Phase I/II Multisite, Randomized, Controlled Study of Monoclonal Antibody VRC01 With Combination Antiretroviral Therapy to Promote Clearance of HIV-1-Infected Cells in Infants
Phase: PHASE1
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
Letter of Amendment #2       
Page 1 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
Letter of Amendment #2 for: 
 
IMPAACT 2008 
Phase I/II Multisite, Randomized, Controlled Study of Monoclonal Antibody VRC01 
with Combination Antiretroviral Therapy  
to Promote Clearance of HIV-1-Infected Cells in Infants 
 
Version 2.0, dated 29 May 2017 
 
 DAIDS Study ID # 20735 
IND # 133,017 Held By DAIDS 
 
Letter of Amendment Date: 22 April 2020 
 
 
 
Table of Contents 
 
Information/Instructions to Study Sites from the Division of AIDS ............................................................ 1 
Letter of Amendment Signature Page ........................................................................................................... 2 
Summary of Modifications and Rationale .................................................................................................... 3 
Implementation ............................................................................................................................................. 4 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2008 
study and must be submitted to site Institutional Review Boards (IRBs) and/or Ethics Committees (ECs) 
as soon as possible for their review and approval. Approval must also be obtained from site regulatory 
entities if applicable per the policies and procedures of the regulatory entities. All IRB/EC and regulatory 
entity requirements must be followed.  
  
Upon obtaining all required IRB/EC approvals and any other applicable regulatory entity approvals, each 
site should immediately begin implementing this LoA. Upon receiving IRB/EC approvals and any other 
applicable regulatory entity approvals, sites are required to submit an LoA registration packet to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC). Sites will 
receive a registration notification for the LoA after the DAIDS PRO verifies that all required registration 
documents have been received and are complete. Sites should not await this notification before 
implementing this LoA.   
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential document files for IMPAACT 2008. If the IMPAACT 2008 
protocol is amended in the future, the contents of this LoA will be incorporated into the next version of 
the protocol. 
 
 
 

 
Letter of Amendment #2       
Page 2 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
IMPAACT 2008 
Phase I/II Multisite, Randomized, Controlled Study of 
Monoclonal Antibody VRC01 with Combination Antiretroviral Therapy 
to Promote Clearance of HIV-1-Infected Cells in Infants 
 
DAIDS Study ID #20735 
 
 
Version 2.0, Letter of Amendment #2 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 

 
Letter of Amendment #2       
Page 3 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
Summary of Modifications and Rationale 
 
The primary purpose of this LoA is to update guidelines for monitoring by the Study Monitoring 
Committee (SMC). Following the first regularly scheduled SMC review of this study, the SMC identified 
no safety concerns and recommended that the third trigger for an SMC safety review specified in protocol 
Section 9.5.2 be revised to specify separate thresholds for hematologic adverse events (anemia and 
neutropenia) and non-hematologic adverse events. The SMC also recommended that the Protocol Team 
set a higher threshold for triggering a review of anemia and neutropenia events. This LoA reflects the 
Protocol Team’s response to the SMC recommendations. 
 
A second purpose of this LoA is to add batch antiretroviral (ARV) resistance testing at study Entry and at 
Week 14 for infants with plasma HIV-1 RNA greater than 500 copies/mL. Combination antiretroviral 
therapy (cART) regimens are selected for infants in this study by primary care providers, consistent with 
local standards of care. At many sites, resistance testing is not routinely performed before or during ARV 
treatment as standard of care. Routine review of cART regimens received by the Protocol Team and the 
SMC has identified diversity in regimens selected across sites and participants. Information on ARV 
resistance mutations present at study Entry (baseline) and at Week 14 (when the primary study outcome 
measure is assessed) will facilitate interpretation of the primary study results.  
 
ARV resistance testing will be performed in batch at a designated centralized laboratory. This testing was 
not explicitly listed as a study-specific evaluation in protocol Version 2.0 but is generally consistent with 
the use of stored blood specimens as described in the protocol and sample informed consent forms. No 
additional blood will be collected for this testing. Results will be provided to participants’ parents or 
guardians and primary HIV care providers.  
 
