$ or dumm$ or mask$)) or (doubl$ adj (blind$ or dumm$ or mask$))).ti,ab. 11. ((tripl$ adj (blind$ or dumm$ or mask$)) or (trebl$ adj (blind$ or dumm$ or mask$))).ti,ab. 12. ((control$ adj (study or studies or trial$)) or rct$1).ti,ab. 13. ((multicent$ or multi-cent$) adj (study or studies or trial$)).ti,ab. 14. ((crossover or cross-over) adj (study or studies or trial$)).ti,ab. 15. ((case control$ or case comparison$) adj (study of studies or trial$)).ti,ab. 16. (cohort adj1 (study or studies or trial$ or analysis or analyses)).ti,ab. 17. or/10-16 18. 9 and 17 Medline 1. Octreotide.sh. 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. 83150-76-9.rn. 10. or/1-9 11. (Multicenter Study or Randomized Controlled Trial or Controlled Clinical Trial).pt. 12. exp Controlled Clinical Trials/ 13. Double-Blind Method.sh. 14. Single-Blind Method.sh. 15. Random allocation.sh. 16. Multicenter studies.sh. 17. Cross-over studies.sh. 18. Cohort studies.sh. 19. (random$ or sham$ or placebo$ or (singl$ adj (blind$ or dumm$ or mask$)) or (doubl$ adj (blind$ or dumm$ or mask$))).ti,ab. 20. ((tripl$ adj (blind$ or dumm$ or mask$)) or (trebl$ adj (blind$ or dumm$ or mask$))).ti,ab. 21. ((control$ adj (study or studies or trial$)) or rct$1).ti,ab. 22. ((multicent$ or multi-cent$) adj (study or studies or trial$)).ti,ab. 23. ((crossover or cross-over) adj (study or studies or trial$)).ti,ab. 24. ((case control$ or case comparison$) adj (study of studies or trial$)).ti,ab. 25. (cohort adj1 (study or studies or trial$ or analysis or analyses)).ti,ab. 26. or/11-25 27. 10 and 26 EMBASE
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DATABASES LIMITS KEYWORDS/DESCRIPTORS 1. *Octreotide/ 2. Octreotid$.ti,ab. 3. Longastatin$.ti,ab. 4. DRG-0115.ti,ab. 5. (SMS-201-995 or SM-201-995 or SAN-201-995).ti,ab. 6. Sandostatin$.ti,ab. 7. SMS-LAR.ti,ab. 8. Sandoz 201-995.ti,ab. 9. Sandostatin.tn. 10. Sandostatin LAR.tn. 11. Omega.tn. 12. Octreotide.tn. 13. Longastatin.tn. 14. or/1-13 15. Randomized Controlled Trial/ 16. exp controlled study/ 17. Double Blind Procedure.sh. 18. Single Blind Procedure.sh. 19. Multicenter study.sh. 20. Crossover procedure.sh. 21. Cohort Analysis.sh. 22. (major clinical study or multicenter study or randomized controlled trial).ti,ab. 23. (random$ or sham$ or placebo$ or (singl$ adj (blind$ or dumm$ or mask$)) or (doubl$ adj (blind$ or dumm$ or mask$))).ti,ab. 24. ((tripl$ adj (blind$ or dumm$ or mask$)) or (trebl$ adj (blind$ or dumm$ or mask$))).ti,ab. 25. ((control$ adj (study or studies or trial$)) or rct$1).ti,ab. 26. ((multicent$ or multi-cent$) adj (study or studies or trial$)).ti,ab. 27. ((crossover or cross-over) adj (study or studies or trial$)).ti,ab. 28. ((case control$ or case comparison$) adj (study of studies or trial$)).ti,ab. 29. (cohort adj1 (study or studies or trial$ or analysis or analyses)).ti,ab. 30. or/15-29 31. 14 and 30 BIOSIS 1. Octreotid$.hw,ti,ab. 2. Longastatin$.tw. 3. DRG-0115.tw. 4. (SMS-201-995 or SM-201-995 or SAN-201-995).tw. 5. Sandostatin$.tw. 6. SMS-LAR.tw. 7. Sandoz 201-995.tw. 8. 83150-76-9.rn. 9. or/1-8 10. (major clinical study or multicenter study or randomized controlled trial).ti,ab,hw. 11. (random$ or sham$ or placebo$ or (singl$ adj (blind$ or dumm$ or mask$)) or (doubl$ adj (blind$ or dumm$ or mask$))).ti,ab,hw. 12. ((tripl$ adj (blind$ or dumm$ or mask$)) or (trebl$ adj (blind$ or dumm$ or mask$))).ti,ab,hw. 13. ((control$ adj (study or studies or trial$)) or rct$1).ti,ab,hw.
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DATABASES LIMITS KEYWORDS/DESCRIPTORS 14. ((multicent$ or multi-cent$) adj (study or studies or trial$)).ti,ab,hw. 15. ((crossover or cross-over) adj (study or study or trial$)).ti,ab,hw. 16. ((case control$ or case comparison$) adj (study of studies or trial$)).ti,ab,hw. 17. (Cohort adj1 (study or studies or trial$ or analysis or analyses)).ti,ab,hw. 18. or/10-17 19. 9 and 18 Performed 26 Jul 2006 1873 unique records after de-duping in Reference Manager Medline In-Process & Other Non-Indexed Citations - 12 Medline – 727 EMBASE - 1047 BIOSIS – 87
Performed biweekly between May 2006 to February 2008
John Wiley & Sons, Inc. The Cochrane Library 2006, Issue 2
(octreotid* OR longastatin* OR sandostatin* OR drg-0115 OR (drg NEXT 0115) OR (sms-201-995) OR (sms NEXT 201 NEXT 995) OR san-201-995 OR (san NEXT 201 NEXT 995) OR sms-lar OR (sms NEXT lar) OR (sandoz NEXT 201-005) OR (sandoz NEXT 201 NEXT 005) – ti,ab,kw 23 Records The Cochrane Database of Systematic Reviews = 3 complete reviews; The Database of Abstracts of Reviews of Effects = 9 records; HTA database = 2 records; The NHS Economic Evaluation Database = 9 records Search re-run in 2006, Issue 3 to obtain clinical trial records 676 records (188 unique records after de-duping in Reference Manager with results of previous systematic review and clinical search) CENTRAL REGISTER OF CONTROLLED TRIALS = 676 records Regular updates performed to September 2007
OHE-IFPMA Database Ltd. HEED: health economic evaluations database June 2006 Issue
All variations of octreotide 17 records
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Grey Literature: Websites of health technology assessment (HTA), related agencies and other databases * NOTE: This section lists the main agencies, organizations, and websites searched; it is not a complete list. For a complete list of sources searched, contact CADTH (http://www.cadth.ca). Health Technology Assessment Agencies Alberta Heritage Foundation for Medical Research (AHFMR) http://www.ahfmr.ab.ca Agence d’Evaluation des Technologies et des Modes d’Intervention en Santé (AETMIS). Québec http://www.aetmis.gouv.qc.ca Canadian Agency for Drugs and Technologies in Health (CADTH) http://www.cadth.ca Centre for Evaluation of Medicines. Father Sean O'Sullivan Research Centre, St.Joseph's Healthcare,Hamilton, and McMaster University, Faculty of Health Sciences. Hamilton, Ontario http://www.thecem.net/ Centre for Health Services and Policy Research, University of British Columbia http://www.chspr.ubc.ca/cgi-bin/pub Health Quality Council of Alberta (HQCA) http://www.hqca.ca Health Quality Council. Saskatchewan. http://www.hqc.sk.ca/ Institute for Clinical Evaluative Sciences (ICES). Ontario http://www.ices.on.ca/ Institute of Health Economics (IHE). Alberta http://www.ihe.ca/ Manitoba Centre for Health Policy (MCHP) http://www.umanitoba.ca/centres/mchp/ Ontario Ministry of Health and Long Term Care. Health Technology Analyses and Recommendations http://www.health.gov.on.ca/english/providers/program/ohtac/tech/techlist_mn.html The Technology Assessment Unit of the McGill University Health Centre http://www.mcgill.ca/tau/ Therapeutics Initiative. Evidence-Based Drug Therapy. University of British Columbia http://www.ti.ubc.ca Health Technology Assessment International (HTAi) http://www.htai.org International Network for Agencies for Health Technology Assessment (INAHTA) http://www.inahta.org
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WHO Health Evidence Network http://www.euro.who.int/HEN Australian Safety and Efficacy Register of New Interventional Procedures – Surgical (ASERNIP-S) http://www.surgeons.org/Content/NavigationMenu/Research/ASERNIPS/default.htm Centre for Clinical Effectiveness, Monash University http://www.med.monash.edu.au/healthservices/cce/ Medicare Services Advisory Committee, Department of Health and Aging http://www.msac.gov.au/ NPS RADAR (National Prescribing Service Ltd.) http://www.npsradar.org.au/site.php?page=1&content=/npsradar%2Fcontent%2Farchive_alpha.html Institute of Technology Assessment (ITA) http://www.oeaw.ac.at/ita/index.htm Federal Kenniscentrum voor de Gezendheidszorg http://www.kenniscentrum.fgov.be Danish Centre for Evaluation and Health Technology Assessment (DCEHTA). National Board of Health http://www.dihta.dk/ DSI Danish Institute for Health Services Research and Development http://www.dsi.dk/engelsk.html Finnish Office for Health Care Technology and Assessment (FinOHTA). National Research and Development Centre for Welfare and Health http://finohta.stakes.fi/EN/index.htm L’Agence Nationale d’Accréditation et d’Evaluation en Santé (ANAES). Ministere de la Santé, de la Famille, et des Personnes handicappés http://www.anaes.fr/anaes/anaesparametrage.nsf/HomePage?ReadForm Committee for Evaluation and Diffusion of Innovative Technologies (CEDIT) http://cedit.aphp.fr/english/index_present.html German Institute for Medical Documentation and Information (DIMDI). Federal Ministry of Health http://www.dimdi.de/static/de/hta/db/index.htm College voor Zorgverzekeringen/Health Care Insurance Board (CVZ) http://www.cvz.nl Health Council of the Netherlands http://www.gr.nl New Zealand Health Technology Assessment Clearing House for Health Outcomes and Health Technology Assessment (NZHTA) http://nzhta.chmeds.ac.nz/ Norwegian Centre for Health Technology Assessment (SMM) http://www.kunnskapssenteret.no/ Basque Office for Health Technology Assessment (OSTEBA). Departemento de Sanidad http://www.osasun.ejgv.euskadi.net/r52-2536/es/
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Catalan Agency for Health Technology Assessment and Research (CAHTA) http://www.gencat.net/salut/depsan/units/aatrm/html/en/Du8/index.html CMT - Centre for Medical Technology Assessment http://www.cmt.liu.se/pub/jsp/polopoly.jsp?d=6199&l=en Swedish Council on Technology Assessment in Health Care (SBU) http://www.sbu.se/ Swiss Network for Health Technology Assessment http://www.snhta.ch/about/index.php European Information Network on New and Changing Health Technologies (EUROSCAN). University of Birmingham. National Horizon Scanning Centre http://www.euroscan.bham.ac.uk National Horizon Scanning Centre (NHSC) http://www.pcpoh.bham.ac.uk/publichealth/horizon NHS Health Technology Assessment /National Coordinating Centre for Health Technology Assessment (NCCHTA). Department of Health R&D Division http://www.ncchta.org/ NHS National Institute for Clinical Excellence (NICE) http://www.nice.org.uk NHS Quality Improvement Scotland http://www.nhshealthquality.org University of York NHS Centre for Reviews and Dissemination (NHS CRD) http://www.york.ac.uk/inst/crd The Wessex Institute for Health Research and Development. Succinct and Timely Evaluated Evidence Review (STEER) http://www.wihrd.soton.ac.uk/ West Midlands Health Technology Assessment Collaboration (WMHTAC) http://www.wmhtac.bham.ac.uk/ Agency for Healthcare Research and Quality (AHRQ) http://www.ahrq.gov/ VA Technology Assessment Program (VATAP) http://www.va.gov/vatap/ ECRI http://www.ecri.org/ Institute for Clinical Systems Improvement http://www.icsi.org/index.asp Technology Evaluation Center (Tec). BlueCross BlueShield Association http://www.bluecares.com/tec/index.html University HealthSystem Consortium (UHC) http://www.uhc.edu/
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Health Economic Bases Codecs. CODECS (COnnaissances et Décision en EConomie de la Santé) Collège des Economistes de la Santé/INSERM http://infodoc.inserm.fr/codecs/codecs.nsf Centre for Health Economics and Policy Analysis (CHEPA). Dept. of Clinical Epidemiology and Biostatistics. Faculty of Health Sciences. McMaster University, Canada http://www.chepa.org Health Economics Research Group (HERG). Brunel University, U.K. http://www.brunel.ac.uk/about/acad/herg Health Economics Research Unit (HERU). University of Aberdeen http://www.abdn.ac.uk/heru/ The Hospital for Sick Children (Toronto). PEDE Database http://pede.bioinfo.sickkids.on.ca/pede/index.jsp University of Connecticut. Department of Economics. RePEc database http://ideas.repec.org Conference Proceedings Searched 2004-2006 when available. American Association of Clinical Endocrinologists (AACE) American Society of Clinical Oncology (ASCO) Digestive Diseases Week; Endocrine Society European Association for the Study of the Liver (EASL) Society of American Gastrointestinal Endoscopic Surgeons (SAGES)
Andrén-Sandberg Å, Flati G, Büchler M. The role of octreotide in preventing complications after pancreatoduodenectomy for cancer. HPB 2000;2(3):299-312.
Andriulli A, Leandro G, Clemente R, Caruso N, Annese V, Perri F. Meta-analysis of somatostatin, octreotide and gabexate in the therapy of acute pancreatitis [abstract]. Gastroenterology 1997;112(4 Suppl):A425.
Andriulli A, Leandro G, Niro G, Lichino E, Conoscitore P, Clemente R, et al. Prophylactic therapy with octreotide is able to reduce morbidity associated to pancreatic surgery: a meta-analytical evaluation [abstract]. Gastroenterology 1997;112(4 Suppl):A425.
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Avgerinos A, Armonis A, Raptis S. Somatostatin and octreotide in the management of acute variceal hemorrhage. Hepatogastroenterology 1995;42(2):145-50.
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Barkun A, Bardou M, Marshall JK. Consensus recommendations for managing patients with nonvariceal upper gastrointestinal bleeding. Ann Intern Med 2003;139(10):843-57.
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Berberat PO, Friess H, Uhl W, Buchler MW. The role of octreotide in the prevention of complications following pancreatic resection. Digestion 1999;60 Suppl 2:15-22.
Bhasin DK, Malhi NJS. Variceal bleeding and portal hypertension: much to learn, much to explore. Endoscopy 2002;34(2):119-28.
Bhasin DK, Siyad I. Variceal bleeding and portal hypertension: new lights on old horizon. Endoscopy 2004;36(2):120-9.
Bretagne JF, Heresbach D. La sclérose endoscopique. Acta Endosc 1995;25(4):347-64.
Burroughs AK. Octreotide in variceal bleeding. Gut 1994;35(3 Suppl):S23-S27.
Burt MG, Ho KKY. Comparison of efficacy and tolerability of somatostatin analogs and other therapies for acromegaly. Endocrine 2003;20(3):299-305.
Büchler MW, Binder M, Friess H. Role of somatostatin and its analogues in the treatment of acute and chronic pancreatitis. Gut 1994;35 Suppl 3:S15-S19.
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Cirillo F. Medical treatment of neuroendocrine gastroenteropancreatic tumors. Med Biol Environ 1997;25(1):3-7.
