Conditions: HIV Infections
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 61
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the safety and antiviral activity to promote clearance of HIV-1 infected cells of VRC01 in infants with HIV beginning combination antiretroviral therapy (cART).

Detailed description:
VRC01 is an experimental human immunoglobulin G1 (IgG1) monoclonal antibody. The purpose of this study was to evaluate the safety and antiviral activity to promote clearance of HIV-1 infected cells of VRC01 received within 12 weeks of birth in infants with HIV initiating cART.

All infants were required to have initiated cART within 14 days before or at study entry. Infants were randomly assigned to either receive VRC01 (VRC01, Arm 1) or not receive VRC01 (No-VRC01, Arm 2). Randomization was stratified by whether the initial cART regimen included an integrase inhibitor.

Infants in the VRC01 arm received VRC01 injections at study entry (Week 0) and Weeks 2, 6, and 10. Infants in the No-VRC01 arm received no study product.

Infants attended study visits at Weeks 1, 2, 3, 6, 7, 10, 11, 14, 16, 20, 24, 36, and 48. Visits included physical examinations, blood and urine collection.

Infants' mothers could optionally be enrolled in the study for one-time specimen collection for exploratory evaluations. Maternal study participation was not required for infant study participation.

The study was closed to enrollment prematurely on March 19, 2020 due to the outbreak of coronavirus disease 2019 (COVID-19) and after enrolling 61 of the targeted 68 infants.

Arms:
arm 1: Infants received VRC01 subcutaneous injections (40 mg/kg) at Weeks 0, 2, 6, and 10. arm 2: Infants did not receive VRC01.

Interventions: intervention 1: VRC01 intervention 2: Combination Antiretroviral Therapy (cART)
Intervention descriptions: intervention 1: 40 mg/kg of VRC01 administered by subcutaneous injection. intervention 2: All infants received non-study provided cART selected by their primary care provider and supplied through non-study sources (i.e., cART not provided through the study).

Protocol document:
ICF_000.pdf: 
 
Appendix II 
Sample Informed Consent Form for Infant Study Participation 
 
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 
With changes from Letter of Amendment (LoA) #1, dated 14 June 2018 
 
Your baby is being asked to participate in the research study named above.  
 
This form gives information about the study.  Please read it, or have it read to you, and ask any questions 
you may have.  We will take as much time as you need to fully understand the study.  We will ask you 
questions to see if we have explained the study clearly.  
 
After you understand the study, if you decide to have your baby participate, you will be asked to sign or 
make your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [insert 
site name] are doing this study. The study is testing an experimental injection called VRC01 in babies 
who have HIV.  HIV is the virus that causes AIDS.   
 
The study will include about 68 babies who are less than 12 weeks old from Botswana, Brazil, Haiti, 
Malawi, South Africa, Zimbabwe, and the United States.  Babies will be in the study for about one year.   
 
The person in charge of the study at [insert site name] is [insert name of IoR].  The United States National 
Institutes of Health are paying for the study. 
 
1. The study is testing VRC01 in babies who have HIV.  
 
The study will test the safety of VRC01 when given to babies who are starting treatment for HIV.  It will 
also test the effect of VRC01 on the amount of HIV that can be found in babies’ blood and blood cells.   
 
VRC01 is an antibody against HIV.  Antibodies are made by the immune system to fight infection.  
Antibodies can also be made in laboratories.  VRC01 is made in a laboratory.   
 
VRC01 has been tested in laboratory experiments and in animals and people.  It has been tested in HIV-
negative adults, HIV-positive adults, and babies born to HIV-positive mothers.  Laboratory experiments 
have shown that VRC01 could help decrease the amount of HIV in the body.  However, we are still in the 
early stages of testing VRC01 to find out what its effects may be.  This will be the first study of VRC01 
in babies who have HIV. 
 


 
2. We do not know if VRC01 may be a useful treatment for HIV. 
 
The study is a first step in testing VRC01 in babies who have HIV.  All babies in the study will be taking 
anti-HIV medicines (ARVs).  We do not know if VRC01 may be a useful treatment when given in 
addition to ARVs.  The study will help us learn about that.  While we are learning about VRC01, it is very 
important that babies keep taking ARVs.  Taking ARVs is the best known way for people who have HIV to 
stay healthy. 
 
3. Only babies who qualify can participate in the study. 
 
If you decide to have your baby join the study, we will first do some tests to see if your baby qualifies.  
More information about the tests is given in #5 (see below).  If your baby qualifies, he or she will be 
entered in the study.  If your baby does not qualify, he or she cannot be entered in the study. 
 
4. It is your decision whether to join the study. 
 
Deciding to have your baby join the study is voluntary (your choice).  You are free to have your baby join 
or not join.  If you decide to have your baby join, you can change your mind and take your baby off the 
study.  Your decisions will have no effect on the medical care that your baby receives at this clinic.  Your 
baby’s access to services, and the benefits and rights he or she normally has, will not be affected.  
 
Take your time and consider your decisions carefully.  If you wish, you can talk to other people about the 
study before you decide.  You can bring other people here to learn about the study with you.   
 
No matter what you decide about the study, your baby should continue to receive standard medical care 
outside of the study.  This includes childhood immunizations, ARVs, and other standard care and 
treatment for children with HIV.  We will tell you where your baby can receive this care if needed.  
 
Finding out if you and your baby qualify 
 
5. We will ask questions, examine your baby, and test your baby’s blood.  
 
To find out if your baby qualifies for the study, we will:  
 
• 
Review your baby’s medical records. 
• 
Ask about your baby’s health and how you are feeding your baby. 
• 
Ask about the ARVs and other medicines you (the baby’s mother) and your baby have taken. 
• 
Give your baby a physical examination. 
• 
Draw your baby’s blood (up to 6 mL or about 1 teaspoon) for tests.  The tests will:  
– Check your baby’s blood cells, liver, and kidneys. 
– Check your baby’s CD4 and CD8 cells.  These cells are part of the immune system, which is the 
part of the body that fights infections.  HIV attacks CD4 cells, so it is important to check the 
number of these cells that can be found in the blood.  
– Confirm that your baby has HIV.  There are certain HIV tests that are required for this study.  If 
the required tests are not in your baby’s medical records, we will do the tests that are needed. 
• 
Talk with you about the study requirements and if your baby will be able to meet these requirements.   
 


 
These procedures will take about 2 hours.  The results of your baby’s blood tests will then be available 
within several days.  We will review the results and all other information to determine if your baby 
qualifies for the study.  We will schedule your baby to come back to the clinic when the results are 
available. 
 
• 
If your baby does not qualify, we will tell you this. Your baby will not be entered in the study and we 
will tell you where your baby can go for any medical care or other services your baby may need.  
 
• 
If your baby does qualify, he or she will be entered in the study.   
 
Entering the study 
 
6. If your baby qualifies, he or she will enter the study within a specified timeframe.  
 
There are certain timeframes for when babies can enter the study.  For example, babies must be less than 
12 weeks old when they enter.  We will explain the timeframes to you so you know what to expect.  
 
On the day your baby enters the study, we will:  
 
• 
Review your baby’s medical records and ask about: 
– Your (the baby’s mother’s) and your baby’s ARVs. 
– Your baby’s health and other medicines. 
– How you are feeding your baby. 
• 
Give your baby a physical examination. 
• 
Collect your baby’s urine for tests to check his or her kidneys. 
• 
Draw your baby’s blood (up to 9 mL or about 2 teaspoons) for tests including:  
– A test of the amount of HIV in your baby’s blood.  This is called your baby’s “viral load.”  The 
viral load should decrease over time as your baby takes ARVs.  
– Tests of the effects of VRC01. 
 
7. Babies will be placed in 1 of 2 groups on the day they enter the study.    
 
Babies placed in one group will be given VRC01.  Babies placed in the other group will not be given 
VRC01.  To test the effects of VRC01, babies given VRC01 will be compared to babies not given 
VRC01.  
 
Each baby will be placed a group at random, [like flipping a coin; sites may insert a different example if 
preferred].  Each baby has a 1-in-2 or 50% chance of being placed in the group that is given VRC01.  The 
study staff cannot choose which group each baby is placed in.  Babies’ parents also cannot choose.  
 
8. Babies in the VRC01 group will be given 4 injections. 
 
Babies in the VRC01 group will be given the first injection of VRC01 when they enter the study.  The 
other injections will be given 2, 6, and 10 weeks later.  The injections will be given in the skin of the 
thigh.  The amount of VRC01 given will depend on the baby’s weight.  The largest amount given will be 
about 4 mL (less than 1 teaspoon).  If the full amount of VRC01 cannot be given in one injection, two 
injections will be given.  Each injection is expected to take about 10-15 minutes. 
 


 
Although babies in the VRC01 group are expected to be given 4 injections, we may not give injections to 
babies who are sick when injections are scheduled to be given.  We may stop giving injections to any 
baby if we determine that more injections might be harmful.  Babies who miss any injections will still 
stay in the study. 
 
9. Babies in the VRC01 group will be checked for reactions to the injections. 
 
After the first injection of VRC01, babies must stay in the clinic for at least 2 hours.  During this time, 
study staff will check for reactions to the injection.  After the other injections, babies must stay in the 
clinic for at least one hour.   
 
[Here and in #19, sites may modify text regarding photographs if IRBs/ECs mandate a separate form for 
obtaining informed consent for photographs.]  If your baby has any reactions to VRC01, such as redness 
where VRC01 in injected, we may take a photo of the reaction.  The photo will help the doctors working 
on the study assess the reaction.  
 
10. All babies will have 13 scheduled visits over 1 year.  
 
Starting 1 week after entering the study, babies will have 11 visits over 6 months. After that, babies will 
have 2 more visits, about 3 months apart.  Each visit will take about 2 hours.  At these visits, we will:  
 
• 
Review your baby’s medical records and ask about: 
– Your (the baby’s mother’s) and your baby’s ARVs. 
– Your baby’s health and other medicines. 
– How you are feeding your baby. 
• 
Give your baby a physical examination. 
• 
Collect your baby’s urine for tests to check his or her kidneys.  
• 
Draw your baby’s blood for tests. The amount drawn will be up to 5 mL (about 1 teaspoon) while the 
baby is less than 3 months old, and up to 20 mL (about 4 teaspoons) as the baby ages to 6 and 12 
months.  At different visits, the tests will check your baby’s: 
– Blood cells, liver, and kidneys. 
– CD4 and CD8 cells. 
– HIV viral load. 
Tests will also check the amount of VRC01 in the blood and the effects of VRC01. 
 
Babies may have more visits if they are sick or need more tests to check on their health.  Additional blood 
or urine may be drawn at these visits if needed. 
 
11. Mothers or caregivers are asked to check on their babies.  
 
After 4 of the study visits, you will be asked to take your baby’s temperature and write down how your 
baby is doing.  You will be asked to do this for 7 days after the visit when your baby enters the study, and 
for 7 days after the visits 2, 6, and 10 weeks later.  For babies in the VRC01 group, these are the visits 
when VRC01 is given, but you will be asked to do this even if your baby is not given VRC01.   
 
We will show you how to write down the information about your baby.  After 3 days, we will telephone 
you to ask for the information you have written down. You can also come to the clinic with your baby or 
have a study staff member come to your home instead of having the telephone call.  If your baby has any 
problems, you will be asked to bring him or her to the clinic.  
 


 
12. If babies need a lumbar puncture, we will save spinal fluid for the study.  
[here and below, sites may use locally appropriate terminology (e.g., “spinal tap”) to refer to lumbar 
puncture] 
 
A procedure called “lumbar puncture” is sometimes done when babies are sick.  This procedure uses a 
needle to collect fluid from the baby’s spine.  The fluid is then tested to find out what may be causing the 
baby to be sick.  No lumbar punctures will be done for this study.  However, if your baby has a lumbar 
puncture outside of the study, we would like to save any spinal fluid that may be left over for tests.  If you 
agree to this, the tests will look for HIV in the fluid.  The tests may also look for other factors related to 
HIV and the immune system in the fluid.   
 
If your baby has a lumbar puncture, and you agree to have the spinal fluid saved, we will ask you to bring 
your baby to the clinic. At this visit, we will: 
 
• 
Review your baby’s medical records 
• 
Ask about your baby’s health and medicines. 
• 
Draw your baby’s blood (2 mL or about half a teaspoon) for tests. The tests may look for HIV in the 
blood and blood cells.  The tests may also look for other factors related to HIV and the immune 
system. 
 
13. Different tests will be done at different laboratories.  
 
We will do tests of your baby’s urine, blood cells, liver, kidneys, CD4 and CD8 cells, and HIV viral load 
here at our laboratory.  We will give you the results of these tests at the next scheduled visit or sooner if 
necessary.  We will explain the results and give you counseling and referrals as needed.   
 
Tests of the amount of VRC01 in the blood and of the effects of VRC01 will be done at different 
laboratories in the United States.  Tests of spinal fluid will also be done in the United States.  Some tests 
may be done while the study is ongoing, others after the study is completed.  The results of these tests are 
for research purposes only.  This means they are not expected to give any information relevant to your 
baby’s health.  The results will not be given to the study staff or to you. 
 
If you agree, some of your baby’s blood will be used for tests of his or her genes.  Genes are passed to 
children from their birth parents.  They affect how people look and how their bodies work.  Differences in 
people’s genes can help explain why some people get a disease while others do not.  For this study, only 
genes related to HIV, the immune system, and the effects of VRC01 will be tested.  The results of these 
tests are for research purposes only and will not be given to the study staff or to you. 
 
14. We may take your baby off the study early. 
 
Babies are expected to stay in the study for about 1 year.  However, we may take your baby off the study 
if: 
 
• 
The study is stopped for any reason. 
• 
We determine that your baby cannot meet the study requirements (for example, if you move away and 
cannot come to the clinic). 
• 
We determine that staying in the study might harm your baby. 
 


 
15. Please tell us if you wish to take your baby off the study. 
 
You are free to take your baby off the study at any time for any reason.  The care that your baby receives 
at this clinic will not be affected, but it is important that we know your decision.  We will ask you to bring 
your baby to the clinic for one last visit.  At this visit we will: 
 
• 
Ask about your (the baby’s mother’s) and your baby’s ARVs. 
• 
Ask about your baby’s health and other medicines. 
• 
Ask about how you are feeding your baby. 
• 
Give your baby a physical examination. 
• 
Draw your baby’s blood (about 15 mL or 3 teaspoons) for tests.  The tests will check: 
– The baby’s blood cells 
– The baby’s CD4 and CD8 cells 
– The baby’s HIV viral load  
– The effects of VRC01 
 
If your baby has been in the study for less than six months, we will also collect urine for tests to check his 
or her kidneys. 
 
We will answer any questions you may have and tell you how to contact us in the future, if you wish. 
 
Risks of the study 
 
16. There is little risk from the study procedures.  
 
Most procedures done in this study are routine medical procedures, with little risk to your baby.  Drawing 
blood can cause pain, swelling, bruising, or bleeding where the needle is inserted.  Rarely, drawing blood 
can cause fainting or infection.  
 
17. VRC01 is experimental.  
 
This means we do not know if VRC01 is safe to use in people.  We also do not know if VRC01 is useful 
as a treatment for HIV.  VRC01 is being tested in research studies to learn more about it, and this study 
will help us learn about VRC01 in babies who have HIV.   
 
VRC01 will be given as an injection in the skin.  This kind of injection can cause stinging, itchiness, 
discomfort, pain, soreness, redness, bruising, swelling, or a small cut where the needle enters the skin.  
Rarely, this kind of injection can cause infection.  
 
As of January 2017, more than 800 HIV-negative and HIV-positive adults have received VRC01 in 
research studies in the United States, Botswana, Malawi, South Africa, Zimbabwe, and other countries.  
Some people had mild or moderate reactions like itchiness, redness, or swelling where VRC01 was 
injected.  Some people felt tired or had mild body discomfort, muscle or joint pain, headache, chills, or 
nausea after receiving injections.  Some people had hives while VRC01 was being given or soon after 
VRC01 was given. In some cases, the hives were severe. One person had chest discomfort and one 
fainted. Some people had abnormal results on tests of their blood cells, liver, or kidneys. These came back 
to normal after a few days or weeks.   
 


 
As of January 2017, 40 babies born to mothers who have HIV have received VRC01 in a research study 
being done by the IMPAACT network in the United States, South Africa, and Zimbabwe. Most of these 
babies had redness, swelling, or a small bruise where VRC01 was injected, which lasted for a short 
time.  No other effects thought to be caused by VRC01 have been seen, and no serious health problems 
have occurred. 
 
It is possible that babies who receive VRC01 in this study could develop “resistance” to VRC01 or other 
antibodies like VRC01.  If resistance develops, the antibodies may not be effective in helping to control 
the baby’s HIV.  In this study, the risk of resistance is minimized by giving VRC01 with ARVs. 
 
18. Other antibodies have caused other side effects.  
 
Other antibodies that are different from VRC01 have been given to people for other illnesses. With those 
antibodies, most side effects happen within the first 24 hours including fever, chills, shaking, nausea, 
vomiting, pain, headache, dizziness, trouble breathing, high or low blood pressure, itchiness, rash, hives, 
lip or face swelling, diarrhea, racing heartbeat or chest pain.  Rarely, some antibodies have caused serious 
reactions that may be life-threatening.  
 
One type of serious reaction may occur soon after getting an antibody.  It includes difficulty breathing 
possibly leading to low blood oxygen, low blood pressure, hives or rash, and swelling in the mouth and 
face.  A second type of serious reaction may occur several days to 3 weeks after getting an antibody.  It 
includes hives or a rash, fever, big lymph nodes, muscle and joint pains, kidney problems, chest 
discomfort and shortness of breath. Rarely, antibodies used to treat other diseases have been linked to a 
blood disorder that interferes with blood clotting, cancer, damage to the heart muscle, and to the body’s 
immune system attacking healthy cells.  
 
These rare side effects and reactions have not been seen in other studies of VRC01.  However, it is 
possible that babies in this study could have these types of reactions.  Babies could also have other side 
effects or reactions that we do not yet know about.  
 
We will closely check on babies in this study for side effects and reactions.  Please contact the study staff 
if any of these problems or any other problems occur. 
 
19. There could be risks of disclosure of your baby’s information. 
 
We will make every effort to keep your baby’s information private and confidential.  Study records and 
specimens will be kept in secure locations.  All specimens and most records will be labeled only with a 
code number.  However, your baby’s name will be written on some records.  Despite our best efforts to 
keep your baby’s information private, it is possible that your baby’s information, including information 
about your baby’s genes, could be obtained by someone who should not have it.  If this were to happen, 
your baby could be treated badly or unfairly.   
 
[Sites may modify this paragraph if IRBs/ECs mandate a separate form for obtaining informed consent 
for photographs.]  If we take photos of any reactions to VRC01, we will not photograph your baby’s face.  
Photos will be labeled only with a code number (not with your or your baby’s name).  Photos will be kept 
securely with other information collected for the study.  Photos also may be shared with other doctors 
working on the study.  The other doctors may be here at [site name] or in other countries.  These doctors 
will not be given your or your baby’s name, and they will be required to keep the photos private and 
confidential.  When the study is completed, the photos will be destroyed.  
 


 
[US sites, insert: To help us protect your privacy, we have obtained a Certificate of Confidentiality that 
protects us from being forced to release information that may identify your baby, such as by the courts or 
police. The certificate cannot be used in all situations, but it can be used to resist demands for information 
that would identify your baby. The certificate does not protect against requests for information from the 
US federal government or from the US Food and Drug Administration. Regardless of the certificate, you 
can release information about your baby’s participation in the study to others, if you wish.] 
 
Benefits of the study 
 
20. There may be no benefit from being in the study.  
 
By joining the study, your baby will be part of the search for new treatments for babies who have HIV.  
However, being in the study may not benefit your baby in any way.   
 
Your baby will have regular visits here and frequent checks on his or her health.  It is possible that the 
examinations and tests done in the study may help your baby stay healthy.  If these procedures show that 
your baby may need medical care that cannot be provided through the study, we will tell you where you 
can go for the care your baby needs.  
 
Other information about the study 
 
21. There are no costs to you or your baby. 
 
There are no costs to you or your baby for the study visits, injections, or procedures.   
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 
22. Your baby’s study records may be reviewed by study staff and groups that oversee the study.  
 
Groups that oversee the study include:   
 
• 
[insert name of site IRBs/ECs] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site drug entities that may review records] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
The IMPAACT Network that is coordinating the study 
• 
Other US, local, and international regulatory entities 
 
The study staff and these groups are required to make every effort to keep study records private and 
confidential.  Your baby’s study information may be disclosed to other authorities if required by law.  
The results of the study may be presented publicly or published.  However, no presentation or publication 
will use your baby’s name or identify your baby personally.   
 
A description of this study will be available on www.ClinicalTrials.gov as required by United States Law.  
This website will not include any information that can identify your baby.  At most, the website will 
include a summary of the results of the study.  You can search this website at any time. 
 


 
23. If your baby gets sick or injured, contact us right away. 
 
Your baby’s health is important to us.  We will make every effort to minimize risks and protect your 
baby’s well-being.  It is possible, however, that your baby could have an illness or injury that is study-
related.  This means that the illness or injury occurred as a direct result of the study injections or other 
study procedures.   
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.]  If a study-
related illness or injury occurs, we will treat your baby or tell you where you can you can get the 
treatment your baby needs.  The cost for this treatment may be charged to you or your health insurance.  
There is no program to pay money or give other forms of compensation for study-related illness or injury 
through [site name or] the United States National Institutes of Health.  
 
Who to contact 
 
24. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your baby’s rights as a research participant or concerns about how your 
baby is being treated in the study:  
[insert name and telephone number of IRB contact person or other appropriate person/organization].  
 
• 
If your baby has health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you want to take your baby off the study:  
[insert name and telephone number of investigator or other study staff]. 
 
 
 


 
Signatures 
 
25. If you decide to have your baby join this study, please sign or make your mark below.  
 
Before deciding whether to have your baby join this study, make sure you have read this form, or had it 
read to you, and that all of your questions have been answered.  You should feel that you understand the 
study, its risks and benefits, and what is expected if you decide to have your baby join.  
 
We will tell you any new information from this study or other studies that may affect your willingness to 
keep your baby in the study.  You can ask questions or request more information at any time.   
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies. Separate consent decisions must 
be documented for storage of residual CSF and for genetic testing]. 
 
 
 


 
Please write your initials or make your mark next to your choices:  
 
 
__________ 
I agree to have my baby join this study 
 
 
 
 
For storage of leftover spinal fluid:  
 
 
 
__________ 
I agree to storage of leftover spinal fluid (if my baby has a lumbar 
puncture outside of the study)  
 
__________ 
I do not agree to storage of leftover spinal fluid (if my baby has a lumbar 
puncture outside of the study)  
 
 
 
 
 
 
For genetic testing:   
 
 
__________ 
I agree to testing of my baby’s genes related to HIV, VRC01, and the 
immune system 
 
__________ 
I do not agree to testing of my baby’s genes  
 
 
 
 
 
 
 
 
 
 
Name of Infant 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Mother 
 
 
Signature of Mother 
  
 
Date 
(or Legal Guardian; print) 
 
(or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
 
(if applicable; print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Consent Process (print) 
 

SAP_006.pdf: 
 
IMPAACT 2008  
Primary Statistical Analysis Plan 
Version 2.0 
 
 
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, LOA#2) 
 
 
ClinicalTrials.gov Identifier: NCT03208231 
 
May 13, 2020 
 
This is IMPAACT 2008 SAP Version 2.0 with names of authors, names of publication writing team 
members and analysis timeline redacted 
 
 
 


IMPAACT 2008 Primary Statistical Analysis Plan 2.0 
 
      
                            May 13, 2020 
 
Page 1 of 8 
 
 
Table of Contents 
1 
Version History ....................................................................................................................................... 2 
2 
Introduction ............................................................................................................................................. 2 
2.1 
Purpose ......................................................................................................................................... 2 
2.2 
Version History .............................................................................................................................. 3 
3 
Study Overview....................................................................................................................................... 3 
3.1 
Study design .................................................................................................................................. 3 
3.2 
Hypotheses .................................................................................................................................... 3 
3.3 
Study objectives and outcome measures...................................................................................... 3 
3.4 
Study monitoring ............................................................................................................................ 4 
4 
Definitions ............................................................................................................................................... 4 
4.1 
Baseline ......................................................................................................................................... 4 
4.2 
Analysis populations ...................................................................................................................... 4 
5 
Statistical methods.................................................................................................................................. 5 
5.1 
General considerations.................................................................................................................. 5 
5.2 
Visit schedule and analysis windows ............................................................................................ 5 
5.3 
Analyses of outcomes measures .................................................................................................. 6 
5.3.1 
Primary safety outcome ..................................................................................................... 6 
5.3.2 
Primary efficacy outcome .................................................................................................. 7 
5.4 
Secondary VRC01 PK outcome .................................................................................................... 7 
6 
Report components ................................................................................................................................ 8 
 
 


 
Page 2 of 8 
 
1 
Version History 
 
Version  Changes Made 
Date Finalized 
1.0 
Original Version 
April 9, 2018 
1.0 
Original Version reviewed to ensure no changes necessary after LOA#1 
February 21, 2019 
2.0 
Responding to changes outlined in LOA#2 
• 
Added new sensitivity analyses to efficacy 
• 
Added wider windows to Week 24, 36 and 48 
• 
Clarified definition of baseline in VRC01 arm 
May 13, 2020 
 
2 
Introduction 
2.1 
Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcomes measures of 
IMPAACT 2008 that will be included in the primary manuscript, and which address the primary and 
secondary objectives of the study.  The Primary SAP outlines the general statistical approaches that will 
be used in the analysis.  It has been developed to facilitate discussion of the statistical analysis 
components among the study team, and to provide agreement between the study team and statisticians 
regarding the statistical analyses to be performed and presented in the primary statistical analysis report.  
It also describes the results for the primary and secondary outcome measures that will be posted on 
ClinicalTrials.gov.  Detailed outlines of tables, figures, and coding descriptions that will be included in the 
Primary Statistical Analysis Report are included in the Analysis Implementation Plan (AIP).  A separate 
Statistical Analysis Plan for Other Objectives and Outcome Measures will be developed once results for 
the Primary and Secondary Objectives are known, and analyses will be presented in a separate report.  
Data for the Primary Statistical Analysis Report will be downloaded once the last infant has completed the 
Week 16 study visit, required laboratory measurements are in the DMC database, all queries have been 
resolved, and the database frozen for analysis.   
The Primary Statistical Analysis Report will be used for submission of results to ClinicalTrials.gov. Results 
for primary outcomes are required to be submitted within one year of the primary completion date (PCD), 
which is the date the last participant is examined for the purposes of data collection for the primary 
outcome measure.  For this study, the PCD is based on 14 weeks of infant follow-up.  Results for 
secondary outcome measures are due one year after the last participant reaches Week 16. A second 
submission to ClinicalTrials.gov will be done once all follow-up is complete to update the adverse event 
tables.   