This LoA also incorporates minor and administrative updates of the following: 
 
• 
Clinical Management Committee (CMC) monitoring of antiviral activity and a description of 
performing sensitivity analyses of antiviral activity 
• 
Protocol team and site rosters 
• 
Websites where DAIDS resources for key aspects of study implementation can be accessed 
• 
References to the NIAID Vaccine Immune T-Cell and Antibody Laboratory (NVITAL) 
 
All of the above are addressed in Sections A-C of this LoA.  
 
Section D of this LoA incorporates the contents of protocol Clarification Memorandum (CM) #2, which 
was issued on 01 April 2020 to safeguard the health and well-being of study participants in the context of 
circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the associated 
coronavirus disease (COVID-19) pandemic. CM #2 provided operational flexibility for conducting study 
visits and procedures when needed to ensure ongoing contact with participants and to prioritize the 
conduct of clinically and scientifically important evaluations when possible. Per the study Sponsor, sites 
were instructed to implement the guidance provided in CM #2 immediately. All sites should continue to 
follow applicable government, health authority, and institutional policies with respect to conduct of study 
visits and procedures during the COVID-19 pandemic, with utmost importance placed on the health and 
well-being of study participants and study staff. Consistent with the instructions provided in CM #2, 
implementation of Section D of this LoA is expected to be time-limited in relation to the COVID-19 
pandemic. In consultation with IMPAACT Network leadership and the study Sponsor, the IMPAACT 
2008 Protocol Team will determine when, in the future, the guidance provided in Section D is no longer 
applicable. When such a determination is made, study sites will be formally notified and instructed to 
inform their IRBs/ECs. 

 
Letter of Amendment #2       
Page 4 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
Implementation 
 
Modifications of protocol text are shown in three sections (A-C) of this LoA. Within each section, 
modifications are generally shown in order of appearance in the protocol. Where applicable, modified 
protocol text is shown using strikethrough for deletions and bold type for additions. Operational guidance 
for conducting study visits and procedures during the COVID-19 pandemic is provided in the fourth 
section (D) of this LoA; conventions for use of strikethrough and bolding do not apply in this section. 
 
A. Update of Guidelines for Monitoring by the SMC  
 
1. In protocol Section 9.5.2, Monitoring by the SMC, Participant Safety, third, fourth, and fifth 
paragraphs: 
 
Triggered SMC reviews will occur in the following scenarios: 
 
1. Any infant in Arm 1 dies or has a Grade 4 adverse event that is judged by the CMC to be related 
to the study product (excluding neutropenia, anemia, and fever) 
 
2. Three or more infants in Arm 1 have a Grade 3 or higher adverse event that is judged by the CMC 
to be related to the study product (excluding neutropenia, anemia, and fever) 
 
3. After at least 25 participants have been enrolled, 20% (across arms) have Grade 3 or higher 
adverse events: 
 
a. 20% across arms have Grade 3 or higher adverse events excluding anemia and 
neutropenia 
b. 50% across arms have Grade 3 or higher anemia or neutropenia 
 
Because Grade 3 and higher neutropenia and anemia are common among infants on ART, and Grade 
3 and higher fever is common due to inter-current illnesses, these events will not be counted in 
scenarios (1) and (2). These events Grade 3 or higher fever will be counted in scenario (3a). Grade 
3 or higher anemia and Grade 3 or higher neutropenia will be counted in scenario (3b).  
 
If either scenario (1), or scenario (2), or scenario (3a) occurs, accrual into the study and 
administration of study product will be paused, and an SMC review will take place within seven days. 
If scenario (3b) occurs, accrual into the study and administration of study product will not be paused, 
and an SMC review will take place within seven days. After a safety trigger has been met and the 
required SMC review has taken place, the threshold for future triggered safety reviews will be 
reset (i.e., the events that triggered a safety review will not be re-counted toward future 
reviews).  
 
B. Addition of ARV Resistance Testing  
 
1. In the Schedule of Evaluations in Appendix I, the listing of infant evaluations to be performed with 
stored plasma and PBMCs for primary, secondary, and other evaluations is updated to include ARV 
resistance testing at Entry and at Week 14, and a new footnote 10 is added, as shown on the next two 
pages of this LoA.  

