P1112 MOP V2.0 – 20 June 2016

P1112 MOP V2.0 Page 1 of 19 20 June 2016

A Multicenter Trial of the International Maternal Pediatric Adolescent AIDS

Clinical Trials Group (IMPAACT)

IMPAACT P1112

Open-Label, Dose-Escalating, Phase I Study to Determine Safety and Pharmacokinetic Parameters of Subcutaneous (SC) VRC01, a Potent Anti-HIV

Neutralizing Monoclonal Antibody, in HIV-1 Exposed Infants

IND # 113,611

MANUAL OF PROCEDURES (MOP)

MOP Version 2.0 June 20, 2016


TABLE OF CONTENTS

GLOSSARY OF TERMS ................................................................................................................................... 4

1.0 INTRODUCTION .................................................................................................................................... 6

1.1 SOURCES OF PROCEDURAL INFORMATION ................................................................................................6 1.2 SITE-SPECIFIC STUDY ACTIVATION PROCESS ..............................................................................................7

2.0 RECRUITMENT OF MATERNAL PARTICIPANTS .............................................................................. 7

3.0 INFORMED CONSENT PROCESS ....................................................................................................... 7

3.1 INTRODUCTION TO THE INFORMED CONSENT ............................................................................................7 3.2 SPECIAL CONSIDERATIONS FOR CONSENTING AT THE TIME OF LABOR AND DELIVERY ...........................................7

4.0 SCREENING .......................................................................................................................................... 8

4.1 SCREENING AND ENROLLMENT LOGS .......................................................................................................8 4.2 MATERNAL AND INFANT SCREENING AND ENTRY PROCEDURES ......................................................................8 4.3 HIV NUCLEIC ACID TESTING FOR DETERMINATION OF INFANT HIV INFECTION STATUS ........................................9

5.0 ENROLLMENT ..................................................................................................................................... 10

5.1 ENROLLMENT PROCEDURES ................................................................................................................ 10 5.2 SUBJECT ENROLLMENT SYSTEM............................................................................................................ 10 5.3 SUBCUTANEOUS INJECTION ................................................................................................................. 10 5.4 ASSESSMENTS FOLLOWING VACCINATION .............................................................................................. 11

6.0 FOLLOW-UP ........................................................................................................................................ 12

6.1 EXPECTATIONS FOR BLOOD PRESSURE MEASUREMENT DURING FOLLOW-UP ................................................... 12 6.2 SPECIAL CONSIDERATIONS FOR INFANTS IDENTIFIED AS HIV-INFECTED .......................................................... 12 6.3 HIV ANTIBODY TESTING AT/AFTER WEEK 48 .......................................................................................... 13

7.0 PHARMACY ......................................................................................................................................... 13

7.1 DOSING OF VRC01 ........................................................................................................................... 13 7.2 THAWING INSTRUCTIONS ................................................................................................................... 15 7.3 STUDY PRODUCT PREPARATION INSTRUCTIONS ....................................................................................... 15

8.0 SPECIMEN COLLECTION AND PROCESSING ................................................................................ 16

8.1 INTRODUCTION ................................................................................................................................ 16


8.2 GENERAL OVERVIEW AND GUIDELINES .................................................................................................. 16 8.3 SPECIMEN CHAIN OF CUSTODY ............................................................................................................ 16 8.4 LABELING SPECIMENS ........................................................................................................................ 17 8.5 LABORATORY DATA MANAGEMENT SYSTEM (LDMS) ............................................................................... 17 8.6 ORAL SECRETIONS COLLECTION AND PROCESSING (SEE LPC FOR ADDITIONAL INFORMATION) ............................. 18 8.7 ADDITIONAL RESOURCES .................................................................................................................... 19

9.0 DATA .................................................................................................................................................... 19

9.1 SOURCE DOCUMENTS ........................................................................................................................ 19 9.2 SCHEDULE OF CASE REPORT FORMS ...................................................................................................... 19 9.3 RESOURCES ..................................................................................................................................... 19

Summary of Changes 13 APR 15 Version 1.0 to 1.1

Glossary Added blood pressure (BP), heart rate (HR), and physical examination (PE)

4.1 Added guidance on CRF completion for screen failures

4.3 Added contact information for labs for US sites that do not have local HIV-1 NAT testing capabilities

5.3 Item c: clarified that part of assembly need not be done in sterile environment Item g: simplified instructions regarding the angle of administration Item m: simplified to move information more appropriate to section 5.4

5.4 Added sections 5.41 and 5.42 to provide details on expected clinical assessments following injections; added details that had previously been in section 5.3

8.3 Updated fax number for Data Managers

11 JUN 15 Version 1.1 to 1.2

5.3 Item a: clarified that birth weight should be recorded, and an identifier other than name may be entered on participant prescriptions