 
Page 3 of 8 
 
2.2 
Version History 
Version 2.0 of the SAP includes additional sensitivity analyses for the primary efficacy outcome measure.  
These were added as it became evident that some infants with good adherence were developing 
resistance to antiretrovirals and not on adequate therapy.  Therefore the ‘per-protocol’ primary analysis 
would not necessarily be capturing only infants on optimal ARV therapy.  This Version also clarified the 
definition of baseline and widened the acceptable study visits windows for Weeks 24, 36 and 48 (widened 
in response to disruptions at the site due to COVID-19).  
3 
Study Overview 
3.1 
Study design 
IMPAACT 2008 is a Phase I/II, multisite, two-arm, randomized, controlled, open-label study to evaluate 
the safety and antiviral activity of VRC01 administered within 12 weeks of birth to HIV-infected infants on 
ART.  Infants are stratified by whether their initial ART regimen includes an integrase inhibitor, and 
randomized with equal probability to receive (Arm 1) or not receive (Arm 2) VRC01.  VRC01 will be 
administered at study entry and Weeks 2, 6, and 10.  All infants must have initiated combination 
antiretroviral therapy (ART) within 14 days before study entry. Infants will be followed for 48 weeks.   
Infants’ mothers may optionally be enrolled in the study for one-time specimen collection at study entry for 
exploratory evaluations.   
This is a small study with limited ability to detect rare safety events.  With 34 infants in each Arm, there is 
a 29% chance of observing at least one adverse event with a true underlying rate of 1%, and a more than 
83% chance of seeing at least one adverse event with higher (>5%) underlying rates.  The study will have 
adequate power (>87%) to detect meaningful differences between the two Arms in changes in HIV-1 DNA 
of 1.0 log10 copies/ml.   
The planned enrollment was 68 infants.  In March 2020, due to the outbreak of COVID-19, accrual was 
closed prematurely with 61 infants enrolled.  The smaller enrollment may reduce power to detect 
differences between Arms for the primary efficacy outcome measure.   
3.2 
Hypotheses 
1. A regimen of four doses of VRC01 (40 mg/kg per dose) will be safe among HIV-1-infected infants 
initiating ART.  
2. HIV-1-infected infants who receive a regimen of four doses of VRC01 (40 mg/kg per dose) in 
addition to ART will experience a greater decrease in the concentration of HIV-1 DNA in PBMCs 
at four weeks after the final dose compared to infants who do not receive VRC01.  
3.3 
Study objectives and outcome measures 
This Primary SAP addresses the following primary and secondary objectives listed in the study protocol. 
Other study objectives in the protocol will be addressed in subsequent analysis plans.  


 
Page 4 of 8 
 
The primary objectives are to assess the: 
1. safety of VRC01 administered with ART (cumulatively through Week 14)  
Outcome measure: grade 3 or higher adverse events including reactogenicity outcomes, 
abnormal laboratory test results, signs, symptoms, and diagnoses occurring from randomization 
through Week 14.  Events resulting in death are grade 5. 
2. effect of VRC01 on HIV-1 DNA concentrations in PBMCs (change from Week 0 to Week 14) 
      Outcome measure: change in HIV-1 DNA concentration in PBMCs from Week 0 to Week 14. 
The secondary objective is:  
1. to assess the pharmacokinetics of VRC01 (through Week 16, Arm 1 only). 
Outcome measures: VRC01 trough concentrations at Weeks 2, 6, 10, 14 and 16 in Arm 1 
(VRC01). 
3.4 
Study monitoring 
Safety will be monitored in real time by the Clinical Management Committee (CMC) and at pre-defined 
time points by the IMPAACT Study Monitoring Committee (SMC) for early safety (when five infants in Arm 
1 have completed their Week 3 visit), pharmacokinetics (when six infants in Arm 1 have received their first 
two doses of VRC01 with PK results up to Week 6), antiviral activity (when half the infants have reached 
Week 14 (based on HIV-1 RNA rather than the primary outcome measure HIV-1 DNA, as the HIV-1 DNA 
data will be run in batch once the last infant reaches Week 16)), and at least yearly.  Ad hoc SMC reviews 
may be requested by the CMC if pre-defined safety criteria occur.   
This is a small Phase I/II study so will not use formal interim statistical stopping rules.  If initial declines in 
HIV-1 RNA are small enough to raise concern with the SMC, additional testing on viral susceptibility to 
VRC01 and antiretroviral concentrations will be obtained and reviewed to determine whether enrollment 
and vaccinations should continue. 
4 
Definitions 
4.1 
Baseline 
“Study entry” or “baseline” is defined as the randomization date.  The value used for baseline (Week 0) 
will be the last evaluation on or before the randomization date.  
4.2 
Analysis populations 
Any infants found to be ineligible and who the study team determines should not be included in any 
analyses will be included in screening, accrual and eligibility summaries only.   
Safety population: Safety analyses will be intent-to-treat and include all eligible infants randomized 
including all multiplets.  


 
Page 5 of 8 
 
Efficacy population: Primary efficacy analyses will use a per-protocol approach, limited to infants who do 
not interrupt ART for more than three consecutive days prior to the Week 14 visit and, if randomized to 
receive VRC01 (Arm 1), who receive at least the first scheduled dose of VRC01, and who have evaluable 
outcome measures at Weeks 0 and 14.  If more than one infant from the same pregnancy is enrolled, one 
infant will be randomly selected to be included in the primary efficacy analysis.    
5 
Statistical methods  
5.1 
General considerations 
Baseline characteristics will be summarized by arm, but there will be no statistical comparisons 
comparing arms because of the randomized study design.   
Statistical tests (all two-sided) will not be adjusted for interim monitoring, multiple comparisons or 
stratification by whether the initial ART regimen includes an integrase inhibitor.  Significance levels          
p-value < 0.05 will be highlighted in the text, but must be interpreted with caution, since there will be many 
statistical tests which will increase the chance of spuriously significant p-values.  Categorical data will be 
summarized using N (%), and continuous data using N, min, Q1, median, Q3, max, and mean (standard 
deviation (SD)) (when appropriate).  Any modifications to outcome measures after the team has seen 
data that were collected after entry will be identified as such in the analysis report. 
5.2 
Visit schedule and analysis windows 
The VRC01 administration and clinic visit schedules are summarized in Figure 1.   
Figure 1: VRC01 administration and clinic visit schedules 
 


 
Page 6 of 8 
 
VRC01 administration occurs at Weeks 0, 2 (±3 days), 6 (±7 days), and 10 (±7 days).  Additional clinic 
visits are scheduled at Weeks 1 (±3 days), 3 (±3 days), 7 (±3 days), 11 (±3 days), 14 (targeted to take 
place on Day 98, with a preferred window of ±7 to +14 days), 16 (targeted to take place on Day 112, with 
an allowable window of -7 to +14 days), 20 (±14 days), 24 (±14 days), 36 (±14 days), and 48 (±14 days) 
(days are relative to randomization date).  Three days after visits when VRC01 is administered, mothers 
(or caregivers) are contacted by study staff to report their infant’s reactogenicity assessments.  The 
allowable window for each three-day contact is -1 to +3 days. If Grade 1 or higher reactogenicity signs or 
symptoms are reported, mothers are instructed to return to the study clinic with their infants as soon as 
possible (within 48 hours) for further evaluation.   
Letter of Amendment #2 was issued April 22, 2020 in response to COVID-19.  To allow additional 
flexibility with the timing of study visits, the allowable windows for the Week 24 and 36 visits were 
broadened from ± 2 weeks to ± 6 weeks, and for the Week 48 visit from ± 2 weeks to -6 to +12 weeks.  
Visits conducted outside the allowable windows were preferred to completely missed visits.   
To ensure consistent exposure time across participants, post-entry analyses include all data collected up 
to and including 16 weeks post randomization (14 weeks plus the 14 days allowed for the Week 14 clinic 
visit to take place), so analyses may include data collected at the Week 16 clinic visit.  For the primary 
safety outcome measure, for example, all laboratory measurements collected, and signs, symptoms and 
diagnoses with onset dates up to 16 weeks post-randomization will be included.   
For summaries of data by clinic visit, analysis visit windows will be formed around each study visit using 
the midpoints between adjacent weeks as cutoffs, and potentially including assessments collected 
outside the recommended visit windows described above. If there are multiple evaluations within the 
window for a given visit and only one evaluation will be summarized, then the evaluation closest to the 
scheduled study week will be used, and the earlier measurement will be used if there are two 
measurements equidistant from the scheduled week.  
5.3 
Analyses of outcomes measures 
5.3.1 
Primary safety outcome 
This analysis will be conducted in the safety population defined in Section 4.2.  The number and 
proportion of infants experiencing at least one primary safety outcome measure will be summarized by 
Arm with exact 95% confidence intervals (CIs), both including and excluding the reactogenicity events 
which can only occur in Arm 1 (VRC01).  Differences in proportions between Arms in systemic safety 
outcomes only will be summarized with an exact 95% CI on the difference.  Proportions in Arm 1 will also 
be summarized only including events assessed by the CMC as related to VRC01 and by type of event 
(e.g., anemia/neutropenia and other).  The types of primary outcome measures will be summarized. 
Deaths and serious adverse events (SAEs) will be listed.  Reactogenicity events will be summarized in 
Arm 1 by maximum grade, maximum diameter and time to resolution.   


 
Page 7 of 8 
 
5.3.2 
Primary efficacy outcome 
This is an analysis in the per-protocol efficacy population defined in Section 4.2.  In the case of multiplets, 
one infant will be chosen at random for the primary analysis.   
Site staff will interview caregivers to determine if ART was not taken consistently.  It is likely that not all 
infants who did not take ART consistently will be identified through these interviews, and that some non-
adherent infants will be included in the primary analysis. 
HIV-1 DNA concentrations are measured at entry and Week 14.  Values will be log10-transformed.  For 
values below the assay detection limit, a value of one half the lower assay limit will be imputed.  For 
values above the detection limit, the upper limit of the assay will be imputed.  Summaries will include (i) 
the proportion of values below/above the assay limit at Week 0 and Week 14, (ii) log10 HIV-1 DNA at 
Week 0 and Week 14, and (iii) change from Week 0 to Week 14.  Changes will be compared by Arm 
using parametric/non-parametric tests as appropriate.  Similar summaries will be conducted using HIV-1 
RNA at all timepoints up to Week 14.   
Sensitivity analyses will repeat the efficacy summaries for HIV-1 DNA: 
i. 
in the event that multiplets are enrolled in the study, re-doing the analysis using the other sibling(s), 
ii. 
restricting the VRC01 Arm to those who received all four injections, 
iii. 
excluding infants who received suboptimal antiretroviral treatment, 
iv. 
excluding infants whose baseline virus is resistant to VRC01 neutralization, as identified at the time 
when HIV-1 DNA concentrations are determined, 
v. 
in the intent-to-treat population including all participants randomized to the study regardless of 
vaccine receipt and ART adherence,  
vi. 
using the last available time point before Week 14 if HIV-1 DNA concentration in PBMCs is missing at 
Week 14, and 
vii. 
with adequate ARV levels as determined by the team pharmacologist. 
How the treatment difference is modified by other covariates will be assessed using multivariable linear 
regression including main effects for treatment, each covariate, and their interaction.  A full list of 
covariates of interest will be identified by the team prior to analysis and may include entry age, site, ARV 
backbone (NVP or LPVr), time on ARVs, CD4% and HIV-1 RNA level, and number of VRC01 doses 
received.   
5.4 
Secondary VRC01 PK outcome 
VRC01 trough concentrations will be summarized using geometric means and 90% confidence intervals 
at Weeks 2, 6, 10, 14 and 16.   Values below the lower limits of the assay will be set to the lower limit.  
Summaries will be compared to those generated from other VRC01 studies (IMPAACT P1112).  Based 
on currently available data, Week 6 concentrations are predicted to fall within the range of 20-70 mcg/mL. 


 
Page 8 of 8 
 
6 
Report components 
Detailed descriptions of the content of each of the following sections are given in the AIP.   
1. Study entry 
a. Screening 
b. Enrollment 
c. Eligibility and stratification errors 
2. Baseline characteristics 
3. Protocol deviations 
4. Study status 
5. Study treatment (VRC01) status 
6. Changes/interruptions to antiretroviral regimen up to Week 14 
7. Adherence 
8. Childhood vaccinations up to Week 14 
9. Safety: 
a. Primary safety outcome 
b. Local injection site reactions (VRC01 Arm) 
c. Deaths 
d. Overall safety 
10. Primary efficacy outcome (HIV-1 DNA) 
a. Evaluability  
b. Primary efficacy outcome 
c. Sensitivity analyses 
11. CD4% at Week 14 and change from baseline 
12. HIV-1 RNA  up to Week 14  
13. VRC01 PK concentrations 

Prot_003.pdf: 
 
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.  
 
 

Prot_005.pdf: 
Clarification Memorandum #2 
Page 1 of 3 
01 April 2020 
IMPAACT 2008 Protocol Version 2.0 
Clarification Memorandum #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 ES # 20735 
IND # 133,017 Held By DAIDS 
 
Clarification Memorandum Date: 01 April 2020   
 
 
Summary of Clarifications 
 
This Clarification Memorandum (CM) is being issued to safeguard the health and well-being of 
IMPAACT 2008 study participants in the context of circulating severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease (COVID-19) pandemic.  
 
As the study Sponsor, the Division of AIDS (DAIDS) has determined that this CM should be 
implemented immediately upon issuance. Consistent with United States Food and Drug Administration 
guidance, institutional review board/ethics committee (IRB/EC) approval of this CM is not required by 
the Division of AIDS prior to implementation. However, given the context of the COVID-19 pandemic 
and the importance of the guidance provided in this CM, sites should submit this CM to IRBs/ECs for 
their information or, if required by the IRBs/ECs, for their review and approval.  
 
The purpose of this CM is to provide 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. 
 
Implementation of this CM 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 this CM is no longer applicable. When 
such a determination is made, study sites will be formally notified and instructed to inform their 
IRBs/ECs. 
 
Please file this CM and any applicable IRB/EC correspondence in your essential document files for 
IMPAACT 2008. 
 
 
 
 


Clarification Memorandum #2 
Page 2 of 3 
01 April 2020 
IMPAACT 2008 Protocol Version 2.0 
Implementation 
 
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 


Clarification Memorandum #2 
Page 3 of 3 
01 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.  

Prot_002.pdf: 
Letter of Amendment #1       
Page 1 of 12 
14 June 2018 
IMPAACT 2008 Protocol Version 2.0 
Letter of Amendment #1 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 ES # 20735 
IND # 133,017 Held By DAIDS 
 
Letter of Amendment Date: 14 June 2018 
 
 
 
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 ............................................................................................................................................. 3 
 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2008 study, 
including the study informed consent forms, 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, using site-specific informed consent forms 
corresponding to this LoA. For participants enrolled in the study before this LoA is approved, re-consent 
should be obtained using site-specific informed consent forms corresponding to 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, corresponding site-specific informed consent forms, all associated IRB/EC and 
regulatory entity correspondence, and all correspondence with the DAIDS PRO in your essential 
documents 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 #1       
Page 2 of 12 
14 June 2018 
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 #1 
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 #1       
Page 3 of 12 
14 June 2018 
IMPAACT 2008 Protocol Version 2.0 
Summary of Modifications and Rationale 
 
The purpose of this LoA is to: 
 
• 
Update the protocol team and study site rosters 
• 
Provide operational flexibility for conducting the Week 14 and Week 16 study visits, at which 
specimens are collected for primary antiviral activity analyses and secondary pharmacokinetics 
analyses, respectively 
• 
Update the protocol and sample informed consent forms consistent with International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) standards and current DAIDS requirements 
pertaining to review of study records 
• 
Correct internal inconsistencies and procedural inaccuracies in the protocol  
 
 
Implementation 
 
Modifications of protocol text are shown below, generally in order of appearance in the protocol. Where 
applicable, modified protocol text is shown using strikethrough for deletions and bold type for additions.  
 
1. The protocol team roster is updated to replace a Protocol Statistician and remove two Protocol Data 
Managers: 
 
Protocol Statisticians 
Konstantia (Nadia) Angelidou, MS  
Jane Lindsey, ScD 
Center for Biostatistics in AIDS Research 
Harvard TH Chan School of Public Health 
651 Huntington Avenue 
Boston, MA 02115 
Phone: (617) 432-2524 
Email: kangelid@sdac.harvard.edu 
Phone: (617) 432-2812 
Email: lindsey@sdac.harvard.edu 
 
Protocol Data Managers  
Amanda Golner, BS  
Frontier Science & Technology Research Foundation (FSTRF)  
4033 Maple Road  
Amherst, NY 14226-1056  
Phone: (716) 834-0900 x7382  
Email: golner@fstrf.org 
 
Jenna Kearly, MPH 
Frontier Science & Technology Research Foundation (FSTRF)  
4033 Maple Road  
Amherst, NY 14226-1056  
Phone: (716) 834-0900 x7249  
Email: kearly.jenna@fstrf.org 


Letter of Amendment #1       
Page 4 of 12 
14 June 2018 
IMPAACT 2008 Protocol Version 2.0 
2. The study site roster is updated to remove two sites and update contact details for three sites: 
 
Site 5011, Boston Medical Center 
Ellen Cooper, MD 
Boston Medical Center 
Division of Pediatric Infectious Diseases 
670 Albany St., Rm. 623 
Boston, MA 02118 
Phone: (671) 414-5588 
Email: ercooper@bu.edu 
 
Site 5030, Emory University School of Medicine  
Ann Chahroudi, MD, PhD  
Division of Pediatrics Infectious Diseases  
Emory University School of Medicine  
E472 HSRB  
1760 Haygood Dr.  
Atlanta, GA 30322-1119  
Phone: (404) 727-9209  
Email: achahro@emory.edu 
 
Site 5055, South Florida CDTC Ft. Lauderdale 
Ana M. Puga, MD, FAAP Lisa-Gaye Robinson, MD, MPH 
Children’s Diagnostic & Treatment Center, Inc. 
1401 South Federal Highway 
Fort Lauderdale, Florida 33316 
Phone: (954) 728-1017 (954) 728-1136 
Email: apuga@browardhealth.org lerobinson@browardhealth.org 
 
Site 30301, Johns Hopkins University Blantyre Clinical Research Site 
Luis Gadama, MBBS FCOG Macpherson Mallewa, MRCPCH, PhD, DTM&H 
College of Medicine-Johns Hopkins Research Project 
PO Box 1131 
Blantyre, Malawi 
Phone: +265 1 875 129 
Email: Lgadama@jhu.medcol.mw mmallewa@mlw.medcol.mw  
 
Site 31890, Harare Family Care  
Tapiwa Grace Mbengeranwa MBChB  
UZ-UCSF University of Zimbabwe College of Health Sciences – Clinical Trials Unit  
(UZCHS-CTU) 
15 Phillips Avenue  
Belgravia  
Harare, Zimbabwe  
Email: tgmbenge@uzcrc.co.zw 
 


Letter of Amendment #1       
Page 5 of 12 
14 June 2018 
IMPAACT 2008 Protocol Version 2.0 
3. Protocol Sections 6.2, 6.6, 6.9, 6.11, and 6.13 are updated to specify correct specimen types for HIV-
1-specific antibody-dependent cellular cytotoxicity (ADCC) and virus neutralization assays. ADCC 
assays will be performed with serum; neutralization assays will be performed with plasma; as such, 
bullet points in the infant Laboratory/Blood row of the procedural tables in these sections are 
corrected as follows:   
 
• Stored serum for ADCC neutralization assay 
 
The correct specimen types are also incorporated into the Schedule of Evaluations, as shown on the 
last five pages of this LoA, and into Section 6.17.1, as follows: 
 
In the event that blood collection must be limited, available specimens should be prioritized for use in 
the following order: (1) hematology, (2) chemistry, (3) HIV RNA, (4) CD4 and CD8 cell count 
and percentage, (5) stored PBMCs and plasma for primary evaluations, (6) stored serum for ADCC 
neutralizing assays, (7) stored plasma and PBMCs for exploratory evaluations. 
 
4. Protocol Sections 6.6 and 6.7 are updated to modify the allowable visit windows for the Week 14 and 
Week 16 Visits, as follows: 
 
Section 6.6 
The Week 14 Visit is targeted to take place on Day 98, counted from the date of randomization as 
Day 0, with an allowable a preferred window of ± 7 days and an allowable window of -7 to +14 
days. In addition to other routine study procedures, blood is collected and stored at this visit for 
primary antiviral activity evaluations. Therefore, 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. Please contact the CMC as soon as possible 
upon awareness of any visit that may not be conducted within the preferred window.    
 
Note: 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).  
 
There is no required sequencing of procedures at this visit. 
 
Week 14 Visit Procedures (Day 98 ± 7 days)  
(Day 98 ± 7 days preferred; Day 98 -7 to +14 days allowed) 
 
Section 6.7 
The Week 16 Visit is targeted to take place on Day 112, counted from the date of randomization as 
Day 0, with an allowable window of ± 7 -7 to +14 days. There is no required sequencing of 
procedures at this visit. 
 
Week 16 Visit Procedures (Day 112 ± 7 -7 to +14 days) 
 
These updates are also incorporated into the Schedule of Evaluations as shown on the last five pages 
of this LoA (Week 14 and Week 16 visit windows updated; footnote 9 added).  
 


Letter of Amendment #1       
Page 6 of 12 
14 June 2018 
IMPAACT 2008 Protocol Version 2.0 
5. Protocol Section 6.14 is updated to correct an internal inconsistency. For consistency with other sub-
sections within Section 6 and the Schedule of Evaluations, Section 6.14 is corrected as follows: 
 
ARV History  
Infant ARV history is collected at the Screening Visit and updated as needed at each scheduled visit 
the Entry Visit and at scheduled follow-up visits as indicated in Section 6 and the Schedule of 
Evaluations. [paragraph continues] 
 
6. In the protocol Table of Contents and Section 8.2, the section title is updated; also in Section 8.2, the 
fifth paragraph is corrected, as follows: 
8.2 
Deferral of Study Product Administration for Adverse Event and Toxicity Management and 
Resolution 
 
Fifth paragraph 
Following required consultation with the CMC, and improvement or resolution of the 
exclusionary condition (if applicable), study product may be administered. Whenever possible, 
infants should be re-scheduled to return to the clinic for product administration within the 
allowable visit window. If the allowable window elapses before adverse event and toxicity 
management requirements are met, the site investigator should consult with the CMC, which 
may approve product administration after the allowable window. 
 
7. Protocol Section 11.2 and the sample informed consent forms in Appendices II-V are updated to 
reflect ICH GCP E6 4.8.10(n) and current DAIDS requirements pertaining to review of study records, 
as follows: 
 
Section 11.2, fourth paragraph, first sentence 
All study records must be accessible for inspection, monitoring, and/or auditing during and after the 
conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, the VRC, the US Food and Drug Administration, site drug regulatory 
authorities, site IRBs/ECs, OHRP, and other applicable US, local, and international regulatory 
entities.  
 
Appendix II, item 22, and Appendix III, item 9 
Groups that oversee the study include:  
 
• 
[insert name of site IRBs/ECs] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site drug entities that may review records] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
The IMPAACT Network that is coordinating the study 
• 
Other US, local, and international regulatory entities 
 
 
 


Letter of Amendment #1       
Page 7 of 12 
14 June 2018 
IMPAACT 2008 Protocol Version 2.0 
Appendix IV, item 7, and Appendix V, item 7 
These groups include:  
 
• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
• 
Other US, local, and international regulatory entities 
 


 
Letter of Amendment #1       
Page 8 of 12 
14 June 2018 
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 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maternal Evaluations (for mothers of enrolled infants who consent to blood collection) 
 
 
 
 
 
 
 
Stored plasma and PBMCs 
for exploratory evaluations 
 
10 mL 
 
 
 
 
 
 
 
 
 
 
 
 
Stored serum for 
exploratory evaluations 
 
10 mL 
 
 
 
 
 
 
 
 
 
 
 
 
Infant Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-related testing history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medications history 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
ARV history 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Immunization history 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Feeding history 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
cART adherence assessment 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Physical examination 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
VRC01 administration1 
(Arm 1 only) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Reactogenicity assessment2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Confirmatory HIV nucleic 
acid test (if needed) 
0-3 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete blood count with 
differential and platelets 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
1 mL 
ALT, AST, ALP, creatinine 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
1 mL 
CD4 and CD8 cell count 
and percentage3 
1 mL 
 
 
 
 
 
 
 
 
 
 
 
 
1 mL 
HIV-1 RNA in plasma4 
(real time) 
 
1 mL4 
 
3 mL4 
 
 
 
3 mL4 
 
 
3 mL4 
 
 
3 mL4 
Urinalysis 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 


 
Letter of Amendment #1       
Page 9 of 12 
14 June 2018 
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 
Infant Evaluations (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored plasma and PBMCs 
for primary, secondary, and 
other evaluations 
 
3-5 mL5 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
5 mL 
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 #1       
Page 10 of 12 
14 June 2018 
IMPAACT 2008 Protocol Version 2.0 
 
Appendix I 
IMPAACT 2008 Schedule of Evaluations:  Week 16 through Week 48 
Study Visit 
Week  
169 
Week  
20 
Week  
24 
Week  
36 
Week  
48 
Early  
D/C7 
CSF 
Collection8 
Visit Window 
-7 to +14 d 
±14 d 
±14 d 
±14 d 
±14 d 
NA 
NA 
Informed consent 
 
 
 
 
 
 
 
 
Maternal Evaluations (for mothers of enrolled infants who consent to specimen collection) 
Stored plasma and PBMCs 
for exploratory evaluations 
 
 
 
 
 
 
 
Stored serum for 
exploratory evaluations 
 
 
 
 
 
 
 
Infant Evaluations 
 
 
 
 
 
 
 
HIV-related testing history 
 
 
 
 
 
 
 
Medical/medications history 
X 
X 
X 
X 
X 
X 
X8 
ARV history 
X 
X 
X 
X 
X 
X 
 
Immunization history 
X 
X 
X 
X 
X 
X 
 
Feeding history 
X 
X 
X 
X 
X 
X 
 
cART adherence assessment 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X 
X 
X 
X 
X 
 
VRC01 administration 
(Arm 1 only) 
 
 
 
 
 
 
 
Reactogenicity assessment 
 
 
 
 
 
 
 
Confirmatory HIV nucleic 
acid test (if needed) 
 
 
 
 
 
 
 
Complete blood count with 
differential and platelets 
 
1 mL 
1 mL 
0-1 mL3 
0-1 mL3 
1 mL7 
 
ALT, AST, ALP, creatinine 
 
1 mL 
1 mL 
 
 
 
 
CD4 and CD8 cell count 
and percentage3 
 
 
1 mL 
1 mL3 
1 mL3 
1 mL7 
 
HIV-1 RNA in plasma4 
(real time) 
3 mL4 
 
3 mL4 
3 mL4 
3 mL4 
3 mL4,7 
 
Urinalysis 
 
 
X 
 
 
[X]7 
 


 
Letter of Amendment #1       
Page 11 of 12 
14 June 2018 
IMPAACT 2008 Protocol Version 2.0 
 
Appendix I 
IMPAACT 2008 Schedule of Evaluations:  Week 16 through Week 48 
Study Visit 
Week  
169 
Week  
20 
Week  
24 
Week  
36 
Week  
48 
Early  
D/C7 
CSF 
Collection8 
Visit Window 
-7 to +14 d 
±14 d 
±14 d 
±14 d 
±14 d 
NA 
NA 
Infant Evaluations (continued) 
 
 
 
 
 
 
Stored plasma and PBMCs 
for primary, secondary, and 
other evaluations 
1 mL 
 
7 mL 
 
7 mL 
5-7 mL7 
 
VRC01 resistance 
(plasma) 
 
 
 
 
 
 
 
VRC01 level  
(plasma) 
X 
 
 
 
 
X 
 
Anti-VRC01 antibodies 
(plasma) 
 
 
X 
 
X 
X 
 
HIV-1 DNA  
(PBMC) 
 
 
X 
 
X 
X 
 
HIV-1 RNA (spliced/ 
unspliced; PBMC) 
 
 
X 
 
X 
X 
 
HIV-1 RNA (inducible; 
PBMC) 
 
 
X 
 
X 
 
 
Neutralization  
(plasma) 
 
 
X 
 
X 
X 
 
ARV levels  
(plasma, adherence) 
 
 
X 
 
X 
X 
 
Stored serum for  
ADCC 
 
 
1 mL 
 
1 mL 
1 mL7 
 
Stored plasma and PBMCs 
for exploratory evaluations6 
X6 
 
2 mL 
5 mL 
7 mL 
2 mL7 
2 mL8 
Cerebral spinal fluid storage 
for exploratory evaluations 
 
 
 
 
 
 
X8 
Total Infant Blood Volume 
4 mL 
2 mL 
16 mL 
9-10 mL 
19-20 mL 
13-15 mL 
2 mL 
 
 
 
 


 
Letter of Amendment #1       
Page 12 of 12 
14 June 2018 
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) 

Prot_004.pdf: 
Clarification Memorandum #1       
Page 1 of 2 
26 April 2018 
IMPAACT 2008 Protocol Version 2.0 
Clarification Memorandum # 1 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 ES # 20735 
IND # 133,017 Held By DAIDS 
 
Clarification Memorandum Date: 26 April 2018   
 
 
Summary of Clarifications and Rationale 
 
This Clarification Memorandum (CM) clarifies that the current version of the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events should be used to grade adverse events. In 
addition, this CM corrects a typographical error: “malnutrition” had inadvertently been retained in 
protocol Section 7.3.3 due to a cut-and-paste error; malnutrition is now removed from this listing.  
 