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APPENDIX 3: FIGURES
*three additional systematic reviews identified after this phase of screening completed and systematic review of RCTs was underway.96-98
Figure A1: Selected Systematic Reviews or Meta-Analyses
103 citations identified from electronic search and
screened
42 citations excluded
5 citations identified from other sources
66 potentially relevant reports retrieved for scrutiny
1 potentially relevant report retrieved from
other sources
52 reports excluded based on: - study design (40) - population (2) - intervention (4) - inappropriate outcome measures (2) - duplicate publication (4)
67 potentially relevant reports
15 relevant systematic reviews*
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321 reports excluded based on: study design (113), population (71), intervention (15), comparator (11), duplicate report of same trial data (9), contained insufficient information (14), unable to retrieve full text copy (18), language (16), other (54)
Figure A2: Selected RCTs and CCTs
2180 citations identified from electronic search and
screened
1730 citations excluded
34 citations identified from other sources
484 potentially relevant reports retrieved for scrutiny (full text,
Figure A8: Patients who are failing initial hemostasis for OCT-SA versus sclerotherapy
Review: Emergency Management of Variceal HemorrhageComparison: 04 OCT-SA versus sclerotherapy Outcome: 02 Number of patients failing initial hemostasis
Study Treatment Sclerotherapy RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI Quality
01 OCT-SA versus sclerotherapy Bildozola 2000 6/39 2/37 3.98 2.85 [0.61, 13.22] B Lopez 1999 5/31 4/33 7.52 1.33 [0.39, 4.51] B Poo 1996 1/22 2/21 3.97 0.48 [0.05, 4.88] B Silva 2004 4/13 3/43 2.70 4.41 [1.13, 17.22] B Yousuf 2000 4/48 2/48 3.88 2.00 [0.38, 10.41] B Subtotal (95% CI) 153 182 22.05 1.95 [1.02, 3.73]Total events: 20 (Treatment), 13 (Sclerotherapy)Test for heterogeneity: Chi² = 3.40, df = 4 (P = 0.49), I² = 0%Test for overall effect: Z = 2.00 (P = 0.04)
Figure A16: Patients with rebleeding after OCT-SA versus vasopressin
Review: Emergency Management of Variceal HemorrhageComparison: 03 OCT-SA versus vasopressin Outcome: 03 Patients with rebleeding
Study OCT-SA Vasopressin RR (random) Weight RR (random)or sub-category n/N n/N 95% CI % 95% CI Quality
Huang 1992 3/20 6/21 33.74 0.53 [0.15, 1.82] B Hwang 1992 6/24 2/24 27.29 3.00 [0.67, 13.40] B Kusumobroto 1994 4/21 7/22 38.97 0.60 [0.20, 1.75] B
Total (95% CI) 65 67 100.00 0.89 [0.33, 2.41]Total events: 13 (OCT-SA), 15 (Vasopressin)Test for heterogeneity: Chi² = 3.76, df = 2 (P = 0.15), I² = 46.8%Test for overall effect: Z = 0.23 (P = 0.82)
0.01 0.1 1 10 100
Favours OCT-SA Favours vasopressin CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk Figure A17: Patients with uncontrolled bleeding who require additional treatments after
OCT-SA versus sclerotherapy
Review: Emergency Management of Variceal HemorrhageComparison: 04 OCT-SA versus sclerotherapy Outcome: 04 Number of patients with uncontrolled bleeding requiring additional treatments
Study OCT-SA Sclerotherapy RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI Quality
01 OCT-SA versus sclerotherapy Bildozola 2000 14/39 8/37 26.22 1.66 [0.79, 3.49] B Lopez 1999 5/31 4/33 12.37 1.33 [0.39, 4.51] B Poo 1996 1/22 2/21 6.54 0.48 [0.05, 4.88] B Subtotal (95% CI) 92 91 45.13 1.40 [0.76, 2.56]Total events: 20 (OCT-SA), 14 (Sclerotherapy)Test for heterogeneity: Chi² = 1.03, df = 2 (P = 0.60), I² = 0%Test for overall effect: Z = 1.09 (P = 0.28)
Total (95% CI) 171 176 100.00 1.23 [0.81, 1.86]Total events: 38 (OCT-SA), 32 (Sclerotherapy)Test for heterogeneity: Chi² = 1.46, df = 4 (P = 0.83), I² = 0%Test for overall effect: Z = 0.97 (P = 0.33)
0.01 0.1 1 10 100
Favours OCT-SA Favours SCL CI=confidence interval; OCT-SA=octreotide short-acting; Quality score: B=allocation concealment unclear; RR=relative risk; SCL=sclerotherapy Prevention of complications after pancreatic surgery
Figure A18: Hospital length of stay after OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgeryComparison: 01 OCT-SA versus placebo or no treatment Outcome: 01 Length of hospital stay (days)
Study OCT-SA placebo/no treatment WMD (fixed) Weight WMD (fixed)or sub-category N Mean (SD) N Mean (SD) 95% CI % 95% CI Quality
Figure A21: Post-surgical occurrence of fluid collection with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgeryComparison: 01 OCT-SA versus placebo or no treatment Outcome: 03 Fluid Collection
Study OCT-SA placebo/no treatment RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 0/10 1/7 2.43 0.24 [0.01, 5.21] B Briceno Delgado 1998 0/16 1/18 1.99 0.37 [0.02, 8.55] B Buchler 1992 8/125 9/121 12.82 0.86 [0.34, 2.16] B Friess 1995 4/122 12/125 16.62 0.34 [0.11, 1.03] B Montorsi 1995 2/111 9/107 12.85 0.21 [0.05, 0.97] B Pederzoli 1994 8/122 13/130 17.64 0.66 [0.28, 1.53] B Stratta 1993 1/13 1/12 1.46 0.92 [0.06, 13.18] B Suc 2004 18/122 23/108 34.20 0.69 [0.40, 1.21] A
Total (95% CI) 641 628 100.00 0.57 [0.40, 0.83]Total events: 41 (OCT-SA), 69 (placebo/no treatment)Test for heterogeneity: Chi² = 4.26, df = 7 (P = 0.75), I² = 0%Test for overall effect: Z = 3.00 (P = 0.003)
0.001 0.01 0.1 1 10 100 1000
Favours OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
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Figure A22: Post-surgical occurrence of infection with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgeryComparison: 01 OCT-SA versus placebo or no treatment Outcome: 04 Infection
Study OCT-SA placebo/no treatment RR (random) Weight RR (random)or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 0/10 2/7 4.77 0.15 [0.01, 2.63] B Briceno Delgado 1998 0/16 2/18 4.58 0.22 [0.01, 4.34] B Buchler 1992 3/125 6/121 15.65 0.48 [0.12, 1.89] B Friess 1995 2/122 1/125 6.68 2.05 [0.19, 22.31] B Pederzoli 1994 2/122 8/130 13.39 0.27 [0.06, 1.23] B Stratta 1993 9/13 5/12 28.26 1.66 [0.78, 3.56] B Yeo 2000 9/104 12/107 26.67 0.77 [0.34, 1.75] A
Total (95% CI) 512 520 100.00 0.72 [0.37, 1.41]Total events: 25 (OCT-SA), 36 (placebo/no treatment)Test for heterogeneity: Chi² = 9.36, df = 6 (P = 0.15), I² = 35.9%Test for overall effect: Z = 0.96 (P = 0.34)
0.001 0.01 0.1 1 10 100 1000
OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
Figure A23: Post-surgical occurrence of pancreatic fistula with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgeryComparison: 01 OCT-SA versus placebo or no treatment Outcome: 05 Pancreatic fistula
Study OCT-SA placebo/no treatment RR (random) Weight RR (random)or sub-category n/N n/N 95% CI % 95% CI Quality
Briceno Delgado 1998 0/16 5/18 1.27 0.10 [0.01, 1.70] B Buchler 1992 22/125 46/121 21.31 0.46 [0.30, 0.72] B Friess 1995 12/122 28/125 15.15 0.44 [0.23, 0.82] B Hesse 2005a 5/56 4/49 5.57 1.09 [0.31, 3.85] B Hesse 2005b 2/20 0/20 1.14 5.00 [0.26, 98.00] B Montorsi 1995 10/111 21/107 13.21 0.46 [0.23, 0.93] B Pederzoli 1994 11/122 24/130 14.07 0.49 [0.25, 0.95] B Suc 2004 21/122 20/108 17.34 0.93 [0.53, 1.62] A Yeo 2000 11/104 10/107 10.94 1.13 [0.50, 2.55] A
Total (95% CI) 798 785 100.00 0.61 [0.44, 0.84]Total events: 94 (OCT-SA), 158 (placebo/no treatment)Test for heterogeneity: Chi² = 12.25, df = 8 (P = 0.14), I² = 34.7%Test for overall effect: Z = 3.01 (P = 0.003)
0.001 0.01 0.1 1 10 100 1000
Favours OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
Figure A24: Post-surgical occurrence of pancreatitis with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgeryComparison: 01 OCT-SA versus placebo or no treatment Outcome: 07 Pancreatitis
Study OCT-SA placebo/no treatment RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 0/10 2/7 12.39 0.15 [0.01, 2.63] B Briceno Delgado 1998 1/16 0/18 2.02 3.35 [0.15, 76.93] B Buchler 1992 0/125 4/121 19.57 0.11 [0.01, 1.98] B Friess 1995 2/122 2/125 8.46 1.02 [0.15, 7.16] B Hesse 2005b 1/20 0/20 2.14 3.00 [0.13, 69.52] B Montorsi 1995 2/111 5/107 21.79 0.39 [0.08, 1.94] B Pederzoli 1994 1/122 6/130 24.87 0.18 [0.02, 1.45] B Suc 2004 2/122 1/108 4.54 1.77 [0.16, 19.25] A Yeo 2000 3/104 1/107 4.22 3.09 [0.33, 29.20] A
Total (95% CI) 752 743 100.00 0.60 [0.31, 1.14]Total events: 12 (OCT-SA), 21 (placebo/no treatment)Test for heterogeneity: Chi² = 9.13, df = 8 (P = 0.33), I² = 12.4%Test for overall effect: Z = 1.55 (P = 0.12)
0.001 0.01 0.1 1 10 100 1000
Favours OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
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Figure A25: Post-surgical deaths with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgeryComparison: 01 OCT-SA versus placebo or no treatment Outcome: 08 Death
Study OCT-SA placebo/no treatment RR (fixed) Weight RR (fixed)or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 0/10 1/7 5.48 0.24 [0.01, 5.21] B Briceno Delgado 1998 0/16 1/18 4.47 0.37 [0.02, 8.55] B Buchler 1992 4/125 7/121 22.43 0.55 [0.17, 1.84] B Friess 1995 2/122 1/125 3.11 2.05 [0.19, 22.31] B Hesse 2005a 1/56 0/49 1.68 2.63 [0.11, 63.15] B Hesse 2005b 0/20 0/20 Not estimable B Lange 1992 0/10 0/11 Not estimable B Montorsi 1995 9/111 6/107 19.26 1.45 [0.53, 3.92] B Pederzoli 1994 2/122 5/130 15.26 0.43 [0.08, 2.16] B Stratta 1993 0/13 0/12 Not estimable B Suc 2004 15/122 8/108 26.76 1.66 [0.73, 3.76] A Yeo 2000 1/104 0/107 1.55 3.09 [0.13, 74.90] A
Total (95% CI) 831 815 100.00 1.10 [0.69, 1.75]Total events: 34 (OCT-SA), 29 (placebo/no treatment)Test for heterogeneity: Chi² = 6.17, df = 8 (P = 0.63), I² = 0%Test for overall effect: Z = 0.39 (P = 0.70)
0.01 0.1 1 10 100
Favours OCT-SA Favours plac / no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk
Figure A26: Post-surgical occurrence of complications with OCT-SA versus placebo or no treatment
Review: Prophylaxis against complications following pancreatic surgeryComparison: 01 OCT-SA versus placebo or no treatment Outcome: 06 Overall complication rate
Study OCT-SA placebo/no treatment RR (random) Weight RR (random)or sub-category n/N n/N 95% CI % 95% CI Quality
Benedetti 1998 1/10 3/7 1.23 0.23 [0.03, 1.81] B Briceno Delgado 1998 2/16 7/18 2.44 0.32 [0.08, 1.33] B Buchler 1992 40/125 67/121 18.63 0.58 [0.43, 0.78] B Friess 1995 20/122 37/125 12.49 0.55 [0.34, 0.90] B Hesse 2005a 6/56 6/49 4.06 0.88 [0.30, 2.54] B Lange 1992 2/10 4/11 2.31 0.55 [0.13, 2.38] B Montorsi 1995 24/111 39/107 13.96 0.59 [0.38, 0.92] B Pederzoli 1994 19/122 38/130 12.25 0.53 [0.33, 0.87] B Suc 2004 35/122 40/108 15.99 0.77 [0.53, 1.12] A Yeo 2000 42/104 36/107 16.65 1.20 [0.84, 1.71] A
Total (95% CI) 798 783 100.00 0.67 [0.53, 0.84]Total events: 191 (OCT-SA), 277 (placebo/no treatment)Test for heterogeneity: Chi² = 15.95, df = 9 (P = 0.07), I² = 43.6%Test for overall effect: Z = 3.38 (P = 0.0007)
0.01 0.1 1 10 100
Favours OCT-SA Favours plac/ no tx CI=confidence interval; OCT-SA=octreotide short-acting; plac/no tx=placebo or no treatment; Quality score: A=allocation concealment adequate, B=allocation concealment unclear; RR=relative risk Bowel Obstruction
Figure A27: Vomiting with OCT-SA versus hyoscine butylbromide
Figure A30: selection of economic evidence for review
95 potentially relevant reports retrieved for scrutiny (full text, if
available)
671 citations identified from electronic search and
screened
576 citations excluded
98 potentially relevant reports
89 reports excluded* based on: Inappropriate study design (62) Inappropriate patient group (14) Inappropriate intervention (11) Inappropriate language (2)
9 reports of 8 studies included
3 potentially relevant articles from other sources
*population, intervention, comparator, and cost elements reviewed simultaneously.
A-55
APPENDIX 4 : TABLES
Table A1: characteristics of trials on acromegaly Study Study design,
funding sources
Patients characteristics Total number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
OCT-LA versus lanreotide Amato 2002147
Open-label RCT, parallel design, funding sources NR
Newly diagnosed patients with active acromegaly; mean age=55 years (range 40-72); 14 women and 9 men
23, 3 OCT-LA10-30 mg IM every 28 days lanreotide 30 mg IM every 7-10 days
24 months 3, unclear
Chanson 2000149
Open-label RCT, parallel design, industry funding
patients with acromegaly, treated with lanreotide (at least 3 injections prior to study day 1; mean duration of treatment 26 months); mean age =47 years (range 18-76); 67 women and 58 men
125, NR OCT-LA 20 mg IM once monthly lanreotide 30 mg IM every 10-14 days
3 months 2, unclear
Jenkins 2000148
Open-label RCT, parallel design, funding sources NR
patients previously treated with surgery or radiation, with or without medical treatment (octreotide or dopamine agonists); age and gender NR
29, NR OCT-LA 10-30 mg IM every 4 weeks lanreotide 30 mg IM every 2 weeks
3 months, 3.5 months
1, unclear
A-56
Table A1: characteristics of trials on acromegaly Study Study design,
funding sources
Patients characteristics Total number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
OCT-SA versus placebo or no treatment Andersen 1995152 Hansen 1994151
active acromegalic patients; mean age=51.9 years (range 26-69); 5 women and 7 men
12, 0 OCT-SA 150-300 μg SC total daily dose Placebo
1 month, follow-up period NR
4, unclear
Colao 1997150
Open-label RCT, parallel design, funding sources NR
acromegalic patients undergoing neurosurgical treatment; mean age=40.3 years (range 18-62) for treatment group and mean=40.9 years (range 18-66) for control; 32 women and 27 men
59, 0 OCT-SA before surgery 150-600 μg SC total daily dose No octreotide before surgery
3-6 months, 12 months
1, unclear
Ezzat 1992154
Double-blind RCT, parallel design, industry funding
serum GH concentration of >2μg/L throughout a 2 h oral glucose (100g) ingestion; mean age=47±2 (SD or SE) years for treatment group and 45±2 years for placebo; gender NR
115, 5 OCT-SA 150-300 μg SC total daily dose Placebo
1 month, 2 months
3, unclear
A-57
Table A1: characteristics of trials on acromegaly Study Study design,
funding sources
Patients characteristics Total number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
Ezzat 1995153
Open-label RCT, parallel design, industry funding
GH>2μg/L following oral glucose administration -pituitary mass of >10mm; mean age=46.5 years (range 21-72) for treatment and 45 years (range 23-74) for control; gender NR
69, NR OCT-SA before surgery 150-300 μg SC total daily dose No octreotide before surgery
4 months, 5 months
1, unclear
Fredstorp 1990155
Fredstorp 1993156
Fredstorp 1994157
Double-blind RCT, parallel design, partial industry funding
patients with active acromegaly (clinical signs and symptoms, elevated GH levels, and GH levels >2μg/L during an OGTT). Patients on bromocriptine stopped treatment 1 month prior. Mean age=51.5 years (range 25-77); 11 women and 9 men
20, 0 OCT-SA 150-600 μg SC total daily dose Placebo
14 days, 20 days
3, unclear
A-58
Table A1: characteristics of trials on acromegaly Study Study design,
funding sources
Patients characteristics Total number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
OCT-SA versus bromocriptine Halse 1990158
Open-label RCT, parallel design, partial industry funding
Patients with signs and symptoms of acromegaly and fasting GH level greater than 2μg/L which remained elevated during OGTT. No patients had surgery during the past 6 months or received radiation during the past 2 years. None had hypersecretion of any pituitary hormone other than GH. Bromocriptine had been discontinued for at least 30 days. Mean age=48.4 years (range 21-67)
26, 3 OCT-SA 300-600 μg SC total daily dose Bromocriptine 7.5-22.5 mg PO daily
2 months, 2.5 months
3, unclear
OCT-LA versus surgery Colao 2006159 (conference proceeding)
Open-label RCT, parallel design, partial industry funding
previously untreated acromegalic patients; mean age=45 years for treatment group and 51 years for control; 60% males
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
OCT-LA versus lanreotide Amato 2002147
OCT-LA 10-30 mg IM every 28 days: 11 lanreotide 30 mg IM 7-10 days: 12
NR NR At 12 months: 31.1±16.1 At 24 months: 34.8±16.5 At 12 months: 26.5±17.3 At 24 months: 30.0±17.2
At baseline: 52.0±31.4 mU/L (mean/SD) At end-point: NR At baseline: 60.2±30.6 mU/L (mean/SD) At end-point: NR
At baseline: 567.8±179.0 ng/mL (mean/SD) At end-point: NR At baseline: 565.7±198.7 ng/mL (mean/SD) At end-point: NR
At 12 months: 3/8* At 24 months: 4/8* At 12 months: 4 At 24 months: 7
At 12 months: 3/8* At 24 months: 4/8* At 12 months: 6 At 24 months: 8
A-60
Table A2: Outcomes for acromegaly Study Number of
patients in each treatment arm
Death (n)
Change in symptom severity
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
Chanson 2000149
OCT-LA 20 mg IM monthly: 98 lanreotide 30 mg IM 10-14 days: 27
1 during the first 3 months (treatment group NR)
Tool: a 5-point verbal rating scale no significant change from baseline no significant change from baseline
no significant change from baseline no significant change from baseline
At baseline: 9.9±1.3 mU/L At end-point: 6.6±0.8 mU/L (mean/SE) At baseline: 9.4±4.4 mU/L At end-point: 8.1±3.4 mU/L (mean/SE)
At baseline: 59±3 nmol/L At end-point: 48±3 nmol/L (mean/SE) At baseline: 50±5 nmol/L At end-point: 49±5 nmol/L (mean/SE)
NR At baseline: 42/90* At end-point: 56/56* At baseline: 11/21* At end-point: 11/21*
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Table A2: Outcomes for acromegaly Study Number of
patients in each treatment arm
Death (n)
Change in symptom severity
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
Jenkins 2000148
OCT-LA 10-30 mg IM every 4 weeks: 18 lanreotide 30 mg IM every 2 weeks: 11
NR NR NR At baseline: 3.1-68.0 mU/L At end-point: NR At baseline: 2.2-47.0 mU/L At endpoint: NR
At baseline: 17.25-102.6 nmol/L At end-point: NR At baseline: 86-904 ng/mL At endpoint: NR
At baseline: 5 At 4 weeks post-treatment: 13 At 6 weeks post-treatment: 12 At baseline: 4 At 10 days post-treatment: 5 At 2 weeks post-treatment: 4 At 3 weeks post-treatment: 3
At baseline: 9 At 4 weeks post-treatment: 12 At 6 weeks post-treatment: 11 At baseline: 4 At 10 days post-treatment: 8 At 2 weeks post-treatment: 6 At 3 weeks post-treatment: 5
A-62
Table A2: Outcomes for acromegaly Study Number of
patients in each treatment arm
Death (n)
Change in symptom severity
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
OCT-SA versus placebo or no treatment Andersen 1995152 Hansen 1994151
OCT-SA: 150-300 μg SC per day Placebo NOTE: number of patients in each group before crossing over NR
NR NR NR At baseline: 48±15 mU/L At end-point: 13±2 mU/L (mean/SE) At baseline: 48±14 mU/L At end-point: 47±14 mU/L (mean/SE)
Outcome reported for 10 of 12 patients at week 4 however the number of patients in each group was not reported.