11 SEP 15 Version 1.2 to 1.3

5.4 Added Table 1-2 to clarify expectations for post-injection assessments 22 JAN 16 Version 1.3 to 1.4

5.3 Section renamed from “Vaccination” to “Subcutaneous Injection”

5.42 Renumbered Tables 1-2 and 1-3 to 5-1 and 5-2, respectively, for consistency with section number

6.1 Added Section 6.1 to clarify that blood pressure is not expected to be recorded at follow-up visits

6.3 Added Section 6.3 to specify HIV antibody testing expectations at/after Week 48

7 Added Section 7 to clarify study product preparation and handling instructions

9.3 Updated Data Manager listing to reflect current team membership

20 JUN 16 Version 1.4 to 2.0

4.2, 4.2.2, 5.1, 6.2, 6.3

Added information regarding Dose Group 3

4.3 Clarified expectations for infant screening HIV-1 NAT test

5.3 Added further specifications for subcutaneous injection procedures

5.4.1, 5.4.2 Added windows for the times of post-injection assessments

6.2 Clarified timing for referring infants with positive HIV-1 confirmatory tests to clinical care

7.1, 7.2, 7.3 Updated dosing tables; moved pharmacy information previously in the protocol to new MOP sections


GLOSSARY OF TERMS

ACTN AIDS Clinical Trials Network AE Adverse Event/Adverse Experience AIDS Acquired Immune Deficiency Syndrome ANA Antinuclear antibody activity ARV Antiretroviral AUC Area-Under-the-Curve BP Blood pressure CAP College of American Pathologists CDC Centers for Disease Control and Prevention CDR Complementarity Determining Regions CLIA Clinical Laboratory Improvement Amendments CRF Case Report Form CRPMC Clinical Research Products Management Center DAERS DAIDS Adverse Experience Reporting System DAIDS Division of Allergy and Infectious Diseases DMC Data Management Center DNA Deoxyribonucleic Acid DPRS DAIDS Protocol Registration System EAE Expedited Adverse Event EIA Enzyme Immunoassay EC Ethics Committee FSTRF Frontier Science & Technology Research Foundation GCP Good Clinical Practice GMP Good Manufacturing Practice HAART Highly active antiretroviral therapy HBIG Hepatitis B immune globulin HIPAA Health Insurance Portability and Accountability Act HIV Human Immunodeficiency Virus HR Heart rate IATA International Air Transport Association IC50 Half maximal inhibitory concentration ICF Informed Consent Form Ig Immunoglobulin IM Intramuscular IMPAACT International Maternal, Pediatric & Adolescent AIDS Clinical Trials Network IND Investigational New Drug IRB Institutional Review Board IV Intravenous LDMS Laboratory Data Management System LPC Laboratory Processing Chart mAb Monoclonal antibody MTCT Mother to child transmission N Number (typically refers to subjects)


NAT Nucleic Acid Testing NIAID National Institute of Allergy and Infectious Disease NICHD Eunice Kennedy Shriver National Institute of Child Health and Human Development NIH National Institutes of Health NVP Nevirapine NVITAL NIAID Vaccine Immune T-Cell and Antibody Laboratory OHRP Office for Human Research Protections PBMC Peripheral Blood Mononuclear Cell PCR Polymerase Chain Reaction PE Physical examination PI Principal Investigator PID Patient Identification Number PK Pharmacokinetic PRO Protocol Registration Office PROM Premature rupture of membranes PTT Partial thromboplastin time RCHSPB Regulatory Compliance and Human Subjects Protection Branch RE Regulatory Entity RNA Ribonucleic Acid RSC Regulatory Support Center RSV Respiratory Syncytial Virus SADR Suspected Adverse Drug Reaction SAE Serious Adverse Event/Serious Adverse Experience SC Subcutaneous SDAC Statistical and Data Analysis Center SES Subject Enrollment System SHIV Simian Human Immunodeficiency Virus SMC Safety Monitoring Committee SOP Standard Operating Procedures SUSAR Suspected, Unexpected Serious Adverse Reactions TCID Tissue Culture Infectious Doses T½ Half-life UNAIDS United Nations AIDS Organization VRC Vaccine Research Center VRC01 Human Monoclonal Antibody (VRC-HIVMAB-060-00-AB) WHO World Health Organization


1.0 INTRODUCTION

1.1 Sources of Procedural Information

All study procedures must be conducted in accordance with the P1112 protocol and this manual. The purpose of this manual is to supplement the protocol, not to replace or substitute for it. In the event that this manual is inconsistent with the protocol, the specifications of the protocol take precedence. Please alert the P1112 Protocol Team of any such inconsistencies. The P1112 protocol and related protocol documents are available on the IMPAACT website: http://www.impaactnetwork.org Please contact the P1112 Protocol Team following the guidance in Table 1-1 for general questions on protocol implementation or study procedures, including clinical, lab, and/or CRF/data-related procedures.

Table 1-1: Communications with the P1112 Study Team

The P1112 Protocol Team is composed of study team members including the IMPAACT Operations Center, Data Management Center, and Central Laboratory. These team members have been designated by the protocol team to receive and reply to study implementation questions. These team members will consult with the Protocol Chair, Co-Chair and/or other team members to ensure that complete and accurate responses are provided to each question.

Submit study implementation, clinical, laboratory and/ or procedural questions via email to [email protected].

Include the protocol number in the subject line of your email message.

State your question in the body of your email message. When the question relates to a specific study participant, include the participant identification number (PID) and relevant background information about the participant.

The responding group member will reply to your question via return email. All persons copied on the original question will be copied on the reply. Other protocol team members may also be copied when relevant.

Replies can generally be expected within one business day. When it may not be possible to provide a complete response within one business day, the person who submitted the question will be provided with an interim response and informed that more time is needed to provide a complete response.