 
Implementation 
 
This CM has been approved by the NIAID and NICHD Medical Officers. Institutional Review 
Board/Ethics Committee (IRB/EC) approval of this CM is not required by the study sponsor prior to 
implementation. However, sites may submit this CM to the responsible IRBs/ECs for their information or, 
if required by the IRBs/ECs, for their approval prior to implementation. 
 
The content of the CM does not impact the sample informed consent forms for the study or the benefit-to-
risk ratio for study participants. This CM should be maintained in each site’s essential documents file for 
IMPAACT 2008. It is the responsibility of the Investigator of Record to ensure that all study staff are 
made aware of this CM. 
 
The modifications included in this CM are listed below in order of appearance in the protocol and will be 
incorporated into the next protocol amendment as specified below. Additions to the text are indicated in 
bold; deletions are indicated by strike-through.   
 
 


Clarification Memorandum #1       
Page 2 of 2 
26 April 2018 
IMPAACT 2008 Protocol Version 2.0 
1. Protocol Section 7.3.3 is updated to specify use of the current Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events and to correct a typographical error, as follows: 
 
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), 
Corrected Version 2.1, dated March July 2017, which is available on the RSC website:   
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 
The only exceptions to the above apply to grading of axillary measured fever, and injection site 
pain/tenderness, and malnutrition, which will be graded as follows […] [see protocol Section 7.3.3] 
 

Prot_001.pdf: 
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 
 
 
 
A Study of the International Maternal Pediatric Adolescent 
AIDS Clinical Trials Network 
 
 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases 
Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
National Institute of Mental Health 
 
 
Study Product Provided by: 
National Institute of Allergy and Infectious Diseases Vaccine Research Center 
 
 
DAIDS Study ID #20735 
IND # 133,017 
 
 
 
 
Protocol Chair: 
 
 
 
Elizabeth McFarland, MD 
 
 
 
 
NIAID Medical Officer:  
 
 
Mary Elizabeth Smith, MD 
 
NICHD Medical Officer:   
 
Rohan Hazra, MD 
 
Clinical Trials Specialists:  
 
Anne Coletti, MS 
 
 
 
 
 
 
 
Charlotte Perlowski, MSPH 
 
 
 
FINAL Version 2.0 
29 May 2017 


IMPAACT 2008, FINAL Version 2.0 
Page 1 of 131 
29 May 2017 
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 
 
TABLE OF CONTENTS 
 
PROTOCOL SIGNATURE PAGE .............................................................................................. 4 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 5 
PROTOCOL TEAM ROSTER .................................................................................................... 8 
SITE ROSTER ..........................................................................................................................11 
SCHEMA ..................................................................................................................................14 
1 
INTRODUCTION ...............................................................................................................16 
1.1 
Background ............................................................................................................................................ 16 
1.2 
VRC-HIVMAB060-00-AB (VRC01) ......................................................................................................... 20 
1.3 
Rationale ................................................................................................................................................ 30 
1.4 
Hypotheses ............................................................................................................................................. 35 
2 
OBJECTIVES ....................................................................................................................36 
2.1 
Primary Objectives ................................................................................................................................. 36 
2.2 
Secondary Objective .............................................................................................................................. 36 
2.3 
Other Objectives ..................................................................................................................................... 36 
2.4 
Exploratory Objectives ............................................................................................................................ 37 
3 
STUDY DESIGN ................................................................................................................37 
4 
STUDY POPULATION ......................................................................................................39 
4.1 
Infant Inclusion Criteria ........................................................................................................................... 39 
4.2 
Infant Exclusion Criteria .......................................................................................................................... 40 
4.3 
Maternal Inclusion Criteria ...................................................................................................................... 42 
4.4 
Co-Enrollment Considerations ................................................................................................................ 42 
4.5 
Recruitment, Screening, and Enrollment Process .................................................................................. 42 
4.6 
Participant Retention .............................................................................................................................. 43 
4.7 
Participant Withdrawal or Termination from the Study ............................................................................ 44 
5 
STUDY PRODUCT CONSIDERATIONS ...........................................................................44 
5.1 
Study Product Regimen .......................................................................................................................... 44 
5.2 
Study Product Formulation and Storage ................................................................................................. 45 
5.3 
Study Product Administration ................................................................................................................. 45 
5.4 
Study Product Supply ............................................................................................................................. 46 
5.5 
Study Product Accountability .................................................................................................................. 46 
5.6 
Final Disposition of Study Product .......................................................................................................... 46 
5.7 
Concomitant Medications ....................................................................................................................... 46 
5.8 
Prohibited and Precautionary Medications ............................................................................................. 48 
 
 


IMPAACT 2008, FINAL Version 2.0 
Page 2 of 131 
29 May 2017 
6 
STUDY VISITS AND PROCEDURES ................................................................................48 
6.1 
Screening Visits ...................................................................................................................................... 49 
6.2 
Entry Visit ............................................................................................................................................... 50 
6.3 
Week 1 Visit ............................................................................................................................................ 52 
6.4 
Week 2, Week 6, and Week 10 Visits ..................................................................................................... 52 
6.5 
Week 3, Week 7, and Week 11 Visits ..................................................................................................... 54 
6.6 
Week 14 Visit .......................................................................................................................................... 55 
6.7 
Week 16 Visit .......................................................................................................................................... 56 
6.8 
Week 20 Visit .......................................................................................................................................... 56 
6.9 
Week 24 Visit .......................................................................................................................................... 57 
6.10 
Week 36 Visit .......................................................................................................................................... 58 
6.11 
Week 48 Visit .......................................................................................................................................... 59 
6.12 
Residual Cerebral Spinal Fluid (CSF) Collection Visit ............................................................................ 60 
6.13 
Early Discontinuation Visit ...................................................................................................................... 61 
6.14 
Infant Histories ........................................................................................................................................ 62 
6.15 
Infant Physical Examinations .................................................................................................................. 63 
6.16 
Monitoring for Reactogenicity ................................................................................................................. 63 
6.17 
Additional Considerations for Laboratory Procedures ............................................................................ 64 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING ...........................................66 
7.1 
Safety-Related Roles and Responsibilities ............................................................................................. 66 
7.2 
Safety-Related Data Collection ............................................................................................................... 67 
7.3 
Expedited Adverse Event (EAE) Reporting ............................................................................................ 68 
8 
PARTICIPANT MANAGEMENT ........................................................................................70 
8.1 
Management of Adverse Events ............................................................................................................. 70 
8.2 
Deferral of Study Product Administration ................................................................................................ 76 
8.3 
Discontinuation of Study Product Administration .................................................................................... 76 
9 
STATISTICAL CONSIDERATIONS ...................................................................................77 
9.1 
General Design Issues ........................................................................................................................... 77 
9.2 
Outcome Measures ................................................................................................................................ 77 
9.3 
Randomization ........................................................................................................................................ 78 
9.4 
Sample Size and Accrual........................................................................................................................ 78 
9.5 
Monitoring ............................................................................................................................................... 83 
9.6 
Analyses ................................................................................................................................................. 88 
10 
CLINICAL PHARMACOLOGY PLAN ...............................................................................91 
10.1 
Pharmacology Objective ......................................................................................................................... 91 
10.2 
Pharmacology Data ................................................................................................................................ 91 
10.3 
Pharmacology Study Design, Modeling, and Data Analysis ................................................................... 91 
10.4 
Pharmacokinetic Analysis ....................................................................................................................... 92 
10.5 
Anticipated Outcomes ............................................................................................................................ 93 
11 
DATA HANDLING AND RECORD KEEPING ...................................................................94 
11.1 
Data Management Responsibilities ........................................................................................................ 94 
11.2 
Essential and Source Documents and Access to Source Data .............................................................. 94 
11.3 
Quality Control and Quality Assurance ................................................................................................... 95 
12 
CLINICAL SITE MONITORING .........................................................................................95 


IMPAACT 2008, FINAL Version 2.0 
Page 3 of 131 
29 May 2017 
13 
HUMAN SUBJECTS PROTECTIONS ..............................................................................95 
13.1 
IRB/EC Review and Approval ................................................................................................................. 95 
13.2 
Vulnerable Participants ........................................................................................................................... 95 
13.3 
Informed Consent ................................................................................................................................... 96 
13.4 
Potential Benefits .................................................................................................................................... 97 
13.5 
Potential Risks ........................................................................................................................................ 97 
13.6 
Reimbursement/Compensation .............................................................................................................. 98 
13.7 
Privacy and Confidentiality ..................................................................................................................... 98 
13.8 
Communicable Disease Reporting ......................................................................................................... 99 
13.9 
Management of Incidental Findings ........................................................................................................ 99 
13.10 Management of New Information Pertinent to Study Participation ......................................................... 99 
13.11 Post-Trial Access to Study Product ........................................................................................................ 99 
14 
ADMINISTRATIVE PROCEDURES ................................................................................ 100 
14.1 
Regulatory Oversight ............................................................................................................................ 100 
14.2 
Protocol Registration ............................................................................................................................ 100 
14.3 
Study Implementation ........................................................................................................................... 101 
14.4 
Protocol Deviation Reporting ................................................................................................................ 101 
14.5 
Critical Event Reporting ........................................................................................................................ 101 
14.6 
ClinicalTrials.gov .................................................................................................................................. 101 
15 
PUBLICATIONS ............................................................................................................. 101 
16 
REFERENCES ................................................................................................................ 102 
 
APPENDICES 
I 
IMPAACT 2008 Schedule of Evaluations .......................................................................................................... 105 
II 
Sample Informed Consent Form for Infant Study Participation ......................................................................... 110 
III 
Sample Informed Consent Form for Maternal Blood Collection and Testing .................................................... 121 
IV 
Sample Informed Consent Form for Specimen Storage and Future Use: Infants ............................................. 125 
V 
Sample Informed Consent Form for Specimen Storage and Future Use: Mothers ........................................... 129 
 
 


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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 
PROTOCOL 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) 
 
 


IMPAACT 2008, FINAL Version 2.0 
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29 May 2017 
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 
 
 
ABBREVIATIONS AND ACRONYMS 
 
ACTG A5342 
A Phase I Study to Evaluate the Safety, tolerability, and Effect of a Human 
Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01) on Markers of HIV 
Persistence in ART-treated, HIV-infected Adults 
ADCC 
Antibody-dependent cellular cytotoxicity 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ART 
Antiretroviral therapy 
ARV 
Antiretroviral  
AST 
Aspartate aminotransferase 
ATI 
Analytic treatment interruption 
bNAb 
Broadly neutralizing monoclonal antibodies 
cART 
Combination antiretroviral therapy 
CBC 
Complete blood count 
CDR 
Complementarity-determining regions 
CFR 
Code of Federal Regulations 
CHO 
Chinese hamster ovary 
CI 
Confidence interval 
CL 
Clearance 
CL/F 
Apparent clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CMC 
Clinical Management Committee 
CNS 
Central nervous system 
CRF 
Case report form 
CRPMC 
NIAID Clinical Research Products Management Center 
CRS 
Clinical research site 
CSF 
Cerebral spinal fluid 
CTLVI 
Cytotoxic T lymphocyte-mediated viral inhibition 
D/C 
Discontinuation 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS 
DAIDS PRO 
Division of AIDS Protocol Registration Office 
ddPCR 
Digital droplet polymerase chain reaction 
DMC 
Data Management Center 
DNA 
Deoxyribonucleic acid 
EAE 
Expedited Adverse Event 
EC 
Ethics committee 
eCRF 
Electronic case report form 
EMLA 
Eutectic Mixture of Local Anesthetics 
 
FDA 
Food and Drug Administration 


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FDAAA 
United States Food and Drug Administration Amendments Act of 2007 
FSTRF 
Frontier Science & Technology Research Foundation 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
HIV 
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HVTN 
HIV Vaccine Trials Network 
HVTN 104 
A Phase I Clinical Trial to Evaluate the Safety and Drug Levels of a Human 
Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01), Administered in 
Multiple Doses Intravenously and Subcutaneously in Different Dosing Schedules 
to Healthy, HIV-Uninfected Adults 
IB 
Investigator’s Brochure 
IBC 
Institutional Biosafety Committee 
ICF 
Informed consent form 
IgG1 
Immunoglobulin G1 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Group 
IMPAACT P1030 
A Phase I/II Study of Lopinavir/Ritonavir in HIV-1 Infected Infants <6 Months 
of Age 
IMPAACT P1112 
Open-Label, Dose-Escalating, Phase I Study to Determine Safety and 
Pharmacokinetic Parameters of Subcutaneous VRC01, a Potent Anti-HIV 
Neutralizing Monoclonal Antibody, in HIV-1 Exposed Infants 
IMPAACT P1115 
Very Early Intensive Treatment of HIV-Infected Infants to Achieve HIV 
Remission: A Phase I/II Proof of Concept Study 
IND 
Investigational New Drug 
IQA 
DAIDS Immunology Quality Assurance program 
IRB 
Institutional Review Board 
IUPM 
Infectious units per million cells 
IV 
Intravenous 
KA 
Absorption rate constant 
LDMS 
Laboratory Data Management System 
LPC 
Laboratory Processing Chart 
LPV/r 
Lopinavir/ritonavir 
mAb 
Monoclonal antibody 
MOP 
Manual of Procedures 
NAT 
Nucleic acid testing 
NHP 
Non-human primate 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
Eunice Kennedy Shriver National Institute of Child Health and Human 
Development 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NRTI 
Nucleoside/nucleotide reverse transcriptase inhibitor 
NVITAL 
NIAID Vaccine Immune T-Cell and Antibody Laboratory 
NVP 
Nevirapine 
OHRP 
Office for Human Research Protections 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase chain reaction 
PID 
Participant Identification Number 
 
PK 
Pharmacokinetics 
qPCR 
Real-time polymerase chain reaction 
QVOA 
Quantitative viral outgrowth assay 


IMPAACT 2008, FINAL Version 2.0 
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RNA 
Ribonucleic acid 
RSC 
Regulatory Support Center 
RV 398 
Safety and Virologic Effect of a Human Monoclonal Antibody,  
VRC-HIVMAB060-00-AB (VRC01), With Broad HIV-1 Neutralizing Activity, 
Administered Intravenously to Adults During Early Acute HIV Infection 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SCA 
Single copy assay 
SD 
Standard deviation 
SDMC 
Statistical and Data Management Center 
SES 
Subject Enrollment System 
SHIV 
Simian/human immunodeficiency virus 
SID 
Study Identification Number 
SMC 
Study Monitoring Committee 
SoE 
Schedule of Evaluations 
SOP 
Standard operating procedures 
SUSAR 
Suspected, unexpected, serious adverse reaction 
TB 
Tuberculosis 
TILDA 
Tat/rev induced limiting dilution assay 
US 
United States 
VQA 
DAIDS Virology Quality Assurance program 
VRC 
Vaccine Research Center 
VRC01 
VRC-HIVMAB060-00-AB, a recombinant human immunoglobulin G1 (IgG1) 
monoclonal antibody 
VRC 601 
A Phase I, Open-Label, Dose-Escalation Study of the Safety and 
Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB 
(VRC01), with Broad HIV-1 Neutralizing Activity, Administered Intravenously 
or Subcutaneously to HIV-Infected Adults 
VRC 602 
A Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of a Human 
Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01), Administered 
Intravenously or Subcutaneously to Healthy Adults 
WHO 
World Health Organization 
 
 


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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 
 
PROTOCOL TEAM ROSTER 
 
Please refer to the study-specific Manual of Procedures (MOP) for detailed guidance on 
managing study-related questions and other communications with the Protocol Team. 
 
Protocol Chair  
Elizabeth (Betsy) McFarland, MD  
Professor of Pediatrics 
University of Colorado School of Medicine 
Pediatric Infectious Diseases  
Children's Hospital Colorado  
13123 East 16th Avenue, B055  
Aurora, CO 80045  
Phone: (303) 724-3447  
Email: betsy.mcfarland@ucdenver.edu 
 
Protocol Co-Chair 
William Borkowsky, MD 
Professor, Department of Pediatrics 
Director, Division of Pediatric Infectious Diseases 
New York University 
550 First Avenue, Room 8W51 
New York, NY 10016 
Phone: (212) 263-6426 
Email: borkow01@gcrc.med.nyu.edu 
 
NIAID Medical Officer 
Mary Elizabeth (Betsy) Smith, MD  
DAIDS/NIAID/NIH 
Maternal, Adolescent and Pediatric Research 
Branch  
5601 Fishers Lane, Room 8B48 
Rockville, MD 20852 
Phone: (240) 292-4788  
Email: betsysmith@niaid.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 
 
Clinical Trials Specialists 
Anne Coletti, MS 
IMPAACT Operations Center 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 
Phone: (919) 544-7040 x11238 
Email: acoletti@fhi360.org 
 
Charlotte Perlowski, MSPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 
Phone: (919) 544-7040 x11480 
Email: cperlowski@fhi360.org 
 
Protocol Pharmacist 
Lynette Purdue, PharmD  
DAIDS/NIAID/NIH 
5601 Fishers Lane, Room 9E28 
Rockville, MD 20852  
Phone: (240) 627-3061  
Email: lpurdue@niaid.nih.gov 
 
Protocol Pharmacologist 
Edmund Capparelli, PharmD 
UCSD 
Pediatric Host-Microbe Systems and Therapeutics 
9500 Gilman Drive 0679  
San Diego, CA 92093-0657  
Phone: (858) 246-0009 
Email: ecapparelli@ucsd.edu 
 


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Protocol Statisticians 
Konstantia (Nadia) Angelidou, MS 
Center for Biostatistics in AIDS Research 
Harvard TH Chan School of Public Health  
651 Huntington Avenue  
Boston, MA 02115  
Phone: (617) 432-2524  
Email: kangelid@sdac.harvard.edu 
 
Camlin Tierney, PhD  
Center for Biostatistics in AIDS Research  
Harvard TH Chan School of Public Health  
651 Huntington Avenue  
Boston, MA 02115-6017  
Phone: (617) 432- 0547 
Email: tierney@sdac.harvard.edu 
 
Protocol Data Managers 
Amanda Golner, BS 
Frontier Science & Technology Research 
Foundation (FSTRF)  
4033 Maple Road  
Amherst, NY 14226-1056  
Phone: (716) 834-0900 x7382  
Email: golner@fstrf.org 
 
Jenna Kearly, MPH 
Frontier Science & Technology Research 
Foundation (FSTRF)  
4033 Maple Road  
Amherst, NY 14226-1056  
Phone: (716) 834-0900 x7249  
Email: kearly.jenna@fstrf.org 
 
Chelsea Krotje, MPH 
Protocol Data Manager 
Frontier Science & Technology Research 
Foundation (FSTRF)  
4033 Maple Road  
Amherst, NY 14226-1056 
Phone: 716-834-0900 x7368 
Email: krotje@fstrf.org 
 
Laboratory Data Manager 
Katelyn Hergott, MPH, MSW 
Frontier Science & Technology Research 
Foundation (FSTRF)  
4033 Maple Road  
Amherst, NY 14226-1056  
Phone: (716) 834-0900, x7212 
Email: hergott@fstrf.org 
 
Laboratory Specialist 
Diane Costello, BS 
University of California at Los Angeles 
MacDonald Research Laboratory 
675 Charles E Young Drive South,  
MRL 4-629 
Los Angeles, CA 90095 
Phone: (703) 862-0820 
Email: dcostello@impaactlabcenter.org 
 
Laboratory Technologist 
Paul Harding, MS  
Pediatric Infectious Disease  
University of Colorado Denver  
Mail Stop 8604 Building P15  
12700 E. 19th Ave Room # 11460-A  
Aurora, CO 80045  
Office: (303) 724-3404  
Lab: (303) 724-3407  
Email: paul.harding@ucdenver.edu 
 
Protocol Immunologist 
Sallie Permar, MD, PhD 
Duke Human Vaccine Institute 
Duke University Medical Center 
Box 103020 
Durham, NC 27710 
Phone: (919) 684-2515 
Email: sallie.permar@duke.edu 
 
Protocol Virologist 
Deborah Persaud, MD 
Johns Hopkins University  
Department of Pediatric Infectious Diseases  
720 Rutland Avenue  
Ross Building, Room 1170  
Baltimore, MD 21205  
Phone: (443) 287-3733  
Email: dpers@jhmi.edu 
 
Protocol Investigator 
Mark Cotton, MMed, FCPaed, DCH, DTM&H, 
PhD  
FAMCRU, Stellenbosch University  
Department Paediatrics and Child Health  
PO Box 241  
Cape Town, 8000 South Africa  
Phone: +27 21 938 4298 
Email: mcot@sun.ac.za 
 


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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 
 
IMPAACT Community Program Associate 
Jonathan Lucas, MPH 
IMPAACT Operations Center 
FHI 360 
359 Blackwell St., Suite 200 
Durham, NC 22701 
Phone: (919) 544-7040 x11458 
Email: jlucas@fhi360.org 
 
IMPAACT Community Advisory Board (ICAB) 
Representative 
Dichaba Siane 
Botswana-Harvard AIDS Institute Partnership 
Botswana CTU 
CRS 12701 & 12702 
Private Bag BO 320 
Gaborone, Botswana 
Phone: +267 738 70951 
Email: dichabasiane@gmail.com 
 
Westat Clinical Research Associate 
Kathryn Myers, BA 
Westat, Inc. 
1441 W. Montgomery Ave. 
Rockville, MD 20850 
Phone: (301) 610-8803 
Email: KathrynMyers@westat.com 
 
Vaccine Research Center Representatives 
Richard Koup 
Deputy Director 
Vaccine Research Center 
40 Convent Drive, Room 3502 
Bethesda, MD 20814 
Tel: (301) 594-8585 
Email: rkoup@mail.nih.gov 
 
Julie Ledgerwood 
Chief, Clinical Trials Program 
Vaccine Research Center 
10 Center Drive, Room 5-2436 
Bethesda, MD 20814 
Tel: (301) 594-8502 
Email: jumartin@niaid.nih.gov 
 
Lucio Gama, PhD 
Director for Scientific Collaborations 
Vaccine Research Center 
40 Convent Drive, Room 3504 
Bethesda, MD 20814 
Tel: (301) 761-7580 
Email: lucio.gama@nih.gov 
 
 
 


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SITE ROSTER 
 
Site 4601, University of California San Diego 
Stephen A. Spector, MD 
Mother-Child-Adolescent HIV Program 
University of California, San Diego 
La Jolla, CA 92093-0672 
Phone: (858) 534-7055 
Email: saspector@ucsd.edu 
 
Site 5011, Boston Medical Center 
Ellen Cooper, MD 
Boston Medical Center  
Division of Pediatric Infectious Diseases 
670 Albany St., Rm. 623 
Boston, MA 02118 
Phone: (671) 414-5588 
Email: ercooper@bu.edu 
 
Site 5030, Emory University School of Medicine 
Ann Chahroudi, MD, PhD 
Division of Pediatrics Infectious Diseases 
Emory University School of Medicine 
E472 HSRB 
1760 Haygood Dr. 
Atlanta, GA 30322-1119 
Phone: (404) 727-9209 
Email: achahro@emory.edu 
 
Site 5048, University of Southern California 
James Homans, MD, MPH 
Maternal Child and Adolescent/Adult Center 
for Infectious Diseases and Virology 
1640 Marengo Street, HRA 300, MC 9264 
Los Angeles, CA 90089-9033 
Phone: (323) 865-1585 
Email: homans@usc.edu 
 
Site 5052, University of Colorado Denver 
Elizabeth (Betsy) McFarland, MD  
University of Colorado School of Medicine 
Pediatric Infectious Diseases  
Children's Hospital Colorado  
13123 East 16th Avenue, B055  
Aurora, CO 80045  
Phone: (303) 724-3447  
Email: betsy.mcfarland@ucdenver.edu 
 
