A Multi-Center Randomized Controlled Study Comparing Alternative

Antibiotic Regimens in Patients Undergoing Tumor Resections with

Endoprosthetic Replacements

PARITY Launch MeetingSeptember 28th, 2012Toronto, ON, Canada

Breakout Session for Research Staff

Agenda

• Study Overview• Screening Patients & Obtaining Consent• Randomization• Case Report Forms (CRFs) Overview• iDataFax Overview• Break• CRF Completion Guidelines• Submitting Adjudication Materials• Study Timelines• Ready, Set, Go!

Study Overview

Current Funding

• Orthopaedic Research & Education Foundation: OREF/MSTS Clinical Research Grant in Orthopaedic Oncology

• Physicians’ Services Incorporated Foundation (Ontario, Canada)

• Private Donation: We would like to thank the Dacol-Manherz family for their generous donation to the PARITY study

Tumor Surgery

• Primary bone tumor of the lower extremity

• Wide resection

• Endoprosthetic Replacement

The Need for the PARITY Study

• Extremely HIGH infection rates

• No guidelines for Antibiotic Prophylaxis in Tumor Surgery

• In General Arthroplasty: • Single pre-operative dose of antibiotics• Antibiotics discontinued within 24 hours of surgery

• Survey shows that antibiotic use varies among Orthopaedic Oncologists (Hasan et al., 2012)

Primary ObjectiveAre 5 days of postoperative antibiotics more effective at decreasing the rate of infection when compared to 24 hours of postoperative antibiotics?

Secondary ObjectivesWhat is the impact of the postoperative antibiotic regimen (24 hours vs. 5 days) on the development of antibiotic-related complications (i.e. gastrointestinal infections, fungal infections, etc.)?

What is the impact on the rate of re-operations?

What is the impact on patient functional outcome after one year?

Primary Outcome• Rates of deep post-operative infections in each of

the study arms. Infection will be defined using the Centers for Disease Control (CDC) definition of deep surgical site infection.

• Infection will be adjudicated by an independent and blinded adjudication committee.

Secondary Outcomes

•Antibiotic-related adverse events•Rate of re-operations•Patient function

▫Musculoskeletal Tumor Society Functional Score (MSTS) – clinician administered

▫Toronto Extremity Salvage Score (TESS) – patient administered

Antibiotic Regimens

• Pre-op: 2g cefazolin 60 mins prior to the of the procedure

• Intra-op:2g cefazolin every 3-4 hours during procedure (standard)

• Post-op: 24 hours cefazolin (2g) followed by 4 days saline (short)

OR 5 days cefazolin (2g)(long)

Blinding

• All antibiotic bags will be identically shrouded

• Patients, surgeons, nurses, research staff, data analysts and the Central Adjudication Committee will be blinded

• Only the pharmacy technician who randomizes the patient and prepares the shrouded antibiotic bags will not be blinded

Trial Organization

STEERING COMMITTEEOverall responsibility for the trial

CENTRAL ADJUDICATION COMMITTEE

Review and classification of all clinical events

DATA MONITORING COMMITTEE Review of adverse

events and stopping rules based on benefit and harm

METHODS AND COORDINATING CENTRE Data management, daily conduct of the trial

PARTICIPATING CLINICAL CENTRES Patient recruitment and follow-up as per

study protocol

PARITY Trial Organization

Inclusion Criteria

• Men and women 15 years of age or older

• Primary bone malignancies or benign aggressive tumors of the lower extremity

• Reconstruction with tumor prosthesis planned Treatment by excision and endoprosthetic reconstruction

• Provision of informed consent

Exclusion Criteria• Current known Methicillin-resistant Staphylococcus

Aureus (MRSA), or Vancomycin Resistant Enterococcus (VRE) colonization

• Documented anaphylaxis or angioedema to penicillin or study antibiotics [Ancef® (cefazolin)]

• Reconstruction to include allograft

• Prior surgery within the surgical field (excluding a biopsy)

• Prior infection within the surgical field

• Current known immunologically-deficient disease conditions (excluding chemotherapy)

• Known renal insufficiency with estimated eGRF 54 mL/min

• Skeletal Immaturity

• Upper extremity tumor

Trial Conduct ProcedurePatient Recruitment, Randomization and Surgical Interventions

Identification of Patients Direct referral-within center Data Collected  

Assessment of Study explanationPatient Eligibility History-review eligibility criteria, Screening Form

and other relevant medical conditionsPhysical Examination Radiographs

Informed Consent, if eligible Informed ConsentMSTS, TESS (baseline)