When a question relates to a specific study participant, a copy of the email exchange should be printed and filed in the participant’s study chart.

http://www.impaactnetwork.org/

mailto:[email protected]


1.2 Site-Specific Study Activation Process

Site selection will be based on solicitation of applications from IMPAACT sites, which will include questions pertaining to site capacity and accrual projections. Based on the responses, the team will determine sites to participate and will submit a site selection plan to IMPAACT leadership. Upon signoff from network leadership, the Operations Center will notify the sites that they may proceed with submission for review by all responsible ECs/IRBs and Drug Regulatory Agencies (DRA), as applicable, and complete the DAIDS Protocol Registration Process upon receipt of all approvals. Further information on the protocol registration process is provided in the DAIDS Protocol Registration Policy and Procedures Manual, which is available on the RSC web site. In addition to successful completion of the site selection and approval processes above, all requirements outlined on the P1112-specific site activation checklist must also be completed prior to study implementation. These elements include but are not limited to: protocol registration of both Version 1.0 and LoA #1; submission and approval of Site Implementation Plan; documentation that study product is on site; and attendance by site staff at P1112 study-specific training. Upon completion of the required elements on the checklist, IMPAACT Operations (CTS) will notify the Randomization Desk of Site Readiness so that the P1112 Subject Enrollment System may be opened for the site.

2.0 RECRUITMENT OF MATERNAL PARTICIPANTS

By definition, the women to be identified for potential enrollment into P1112 will be at high risk of transmitting HIV to their infants. It will be essential, therefore, that the P1112 recruitment and screening process in no way interferes with the appropriate HIV management of the mother and PMTCT of the infant. Sites are encouraged to utilize and/or establish close ties with potential referral sources, e.g., L&D wards, adult ID clinics, local departments of health. It is understood that there will need to be a significant investment of time and energy in establishing/maintaining those referral sources to yield potential P1112 participants.

3.0 INFORMED CONSENT PROCESS

3.1 Introduction to the Informed Consent

Follow the IMPAACT SOP for obtaining and documenting the informed consent (IC) process. See page 18 of the DAIDS Source Documentation Requirements SOP for more information: http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/sourcedocappndx.pdf

3.2 Special Considerations for Consenting at the Time of Labor and Delivery

Sites should refer to existing SOPs or guidelines governing the consent of women during the time of Labor and Delivery. When the informed consent process is initiated during labor, site staff should proactively suspend the process if the potential maternal participant enters the final stages of labor or otherwise experiences duress that would preclude obtaining informed and voluntary consent. In such cases, the informed consent process will be resumed after delivery.

http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/sourcedocappndx.pdf

http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Documents/sourcedocappndx.pdf


4.0 SCREENING

4.1 Screening and Enrollment Logs

Per the DAIDS policy for Essential Documents, study sites are required to document screening (including screening failures) and enrollment activity on screening and enrollment logs. Screening and enrollment/randomization logs may be separate or combined. A screened subject is defined as having signed the study consent. The Screening and Enrollment Logs should be maintained in the Investigator Study Binder. Logs should include the following information:

Initials of the subject

Screening Number (PS number, if mother receives one)

PID if patient receives one

Date screened

Race

Gender

Status of screening, such as pass/fail

For all screen failures, indicate why the subject is unable to participate

Date enrolled

If not enrolled, indicate reason In addition, complete the SCR0037-IMPAACT P1112 SCREENING FAILURE AND NON-ENROLLMENT CRF for all mother-infant pairs who screen but do not enroll. For additional information, refer to the NIAID/DAIDS website: http://www3.niaid.nih.gov/about/organization/daids/

Assignment of Participant ID Numbers (PID) The PID is assigned at the site from a list that is generated by the DMC and sent to the sites. If a participant has been enrolled on another affiliated network study (e.g., IMPAACT or ACTG), that PID is carried with her/him. A new PID number would not be assigned.

4.2 Maternal and Infant Screening and Entry Procedures

4.2.1 Maternal Screening

During this initial screening visit, detailed study information will be presented to the participant. Maternal screening may be performed within 30 days prior to birth, or after birth, provided that the infant is enrolled (or anticipated to be enrolled) and can receive the dose of VRC01 less than 72 hours after birth for Dose Groups 1 and 2, or less than 5 days after birth for Dose Group 3. At time of screening, and prior to enrolling mother-infant pair, obtain maternal screening number from the PS2001-IMPAACT Screening Checklist. This checklist is part of the Subject Enrollment System (SES), located on the IMPAACT Data Management Center (DMC) Website at www.fstrf.org. Screening and entry can be performed on the same date. At screening, women will provide informed consent for screening and study participation, and blood will be collected for HIV diagnostic testing if not present in medical record. Please see section 4.11 of the protocol and section 5.1 below for appropriate documentation of maternal HIV infection.

http://www3.niaid.nih.gov/about/organization/daids/


4.2.2 Infant Screening

Screening evaluations should be completed as soon as possible after birth. Maternal and infant enrollment will not occur until both have been confirmed for eligibility. Infant eligibility for study drug must also be complete and documented before administering study drug. To ensure the child is in good health and eligible for the study, the following procedures will be completed:

Obtain a complete medical history at birth and perform a physical exam

Collect blood samples and perform appropriate testing according to Appendix IB (Dose Group 1 or 2) or Appendix ID (Dose Group 3) of the protocol

As a precursor to enrollment, complete the P1112 Eligibility Checklist to document eligibility. NOTE: eligibility criteria for both mother and infant are collected within the same checklist. Both must be eligible in order to enroll.