Site 5055, South Florida CDTC Ft. Lauderdale 
Ana M. Puga, MD, FAAP 
Children’s Diagnostic & Treatment Center, Inc. 
1401 South Federal Highway 
Fort Lauderdale, Florida 33316 
Phone: (954) 728-1017 
Email: apuga@browardhealth.org 
 
Site 5072, Hospital Federal dos Servidores do 
Estado 
Maria Leticia Santos Cruz, PhD 
Hospital Federal dos Servidores do Estado 
Rua Sacadura Cabral, 178, Anexo 4, 4 andar, Setor 
de Pesquisa do Serviço de Doenças Infecciosas e 
Parasitarias 
Saude, Rio De Janeiro, RJ, Brasil 
20221-903 
Phone: +55 21 22330018 
Email: mleticia@diphse.com.br 
 
Site 5092, Johns Hopkins University 
Allison Agwu, M.D, ScM, FAAP, FIDSA 
Johns Hopkins University School of Medicine 
200 North Wolfe Street, room 3145 
Baltimore, MD  21287 
Phone: (410) 614-3917 
Email: ageorg10@jhmi.edu 
 
Site 5097, Hospital Geral de Nova Iguaçu 
Ivete Martins Gomes 
953 Posse 
Nova Iguaçu, RJ, Brasil 
26030-350 
Phone: +55 21 26676059 
Email: ivetegomes63@gmail.com 
 
Site 5112, David Geffen School of Medicine at 
UCLA 
Jaime G. Deville, M.D 
David Geffen School of Medicine at UCLA 
Department of Pediatrics, Infectious Diseases 
10833 Le Conte Avenue, MDCC 22-442 
Los Angeles, CA 90095-1752 
Phone: (310) 825-9660 
Email: jdeville@mednet.ucla.edu 
 


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Site 8051, Shandukani Clinical Research Site 
Masebole Masenya, MBChB 
Shandukani Research  
2nd Floor, Wits RHI, Hillbrow Health Precinct 
Corner Esselen Street & Klein Street 
Hillbrow, 2001 
Johannesburg, South Africa 
Phone: +27 11 358 5500 ext 5923 
Email: mmasenya@wrhi.ac.za 
 
Mhleli Masango, MBChB 
Shandukani Research  
2nd Floor, Wits RHI, Hillbrow Health Precinct 
Corner Esselen Street & Klein Street 
Hillbrow, 2001 
Johannesburg, South Africa 
Phone: +27 11 358 5500 ext 5944  
Email: mmasango@wrhi.ac.za 
 
Site 8052, Perinatal HIV Research Unit Soweto 
Sylvia Dittmer, MBBCh  
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 
 
Site 8950, Family Clinical Research Unit (FAM-
CRU) Stellenbosch University 
Mark Cotton, MMed, FCPaed, DCH, DTM&H, 
PhD  
FAMCRU, Stellenbosch University  
Department Paediatrics and Child Health  
PO Box 241  
Cape Town, 8000 South Africa  
Phone: +27 21 938 4298 
Email: mcot@sun.ac.za 
 
Site 12001, University of North Carolina Lilongwe 
Clinical Research Site 
Portia Kamthunzi MBBS, MTropaed, DTCH 
UNC Project 
Private Bag A-104  
Lilongwe, Malawi 
Phone: +265 (0) 1 755 056 
Email: pkamthunzi@unclilongwe.org 
 
Site 12701, Gaborone Prevention/Treatment Trials 
Clinical Research Site 
Gaerolwe R. Masheto, MD, PGDipFamMed 
Botswana Harvard AIDS Institute Partnership 
Princess Marina Hospital Plot 1836 North Ring 
Road  
Gaborone, Botswana 
Phone: +267 3975999 
Email: gmasheto@bhp.org.bw 
 
Site 12702, Molepolole Prevention/Treatment 
Trials Clinical Research Site 
Gaerolwe R. Masheto, MD, PGDipFamMed 
Botswana Harvard AIDS Institute Partnership 
Princess Marina Hospital Plot 1836 North Ring 
Road  
Gaborone, Botswana 
Phone: +267 3975999 
Email: gmasheto@bhp.org.bw 
 
Site 30022, Les Centres GHESKIO 
Jean William Pape, MD 
Les Centres GHESKIO 
33, Blvd. Harry Truman 
Port-au-Prince, Haiti 
Phone: 011-509-2940-1431 
Email: jwpape@gheskio.org 
 
Site 30300, CAPRISA Umlazi 
Dr Moherndran Archary, MBChB, DCH, 
FCPaeds, Paeds ID 
1358 Mangosuthu Highway, Prince Mshiyeni 
Memorial Hospital, Philasande Clinic, Umlazi, 
KwaZulu-Natal, 4066 
South Africa 
Phone: +27-31-2604318 
Email: archary@ukzn.ac.za 
 
Site 30301, Johns Hopkins University Blantyre 
Clinical Research Site 
Luis Gadama, MBBS FCOG 
College of Medicine-Johns Hopkins Research 
Project 
PO Box 1131 
Blantyre, Malawi 
Phone: +265 1 875 129 
Email: Lgadama@jhu.medcol.mw 
 


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Site 31890, Harare Family Care 
Tapiwa Grace Mbengeranwa MBChB 
UZ-UCSF 
15 Phillips Avenue 
Belgravia 
Harare, Zimbabwe 
Email: tgmbenge@uzcrc.co.zw 
 
 
 


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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 
 
SCHEMA 
 
 
Purpose: 
 
 
To evaluate the safety and antiviral activity of VRC01 administered in 
addition to combination antiretroviral therapy (cART) to HIV-1-infected 
infants to promote clearance of HIV-1-infected cells.  
 
Design:  
 
 
Phase I/II, multisite, two-arm, randomized, controlled, open-label study. 
 
Study Population: 
 
HIV-1-infected infants initiating cART within 12 weeks of birth. 
Infants’ mothers may optionally be enrolled in the study for one-
time specimen collection for exploratory evaluations.  
 
Sample Size: 
 
 
68 infants 
 
Study Product:  
 
Infants will be randomly assigned in a 1:1 ratio to either receive VRC01 
(Arm 1) or not receive VRC01 (Arm 2).  Infants assigned to Arm 1 will be 
administered subcutaneous injections of VRC01 (40 mg/kg) at study Entry 
(Week 0) and at study Weeks 2, 6, and 10.  Infants assigned to Arm 2 will 
receive no study product. 
 
Study Duration:  
 
Approximately two years.  Accrual is expected to require approximately one 
year, and each infant will complete 48 weeks of follow-up. 
 
Primary Objectives: 
To assess the following among HIV-1-infected infants: 
• 
Safety of VRC01 administered with cART (cumulatively through Week 14)  
• 
Effect of VRC01 on HIV-1 DNA concentrations in peripheral blood mononuclear cells (change from 
Week 0 to Week 14)  
  
Secondary Objective: 
To assess the following among HIV-1-infected infants: 
• 
Pharmacokinetics of VRC01 (through Week 16) 
 
Other Objectives: 
To assess the following among HIV-1-infected infants: 
• 
Longer-term safety of VRC01 administered with cART (cumulatively through Week 48) 
• 
Development of anti-VRC01 antibodies (at Weeks 14, 24, and 48) 
• 
Effect of VRC01 on time to achieve plasma HIV-1 RNA below 40 copies/mL (through Week 48) 
• 
Effect of VRC01 on biomarkers of HIV persistence in peripheral blood mononuclear cells: 
– HIV-1 DNA concentration (at Weeks 24 and 48)  
– HIV-1 RNA concentration (multiply-spliced and unspliced; at Weeks 14, 24, and 48) 
– Total inducible HIV-1 RNA concentration (at Weeks 24 and 48) 
• 
Effect of VRC01 on HIV-1-specific antibody-dependent cellular cytotoxicity and virus neutralization 
against infant viral isolates (at Weeks 14, 24, and 48) 
 


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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 
 
 
Figure 1 
Overview of Study Design  
 
 
 
 
 


IMPAACT 2008, FINAL Version 2.0 
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1 
INTRODUCTION 
 
1.1 
Background  
 
1.1.1 
Global Impact of Pediatric HIV and Need for Interventions to Induce ARV-Free Remission 
 
There are an estimated 1.8 million children living with HIV-1 worldwide. In 2015, an estimated 
150,000 new perinatal cases occurred [1].  This is despite progress over the past two decades in 
identifying strategies to dramatically reduce in utero, peripartum, and breastfeeding HIV-1 
transmission.  With this pattern of ongoing HIV-1 transmission to infants, it is critical to continue 
to direct efforts towards identifying novel strategies for the treatment of HIV-1 infection in 
infants, who face a lifetime of antiretroviral therapy (ART) due to almost immediate 
establishment of HIV-1 reservoirs that re-establish viremia when treatment is stopped [2-4].   
 
Achieving low concentrations of HIV-1 infected cells on combination antiretroviral therapy 
(cART) is emerging as a biomarker that is predictive of time to rebound when cART is stopped 
[5].  Very early therapy, within 48 hours of life, may result in early restriction of the HIV-1 
reservoir [6], and this approach to HIV-1 treatment is currently under study in another IMPAACT 
protocol (P1115).  However, for many infants, HIV-1 infection is not identified until one to three 
months of age, even in settings with access to early infant diagnosis [7, 8].  In IMPAACT P1030, 
infants received cART initiated at two to three months of age, but this was not sufficient to block 
HIV-1 reservoir formation [9].  In addition, the time to achieving undetectable plasma viremia 
among early treated infants is prolonged, with many infants continuing to have detectable plasma 
virus beyond the first 24 weeks of therapy [10].  Early infant HIV-1 treatment is challenged by 
erratic drugs levels related to adherence lapses, somatic growth, or concurrent illnesses that affect 
drug intake, all common problems among young infants taking cART.  Therefore, novel 
treatments for infants that restrict HIV-1 reservoir establishment and have long acting antiviral 
activity are needed.  
 
Broadly neutralizing monoclonal antibodies (bNAbs) are an emerging class of HIV-1 therapeutics 
with direct antiviral properties, largely mediated through virus neutralization [11-13].  However, 
bNAbs may also facilitate viral clearance through antibody dependent cellular cytotoxicity 
(ADCC) [14], which promotes killing of HIV-1 infected cells [15].  Combining ART with bNAbs 
offers a novel approach to HIV-1 therapeutics for infected infants that will perhaps result in faster 
clearance of plasma viremia and HIV-1-infected cells, thereby lowering viral reservoir size.  This 
will be the focus of the clinical trial. It is hypothesized that concurrent administration of bNAbs 
with cART will hasten clearance of viremia and HIV-1 producing cells and lead to lower 
reservoir size. 
 
1.1.2 
Characteristics of Viral Reservoirs in Early Treated Infants  
 
Dynamics of HIV-1 DNA decay in early treated infants 
 
The dynamics of decay of HIV-1-infected cells was recently studied during the first two years of 
cART in perinatally-infected infants initiating cART at a median of two months of age in the 
IMPAACT P1030 study [9].  The IMPAACT P1030 study was a multicenter, Phase I/II, open-
label trial of lopinavir/ritonavir (LPV/r) for treatment of HIV-1-infected infants between 4 weeks 
and 6 months of age in which the pharmacokinetic properties of LPV/r were established [10, 16].  
Lopinavir/ritonavir (LPV/r)-based cART remains the mainstay of treatment for HIV-1-infected 
infants, for whom ARV drugs are extremely limited.  Prior to cART, the median concentration of 


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HIV-1-infected cells (measured by the concentration of cellular HIV-1 DNA, also known as 
proviral DNA) in peripheral blood mononuclear cells (PBMC) was 3.16 log10 [IQR:1.7, 3.0] HIV-
1 DNA copies/million PBMC.  By 24 weeks of cART, the concentration of cellular HIV-1 DNA 
decreased by approximately one log.  After two years of plasma virus suppression, proviral HIV-
1 DNA remained detectable in 100% of 12 infants at a median concentration of approximately 
1.99 log10 copies/million PBMCs.  Concentrations of 2-LTR circles (episomal HIV-1 DNA that is 
usually cited as a measure of ongoing virus replication) were also high at baseline (median 2.0 
log10 copies/ million PBMCs) and persisted at a median concentration of 1.0 log10 copies/million 
PBMC even after 96 weeks of cART. The primary correlate of infected cell concentration at 96 
weeks of cART was pre-cART infected cell concentrations.  Pre-cART infected cell 
concentrations were associated with time to suppression of plasma viremia, in support of the 
notion that infected cells generated before cART are the dominant virus producing cells during 
treatment.  
 
HIV-1 multiply-spliced (a marker of productively infected cells) and unspliced (a marker of 
transcriptionally active genomes) transcripts were detected in 100% and 93%, respectively, of the 
15 infants studied [9].  After two years of treatment, HIV-1 RNA transcripts (unspliced) were 
detectable in six of eight infants, although most were unspliced [9].   
 
Measures of the latent reservoir in early treated infants 
 
Persistent infection with replication competent HIV-1 latent in resting memory CD4+ T cells, the 
source of rebound viremia following cART cessation and precluding cure, was detected in 86% 
of the 14 infants in the P1030 trial who were tested at 24 weeks of treatment (approximately eight 
months of age). Thus, latent HIV-1 reservoir cells at concentrations readily detectable by the 
standard quantitative viral outgrowth assay (QVOA) are established even with cART started at a 
median age of two months [17].  As would be expected, HIV-1 DNA concentrations in PBMC 
(which measures both replication competent and defective virus) exceeded the frequency of 
resting CD4+ T cells bearing replication-competent virus (infectious units per million cells or 
IUPM) at all time points tested.  HIV-1 DNA concentrations and the IUPM in resting CD4+ T 
cells were correlated (but present at 66-fold excess) at 24 weeks of cART (ρ=0.66, p=0.028) but 
not at 48 and 96 weeks of cART, supporting depletion of replication-intact genomes over the time 
course of cART [9]. Therefore, at least through 24 weeks of cART, HIV-1 DNA concentrations 
provide a reasonable measure of persistence of the clinically relevant, replication-competent 
reservoir cells, although an overestimate by a median of 66-fold [9].   
 
Another more sensitive assay to detect inducible transcriptionally active HIV-1 genomes is the 
tat/rev inducible limiting dilution assay (TILDA). TILDA detects inducible HIV-1 genomes 
following T-cell stimulation in vitro. TILDA measures cells containing HIV-1 genomes that can 
be induced to produce multiply-spliced (msRNA). The unit of measurement is ms-RNA cells per 
million. TILDA estimates of the frequencies of infected cells persisting in HIV-infected adults on 
ART are 48-fold greater than the QVOA and 6-27 times lower than HIV-1 DNA, which also 
measures non-inducible proviral genomes. TILDA has not been studied in pediatric populations 
but will be used as a reservoir measure in this study. Preliminary studies show detection of 
inducible ms-transcripts in CD4+ T cells of ART-suppressed HIV-1- infected children 
(preliminary data; Persaud Laboratory). 
 
 
 


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Antiviral effects of bNAbs 
 
Non-human primate studies 
Several HIV-1-specific bNAbs, including VRC01 mAb — the antibody to be evaluated in this 
study — have been studied in mice [18], non-human primates (NHP) with recombinant simian 
immunodeficiency virus expressing HIV-1 envelope (SHIV) [15, 19, 20], and in HIV-1-infected 
humans [12, 13].  The NHP studies in chronically infected ART-naïve macaques demonstrated 
the antiviral effects of bNAbs with a rapid and steep decline in plasma SHIV RNA concentrations 
to undetectable viral load levels within four to seven days of treatment that was sustained for a 
median of 56 days after antibody infusion [15, 19].  In one study in NHP, bNAbs led to improved 
immune status as measured by increased cell-mediated viral inhibition (CTLVI), Gag-specific 
responses, cellular proliferation, and less end-stage T cell differentiation [15].  The bNAbs 
eliminate free virus through antibody-antigen complex-mediated clearance mechanisms, but those 
with an appropriate Fc, such as IgG1, will also engage particular Fc receptors that induce ADCC 
to eliminate infected cells [14].  The NHP studies found a decrease in SHIV DNA in PBMC and 
in lymph node and gut mucosa [15], supporting antiviral activity in tissues.  Recent studies in 
acute SHIV infection found that bNAbs combined with ART, when compared to ART only, 
delayed rebound after treatment interruption [21].  A study in acute SIV infection with a single 
infusion at 10 days after viral inoculation of VRC01 or a combination of two bNAbs (VRC07-
523 and PGT121) demonstrated plasma virus suppression and reduction of cell-associated virus 
in peripheral blood and lymph nodes, with preferential protection of naïve CD4+ T cells [20]. 
 
A recent study demonstrated prevention of long term reservoir formation and viral eradication 
with a combination of bNAbs given very early to infant macaques with acute SHIV-infection 
[22].  Newborn macaques were inoculated orally with an infectious dose of SHIVSF162P3 which 
resulted in virus disseminated to multiple tissue sites as determined by necropsy of a subset of 
animals at 24 hours.  However, the infant macaques that received a combination of two bNAbs 
(VRC07-523 and PGT121) started at 24 hours after inoculation were free of detectable virus in 
the blood as well as integrated virus in lymph nodes at week 12 and in tissues at 24 weeks.  
VRC07-523 is an engineered clonal relative of VRC01 with increased neutralization and 
improved potency against SHIVSF162P3. The bNAb PGT121 interacts with variable regions and 
glycans of HIV-1 gp120.  This study suggests that very early passive immunotherapy, but given 
after dissemination beyond the directly draining lymph nodes, restricted the establishment of viral 
reservoirs.  The same study found that VRC01 given in advance of oral SHIV inoculation was 
effective in preventing infection.  
 
Human trials 
Two bNAb, VRC01 and 3BNC117, were found to be safe and to reduce plasma viremia in HIV-
1-infected adults not receiving ART [12, 13].  In both studies, viremic adults receiving a single 
IV infusion of bNAb had significant decreases (1-2 log10) in plasma HIV RNA levels.  As plasma 
levels of the bNAb declined, or after selection of virus resistant to neutralization by the respective 
bNAb, the plasma virus increased.  However, the bNAb were given as a single dose and without 
other antiviral agents so ongoing suppression would not be expected. The study of VRC01 also 
administered the bNAb to virally suppressed, HIV-1-infected adults on cART [12].  Although no 
changes in markers of HIV-1 persistence were found, the participants received only two doses of 
bNAb, were already on long term suppressive cART, and had chronic latent viral reservoirs; 
therefore, the frequency of cells expressing HIV-1 antigens that would be targeted by bNAb is 
expected to be very low such that detectable changes in HIV-1 biomarkers of persistence might 
require prolonged treatment to be apparent. The viral dynamics during early treatment of early 
infection (i.e., the setting for this study), are different from the viral dynamics in the setting of 
chronic HIV-1 infection treated with cART [23].   


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The effect of VRC01 administration during analytic treatment interruption (ATI) has been 
investigated in two studies among adults with viral suppression achieved with cART started 
during chronic HIV-1 infection [24].  In one study (A5340), among 13 evaluable participants who 
underwent ATI, 38% remained suppressed at the week 4 visit, compared to 13% of historic 
controls (p = 0.04).  By week 8, only one of 13 (8%) maintained viral suppression compared to 
3% of historic controls (p = 0.44).  Similarly in the other study (I5-I-0140), the time to plasma 
viral rebound was longer than in historical controls.  Eighty percent of participants versus 13% of 
controls had viral suppression at week 4 (p < 0.001) and 10% and 3%, respectively, had viral 
suppression at week 8 (p = 0.37).  In these studies using VRC01 as monotherapy during ATI, 
there was emergence of VRC01-resistant virus, further evidence that the bNab had viral activity.  
These studies indicate that VRC01 given alone during ATI is not sufficient to maintain viral 
suppression.  In contrast to these studies, IMPAACT 2008 does not include ATI and is focused on 
the effects of VRC01 given in combination with cART on makers of HIV-1 persistence.  In 
addition, VRC01 will be administered during early cART, a period of active viremia, rather than 
during established treatment.   
 
Potential of monoclonal antibodies to reduce plasma viremia and viral reservoirs  
 
There are several potential mechanisms by which bNAbs may enhance cART to promote faster 
clearance of HIV-1-infected cells in perinatal infection [25]. At the time of initiation of cART, 
there is active viremia and viral replication.  The neutralizing activity of bNAb may augment 
cART to clear free infectious virus, thereby more rapidly controlling viremia.  A second 
mechanism may be elimination of infected cells through ADCC or through enhancement of other 
humoral immune responses stimulated by virus antibody complexes [20, 26].  Longer-lived cells 
contribute to plasma viremia during second-phase decay including tissue macrophages, partially 
activated CD4+ T cells, and recently re-activated, latently infected CD4+ T cells [23].  These 
virus-expressing cells serve as continued sources of virus production and can contribute to 
ongoing cycles of virus replication, if at any time point during treatment drug concentrations are 
compromised due to non-adherence, somatic growth, or concurrent illnesses that affect drug 
intake, all common problems among young infants taking cART.  Since bNAbs bind to free virus 
[27], administration of VRC01 during the second phase decay after initiation of cART may 
reduce ongoing virus replication and reservoir seeding [28].  Although viral escape to bNAbs, 
including VRC01, has been observed in trials using bNAbs as monotherapy for HIV-1 infected 
adults [12], this study uses VRC01 in combination with cART and thus resistance is much less 
likely.  
 
Importantly, among HIV-1-infected infants, founder viruses are generally neutralized by VRC01 
[29, 30], likely due to VRC01 binding to a highly conserved epitope (the CD4 binding site) [31]. 
In addition, a study of untreated HIV-1-infected Kenyan infants demonstrated that higher titers of 
transplacental maternal antibodies that mediate ADCC activity are associated with improved 
infant survival [32].  This study provides support that HIV-1-infected infant immune cells can use 
passively acquired antibodies to mediate ADCC, providing promise for potential benefit from 
VRC01, which may enhance ADCC.   
 
Infants with untreated perinatal HIV-1 are capable of generating neutralizing antibody later in 
infancy [33].  However, effective cART treatment begun during early infancy blunts the infant 
HIV-1 antibody response, and 50% or more of children effectively treated from infancy will lack 
long-lasting HIV-1-specific antibodies [34].  Therefore, it is expected that many early treated 
infants will have neither neutralizing antibody nor ADCC once maternal antibody wanes.  The 
lack of production of autologous anti-HIV-1 antibodies with early treatment of perinatal infection 
provides additional rationale for testing whether adding bNAb as an adjunct to cART will hasten 


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clearance of plasma virus and virus-producing cells and ultimately reduce residual HIV-1-
infected cells compared with cART alone. 
 
1.2 
VRC-HIVMAB060-00-AB (VRC01) 
 
VRC01 is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody produced in a 
Chinese Hamster Ovary (CHO) cell line that binds to the CD4 binding site of gp120.  The VRC01 
mAb was originally isolated from an adult infected with HIV-1 for more than 15 years who 
maintained viral control without cART [31].  Using novel methods to isolate and screen memory 
B lymphocytes from the peripheral blood mononuclear cells (PBMC) of HIV-1-infected donors, 
investigators at the Vaccine Research Center (VRC) were able identify this antibody clone. At a 
concentration of 50 mcg/mL, VRC01 was found to neutralize more than 90% of genetically 
diverse heterologous strains of HIV-1, and at a concentration of 1 µg/mL, more than 70% are 
neutralized [31].  Since the initial isolation and characterization of the VRC01 mAb, subsequent 
investigations on longitudinal serum samples show that VRC01-like epitopes are induced in a 
subset of HIV-1-infected individuals but take years to develop [35]. 
 
The structure of VRC01 complexed with the HIV-1 core glycoprotein (gp) 120 has been 
determined.  It is highly affinity-matured, has a disulfide link between complementarity-
determining regions (CDR) hypervariable loop 1 (H1) and hypervariable loop 3 (H3) and has a 
glycan in the variable (V) region of the light chain [36].  However, none of these features appears 
to affect its binding affinity or neutralization activity [36].  VRC01 does not have an unusually 
long CDR-H3 region like some other HIV-1 neutralizing antibodies.  It is not self- or poly-
reactive, lacks anti-phospholipid antibody activity (see Investigator’s Brochure (IB)), and it does 
not bind to human adult or fetal tissue.  These features suggest that mAb administration will not 
precipitate adverse immune phenomena. 
 
The VRC01 mAb has many characteristics that make it an outstanding bNAb for this study.  It 
has high potency with in vitro neutralizing activity at concentrations that are readily achievable in 
plasma [31]. The anti-viral breadth of VRC01 is greater than many other bNAb thus far 
discovered [31].  VRC01 is an IgG1, thereby allowing it to mediate ADCC, an activity which 
may be an important mechanism to eliminate infected cells [14, 37].  This bNAb is advancing 
rapidly in clinical development for prevention and treatment of HIV-1 infection, including in 
HIV-1-exposed infants (see Clinical Studies below).  Information from Preclinical and Clinical 
studies of VRC01 are summarized below; additional details are provided in the IB. 
 
1.2.1 
Preclinical Studies 
 
1.2.2 
Preclinical GLP Toxicology Study 
 
A repeat dose intravenous (IV) and subcutaneous (SC) toxicity study (SRI Study No. M896-11) 
was performed by SRI International (Menlo Park, CA) with VRC-HIVMAB060-00-AB (VRC01) 
in male and female Sprague-Dawley rats in accordance with US FDA “Good Laboratory Practice 
(GLP) for Nonclinical Laboratory Studies.”  This study was conducted with a pre-GMP pilot lot 
of VRC01 using a purification process similar to that of the GMP clinical-grade drug product.  
 
For the safety assessment, vehicle or 4 mg/kg, 40 mg/kg, or 400 mg/kg VRC01 was administered 
by tail vein injection on days 1 and 8 to Groups 1 through 4, respectively.  An additional group 
(Group 5) received 40 mg/kg VRC01 via SC administration to the dorsal scapular region on days 
1 and 8.  


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Results obtained showed that both IV and SC routes of administration were well tolerated in the 
rats.  All animals survived until their scheduled necropsy.  No findings or changes were seen in 
clinical observation, body weight, food consumption, body temperature, injection site irritation, 
hematology, coagulation, or organ weight evaluations that are attributed to administration of 
VRC01.  VRC01 administration resulted in small, transient, dose-dependent increases in aspartate 
aminotransferase (AST) and alkaline phosphatase (ALP) on day 9, one day after the second dose.  
The increase in AST was up to 1.5-fold when compared with prestudy levels; the increase in ALP 
was up to 2.3-fold.  By day 30, AST values had returned to normal, and ALP values were 
returning to normal.  The small and transient elevations in AST and ALP are of minimal 
toxicological significance because of the following: (1) the animals had recovered or were 
recovering by Day 30; (2) there were no corresponding histopathology findings in the organs 
typically associated with AST and/or ALP increases (liver, kidney, muscle, bone, or intestines); 
and (3) other biomarkers of liver or kidney damage such as alanine aminotransferase, creatinine, 
blood urea nitrogen, and electrolytes were not meaningfully affected after administration of 
VRC01. 
 