 
Letter of Amendment #2       
Page 5 of 13 
 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
Appendix I 
IMPAACT 2008 Schedule of Evaluations:  Screening through Week 14 
Study Visit 
Screen 
Entry 
Entry  
+3d 
Week 
1 
Week 
2 
Week 
2+3d 
Week 
3 
Week 
6 
Week 
6+3d 
Week 
7 
Week 
10 
Week 
10+3d 
Week 
11 
Week 
149 
Visit Window 
-30 d 
Day 0 
-1/+3 d 
±3 d 
±3 d 
-1/+3 d 
±3 d 
±7 d 
-1/+3 d 
±3 d 
±7 d 
-1/+3 d 
±3 d 
-7/+14 d 
Urinalysis 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
Infant Evaluations (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored plasma and PBMCs 
for primary, secondary, and 
other evaluations 
 
3-5 mL5 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
5 mL 
ARV resistance10 
(plasma) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
VRC01 resistance 
(plasma) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
VRC01 level  
(plasma) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Anti-VRC01 antibodies 
(plasma) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV-1 DNA  
(PBMC) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV-1 RNA (spliced/ 
unspliced; PBMC) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV-1 RNA (inducible; 
PBMC) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Neutralization  
(plasma) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
ARV levels  
(plasma, adherence) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Stored serum for  
ADCC 
 
1 mL 
 
 
 
 
 
 
 
 
 
 
 
1 mL 
Stored plasma and PBMCs 
for exploratory evaluations6 
 
0-2 mL6 
 
 
X6 
 
 
X6 
 
 
X6 
 
 
0-2 mL6 
Cerebral spinal fluid storage 
for exploratory evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total Infant Blood Volume 
3-6 mL 
5-9 mL 
— 
5 mL 
1 mL 
— 
2 mL 
4 mL 
— 
2 mL 
4 mL 
— 
2 mL 
12-14 
mL 
 

 
Letter of Amendment #2       
Page 6 of 13 
 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
Appendix I Footnotes 
 
1. At Entry and Weeks 2, 6, and 10, for infants in Arm 1, blood collection must precede administration of VRC01. 
2. Refer to Section 6.16. 
3. CD4 and CD8 cell counts and percentages are generally expected to require 1 mL of blood.  At sites where a complete blood count (CBC) is 
needed to obtain both cell counts and percentages, 1 mL may be collected to perform the CBC at Week 36 and Week 48 (at other sites, the CBC is 
not required at these visits). 
4. At Entry, collect 1 mL and dilute as needed to perform the HIV-1 RNA assay.  At all other time points, collect 3 mL and process specimen for 
storage of PBMCs in addition to plasma for the RNA assay, if possible. 
5. At Entry, collect 3 mL for storage for primary, secondary, and other evaluations if the infant weighs <3 kg; collect 5 mL if the infant weighs ≥3 
kg. 
6. At Entry and Week 14, collect 2 mL for storage for exploratory evaluations only if the infant weighs ≥ 3 kg at the visit; otherwise, do not 
collect any blood for exploratory evaluations at these visits.  At Weeks 2, 6, 10, and 16, no additional blood is collected for exploratory 
evaluations but any plasma and PBMCs remaining from specimens collected for primary, secondary, and other evaluations will be stored for 
exploratory purposes (indicated with “X6”).  
7. Refer to Section 6.13. Infants who are withdrawn or terminated before completing the Week 24 Visit should have urinalysis performed and 5 mL 
of blood drawn for storage for primary, secondary, and other evaluations; infants who are withdrawn or terminated after the Week 24 Visit 
should not have urinalysis performed and should have 7 mL of blood drawn for storage for primary, secondary, and other evaluations.  For all 
infants, laboratory evaluations that have been performed within the two weeks prior to the Early D/C Visit need not be repeated. 
8. Refer to Section 6.12. 
9. The Week 14 Visit is targeted to take place on Day 98, with a preferred window of ±7 days and an allowable window of -7 to +14 days. Every 
effort should be made to conduct this visit as close as possible to the target date and within the preferred window. If the visit cannot be conducted 
within the preferred window, the visit may be conducted within the allowable window with approval in advance from the CMC. Also note that the 
Week 14 and Week 16 allowable visit windows overlap by a period of seven days. The Week 14 Visit should preferably be conducted before this 
period of overlap. However, if this is not possible, the Week 14 Visit may be conducted during the period of overlap and, in this case, the Week 14 
and Week 16 Visits may be combined (i.e., all Week 14 and Week 16 visit procedures may be performed on one day).  
10. Resistance testing will be performed at Entry and at Week 14 for infants with HIV-1 RNA >500 copies/mL. 