Study staff will notify parents as to whether the subject is eligible for the study.

4.3 HIV Nucleic Acid Testing for Determination of Infant HIV Infection Status When HIV-1 NAT is specified in this protocol, the assay used must detect HIV-1 DNA (with or without RNA detection), because there is a possibility that the VRC01 will suppress HIV-1 RNA. The one exception is for the infant screening HIV-1 NAT test for which a test that detects only HIV-1 RNA is allowed if the sample was obtained prior to 48 hours of life, prior to administration of VRC01, and tested in a laboratory with CLIA approval (U.S. sites) or VQA approval (Non-U.S. sites). This is allowed so that sites will not have to obtain an HIV-1 NAT in addition to an HIV-1 RNA test obtained clinically in advance of study enrollment. Qualitative or quantitative results are acceptable for HIV-1 NAT. Sites should assure that the laboratory used for HIV-1 NAT testing will provide real time results.

For U.S. sites, HIV-1 NAT testing must be run in a CLIA-approved laboratory. o Two laboratories that have the appropriate HIV-1 NAT testing are listed below,

which may be a resource for US sites that do not have testing available through their local lab. Other CLIA-approved laboratories with the required test are also acceptable.

Lab Test Code Contact Phone # E-mail address

Quest Special Studies 8401X Larry Hirsch 410-536-1622 [email protected]

Special Infectious Disease Laboratory Lurie Children's Hospital of Chicago LDMS 046

HIV DNA PCR Test Code: IDNA

Jason Rippe 312-227-6290 Fax: 312-227-9470

[email protected]

For non-U.S. sites, the HIV-1 NAT must be run at a VQA-certified laboratory. A list of approved labs can be found at the following site o https://www.hanc.info/labs/labresources/vqaResources/ptProgram/vqaLabs/Pag

es/default.aspx



https://www.hanc.info/labs/labresources/vqaResources/ptProgram/vqaLabs/Pages/default.aspx

https://www.hanc.info/labs/labresources/vqaResources/ptProgram/vqaLabs/Pages/default.aspx


5.0 ENROLLMENT

5.1 Enrollment Procedures

Maternal enrollment procedures: Assure that mother meets inclusion/exclusion criteria. Maternal HIV diagnostic testing For enrollment to the study, women must have positive results known on Sample #1. Results of Sample #2 may be pending at the time of enrollment. US sites

Sample #1 may be tested by non-study clinical laboratories.

Sample #2 must be performed in a CAP/CLIA-approved laboratory.

International sites

Sample #1 may be tested by clinical (non-study) or PEPFAR programs.

Sample #2 must be performed in a laboratory that operates according to GCLP guidelines and participates in appropriate external quality assurance program.

Obtain maternal history including data as specified in Protocol Appendix IA. Obtain maternal blood samples for storage. See LPC for details. Infant enrollment procedures Refer to Protocol Appendix IB for Dose Groups 1 and 2 and Appendix ID for Dose Group 3.

5.2 Subject Enrollment System

Subjects meeting all the study inclusion criteria and none of the exclusion criteria will be enrolled in IMPAACT P1112 by utilizing the Subject Enrollment System (SES) located on the IMPAACT Data Management Center (DMC) Website at www.fstrf.org.

Maternal screening number must be entered into checklist

Mother and infant eligibility criteria are collected within the same checklist

Both mother and infant must be eligible in order to enroll

5.3 Subcutaneous Injection

As per protocol, VRC01 will be administered subcutaneously, by slow push in the thigh using a BD Safety-Lok™ infusion set with a 25 G x 0.75-inch needle with 7 inches of tubing and a luer lock adapter. The study nurse/coordinator will assemble the following materials for SC injection:

Alcohol wipes

Sterile Gauze

Bandage

One BD Safety-Lok™ infusion set with a 25 G x 0.75-inch needle with 7 inches of tubing and a luer lock adapter item (number 367294) is provided by the study pharmacist with each study drug syringe dispensed.

Tape

http://www.fstrf.org/


a. Once eligibility has been confirmed and the subject has been enrolled in the study, a prescription, including the subject’s name or other identifier (e.g., PID), DOB, and birth weight should be signed by one of the investigators listed on the CRS FDA Form 1572. The signed prescription and documentation that the subject’s parent/legal guardian has provided signed informed consent for the study must be provided to the research pharmacist in order to dispense study drug.

i. Obtain study drug from the research pharmacy. VRC01 is stable in syringe until the expiration time marked on the syringe at 2-8ºC and controlled room temperature (15°C to 25°C [59°F to 77°F]).

b. Wash hands per institutional policy. c. Remove luer lock adapter aseptically from the end of the tubing. Attach butterfly

tubing dispensed by the research pharmacy to the syringe dispensed by the research pharmacy. This does not need to be done in the pharmacy and/or in a sterile environment.

d. Prime tubing with just enough study drug to fill the tubing. The first drop of study drug should be visible at the tip of the needle.