Other than erythema/red discoloration of the administration site in one male in the SC group on 
day 9, there were no other gross necropsy observations attributable to VRC01 administration.  
There were no histopathology findings considered related to IV administration of VRC01.  
However, histopathology evaluation revealed subacute inflammation at the SC injection site on 
day 9, one day after injection, in all 10 SC administered rats; dermal inflammation was usually 
minimal or mild while SC inflammation was usually mild, moderate, or marked.  By day 30, this 
inflammation had completely resolved, and the SC dose site was normal in all rats.  
 
This GLP repeat dose toxicology study, which included an IV dose 10 times higher than the 
intended dose in humans, supports both the IV and SC administration of VRC01 in human 
studies. 
 
1.2.3 
Tissue Cross-Reactivity GLP Study of VRC01 with Human Tissues in vitro 
 
A tissue cross-reactivity study of VRC01 using normal adult and neonatal human tissues in vitro 
(Testing Facility Study No. A255-12) was performed by Charles River Laboratories (Reno, NV) 
in accordance with US FDA “Good Laboratory Practice for Nonclinical Laboratory Studies” 
(GLP).  The tissue panels used as the test system for this in vitro cross-reactivity study included 
all of the tissues on the “Suggested list of human tissues to be used for immunohistochemical or 
cytochemical investigations of cross reactivity of monoclonal antibodies” in Annex I of the 
“European Medicines Agency Guideline on Development, Production, Characterization and 
Specifications for Monoclonal Antibodies and Related Product, Adopted by the Committee for 
Medicinal Products for Human Use on December 18, 2008” and all of the tissues recommended 
in the FDA/Center for Biologics Evaluation and Research “Points to Consider in the Manufacture 
and Testing of Monoclonal Antibody Products for Human Use (February 28, 1997).”  In addition, 
the tissue cross-reactivity study used additional neonate/infant tissues suggested by the FDA to 
support trials in infants.  
 
To determine the cross-reactivity of VRC01 binding, VRC01 was applied to cryosections from a 
full panel of tissues from normal human adults and a limited panel of human neonatal tissues, 
immunohistochemically detected using a biotinylated rabbit anti-human IgG secondary antibody, 
and binding was visualized with a streptavidin-horseradish peroxidase complex and a 
diaminobenzidine chromogen substrate.  VRC01 binding was evaluated at concentrations of 5 
and 50 mcg/mL.   
 


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Specific VRC01 staining was not observed in any normal adult human or neonatal human tissues 
evaluated.  Therefore, in vitro evaluation of cross-reactivity in tissue specimens did not identify 
potential tissue sites or organ systems to more thoroughly evaluate in subsequent preclinical 
studies, and it supports the future use of VRC01 in humans.  
 
1.2.4 
Nonhuman Primate Studies of VRC01 
 
Several non-GLP studies of VR01 have been completed in non-human primates (NHP) to assess 
for preclinical evidence of antiviral activity and potential efficacy in human HIV-1 infection.  A 
summary of these studies is provided in Table 1 below.  Additional details are provided in the IB. 
 
Table 1 
Preclinical Proof-of-Concept Studies Performed with VRC01 in NHP 
Study Purpose 
Study Outcome 
Pharmacokinetics 
Demonstration of plasma and secretion 
concentrations of VRC01 given by IV or 
SC routes in rhesus macaques 
Kinetics of decay of 40 mg/kg of VRC01 
given IV or SC in plasma, rectal, vaginal and 
nasal secretions established 
Effect on protection from viral challenge  
Demonstration of challenge-protection 
against intrarectal high-dose SHIV-SF162P3 
in male rhesus macaques 
100% protection from challenge 
demonstrated at 20 mg/kg dose administered 
IV 
Demonstration of challenge-protection 
against intravaginal high-dose SHIV-SF162P3 
in female rhesus macaques 
100% protection from challenge 
demonstrated at 20 mg/kg dose administered 
IV 
Demonstration of challenge-protection 
against intrarectal high-dose SHIV-BaL 
in male rhesus macaques 
100% protection from challenge 
demonstrated at 20, 5, and 1.25 mg/kg dose 
administered IV 
Demonstration of challenge-protection against 
oral inoculation of SHIV-SF162P3 in 
newborn rhesus macaques 
100% protection (2/2) from challenge at 20 
mg/kg subcutaneously and partial protection 
(4/5) at 5mg/kg.  
Effects on viremia after infection 
Demonstration of effect of VRC01 during 
the acute and chronic phases of SHIV 
SF162P3 infection in rhesus macaques 
The administration of VRC01 (40 mg/kg 
dose administered IV) during the acute phase 
of infection led to a reduction of peak 
viremia and control of viremia during the 
chronic phase of infection. 
 
1.2.5 
Clinical Studies 
 
Clinical evaluation of VRC01 in humans began in September 2013.  Since that time, clinical 
studies have been planned, initiated, and/or completed in the US and internationally to evaluate 
the product for preventive and therapeutic indications, in adult and pediatric populations (see 
Table 2).  As of 10 January 2017, VRC01 had been administered in doses ranging from 1 mg/kg 
to 40 mg/kg to more than 840 HIV-uninfected and HIV-infected adults and to 40 HIV-uninfected 
infants.  Further information pertaining to each study is provided below; across all studies, there 
have been no serious adverse events related to VRC01 that required expedited reporting to drug 
regulatory authorities and no study safety pauses for adverse events.   
 
  


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Table 2 
Completed and Planned Studies of VRC01 
Study 
Study  
Design 
Participant  
Population 
Dosage (mg/kg) route x numbers of administrations 
Target Accrual 
VRC01/placebo 
VRC 601 
(Completed, [12]) 
Phase I, open label,  
dose escalation of 
VRC01 
HIV-infected 
adults 
1 mg/kg IV x 2 doses 
5 mg/kg IV x 2 doses 
5 mg/kg SC x 2 doses 
20 mg/kg IV x 2 doses 
40 mg/kg IV x 2 doses 
23 
(up to 5 per dose group;  
11 in 40 mg/kg) 
VRC 602 
(Completed [38]) 
Phase I, open label,  
dose escalation of 
VRC01 
Healthy  
adults 
5 mg/kg IV x 2 doses 
5 mg/kg SC x 2 doses 
Placebo SC x 2 doses 
20 mg/kg IV x 2 doses 
40 mg/kg IV x 2 doses 
23/5 
(5 per dose group) 
VRC 606 
(Enrolling) 
Phase I, open label,  
dose escalation of 
VRC01 and VRC01LS 
Healthy  
adults  
aged 18-50 years 
Four dose escalation groups (Groups 1-4) to assess 
VRC01LS administered IV and SC once per participant 
Two groups (Groups 5 and 6) to assess VRC01LS at  
5 mg/kg SC or at 20 mg/kg IV administered every 12 
weeks for a total of three administrations per participant 
Two groups (Groups 7 and 8) to assess VRC01 at  
5 mg/kg SC or at 20 mg/kg IV administered every 4 
weeks for a total of two administrations per participant 
49/0 
IMPAACT P1112  
(Ongoing) 
Phase I, open label,  
dose escalation of 
VRC01 
Newborn infants  
of HIV-infected 
mothers 
Dose Group 1: 20 mg/kg SC x 1 dose 
Dose Group 2: 40 mg/kg SC x 1 dose 
Dose Group 3: 40 mg/kg SC at ≤ 5 days of life 
then, 20 mg/kg SC q 4 weeks for minimum of 24 weeks 
and no more than 72 weeks while breastfeeding (in 
addition to standard perinatal ARV prophylaxis for all 
arms) 
52/0 
(13 per dose group) 


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Table 2 
Completed and Planned Studies of VRC01 
Study 
Study  
Design 
Participant  
Population 
Dosage (mg/kg) route x numbers of administrations 
Target Accrual 
VRC01/placebo 
HVTN 104 
(Completed) 
Phase 1, multicenter 
randomized trial,  
Groups 1, 2, 4, and 5 are 
open-label VRC01 and 
Group 3 is double-blind, 
placebo controlled 
 
HIV-uninfected 
adults 
aged 18-50 years  
Group 1 (open-label): 40 mg/kg, IV at Month 0 then 20 
mg/kg IV at Month 1, 2, 3, 4, 5 
Group 2 (open-label): 40 mg/kg IV at month 0 then 40 
mg/kg IV at month 2, 4 
Group 3 (double-blind): 40 mg/kg IV at month 0 then 5 
mg/kg SC at month 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 
5.5 
Group 3 (placebo controlled) IV placebo at month 0 then 
SC placebo at month 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 
5.5  
Group 4 (open-label): 10 mg/kg IV at Month 0, 2, and 4 
Group 5 (open-label): 30 mg/kg IV at Month 0, 2, and 4 
Group 1: 20/0 
Group 2: 20/0 
Group 3 (double blind): 
20/0 
Group 3 (placebo 
controlled): 0/4 
Group 4: 12/0 
Group 5: 12/0  
HVTN 116 
(Open to accrual) 
Phase I, multicenter, 
randomized, open-label 
VRC01 and VRC01LS 
HIV-uninfected 
adults  
aged 18-50 years 
Group 1: VRC01 10 mg/kg IV at Month 0, Month 2, 
Month 4, and Month 6 
Group 2: VRC01 30 mg/kg IV at Month 0, Month 2, 
Month 4, and Month 6 
Group 3: VRC01LS 30 mg/kg IV Month 0, Month 3, 
and Month 6 
Group 4: VRC01 30 mg/kg IV at Month 0 
Group 5: VRC01LS 30 mg/kg IV at Month 0 
101/0 
HVTN 703/ 
HPTN 081 
(Ongoing) 
Phase 2b, multicenter 
randomized trial, 
double-blind, placebo 
controlled VRC01 
HIV-uninfected  
sub-Saharan 
African women 
aged  
18-40 years 
Group 1: 10 mg/kg IV at Weeks 0, 8, 16, 24, 32, 40, 48, 
56, 64, and 72 
Group 2: 30 mg/kg IV at Weeks 0, 8, 16, 24, 32, 40, 48, 
56, 64, and 72 
Group 3: IV placebo at Weeks 0, 8, 16, 24, 32, 40, 48, 
56, 64, and 72 
1000/500 
HVTN 704/ 
HPTN 085 
(Ongoing) 
Phase 2b, multicenter 
randomized trial, 
double-blind, placebo 
controlled VRC01 
HIV-uninfected 
men and 
transgender 
persons who have 
sex with men  
aged 18-50 years 
Group 1: 10 mg/kg IV at Weeks 0, 8, 16, 24, 32, 40, 48, 
56, 64, and 72 
Group 2: 30 mg/kg IV at Weeks 0, 8, 16, 24, 32, 40, 48, 
56, 64, and 72 
Group 3: IV placebo at Weeks 0, 8, 16, 24, 32, 40, 48, 
56, 64, and 72 
1800/900 


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Table 2 
Completed and Planned Studies of VRC01 
Study 
Study  
Design 
Participant  
Population 
Dosage (mg/kg) route x numbers of administrations 
Target Accrual 
VRC01/placebo 
A5342 
(Participants off study 
and primary analysis 
completed) 
Phase 1, multicenter 
randomized trial, 
double-blind, placebo 
controlled VRC01 
HIV-infected 
adults 
Arm A:  Two infusions of VRC01 (40 mg/kg) IV at 
weeks 0 and 3 and two infusions of placebo IV at weeks 
6 and 9 
Arm B: Two infusions of placebo IV at weeks 0 and 3 
and two infusions of VRC01 (40 mg/kg) IV at weeks 6 
and 9 
20/20 
A5340 
(Participants off study 
and primary analysis 
completed [24]) 
Phase 1, open label 
VRC01 
HIV-infected 
adults 
40 mg/kg IV x 3 doses; One each on days 0, 21, and 42. 
ATI during VRC01 treatment. 
15/0 
 
15-I-01040 
(Closed to 
accrual, [24]) 
Phase I/II, open label 
VRC01 
HIV-infected 
adults 
40 mg/kg IV x 3-8 doses, given on days -3, 14, 28, and 
monthly up to 6 months. ATI during VRC01 treatment. 
10/0 
RV397 
(Closed to accrual) 
Phase II single center 
randomized placebo 
controlled trial of 
VRC01 
HIV-infected 
adults, acutely 
treated  
Arm 1: 40 mg/kg/dose VRC01 IV at Weeks 0, 3, 6, 9, 
12, 15, 18, 21 and 24 
Arm 2: Placebo IV at the same time points 
ART interruption will occur at week 0 
Arm 1: 18 
Arm 2: 6 
RV398 
(Ongoing) 
Phase I multicenter 
randomized placebo 
controlled trial of 
VRC01 
HIV-infected 
adults with acute 
HIV infection 
Arm 1: Immediate ART and placebo infusion at Week 0 
Arm 2: Immediate ART and single infusion of 40 mg/kg 
VRC01 IV at Week 0 
Arm 3: Single infusion of 40 mg/kg VRC01 IV at Week 
0 and ART at Week 1 
24 (8 per arm) 
IMPAACT 2008 
(Pending) 
Phase I/II, multicenter 
randomized trial, open 
label VRC01 
HIV-infected 
infants aged  
up to 84 days 
Arm 1: 40 mg/kg/dose SC at Weeks 0, 2, 6, 10 with 
cART (provided outside the study) 
Arm 2: cART (provided outside the study) 
34/34 
 
 
 


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Completed studies include first-in-humans dose escalation studies for safety, tolerability, and PK 
of IV and SC routes in HIV-1-infected (VRC 601) [12] and HIV-1-uninfected (VRC 602) [38] 
adults as well as a study (HVTN 104) that evaluated serial dosing using several different IV or 
SC doses with different dosing schedules among HIV-uninfected adults [39].  Two Phase 2b 
studies are ongoing to evaluate the safety and efficacy of VRC01 in preventing HIV infection 
among adults (HVTN 703/HPTN 081 and HVTN 704/HPTN 085).  Also ongoing is a Phase I 
study (IMPAACT P1112) evaluating single and repeated doses of VRC01 to HIV-exposed infants 
for a prevention indication (i.e., for prevention of perinatal transmission) [40].   
 
Studies of VRC01 for therapeutic indications are also ongoing.  These include studies of the 
safety and virologic effects of VRC01 in acute HIV infection (RV398), in chronic infection 
(A5342) [41], and during ATU (RV397, A5340, 15-I-0140) [24].  Two of the studies (A5342,  
15-I-0140) include evaluation of the effects of VRC01 on markers of HIV persistence. 
 
1.2.6 
VRC 601 
 
VRC 601 (NCT01950325) is titled, “A Phase I, Open-Label, Dose-Escalation Study of the Safety 
and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01), 
with Broad HIV-1 Neutralizing Activity, Administered Intravenously or Subcutaneously to HIV-
Infected Adults.” 
 
VRC 601 was the first study of the VRC01 mAb in HIV-1-infected participants [12].  It was a 
dose-escalation study to examine safety, tolerability, dose, PK, and anti-antibody immune 
responses.  VRC 601 opened in September 2013 as a single-site study at the NIH Clinical Center, 
Bethesda, Maryland. Twenty-three evaluable HIV-1-infected participants, including 15 aviremic 
ARV-treated participants and eight viremic non-ARV treated participants received one or two 
doses of VRC01 IV or SC at doses ranging from 1 mg/kg to up to 40 mg/kg. The eight viremic 
patients received a single dose of study product IV and at 40 mg/kg.  The first infusion at 1 mg/kg 
IV was administered in the VRC 601 study on September 30, 2013.  Beginning on March 28, 
2014, the dose escalation proceeded according to the schema.  The first 40 mg/kg IV 
administration in this study occurred May 12, 2014, and the last infusion in VRC 601 occurred on 
April 6, 2015.  There were a total of 36 infusions in 23 participants.  All IV and/or SC infusions 
were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicity.  There were 
no moderate or severe local or systemic reactions.  One participant had mild tenderness at the 
injection site.  Systemic events reported in the three days post-infusion included headache (7), 
myalgia (6), malaise (4), nausea (4), joint pain (3), and fever (1); all were mild [12].   
 
VRC 601 demonstrated antiviral effect. A single 40 mg/kg IV dose led to a 1.1 to 1.8-log10 drop 
in plasma viral load in 6 of the 8 viremic participants not on ART [12].  Two viremic participants 
had only a marginal drop in plasma viral loads of 0.26 and 0.18 log10 copies/mL, respectively; 
however, these two individuals were found to have baseline virus that was relatively 
neutralization resistant.  Two adults, who had baseline plasma viremia <1000 copies/mL, had 
sustained suppression of viremia for over 20 days, until the plasma level of VRC01 decreased.  
The adults with higher baseline plasma viremia had evidence of outgrowth of escape variants in 
rebound viremia.  These data indicate that a single dose of VRC01 at 40 mg/kg IV given as 
monotherapy resulted in an average virus load significantly decreased between days 3 and 21 
after infusion compared to baseline, with the nadir at day 9.  A 0.5 log10 copies/mL or greater 
decrease in plasma viral load is considered a positive antiviral response to a single ARV drug.  
Among the ART-treated, virally suppressed adults, no change in proviral DNA load was observed 
after receiving two infusions of VRC01.  However, the study demonstrated a VRC01-mediated 
anti-viral effect, with preferential suppression of neutralization-sensitive strains. 


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1.2.7 
VRC 602 
 
VRC 602 (NCT01993706) is titled, “A Phase I Dose-Escalation Study of the Safety and 
Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01), 
Administered Intravenously or Subcutaneously to Healthy Adults.” 
 
VRC 602 was the first study of the VRC01 mAb in HIV-1-uninfected adults [38].  It was a dose-
escalation study to examine safety, tolerability, dose, and PK of VRC01.  VRC 602 opened in 
December 2013 as a single-site study at the NIH Clinical Center, Bethesda, Maryland, and the 
final infusion was administered in August 2014.  There were three open-label, dose-escalation 
groups receiving intravenous doses at Week 0 and Week 4 (5 mg/kg, 20 mg/kg, 40 mg/kg) and 
one double-blinded, placebo-controlled group for SC administration (5 mg/kg).  Cumulatively, 28 
participants received 43 doses of VRC01, including five participants who each received two SC 
5mg/kg doses.  As observed in VRC 601, the IV and/or SC infusions were well tolerated with no 
SAEs or dose-limiting toxicity [38].  There were only mild local reactions (5/23 participants) 
limited to redness and tenderness which were more common for the SC dose recipients.  
Similarly, only mild systemic reactions (nausea, headache, myalgia, malaise) were observed in a 
minority of participants.  Anti-VRC01 antibody responses were not detected, and the mAb 
retained its expected neutralizing activity in serum.   
  
1.2.8 
HVTN 104  
 
HVTN 104 (NCT0216526) is titled, “A Phase I Clinical Trial to Evaluate the Safety and Drug 
Levels of a Human Monoclonal Antibody, VRC-HIVMAB060-00-AB (VRC01), Administered in 
Multiple Doses Intravenously and Subcutaneously in Different Dosing Schedules to Healthy, 
HIV-Uninfected Adults.” 
 
HVTN 104 examined safety profiles and serum levels of five different regimens for IV and SC 
administration of VRC01 to 88 healthy, HIV-1-uninfected adults.  The study had five arms: 
Group 1 evaluated IV administration of a 40 mg/kg loading dose, with two subsequent 20 mg/kg 
doses given at eight-week intervals.  Groups 2, 4, and 5 evaluated three infusions of 40 mg/kg, 10 
mg/kg, or 30 mg/kg respectively given eight weeks apart.  Group 3 evaluated 5 mg/kg given SC 
every two weeks for 24 weeks.  The first participant was enrolled in September 2014 and follow-
up was completed in March 2016.   
 
A total of 249 IV infusions and 208 SC injections were administered during study, and were very 
well tolerated.  Most participants had either no local reaction or only mild (Grade 1) local 
reactogenicity from a particular infusion or injection.  For 76% of infusions or injections, 
participants reported no systemic reactogenicity symptoms. When present, most systemic 
symptoms were mild, with malaise/fatigue, myalgias, and headaches being most common. Of 
three participants who reported severe (Grade 3) systemic reactogenicity symptoms, two had 
concurrent viral infections, and one had malaise lasting one day. 
 
Adverse events attributed to study product administration on the basis of temporal relationship 
and other considerations have included AST, ALT and creatinine elevation, decreased neutrophil 
count, diarrhea, chest discomfort, herpes zoster, generalized rash, and pruritus at the 
administration site.  These laboratory changes and clinical events resolved and did not require 
discontinuation of study product administration. Adverse events attributed to study product 
administration (VRC01 or placebo) on the basis of temporal relationship for which the schedule 
of study product administration was discontinued included chest discomfort (in one placebo 


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recipient) and generalized rash in one participant (slightly raised and very itchy).  Symptoms 
developed three days after the second dose of study product and had resolved by the next day.    
 
1.2.9 
HVTN 703/HPTN 081 and HVTN 704/085  
 
HVTN 703/HPTN 081 and HVTN 704/085 (NCT02568215 and NCT02716675) are Evaluating 
the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection among 
women, and men and transgender persons who have sex with men.  In these Phase IIb studies, 
HIV-uninfected participants are randomly assigned to receive ten intravenous infusions of either 
10 mg/kg of VRC01, 30 mg/kg of VRC01, or placebo over a period of 72 weeks.  As of 2 January 
2017, 941 participants had been enrolled in these studies and approximately 2500 infusions had 
been administered.   
 
Infusions have generally been well tolerated to date.  As of 2 January 2017, no related SAEs have 
been reported and most study participants had no local or systemic reactogenicity symptoms from 
a particular infusion.  When present, local and systemic reactogenicity symptoms were of mild or 
moderate severity.  Infusion site pain and/or tenderness developed in 26% of participants.  
Infusion site erythema and/or induration developed in 9% of participants.  The most common 
systemic reactogenicity events were malaise (21%), headache (19%), headache followed by nausea 
(8%), and myalgia (7%).   
 
Six participants have experienced urticaria deemed related to the blinded study product (severe in 
one participant, mild to moderate in the other five participants).  Urticaria developed at the first 
infusion in five participants and at the fourth infusion in one participant.  Urticaria developed 
during the infusion in four of six participants (within approximately 10 to 40 minutes into the 
infusion) resulting in an incomplete administration of study product.  Urticaria developed after 
completion of the infusion in the other two participants (from 10 minutes up to two days after the 
infusion).  In all six participants, urticaria resolved the same day spontaneously or with 
antihistaminics.  One dose of IV steroids was administered to one participant with severe 
urticaria.  Study product administration (IV infusion of VRC01 or placebo) was discontinued in 
all six participants with urticaria. 
 
1.2.10 IMPAACT P1112  
 
IMPAACT P1112 (NCT02256631) is titled, “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.” 
  
P1112 is a Phase I trial enrolling at birth HIV-1-exposed infants at higher risk of transmission to 
determine the PK and safety of VRC01, given with standard-of-care ARV perinatal prophylaxis, 
as a potential modality to further reduce peripartum and postpartum breast milk HIV-1 
transmission.  There are three dose groups.  Dose Group 1 (n=13) received a single dose of 
VRC01 at 20 mg/kg SC.  Dose Group 2 (n=14) received a single dose of 40 mg/kg SC.  In Dose 
Group 3 (n=13), breastfed infants receive a first dose of 40 mg/kg SC followed by monthly doses 
of 20 mg/kg for at least 24 weeks and until cessation of breastfeeding (up until 72 weeks). 
VRC01 has been well tolerated at 20 mg/kg and 40 mg/kg SC [40].  As of 12 January 2017, there 
have been no related SAEs, no systemic reactions, and no urticarial reactions.  Local reactions 
(erythema, induration, or edema) have been common, occurring in six and 11 infants in the 20 
and 40 mg/kg dose groups, respectively, and in six infants in Dose Group 3 as of 17 January 


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2017. All local reactions were grade mild or moderate and all but one resolved within four hours 
of injection.      
 
1.2.11 Therapeutic Studies (ACTG 5340, I5-I-0140, RV 398, RV 397, ACTG 5342)    
 
There are five studies being conducted in HIV-1-infected adults, each designed to evaluate safety 
and anti-viral activity of VRC01 in different stages of HIV-1 infection (see Table 2).  As of 23 
March 2017, about 89 HIV-1-infected participants have received VRC01 in these studies.  
Cumulatively across all studies, there have been no SAEs related to VRC01 that required 
expedited reporting to the FDA or other regulatory authorities and no study safety pauses for 
adverse events.  The unsolicited adverse events in all studies have been mild or moderate in 
severity except for an unrelated, grade 3 neutropenia in 15-I-0140.  One participant in RV 397 
received an incomplete administration of study drug and permanent discontinuation of study drug 
secondary to an infusion reaction consisting of grade 2 urticaria and grade 1 pruritus and nausea.  
The nausea resolved without intervention, and the urticaria and pruritus resolved with IV 
chlorpheniramine and dexamethasone.   
 
1.2.12 Summary of Safety in Clinical Trials  
 
In summary, as of January 2017, over 800 HIV-1-uninfected and infected adults and 40 HIV-1-
exposed infants have received one or more VRC01 administrations, with the number of infusions 
exceeding 2500.  There have been no SAEs related to VRC01 that required expedited reporting to 
the FDA or other regulatory authorities and no study safety pauses for adverse events.  A non-
serious occurrence of severe (grade 3) urticaria was submitted to regulatory authorities as a safety 
report because urticaria, at grade 3 severity, was not reported in the prior IB (Version 6.0, dated 5 
October 2016).  There have been mild to moderate injection site reactions with subcutaneous 
infusion that have been transient and self-limited.  There have been rare episodes of urticaria 
associated with infusions.  When present, most systemic reactions (only in adults to date) after 
administration of VRC01 SC or IV have been mild and have included malaise, myalgia, 
headache, chills, nausea, and joint pain.     
 
1.2.13 Pharmacokinetics  
 
The PK results in HIV-infected and uninfected adults for VRC 601 and 602 have been published 
[12, 38] and are detailed in the IB. These results indicate that PK parameters are comparable in 
these two adult populations.  
 
At 28 days after second administration of 20 mg/kg and 40 mg/kg IV, mean VRC01 serum levels 
were 55.9±16.8 and 88.9±40.4 mcg/mL in uninfected adults, and were 46.0±26.7 and 64.9±56.7 
mcg/mL in HIV-infected adults, respectively.  The time to maximum concentration (Tmax) is 
about one to three hours after IV administration and about one to three days after SC 
administration.  For uninfected and infected participants, the terminal half-life was 15+3.9 and 
12+4.5 days for IV dosing and 17+2.9 and 11+5 days for SC dosing, respectively.  
 