 
Letter of Amendment #2       
Page 7 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
2. In Section 5.7.1, Concomitant ARVs, second paragraph: 
 
Site clinicians may order real-time non-study-provided ARV resistance testing at their discretion to 
inform regimen management and ARV selection; if such testing is performed, results will be entered 
into eCRFs. The details of each regimen change will be source documented and entered into eCRFs, 
including the specific reason for the change.  
 
Note: ARV resistance testing will also be performed in batch using stored samples at Entry and at 
Week 14 for infants with plasma HIV-1 RNA >500 copies/mL. The results of this testing will be 
provided to site clinicians for entry into eCRFs and provision to participants’ parents or guardians. 
Site clinicians will also provide the results to participants’ primary HIV care providers if agreed to 
by the parent or guardian.  
 
3. In Section 6.17.2, Specimen Preparation, Testing, Storage, and Shipping, third paragraph: 
 
Specimens stored at site laboratories for the primary antiviral activity outcome — concentration of 
HIV-1 DNA in PBMCs at Week 14 — are expected to be requested for shipment once all enrolled 
infants have reached Week 14 of follow-up; specimens for ARV drug concentration assays, and 
VRC01 resistance assays, and ARV resistance assays are also expected to be requested at this time. 
 
4. In Section 13.9, Management of Incidental Findings, first paragraph: 
 
Site clinicians will inform infants’ parents or legal guardians of all clinically meaningful physical 
exam findings and laboratory test results, including hematology and chemistry test results, CD4/CD8 
cell counts, and HIV-1 RNA levels, and ARV resistance test results. Site clinicians will also 
provide ARV resistance test results to infants’ primary HIV care providers if agreed to by the 
parent or guardian. When applicable, site clinicians will provide referrals to non-study sources of 
medical care further evaluation and/or treatment of these findings. 
 
C. Other Minor and Administrative Updates  
 
1. In the Abbreviations and Acronyms listing, reference to the NIAID Vaccine Immune T-Cell and 
Antibody Laboratory is removed: 
 
NVITAL 
NIAID Vaccine Immune T-Cell and Antibody Laboratory 
 
2. On the Protocol Title Page and in the Protocol Team Roster, updates are incorporated to reflect 
current team membership: 
 
Protocol Title Page 
 
NIAID Medical Officers:  Mary Elizabeth Smith, MD 
 
 
 
 
Dwight Yin, MD, MPH 
 
NICHD Medical Officer: 
Rohan Hazra, MD Sai Majji, PhD 
 

 
Letter of Amendment #2       
Page 8 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
Protocol Team Roster 
 
NIAID Medical Officers 
Dwight Yin, MD, MPH 
Maternal Adolescent and Pediatric Research Branch 
Prevention Sciences Program 
DAIDS/NIAID/NIH 
5601 Fishers Lane 
Room 8B37, MSC 9831 
Rockville, MD 20852 
Phone: (240) 292-4791 
Email: dwight.yin@nih.gov 
 
NICHD Medical Officer 
Rohan Hazra, MD  
Eunice Kennedy Shriver National Institute of Child Health and Human Development  
6710B Rockledge Drive, Room 2113, MSC 7002 
Bethesda, MD 20817 
Phone: (301) 435-6868  
Email: hazrar@mail.nih.gov 
Sai Majji, PhD 
Maternal and Pediatric Infectious Disease Branch 
Eunice Kennedy Shriver National Institute of Child Health and Human Development 
6710B Rockledge Drive Room 2159C 
Bethesda, MD 20817 
Phone: 301-402-8048 
Email: sai.majji@nih.gov 
 
Protocol Investigators 
Alka Khaitan, MD 
Indiana University School of Medicine 
Ryan White Center for Pediatric Infectious Diseases & Global Health 
705 Riley Hospital Drive, Suite 3032, Phase 3 
Indianapolis, IN 46202 
Phone: (317) 944-3698 
Email: akhaita@iu.edu 
 