3 NR
NR
A-63
Table A2: Outcomes for acromegaly Study Number of
patients in each treatment arm
Death (n)
Change in symptom severity
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
Colao 1997150
OCT-SA before surgery 150-600 μg SC per day: 22 No octreotide before surgery: 37
0 1 (occurred after surgery)
NR NR At baseline: 71.4±15.8 μg/L At end-point: 5.5±1 μg/L (mean/SE) At baseline: 76.4±15.7 μg/L (mean/SE) At end-point: 35.4±122.2 μg/L (mean/ SD)†
At baseline: 518±60 μg/L At end-point: 223.5±18.8 μg/L (mean/SE) At baseline: 693±86.8 μg/L (mean/SE) At end-point: 351.2±224.8 μg/L (mean/ SD)†
15 (after surgery) 13 (after surgery)
12 (after surgery) 11 (after surgery)
A-64
Table A2: Outcomes for acromegaly Study Number of
patients in each treatment arm
Death (n)
Change in symptom severity
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
Ezzat 1992154
OCT-SA 150-300 μg SC per day: 60 Placebo: 55
NR NR NR At baseline: 39±11 μg/L At 2 weeks: 9±2 μg/L (mean/SE) At baseline: 19±4 μg/L At 2 weeks: 17±4 μg/L (mean/SE)
At baseline: 5100±400 U/L At 2 weeks: 2400±400 U/L (mean/SE) At baseline: 4900±500 U/L At 2 weeks: 4900±500 U/L (mean/SE)
sub-group analysis at 2 weeks: normalized in 49% [95% CI 36-62%] of 39 patients with abnormal values placebo NR
sub-group analysis at 2 weeks: normalized in 58% [95%CI 44-72%] of patients with initially abnormal values
A-65
Table A2: Outcomes for acromegaly Study Number of
patients in each treatment arm
Death (n)
Change in symptom severity
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
Ezzat 1995153
OCT-SA before surgery 150-300 μg SC per day: 34 No octreotide before surgery: 35
NR NR NR At baseline: 49±9 μg/L Prior to surgery: 17±4 μg/L After surgery: 11±6 μg/L (mean/SE) At baseline: 42±14 μg/L After surgery: 22±11 μg/L (mean/SE)
At baseline: 6894±971 U/L Prior to surgery: 2442±406 U/L After surgery: 1801±318 U/L (mean/SE) At baseline: 8813±1221 U/L After surgery: 5188±1649 U/L (mean/SE)
NR NR
Fredstorp 1990155 Fredstorp 1993156
OCT-SA 150-600 μg SC per day:
NR NR NR After 2 weeks: GH significantly decreased in
significant reduction during (but not after) 2
At baseline: 0 At end-
At baseline: 1 At end-
A-66
Table A2: Outcomes for acromegaly Study Number of
patients in each treatment arm
Death (n)
Change in symptom severity
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
Fredstorp 1994157
A-67
Table A2: Outcomes for acromegaly Study Number of
patients in each treatment arm
Death (n)
Change in symptom severity
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
OCT-SA versus bromocriptine Halse 1990158
OCT-SA 300-600 μg SC per day: 13 Bromocriptine 7.5-22.5 mg PO daily: 13
NR Tool: composite of 19 items scored as 0=absent/subsided, 1=mild, 2=moderate, 3=severe At baseline: 18.6 At 8 weeks: 10.3 At 10 weeks: 17.0 At baseline: 22.4 At 8 weeks: 15.6 At 10 weeks: 21.0
1 patient showed reduction in tumour size
At baseline: 13.8±5.2 μg/L At 8 weeks: 2.9±0.7 μg/L At 10 weeks: 1.25±4.4 μgL (mean/SE) At baseline: 18.8±7.5 μg/L At 8 weeks: 5.4±1.2 μg/L At 10 weeks: 13.8±4.4 μg/L (mean/SE)
At baseline: 3.0 ±0.4 U/mL At 8 weeks: 1.4±0.4, p<0.01 (n=12) (mean/SE) At baseline: 2.9±0.4 U/mL At 8 weeks: 2.1±0.3, p<0.01 (n=11) (mean/SE)
4/12* 2/11*
8/12‡ 4/11‡
A-68
Table A2: Outcomes for acromegaly Study Number of
patients in each treatment arm
Death (n)
Change in symptom severity
Change in tumour size as % volume reduction (mean±SD)
Change in GH level
Change in IGF-1 level
Number of patients attained normal GH
Number of patients attained normal IGF-1
OCT-LA versus surgery Colao, 2006159 (conference proceeding)
OCT-LA 20-30 mg IM monthly: NR Surgery: NR
NR NR 73% of patients had >20% reduction in tumour size 95% of patients had significant tumour shrinkage
At baseline: octreotide group was 2 fold higher than surgery group. At end-point: NR
NR NR NR
*Available cases; † The mean and standard deviation were calculated from data provided by Professor Annamaria Colao, Federico II University, Naples: unpublished data, 2007; ‡ reported as somatomedin-C levels, former name for IGF-1; GH=growth hormone; IGF-1=insulin-like growth factor; IM=intramuscular; mU/L=milliunits per litre; nmol/L=nanomoles per litre; NR= not reported; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting; PO=oral; SC=subcutaneous; SD=standard deviation; SE=standard error
A-69
Table A3: Withdrawals or drop-outs in acromegaly RCTs Treatment Control Study Sample
size, ITT Number Reason Number Reason
Amato 2002147
23, no 3 lost to follow-up: 1 chose surgery; 2 lost to hospital control
0 --
Ezzat 1992154
115, yes 3 1 left country; 1 had headache relief and refused to enter wash-out phase; 1 had headaches
2 1 had adverse events; 1 was non-compliant
Halse 1990158
26, no 1 Throat spasms and flushing after injection
2 1 developed hypotension after the 1st dose; 1 had a CVI on day 5
CVI=cerebrovascular ischemic event; ITT=intention to treat
A-70
Table A4: Harm reported in RCTs of acromegaly Study Treatment
Duration (total
patients)
Reported harm: treatment
Reported harm: control
OCT-LA versus lanreotide Jenkins 2000148 3 months
(n=29) Discomfort on injection, excess flatulence, diarrhea, mild abdominal pain.
OCT-SA versus placebo One patient discontinued treatment due to headaches.
NR
Ezzat, 1992154 1 month (n=115)
88% (53) patients had diarrhea and nausea. (p<0.001)
33% (18) patients had diarrhea and nausea.
Fredstorp 1990155
14 days (n=20)
Abdominal discomfort and pain, loose stools, pale stools, and diarrhea, n=7, p=0.05
Abdominal discomfort and pain, loose stools, pale stools, and diarrhea, n=1
OCT-SA versus bromocriptine One discontinued treatment due to throat spasms, flushing and shallow breathing.
One discontinued treatment due to hypotension and one due to hemiparesis.
Halse 1990158 2 months (n=26)
Diarrhea, loose stools, flatulence.
Constipation. One patient had dizziness with high-dose bromocriptine.
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA versus placebo or no treatment Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
International Octreotide Varices Study Group 1996165 (abstract)
double blind RCT, parallel design, industry funded
Clinical suspicion of variceal bleeding (enrolled prior to endoscopy) Age, sex: NR
OCT-SA 50 µg/h IV Placebo
383 (194 with variceal bleeding), exclusions from analysis not clear
5 d, 90 d
2,unclear
El Sayed 1995166 (abstract)
open label RCT, parallel design, funding sources NR
acute bleeding from esophageal varices Age, sex: NR
OCT-SA 25 µg/h IV Conservative treatment
100, NR
2 d, NR
1, unclear
A-72
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Besson 1995167 Silvain 1995279 (abstract)
Besson 1995280 (abstract)
double blind RCT, parallel design, partial industry funding
Cirrhotic patients with endoscopically confirmed active or recently (<24h) bleeding varices Mean age=56 years 152 men and 47 women
OCT-SA 25 µg/h IV + sclerotherapy Placebo + sclerotherapy (2% polidocanol) All patients: repeat sclerotherapy day 5 to 7
199, 0 5 d, 15 d
5, adequate
A-73
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Farooqi 2000169
open label RCT, parallel design, funding sources NR
Cirrhotic patients with endoscopically confirmed acute esophageal variceal bleed (<24 h in duration) Mean age= OCT-SA 39.4, sclerotherapy 38.9 years 79 men and 62 women
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Morales 2007168
open label RCT, parallel design, no industry funding
Cirrhotic patients with active or recent esophageal variceal bleeding confirmed by endoscopy Mean age=51.8 years (range 20-80) 45 men and 23 women
OCT-SA 50 µg LD then 50 µg/h for 24 h then 25 µg/h IV for 24 h + sclerotherapy Placebo + sclerotherapy (5% ethanolamine oleate) Patients underwent ligation starting at day 3 (if indicated)
70, 2 (did not meet inclusion criteria)
2 d, 7d
3, unclear
A-75
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Primignani 1995170 (interim report)
De Franchis 1992281 (abstract)
Double blind RCT, parallel design, funding sources NR
Patient with cirrhosis and first or recurrent variceal hemorrhage (active or recent bleed) if hemodynamically stable for 24 hours after bleeding stopped. Mean age= 59 years 37 men and 21 women
OCT-SA 100 µg 3 times per day SC + sclerotherapy Placebo + sclerotherapy All patients: emergency treatment to achieve hemostasis in the first 24 h (sclerotherapy, tamponade, terlipressin or somatostatin) Sclerotherapy on day 1, 8, 15 and 29 if varices still present
58, 12 29 d, 120 d
5, adequate Not included in meta-analysis due to population characteristics Study results NS at interim analysis so trial was terminated.
A-76
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Shah 2005171
Shah 1996282 (abstract)
open label RCT, parallel design, funding sources NR
Adult patients with cirrhosis and endoscopically confirmed active or recent variceal bleeding Mean age= OCT-SA 49.5, sclerotherapy 50 years 68 men and 37 women
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Souza 2003175 (abstract)
Double blind RCT, parallel design, funding sources NR
Patients with cirrhosis or hepatoesplenic shistosomiasis with suspected gastroesophageal variceal bleeding (randomized prior to endoscopy) Age and sex: NR
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Zuberi 2000176
Zuberi 1999283 (abstract)
Zuberi 1999284 (abstract)
Double blind RCT, parallel design, funding sources NR
First episode of variceal bleeding from esophageal or gastric junctional varices. Excluded Child class C patients Mean age= 38.4 years 56 men and 14 women
OCT-SA 50 µg/h + sclerotherapy Placebo + sclerotherapy (ethanolamine oleate) All patients: lansoprazole 30 mg daily for 14 days
70, NR 5 d, hospital stay
4, adequate
A-80
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Abd-Elrazek 2005177 (abstract)
open label RCT, parallel design, funding sources NR
Cirrhotic patients with bleeding varices and impaired consciousness due to grade III-IV hepatic encephalopathy. Age and sex: NR Data for group III not extracted (patients were not randomized, n=60)
OCT-SA infusion (dose NR) as initial therapy; elective endoscopic therapy after consciousness improved emergency endoscopic therapy at presentation
60, NR NR, hospital stay
1, unclear Data excluded from meta-analysis due to population characteristics
A-81
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Freitas 2000178
open label RCT, parallel design, funding sources NR
Group I: endoscopically confirmed recent bleeding from esophageal varices Mean age=: OCT-SA 55, sclerotherapy 56 years 76 men and 35 women
OCT-SA 25 µg/h IV sclerotherapy (absolute ethanol) All patients: sclerotherapy or ligation after 48 hours
111, NR 2 d, 30 d
2, unclear
Group II: endoscopically confirmed active bleeding from esophageal varices Mean age: OCT-SA 57, sclerotherapy 54 years 65 men and 21 women
OCT-SA 25 µg/h IV + sclerotherapy sclerotherapy (absolute ethanol) All patients: sclerotherapy or ligation after 48 hours
86, NR 2 d, 30 d
A-82
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Study Study
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Sivri 2000180
open label RCT, parallel design, partial industry funding
Adult patients with active bleeding from esophageal or cardial varices at endoscopy Mean age= OCT-SA 46, sclerotherapy 48 years 16 men and 36 women
OCT-SA 50 µg LD then 50 µg/h + sclerotherapy after 72 hours Sclerotherapy (1% polidocanol)
66 episodes (52 patients), NR
12 h, hospital stay
2, unclear
A-84
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus sclerotherapy (after 48-72 hours) versus placebo or no treatment plus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Sung 1993181
Sung 1993288 (abstract)
open label RCT, parallel design, industry funded
Active or recent variceal hemorrhage at endoscopy; age > 16 years Mean age= OCT-SA 54.7, sclerotherapy 56.7 years 83 men and 15 women
OCT-SA 50 µg LD then 50 µg/h + elective sclerotherapy after 48 hours Sclerotherapy (3% sodium tetradecyl sulphate)
100, 2
2 d, 30 d
3, unclear
A-85
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA plus ligation versus placebo or no treatment plus ligation Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Sung 1995182
Sung 1995289 (abstract)
open label RCT, parallel design, industry funded
Endoscopically confirmed acute or recent esophageal bleeding; ≥16 years; portal hypertension. Mean age= OCT-SA 58, ligation 56 years 67 men and 27 women
OCT-SA 50 µg LD then 50 µg/h IV + ligation ligation All patients: repeat ligation at day 5
100, 6 excluded, 4 lost to follow-up
5 d, 1 year
2, unclear
A-86
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA versus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Bildozola 2000183 Kravetz 1996198 (abstract)
open label RCT, parallel design, partial industry funding
Adult cirrhotic patients with endoscopically confirmed variceal bleeding Mean age= OCT-SA 52.6, sclerotherapy 52.5 years 60 men and 16 women
OCT-SA 100 µg IV LD, then 50 µg/h for 48 hours, then 100 µg every 8 hours SC for 72 hours Sclerotherapy (2% polidocanol)
84, 8 5 d, 5 d
3, unclear
A-87
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA versus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
El-Jackie 1998184 (abstract)
open label RCT, parallel design, funding sources NR
Patients with schistosomal portal hypertension and actively bleeding varices at endoscopy Age and sex: NR
OCT-SA 50 µg LD then 50 µg/h IV sclerotherapy (5% ethanolamine oleate)
100, NR 2 d, hospital stay
1, unclear Not included in meta-analysis due to population characteristics
Lopez 1999185 (abstract)
Open label RCT, parallel design, funding sources NR
Cirrhotic patient with acute esophageal variceal bleeding confirmed by endoscopy Mean age=53 years 27 men and 37 women
OCT-SA 50 µg/h IV sclerotherapy (polidocanol)
64, NR 24 h, 24 h 1, unclear
A-88
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Poo 1996186 (abstract)
open label RCT, parallel design, funding sources NR
cirrhotic patients with acute esophageal variceal hemorrhage Age and sex: NR
OCT-SA 50 µg/h IV Sclerotherapy (1% polidocanol)
43, 1 2 d, 30 d
1, unclear
A-89
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Shaikh 2002187 (abstract only)
Open label RCT, parallel design, funding sources NR
variceal bleeding Age and sex: NR
OCT-SA 50 µg/h IV for 48 hours then 50 µg every 8 hours SC for 3 days OCT-SA + sclerotherapy sclerotherapy (ethanolamine) (Sclerotherapy on day 1, 8, 15 and 29. Not clear if all groups received therapy)
564, NR 5 d, 30 d
1, unclear Data extracted from abstract. Unable to obtain full text
A-90
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA versus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Silva 200499
open label RCT, parallel design, funding sources NR
Cirrhotic patients with acute variceal bleeding. Not clear if randomized before or after endoscopy Mean age= OCT-SA + sclerotherapy 60, OCT-SA 63, sclerotherapy 61 years 54 men and 38 women
OCT-SA 50 µg LD then 50 µg/h + sclerotherapy or ligation OCT-SA 50 µg LD then 50 µg/h sclerotherapy or ligation
92, NR 5 d, 42 d
1, unclear Data extracted from English abstract and some tables.