Preliminary PK parameters determined in IMPAACT P1112 are available for HIV-exposed 
infants receiving single SC doses of VRC01 at 20 mg/kg/dose and 40 mg/kg/dose.  Mean (SD) 
day 28 levels were 39.3 (14.9) mcg/mL and 75.2 (21.4) mcg/mL for the 20 and 40 mg/kg doses, 
respectively.  For the 20 mg/kg dose group, the estimated serum half-life was 19.7 (5) days. Peak 
levels occurred at a median of two days and one day for the 20 and 40 mg/kg doses [40]. These 


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PK data for newborns in IMPAACT P1112 are consistent with the PK parameters observed in 
adults.  
 
1.3 
Rationale 
 
Perinatal HIV-1 infection offers a unique population to determine whether early combination 
therapy plus bNAbs can limit HIV-1 reservoirs.  It is hypothesized that, for HIV-1-infected 
infants, combining the bNAb VRC01, as a long-acting antiviral and potential immune effector 
agent, with cART will decrease HIV-1 reservoirs and significantly reduce levels of HIV-1-
infected cells in peripheral blood.  This is a patient population for which the timing f HIV 
acquisition is known and can be targeted.  These early treated infants will have blunted 
production of endogenous HIV-1-specific antibody [34]; therefore, passive immunotherapy may 
have great benefit.  Initiation of cART in early infancy reduces the frequency of HIV-1 latently 
infected cells with long-term virologic suppression [3]; adjunctive treatment with bNAbs, which 
may reduce plasma viremia and eliminate infected cells, may further impact on the size of the 
reservoir.  The time to suppression of plasma viremia after cART during infancy is prolonged for 
many infants, up to one year [10], and viral decay may be accelerated with the addition of bNAbs 
[20].  The bNAbs, with their long half-life and lack of requirement for daily adherence, may 
provide enhanced antiretroviral activity during periods of suboptimal cART levels, which are 
common among young infants.  Although viral resistance has been observed to arise rapidly when 
bNAbs are administered as partially suppressive mono-therapy during active viral replication [12, 
13], this study uses bNAb in combination with cART, likely avoiding induction of resistance.  
Moreover, administering bNAb with cART during early infection and during initial cART has 
potential to both neutralize the virus, thereby reducing the potential for ongoing low-level 
replication, and also potentially eliminate HIV-1-expressing cells through ADCC. 
   
1.3.1 
Rationale for Study Design and Population 
 
This is a Phase I/II, multisite, two-arm, randomized, controlled, open-label study to evaluate the 
safety and antiviral activity of VRC01 among 68 HIV-1-infected infants initiating cART within 
12 weeks of birth.  Enrolled infants will be randomly assigned in a 1:1 ratio to either receive 
VRC01 (Arm 1) or to not receive VRC01 (Arm 2).  Infants in both arms will continue to receive 
cART throughout their participation in the study.  The open-label study design was selected to 
avoid exposure to the discomfort and risk of a placebo injection for infants randomized to Arm 2.  
However, the study is designed such that evaluations are the same between arms, with the 
exception of assessment of for local reactions at site of VRC01 administration, which will occur 
only in Arm 1.    
 
Infants aged up to 12 weeks will be eligible for this study.  This young population is chosen as 
previous work has documented that effective, long-term treatment at this age is associated with 
lower levels of HIV-1 reservoirs compared to infants and children initiating treatment at older 
ages [3].  In addition, this is the age at which early cART may preclude the development of anti-
HIV-1 antibodies, making this a unique population for this study [34].   
 


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Infants must receive their first dose of VRC01 no more than 14 days after starting their first 
cART regimen.  The study goal is to evaluate the safety and effect of VRC01 on HIV-1 DNA 
concentrations at 14 weeks; other objectives also include effects on kinetics of viral decay during 
first and subsequent phases of plasma viral load decay.  Initiation of cART is recommended for 
infants as soon as possible after diagnosis of HIV-1 infection for its lifesaving effect [7].  
Depending on where the infant’s HIV-1 initial care is located, it may not be possible to 
orchestrate study entry and VRC01 dosing to coincide with the day of cART initiation.  
Therefore, the study will allow infants to receive the first dose of VRC01 within two weeks after 
cART initiation, since delaying cART could result in a potentially unsafe deviation from standard 
of care or present a significant barrier to study accrual.  Nevertheless, it is expected that infants 
receiving their first dose of VRC01 within two weeks of starting cART will still have high levels 
of plasma virus, given the high levels of plasma viremia that occur in perinatal infection.  
 
1.3.2 
Rationale for Dose Regimen 
 
The dosing regimen selected for this study is based on pharmacokinetic (PK) modeling using data 
from the VRC 601 and 602 studies in HIV-1-infected and uninfected adults and the IMPAACT 
P1112 study in HIV-exposed infants (Figures 2 and 3 in Section 10).  Subcutaneous dosing is 
planned, because this route will be feasible in larger trials and will avoid the potential for 
participants to miss doses due to inability to obtain intravenous access in the participating infants.  
Subcutaneous dosing also allows this study to build on the safety and PK data obtained from 
IMPAACT P1112, which is using a subcutaneous route.  
 
The regimen of 40 mg/kg dose at 0, 2, 6, and 10 weeks was selected for this study based on PK 
modeling using data from the VRC 601, VRC 602, and P1112 studies and the dose used in adult 
studies of VRC01 for antiviral activity.  The optimal plasma level of VRC01 required for anti-
viral activity is yet to be defined in human trials, although viremic adults with low baseline 
plasma virus concentration have sustained suppression until VRC01 plasma levels dropped to 10 
mcg/ml [12].  Likewise, the in vivo level of VRC01 to mediate ADCC activity is unknown.  
Therefore, targeted plasma levels for this study are selected based on the preclinical studies of 
VRC01 demonstrating that over 91% of viral isolates tested across clades are neutralized at an 
ID50 of 50 mcg/ml with more than 70% neutralized at 1 mcg/ml [31].  Notably, the geometric 
mean IC50 for HIV-1 strains from all clades tested is 0.33 mcg/mL.  The PK modeling based on 
adult studies of VRC01 indicates that using a subcutaneous dose of 40 mg/kg will achieve an 
initial mean peak of approximately 450 mcg/mL, greatly exceeding the 50 mcg/mL associated 
with broad neutralization for VRC01 in vitro.  In order to maintain levels above 50 mcg/ml 
during the initial weeks of treatment, a second dose will be given two weeks after the first dose.  
The third and fourth doses will be given at four-week intervals with the final dose at Week 10.  
This regimen is projected to maintain mean VRC01 levels above 50 mcg/ml through the first 16 
weeks after starting cART, covering the median time to undetectable plasma viremia for infants 
treated in P1030 [10, 16].  The 40 mg/kg dose has been administered to HIV-1-exposed newborns 
in IMPAACT P1112 and has been well tolerated to date; preliminary PK data suggest that the PK 
is similar to that observed in the adult studies [40].   
 


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1.3.3 
Rationale for Study Endpoints—Virologic 
 
Several biomarkers have been identified for quantifying HIV-1 persistence in infected persons; 
details of these measures, their advantages and limitations are summarized in Table 3. 
 
For this study, total HIV-1 cell-associated DNA will be used as the primary outcome measure to 
assess effects of VRC01 in combination with cART.  As shown in Table 3, each biomarker 
provides different information on the state of HIV-1 persistence and each has different 
limitations, with HIV-1 DNA being the most feasible and reliable biomarker to estimate the total 
burden of circulating HIV-1 infected cells using the small blood volumes in this study.  Detailed 
analyses have recently been performed on the various biomarkers using samples collected during 
standard lopinavir-based early cART in IMPAACT P1030 [9], and these data were used to 
calculate the sample size for this study.  In addition, HIV-1 DNA quantification has been 
performed on approximately 600 pediatric samples to date for studies of HIV-1 DNA dynamics 
during long-term cART in children, and wide differences have been observed in the 
concentrations of HIV-1-infected cells persisting in children on effective cART [3].  While this 
biomarker overestimates the number of clinically-relevant infected cells due to detection of both 
defective and replication-intact genomes, it is correlated with the number CD4+ resting T cells 
infected with latent replication competent HIV-1 [9] and should provide an overall estimate of 
clearance of infected cells during the first few months of cART.  
 
Planned analyses of cell-associated HIV-1 RNA and inducible HIV-1 RNA (TILDA) [44] will 
provide additional information on the transcriptional activity of the cells and the size of the 
inducible reservoir along with their potential for clearance by bNAbs [9].  While the TILDA 
provides a more sensitive marker of the clinically-relevant inducible reservoir compared with 
HIV-1 DNA load, larger blood volumes are required to obtain purified total CD4+ T cells for the 
assay.  Given that most study participants will be from sub-Saharan Africa, wide variation in the 
yield of viable cells following specimen storage and shipment is anticipated.  In some cases, 
insufficient cells will preclude measurement of the inducible reservoir.  The TILDA will therefore 
be used as an additional measure in this first proof-of-concept study.  
 
The study of two doses of VRC01 administered to six adults with chronic HIV-1 infection on 
established cART did not find significant decline in any of the biomarkers of HIV-1 persistence 
examined, including most of those listed in Table 3 [12]. However, this study will be evaluating 
the effect of VRC01 in a very different scenario—during early treatment of acute infection of 
infants who lack early autologous antibody production—and results from either acutely or 
chronically infected adults cannot be assumed to predict the effects of VRC01 for this infant 
population. 
 
 


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Table 3 
Biomarkers to Quantify HIV-1 Persistence in Peripheral Blood 
Biomarker 
(Units) 
Assay Measure 
Origin 
Assay 
Advantages 
Limitations 
DNA 
(copies/million cells) 
Total HIV-1 DNA 
Cell-associated 
ddPCR or 
qPCR 
Relatively Inexpensive 
and simple 
High throughput 
 Not a strict measure of HIV-
1 “reservoir” as most of the 
DNA species fail to integrate 
or harbor defective genomes 
Episomal DNA 
(2LTR) 
Cell-associated 
ddPCR; qPCR 
Conflicting data on the 
labile nature of 2LTR 
Conflicting data on the labile 
nature of 2LTR 
RNA 
(copies/ml) 
 
 
 
 
(copies/1000 ng 
cellular RNA) 
 
  
Residual viremia  
Plasma  
Single Copy 
Assay (SCA) 
Measure of ongoing virus 
producing cells 
Variability increases at low 
limit of detection; infectious 
nature unknown; requires 3-
4 mL plasma 
Unspliced mHIV-1 
RNA 
Cell-associated 
ddPCR; qPCR 
Measure transcriptionally 
active genomes 
May represent read-through 
transcripts 
Multiply spliced 
HIV-1 RNA  
Cell-associated 
qPCR 
Measure transcriptionally 
active genomes; ongoing 
replication, virus-specific 
transcripts 
Undetectable with effective 
cART 
Quantitative Viral 
Outgrowth Assay  
(Infectious Units per 
Million Cells-IUPM) 
Replication-
competent  
HIV-1-genomes 
Resting or total CD4+ 
T cells 
Co-culture 
Measure of clinical 
relevant, replication-
competent genomes 
Limited by blood volume 
Expensive and time-
consuming 
Total inducible HIV-1 
RNA concentration 
(TILDA; cells 
expressing multiply 
spliced RNA per 
million CD4+ T cells) 
 
Inducible 
HIV-1 genomes 
Total CD4+ T cells 
T cell 
stimulation 
Measure of inducible 
genomes 
No outgrowth for genetic 
characterization of the 
reservoir 
 


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1.3.4 
Rationale for Study Endpoints—Immunologic 
 
The study will evaluate the effect of VRC01 on anti-HIV-1 neutralization and ADCC activity in 
infant blood.  The responses will be evaluated against autologous virus isolated from the baseline 
sample and a panel of infant founder viruses.  Assessment of these responses will be a key to 
understanding the mechanism of anti-viral effects of VRC01 and is therefore included as another 
study objective.  Plasma neutralization responses and ADCC activity against a multiclade panel 
of viruses will be measured and correlated to the viral kinetics.  Assessment of autologous 
neutralizing activity after VRC01 is no longer circulating will be also be of interest since 
administration of passive anti-SHIV antibody to SHIV-infected infant macaques resulted in 
improved production of endogenous neutralizing antibody [45].  
 
In VRC 601, two of eight (25%) of individuals harbored HIV-1 that is relatively resistant to 
VRC01 [12].  Although this proportion is higher than expected based on the activity of VRC01 
against panels of tier 2 virus, this study plans for an analysis that will exclude infants determined 
to have baseline virus with VRC01 neutralization resistance.  Infants will not be screened for 
VRC01 neutralization in advance of entry, which would delay initiation of treatment, but the 
sensitivity of the infant’s baseline virus to VRC01 will be determined after trial completion.  
Antibodies against VRC01 have not been detected to date in the studies of VRC01 in adults and 
are not expected, since the antibody is fully humanized.  However, the study will test to 
determine if anti-VRC01 Ab arise.   
 
1.3.5 
Rationale for Cerebral Spinal Fluid Collection 
 
The central nervous system (CNS) is likely an important anatomic HIV-1 reservoir [46]; thus, it 
would be desirable to assess the concentration of bNAbs in cerebral spinal fluid (CSF) in infants, 
as well as evaluating the effect on viral persistence in the CNS.  There are no human data at 
present on the levels of VRC01 in CSF, but the levels in adults would be expected to be low 
based on studies of other IgG1 antibodies used for immunotherapeutics [47].  In young infants, 
the blood brain barrier may be more permeable [48], which may present an opportunity for higher 
concentrations of mAbs to be present in CSF.  This study includes provisions to store any residual 
CSF left over after clinical testing is complete from participants who have a lumbar puncture for 
clinical care.  These “opportunistic samples” will be analyzed for the concentration of VRC01, as 
well as HIV-1 nucleic acid and inflammatory biomarkers.  If this study demonstrates an effect on 
viral reservoir in the peripheral circulation, subsequent clinical trials may be justified to include 
research-specific procedures to evaluate CNS and tissue reservoirs such as gut or lymphoid tissue. 
 
1.3.6 
Rationale for Other Specimen Collection for Exploratory Evaluations — Infant 
 
It will be important to understand the mechanism and covariates for the effect of VRC01 on 
viremia and latent virus.   This will require additional assays to be conducted. Since there will 
be limited specimens and since the precise effects of VRC01 on viral persistence are yet 
unknown, the specific exploratory objectives to be tested will be determined after the study is 
complete.  However, specimens will be obtained and stored pending the completion of the 
study for these tests.  Examples of the objectives may include additional assessments of the 
viral reservoir, inflammation, and immune activation.  Assays to determine the frequency of 
replication competent virus may be performed if sufficient cells are available.  This measure of 
infectious virus persistence is obtained by the quantitative viral outgrowth assay which detects 
only persistent replication-competent genomes. Knowing the frequency at which HIV-1 
replication-competent reservoirs persists in perinatal infection following standard cART versus 


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when combined with VRC01 will provide important information on the long-term effects of 
this novel treatment strategy.  Markers of immune activation and inflammation may serve as 
markers of viral persistence so these may be examined.  HIV-1-specific immune responses 
may be evaluated to assess for enhancement of responses to VRC01 as observed in NHP 
models [15].  The impact of VRC01 on HIV-1 envelope sequence evolution in participants 
with persistent viremia may be evaluated to determine if there is viral escape from the 
passively administered antibody [12]. The effect of endogenous VRC01-like antibodies at 
baseline (as a result of transplacental transfer) on the impact of VRC01 on markers of HIV-1 
persistence might be evaluated since this may impact the pharmacokinetics and therefore 
clinical effect. In addition to the above, exploratory evaluations may include genetic testing 
(e.g., for different alleles for Fc function, IgG1 alleles, or HLA).  A correlation of 
polymorphisms in CCR5 (or other markers of HIV disease outcomes) and Fc receptors (or 
other markers of immune function) with VRC01 activity may be of interest since these genetic 
variables could have a strong impact on the antibody-mediated viral clearance.   
 
1.3.7 
Rationale for Specimen Collection for Exploratory Evaluations — Maternal  
 
There are no published data on interactions between autologous maternal HIV-1-specific 
antibodies and the clinical or virologic impact of bNAbs.  It is therefore valuable to archive 
maternal samples to assess these interactions, and for detailed characterization of maternal and 
infant transmission events and virus evolution in the context of bNAbs, with respect to selection 
of transmitted variants or de novo escape under monoclonal antibody pressure, if this outcome is 
observed in the study. 
 
1.3.8 
Summary 
 
This study will evaluate whether the bNAb VRC01 given as an adjunct to cART, with the first 
dose administered within two weeks of the start of cART, to HIV-1-infected infants aged up to 12 
weeks, will lead to lower infected cell concentrations at four weeks after receipt of four doses of 
VRC01.  The study will also examine the effects at 24 and 48 weeks.  As another study objective, 
the extent to which plasma viremia and transcriptionally active cells are diminished compared to 
cART-only treated infants will be examined. A study of bNAb in early therapy of an infant 
population is distinct from studies of acute HIV infection in adults because this infant population 
is expected to have limited autologous production of HIV-1-specific antibodies.  
 
1.4 
Hypotheses 
 
• 
A regimen of four doses of VRC01 (40 mg/kg per dose) will be safe among HIV-1-infected 
infants initiating cART.  
 
• 
HIV-1-infected infants who receive a regimen of four doses of VRC01 (40 mg/kg per dose) 
in addition to cART will experience a greater decrease in the concentration of HIV-1 DNA in 
PBMCs at four weeks after the final dose compared to infants who do not receive VRC01.  
 
 


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2 
OBJECTIVES 
 
 
 
2.1 
Primary Objectives 
 
 
The primary objectives of this study are to assess the following among HIV-1-infected infants: 
 
2.1.1 
Safety of VRC01 administered with cART (cumulatively through Week 14)  
 
2.1.2 
Effect of VRC01 on HIV-1 DNA concentrations in PBMCs (change from Week 0 to 
Week 14)  
  
2.2 
Secondary Objective 
 
A secondary objective of this study, which will be evaluated approximately concurrently with the 
primary objectives, is to assess the following among HIV-1-infected infants: 
 
2.2.1 
Pharmacokinetics of VRC01 (through Week 16) 
 
2.3 
Other Objectives 
 
Other objectives of this study are to assess the following among HIV-1-infected infants: 
 
2.3.1 
Longer-term safety of VRC01 administered with cART (cumulatively through Week 48) 
 
2.3.2 
Development of anti-VRC01 antibodies (at Weeks 14, 24, and 48) 
 
2.3.3 
Effect of VRC01 on time to achieve plasma HIV-1 RNA below 40 copies/mL (through 
Week 48) 
 
2.3.4 
Effect of VRC01 on biomarkers of HIV persistence in PBMCs: 
 
– HIV-1 DNA concentration (at Weeks 24 and 48)  
– HIV-1 RNA concentrations (multiply-spliced and unspliced; at Weeks 14, 24, and 
48) 
– Total inducible HIV-1 RNA concentration (at Weeks 24 and 48) 
 
2.3.5 
Effect of VRC01 on HIV-1-specific ADCC and virus neutralization against infant viral 
isolates (at Weeks 14, 24, and 48). 
 


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2.4 
Exploratory Objectives 
 
Biological specimens will be collected over the course of this study for exploratory investigations 
related to the virologic and immunologic mechanisms of action of VRC01.  The specific 
investigations undertaken will be guided by the primary, secondary, and other outcomes of the 
study and may include additional assessments of the viral reservoir, inflammation, and immune 
activation; ARV concentrations may also be explored if considered important for the 
interpretation of primary, secondary, and other outcomes.  HIV-1-specific immune responses may 
be evaluated to assess for enhancement of responses to VRC01 as observed in NHP models.  
VRC01 concentrations and markers of viral persistence may be evaluated in CSF if samples are 
available following lumbar puncture for clinical care.  Human genotyping for alleles associated 
with HIV disease outcomes or immune function may be performed to explore associations with 
differences in the effect of VRC01.  
 
For illustrative purposes, a listing of potential exploratory objectives is provided in Table 4. This 
listing will be further refined and prioritized by the Protocol Team after the primary, secondary, 
and other outcomes are assessed and before any exploratory evaluations are undertaken.  
 
Table 4 
Potential Exploratory Objectives for IMPAACT 2008 
To explore the following among HIV-1-infected infants: 
• 
Impact of VRC01 on the following biomarkers:  
– Titer of replication competent virus in PBMCs 
– Soluble markers of inflammation and monocyte activation  
– Activation and differentiation of peripheral CD4 and CD8 T lymphocytes (e.g., memory 
phenotype, CD38, HLA-DR, PD-1) 
– Change from baseline and persistence of episomal HIV-1 DNA as measured by 2-LTR circles  
• 
Impact of VRC01 on cell-mediated viral inhibition, CD4 T-cell proliferation, cell-mediated 
cytotoxicity 
• 
Impact of VRC01 on HIV-1 envelope sequence evolution in participants with persistent viremia 
• 
Effect of endogenous VRC01-like antibodies at baseline (maternal) on the impact of VRC01 on 
markers of HIV-1 persistence 
• 
Concentrations of VRC01 and markers of HIV-1 persistence in CSF 
• 
Correlation of polymorphisms in CCR5 (or other markers of HIV disease outcomes) and Fc 
receptors (or other markers of immune function) with VRC01 activity 
 
 
3 
STUDY DESIGN 
 
This is a Phase I/II, multisite, two-arm, randomized, controlled, open-label study to evaluate the 
safety and antiviral activity of VRC01 among HIV-1-infected infants initiating cART within 12 
weeks of birth.  Refer to Figure 1 for an overview of the study design and Section 4 for details 
regarding the study population.  A total of 68 infants are expected to be enrolled at study sites 
located in Botswana, Brazil, Haiti, Malawi, South Africa, Zimbabwe, and the US. 
 
Infants enrolled in this study may have acquired HIV-1 infection in utero or peripartum or 
postpartum; they may be breastfed or formula fed prior to and after enrolling in the study.  They 
may have received ARVs for prophylaxis or treatment prior to study entry, consistent with the 
eligibility criteria in Sections 4.1 and 4.2.   
 


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Enrolled infants will be randomly assigned in a 1:1 ratio to either receive VRC01 (Arm 1) or to 
not receive VRC01 (Arm 2).  Infants in both arms will continue to receive cART throughout their 
participation in the study.  Each infant’s cART regimen will be selected by his or her primary 
care provider and supplied through non-study sources (i.e., cART will not be provided through 
the study).  Infants assigned to receive VRC01 will be administered 40 mg/kg at study Entry 
(Week 0) and at study Weeks 2, 6, and 10 by subcutaneous injection.  To maximize the potential 
activity of VRC01 within the first phase of viral decay following cART initiation, the first dose of 
VRC01 will ideally be administered on the day of cART initiation; however, cART may be 
initiated up to 14 days prior to study entry and first dose of VRC01.  To minimize discomfort and 
potential risks, infants assigned to Arm 2 will not receive placebo injections; therefore, random 
assignments will not be blinded. 
 
Enrolled infants will be followed for 48 weeks, with safety, pharmacokinetic, and antiviral 
activity evaluations performed throughout the duration of follow-up as specified in Appendix I.   
 
An interim analysis of safety will be conducted when the first five infants in Arm 1 have 
completed their Week 3 visits; refer to Section 9.5.1 for a description of this analysis.   The 
primary safety outcome will be assessed among all infants through Week 14, i.e., four weeks after 
the last dose of VRC01 for infants in Arm 1, through collection of medical history information, 
physical examinations, reactogenicity assessments, and laboratory testing.  This outcome will also 
be assessed throughout the duration of follow-up, i.e., through Week 48.   
 
The primary antiviral activity outcome — change in concentration of HIV-1 DNA in PBMCs — 
will be assessed at Week 14.  The sample size of 34 infants per arm was selected to provide at 
least 20 infants per arm who are considered evaluable for analysis of this outcome.  To be 
considered evaluable, infants in both arms must not interrupt cART for more than three 
consecutive days prior to the Week 14 visit; infants in Arm 1 also must receive at least the first 
scheduled dose of VRC01.  This analysis is expected to be performed once all enrolled infants 
have reached Week 14 of follow-up. 
 
Change in concentration of HIV-1 DNA in PBMCs will also be assessed at Weeks 24 and 48; 
other analyses will also include infants who are not considered evaluable per the strict criteria 
described above.  Other outcomes, including additional markers of viral persistence, will likewise 
be assessed at Weeks 14, 24, and 48.  Specimens required for these evaluations will be collected 
and stored for batched testing.  Plasma HIV-1 RNA levels will also be assessed as a study 
outcome; these assays will be performed in real-time to inform participant management as well as 
the interim analysis of antiviral activity described below.  Refer to Section 9.6 for a description of 
the statistical analyses planned to evaluate primary, secondary, and other outcomes.  
 
As described in Section 1.3.2, the regimen of VRC01 administered in this study is expected to 
maintain targeted concentrations of VRC01.  To confirm that targeted concentrations are being 
achieved, 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 available samples collected for evaluation of VRC01 concentrations will be analyzed.  
Currently available data suggest that dose adjustment will not be necessary to achieve targeted 
concentrations; therefore, the study will not be paused pending the results of the interim analysis.  
Nonetheless, a dose adjustment may be considered if indicated based on the findings of the 
interim PK analysis.  
 


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An interim analysis of antiviral activity will also be performed.  As described in greater detail in 
Section 9.5.2, when approximately half of the targeted number of infants have reached Week 14, 
the Study Monitoring Committee (SMC) will review HIV-1 RNA levels and other relevant data 
and provide recommendations on any action to be taken with respect to ongoing study conduct.   
 
In addition to the evaluations and analyses described above, biological specimens will be 
collected and stored for exploratory investigations of the virologic and immunologic mechanisms 
of action of VRC01.  Infant blood will be collected for this purpose, as will blood from 
consenting mothers.  For any infant who undergoes lumbar puncture for clinical care during 
follow-up, residual samples of CSF will be obtained and stored for this purpose, if possible.  The 
specific evaluations to be performed with these specimens, and whether to test all specimens 
versus those of relevant subsets of participants, will be determined based on the primary, 
secondary, and other outcomes of the study and on state-of-the art assays available at the time.   
 
Note:  Mothers who consent to specimen collection for study purposes will be enrolled in the 
study but then discontinued from follow-up immediately upon completion of specimen collection. 
 
     
4 
STUDY POPULATION 
 
This study will be conducted among 68 HIV-1-infected infants initiating cART within 12 weeks 
of birth.  Infants will be selected for study participation according to the criteria in Sections 4.1 
and 4.2; infants’ mothers will be selected for specimen collection and storage according to the 
criteria in Section 4.3.  The study-specific approach to recruitment, screening, and enrollment is 
described in Section 4.5.  Considerations related to participant retention and withdrawal/ 
termination from the study are provided in Sections 4.6 and 4.7, respectively. 
 