e. Place the infant on his/her back on a clean surface and expose the legs. Select the appropriate site on the thigh where the skin and subcutaneous tissue can be pinched. Clean the front of the thigh(s) with alcohol wipes where the injection will be administered. Whenever possible, try to avoid using the thigh where newborn vaccines were administered, or a site where the tissue/skin is irritated.

f. Stabilize the thigh. g. Pinch the skin and subcutaneous tissue and insert the needle quickly into the pinched

skin. Insert the needle directed toward the head with the needle at an angle (i.e., not perpendicular, to avoid IM administration).

h. Check for blood return. If blood return occurs, remove the needle, select another site, and repeat steps e - h.

i. If needed, use loose tape to secure the hub of the butterfly needle. j. Push slowly (over 1 minute if possible). k. Remove needle from thigh and place a bandage. Repeat this process with the second

syringe if the study drug is being administered as two separate doses. If the dose is split into two separate injections AND one thigh is used for routine clinical care injections (e.g., hepatitis B immunization), then the second part of the split dose may be administered in the same thigh as the first, but at a distinct site. If no routine clinical care injections are administered, then the split doses should be administered one into each thigh. NOTE: calculations for study drug account for drug that remains in the tubing. Do not attempt to flush TUBING AT END OF INJECTION.

l. Document dose, time started and location(s) for each dose given. See/complete VCW0072-Injection Vaccine Record CRF.

m. Observe the subject for at least 4 hours after study treatment injection, with initial assessments at 15, 30 and 60 minutes post dose. See section 5.4 for more details.

5.4 Assessments Following Vaccination

For any adverse events that fall outside of the reporting scope of the VCW0073-Injection Vaccine Observation-II CRF, record on the PE6832-Signs and Symptoms-III and/or PE6852-Diagnoses-III CRFs.

5.4.1 Monitoring Within the First Hour After Injection

At 15 and 30 minutes (± 5 minutes) after injection, observe infant and visually inspect injection site. Count heart rate and respiratory rate. If observation suggests reaction, complete a targeted PE. See Table 1-2 below. Document any local and/or system reactions, as well as temperature, on the VCW0073-Injection Vaccine Observation-II CRF.


5.4.2 Monitoring (Assessment of Pain and Grading) at 1 and 4 Hours After Injection

At 1 hour and 4 hours (± 30 minutes) post injection, observe infant and visually inspect site. Check temperature, BP, HR and respiratory rate. Gently palpate injection site to determine induration and tenderness. See Table 5-1 below.

Table 5-1: Expectations for Post-Injection Assessments

Time HR RR Visual assessment of

child (including looking at injection site)

Temp BP Palpation of injection site

Complete exam

0 (baseline) X X X X X N/A X

15 min X X X * * * *

30 min X X X * * * *

60 min X X X X X X *

4 hours X X X X X X *

*Perform as needed, i.e., if HR or RR change significantly or if visual assessment of child including injection site suggest a possible local or system reaction. An assessment for pain should take place 1 hour after the injection (± 30 minutes); results should be recorded on VCW0073-Injection Vaccine Observation-II CRF. As per section 7.3 of the protocol, P1112 will use the following injection site pain grading table to assess post-vaccination pain rather than the DAIDS AE Grading Table. (The DAIDS AE Grading Table should be used for grading all other AEs.)

Table 5-2: P1112 Grading of Injection Site Pain

Parameter Grade 1 Mild

Grade 2 Moderate

Grade 3 Severe

Grade 4

Injection site pain

Mild reaction to light touch with no or minimal limitation of movement of limb

Persistent crying with no or light touch, or significant limitation of movement of extremity

Persistent crying > 1 hour or interfering with infant’s ability to sleep or eat

Inconsolable crying >2 hours

6.0 FOLLOW-UP

6.1 Expectations for Blood Pressure Measurement during Follow-up

At follow-up visits (i.e., visits after VRC01 has been administered and Post-Injection Assessments completed), blood pressure is not expected to be recorded as part of vital signs.

6.2 Special Considerations for Infants Identified as HIV-Infected

Infants with a positive HIV-1 NAT at any time point will have study visits scheduled according to Appendix IC in conjunction with Appendix IB (Dose Groups 1 and 2) or Appendix ID (Dose Group 3). The first Appendix IC visit (confirmatory) should occur as soon as possible but no later than 14 days after the site collected the blood for the 1st positive HIV-1 NAT result. Infants with positive HIV-1 confirmatory tests will be referred to clinical care within 7 days of the site receiving the confirmatory positive result. Infants may be referred to clinical care in advance of the result of the confirmatory test. Infants will start antiretroviral treatment as determined by their clinician. HIV RNA-1 testing obtained per Appendix IC should be quantitative and obtained in a VQA-certified (international sites) or CLIA-approved (US sites) laboratory. The same laboratory


should be used throughout the study for HIV-1 RNA testing if possible. Testing obtained for clinical care which meets the instructions per Appendix IC may be used for the study results (i.e. duplicate testing should be avoided).