IMPAACT Community Advisory Board (ICAB) Representatives 
Maggie Peggy Malola 
Area 1 / Falls 
Lilongwe City, Malawi 
Phone: +265 995 452101 
Email: malolamaggie@yahoo.com 
 
Protocol Data Managers  
Chelsea Krotje, MPH  
Frontier Science & Technology Research Foundation (FSTRF) Frontier Science Foundation 
[…] 
Email: krotje@fstrf.org krotje@frontierscience.org 
 

 
Letter of Amendment #2       
Page 9 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
Lindsey Miller, PhD 
Frontier Science Foundation 
4033 Maple Road  
Amherst, NY 14226-1056  
Phone: (716) 834-0900 x7374 
Email: lmiller@frontierscience.org 
 
Kira Bacon, BA 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226-1056  
Phone: (716) 834-0900 x7269 
Email: kbacon@frontierscience.org 
 
Laboratory Data Manager 
Katelyn Hergott, MPH, MSW 
Colleen Foley, MS 
Frontier Science & Technology Research Foundation (FSTRF) Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900, x7212 
Email: hergott@fstrf.org 
Phone: (716) 834-0900, x7267 
Email: foley@frontierscience.org 
 
Collaborator  
Jintanat Ananworanich, MD, PhD  
The Henry M. Jackson Foundation for the Advancement of Military Medicine  
6720-A Rockledge Dr., Suite 400  
Bethesda, MD, 20817  
Phone: (301) 500-3949  
Email: jananworanich@hivresearch.org 
 
3. In the Site Roster, the member listing is updated to reflect a change of site investigator: 
 
Site 8052, Perinatal HIV Research Unit Soweto  
Sylvia Dittmer, MBBCh  
Avy Violari, FCPaed  
Perinatal HIV Research Unit  
Chris Hani Baragwanath Academic Hospital  
PO Box 114, Diepkloof  
Soweto  
Johannesburg, South Africa  
Phone: +27 11 989 9769   
Email: dittmers@phru.co.za  
Phone: 27-11-989-9703 
Email: violari@mweb.co.za 
 

 
Letter of Amendment #2       
Page 10 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
4. In several protocol sections, references to websites are updated: 
 
Section 7.3.1, EAE Reporting to DAIDS, first and second paragraphs 
 
Requirements, definitions, and methods for expedited reporting of adverse events are outlined in 
Version 2.0 of the DAIDS EAE Manual, which is available on the DAIDS Regulatory Support Center 
(RSC) website at: 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual 
https://rsc.niaid.nih.gov/clinical-research-sites/manual-expedited-reporting-adverse-events-
daids 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting system, 
must be used for EAE reporting to DAIDS. In the event of system outages or technical difficulties, 
EAEs may be submitted via the DAIDS EAE Form. This form is available on the DAIDS RSC 
website at: 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids/paper-eae-reporting. 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting 
 
Section 7.3.3, Grading Severity of Events, first paragraph 
 
For infants in both study arms, adverse events will be graded according to the Division of AIDS 
Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), 
Version 2.1, dated March 2017, which is available on the DAIDS RSC website: 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-event-grading-tables 
 
Section 11.2, Essential and Source Documents and Access to Source Data, first paragraph 
 
All DAIDS policies referenced in this section are available at: 
www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
Section 11.3, Quality Control and Quality Assurance 
 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the DAIDS policy on 
Requirements for Clinical Quality Management Plans, which is available at: 
www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
Section 14.2, Protocol Registration, fourth paragraph 
 
For additional information on the protocol registration process and specific documents required for 
initial and amendment registrations, refer to the current version of the DAIDS Protocol Registration 
Manual, which is available at on the RSC website: 
http://rsc.tech-res.com/clinical-research-sites/protocol-registration/policy-manual 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 

 
Letter of Amendment #2       
Page 11 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
5. In protocol Section 9.5.1, Monitoring by the Protocol Team, Antiviral Activity: 
 
The CMC will monitor plasma HIV-1 RNA levels as a real-time measure of antiviral activity. 
The SDMC will generate individual RNA profiles for each infant and summary descriptive 
statistics for the change from baseline (Week 0) across arms for routine review by the CMC. 
 