  All eligible patients who consent to the trial

  

Randomization 24 hour web-based system Baseline FormKey patient information recorded Randomization Form

Randomization assigned 

Surgery Either short or long arm Surgical Form

Surgical protocols will be followed 

Trial Conduct ProcedureFollow Up Schedule

2 Weeks Assessment of outcome events Follow-Up Forms  

6 Weeks Assessment of outcome events Follow-Up Forms  

3 Months Assessment of outcome events Follow-Up FormsMSTS, TESS

6 Months Assessment of outcome events Follow-Up FormsMSTS, TESS

 

9 Months Assessment of outcome events Follow-Up Forms

 

12 Months Assessment of outcome events Follow-Up Forms

MSTS, TESS  

*Follow Up Forms include AEs, SAEs, infections, re-operations, protocol deviations or wound healing problems, and other appropriate forms.

Trial Conduct ProcedurePatient Recruitment, Randomization and Surgical Interventions

Identification of Patients Direct referral-within center Data Collected  

Assessment of Study explanationPatient Eligibility History-review eligibility criteria, Screening Form

and other relevant medical conditionsPhysical Examination Radiographs

Informed Consent, if eligible Informed ConsentMSTS, TESS (baseline)

  All eligible patients who consent to the trial

  

Randomization 24 hour web-based or telephone Baseline FormEligibility criteria reviewed again Randomization FormKey patient information recorded Randomization assigned

 

Surgery Either short or long arm Surgical Form

Surgical protocols will be followed 

Screening Patients and Obtaining Informed Consent

Patient Screening

• It is VERY IMPORTANT that ALL patients with a primary bone tumor of the lower extremity are screened!

• Classify patients as:

Included Excluded Missed

• Complete Screening Form 1.1

Patient Study IDIncluded Patients • IDs start at 1001 (assigned by site research staff)

Missed Patients• IDs start at 2001 (assigned by site research staff)

Excluded Patients• IDs start at 3001 (assigned by site research staff)

Obtaining Informed Consent

• Research staff meets with the patient to discuss the trial and review the Information Sheet/Consent Form

• Patient reads the Information Sheet/Consent Form

• Research staff ask the patient to describe the key aspects of the study in their own words

• Research staff explains the requirements for follow-up visits and completing questionnaires

• Signature of consent form by patient and research staff (copy provided to patient)

*If the patient is unable to give informed consent, the legally authorized representative will be approached by the research staff and the same process will be followed

Randomization

Trial Conduct ProcedurePatient Recruitment, Randomization and Surgical Interventions

Identification of Patients Direct referral-within center Data Collected  

Assessment of Study explanationPatient Eligibility History-review eligibility criteria, Screening Form

and other relevant medical conditionsPhysical Examination Radiographs

Informed Consent, if eligible Informed ConsentMSTS, TESS (baseline)

  All eligible patients who consent to the trial

  

Randomization 24 hour web-based system Baseline FormKey patient information recorded Randomization Form

Randomization issued to patient 

Surgery Either short or long arm Surgical Form

Surgical protocols will be followed 

• Obtain Informed Consent

• Complete Baseline Characteristics Forms

• Complete Tumor Characteristics Forms

• Complete

MSTS (physician completes)

TESS (patient completes)

• Complete top half of the Randomization Form

Before Randomization

Randomization

WHO Pharmacy Team Member at each site

WHAT Randomize patients to short arm (24 hours) or long arm (5 days)

WHEN At or near incision time; before surgery completed

WHERE Online randomization system (www.randomize.net)

WHY To minimize bias

Randomization is a Team Effort! The pharmacist will randomize the patient but only after the site research staff provides them with the required information.

Before Randomizing a Patient, the Site Coordinator Must:

• Apply inclusion and exclusion criteria to the patient

• Obtain signed patient consent or proxy• Have agreement to randomize from the

surgeon/resident/fellow

Before Randomizing a Patient, the Pharmacist Must:

• Know the site’s username and password for www.randomize.net

• Receive from the site research staff the partially completed Randomization Form which includes the patient’s date of birth, the patient’s tumor location (femur or tibia) and the patient’s ID

• Have a pen to record the treatment allocation

www.randomize.net

Troubleshooting Randomization If you run into any problems randomizing a patient you can call randomize.net at (613) 366-4796 or email them at info@randomize.net.