4.1 
Infant Inclusion Criteria 
 
All of the criteria listed below must be met in order for infants to be included in this study.   
 
4.1.1 
Parent or legal guardian is willing and able to provide written informed consent for infant 
participation in the study, including collection and storage of biological specimens for 
exploratory virology and immunology investigations.  
 
4.1.2 
Infant is within 12 weeks (84 days) of birth at study entry. 
 
4.1.3 
Infant weighs at least 2500 g at study entry. 
 
4.1.4 
Infant has confirmed HIV-1 infection based on positive results from two samples (whole 
blood or plasma) collected at different time points using the following methods: 
 
• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One total HIV nucleic acid test 
 


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At least one of the two samples must be tested in a CLIA-certified (US sites) or VQA-
certified (non-US sites) laboratory.  For tests performed in other (non-certified) settings, 
adequate source documentation including the date of specimen collection, date of testing, 
test performed, and test result must be available. 
 
4.1.5 
Infant has the following laboratory values at screening (with samples collected for testing 
within 30 days prior to entry): 
 
• 
CD4 lymphocyte percentage greater than 15 
• 
Severity grade 1 or lower hemoglobin, platelet count, and absolute neutrophil count  
• 
Severity grade 1 or lower ALT, AST, and alkaline phosphatase 
 
See Section 7.3 for guidance on severity grading. 
 
4.1.6 
Infant’s initial cART regimen has been selected and documented at study entry, prior to 
randomization, with the first dose taken on the day of randomization or within 14 days 
prior to the day of randomization.  
 
4.1.7 
Infant is expected to be available for 48 weeks of follow-up at study entry. 
 
4.1.8 
Parent or legal guardian is willing and able to complete reactogenicity memory aids for 
study purposes, based on parent/guardian report. 
 
4.2 
Infant Exclusion Criteria 
 
Infants must be excluded from the study if any of the following are identified at any time prior to 
randomization:  
 
4.2.1 
Infant or infant’s mother received exclusionary active or passive HIV-specific 
immunotherapy, as follows: 
 
• 
Infant received any active or passive HIV-specific immunotherapy prior to study 
entry. 
• 
Infant’s mother received any active HIV-specific immunotherapy prior to infant 
study entry. 
• 
Infant’s mother received any passive HIV-specific immunotherapy within two years 
prior to infant study entry. 
• 
If infant’s mother is breastfeeding:  mother is planned to receive any active or passive 
HIV-specific immunotherapy at any time during infant study participation.  
 


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4.2.2 
Infant initiated a combination of three or more ARVs, all at or above recommended 
treatment doses, within 48 hours of birth. Recommended treatment doses are as follows: 
 
NRTIs 
As per WHO or US Department of Health and Human 
Services pediatric treatment guidelines 
NVP 
At least 8 mg for infants weighing up to 2 kg, at least 12 
mg for infants weighing more than 2 kg 
LPV/r 
300 mg/75 mg per m2 of body surface area twice daily 
 
All other ARVs 
Consult with IMPAACT 2008 Clinical Management 
Committee (CMC) 
 
Note:  Regimens comprised of fewer than three ARVs, or of three ARVs with at least one 
ARV below the recommended treatment dose, are permitted, even if initiated within 48 
hours of birth.  
 
4.2.3 
Infant received within 30 days prior to study entry, or is identified as requiring, any of the 
following:   
 
• 
Chronic (more than 14 days) systemic steroid treatment 
• 
Immunoglobulin treatment 
• 
Immunomodulators (interleukins, interferons, cyclosporin) 
• 
Cytotoxic chemotherapy 
• 
Treatment for active tuberculosis (TB) disease 
• 
Any investigational agent 
 
Note:  Treatment for latent TB infection is permitted. 
 
4.2.4 
Infant has any documented or suspected clinically significant medical illness, clinically 
significant congenital anomaly, or immediately life-threatening condition that, in the 
opinion of the site investigator or designee, would interfere with the infant’s ability to 
comply with study requirements. 
 
4.2.5 
Infant has any other condition that, in the opinion of the site investigator or designee, 
would make participation in the study unsafe, complicate interpretation of study outcome 
data, or otherwise interfere with achieving the study objectives.  
 
 
 


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4.3 
Maternal Inclusion Criteria 
 
The mothers of enrolled infants will be asked to consent to blood collection and storage for this 
study.  The following criteria must be met in order for mothers to undergo blood collection for 
this purpose: 
 
4.3.1 
Mother is willing and able to provide independent written informed consent for blood 
collection and storage for virology and immunology investigations.  
 
 
4.3.2 
Mother has no documented or suspected condition that, in the opinion of the site 
investigator or designee, would make blood collection unsafe. 
 
Note:  Maternal study participation is not required for infant study participation. 
 
4.4 
Co-Enrollment Considerations 
 
Co-enrollment in other studies is not precluded, although careful consideration must be given to 
visit burden, blood draw volumes, and interpretation of outcome data across studies.  Given these 
considerations, requests for co-enrollment must be approved in advance by the Protocol Teams of 
both studies.  Requests for such approval should be emailed to the CMC.   
 
4.5 
Recruitment, Screening, and Enrollment Process 
 
Recruitment methods for this study may vary across sites but are expected to rely on active 
identification and referral of infants newly diagnosed with HIV infection in each study site 
community.  In some communities, infants of known HIV-infected mothers may be tested for 
HIV infection within hours to days after birth.  In other communities, routine testing occurs at 4-6 
weeks of age.  Testing may also be performed at later time points in response to signs and 
symptoms of infection.  Because infected infants are expected per current standards of care to 
initiate cART immediately upon diagnosis of infection, active referral from HIV testing providers 
will be necessary to permit enrollment in the study as soon as possible after initiation of cART. 
 
Upon identification of a potentially eligible infant, study staff will provide information about the 
study to the infant’s parent or legal guardian.  Each parent or guardian who expresses interest in 
learning more about the study will be provided additional information, education, and counseling 
as part of the study informed consent process.  The process will include detailed review of the 
study informed consent forms, time to address any questions or concerns the parent or guardian 
may have, and an assessment of the parent’s or guardian’s understanding before proceeding to the 
informed consent decision.  The process will be fully documented, and only parents or guardians 
who are able to demonstrate understanding will be asked to provide written informed consent for 
study participation.   
 


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Eligibility screening will be initiated after written informed consent is provided.  Each site must 
establish standard operating procedures (SOPs) for eligibility determination that describe where 
and when screening procedures will be performed; roles and responsibilities for performing the 
required procedures; roles and responsibilities for assessing and confirming eligibility; and 
procedures for documenting the process, taking into consideration the required timing of 
enrollment (randomization).  Screening evaluations must be performed within 30 days prior to 
randomization, and randomization must occur within 84 days of birth and within 14 days after 
initiation of cART; initial cART regimens must be selected and documented prior to 
randomization.   
 
Infants who are found to meet the study eligibility criteria will be randomized to one of the two 
study arms, and infants randomized to Arm 1 will be administered their first dose of VRC01 on 
the day of randomization.  If the first dose cannot be administered on the day of randomization 
for any reason, the CMC should be contacted immediately.  On a case-by-case basis, the CMC 
may permit administration of VRC01 after the day of randomization, within 14 days after 
initiation of cART. 
 
The IMPAACT Data Management Center (DMC) Subject Enrollment System (SES) will be used 
to assist with tracking the screening and enrollment process.  When informed consent is obtained, 
a participant identification number (PID) will be assigned to the infant, and a study-specific 
screening number will be obtained through the SES.  For infants found to be eligible, 
randomization will occur upon successful entry of required eligibility data into the SES.  
Successful entry into the SES will generate a study identification number (SID) and, for infants 
randomized to Arm 1, prescribing information for the study product (VRC01) regimen.  In the 
event that twins (or other multiplets) are found to be eligible for the study, both (all) infants will 
be randomized to the same arm.  For infants who are found to be ineligible for the study, or who 
do not enroll in the study for any reason, an electronic case report form (eCRF) will be entered to 
record the screening outcome.  Refer to Section 9.5 for more information on monitoring 
participant accrual in this study.  
 
As part of the study informed consent process, infants’ mothers will be asked to consent to 
collection and storage of their own blood for exploratory virology and immunology 
investigations.  This consent is optional.  For mothers who choose to provide consent and are 
assessed as eligible, a PID will be assigned and registered in the SES for purposes of sample 
collection and storage only. Maternal blood will be collected at the time of infant entry into the 
study or within seven days thereafter; immediately following blood collection, mothers will be 
discontinued from follow-up. 
 
4.6 
Participant Retention 
 
Once an infant is enrolled in this study, study staff will make every effort to retain him or her for 
the protocol-specified duration of follow-up, i.e., through Week 48, thereby minimizing potential 
biases and loss of statistical power associated with loss-to-follow-up.  Infants in Arm 1 will be 
retained in follow-up regardless of the number of doses of VRC01 received.  Refer to Section 9.5 
for more information on monitoring participant retention in this study. 
                                                                      


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4.7 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant retention efforts referenced above, infants may be withdrawn from 
the study by their parents or legal guardians.  Infants may also be terminated from the study by 
the site investigator or designee under the following circumstances: 
 
• 
Infant re-locates away from the study site and cannot be transferred to another site or is 
otherwise determined to be lost-to-follow-up 
• 
Investigator or designee determines that continued participation in the study would be unsafe 
or otherwise not in the best interest of the infant 
• 
The study is stopped or canceled by the sponsors, government or regulatory authorities, or 
site IRBs/ECs  
 
For any infant who is withdrawn or terminated from the study prior to scheduled completion of 
follow-up, study staff will document the reason for the withdrawal or termination in detail and 
will make every effort to complete final evaluations of the infant as described in Section 6.13.  In 
the event that the circumstances that led to an infant’s withdrawal or termination change (e.g., the 
family returns to the study site area after having re-located previously), the site investigator or 
designee should contact the CMC to discuss options for resumption of follow-up. 
 
 
5 
STUDY PRODUCT CONSIDERATIONS 
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for standard pharmacy operations.   
 
Study product is defined for this study as VRC-HIVMAB060-00-AB (VRC01).  
 
Refer to Figure 1 for an overview of the study design and study product dosing scheme and to the 
VRC-HIVMAB060-00-AB (VRC01) IB for further information about the study product.  In the 
event that the IB is revised to specify updated study product storage or thawing procedures, the 
IB will take precedence over the specifications of this section of the protocol. 
 
5.1 
Study Product Regimen 
 
Arm 1: 40 mg/kg of VRC01 by subcutaneous injection at study Entry (Week 0) and study Weeks 
2, 6, and 10 in addition to (non-study) cART.  Tables listing the volume of study product 
needed to provide the specified dose by infant weight band will be provided in the study-
specific Manual of Procedures (MOP). 
 
Arm 2: No VRC01 in addition to (non-study) cART. 
 
Each infant’s cART regimen will be selected by his or her primary care provider and supplied 
through non-study sources (i.e., ARVs will not be provided through the study).  Refer to Section 
5.7.1 for more information on concomitant ARVs.  
 


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5.2 
Study Product Formulation and Storage 
 
VRC01 will be supplied in 3 mL glass vials.  The vials are filled to 2.25 ± 0.1 mL at a 
concentration of 100 (±10) mg/mL.  The vials contain a clear, colorless to yellow liquid 
essentially free of visible particles; some opaque or translucent particles may be present.  The 
formulation buffer is composed of 25 mM sodium citrate, 50 mM sodium chloride, and 150 mM 
L-arginine hydrochloride at pH 5.8.  The vials are intended for single use only and thus contain 
no preservative.  
 
The VRC01 product label designates long-term storage at -35°C to -15°C (-31°F to 5°F).  At 
clinical research sites, storage in a qualified, continuously monitored, temperature-controlled 
freezer with temperature excursions from -45°C to -10°C (-49°F to 14°F) is acceptable. 
 
Following thawing, vials of VRC01 may be stored for up to 24 hours at controlled room 
temperature (maximum 27°C) and/or up to 4 weeks at 2°C to 8°C. If stored at 2°C to 8°C, vials 
should be equilibrated to controlled room temperature (maximum 27°C) for a minimum of 30 
minutes and may be held at room temperature for up to 8 hours prior to product preparation. The 
product may not be stored in direct sunlight.   
 
For subcutaneous administration, the required volume of VRC01 will be loaded into a 5 or 10 mL 
sterile syringe.  Preparation must be performed using aseptic technique in a laminar flow 
biosafety cabinet.  Prepared syringes containing VRC01 may be stored at 2°C to 8°C for up to 24 
hours or at controlled room temperature (maximum 30°C) for up to 4 hours (unless institutional 
policies specify shorter expiry timeframes, in which case institutional policies should be 
followed).  The product may not be stored in direct sunlight.  
 
Refer to the study-specific MOP for further information on product storage, thawing, preparation, 
and stability. 
 
5.3 
Study Product Administration 
 
Topical anesthetic preparations (e.g., EMLA) should not be applied prior to VRC01 
administration. 
 
VRC01 will be administered subcutaneously by slow push in the thigh using an RMS High-Flo 
Subcutaneous Safety Needle Set with a 26-gauge needle. Dose volumes are expected to range 
from 0.8 to 4.0 mL, corresponding to infant weights ranging from 2 to 10 kg. Refer to the study-
specific MOP for weight-based dosing tables and detailed instructions for use of RMS needle 
sets. All dose volumes are expected to be administered as a single infusion over approximately  
5-10 minutes; up to 15 minutes may be required for the largest dose volumes.  However, if 
appropriate for an infant’s size, a divided dose may be infused at two sites.   
 
When administering VRC01, the thigh in which concomitant immunizations may have been 
administered within the preceding two weeks should be avoided, if possible, as should any site 
where the skin or tissue is irritated.  The location of each injection site (left or right thigh) must be 
documented.  
 
If an immediate hypersensitivity reaction occurs during administration, administration should be 
stopped consistent with instructions provided in the study-specific MOP. 
 


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Refer to Section 6.16 for more information on monitoring for reactogenicity following each 
administration of VRC01. 
 
5.4 
Study Product Supply 
 
VRC01 will be provided by the VRC and made available to study sites through the NIAID 
Clinical Research Products Management Center (CRPMC).  RMS High-Flo Subcutaneous Safety 
Needle Sets with 26-gauge needles will be purchased centrally and made available to sites 
through the CRPMC.  Upon successful completion of protocol registration procedures, VRC01 
and infusion sets may be obtained by the site pharmacist following instructions provided in the 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 
 
5.5 
Study Product Accountability 
 
Site pharmacists must maintain complete records of all study product supplies and needle sets 
received from the CRPMC.  The product lot number associated with each dose of VRC01 
administered will be recorded in participant study records and entered into eCRFs.  
 
5.6 
Final Disposition of Study Product  
 
Partially used vials are not permitted to be administered to other study participants or used for in 
vitro experimental studies.  Any unused portion of entered vials, any used syringes, and any 
unused filled syringes should be disposed of in a biohazard container and incinerated or 
autoclaved per approved local site policy.   
 
Any unopened vials that remain at US sites after the study is completed or terminated will be 
returned to the CRPMC.  At non-US sites, any unopened vials that remain after the study is 
completed or terminated will be destroyed.  Site pharmacists will follow the relevant instructions 
for return or destruction of unused study product provided in the Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks.   
 
5.7 
Concomitant Medications  
 
All concomitant medications received by enrolled infants — including prescription and non-
prescription (over-the-counter) medications; immunizations and other preventive medications; 
therapeutic foods and nutritional supplements; and alternative, complementary, and traditional 
medications and preparations — must be source documented as part of the medical and 
medications histories obtained at each study visit.  As described in greater detail in the remainder 
of this section, the following concomitant medications must also be entered into eCRFs: 
 
• 
ARVs 
• 
Immunizations 
• 
Immunosuppressive medications 
• 
Active or passive immunotherapy agents 
• 
Medications or other treatments administered by injection in the thigh 
• 
All other medications received through Week 16 of follow-up 
 


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5.7.1 
Concomitant ARVs  
 
All ARVs received by enrolled infants must be source documented and entered into eCRFs as 
part of the ARV exposure history obtained at each study visit.  Likewise, ARVs taken by each 
infant’s mother, to which the infant may have been exposed in utero or through breast milk, will 
be source documented and entered into eCRFs.  
 
Each infant’s initial cART regimen will be selected by his or her primary care provider and 
supplied through non-study sources.  Regimen changes are permitted during follow-up in 
response to intolerance, toxicity, incidence of concomitant illnesses (e.g., tuberculosis) and/or 
virologic or immunologic failure, consistent with local standards of care and the clinical 
judgement of the treating clinician.  Site clinicians may order 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.  
 
5.7.2 
Concomitant Immunizations  
 
All immunizations received by enrolled infants must be source documented and entered into 
eCRFs as part of the immunization history obtained at each study visit.   
 
Enrolled infants are expected to receive immunizations in accordance with country-specific 
standard immunization schedules.  Study staff should facilitate these immunizations in order to 
minimize visit burden, ensure compliance with both the study product administration schedule 
and the standard immunization schedule, and optimize documentation of all immunizations 
received.   
 
For infants in Arm 1, immunizations may be administered on the same day as VRC01.  In this 
case, for immunizations that are administered by injection in the thigh, the immunizations should 
preferably be administered in the thigh opposite of the VRC01 injection; if that is not possible, 
the immunization should be administered at least 2.4 cm away from the site of VRC01 injection, 
and each injection site should be marked so that each can be clearly identified for purposes of 
assessment of injection site reactions.  
 
5.7.3 
Other Concomitant Medications  
 
In addition to the concomitant ARVs and immunizations described in Sections 5.7.1 and 5.7.2, all 
other concomitant medications received by enrolled infants must be source documented as part of 
the medical and medications history obtained at each visit.  Through Week 16, all concomitant 
medications must also be entered into eCRFs.  After Week 16, only ARVs, immunizations, 
immunosuppressive medications, and medications or other treatments administered by injection 
in the leg(s) where VRC01 has been administered are required to be entered into eCRFs. 
 


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5.8 
Prohibited and Precautionary Medications  
 
Enrolled infants should not receive any of the following: 
 
• 
Investigational products (other than VRC01) 
• 
Immunoglobulin-based treatments  
• 
Immunosuppressive medications for a duration of greater than 14 days 
• 
Topical anesthetic preparations (e.g., EMLA) applied to the VRC01 injection site 
 
In the event that a need for one or more such medications is identified, the site investigator or 
designee should consult the CMC. 
 
Antipyretic and pain relief medications should not be used for prophylaxis in anticipation of 
possible reactions to VRC01 administration but may be provided to treat elevated temperatures 
and pain/tenderness that may occur after administration. 
 
 
6 
STUDY VISITS AND PROCEDURES 
 
An overview of the study visit and evaluation schedule is provided in Appendix I; blood draw 
volumes for each visit are also detailed in Appendix I.  Presented in this section is additional 
information on visit-specific study procedures.  As indicated in Appendix I, optional maternal 
evaluations are performed for consenting mothers only at study Entry.  Thereafter, only infant 
evaluations are performed. 
 
All visits and procedures must be performed at the approved clinical research site or approved 
associated facilities and must be documented in accordance with the NIAID Division of AIDS 
(DAIDS) policies for source documentation; refer to Section 11 for more information on 
documentation and data management requirements.  Refer to Section 7.3 for information on 
expedited adverse event (EAE) reporting, which may be required at any time during follow-up.  
All procedures specified to be performed at scheduled visits should ideally be performed on the 
same day.  However, if this is not possible (e.g., if a participant must leave the clinical research 
site before all procedures can be performed), visits may be split, with procedures performed on 
more than one day within the allowable visit window. 
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks consistent with site SOPs, including but not limited to collecting, reviewing, and 
updating demographic and locator information; reviewing elements of informed consent; 
scheduling telephone contacts and visits; providing instructions for contacting study staff between 
visits; providing visit reminders; and following up on missed visits.  All such tasks should be 
documented consistent with site SOPs.  Study staff should inform mothers (or other authorized 
guardians if applicable) of clinically meaningful physical exam findings and laboratory test 
results when available. 
 


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6.1 
Screening Visits 
 
Refer to Section 4.5 for a description of the study recruitment, screening, and enrollment process.   
   
Screening may be initiated after written informed consent is obtained.  Screening procedures may 
be performed on multiple days, including on the date of enrollment (randomization); all screening 
procedures must be performed within 30 days prior to randomization.  
 
For potential participants who do not meet eligibility criteria, screening may be discontinued once 
ineligibility is determined (enter the relevant eCRF to record the screening outcome).   
 
Screening Visit Procedures (within 30 days prior to Entry) 
Administrative 
and Regulatory 
• Obtain written informed consent  
• Assign PID to infant; also assign PID to mother if she 
consents to maternal specimen collection 
• Obtain infant screening number from SES 
Clinical 
• Obtain available medical records and infant history 
information (since birth) 
– HIV-related testing 
– Medical/medications including ARVs (all exposures) 
– Immunizations  
– Feeding 
• Perform physical examination  
Laboratory 
Infant blood 
Collect blood for: 
• Confirmatory HIV NAT (if needed per Section 4.1.4) 
• Complete blood count with differential and platelets  
• ALT, AST, ALP, creatinine 
• CD4 and CD8 cell count and percentage 
 
 
 


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6.2 
Entry Visit 
 
Refer to Section 4.5 for a description of the study recruitment, screening, and enrollment process.   
 
All Entry Visit procedures are expected to be performed on the day of enrollment, which is 
defined as the day of randomization.  Procedures that may provide information relevant to 
eligibility for the study (e.g., medical history, physical examination), should be performed first, 
prior to final eligibility determination. Eligibility must be confirmed and the infant’s initial cART 
regimen must be documented prior to randomization.  In the event that an infant is found to be 
ineligible on the scheduled day of enrollment, randomization should not occur (enter the relevant 
eCRF to record the screening outcome).    
 
For infants randomized to Arm 1, the first dose of VRC01 will be administered on the day of 
randomization.  If the first dose cannot be administered on the day of randomization for any 
reason, the CMC should be contacted immediately.  On a case-by-case basis, the CMC may 
permit administration of the first dose after the day of randomization, within 14 days after 
initiation of cART.  If such permission is granted, the infant’s eligibility for the study must be re-
confirmed and documented on the day of administration of the first dose, prior to administering 
the dose.  
 
Additional requirements for sequencing of procedures at the Entry Visit for infants randomized to 
Arm 1 are as follows: 
 
• 
Physical examination should occur prior to randomization (as described above) and must 
precede prescribing and administering of VRC01 
– Weight measurement is required for prescribing 
– Assessment of vital signs and visual inspection of the injection site must precede 
administration 
• 
Randomization must precede prescribing of VRC01 
• 
Prescribing must precede dispensing and administering of VRC01 
• 
Blood collection must precede administering of VRC01 
• 
Monitoring for injection site reactions must be performed for two hours after administering 
VRC01 as described in Section 6.16 
 
On the day of this visit and on the following six days, reactogenicity assessments will be 
performed and documented as described in Section 6.16.    
 


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Entry Visit Procedures (Day 0) 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist 
data into SES to enroll/randomize the infant, print and file a 
copy of the confirmation file 
• For consenting mothers: Complete paper-based eligibility 
checklist, enter checklist data into SES to enroll the mother, 
print and file a copy of the confirmation file 
Clinical 
• Obtain infant history information (since last visit)* 
– HIV-related testing 
– Medical/medications including ARVs (all exposures) 
document initial cART regimen prior to randomization 
– Immunizations  
– Feeding 
• Perform physical examination* 
• Assess adherence to cART if infant initiated cART prior to 
study entry 
• For infants in Arm 1: Monitor for reactogenicity for two 
hours after administering VRC01 per Section 6.16 
• Provide instructions for completing reactogenicity memory 
aid 
Study Product 
 
For infants in Arm 1: 
• Prescribe VRC01 
• Prepare and dispense VRC01 
• Administer VRC01 
Laboratory 
Infant blood  
Collect infant blood for: 
• HIV-1 RNA 
• Stored plasma and PBMCs for primary, secondary, and 
other evaluations 
• Stored serum for neutralizing assay 
• Stored plasma and PBMCs for exploratory evaluations if 
infant weighs ≥ 3 kg at the visit 
Infant urine 
Collect urine for: 
• Dipstick urinalysis; if 1+ for protein, blood, or leukocytes, 
perform microscopic evaluation 
Maternal 
blood  
If mother has consented, collect blood and store plasma, 
PBMCs, and serum for exploratory evaluations 
 *Perform prior to randomization. 
 
Note:  For consenting mothers, blood should ideally be collected at the Entry Visit; however, 
these specimens may be collected within seven days after the Entry Visit.  No further maternal 
evaluations are performed following specimen collection; therefore, mothers will be discontinued 
from follow-up immediately upon completion of specimen collection. 
 


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6.3 
Week 1 Visit 
 
The Week 1 Visit is targeted to take place on Day 7, counted from the date of randomization as 
Day 0, with an allowable window of ± 3 days.  There is no required sequencing of procedures at 
this visit.  
 
Week 1 Visit Procedures (Day 7 ± 3 days) 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications 
– Reactogenicity 
• Perform physical examination 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
 
• None 
Laboratory 
Blood 
Collect blood for: 
• Complete blood count with differential and platelets 
• ALT, AST, ALP, creatinine 
• HIV-1 RNA (with storage of residual PBMCs if possible) 
Urine 
 
Collect urine for: 
• Dipstick urinalysis; if 1+ for protein, blood, or leukocytes, 
perform microscopic evaluation 
 
6.4 
Week 2, Week 6, and Week 10 Visits 
 
The Week 2, Week 6, and Week 10 visits are targeted to take place on Days 14, 42, and 70, 
respectively, counted from the date of randomization as Day 0.  The allowable visit window for 
the Week 2 visit is ± 3 days.  The allowable visit window for the Week 6 and Week 10 visits is ± 
7 days.   
 
For infants randomized to Arm 2, there is no required sequencing of procedures at these visits.  
For infants randomized to Arm 1, because VRC01 is scheduled to be administered at these visits, 
the following sequencing of procedures is required at these visits: 
 
• 
Physical examination must precede prescribing and administering of VRC01 
– Weight measurement is required for prescribing 
– Assessment of vital signs and visual inspection of the injection site must precede 
administration 
• 
Confirmation of eligibility to receive VRC01 must precede administering of VRC01 
• 
Prescribing must precede dispensing and administering of VRC01 
• 
Blood collection must precede administering of VRC01 
• 
Monitoring for injection site reactions must be performed for one hour after administering 
VRC01 as described in Section 6.16 
 
On the day of each of these visits and the following six days, reactogenicity assessments will 
be performed and documented as described in Section 6.16.   
 