6.3 HIV Antibody Testing at/after Week 48

For Dose Groups 1 and 2, per protocol Appendix IB (Schedule of Evaluations), HIV antibody testing will be performed at/after Week 48. The visit status should be left blank on CRFs until results of this testing are received. In addition, sites should notify participants’ families of the results of this testing. If an infant remains HIV antibody positive at Week 48, he/she will remain on study and be seen in the clinic for repeat HIV antibody testing every three months until results are negative (per protocol Appendix IB, footnote 21). For Dose Group 3, HIV antibody testing will be performed according to Appendix ID, footnote 13. Notify the team if the HIV antibody test is positive for Dose Groups 1 and 2 at or after week 48 or for Dose Group 3, at 12 weeks after complete cessation of breast feeding.

7.0 PHARMACY

7.1 Dosing of VRC01

Table 7-1: Product Volume by Weight Band to Achieve a 20 mg/kg Dose with Additional Volume to Add to Syringe to Fill Tubing Dead Space in Study-Supplied Infusion Set Administration with One Syringe (dose volume equal or less than 1.0 mL)

Weight Band Dose 20 mg/kg

Dose Volume

Additional Volume to Withdraw

Total Volume to Withdraw

into Syringe

2.0 kg to <2.3 kg 40 mg 0.4 mL 0.3 mL 0.7 mL

2.3 kg to <2.8 kg 50 mg 0.5 mL 0.3 mL 0.8 mL

2.8 kg to <3.3 kg 60 mg 0.6 mL 0.3 mL 0.9 mL

3.3 kg to <3.8 kg 70 mg 0.7 mL 0.3 mL 1.0 mL

3.8kg to <4.3 kg 80 mg 0.8 mL 0.3 mL 1.1 mL

4.3 kg to <4.8 kg 90 mg 0.9 mL 0.3 mL 1.2 mL

4.8 kg to <5.3kg 100 mg 1.0 mL 0.3 mL 1.3 mL


Table 7-2: Product Volume by Weight Band to Achieve a 40 mg/kg Dose with Additional Volume to Add to the Syringe to Fill Tubing Dead Space in Study-Supplied Infusion Set Decisions about when to split the dose vs administer the injection as a single dose are up to the clinician at the site. The clinician can opt to split smaller volumes or administer larger volumes as a single injection. The important point is that, if the dose is being split, each syringe needs a separate administration set (butterfly) and an additional 0.3 mL volume of VRC01 in order to flush the tubing.

Table 7-3: Product Volume by Weight Band to Achieve a 20 mg/kg Dose with Additional Volume to Add to Each of Two Syringes to Fill Tubing Dead Space in Study-Supplied Infusion Set: Administration with Two Syringes

Weight Band

Dose 20 mg/kg

Total Dose Volume

Volume in Each Syringe

Additional Volume to Withdraw into Each Syringe

Total Volume to Withdraw into Each Syringe

5.3 to < 6.5 kg 120 mg 1.2 mL 0.6 mL 0.3 mL 0.9 mL

6.5 to <7.5 kg 140 mg 1.4 mL 0.7 mL 0.3 mL 1.0 mL

7.5 to <8.5 kg 160 mg 1.6 mL 0.8 mL 0.3 mL 1.1 mL

8.5 to <9.5 kg 180 mg 1.8 mL 0.9 mL 0.3 mL 1.2 mL

9.5 to <10.5 kg 200 mg 2.0 mL 1.0 mL 0.3 mL 1.3 mL

10.5 to <11.5 kg 220 mg 2.2 mL 1.1 mL 0.3 mL 1.4 mL

11.5 to <12.5 kg 240 mg 2.4 mL 1.2 mL 0.3 mL 1.5 mL

12.5 to <13.5 kg 260 mg 2.6 mL 1.3 mL 0.3 mL 1.6 mL

13.5 to <14.5 kg 280 mg 2.8 mL 1.4 mL 0.3 mL 1.7 mL

14.5 kg to 15.5 kg 300 mg 3.0 mL 1.5 mL 0.3 mL 1.8 mL

Weight Band Dose 40 mg/kg

Total Dose

Volume

Number of

syringes

Dose Volume in Each Syringe

Additional Volume to Withdraw into Each Syringe

Total Volume to withdraw into Each Syringe

2.0 kg to <2.2 kg 80 mg 0.8 mL 1 0.8 mL 0.3 mL 1.1 mL














7.2 Thawing Instructions

Thaw vial(s) of VRC01 at controlled room temperature 15°C to 27°C (59°F to 80°F) for a minimum of one hour up to a maximum of 24 hours. Continue to thaw the vial(s) until the fluid is a clear, colorless to yellow liquid and no particles are observed. VRC01 vials must either be used to prepare a syringe for subcutaneous injection or placed in a refrigerator at 2°C to 8°C (36°F to 46°F) before reaching the maximum storage of 24 hours at controlled room temperature; VCR01 in a vial may be stored up to 4 weeks at 2°C to 8°C (36°F to 46°F). After storage at 2°C to 8°C (36°F to 46°F), vials may be held at room temperature for a maximum of 8 hours prior to product preparation. VRC01 is a highly concentrated protein solution and may develop white-to-translucent particles after thawing. Vial(s) of VRC01 containing particles at 24 or fewer hours after being thawed should be placed in the refrigerator for possible future use, because particles may continue to dissipate at 2°C to 8°C. Vials of VRC01 that previously contained particles but subsequently become clear of particles may be used. Vials that continue to have visible particles after a maximum of 24 hours at controlled room temperature or up to 4 weeks at 2°C to 8°C (36°F to 46°F) are not to be used and will be disposed of as instructed in protocol Section 5.6. Report to the protocol pharmacist the quantity and the reason for the disposal of any unused vials. VRC01 in a syringe for subcutaneous injection may be stored at 2°C to 8°C (36°F to 46°F) or controlled room temperature (maximum 27°C) for up to 7 days. If the syringe is stored at 2°C to 8°C, the syringe should be equilibrated to controlled room temperature (maximum 27°C) for a minimum of 30 minutes and may be additionally held at room temperature for up to 24 hours prior to and during product administration. Do not store in direct sunlight.