Case Report Forms (CRFs)Overview

Completing CRFs

CRF Corrections

Show original answers, initial & date all changes

Do NOT make corrections this way

Submitting CRFs

• Before submitting, check CRFs for accuracy, completeness, and legibility

• The most efficient and preferred method of submitting case report forms to the PARITY Methods Centre is by Electronic Data Capture (EDC), via the secure iDataFax website

• Scanned CRFs, saved in PDF format, can be sent to iDataFax using DFSend – a program that comes with iDataFax.

iDataFax Overview

What is iDataFax?

A direct computer data management system for collecting study CRFs, including:

• Intelligent Character Recognition

• Automated Quality Control (QC) report system

• Increased speed & efficiency of data collection

• Improved data quality through continuous monitoring & QC reports

37

METHODSCENTER

Quality Control Reports

• QC Reports run every two weeks

• Sent out by email to each site

• Identifies and lists all items in the CRFs which are incomplete, unclear, illegible, or missing

• Respond by entering the corrections to the ORIGINAL CRF in iDataFax or by resending the corrected page as a PDF file through DFSend

• Initial and date all changes (iDataFax does this automatically)

Quality Control (QC) Reports

Agenda

• Study Overview• Screening Patients & Obtaining Consent• Randomization• CRF Overview• iDataFax Overview• Break• CRF Completion Guidelines• Submitting Adjudication Materials• Study Timelines• Ready, Set, Go!

CRF Completion Guidelines

Patient Contact Form (L-1 and L-2)

• Do NOT forward this to the Methods Centre

• Additional contacts who do NOT live with the patient

• US Sites: Release of Records HIPAA Authorization required to request records from primary care physician

Randomization Form (2.1)• Questions 1 – 3:

completed by RC

• Questions 4 – 5: completed by Pharmacist/Technician

• Pharmacist to submit completed form to the Methods Centre within 1 business day of patient randomization & file separate from all other patient data

Attending Surgeons (3.1)

• List surgeon names

• Indicate level of expertise:

• Number of cases performed in the last year

• Number of cases performed over entire career

Baseline Characteristics Form (4.1 – 4.3)

• Ethnicity• Location of Tumor• Other known

malignancies or metastases

• History details• Patient medication• Preoperative treatment

modalities (chemo and/or radiation)

• Mode of delivery

Tumor Characteristic Form (5.1)

• Type of tumor

• Type of biopsy performed

• Indicate if soft tissue mass exits, its dimensions & location

• If positive, specify organism

• Indicate if there is skin, muscle, and/or vascular involvement

Surgical Report Forms (6.1 – 6.3)

• Captures all surgery details including:

• Operative time

• Type of sterilization

• Length of incision

• Amount of skin/muscle excised

• Length of bone resected

• Prosthesis type

Surgical Pathology Report Form (7.1)

• To be completed following surgery, once diagnosis finalized

• Name of pathologist

• Tumor pathology and subtype, if any (i.e., fibroblastic osteoscarcom)

• Tumor grade, margin details, percent necrosis, vascular invasion

Peri-Operative Form (8.1 – 8.2)

• To be completed prior to discharge

• Collects details of hospital stay (i.e., catheter use, number of patients in room, dressing changes)

• Record discharge details

• Record wound vac details, if any

Follow-up Form (9.1 – 9.3)

• Indicate Follow-Up Number

• Ensure patients have pre-arranged appointments

• Call “no shows”

• Methods Centre will send lists of patients with upcoming follow-ups in bi-weekly QC reports

Visit Windows Follow Up Visit Visit Window

2 Weeks 1 week – 3 weeks

6 Weeks 4 weeks to 8 weeks

3 Months 2 months – 4 months

6 Months 5 months – 7 months

9 Months 8 months – 11 months

12 Months 12 months

Tumor Site Infection Form (10.1 – 10.3)

• Infection assessed at each F/U visit

• Complete a separate form for each infection related to the randomized tumor

• Record infection type (superficial, deep, organ/space)

• Provide details

Protocol Deviation Form (11.1)

• To be completed at any stage

• Continue to follow patients even if deviation has occurred

• Answer “yes” or “no” to each question and provide details

Surgical Report From: Re-operations (12.1 – 12.3)

• Record details of any additional surgeries related to the randomized tumor

• A separate Re-Operations Form should be filled out for each re-operation

• Indicate F/U visit when decision was made to re-operate

Adverse Event Form (13.1)• Record all operative/ non-

operative events related to the randomized tumor

• Record unexpected or SAEs (fatal, life threatening, permanent disability, repeat/prolonged hospitalization)

• AEs/SAEs must be reported to the Methods Centre and the local ethics board accordingly