A-91
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus sclerotherapy Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Yousuf 2000188
open label RCT, parallel design, funding sources NR
Cirrhotic patients with acute esophageal variceal bleeding as confirmed on endoscopy. Age=OCT-SA 46, sclerotherapy 45 years 75 men and 21 women
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA versus Balloon Tamponade Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
McKee 1992189
McKee 1990203
open label RCT, parallel design, partial industry funding
Active bleeding from esophageal varices at endoscopy Mean age= OCT-SA 49.9, tamponade 51.6 years 34 men and 6 women
OCT-SA 25 µg/h Balloon tamponade All patients: sclerotherapy after 48 hours
40 episodes (31 patients), 0
2 d, 9 d 24-48 h, 9 d
2, unclear
A-93
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA versus somatostatin Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Vlachogiannakos 2007197
double blind RCT, parallel design, no industry funding
Adult patients with cirrhosis and acute upper gastrointestinal bleeding Median age, OCT: 51, somatostatin: 56 years 27 men, 6 women
OCT-SA 50 µg/h IV Somatostatin 250 µg/h IV All patients received ligation or sclerotherapy (ethanolamine). Ligation was repeated every 7-10 d as indicated. Bleeding ulcers were injected with epinephrine.
33, NR 5 d, 42 d 2, unclear The source of bleeding for one patient in each group was peptic ulcer
A-94
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA versus terlipressin Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Cho 2006100
Cho 2006199 (abstract)
open label RCT, parallel design, funding sources NR
Cirrhotic patients with acute variceal bleeding Not clear if patients randomized before or after endoscopy Age=OCT-SA 56, terlipressin 53 years 74 men and 14 women
OCT-SA 25 µg/h IV + ligation Terlipressin 2 mg LD then 1 mg every 4 hours IV + ligation
88, NR 5 d, 42 d 3 d, 42 d
1, unclear Data extracted from English abstract and tables only
A-95
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus terlipressin Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Pedretti 1994190
single blind (patients) RCT, parallel design, no industry funding
Cirrhotic patients with active or recent bleeding due to esophageal or gastric varices at endoscopy. Mean age= octreotide 64.7, terlipressin 66.7 years 35 men and 25 women
OCT-SA 100 µg LD then 25 µg/h IV for 24 hours, then 100 µg three times a day SC terlipressin 2 mg IV every 4 hours for 24 hours, then 2 mg every 6 hours for 1 day, then 1 mg every 6 hours
60, 0 7 d, 67 d 3, unclear
Salih 2005191 (abstract)
Single blind RCT, parallel design, no industry funding
Cirrhotic patients with esophageal variceal bleeding Age and sex: NR
OCT-SA 100 µg LD then 50 µg/h IV + ligation Terlipressin 2 mg LD then 1 mg every 6 hours IV + ligation
209, NR 3 d, NR 1, unclear
A-96
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus terlipressin Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Silvain 1993192
Silvain 1992200 (abstract) Fort 1991201 (abstract) Silvain 1991202 (abstract)
open label RCT, parallel design, no industry funding
Patients with cirrhosis and acute variceal bleeding at endoscopy (varices in esophagus or esophagogastric junction) Mean age= OCT-SA 57, terlipressin 58 years 69 men and 18 women
OCT-SA 25 µg/h IV for 12 hours, then 100 µg SC x 2 doses terlipressin 2 mg LD then 1 mg IV every 4 hours + transdermal nitroglycerin: 10 mg every 12 hours
87 episodes (84 patients), NR
24 h, 30 d
2, unclear Study terminated early due to major adverse events in terlipressin group
A-97
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding
OCT-SA versus vasopressin Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Huang 1992193
open label RCT, parallel design, funding sources NR
cirrhotic patients with active variceal bleeding at endoscopy mean age= OCT-SA 46.7, vasopressin 51.1 years 33 men and 8 women
OCT-SA 100 µg LD then 25 µg/h IV Vasopressin 0.4 units/min IV
41, 0 24 h, hospital stay
2, unclear
Hwang 1992194
open label RCT, parallel design, partial industry funding
Cirrhotic patients with acute variceal bleeding at endoscopy Mean age= OCT-SA 59, vasopressin 63 years 45 men and 3 women
OCT-SA 100 µg LD then 25 µg/h IV Vasopressin 0.4 units/min IV
48, 0 24 h, 42 d
2, unclear
A-98
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus vasopressin Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Kusumobroto 1994195 (abstract)
open label RCT, parallel design, funding sources NR
endoscopically confirmed bleeding esophageal varices age and sex: NR
OCT-SA 100 µg LD then 25 µg/h IV Vasopressin 0.5 units/min for 20-60 min IV, every 3 to 6 hours Balloon tamponade
61, NR 8- 24 h, 24 h 1, unclear
A-99
Table A5: Characteristics of included RCTs on emergency management of variceal bleeding OCT-SA versus vasopressin Study Study
design, funding sources
Patient characteristics
Treatment arms
Number randomized, withdrawals
Treatment duration, Follow-up
Jadad score, allocation concealment
Notes
Zhang 2002196
open label RCT, parallel design, no industry funding
Endoscopically confirmed acute esophageal and gastric variceal bleeding associated with hepatitis B cirrhosis. Mean age=47.5 years 194 men and 30 women
OCT-SA 1.7 µg/kg LD then 0.014 µg/kg/min IV Vasopressin 0.005 units/kg LD then 0.002 units/kg/min IV + glyceryl trinitrate 0.35 µg/kg/min IV Somatostatin 5 µg/kg LD then 0.07 µg/kg/min IV
224, NR 3 d, 3 d
1, unclear
d = day(s); h = hour(s); IV = intravenous; LD = loading dose; NR = not reported; OCT-SA =octreotide short-acting; RCT=randomized controlled trial; SC = subcutaneous
A-100
Table A6: Outcomes for Variceal bleed OCT-SA versus placebo or no treatment Study Treatment
arms * (n)
Number of deaths (in hospital or ≤ 10 days)
Number of deaths (> 10 days)
Number of patients failing initial hemostasis
Number of patients with rebleeding
Number of patients with uncontrolled bleeding requiring other treatments
Number of blood transfusion (units)†
Length of hospital stay (days) †
Other
OCT-SA 50 µg/h 189 (variceal bleed 87)
NR 42/189 (90 d)
NR NR 71/123 (all bleeds) 56/87 (variceal bleed) (5 d)
No difference in blood transfusions
NR International Octreotide Varices Study Group 1996165
(abstract) Placebo 194 (variceal bleed 106)
NR 53/194 NR NR 82/137 (all bleeds) 73/106 (variceal bleed), NS
NR
OCT-SA 25 µg/h 50
NS difference at 2 d
NR NR NR NR NR NR Overall control of bleeding 90%
El Sayed 1995166
(abstract)
Conservative treatment 50
NR NR NR NR NR NR NR 66% p<0.01
A-101
Table A6: Outcomes for Variceal bleed
OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy Study Treatment
arms * (n)
Number of deaths (in hospital or ≤ 10 days))
Number of deaths (> 10 days)
Number of patients failing initial hemostasis
Number of patients with rebleeding
Number of patients with uncontrolled bleeding requiring other treatments
Number of patients with uncontrolled bleeding requiring other treatments
Number of blood transfusion (units)†
Length of hospital stay (days) †
Other
Vlachogiannakos 2007197†
OCT-SA 50 µg/h 16
0 (5 d) 1 (42 d) NR 4 (42 d) NR Median (range) 3.3 (0-6) (5 d)
NR Treatment failure (failed hemostasis, rebleeding or death within 5 d) 8
somatostatin 17
1 2, p=0.98 NR 3, p=0.688 NR 0.5 (0-4.5), p=0.009
NR 2, p=0.025
A-119
Table A6: Outcomes for Variceal bleed
OCT-SA versus Terlipressin Number of blood transfusion (units)†
Study Treatment arms * (n)
Number of deaths (in hospital or ≤ 10 days)
Number of deaths (> 10 days)
Number of patients failing initial hemostasis
Number of patients with rebleeding
Number of patients with uncontrolled bleeding requiring other treatments
Length of hospital stay (days) †
Other
OCT-SA 25 µg/h + ligation 45
NR 8 (42 d) 2 4 (5d) 11 (42 d)
NR NR 13.1 ± 9.9**
Cho 2006100
terlipressin + ligation 43
NR 6 1 5 (5 d) 12 (42 d)
NR NR 10.0 ± 6.8** (NS)
OCT-SA 25 µg/h 30
1 (7 d) 3 (67 d) 7 (24 h) 0 (7 d) 2 (67 d)
1 (balloon tamponade) (<24 h) 7 (SCL) (>24 h)
1.7 ± 1.4 (24 h)
NR Pedretti 1994190
terlipressin 30
2 4 14 0 (7 d) 2 (67 d)
14 (SCL) (>24 h)
1.8± 1.5, NS
NR
A-120
Table A6: Outcomes for Variceal bleed
OCT-SA versus Terlipressin Number of blood transfusion (units)†
Study Treatment arms * (n)
Number of deaths (in hospital or ≤ 10 days)
Number of deaths (> 10 days)
Number of patients failing initial hemostasis
Number of patients with rebleeding
Number of patients with uncontrolled bleeding requiring other treatments
Length of hospital stay (days) †
Other
OCT-SA 50 µg/h + ligation 102
3 NR 1 NR NR 4.0± 2.6** 5.2±2.0** Salih 2005191
(abstract)
terlipressin + ligation 107
5 NR 3 NR NR 3.7± 2.2** NS
4.5±1.5** p=0.004
OCT-SA 25 µg/h 46 (episodes)
3 (48 h) 10 (30 d) 10 (12 h) 10 (48 h) 15 (30 d)
8 (12 h) 5 (>12-24 h) 3 (>24-48 h)
Mean 1 (range 0-5) ( 24 h)
NR Silvain 1993192
terlipressin + nitroglycerin 41 (episodes)
5 11 17 5 (48 h) 6 (30 d)
12 (12 h) 0 (>12-24) 4 (>24-48 h)
3 (range 0-13) P=0.012
NR
A-121
Table A6: Outcomes for Variceal bleed
OCT-SA versus Vasopressin Number of blood transfusion (units)†
Study Treatment arms * (n)
Number of deaths (in hospital or ≤ 10 days)
Number of deaths (> 10 days)
Number of patients failing initial hemostasis
Number of patients with rebleeding
Number of patients with uncontrolled bleeding requiring other treatments
Length of hospital stay (days) †
Other
OCT-SA 25 µg/h 20
5 (in hospital)
NR 5 (6 h) 3 (24 h) NR 3.4 ± 3.2 (24 h)
NR Huang 1992193
vasopressin 21
9 NR 8 6 NR 5.2 ± 2.7 P<0.05
NR
OCT-SA 25 µg/h 24
11 (in hospital)
11 (42 d) 3 (6 h) 6 (24 h) NR 615 mL ± 472 (24 h)
NR Hwang 1992194
vasopressin 24
11 12 11 2 NR 771 ± 909 (NS)
NR
OCT-SA 25 µg/h 21
NR NR 3 (24 h) 4 NR NS difference between groups
NR
vasopressin 22
NR NR 5 7 NR NR
Kusumobroto 1994195
(abstract)
Balloon tamponade 18
NR NR 1 2 NR NR
A-122
Table A6: Outcomes for Variceal bleed
OCT-SA versus Vasopressin Study Treatment
arms * (n)
Number of deaths (in hospital or ≤ 10 days)
Number of deaths (> 10 days)
Number of patients failing initial hemostasis
Number of patients with rebleeding
Number of patients with uncontrolled bleeding requiring other treatments
Number of blood transfusion (units)†
Length of hospital stay (days) †
Other
OCT-SA 0.014 µg/kg/min 73
NR NR 11 (72 h) NR NR NR NR Bleeding control 75.3% (24 h) 80.8% (48 h)
vasopressin + glyceryl trinitrate 83
NR NR 29 NR NR NR NR 51.8% 59.0%
Zhang 2002196
somatostatin 68
NR NR 7 NR NR NR NR 80.9% 86.8%
* Refer to Appendix 4 Table A2.1 for complete description of treatments † mean ± SD unless otherwise stated ‡ not clearly stated if standard deviation or standard error ** not clearly stated if mean, median, standard deviation or standard error BT=balloon tamponade; d=day(s); kg=kilogram; min=minute; h=hour(s); NR=not reported; NS= not significant; OCT-SA= octreotide short-acting; SCL=sclerotherapy; SD=standard deviation; SE=standard error;
A-123
Table A7: Variceal bleed RCT - Patient Characteristics Study Treatment
arms Mean age ± SD, years
Number of males/ females
Child Class C (n/N)
Active bleeding at endoscopy (n/N)
OCT-SA versus placebo or no treatment OCT-SA NR NR 46/123 NR Internationa
l Octreotide Varices Study Group 1996165
placebo 45/137
OCT-SA El Sayed 1995166 Conservative
treatment
NR NR NR NR
OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy
OCT-SA + sclerotherapy
56 (range 33-78)
72/26 26/98 42/98 Besson 1995167
Placebo + sclerotherapy
56 (range 28-79)
80/21 47/101 47/101
OCT-SA + sclerotherapy
39.4 40/32 20/72 NR Farooqi 2000169
sclerotherapy 38.9 39/30 18/69 NR OCT-SA + sclerotherapy
52.2 27/13 24/40 26/40 Morales 2007168
Placebo + sclerotherapy
51.4 18/10 10/28 13/28
OCT-SA + sclerotherapy
59.1 ± 11.0 19/7 11/26 11/26 Primignani 1995170
Placebo + sclerotherapy
59.2 ± 10.2 18/14 16/32 8/32
OCT-SA + sclerotherapy
49.5 ± 14.2* 32/19 11/51 23/51 Shah 2005171
Placebo + sclerotherapy
50.0 ± 12.3* 36/18 14/54 24/54
OCT-SA + sclerotherapy
48.6 ± 12.5* 79/14 14/93 NR Shiha 1996172
sclerotherapy 50.5 ± 11.5* 75/21 12/96 OCT-SA plus sclerotherapy versus placebo or no treatment plus sclerotherapy
OCT-SA + sclerotherapy
Signorelli 1996173
Somatostatin +
NR NR NR NR
A-124
Table A7: Variceal bleed RCT - Patient Characteristics Study Treatment
3 refused treatment but continued follow up (2), withdrew on medical advice (1)
9 adverse effects (1), on medical advice (3) (3 of 4 patients continued follow up) lost to follow up before day 30 (3) lost to follow up between day 30 and 90 (2)
Souza 2003175
143, no
NR Patients were randomized prior to endoscopy: 112 patients analyzed, data for 31 patients NR
NR See treatment*
Sung 1993181
100, no
1 Refused treatment after day 1
1 Bleeding source was gastric varices
Sung 1995182
100, no
4 hepatocellular carcinoma or bleeding gastric varices (3); Lost to follow up (1) Not completed 1 year of follow up (14)
6 hepatocellular carcinoma or bleeding gastric varices (3); lost to follow up (3) Not completed 1 year of follow up (7)
A-128
Table A8: Study withdrawals or losses to follow-up: Variceal bleeding
ITT analysis possible for mortality data (1 of the 8 excluded patients died. The patient was enrolled in the OCT-SA group)
Poo 1996186 43, no
0 1 One patient missing from the mortality outcome, reason NR
* reason for dropouts were not separated by treatment arms ITT=intention to treat; NR=not reported; OCT-SA=octreotide short acting
A-129
Table A9: Trial characteristics for GEPNETs Study Study design,
funding sources
Patients characteristics Number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
OCT-SA versus lanreotide O’Toole 2000204 Ruszniewski 1992205 (abstract)
Open-label RCT, crossover design, partial industry funding
Patients with carcinoid tumours with symptoms, such as diarrhea or flushes. Patients had not been treated previously with somatostatin analogues or had discontinued their treatment for a sufficient time to allow the reappearance of symptoms. Age OCT-SA=63±11.1 years; lanreotide=64±10.8 years; 17 women and 16 men
33, 5 OCT-SA 400-600 μg SC total daily dose lanreotide 30 mg IM every 10 days
30 days
2, unclear
OCT-SA versus OCT-LA Rubin 1999206 Anthony 1999207
Double-blind, RCT, parallel design, industry funding
Men and non-pregnant, non-lactating women at least 18 years of age with a diagnosis of carcinoid tumour with carcinoid syndrome. Symptoms of flushes and diarrhea well controlled by OCT-SA SC during a 2-week
93, 14 OCT-SA 300-900 μg SC total daily dose OCT-LA 10 mg IM every 4 weeks OCT-LA 20 mg IM every 4weeks OCT-LA 30 mg IM
24 weeks 2, unclear
A-130
Table A9: Trial characteristics for GEPNETs Study Study design,
funding sources
Patients characteristics Number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
screening period, during which patients received 0.3-0.9 mg OCT-SA SC daily. Symptoms must have returned during a washout period of 3-5 days. Mean age=59.5 years; 41 women and 52 men