7.3 Study Product Preparation Instructions

1. Calculate the total milligrams of VRC01 required and the total number of vials required based on a 2 mL withdrawal volume of VRC01.

2. Gently swirl the vials for 30 seconds to avoid foaming. DO NOT SHAKE THE

VIALS. Keep the vials upright at all times until ready to withdraw the contents. Do not invert the vials during inspection.

3. Observe the vials for particles. If upon inspection particles are observed, follow

the instructions under Thawing Instructions. 4. Withdraw the required volume (see MOP Table 7-1, Table 7-2, or Table 7-3) using

aseptic technique into a sterile syringe; use the tables to determine the required volume for one or two syringes as appropriate for the participant’s weight.

5. Label the syringe(s) with an expiration date of 7 days from the time of preparation.

Dispense one BD Safety-Lok™ infusion set with a 25 G x 0.75-inch needle with 7 inches of tubing and a luer lock adapter (item number 367294) for each syringe dispensed.


8.0 SPECIMEN COLLECTION AND PROCESSING

This section contains general information related to laboratory considerations for P1112. For detailed information on tests and specimens required for each visit, please refer to the Schedule of Evaluations (protocol Appendix I) and the P1112 LPC (www.impaactnetwork.org).

8.1 Introduction

Regardless of where tests are performed, personnel who collect specimens and/or perform assays must be trained in proper collection, handling, testing and associated QA/QC procedures prior to performing the tests for study purposes. Training documentation must be available for inspection at any time. All laboratory activities should be conducted in accordance with accepted Good Clinical Laboratory Practice (GCLP), the IMPAACT and ACTG Network Laboratory Joint Laboratory Manual and site-specific Standard Operating Procedures (SOPs) for proper collection, processing, labeling, and transport of specimens. Transport of all specimens must comply with federal, state, local, IATA and ACTG/IMPAACT specimen shipping regulations. As the transmission of HIV and other blood-borne diseases can occur through contact with contaminated needles, blood and blood products, appropriate precautions should be employed by all personnel when drawing blood and handling clinical specimens for this study in both the clinical and laboratory setting, as recommended by the Centers for Disease Control and Prevention (CDC). Respiratory infections may be transmitted by droplet aerosolization and fomites. All study staff should take appropriate precautions when collecting and handling biological specimens. Guidance on Universal Precautions/ Body Substance Isolation is available from the US Centers for Disease Control and Prevention:

http://www.cdc.gov/ncidod/dhqp/bp_universal_precautions.html

http://www.cdc.gov/ncidod/dhqp/gl_isolation_standard.html

8.2 General Overview and Guidelines

Key elements of specimen management include collection, transport, storage and shipping. Also essential for clinical trials is a Chain of Custody which refers to the tracking of specimens and results. It is essential that all staff collecting P1112 specimens have been trained in proper collection techniques, container types, and any special requirements. Specimens must be transported within predefined time limits to the laboratory under proper conditions. The remainder of this section provides information intended to standardize specimen collection and laboratory procedures across sites.

8.3 Specimen Chain of Custody

All IMPAACT sites must have a Standard Operating Procedure (SOP) for Chain of Custody in place. The Chain of Custody must track when specimens are transferred between clinics, processing units, and laboratories. Internal movements of specimens within the same laboratory do not need to be tracked. Laboratories with Laboratory Information Management Systems (LIMS) or the Laboratory Data Management System (LDMS) may be able to track most Chain of Custody information electronically. Tracking forms with specific information must accompany specimens. Required information includes the following: the PID/SID, collection time and date, and visit code for each specimen. Subject names or initials may NOT be used on research samples or the accompanying tracking forms.

http://www.impaactnetwork.org/

http://www.cdc.gov/ncidod/dhqp/bp_universal_precautions.html


8.4 Labeling Specimens

All samples collected at a study visit must be labeled at the time of collection with the PID, visit number, and collection date. If collecting PK specimens, time and time unit are also required. Information on the specimen containers must match the information on the tracking forms. All samples must be entered into the LDMS system and aliquots must be labeled using standard LDMS-generated barcode labels.