6. In protocol Section 9.6.3, Other Analyses, Antiviral Activity, third paragraph: 
 
Other analyses will additionally include sensitivity analyses of the primary outcomes, in particular 
restricting the VRC01 analysis set to those infants who received all four injections; excluding 
infants who received suboptimal antiretroviral treatment; including infants who comprise the 
intent-to-treat analyses population; and performing analyses with alternative censoring and 
imputation methods. These analyses will be further specified in the statistical analysis plan.  
 
7. In Section 10.2, Pharmacology Data, reference to the NIAID Vaccine Immune T-Cell and Antibody 
Laboratory is removed and replaced with more general references to the laboratory specified in the 
Laboratory Processing Chart (LPC): 
 
Data expected to be used for PK analyses include the following: demographics (sex and age); 
height and weight; VRC01 dosing details (date, time, dose administered, administration location); 
and sample collection details (date and time of collection). For each infant randomized to Arm 1, 
seven samples are expected to be collected for PK evaluations, at study Entry (Day 0) and Weeks 
2, 6, 10, 14, and 16. Samples collected at Entry and Weeks 2, 6, and 10 will be collected prior to 
VRC01 dosing. All sample collection data will be documented in LDMS. 
 
Assay Location:  Plasma samples will be shipped to the NIAID Vaccine Immune T-Cell and Antibody 
Laboratory (NVITAL) laboratory specified in the LPC, where they will be assayed for 
concentrations of VRC01.  
 
Assay Methods:  All assay methods will be immune-based, standardized with a filed Methods Report, 
and performed under Good Clinical Laboratory Practice conditions at NVITAL the laboratory 
specified in the LPC. 
 
Reporting of Assay Data:  Real-time PK evaluations will not be performed in this study.  Assay data 
are expected to be evaluated at two time points:   
 
• 
An interim PK analysis will be undertaken when six infants randomized to Arm 1 have received 
two doses of VRC01 and have specimens available for analysis through Week 6.  At this time, all 
PK samples collected from all infants thus far will be shipped and assayed at NVITAL the 
laboratory specified in the LPC.  These results will be compared to those predicted from 
IMPAACT P1112 with an emphasis on VRC01 concentrations, and their variability, prior to 
dosing at Weeks 2 and 6.  As described in section 9.5, results will then be reported to the CMC 
and SMC for purposes of assessing whether a dose adjustment may be indicated.  
 
• 
A final PK analysis will be undertaken after study completion.  All remaining PK samples will be 
shipped and assayed at NVITAL the laboratory specified in the LPC after completion of 
follow-up.  All VRC01 concentration data (including data from the interim analysis) will be 
combined for final analysis and final results will be reported to the Protocol Team. 
 

 
Letter of Amendment #2       
Page 12 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
D. Operational Guidance from Protocol Clarification Memorandum (CM) #2, dated 01 April 2020 
 
This CM provides operational guidance to study sites from the IMPAACT 2008 Protocol Team. The 
Protocol Team acknowledges that the extent to which site operations may be disrupted by the COVID-19 
pandemic may vary across sites and over time. All sites should follow applicable government, health 
authority, and institutional policies with respect to conduct of study visits and procedures, with 
utmost importance placed on the health and well-being of study participants and study staff. Site 
investigators should continue to follow current protocol specifications for communication with the 
Protocol Team and/or Clinical Management Committee and should contact the Clinical Management 
Committee (impaact.2008cmc@fstrf.org) with any questions or concerns regarding this CM or 
management of study participants.  
 
Visit Scheduling 
• 
Sites that anticipate operational disruptions or closures in the near future are advised to conduct study 
visits early in the allowable visit window. Visits conducted prior to opening of the allowable window 
would also be preferred to completely missing a visit at a later date. 
• 
Sites that are currently experiencing operational disruptions or closures are advised to conduct study 
visits late in the allowable visit window. Visits conducted after closing of the allowable window 
would also be preferred to completely missed visits.  
• 
Effective with the issuance of this CM, the allowable window for the Week 24 and Week 36 visits is 
broadened to ±6 weeks; the allowable visit window for the Week 48 visit is broadened to -6 to +12 
weeks. 
• 
In the event that any scheduled visits or procedures are missed, all participants should remain on-
study for the full duration of follow-up (i.e., through the Week 48 visit) if possible.    
 