every 4 weeks
OCT-SA versus placebo Jacobsen 1995209
Double-blind RCT, crossover design, partial industry funding
Histologically proven NET, at least one symptom related to the tumour disease; the symptoms had to interfere with daily activity and curtain well-being during the week preceding inclusion. Mean age=56.5 (range 30-72); six women and 5 men
11, 2 OCT-SA 200 μg SC total daily dose Placebo
4 weeks 5, adequate
Saslow 1997208
Double-blind RCT, parallel design, partial industry funding
Histologically proven metastatic carcinoid disease due to primary mid-gut tumours, associated diarrhea (at least 4 bowel
12, 0 OCT-SA 50 μg SC every 8 hours Placebo
24 hours 3, unclear
A-131
Table A9: Trial characteristics for GEPNETs Study Study design,
funding sources
Patients characteristics Number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
movements per day), and intestinal resections limited to <100 cm of small bowel or ≤ 30 cm of small bowel with proximal ascending colon and ileocecal valve. Mean age=62 years (range 54-71); 5 women and 7 men
OCT-SA versus lanreotide O’Toole 2000204 Ruszniewski, 1992205 (abstract)
OCT-SA 400-600 μg SC per day: 16 lanreotide 30mg IM every 10 days: 17
NR NR NR >50% decrease in frequency of flushes: 36% (5/ 14) >50% decrease in frequency of stools: 86% (12/ 14) >50% decrease in frequency of flushes: 31% (4/ 14) >50% decrease in frequency of stools: 79% (11/ 14)
At baseline: 57.4±102.2 At end-point: 32.3±82.1 (mean/SD) At baseline: 94.3±124.9 At end-point: 29.1±123.5 (mean/SD) total n=24
OCT-SA versus OCT-LA Rubin 1999206 Anthony 1999207
OCT-SA 300-900 μg SC per day: 26 OCT-LA 10 mg IM
NR 0 0
At 20 and 24 weeks: 59% (14/ 24) 67% (12/ 18)
Number of stools per day (median) At baseline: 6 At end-point: 2.8 Number of flushing per day (median) At baseline: 4 At end-point: 0.2 Number of stools per day (median)
At baseline: 48.5 (12.3-223.4) (median/range; n=20) At end-point: 35.4 (0.1-240.0) (median/ range; n=21) At baseline: 72.7 (5.4-826.9) (median/ range;
A-133
Table A10: Outcomes for GEPNETs Number
of patients in each treatment arm
Change in HRQL Deaths Treatment success rates
Change in symptom severity
Change in 5-HIAA level (mg/ 24 hour urine)
every 4 weeks: 22 OCT-LA 20 mg IM every 4 weeks: 20 OCT-LA 30 mg IM every 4 weeks: 25
1 2
71% (11/ 15)* 61% (13/ 22)* Results were similar for ITT
At baseline: 5.9 At end-point: 3 Number of flushing per day (median) At baseline: 4 At end-point: 1 Number of stools per day (median) At baseline: 5.3 At end-point: 2 Number of flushing per day (median) At baseline: 4.9 At end-point: 1.1 Number of stools per day (median) At baseline: 5.3 At end-point: 2.5 Number of flushing per day (median) At baseline: 5.9 At end-point: 0.5 Total n for stool outcome=47
n=14) At end-point: 68.9 (3.2-717.8) (median/ range; n=14) At baseline: 52.6 (3.1-513.3) (median/ range; n=13) At end-point: 24.0 (2.8-223.3) (median/ range; n=14) At baseline: 83.0 (10.3-230.9) (median/ range; n=14) At end-point: 77.2 (0.6-473.3) (median/ range; n=20) Median 24 hours urinary 5-HIAA were equally
A-134
Table A10: Outcomes for GEPNETs Number
of patients in each treatment arm
Change in HRQL Deaths Treatment success rates
Change in symptom severity
Change in 5-HIAA level (mg/ 24 hour urine)
population Total n for flushing outcome=33
controlled by the different doses of OCT-LA
OCT-SA versus placebo Saslow 1997208
OCT-SA 50μg SC every 8 hours: 6 Placebo: 6
NR NR NR Tool: 10cm analogue scale; 0=no flushing/ abdominal pain to 10=worst flushing/ abdominal pain Flushing: 0.2±0.2 (mean/SE) Abdominal pain: 0.9±0.8 (mean/SE) Flushing: 0.9±0.2 (mean/SE) Abdominal pain: 1.5±0.5 (mean/SE)
At baseline: 105 (33-194) At baseline: 171 (21-405)
Jacobsen 1995209
OCT-SA 200μg SC per day: nr Placebo: nr
NR NR NR NR For patients who started with octreotide, pre-treatment values were restored during placebo treatment.
Table A11: withdrawals or drop-outs in GEPNETs trials
Treatment Control Study Sample size, ITT
Number Reason Number Reason
O’Toole 2000*204
33, no 2 Worsening of symptoms
3 2 worsening of symptoms; 1 transient occlusive syndrome
Rubin 1999206
93, no† 2 2 consent of withdrawals; 4 failed to return for scheduled visit; 1 adverse event; 2 treatment failure; 1 unknown; 3 deaths; 1 NR
12 (2 in 10 mg group; 5 in 20 mg group and 3 in 30 mg group)
See treatment‡
Jacobsen 1995209
11, no 2 1 allergic reaction; 1 worsening of nausea
0 --
*Drop-outs also reported in an abstract published in 1992 by Ruszniewski et al.205 †Authors reported that the results were similar for the ITT population but did not provide absolute numbers ‡reasons for drop-outs were not separated by treatment arms ITT=intention-to-treat; NR=not reported
A-136
Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery
Study Study design, funding sources
Patient characteristics Number of patients randomized, withdrawals, number patients inoperable*
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
Benedetti 1998217
Benedetti 1998223
Open, RCT, parallel, funding not reported
Pancreas transplantation Mean age= octreotide 33.5±7.2; Control 37.4±5.5 years (SD or SE) Men: 12; Women: 5
17, 1, 0 OCT-SA 100 µg SC three times daily, initiated pre-operatively No treatment
5 days, >6 months (average 18 months)
1, unclear
Briceño Delgado, 1998216
Open, RCT, parallel, funding not reported
Pancreaticoduodenectomy for malignancy or chronic pancreatitis Age (?mean or median)= octreotide 53 (28-73); Control 52 (20-69) years Men: 25; Women 9
34, 1, 0 OCT-SA100 µg SC three times daily, initiated post-operatively No treatment
Double-blinded, RCT, parallel, partial industry funding
Patients suitable for elective pancreatic resection because of pancreatic or periampullary tumours, or chronic pancreatitis Median age= octreotide 51 (19-75); Placebo 52 (20-80) years Men: 174; Women: 72
322, 0, 76 OCT-SA100 µg SC three times daily, initiated pre-operatively Placebo
7 days 4, unclear
A-137
Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery Study Study
design, funding sources
Patient characteristics Number of patients randomized, withdrawals, number patients inoperable*
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
Friess 199526 Double-blinded, RCT, parallel, partial industry funding
Patients with chronic pancreatitis, suitable for pancreatic resection or pancreatic duct anastomosis Median age= octreotide 48 (19-72) and placebo 47 (20-76) years Men: 194; Women: 53
280, 0, 33 OCT-SA 100 µg SC three times daily initiated pre-operatively Placebo
8 days, 90 days 4, unclear
Hesse 2005a212 Open label, RCT, parallel, funding not reported
Patients with malignant or benign tumours or pancreatitis who underwent pancreatic surgery and subsequent pancreatico-jejunostomy Mean age ±SD= octreotide 59.93±12.5; Control 58.98±13.7 years Men: 78; Women: 27
105, 1, 0 OCT-SA 100 µg SC three times daily initiated peri-operatively No treatment
7 days 2, unclear
Hesse 2005b213
Open label, RCT, parallel, funding not reported
pancreas transplantation Mean age= octreotide 43.3±7.1; Control 44.1±7.9 years (SD or SE not indicated) Men: 28; Women: 12
40, 0,0 OCT-SA 100 SC µg, three times daily initiated peri-operatively No treatment
7 days, mean 26.5 months±11.3 7 days, 25.5 months±11.1
2, unclear
A-138
Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery Study Study
design, funding sources
Patient characteristics Number of patients randomized, withdrawals, number patients inoperable*
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
Lange 1992221 Double-blinded, RCT, parallel, funding not reported
Cancer patients scheduled for surgery for pancreatic endocrinic tumour Median age= octreotide 47 (26-69; Placebo: 46 (23-65) years Men: 11; Women: 10
21, 2, 0 OCT-SA SC, day 1 post-operatively:50 µg three times daily, day 2:100 µg , three times daily; day 3 onwards:150 µg, three times daily Placebo
Continued until 3 days after drain removal; mean days to drain removal: octreotide:20.2 placebo:25.4
4, unclear
Montorsi 1995218
Double-blinded, RCT, parallel, funding not reported
elective pancreatic resection for neoplastic or chronic inflammatory disease of pancreas and periampullary region Age (mean±SD)= octreotide: 56.4±10.8; placebo:56.9±12.5 years Men: 131; Women 87
278, 6, 54 (218 considered in the analysis)
OCT-SA 100 µg SC three times daily initiated pre-operatively Placebo
7 days, 60 days 4, unclear
Pederzoli 1994219
Bassi 1994230
Double-blinded, RCT, parallel, industry funding
elective pancreatic surgery or drainage procedures for tumours of the pancreas or periampullary region, or for chronic pancreatitis, Age (mean±SE)= octreotide:52.6±1.1;
303, 10, 45 (252 considered in the analysis)
OCT-SA 100 µg SC three times daily initiated pre-operatively Placebo
7 days 5, unclear
A-139
Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery Study Study
design, funding sources
Patient characteristics Number of patients randomized, withdrawals, number patients inoperable*
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
placebo:53.6±1.2 years Men: 153; Women 99
Stratta, 1993220 Open, RCT, parallel, funding not reported
Pancreas transplantation Mean age= octreotide 35.3±5.7 (SD); Control 35.5±5.5 (SD) years Men:15; Women:10
Single-blinded, RCT, parallel design, funding not reported
Patients undergoing pancreaticoduodenectomy followed by anastomosis or distal pancreatectomy, malignant or benign disease, or chronic pancreatitis Mean age=octreotide 56±14(SD) (16-81); Control 57±12(SD) (24-80) years Men: 131; Women: 99
230, 0, 0 OCT-SA 100 µg SC three times daily initiated peri-operatively No treatment
10 days 3, adequate
Yeo 2000215 Double blinded, RCT, parallel, , funding not
Patients with malignant or benign tumour or pancreatitis who underwent pancreaticoduodenectomy
383, 40, 132 (211 considered in the analysis)
OCT-SA 250 µg SC three times daily initiated pre-operatively
7 days 5, adequate
A-140
Table A12: Trial characteristics for prophylaxis of complications after pancreatic surgery Study Study
design, funding sources
Patient characteristics Number of patients randomized, withdrawals, number patients inoperable*
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
reported, with pancreatic-enteric anastomosis Mean age±SE= octreotide 63.9±1.3; Control 65.5±1.1 years Men: 111; Women: 100
Placebo
*Patients were randomized prior to their surgical procedure. Once in surgery, patients were deemed inoperable if they had an unresectable lesion or because a procedure not anticipated in the protocol was required; OCT-SA=octreotide short-acting; RCT=randomized controlled trial; SC=subcutaneous; SD=standard deviation; SE=standard error
Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment
arms, n * Pancreatitis Pancreatic
fistula Fluid collection †
Bleeding †
Infection (infection type)
Abscess Death Overall complication rate
Length of hospital stay (days)
Benedetti, 1998217
Benedetti, 1998223
OCT-SA 300 µg SC per day N=10 No treatment N=7
0/10 2/7
NR NR
0/10 1/7
NR NR
0/10 2/7 (intra-abdominal infection)
NR NR
0/10 1/7
1/10 3/7
NR NR
A-141
Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment
Mean= 22.1±1.5 (SD or SE) mean= 26.2±1.9 (SD or SE)
A-142
Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment
arms, n * Pancreatitis Pancreatic
fistula Fluid collection †
Bleeding †
Infection (infection type)
Abscess Death Overall complication rate
Length of hospital stay (days)
Friess, 199526
OCT-SA 300 µg SC per day N=122 Placebo N=125
2/122 2/125
12/122 28/125
4/122 12/125
7/122 4/125
2/122 1/125 (sepsis)
5/122 2/125
2/122 1/125
20/122 37/125
Median (range): 14 (8-80); mean±SD‡: 17.25±10.31 Median (range): 15 (7-71) mean±SD‡:16.55±8.08
Hesse 2005a212
OCT-SA 300 µg SC per day N=56 No treatment N=49
NR NR
5/56 4/49
NR NR
2/56 1/49
NR NR
NR NR
1/56 0/49
6/56 6/49
mean±SD 23.12±15.08 20.36±8.07
Hesse, 2005b213
OCT-SA 300 µg SC per day N=20 No treatment N=20
1/20 0/20
2/20 0/20
NR NR
2/20 3/20
NR NR
NR NR
0/20 0/20
NR NR
NR NR
Lange, 1992221
OCT-SA 150 µg to 450 µg SC per day
NR
NR
NR
NR
NR
1/10
0/10
2/10
NR
A-143
Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment
arms, n * Pancreatitis Pancreatic
fistula Fluid collection †
Bleeding †
Infection (infection type)
Abscess Death Overall complication rate
Length of hospital stay (days)
N=10 Placebo N=11
NR
NR
NR
NR
NR
1/11
0/11
4/11
NR
Montorsi. 1995218
OCT-SA 300 µg SC per day N=111 Placebo N=107
2/111 5/107
10/111 21/107
2/111 9/107
8/111 9/107
NR NR
4/111 3/107
9/111 6/107
24/111 39/107
Mean±SD** 19.1± 9.6 19.5 ±12.9
Pederzoli, 1994219 Bassi 1994230
OCT-SA 300 µg SC per day N=122 Placebo N=130
1/122 6/130
11/122 24/130
8/122 13/130
3/122 2/130
2/122 8/130 (sepsis)
3/122 6/130
2/122 5/130
19/122 38/130
NR NR
Stratta 1993220
OCT-SA 200 µg SC per day N=13 No treatment N=12
NR NR
NR NR
1/13 1/12
NR NR
9/13 5/12 (major infection)
NR NR
0/13 0/12
NR NR
NR NR
A-144
Table A13: Outcomes for prophylaxis of complications after pancreatic surgery Study treatment
arms, n * Pancreatitis Pancreatic
fistula Fluid collection †
Bleeding †
Infection (infection type)
Abscess Death Overall complication rate
Length of hospital stay (days)
Suc 2004214
Oberlin 2000228
OCT-SA 300 µg SC per day N=122 No treatment N=108
2/122 1/108
21/122 20/108
18/122 23/108
16/122 10/108
NR NR
NR NR
15/122 8/108
35/122 40/108
median (range) 17 (7-130) 19 (6-109), NS
Yeo 2000215
OCT-SA 750 µg SC per day N=104 Placebo N=107
3/104 1/107
11/104 10/107
NR NR
NR NR
9/104 12/107 (wound infection)
9/104 5/107
1/104 0/107
42/104 36/107
mean±SE 13.1±1.1 11.9±0.6
* refer to Appendix 4 Table A12 for a complete description of the treatments; † bleeding was described as: hemorrhage; abdominal hemorrhage; or intra-abdominal or digestive tract hemorrhage or both, in four reports; ‡ The mean and standard deviation were provided by Professor Helmut Friess, University of Berne, Switzerland: unpublished data, 2007; ** The mean and standard deviation were provided by Professor Marco Mortorsi, University of Milan, Milan: unpublished data, 2007; NR=not reported; NS=not significant; OCT-SA=octreotide short acting; SC=subcutaneous; SD=standard deviation; SE=standard error; SS=statistically significant
A-145
Table A14: Withdrawals in prophylaxis of complications after pancreatic surgery RCTs Treatment Control Study Sample
size, ITT Number Reason Number Reason
Lange 1992221 21, yes 1 Prolonged ileus and nausea
1 Prolonged copious drain output requiring total parenteral nutrition
6 patients were withdrawn due to protocol violations (treatment group not specified) 4 patients stopped therapy early but were evaluable
Pederzoli, 1994219 Bassi, 1994230
303, no
Of the 4 evaluable patients, 1 discontinued treatment due to adverse events.