8.5 Laboratory Data Management System (LDMS)

The LDMS must be used at all sites to track the collection, storage, and shipment of the laboratory specimens. Detailed instructions for use of the LDMS are available at: http://www.fstrf.org/ldms. All sites should upgrade to the most current version of the LDMS as soon as possible. For supported label and printer options, refer to the product listing documents located on the LDMS Client Reference Guides page on the FSTRF Portal. Contact LDMS user support for further information. Due to the high variability in blood volumes obtained from infant samples, the required number of aliquots, the need for a minimum aliquot volume and PBMC storage, preloads in the LDMS will not be implemented with this study. Please refer to the LPC for all plasma, serum and PBMC storage. Questions about LDMS, shipping and storage for this protocol should be raised with the Laboratory Data Manager at FSTRF:

Christopher Hensel, FSTRF

Phone: (716) 834-0900, extension 7478 Email: [email protected]

8.5.1 24-Hour LDMS User Support

Technical support is also available from LDMS User Support. Usual business hours from LDMS user support are 12 AM - 6:00 PM Eastern Time in the US (ET) Monday through Friday. During business hours, please contact LDMS User support as follows:

Email: [email protected] Phone: (716) 834-0900, extension 7311

Fax: (716) 898-7711

8.5.2 Off-Hours Contact Information

If you are locked out of your LDMS or are experiencing errors that prevent you from completing your LDMS lab work during off-hours, page LDMS User Support using the LDMS Web Pager utility. Alternatively, you may e-mail the paging system directly at [email protected]. Please allow at least 15 minutes to get a response before sending another e-mail to the paging system.

Additional Resources: LDMS website: http://www.fstrf.org/ldms/ FSTRF portal: http://www.fstrf.org/portal/

http://www.fstrf.org/ldms



http://www.fstrf.org/ldms/

http://www.fstrf.org/portal/


8.6 Oral Secretions Collection and Processing (see LPC for additional information)

Two oral samples are collected for each subject using two Weck-Cel sponges for each subject: one sublingual and one buccal.

8.6.1 Supplies and Equipment List (ordering information can be found in the LPC)

1. Weck-Cel sponges-two per collection

a.

2. Spin-X tubes-two

a. 3. Sterile phosphate buffered saline (PBS) without calcium and magnesium 4. Container for Spin-X tubes 5. Container for wet ice 6. Wet ice or cold pack 7. Cooler for transport 8. Scissors

8.6.2 Procedure for Collection and Processing of Oral Secretions

1. Prior to collecting the sample, aseptically place 50 uL of sterile PBS (without Calcium and Magnesium) into the top chamber of each of two Spin-X tubes (the chamber that has a filter at the bottom). This can be done up to 5 days in advance of using the Spin-X tubes. Store at 2-8oC.

2. Ideally specimen collection should be done after subject has had no food or drink for 15-30 minutes.

3. Use separate Spin-X tubes for the sublingual and the buccal samples. 4. Prior to collection, the infants buccal mucosa and sublingual mucosa will be wiped

with a sterile gauze pad (pad may be moistened with water) to remove any food/milk particles.

5. Label Spin-X tubes with PID, SID, visit day, date and sample type. a. Sublingual Collection: Place 1 dry sterile sponge in the floor of mouth

(under tongue) for 1 minute. b. Buccal Collection Place 1 dry sterile sponge against the cheek mucosa

on one side for 1 minute. 6. For each sponge: Place sponge into upper chamber of the Spin-X tube containing

the 50ul PBS (Ca/Mg free). a. Cut off and discard the handle of the sponge so that the sponge head will fit

in the top section of the Spin-X in contact with the PBS. b. Fasten the snap top of the Spin-X tube securely. c. Put the Spin-X tube upright into a water tight primary container or sealed

plastic bag and into a secondary container so that the primary container is surrounded by wet ice or in contact with a cold pack.

7. Transport to the specimen processing lab so that processing occurs within 60 minutes (see LPC for processing instructions).


8.7 Additional Resources

ACTG/IMPAACT Laboratory Manual: http://www.hanc.info/labs/Pages/actgimpaactlabmanual.aspx ACTN Specimen Processing Guide: http://www.hanc.info/labs/Pages/actgimpaactlabmanual.aspx

ACTN Guidelines for Shipping Diagnostic Specimens: http://www.hanc.info/labs/Pages/actgimpaactlabmanual.aspx

ACTN Guidelines for Shipping Infectious Substances: http://www.hanc.info/labs/Pages/actgimpaactlabmanual.aspx

9.0 DATA

9.1 Source Documents

Demographic, sample collection, clinical examination, and AE data must be collected and recorded by the Investigator’s designated personnel, directly on chart documents or investigator spreadsheets, and maintained as source documents.

All documentation must be made available to the monitor at scheduled monitoring visits.

9.2 Schedule of Case Report Forms

The IMPAACT P1112 CRF schedule and forms can be found on the FSTRF portal:

Log in to the FSTRF portal at www.fstrf.org

Go to IMPAACT

Under the “Case Report Forms” tab select “Forms Management Utility”

In the “Forms Management Utility” use the drop downs to select “P1112” for the CRF schedule and forms

9.3 Resources

Questions regarding data management should be directed to the P1112 Data Managers: Bobbie Graham, BS FSTRF 4033 Maple Road Amherst, NY 14226-1056 Phone: (716) 834-0900 x 7265 Fax: (716) 834-8432 E-mail: [email protected] Benjamin Johnston, BS FSTRF 4033 Maple Road Amherst, NY 14226-1056 Phone: (716) 834-0900 x 7407 Fax: (716) 834-8432 E-mail: [email protected] For additional queries, you may contact the Randomization Help Desk at 716-834-0900 EXT 7200 or email [email protected]

http://www.hanc.info/labs/Pages/actgimpaactlabmanual.aspx




http://www.fstrf.org/




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