Prioritization of Study Visit Procedures 
• 
Sites with full capacity to conduct study visits in-person at the study clinic should continue to do so in 
full compliance with the protocol.  
• 
Sites may also conduct study visits — in full or in part — off-site if permitted by applicable 
government, health authority, and institutional policies. Where this option is permitted, site staff 
should communicate with participants’ caregivers to determine in advance where and when such 
visits will take place, with adequate protections for safety, privacy, and confidentiality. Off-site visit 
procedures should be conducted by site staff who are adequately qualified and trained to conduct the 
procedures, as determined by the site Investigator of Record (IoR), with attention paid to occupational 
health, biohazard containment, and specimen and data chain of custody. These staff should also be 
adequately qualified and trained to immediately assess and/or manage any adverse events or social 
impacts that may occur during the visits. If adverse events requiring further evaluation or 
management are identified during an off-site visit, staff conducting the visit should arrange for 
appropriate clinical management, in consultation with the IoR or designee as needed.  
• 
Sites with limited capacity to conduct study visits should prioritize the visits outlined below for 
participants in both study arms. When applicable, specimen collection should be prioritized per 
protocol Section 6.17.1.  
- First priority visits:   
• 
Weeks 2, 6, and 10: These visits include VRC01 administration (for Arm 1 participants) and 
specimen collection (for all participants). VRC01 administration must be performed on-
site with personnel and supplies available in case of an immediate hypersensitivity reaction. 
If these visits cannot be conducted on-site, procedures other than VRC01 administration may 
be performed off-site if the requirements listed above, particularly the requirements 
pertaining to specimen collection and transport, can be met. If specimen collection cannot be 

 
Letter of Amendment #2       
Page 13 of 13 
22 April 2020 
IMPAACT 2008 Protocol Version 2.0 
performed off-site, other visit procedures (e.g., history taking, cART adherence assessment) 
may be performed remotely rather than in-person.  
• 
Week 14: These visits include specimen collection for assessment of primary study outcome 
measures. These visits may be conducted off-site if the requirements listed above, particularly 
the requirements pertaining to specimen collection and transport, can be met. If specimen 
collection cannot be performed off-site, other visit procedures (e.g., history taking, cART 
adherence assessment) may be performed remotely rather than in-person.  
• 
Weeks 3, 7, and 11: These visits should be conducted in-person (on-site or off-site) whenever 
possible. If in-person visits are not possible, reactogenicity assessments and history taking 
may be performed remotely.   
- Second priority visits: 
• 
+3-Day Contacts after Weeks 2, 6, and 10: Per protocol Section 6.16, these contacts may be 
conducted remotely. 
• 
Weeks 24, 36, and 48: These visits involve specimen collection and may be conducted off-
site if the requirements listed above can be met. If specimen collection cannot be performed 
off-site, other visit procedures (e.g., history taking, cART adherence assessment) may be 
performed remotely rather than in-person.  
- Third priority visits:  
• 
Weeks 16 and 20: These visits are of lowest priority. They involve specimen collection and 
may be conducted off-site if the requirements listed above can be met. If specimen collection 
cannot be performed off-site, other visit procedures (e.g., history taking, cART adherence 
assessment) may be performed remotely rather than in-person. 
 
Study Drug Supply 
• 
No changes in procedures for preparing, dispensing, or administering study product (VRC01) are 
permitted. These procedures must be performed on-site to ensure adherence to product temperature 
requirements. In addition, study product must be administered in a clinical setting to ensure 
appropriate management in the rare event of an acute hypersensitivity reaction. 
 
Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for IMPAACT 2008.  
• 
Documentation should be entered in participant study charts in real-time should any of the following 
occur: 
- Missed visits  
- Out-of-window visits 
- Off-site visits (document the location of the visit) 
- Incomplete or partial visits (document which procedures were performed and which were not) 
- Remote contacts performed in lieu of in-person visits (document method used to complete the 
contact and which procedures were performed) 
- Any other participant contacts  
• 
In consultation with the Division of AIDS, the IMPAACT Network is developing comprehensive 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures during the COVID-19 pandemic. Once this Network-
level guidance is available, it will be provided in a separate communication to all sites.