Of the 4 evaluable patients, 2 died and 1 had post-operative pancreatitis
Montorsi 1995218
278, no 6 withdrawn due to protocol violations (treatment group not reported)
Yeo 2000215 383, no 40 Did not receive OCT-SA for at least 5 days
0 N/A
ITT=intention to treat; N/A=not applicable; OCT-SA=octreotide short acting
Table A15: Harms reported in RCTs for prophylaxis of complications after pancreatic surgery
Study Treatment group, n
Number patients with adverse events, Dropouts due to adverse events
Pain at injection site
Gastro-intestinal tract
Other adverse events (OCT-SA, control)
Buchler 1992222
OCT-SA 125 placebo 121
NR, 2 NR , 1
31 25
NR NR
2 patients with itching and temporary migrant exanthema, treatment group NR
Briceno Delgado 1998216
OCT-SA 16 placebo 18
NR, 1 NR, NR
14 NR
NR NR
cutaneous infection at injection site (1, NR)
A-146
Table A15: Harms reported in RCTs for prophylaxis of complications after pancreatic surgery
Study Treatment group, n
Number patients with adverse events, Dropouts due to adverse events
prolonged copious drain output requiring total parenteral nutrition (0, 1)
Montorsi 1995218
OCT-SA 111 placebo 107
3, 0 3, 0
NR NR
3 3
NR NR
Pederzoli 29936219
OCT-SA 122 placebo 130
4, 1 NR, NR
NR NR
1 NR
biliary sludge (1, NR), rash (1, NR)
Suc 2004214 OCT-SA 122 placebo 108
NR, 0 NR, 0
NR NR
NR NR
NR NR
Yeo 2000215 OCT-SA 104 placebo 107
0, 0 0, 0
NR NR
NR NR
NR NR
NR=not reported: OCT-SA=octreotide short-acting
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Table A16: Bowel obstruction study characteristics Study Study
Design, Funding Sources
Patient Characteristics
Treatment Arms Number Randomized, Withdrawals
Treatment Duration, Follow-up
Jadad Score, Allocation Concealment
Mercandante 2000232
open label RCT, parallel design, funding sources NR
Cancer patients with inoperable bowel obstruction mean age= 66.8 years (range 52-81) 2 men and 13 women ECOG score >2: n= 15 Setting: home care, surgical or oncology ward
18, 3 (patients died or data was lost; treatment allocation NR)
3 days, 3 days
2, unclear
Mystakidou 2002233
double blind RCT, parallel design, funding sources NR
advanced metastatic cancer with inoperable bowel obstruction OCT-SA= median age 64.5 years (range 42-77), hyoscine: median age 63 years (47-74) 36 males, 32 females ECOG score >2: n= 46 Setting: home care
Table A18: Trial characteristics for refractory diarrhea
Study Study design, funding sources
Patient characteristics Treatment arms Total number of patients randomized, withdrawals
Treatment duration, follow-up
Jadad score, allocation concealment
Chemotherapy patients Cascinu 199432
Double-blind RCT, parallel design, funding not reported
previous diarrhea (three or more loose bowel movements in the 24 hour period after a course of cisplatin (CDDP). White blood cell count over 3,000/mm3 Median age= octreotide 61 (38-70); Placebo 60 (43-68) years Men: 23; Women 20
OCT-SA 2 doses of 100 µg SC Placebo
43, 0 6 h, 24 h
3, unclear
A-151
Table A18: Trial characteristics for refractory diarrhea Study Study
design, funding sources
Patient characteristics Treatment arms Total number of patients randomized, withdrawals
Treatment duration, follow-up
Jadad score, allocation concealment
Cascinu, 199331 Cascinu, 1992241 (abstract)
Single-blinded (assessor) RCT, parallel design, funding not reported
Grade 2 (4 to 6 stools per day or nocturnal stools or moderate cramping) or grade 3 (7 to 9 stools per day or incontinence or severe cramping) diarrhea as described in the National Cancer Institute Common Toxicity criteria. WBC count>3,000/µL Median age= octreotide 57 (46-65); Loperamide 59 (42-68) years Men 22; Women 19
OCT-SA 100 µg SC twice daily Loperamide 4 mg PO initial dose then 2 mg PO four times daily
41, 0 3 days 3, unclear
Gebbia 1993238
Open label, RCT, parallel design, funding not reported
WHO grade 3 or 4 diarrhea after chemotherapy. Mean age= octreotide 58; Loperamide 56 years Men 24; Women 16
OCT-SA 500 µg SC three times daily Loperamide 4 mg PO three times daily
40, 0 If no resolution after 4 d, discontinued and hospitalized. If responding to treatment, continued until complete resolution
2, unclear
Geller 1995239
Open label,
patients receiving chemotherapy for
OCT-SA 150 µg IV over 24 h, doubled
36, 5 Primary end-point at 48 h.
3, unclear
A-152
Table A18: Trial characteristics for refractory diarrhea Study Study
design, funding sources
Patient characteristics Treatment arms Total number of patients randomized, withdrawals
Treatment duration, follow-up
Jadad score, allocation concealment
Geller 1993242 (abstract)
RCT, parallel design, Industry funding
leukemia for bone marrow transplant Stool volume ≥600 mL in 24 hours Mean age= octreotide 48 (30-65); Loperamide 45 (26-68) years Men 19; Women 17
every 48 h if no resolution; maximum 2400 µg Loperamide 4 mg PO four times daily
If major response, patient continued on dosage level until stool was non-liquid for 24 hrs or there was no stool output for 48 h. Loperamide discontinued if no response at 48 h.
A-153
Table A18: Trial characteristics for refractory diarrhea Study Study
design, funding sources
Patient characteristics Treatment arms Total number of patients randomized, withdrawals
Treatment duration, follow-up
Jadad score, allocation concealment
Nikou 1994240
Open label, RCT, parallel design, funding not reported
at least grade 3 diarrhea (7 to 9 stools per day; NCI toxicity criteria) Mean age= octreotide group: 59 (47-76); loperamide: 62 (49-80) years Men 9; Women 7
OCT-SA 100 µg titrated to 300 µg SC three times daily Loperamide, 2 mg PO four times daily
16, 0 Until resolution (OCT-SA ≤ 3 days, treatment duration not reported for loperamide)
2, unclear
A-154
Table A18: Trial characteristics for refractory diarrhea Study Study
design, funding sources
Patient characteristics Treatment arms Total number of patients randomized, withdrawals
open-label RCT, parallel design, funding not reported
AIDS (according to CDC criteria) with uncontrolled diarrhea resistant to usual doses of antidiarrheal treatment for at least 4 weeks. Age (mean±SD)= octreotide 36±9 (25-54); Control 38±10 (27-58) years Men: 20; Women 0
OCT-SA 100 µg SC three times daily to a maximum dose of 300 µg three times daily on third day Placebo SC injection+ Loperamide 2mg PO three times daily to a maximum dose of 6mg PO three times daily on day 3 + Diphenoxylate 2.5 mg PO three times daily to a max dose of 7.5mg PO three times daily on day 3
20, 0
10 days
2, unclear
A-155
Table A18: Trial characteristics for refractory diarrhea Study Study
design, funding sources
Patient characteristics Treatment arms Total number of patients randomized, withdrawals
Treatment duration, follow-up
Jadad score, allocation concealment
Simon 1995236 Simon 1994237 (abstract)
Double-blinded, RCT, parallel, partial Industry funding
HIV antibody-positive, diarrhea for more than 6 weeks despite 4 weeks of conventional dosing regimens of antidiarrheal agents, and for patients with gastrointestinal infection, continued diarrhea despite 2 weeks of potentially curative therapy Mean age=octreotide 37.0±0.9; Placebo 37.3±1.0 years Men: 123; Women: 6
OCT-SA 100 µg SC three times daily to a maximum dose 300 µg SC three times daily Placebo The mean stool weight in the last 72 hours of the seven day period determined whether the dose was increased
129, 21 (16 dropouts and 5 excluded from analysis)
21 days 5, unclear
CDC=Centre for Disease Control; d=day(s); h=hour(s); HIV=human immunodeficiency virus; IV=intravenous; max=maximum; NCI=National Cancer Institute; OCT-SA=octreotide short-acting; PO=oral; RCT=randomized controlled trial; SC=subcutaneous; SD=standard deviation; WBC=white blood count; WHO=World Health Organization
A-156
Table A19: Refractory diarrhea study outcomes Study Treatment arms, n Complete or major resolution of
diarrhea (n/N)
Chemotherapy patients
OCT-SA versus placebo
OCT-SA 2 doses of 100 µg SC n=23
22/23 Cascinu 199432
Placebo n=20
5/20
OCT-SA versus loperamide
OCT-SA 100 µg SC twice daily n=21
19/21 Cascinu 199331
Loperamide 4 mg PO initial dose then 2 mg PO four times daily n=20
3/20
OCT-SA 500 µg SC three times daily n=20
19/20 Gebbia 1993238
Loperamide 4 mg PO three times daily n=20
15/20
OCT-SA 150 µg IV over 24 h, doubled every 48 h if no resolution, maximum 2400 µg n=22
10/22 Geller 1995239
Loperamide 4 mg PO four times daily n=14
12/14
OCT-SA 100 µg to 300 µg SC three times daily n=8
8/8 Nikou 1994240
Loperamide 2 mg PO four times daily n=8
2/8
HIV-AIDS patients
OCT-SA versus placebo
OCT-SA 100 to 300 µg SC three times daily n=76
34/74 Simon 1995236
Placebo n=53
18/50
OCT-SA versus placebo and anti-diarrheal agents
OCT-SA 100 to 300 µg SC three times daily n=10
2/10 Garcia Compean 1994234
Placebo + loperamide 2 to 6 mg PO three times daily + diphenoxylate 2.5 to 7.5 mg PO three times daily n=10
Table A20: Withdrawals reported in refractory diarrhea RCTs Treatment Control Study Sampl
e size, ITT Number Reason Number Reason
Chemotherapy patients Geller 1995239
36, yes 4 Did not receive treatment due to lost IV access, infusion pump malfunction, drug not administered, or failure to quantify stool. Outcomes were included in ITT analysis
1 Did not receive drug due to difficulty swallowing. Outcomes were included in ITT analysis
HIV-AIDS patients Simon 1995236
129, no 8 adverse events (3), illness deemed unrelated to study medication (1), lack of cooperation (1), protocol violation (1), either new/experimental antimicrobial therapy was initiated (3), exclusion criteria for study identified after completion of study (2)
13 adverse events (4), illness deemed unrelated to study medication, (3), lack of cooperation (2), protocol violation (1), new/experimental antimicrobial therapy was initiated (3), exclusion criteria for study identified after completion of study (3)
Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study
design, funding sources
Patients characteristics Total number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
OCT-LA versus placebo Barbare 2005244 (conference proceeding)
Open-label RCT, parallel design, industry funding
Histologically proven hepatocellular carcinoma or diagnosis based on the association of cirrhosis, serum AFP>500 μg/L and typical imaging findings. Advanced hepatocellular carcinoma not suitable for surgery, percutaneous ablation or chemoembolization. Mean age=68 years (range 38- 87); 37 woman and 229 men
266, NR OCT-LA 30 mg IM every month Placebo
NR
1, unclear
Becker 2007243 Allgaier 2003290 (abstract)
Double-blind RCT, parallel design, partial industry funding
previously untreated patients with histologically confirmed hepatocellular carcinoma and no indication for surgery or any local treatment. Median age=67.1±8.9 (?SE or SD) years for treatment group and 65.1±8.8 years for control; 14 women and 105 males
119, 1 OCT-LA 30 mg IM every month Placebo
Treated until death, followed 30.2±8.6 months (median) Followed 32.5±7.5 months (median)
5, adequate
A-160
Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study
design, funding sources
Patients characteristics Total number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
OCT-LA versus no treatment Yuen 2002245 Open-label
RCT, parallel design, partial industry funding
patients who were ineligible for surgery or TACE, histological proven hepatocellular carcinoma or serum AFP of >400ng/ml with typical imaging findings of hepatocellular carcinoma by CT or hepatic angiogram, serum bilirubin <100 micromole/L, and PT <18 seconds. Median age=54.8 years (range 26.6-78.8) for treatment and 61.7 years (range 36-78.4) for control; 5 women and 65 men
70, NR OCT-LA 30 mg IM every month No treatment
24 weeks, 26 weeks
3, unclear
OCT-LA with tamoxifen versus tamoxifen alone Verset248 Open-label Hepatocellular carcinoma 109, 10 OCT-LA 30 mg Median 3, unclear
A-161
Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study
design, funding sources
Patients characteristics Total number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
Verslype 2006291 (conference proceeding)
RCT, parallel design, industry funding
not amenable to curative resection, liver transplantation or local treatment; KPS≥60, life expectancy of ≥2 months. Median age=64.5 years (range 39-84) for treatment; 68 years (range 38-83) for control; 21 women and 88 men
IM every month + tamoxifen 20 mg PO daily tamoxifen 20 mg PO daily
number of octreotide doses=2 (range 1-31), followed until death median 3 months (range 0.1-31 months)
OCT-SA versus no treatment Farooqi 2000247 Open-label
RCT, parallel design, funding source NR
histology proven hepatocellular carcinoma and increased levels of serum AFP. Mean age=53.1 years for treatment group and 51.7 years for control, p>0.05; 4 women and 5 men
13, 0 OCT-SA 500 µg SC total daily dose No treatment
6 weeks, 12 weeks Followed 12 weeks
1, unclear
A-162
Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study
design, funding sources
Patients characteristics Total number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
Kouroumalis 1998246
Open-label RCT, parallel design, funding source NR
liver biopsy diagnosis of hepatocellular carcinoma and/or increased levels of AFP >500ng/L with compatible liver ultrasound, CT scan, or hepatic angiography. Median age=69 years (range 53-84) for treatment group and 68 years (range 52-87) for control; 10 women and 48 men
58, 4 OCT-SA 500 µg SC total daily dose No treatment
Treated until patient withdrawal or death, followed 14.1±2.17 months (mean/SE) Followed 6.6±1.36 months (mean/SE)
3, unclear
OCT-SA and OCT-LA versus placebo Dimitroulopoulos 2007249 Dimitroulopoulos 2004292 (abstract)
Double-blind RCT, parallel design,
patients with cirrhosis (stage A-B) due to hepatitis B or C and advanced hepatocellular carcinoma. Those with
61, 7 OCT-SA 0.5 mg SC every 8 hours for 6 weeks, then OCT-LA IM 20
Treatment duration until patient withdrawal or
3, unclear
A-163
Table A22: Trial characteristics for hepatocellular carcinoma RCTs Study Study
design, funding sources
Patients characteristics Total number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
Dimitroulopoulos 2005293 (conference proceeding)
funding source NR
intense uptake of radionuclear compound (111-Indium labelled octreotide) were randomized. Mean age = 69.4±6.3 (SE) years for treatment group and 69.5±5.6 years for control; 18 women and 43 men
mg at the end of week 4 and 8, and OCT-LA 30 mg IM at the end of week 12 and every 4 weeks thereafter. For the period between week 4 and 6, OCT-SA 0.5 mg SC was given every 8 hours. Placebo, oral
Table A23: Outcomes for hepatocellular carcinoma RCTs
Study Number of patients in each treatment arm
Death (n)
Survival time since randomization (median in months)
Change in HRQL from baseline
Change in tumour size
Tumour response rates
Change in AFP level
OCT-LA versus placebo Barbare 2005244 (conference proceeding)
OCT-LA 30 mg IM every month: 134 placebo: 132
NR 6.5 (range 4.7-7.0) 7.3 (range 5.5-8.6)
NR NR NR NR
A-165
Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of
patients in each treatment arm
Death (n)
Survival time since randomization (median in months)
Change in HRQL from baseline
Change in tumour size
Tumour response rates
Change in AFP level
Becker 2007243 Allgaier 2003290 (abstract)
OCT-LA 30 mg IM every month: 60 placebo: 59
54 52
4.7 5.3 RR=1.1 [95%CI: 0.76-1.63], p=0.59
Tool: EORTC QLQ-C30 p=NS p=NS
At baseline: 7.6±3.5 cm (mean/SD) At end-point: Tumour regression did not occur in any patient. At baseline: 7.4±4.0 cm (mean/SD) At end-point: Tumour regression did not occur in any patient. For stable or progressive disease: no significant difference on tumour growth or response between groups
NR At baseline: 49% of patients had <400ng/mL At end-point: NR At baseline: 61% of patients had <400ng/mL At end-point: NR
A-166
Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of
patients in each treatment arm
Death (n)
Survival time since randomization (median in months)
Change in HRQL from baseline
Change in tumour size
Tumour response rates
Change in AFP level
OCT-LA versus no treatment Yuen 2002245
OCT-LA 30 mg IM every month: 35 No treatment: 35
32 33
1.93 1.97
Tool: KPS no improvement no improvement
NR At 14 weeks: 1 static disease; 6 tumour progression 1 tumour regression; 2 static disease; 5 tumour progression
At baseline: median=19,177ng/mL (range 2-864,030) At endpoint: median=41,897ng/mL (range 3-73,707) At baseline: median= 721 ng/mL (range 1-475,271) At end-point: NR No significant difference in % of patients with AFP reduction between groups.