• Please note: Death as a result of a pre-existing condition (i.e., expected or unexpected) should be captured as an SAE

Missed Follow-Up Form (14.1)

• Complete if patient cannot return for a follow-up visit

• Record date and reason

Early Withdrawal Form (15.1 – 15.5)• Do not withdraw a

patient until all options for following them have been exhausted

• EW forms for reasons other than death will not be accepted until the site has negotiated with the patient

Wound Healing Problem Form (16.1)

• Wound healing problems assessed at each F/U visit

• Complete a separate form for each WHP related to the randomized tumor

• Record treatment (antibiotics/reoperation)

• Record outcomes

• Send adjudication materials

Antibiotics Log (17.1)

• PARITY study drug administrations should be included on this log

• Any additional antibiotics (not related to PARITY) should also be recorded

• Entire log should be re-sent each time it is updated

Cultures Form (18.1)• Report all cultures

taken from the randomized tumor site

• Indicate if cultures were taken before initial tumor incision

• Record date, site and results

• If positive, specify organism

• Resend each time this form is updated

MSTS-87 Survey (19.1-19.6)

• Completed by Orthopaedic Oncologist or designee

• 6 item questionnaire

• Measures physical function

• Completed at the baseline (prior to surgery) and at the 3 month, 6 month and 12 month follow-up visits.

MSTS-93 Survey (20.1)

• Completed by Orthopaedic Oncologist or designee

• 6 item questionnaire

• Measures physical function

• Completed at the baseline (prior to surgery) and at the 3 month, 6 month and 12 month follow-up visits.

TESS Survey (21.1 – 21.5)• Self-administered

• 33 item questionnaire

• Evaluates how difficult it is for them to carry out normal, everyday activities

• Patients choose answers that best describe their abilities over the week leading up to their visit

• Completed at the baseline (prior to surgery) and at the 3 month, 6 month and 12 month follow-up visits.

Deaths

• Report deaths on Adverse Event Form 9.1-9.2

• Select ‘Early W/D’ as the follow-up number on the AE Form 13.1

• Submit an Early Withdrawal From 15.1-15.3 • Question 13: select ‘Yes’ since deaths are considered

AEs, so the patient will have at least one new AE to report

• Make sure the dates of the EW and AE forms are the same (this should be the date of death)

Submitting Materials for Adjudication

Submitting Materials for Adjudication• Adjudicating: infections, antibiotic related

complications and death

• Relevant CRFs will include reminders to submit materials for adjudication

• All radiograph images and clinical notes must be blinded before submitting to the Methods Centre

• Materials can be sent to the Methods Centre by email or fax

Radiographs• Pre-op & post-op images & any

images taken since surgery

• No patient or site identifiers on the image

• JPEG, TIFF or DICOMM images

• Please label the file in this format: Site#_Patient#_Date_View

• Date must be in DDMMMYYYY format

• Example: 01_1003_12Jul2012_ap

This x-ray is from site 01 for the third included patient. The x-ray was taken on July 12th, 2012 and is the AP pelvis view.

Clinical Notes• Required for adjudication

• All clinic & hospital notes

• No patient identifiers on the image (includes site name and patient name)

• Preferred method of submission is by scanning (fax or courier is also acceptable)

• Please label the file in this format: Site#_Patient#_Date_Note Type

• Date must be in DDMMMYYYY format

• Example: 01_1003_12Jul2012_clincal note

NB: ‘Note Type’ could also include: consultation note, operative note, AE note, revision surgery note, etc.

Study Timelines

Study Timelines

Activity Timeline

Start- Up June 2012 – November 2012

Patient Enrolment November 2012 – November 2013

Patient Follow-Up November 2012 – November 2014

Ready, Set, Go!

Ready, Set, Go! Approval from local Research Ethics Board/Institutional

Review Board

Signed Clinical Trial Agreement with McMaster University

Methods Centre will Send Site:

• Manual of Operating Procedures Site Operation Manual

• Login Credentials for randomization system

• Login Credentials for iDataFax

• iDataFax Manual & DF Send Manual

• CRF Binders

Methods Centre staff will schedule a start-up teleconference upon request.

Methods Centre Contact Information

Marilyn Swinton, Research CoordinatorTel: 905.527.4322 ext. 44983Cell: 289.244.3997Fax: 905.523.8781Email: swinton@mcmaster.ca

Antonella Racano, Research AssistantTel: 905.521.2100 ext. 43807Fax: 905.381.7034Email: rcanoa@mcmaster.ca

Thank You!!