OCT-LA with tamoxifen versus tamoxifen alone Verset248 OCT-LA 55 median 3 At 3 months: NR At 3 months: At 3 months:
A-167
Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of
patients in each treatment arm
Death (n)
Survival time since randomization (median in months)
Change in HRQL from baseline
Change in tumour size
Tumour response rates
Change in AFP level
Verslype 2006291 (conference proceeding)
30 mg IM every month + tamoxifen
(95%CI: 1.4-4.5)
Median KPS=80 (95%CI: 40-100), n=25
tumour progression: 13/ 20
increase>25%: 10/18
A-168
Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of
patients in each treatment arm
Death (n)
Survival time since randomization (median in months)
Change in HRQL from baseline
Change in tumour size
Tumour response rates
Change in AFP level
A-169
Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of
patients in each treatment arm
Death (n)
Survival time since randomization (median in months)
Change in HRQL from baseline
Change in tumour size
Tumour response rates
Change in AFP level
OCT-SA versus no treatment Farooqi 2000247
OCT-SA 500 µg SC per day: 6 no treatment: 7
NR NR Tool: appetite, pain in right hypochondrium, body weight, and feeling of well-being appetite became normal: 5; pain in right hypochondrium disappeared: 4; Feeling of well-being returned: 4 appetite: 0; pain in right hypochondrium disappeared: 1; feeling of well-being returned: 0
At baseline: 7.8±1.9 cm (mean/SD) At 3 months: 11.4±1.4 cm (mean/SD) At baseline: 7.6±1.6 cm (mean/SD) At 3 months: 19±1.2 cm (mean/SD)
NR At baseline: 220±17 ng/mL (mean/SD) At 3 months: 60±21 ng/mL (mean/SD) At baseline: 206±14 ng/mL (mean/SD) At 3 months: 1054±21 ng/mL (mean/SD)
A-170
Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of
patients in each treatment arm
Death (n)
Survival time since randomization (median in months)
Change in HRQL from baseline
Change in tumour size
Tumour response rates
Change in AFP level
Kouroumalis 1998246
OCT-SA 500 µg SC per day: 28 No treatment: 30
At 6 months:7 At 12 months:12 At 6 months:19 At 12 months: 26
Tool: Appetite, body weight, and the general feeling of well being were used as criteria improvement in feeling of well being:15 (53.6%); increase in appetite:24 (85.7%); improvement in body weight:12 (42.8%) no difference
At baseline: 3 small, 5 medium, 11 large, 9 multiple tumours At 6-12 months: small tumours disappeared in 5 patients; size in 4 patients remained unchanged; size in all other patients increased gradually At baseline: 1 small, 6 medium, 10 large, 13 multiple tumours. The tumour size gradually increased.
tumour progression: 19 tumour progression: 30
NR
A-171
Table A23: Outcomes for hepatocellular carcinoma RCTs Study Number of
patients in each treatment arm
Death (n)
Survival time since randomization (median in months)
Change in HRQL from baseline
Change in tumour size
Tumour response rates
Change in AFP level
OCT-SA and OCT-LA versus placebo Dimitroulopoulos 2007249 Dimitroulopoulos 2004292 (abstract) Dimitroulopoulos 2005293 (conference proceeding)
OCT-SA 1.5 mg SC per day for 6 weeks, then OCT-LA IM 20 to 30 mg at week 4 and every 4 weeks: 31 Placebo: 30
All patients had died at the end of the follow-up period except one (octreotide) that died 4 weeks later
12.3 (interquartile range 7.0-18.0) 7.0 (interquartile range 4.8-8.5)
Tool: QLQ-C30 At 12 months: 22% decrease in score 39% decrease in score
NR NR At baseline: 2714±5049 (units NR) At end-point: NR At baseline: 3096±4500 (units NR) At end-point: NR
AFP=α fetoprotein; CI=confidence interval; EORTC QLQ-C30=European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; HRQL= health-related quality of life; IM=intramuscular; KPS= Karnofsky performance status scale; OCT-LA=octreotide long acting; OCT-SA=octreotide short-acting; NR= not reported; NS=not significant; RCT=randomized controlled trial; RR=relative risk; SC=subcutaneous; SD= standard deviation; SE=standard error
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Table A24: Withdrawals or drop-outs in hepatocellular carcinoma RCTs
treatment control Study Sample size, ITT
Number Reason Number Reason
Becker 2007243
119, yes 1 Lost to follow-up 0 --
Verset248 109, yes 6 4 lost to follow-up; 1 received a transplant; 1 suffered an adverse event
4 2 lost to follow-up; 1 suffered an adverse event; 1 had transarterial chemoembolization
Kouroumalis 1998246
58, yes 4 NR 0 --
Dimitroulopoulos 2007249
61, yes 7 6 had diarrhea; 1 refused treatment
0 --
ITT=intention to treat; NR=not reported; RCT=randomized controlled trial
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Table A25: Harm reported in RCTs for hepatocellular carcinoma
Study Treatment Duration (total
patients)
Reported harm: treatment
Reported harm: control
OCT-LA versus placebo Barbare 2005244 NR (266) 0.7% (1/134)
OCT-LA versus no treatment Yuen 2002245 24 weeks (70) No significant adverse
events observed NR
OCT-LA with tamoxifen versus tamoxifen alone Verset248 2 months (109) 1/56 discontinued
treatment due to diarrhea*
3/53 discontinued treatment due to adverse events (digestive n=1; flush n=1; gynecomastia n=1)
OCT-SA versus no treatment Farooqui 2000247 6 weeks (13) 33% (2/6) diarrhea NR Kouroumalis 1998246
Until death or withdrawal (58)
40% (11/28) diarrhea NR
*not significant compared to control group NR=not reported, OCT-LA=octreotide long acting, OCT-SA=octreotide short-acting; RCT=randomized controlled trial
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Table A26: Pancreatic cancer study characteristics Study Study design,
funding sources
Patient Characteristics
Number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
Cascinu 199548
RCT, parallel, open label, funding sources NR
Advanced gastrointestinal cancer refractory to chemotherapy, <75 years of age, ECOG performance status of 0-2, measurable disease Median age=octreotide 68 (range 39-71) Control 66 (44-72) years Men: 65; Women: 42
107 (32 with pancreatic cancer), withdrawals NR
OCT-SA 200 µg SC three times per day, 5 days per week no treatment
until disease progression, unacceptable toxicity or patient refusal (mean treatment duration 12 weeks, range 6 - 32)
3, inadequate
Maurer 1998252 (abstract) Salvia 1998253 (abstract) Pederzoli 1998255
RCT, parallel, double blind, partial industry funding
Unresectable stage 2, 3 or 4 pancreatic cancer Age and sex: NR
190, 5 OCT-LA 160 mg IM monthly Placebo
NR 2, unclear
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Table A26: Pancreatic cancer study characteristics Study Study design,
funding sources
Patient Characteristics
Number of patients randomized, withdrawals
Treatment arms Treatment duration, follow-up
Jadad score, allocation concealment
Schlag 1998254 (abstract) Roy 1998256 (abstract)
RCT, parallel, double blind, partial industry funding
Unresectable stage 3 and 4 pancreatic cancer Age and sex: NR
284, 3 OCT-LA, 160 mg dosing interval NR Placebo All patients: 5-FU 225 mg/m2/d IV for 8 weeks, then one week rest.
NR (5-FU was administered for 8 weeks; length of octreotide treatment NR)
2, unclear
Burch 200045 RCT, parallel open label, no industry funding
Locally unresectable, residual, recurrent or metastatic ductal adenocarcinoma of the pancreas; ECOG status of 0-1; Median age= octreotide 65 (range 46-83); 5-FU 61 (37-72); 5-FU+LV 64 (28-83) years Men:64; Women: 30
96, 12 OCT -SA 200 µg or 500 µg SC three times per day 5-FU 500 mg/m2 IV for 5 days, repeated every 5 weeks 5-FU 425 mg/m2 IV plus leucovorin 20 mg/m2 for 5 days, repeated every 5 weeks
*Time to progression considered appearance of new areas of disease; decrease of >1 level on Eastern Cooperative Oncology Group (ECOG) performance scale, development of new jaundice or ascites, definite increase in areas of existing disease, or >25% increase in measurements of indicator lesions. 5-FU= 5-fluouracil; CI=confidence interval; IV-intravenous; NR=not reported; OCT-SA=octreotide short-acting; OCT-LA= octreotide long-acting; SC=subcutaneous
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Table A28: Harm reported in RCTs for pancreatic cancer
Patients diagnosed with acromegaly and treated with surgery and medication
OCT-SA doses, outcomes and compliance rates from a longitudinal chart review (over 4.5 years). Cross sectional data on doses prescribed or reimbursed from 3 other jurisdictions. OCT-LA doses were inferred.
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Table A29: Characteristics of included economic studies Author Location and
funding source
Study design, Outcomes
Perspective Time horizon,
Discounting
Intervention and
comparator
Population Data sources
Moore 200283 UK, non-industry funding
Cost-effectiveness and cost utility analysis (decision analytic model) Cost per LYS and QALY.
Not stated (direct medical costs only)
Not stated Somatostatin analogues (OCT-LA and lanreotide, combined) compared to bromocriptine, cabergoline, and no therapy
Acromegalic patients using medications as adjuvant to surgery or radiotherapy
Estimates for modelling based on data from observational studies or from expert panel; costs from various sources
Cost-effectiveness analysis (Markov model) Cost per bleed prevented
Not stated Not stated OCT-LA or propanolol used in 1o and 2 o prevention. Reference case was no treatment (usual care) for 1o prevention and ligation for 2 o prevention.
Patients requiring treatment for 1o and 2 o prevention of esophageal variceal hemorrhage.
Efficacy from published meta-analyses and RCTs; cost data from Red Book and AHCPR HCUP-3 national data set.
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Table A29: Characteristics of included economic studies Author Location and
funding source
Study design, Outcomes
Perspective Time horizon,
Discounting
Intervention and
comparator
Population Data sources
GEPNET Schonfeld 1998260
US, industry funded
Cost-effectiveness analysis (Markov model) Cost per year of remission gained and cost per year of life saved
Payer, insurer or patient (direct medical costs only)
Until death The discount rate was 5% per annum.
OCT-SA and usual care versus usual care (i.e., OCT-SA not available)
Patients with carcinoid syndrome and/or VIPomas, with disease extensive enough to warrant liver resection.
An expert panel was used to estimate health state values and quantities of resources utilized. The unit costs for health professionals, medications, diagnostic and therapeutic procedures, were from different data sources.
Novartis Pharmaceuticals Canada Inc. May 1999 (Unpublished Data)
Canada, industry funded
Cost-minimization study
Drug plans One month, discounting N/A
OCT-SA versus OCT-LA
Patients with carcinoid syndrome and VIPomas
Efficacy and dosage based on a RCT (Rubin 1999206). Drug costs supplied by manufacturer.
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Table A29: Characteristics of included economic studies Author Location and
funding source
Study design, Outcomes
Perspective Time horizon,
Discounting
Intervention and
comparator
Population Data sources
Complications after pancreatic surgery Rosenberg 199924 Rosenberg 199725 (abstract)
Canada, partial industry funding
Cost-effectiveness analysis (decision analytic model) Cost per patient
Not stated (direct medical costs only)
Six months, discounting N/A
OCT-SA versus placebo
Patients undergoing pancreatic resection
Complication rates based on a meta-analysis of double-blind, RCTs. Costing model 1: Per diem hospital costs from Statistics Canada. Incremental LOS based on expert opinion. Model 2: costs of hospitalization from Ontario Case Costing Project.
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Table A29: Characteristics of included economic studies Author Location and
funding source
Study design, Outcomes
Perspective Time horizon,
Discounting
Intervention and
comparator
Population Data sources
Vanounou 2007259
US, funding sources not reported
Cost-benefit analysis Cost savings, cost benefit ratio
Not stated (hospital medical costs only)
1 month, discounting N/A
OCT-SA versus usual care
Patients undergoing pancreatico-duodenectomy
Costs and effectiveness based on a cohort of 227 patients from a single institution. Costs of index hospitalization plus readmissions within 30 days were included.
AHCPR HCUP-3=Agency for Health Care Policy and Research Healthcare Cost and Utilization Project; GH=growth hormone; HRQL=health related quality of life; LOS=length of stay; LYS=life-years saved; N/A=not applicable; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting; QALY= quality adjusted life-years; RCT=randomized controlled trial; VIPoma=vasoactive intestinal polypeptide secreting tumour.
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Table A30: Results of economic evaluations included in review
Author Currency and Year
Estimates of cost and effectiveness
Incremental Results Conclusions and Limitations
Acromegaly Novartis Pharmaceuticals Canada Inc. January 1999 (Unpublished Data)
C$ (year not stated)
Cost (19 months) OCT-SA = $21,752 OCT-LA = $28,637 Percent of patients who achieved a GH concentration of less than 2 µg/L (i.e., treatment success) OCT-SA = 38.6% OCT-LA = 54.6%
Cost per successfully treated patient over 19 months OCT-SA = C$56,353 OCT-LA = C$52,448 Incremental cost-efficacy ratio over the whole 19 months is equal to C$43,031
The study authors concluded that the cost per successfully treated patient tends to be lower with OCT-LA than OCT-SA. Treatment success defined using a short term surrogate marker (GH level) and success rates were based on a single uncontrolled observational study (patients crossed over from OCT-SA to OCT-LA treatment).294 In the analysis, the proportion of patient receiving OCT-LA 10mg, 20mg or 30 mg doses were assumed to be 10%, 70% and 20% respectively. These doses were lower that those reported in Lancranjan et al.294 (89 patients received long-term treatment with OCT-LA 20 and 30 mg, and 12 patients received 40 mg). No sensitivity analyses were conducted to assess the uncertainty around parameter values.
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Table A30: Results of economic evaluations included in review Author Currency
and Year Estimates of cost and
effectiveness Incremental Results Conclusions and Limitations
Wilson, 1999 (Unpublished Data)
C$ (year not stated)
Disaggregated results not reported.
OCT-LA would incur incremental cost of $3,000 to $7,000 per year per additional patient being cured depending on whether patients have macroadenomas or microadenomas. Cure defined as GH level < 2μg/L).
Details of the model, data parameters and analysis were not provided by the authors, thus making it difficult to assess the validity of the study. Effectiveness of two treatments assumed to be equivalent except for improved compliance with OCT-LA (assumed compliance rates not provided). Doses of OCT-SA obtained mainly from a retrospective chart review of one specialty clinic. Assumptions used when converting OCT-SA doses to equivalent OCT-LA doses were not reported.
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Table A30: Results of economic evaluations included in review Author Currency
and Year Estimates of cost and
effectiveness Incremental Results Conclusions and Limitations
Moore 200283 GB£ (year not stated)
Cost for 1st year treatment: OCT-LA: £11,544 (range 9,329-13,728) lanreotide: £9,328 (9,046-15,874) bromocriptine: £824 (514-1,110) cabergoline: £996 (649-2,101) no therapy: £0 Deaths: somatostatin analogues: 0.00238 cabergoline: 0.00253 bromocriptine: 0.00289 no therapy: 0.00306 QALY: somatostatin analogues: 0.838 cabergoline: 0.821 bromocriptine: 0.763 no therapy: 0.738
IC/LYS: £64,5 M (range £29M-300M) for somatostatin analogues over cabergoline and £18.6M (£1.3 M - 35.9M) over bromocriptine IC/QALY: £531,000 (£253,000 - 3.2M) for somatostatin analogues over cabergoline and £126,000 (£111,000 – 126,000) over bromocriptine
Treatment efficacy based on GH levels attained (<2.5 µg/L, 2.5 - 10.0 µg/L, > 10 µg/L) which were then extrapolated to LYS or QALY. Mortality ratios and GH levels based on several cohort studies. The authors stated that patients may not be comparable across these cohorts. HRQL data was assumed. Thus there is uncertainty in the incremental results. In the model, the costs for OCT-LA and lanreotide were averaged and analyzed as a class. The cost of lanreotide used in the analysis was lower due to a local cost-sharing program sponsored by manufacturer. Without cost-sharing, annual cost increased to £11,868. Generalizability would be improved if a separate analysis for OCT-LA and lanreotide had been conducted and the full range of costs explored in sensitivity analysis.
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Table A30: Results of economic evaluations included in review Author Currency
and Year Estimates of cost and
effectiveness Incremental Results Conclusions and Limitations
Disaggregated results not stated Assumed octreotide was 30%, 40% or 50% more effective than propranolol
Cost per bleed prevented compared to reference case. 1. Propranolol (1o) plus
ligation and propranolol (2o): US-$24,600
2. Propranolol (1o) plus ligation and OCT-LA (2o): US-$22,900
3. OCT-LA (1o) plus ligation and propranolol (2o): US$517 to US$5,506 (octreotide 50% to 30% more effective than propranolol, respectively)
4. OCT-LA (1o) plus ligation and OCT-LA (2o): US$593 to US$5,836 (OCT 50% to 30% more effective than propranolol, respectively)
The study authors concluded that once a month administration of OCT-LA provides a cost-effective prophylactic option. Abstract provided insufficient details to draw any conclusions regarding the cost-effectiveness of octreotide. In addition, there is some uncertainty if the study met the inclusion criteria for population and intervention.
GEPNET Schonfeld 1998260
US$ 1994 (Costs that were
Carcinoid tumour: octreotide: treatment cost is US$76,400 from time of initial
Carcinoid tumour: Incremental cost per year of remission
Study authors concluded that octreotide was cost-effective in terms of cost per year of life saved
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Table A30: Results of economic evaluations included in review Author Currency
and Year Estimates of cost and
effectiveness Incremental Results Conclusions and Limitations
collected in earlier reference years were converted to 1994 dollars.)
liver metastases resection to death, with 3.88 years in remission and 4.05 years of life. Usual care: US$74,800 with 1.76 years in remission and 1.98 years of life. VIPoma: octreotide: treatment cost is US$76,100 from time of initial resection of liver metastases to death, with 2.39 years in remission and 2.60 years of life. Usual care: US$80,000 with 1.09 years in remission and 1.32 years of life.
gained=US$736 Incremental cost per year of life saved=US$752 for octreotide versus usual care VIPoma: The scenario with octreotide is dominant (less expensive and more effective).
for carcinoid tumour and was cost saving for VIPoma patients. Validity of results may be questioned considering that all health state values and resources utilized were obtained from an expert panel. Although sensitivity analysis was conducted, considerable uncertainty remains. octreotide has shown efficacy in altering disease symptoms but it is unclear what impact it may have on mortality. Years of life saved may not be the most appropriate outcome measure.
A-189
Table A30: Results of economic evaluations included in review Author Currency
and Year Estimates of cost and
effectiveness Incremental Results Conclusions and Limitations
Novartis Pharmaceuticals Canada Inc. May 1999 (Unpublished Data)
C$ 1999 Average monthly cost OCT-SA C$1,567 based on mean average daily dose of 567 μg. Range varies from C$270 to 4,077 depending on dose. Costs include $26 per month for syringes. Average monthly cost OCT-LA C$1,487 assuming 33% patients on 10mg, 30% patients on 20mg and 37% patients on 30mg (syringe costs included in drug price). Monthly costs range from C$1,102 to 1,840.
N/A Equivalent efficacy was assumed based on a single RCT of 24 week duration (N=93). The dosages used in the analysis were also based on this clinical trial; validation with doses used in clinical practice would be informative. The perspective was narrow thus the cost of administering OCT-LA was excluded (intramuscular injection requires health care professional). Study concluded that, on average, OCT-LA was cost neutral to drug plans. The authors also stated that the reduction in the number of injections required with OCT-LA versus OCT-SA was associated with more convenience and quality of life for patients.
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Table A30: Results of economic evaluations included in review Author Currency
and Year Estimates of cost and
effectiveness Incremental Results Conclusions and Limitations
Complications after pancreatic surgery Rosenberg 199924 Rosenberg 199725 (abstract)
C$ (year not stated)
Complication rates from the meta-analysis Pancreatic fistulas OCT-SA: 10.7% (95% CI 7.9-13.4) Placebo: 23.4% (95% CI 19.7-27.1) Fluid collection OCT-SA: 3.6 % (95% CI 1.9-5.2) Placebo: 8.8% (95% CI 6.2-11.3) Expected cost of therapy (direct medical costs) Model 1 OCT-SA: C$884 Placebo: C$1,737 Model 2 OCT-SA: C$12,568 Placebo: C$14,210
Model 1: on average, OCT-SA use saved C$853 per patient. In a cohort of 100 patients, 16 incremental patients would avoid complications. (dominant strategy) Model 2: on average, OCT-SA use saved C$1,642 per patient. In a cohort of 100 patients, 16 incremental patients would avoid complications. (dominant strategy)
The authors concluded that, when compared to placebo, the use of OCT-SA was more effective and less costly. One-way and two-way sensitivity analysis showed that the model was robust to changes. In model 1 the incremental LOS associated with a fistula was based on expert opinion (21 days). This however was tested with sensitivity analysis. OCT-SA became cost neutral if the incremental LOS was reduced to 2.9 days. Only the cost of treating fistulas was included in the analysis. This however biased the results in favour of placebo. In model 2 the case costing was based on data from 2 Ontario hospitals (35 patients). Generalizability would be improved if a larger sample was used and if hospitals from other jurisdictions were included.
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Table A30: Results of economic evaluations included in review Author Currency
and Year Estimates of cost and
effectiveness Incremental Results Conclusions and Limitations
Vanounou 2007259 US$ (year not stated)
Overall hospital costs (index admission plus re-admission within 30 days) OCT-SA: US$ 18,510 No therapy: US$ 18,723, p=0.76 Weighted average cost [median cost per severity of fistula (grade A, B or C*) multiplied by probability of each fistula grade.] OCT-SA: US$ 24,227 No therapy: US$ 19,978 Incidence of fistulas by grade OCT-SA: (A) n=8, 8%; (B/C) n=15, 15% No therapy: (A) n=18, 14%; (B/C) n=19, 15%, no significant difference in incidence rates
OCT-SA versus no therapy resulted in US$ 4,249in cost savings per patient with a cost benefit ratio of 5.80. Use of OCT-SA in patients at low risk resulted in overspending of $US 781. In patients at high risk of fistulas, OCT-SA resulted in cost savings of US$11,849 per patient with a cost benefit ratio of 16.17. Analyses based on weighted average costs.
The study authors concluded that the use of OCT-SA in patients at low risk of fistulas represents an inefficient allocation of resources whereas its use in high risk patients is cost-saving. A typical cost-benefit analysis values the change in clinical outcomes in monetary terms and compares that with the dollar value of the change in costs. There was no attempt to put a monetary value on clinical outcomes in this case. The analysis only involved the cost side, so it cannot be considered a true cost-benefit analysis. All data were based on a retrospective cohort from a single institution. Costs were collected from 2001 to 2007 however the method used to correct for inflation was not reported. Sensitivity analyses were conducted to investigate risk factors for fistulas however no analysis was done for uncertainty related to costs. There were only 6 patients (3%) in total who developed the most severe fistulas which are associated with the most extremes in cost. The limited number of these patients, particularly for the subgroup analyses, contributes to uncertainty in the results.
* International Study Group on Pancreatic Fistula classification scheme: (A) transient asymptomatic fistulas defined by elevated amylase levels in post-operative percutaneous drainage, (B) clinically apparent, symptomatic fistulas that require diagnostic evaluation and intervention, (C) severe manifestations that tend to cause major deviations in clinical recovery and require significant interventions; GH=growth hormone; HRQL=health related quality of life; IC=incremental cost; LYS=life-years saved; OCT-LA=octreotide long-acting; OCT-SA=octreotide short-acting; QALY= quality adjusted life-years
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Table A31: Quality assessment of economic studies Assessment question Schonfeld260 Novartis * Moore83 Wilson L.† Novartis ‡ Rosenberg24,25 Vanounou259 Arcona261
Indication GEPNET GEPNET Acromegaly Acromegaly Acromegaly Pancreatic surgery
Pancreatic surgery Variceal bleed
BMJ Economic Evaluations Checklist257 Study design Research question is stated Y N Y Y Y Y Y Y Economic importance of research question is stated Y NC Y Y Y Y Y N
Viewpoint(s) of analysis clearly stated and justified Y N N Y Y N N N
Rationale for choosing alternative programs or interventions compared stated
Y N Y Y Y Y Y N
Alternatives being compared clearly described Y Y Y Y Y Y Y Y
Form of economic evaluation used stated Y Y Y Y Y Y Y Y
Choice of economic evaluation justified in relation to questions addressed
Y Y Y Y Y Y N Y
Data collection Source(s) of effectiveness estimates used stated Y Y Y Y Y Y Y Y
Details of design and results of effectiveness study given (if based on 1 study)
NA N NA Y N NA Y N
Details of method of synthesis or meta-analysis of estimates given (if based on overview of effectiveness studies)
NA NA NA N N Y NA N
Primary outcome measure(s) for economic evaluation stated Y Y Y Y Y Y Y Y
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Table A31: Quality assessment of economic studies Assessment question Schonfeld260 Novartis * Moore83 Wilson L.† Novartis ‡ Rosenberg24,25 Vanounou259 Arcona261
Indication GEPNET GEPNET Acromegaly Acromegaly Acromegaly Pancreatic surgery
Pancreatic surgery Variceal bleed
Methods to value health states and other benefits stated Y NA Y ** NA NA NA NC
Details of subjects from whom valuations obtained given NC NA N ** NA NA NA NC
Productivity changes (if included) reported separately NA NA NA ** N NA NA NA
Relevance of productivity changes to study question discussed
NA NA NA ** NA NA NA NA
Quantities of resources reported separately from unit costs N NA Y NC Y Y N N
Methods for estimation of quantities and unit costs described
NC NA Y Y N Y Y NC
Currency and price data recorded Y Y Y Y Y Y Y N
Details of price adjustments for inflation or currency conversion given
N NA N ** N N N N
Details of model used given Y NA Y ** N Y NA NC Choice of model used and key parameters on which it is based justified
Y NA Y ** Y Y NA NC
Analysis and interpretation of results Time horizon of costs and benefits stated Y N N ** N Y Y NC
Discount rate(s) stated Y N N ** N NA NA N Choice of rate(s) justified N NA N ** N NA NA N
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Table A31: Quality assessment of economic studies Assessment question Schonfeld260 Novartis * Moore83 Wilson L.† Novartis ‡ Rosenberg24,25 Vanounou259 Arcona261
Indication GEPNET GEPNET Acromegaly Acromegaly Acromegaly Pancreatic surgery
Pancreatic surgery Variceal bleed
Explanation given if costs or benefits not discounted NA N N ** N N NA N
Statistical test and confidence intervals given for stochastic data
N N N ** N Y Y N
Approach to sensitivity analysis given Y N Y ** N Y Y NC
Choice of variables for sensitivity analysis justified Y N Y ** N Y N N
Ranges over which variables varied stated
NC N Y ** N Y N NC
Relevant alternatives compared Y Y Y Y Y Y Y NC
Incremental analysis reported Y N Y Y Y Y Y Y
Major outcomes presented in disaggregated and aggregated forms
Y N Y NC N Y Y N
Answer to study question given Y NA Y Y Y Y Y Y
Conclusions follow from data reported
Y Y Y Y Y Y Y Y
Conclusions accompanied by appropriate caveats
Y Y N Y Y Y Y N
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Table A31: Quality assessment of economic studies Assessment question Schonfeld260 Novartis * Moore83 Wilson L.† Novartis ‡ Rosenberg24,25 Vanounou259 Arcona261
Indication GEPNET GEPNET Acromegaly Acromegaly Acromegaly Pancreatic surgery
Pancreatic surgery Variceal bleed
Quality assessment of economic studies – Part 2 Assessment question Schonfeld260 Novartis* Moore83 Wilson L.† Novartis‡ Rosenberg24,25 Vanounou259 Arcona261
Drummond Checklist for Assessing Economic Evaluations (partial)258 3. Was the effectiveness of the program of services established? a) Was this done through a randomized, controlled clinical trial? If so, did the trial protocol reflect what would happen in regular practice?
N N N N N NA N NC
b) Were effectiveness data collected and summarized through a systematic overview of clinical studies? If so, were the search strategy and rules for inclusion or exclusion outlined?
N N N N N Y N NC
c) Were observational data or assumptions used to establish effectiveness? If so, what are the potential biases in results?
N N Y Y Y Y Y NC
*Novartis Pharmaceuticals Canada Inc. Canada, May 1999 (Unpublished Data); †Wilson L. 1999, Canada (Unpublished Data); ‡Novartis Pharmaceuticals Canada Inc. Canada. January 1999 (Unpublished Data); **author was unable to supply the appendices to the report where additional data was reported; GEPNET=gastroenteropancreatic neuroendocrine tumours; N=no; NA=not applicable; NC=not clear; Y=yes;
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Table A32: Prevalence data and sources Prevalence data Source GEPNET GEPNETs are rare, with an estimated U.S. prevalence of < 5.6 cases per 100,000 of the population. VIPomas and carcinoid tumours account for approximately 60% of these cases. Data used in prevalence table: 3.36 per 100,000 of population or 0,000034
295
Acromegaly Prevalence rate for Canada is 60 per million or 0,00006 296 Prevention of complications after pancreatic surgery • 20% of pancreatic cancers can be removed surgically • 28,447 individuals 5 year prevalence rate 2004. Pancreatic cancer US
Estimated Complete Prevalence Counts on 1/1/2004 All Ages, First Malignant Cancer Only By Cancer Site, Sex, and Race
• US population in 2004 • Morbidity rate after pancreatic surgery of 30% to 40 (this data provide
for information purposed only) • Total morbidity rate after pancreatic surgery found to be 38.4%
(N=331 patients) • 80,000 acute pancreatitis each year which is equivalent to 0.027% (No
data found on the proportion of patients requiring surgery due to pancreatitis)
297 298 299 300 301 302
Bleeding esophageal varices Canadian rate 100 per 100,000 per year 303 Hepatocellular carcinoma 19,429 individuals 5 year prevalence rate 2004. Liver cancer US Estimated Complete Prevalence Counts on 1/1/2004 All Ages, First Malignant Cancer Only By Cancer Site, Sex, and Race US population in 2004 (298,213,000) Hepatocellular carcinoma accounts for 80% to 90% of all liver cancers.
304 299 305
Diarrhea related to Chemotherapy The overall prevalence of cancer in the Canadian population is approximately 2% among men and 2.5% among women Incidence/ Prevalence Numbers: 10% of all advanced cancer patients experience acute or persistent diarrhea. One third of those are severe diarrheas. (Canadian source)
306 307
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Table A32: Prevalence data and sources Prevalence data Source Diarrhea related to Ileostomy Data not found Diarrhea related to HIV-AIDS At the end of 2002, an estimated 56,000 (46,000-66,000) people in Canada were living with HIV infection (including AIDS), which represents an increase of about 12% from the point estimate of 49,800 at the end of 1999. Population in 2002: 31,372,600
308 309
Diarrhea related to Crohn’s disease The US prevalence, or overall number of cases, is 198.5 per 100,000 for Crohn's and 169.7 per 100,000 for ulcerative colitis. Prevalence has increased since 1989, when the rates of Crohn's and ulcerative colitis were 152 and 127 respectively Prevalence of diarrhea in Crohn’s disease in Iran: 77.1% (unable to locate Canadian data)
310 311
Short Bowel Syndrome 1.8 to 3 per million (Data from Australia and US, an average was used) 312-314 Bowel obstruction Incidence of the disease in US is 0.2%. Approximately 1 in 500 or 0.20% or 544,000 people in US. (Incidence was used in this case, since bowel obstruction is an acute condition). US - Inoperable cases between 6 and 50% (data used in prevalence table: 28%)
315 316
Pediatric Hyperinsulinism Incidence rate in the US: 1/25,000 to 1/50,000 50 Pancreatic cancer 28,447 individuals 5 year prevalence rate 2004. Pancreatic cancer US Estimated Complete Prevalence Counts on 1/1/2004 All Ages, First Malignant Cancer Only By Cancer Site, Sex, and Race US population in 2004
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