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Week 2 (Day 14 ± 3 days), Week 6 (Day 42 ± 7 days), and Week 10 (Day 70 ± 7 days)  
Visit Procedures 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications including ARVs (all exposures) 
– Immunizations  
– Feeding 
• Assess adherence to cART 
• Perform physical examination including inspection of prior 
injection sites and pre-injection inspection of planned 
injection site for this visit for infants in Arm 1 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
• For infants in Arm 1: Confirm eligibility to receive VRC01 
• For infants in Arm 1: Monitor for reactogenicity for one hour 
after administering VRC01 per Section 6.16 
• Review instructions for completing reactogenicity memory 
aid as needed 
Study Product 
 
For infants in Arm 1: 
• Prescribe VRC01 
• Prepare and dispense VRC01 
• Administer VRC01 
Laboratory 
Blood 
Collect blood for: 
• HIV-1 RNA (with storage of residual PBMCs if possible) 
(Weeks 6 and 10) 
• Stored plasma and PBMCs for primary, secondary, and 
other evaluations 
 
 


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6.5 
Week 3, Week 7, and Week 11 Visits 
 
The Week 3, Week 7, and Week 11 visits are targeted to take place on Days 21, 49, and 77, 
respectively, counted from the date of randomization as Day 0.  The allowable visit window for 
these visits is ± 3 days.  There is no required sequencing of procedures at these visits.   
 
Week 3 (Day 21 ± 3 days), Week 7 (Day 49 ± 3 days), and Week 11 (Day 77 ± 3 days)  
Visit Procedures 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications  
– Reactogenicity 
• Perform physical examination 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
 
• None 
Laboratory 
Blood 
Collect blood for: 
• Complete blood count with differential and platelets 
• ALT, AST, ALP, creatinine 
 
 


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Week 14 Visit 
 
The Week 14 Visit is targeted to take place on Day 98, counted from the date of randomization as 
Day 0, with an allowable window of ± 7 days.  In addition to other routine study procedures, 
blood is collected and stored at this visit for primary antiviral activity evaluations.  There is no 
required sequencing of procedures at this visit.  
 
Week 14 Visit Procedures (Day 98 ± 7 days) 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications including ARVs (all exposures) 
– Immunizations  
– Feeding 
• Assess adherence to cART 
• Perform physical examination 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
 
• None 
Laboratory 
Blood 
Collect blood for: 
• Complete blood count with differential and platelets  
• ALT, AST, ALP, creatinine 
• CD4 and CD8 cell count and percentage 
• HIV-1 RNA (with storage of residual PBMCs if possible) 
• Stored plasma and PBMCs for primary, secondary, and other 
evaluations 
• Stored serum for neutralization assay 
• Stored plasma and PBMCs for exploratory evaluations if 
infant weighs ≥ 3 kg at the visit 
Urine 
Collect urine for: 
• Dipstick urinalysis; if 1+ for protein, blood, or leukocytes, 
perform microscopic evaluation 
 
 
 
 
 


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Week 16 Visit 
 
The Week 16 Visit is targeted to take place on Day 112, counted from the date of randomization 
as Day 0, with an allowable window of ± 7 days.  There is no required sequencing of procedures 
at this visit.  
 
Week 16 Visit Procedures (Day 112 ± 7 days) 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications including ARVs (all exposures) 
– Immunizations  
– Feeding 
• Assess adherence to cART 
• Perform physical examination 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
 
• None 
Laboratory 
Collect blood for: 
• HIV-1 RNA (with storage of residual PBMCs if possible) 
• Stored plasma and PBMCs for primary, secondary, and other 
evaluations 
 
6.8 
Week 20 Visit 
 
The Week 20 Visit is targeted to take place on Day 140, counted from the date of randomization 
as Day 0, with an allowable window of ± 14 days.  There is no required sequencing of procedures 
at this visit. 
 
Week 20 Visit Procedures (Day 140 ± 14 days) 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications including ARVs (all exposures) 
– Immunizations  
– Feeding 
• Assess adherence to cART 
• Perform physical examination 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
 
• None 
Laboratory 
Collect blood for: 
• Complete blood count with differential and platelets 
• ALT, AST, ALP, creatinine 
 
 


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Week 24 Visit 
 
The Week 24 Visit is targeted to take place on Day 168, counted from the date of randomization 
as Day 0, with an allowable window of ± 14 days.  There is no required sequencing of procedures 
at this visit.  
 
Week 24 Visit Procedures (Day 168 ± 14 days) 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications including ARVs (all exposures) 
– Immunizations  
– Feeding 
• Assess adherence to cART 
• Perform physical examination 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
 
• None 
Laboratory 
Blood 
Collect blood for: 
• Complete blood count with differential and platelets  
• ALT, AST, ALP, creatinine 
• CD4 and CD8 cell count  
• HIV-1 RNA (with storage of residual PBMCs if possible) 
• Stored plasma and PBMCs for primary, secondary, and other 
evaluations 
• Stored serum for neutralization assay 
• Stored plasma and PBMCs for exploratory evaluations 
Urine 
Collect urine for: 
• Dipstick urinalysis; if 1+ for protein, blood, or leukocytes, 
perform microscopic evaluation 
 
 
 


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Week 36 Visit 
 
The Week 36 Visit is targeted to take place on Day 252, counted from the date of randomization 
as Day 0, with an allowable window of ± 14 days.  There is no required sequencing of procedures 
at this visit.  
 
Week 36 Visit Procedures (Day 252 ± 14 days) 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications including ARVs (all exposures) 
– Immunizations  
– Feeding 
• Assess adherence to cART 
• Perform physical examination 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
 
• None 
Laboratory 
Collect blood for: 
• CD4 and CD8 cell count and percentage and complete blood 
count if needed for calculation of absolute cell counts 
• HIV-1 RNA (with storage of residual PBMCs if possible) 
• Stored plasma and PBMCs for exploratory evaluations 
 
At this visit, information and counseling will be provided to the infant’s parent or guardian to 
begin to prepare for study exit at the Week 48 visit.  Referrals to non-study care and treatment 
will be discussed if applicable, and the importance of retention in care and adherence to cART 
will be emphasized.   
 
 
 
 
 


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Week 48 Visit 
 
The Week 48 Visit is the last scheduled follow-up visit.  It is targeted to take place on Day 336, 
counted from the date of randomization as Day 0, with an allowable window of ± 14 days.  There 
is no required sequencing of procedures at this visit.  
 
Week 48 Visit Procedures (Day 336 ± 14 days) 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications including ARVs (all exposures) 
– Immunizations  
– Feeding 
• Assess adherence to cART 
• Perform physical examination 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
 
• None 
Laboratory 
Collect blood for: 
• CD4 and CD8 cell count and percentage and complete blood 
count if needed for calculation of absolute cell counts 
• HIV-1 RNA (with storage of residual PBMCs if possible) 
• Stored plasma and PBMCs for primary, secondary, and other 
evaluations 
• Stored serum for neutralization assay 
• Stored plasma and PBMCs for exploratory evaluations 
 
At this visit, prior discussion of continuation in non-study care and treatment will be reviewed, 
with information, counseling, and/or referrals provided if needed.  Arrangements will be made to 
provide the infant’s parent or guardian with the infant’s final CD4/CD8 cell count and HIV-1 
RNA level (viral load).  The parent or guardian will also be informed of how to contact study 
staff with any post-study questions and how to learn about the results of the study when available.  
 
 
 


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Residual Cerebral Spinal Fluid (CSF) Collection Visit 
 
Lumbar punctures will not be performed for this study.  However, for any infant who undergoes 
lumbar puncture for clinical care during follow-up, residual CSF should ideally be stored for 
exploratory evaluations.  Infants’ mothers (or legal guardians) will be asked to provide optional 
informed consent for this; consent may be declined with no impact on other aspects of infant 
study participation.  For infants for whom informed consent is provided, and who have a lumbar 
puncture for clinical care during follow-up, within seven days (inclusive) after the lumbar 
puncture, residual CSF should be retrieved and stored when available, and the evaluations 
indicated in the “CSF Collection” column of the Schedule of Evaluations in Appendix I (and 
described below) should be performed.  If these evaluations cannot be performed within seven 
days, the site investigator should contact the CMC for further guidance.  If the residual CSF 
cannot be retrieved and stored for any reason, the evaluations indicated in the “CSF Collection” 
column of the Schedule of Evaluations in Appendix I (and described below) should not be 
performed.   
 
CSF Collection Visit Procedures (within 7 days after lumbar puncture) 
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain available medical records and medical/medications 
history since the last visit to document the clinical indication 
for the lumbar puncture and the results of clinical care 
evaluations of the CSF including cell count and differential, 
protein, glucose, and microbiologic testing results 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
Laboratory 
• None 
Laboratory 
Blood 
Collect blood for: 
• Stored plasma and PBMCs for exploratory evaluations 
CSF 
Retrieve and store residual CSF for exploratory evaluations 
 
 
 
 


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Early Discontinuation Visit 
 
Refer to Section 4.7 for criteria for infant withdrawal or termination from the study.  For any 
infant who is withdrawn or terminated from the study prior to the scheduled completion of 
follow-up at Week 48, every effort should be made to perform a final series of study evaluations, 
if possible, according to the “Early D/C” column of the Schedule of Evaluations in Appendix I.  
However, any laboratory evaluations performed within the two weeks prior to the Early 
Discontinuation Visit need not be repeated at the Early Discontinuation Visit. 
 
Early Discontinuation Visit Procedures  
Administrative 
and Regulatory 
• None 
Clinical 
• Obtain history information (since last visit) 
– Medical/medications including ARVs (all exposures) 
– Immunizations  
– Feeding 
• Assess adherence to cART 
• Perform physical examination 
• Identify/review/update adverse events (abnormal lab values, 
signs, symptoms, diagnoses) 
• Perform additional evaluations per Section 8.1 and/or if 
clinically indicated (consult CMC if indicated) 
Study Product 
 
• None 
Laboratory 
Blood 
If not done within the prior two weeks, collect blood for: 
• Complete blood count with differential and platelets 
• CD4 and CD8 cell count and percentage  
• HIV-1 RNA (with storage of residual PBMCs if possible) 
• Stored plasma and PBMCs for primary, secondary, and other 
evaluations 
• Stored serum for neutralization assay  
• Stored plasma and PBMCs for exploratory evaluations 
Urine 
If the Early Discontinuation Visit occurs prior to the Week 24 
Visit, collect urine for: 
• Dipstick urinalysis; if 1+ for protein, blood, or leukocytes, 
perform microscopic evaluation 
 
Arrangements should be made to provide the infant’s parent or guardian with clinically 
meaningful test results from the Early Discontinuation visit.  The parent or guardian should be 
provided information on how to remain in contact with study staff (if desired) and learn about the 
results of the study when available.  The parent or guardian should also be provided information 
and referrals, as applicable, to non-study sources of care and treatment for the infant. 
 
 
 


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Infant Histories 
 
HIV-Related Testing 
 
Infant HIV-related testing history information is collected at the Screening Visit and updated as 
needed at the Entry Visit.  Available source documentation should be obtained and data entered 
into eCRFs for all of the following:  all documented HIV diagnostic tests since birth, all 
documented quantitative HIV-1 RNA tests since birth, all documented CD4 cell counts and 
percentages since birth, and all documented ARV resistance testing since birth.  As indicated in 
Section 5.7.1, the results of any ARV resistance testing performed during follow-up will also be 
entered into eCRFs. 
 
Medical and Medications History 
 
Infant medical and medications history information is collected at the Screening Visit and 
updated at each scheduled visit.  A baseline history is established at the Screening and Entry 
Visits, and interval (since the last visit) histories are documented at follow-up visits.  History 
information should be collected from the infant’s parent or guardian and all available medical 
records should be obtained to source document infant medical and medications histories, to the 
extent possible, since birth.  During follow-up, the following should be source documented based 
on parental/guardian report and all available medical records:  current status of conditions that 
were ongoing at the previous visit; current status of medications that were ongoing at the previous 
visit; occurrence of any new conditions since the last visit; use of any new medications since the 
last visit.  Refer to Section 7.2 for requirements for entering signs, symptoms, and diagnoses into 
eCRFs and to Section 5.7 for requirements for entering concomitant medications into eCRFs. 
 
ARV History 
 
Infant ARV history is collected at the Screening Visit and updated as needed at each scheduled 
visit.  All of the following should be source documented and entered into eCRFs:  all exposures to 
ARVs in utero, all exposures to ARVs through breast milk, and all exposures to ARVs through 
direct ingestion, prior to study entry and throughout follow-up.  See also Section 5.7.1.  As 
indicated above for other medical history information, parental/guardian report of ARV history 
should be supplemented with available medical records whenever possible.  
 
Immunization History 
 
Infant immunization history is collected at the Screening Visit and updated as needed at each 
scheduled visit.  All immunizations should be source documented and entered into eCRFs.  See 
also Section 5.7.2.  As indicated above for other medical history information, parental/guardian 
report of immunization history should be supplemented with available medical records whenever 
possible. 
 
Feeding History  
 
Infant feeding history is collected at the Screening Visit and updated as needed at each scheduled 
visit.  All of the following should be sourced documented and entered into eCRFs:  feeding 
method, including whether the infant has been breastfed or formula fed; date of last exposure to 
breast milk (if applicable); and other types of foods received.  Any therapeutic foods received 
should be documented as concomitant medications; see also Section 5.7.   


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6.15 
Infant Physical Examinations  
 
A physical examination is required at each scheduled study visit.  Each examination should 
include the following: 
 
• 
Head circumference measurement 
• 
Weight measurement 
• 
Length measurement 
• 
Vital signs including temperature, heart rate, respiratory rate; blood pressure (if possible) 
should also be measured at Entry and Weeks 2, 6, and 10 
• 
Auscultation of chest 
• 
Examination of skin, eyes, mouth, neck, abdomen, extremities (including the study product 
injection site) 
• 
Examination of other body systems driven by prior and new signs, symptoms, and diagnoses 
 
At all visits, additional assessments may be performed at the discretion of the examining 
clinician.  All exam findings will be source documented and entered into eCRFs if applicable per 
the instructions in Section 7.2 below.  
 
6.16 
Monitoring for Reactogenicity  
 
Reactogenicity outcomes will be source documented and entered into eCRFs as specified in 
Section 7.2 below.  Refer to Section 8 for further information on management of reactogenicity 
events.  
 
Monitoring by Site Clinicians 
 
Site clinicians will monitor infants randomized to Arm 1 for reactogenicity on each day of 
administration of VRC01, i.e., at Entry and at Weeks 2, 6, and 10:  
 
• 
Prior to each injection, as part of the physical exam required at the visit, the infant’s skin, 
temperature, heart rate, respiration rate, and blood pressure (if possible) will be assessed, and 
the site of injection will be visually inspected. 
 
• 
At 15 and 30 minutes (±5 minutes) after each injection, the infant’s skin, heart rate, and 
respiration rate will be assessed, and the site of injection will be visually inspected.  If these 
assessments suggest a possible local or systemic reaction, the infant’s temperature and blood 
pressure should be assessed, and a physical examination of relevant body systems and any 
other clinically indicated procedures should be performed.  
 
• 
One hour (±15 minutes) after each injection, the infant’s skin, temperature, heart rate, 
respiration rate, and blood pressure (if possible) will be assessed.  The site of injection will be 
visually inspected and gently palpated to assess for induration and tenderness.  On Day 0, 
these assessments will also be performed two hours (±15 minutes) after injection.  If these 
assessments suggest a possible local or systemic reaction, a physical examination of relevant 
body systems and any other clinically indicated procedures should be performed. 
 


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• 
If any grade 3 or higher local or systemic reaction is identified following any injection, the 
infant should be observed at the study site for at least two hours after administration of 
VRC01 (see Section 8). 
 
Note:  If any scheduled dose of VRC01 is missed for any reason, the above-listed monitoring is 
not required on the date of the scheduled dose.  
 
At all time points, additional assessments may be performed at the discretion of the examining 
clinician.  The findings of all reactogenicity assessments will be source documented and entered 
into eCRFs.  Site clinicians may choose to photograph observed reactions and to share 
photographs with the CMC for awareness and to assist with evaluation of the reaction; all grade 3 
or higher reactions should ideally be photographed. Standard precautions will be followed to 
ensure that participant privacy and confidentiality are protected when photographs are shared.   
 
Monitoring by Mothers (or Caregivers) including +3-Day Contacts 
 
The mothers (or caregivers) of infants in both arms will be instructed to complete memory aid 
documents to record infant signs and symptoms for seven days following the Entry and Week 2, 
6, and 10 visits (VRC01 administration visits), beginning on the day of each visit.  The memory 
aids will capture mothers’ assessments of local injection site reactions (redness, warmth, 
swelling, tenderness) for infants in Arm 1) and systemic signs and symptoms (temperature, rash, 
swelling of joints, vomiting, diarrhea, alertness, feeding, sleeping, irritability) for infants in both 
arms.  For infants in Arm 1, if any scheduled dose of VRC01 is missed, monitoring for local 
injections site reactions is not required, but monitoring for systemic signs and symptoms should 
still be performed.  
 
Three days after visits at which VRC01 is administered, mothers (or caregivers) will be contacted 
by study staff to report their reactogenicity assessments by telephone.  In-person or home visits 
may also be substituted for telephone contacts if preferred by study staff or mothers.  Seven days 
after each visit (i.e., at Weeks 1, 3, 7, and 11), an in-person visit will be conducted.  The 
allowable window for the three-day contacts is -1 to +3 days; the allowable window for the 
seven-day visits is ±3 days.  During the three-day contacts and seven-day visits, study staff will 
ask mothers questions that follow the format of the memory aid document, probing as needed to 
clarify relevant details, and will record reported signs and symptoms on study-specific source 
documents.  Mothers will also be instructed to proactively contact study staff at any time between 
contacts and visits if any grade 1 or higher signs or symptoms are identified.  If grade 1 or higher 
reactogenicity signs or symptoms are reported, mothers will be instructed to return to the study 
clinic with their infants as soon as possible (within 48 hours) for further evaluation.   
 
As specified in Section 7.2, all reactogenicity findings will be entered into eCRFs. 
 
6.17 
Additional Considerations for Laboratory Procedures 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, which 
is available at: 
www.niaid.nih.gov/research/daids-clinical-research-laboratory-specimens-management 
 


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6.17.1 Specimen Collection 
 
Specimens will be collected for this study as indicated in the Schedule of Evaluations in 
Appendix I and per detailed guidance provided in the Laboratory Processing Chart (LPC), which 
will be available on the IMPAACT web site: www.impaactnetwork.org.   
 
In accordance with US National Institutes of Health (NIH) recommendations, infant blood 
collection will not exceed 5 mL/kg in a single day or 9.5 mL/kg in any eight-week period.  In the 
event that blood collection must be limited, available specimens should be prioritized for use in 
the following order: (1) hematology, (2) chemistry, (3) HIV RNA, (4) CD4 and CD8 cell count 
and percentage, (5) stored PBMCs and plasma for primary evaluations, (6) stored serum for 
neutralizing assays, (7) stored plasma and PBMCs for exploratory evaluations. Exceptions to the 
above apply at Entry and at Weeks 14, 24, and 48 when highest priority should be given to 
storage of plasma and PBMCs for primary, secondary, and other evaluations, which includes 
HIV-1 DNA concentration assays for primary antiviral activity evaluations. 
 
6.17.2 Specimen Preparation, Testing, Storage, and Shipping 
 
All specimens collected for this study will be labeled, transported, processed, tested, stored, 
and/or shipped in accordance with the DAIDS policy referenced in Section 6.17, site and local 
laboratory SOPs, and the LPC.  The frequency of specimen collection and testing will be directed 
by the Schedule of Evaluations and specifications for clinical management provided in Section 8.  
The Laboratory Data Management System (LDMS) will be used to document specimen 
collection, testing, storage, and shipping as specified in the LPC.  
 
Quantitative plasma HIV-1 RNA assays performed to assess viral load at time points specified in 
the SoE must be performed in laboratory that is CLIA-certified (US sites) or VQA-certified (non-
US sites) for the assay performed.  At least one of the diagnostic tests used to confirm infant HIV 
infection per Section 4.1.4 must be performed in a CLIA-certified (US sites) or VQA-certified 
(non-US sites).  Blood collected for HIV-1 RNA assays should be processed for storage of 
PMBCs in addition to plasma for the RNA assay, when possible.  PBMCs must be processed and 
cryopreserved in a laboratory that is IQA-certified using methods consistent with the HIV/AIDS 
Network Coordination Cross-Network PBMC Processing SOP which is available at: 
www.hanc.info/labs/labresources/procedures/Pages/pbmcSop.aspx 
 
Specimens stored at site laboratories for the interim PK analysis of VRC01 concentrations are 
expected to be requested for shipment when the required specimens (through Week 6) have been 
collected from a minimum of six infants in Arm 1 who received the first two scheduled doses of 
VRC01; all additional specimens stored for PK analysis of VRC01 concentrations are expected to 
be requested once all participants have reached Week 16 of follow-up. 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 are also expected to be requested at this time.  Other specimens stored for 
secondary, other, and exploratory evaluations are expected to be tested after follow-up has been 
completed.  However, if specimens for ARV drug concentration assays, VRC01 resistance assays, 
and HIV-1 DNA concentration assays are required earlier based on the findings of the interim 
analysis of plasma HIV-1 RNA levels described in Section 9.5.2, these specimens will be 
requested for shipment as needed.  Alternative specimen shipping arrangements may be specified 
by the protocol team as needed.  Detailed shipping instructions will be provided in the LPC. 
 


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After all primary, secondary, and other evaluations are performed, any remaining samples will be 
retained for exploratory evaluations. After all exploratory evaluations are performed, residual 
specimens may be of interest for future research use.  Infants’ parents or legal guardians will be 
asked to provide written informed consent for future research use of these specimens, if permitted 
by site IRBs/ECs and other applicable review bodies.  Parents may choose to provide or to 
decline informed consent for future research use of residual specimens with no impact on other 
aspects of infant study participation.   
 
6.17.3 Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as currently recommended by the US Centers for Disease Control and 
Prevention, NIH, and other applicable agencies.  All specimens will be shipped using packaging 
that meets requirements specified by the International Air Transport Association Dangerous 
Goods Regulations for UN 3373, Biological Substance, Category B, and Packing Instruction 650. 
Culture isolates, if obtained in this study, are to be shipped as specified for UN 2814 Category A 
Infectious Substances. 
 
 
7 
SAFETY ASSESSMENT, MONITORING, AND REPORTING 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study.  Sections 7.1-7.3 describe safety-related roles, responsibilities, and 
procedures for site investigators.  The safety monitoring roles of the CMC and the IMPAACT 
Study Monitoring Committee (SMC) are briefly referenced in Section 7.1 and described in 
greater detail in Section 9.5. 
 
Unless otherwise noted, the specifications of this section apply to infants in both study arms. 
 
7.1 
Safety-Related Roles and Responsibilities 
 
7.1.1 
Site Investigators 
 
Site investigators are responsible for continuous monitoring of all study participants and for 
alerting the CMC if unexpected concerns arise.  Refer to Section 8.1 for a listing of adverse 
events requiring notification to the CMC within 72 hours of site awareness of the event.   
 
Site investigators will enter safety-related data into eCRFs as indicated in Section 7.2 and 
complete expedited adverse event (EAE) reporting as indicated in Section 7.3.  Site investigators 
are also responsible for prompt reporting to their IRBs/ECs and other applicable review bodies of 
any unanticipated problems involving risks to participants or others. 
 


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7.1.2 
Clinical Management Committee (CMC) 
 
The following Protocol Team members comprise the CMC:  Chair and Co-Chair, Medical 
Officers, Immunologist, Virologist, Pharmacologist, Statisticians, Data Managers, Clinical Trials 
Specialists, and at least one international Protocol Investigator.  The CMC will provide guidance 
as needed to site investigators regarding all aspects of participant management, including but not 
limited to questions of participant eligibility and management of adverse events, study product 
administration, cART regimens, and other concomitant medications. Refer to Section 8 for more 
information on participant management. 
 
On behalf of the Protocol Team, the CMC will monitor participant safety through routine review 
of study data reports as described in Section 9.5.1. 
 
7.1.3 
Study Monitoring Committee (SMC)  
 
An independent IMPAACT Study Monitoring Committee (SMC) will monitor participant safety 
through routine and as needed reviews of study data.  Refer to Section 9.5.2 for more information 
on the composition and role of the SMC in monitoring this study.   
 
7.2 
Safety-Related Data Collection 
 
For this study, the term adverse event is used to refer to any untoward medical occurrence 
identified in an enrolled infant, which does not necessarily have a causal relationship with the 
study product.  An adverse event can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease occurring after enrollment in the study, 
whether or not related to the study product.  This definition of adverse event will be applied to 
infants in both arms of this study, beginning at the time of randomization.  Any unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or disease identified 
prior to randomization will be considered a pre-existing condition.  
 
For infants in both study arms, pre-existing conditions and adverse events identified in this study 
will be source documented and entered into eCRFs as reactogenicity outcomes, abnormal 
laboratory test results, signs, symptoms, or diagnoses, as described below.  The severity of all 
pre-existing conditions and adverse events identified among infants in both study arms will be 
graded as described in Section 7.3.3.  For infants in Arm 1, the relationship of all adverse events 
to VRC01 will be assessed as described in Section 8.1. 
 
Reactogenicity outcomes:  The reactogenicity assessments described in Section 6.16 will be 
performed at Entry and Weeks 2, 6, and 10, and on the six days following each of these visits.  
For infants in Arm 1, local injection site reactions and systemic signs and symptoms will be 
assessed.  For infants in Arm 2, systemic signs and systems will be assessed.  All findings from 
these assessments will be entered into eCRFs.  
 
Laboratory test results:  The results of all protocol-specified screening and entry laboratory tests 
that are performed in real time at site laboratories will be entered into eCRFs.  During follow-up, 
through Week 16, all grade 1 or higher results will be entered into eCRFs.  Thereafter, all grade 2 
or higher results will be entered.  The same eCRF data entry is required for infants in both study 
arms.  
 


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Signs, symptoms, and diagnoses:  All signs, symptoms, and diagnoses identified from 30 days 
prior to entry (or from birth for infants who are less than 30 days of age at entry), up until the 
time of randomization, will be entered into eCRFs as pre-existing conditions.  During follow-up, 
through Week 16, all grade 1 or higher signs, symptoms, and diagnoses will be entered into 
eCRFs.  Thereafter, all grade 2 signs, symptoms, and diagnoses will be entered into eCRFs.  All 
diagnoses will be entered consistent with the relevant diagnosis appendix (available at 
www.frontierscience.org).  The same eCRF data entry is required for infants in both study arms.  
 
Throughout follow-up, for infants in both study arms, the following will be further evaluated, 
with additional data entered into Event Evaluation eCRFs (refer to the study-specific MOP for 
more information on these eCRFs): 
 
• 
Grade 3 or higher laboratory test results, signs, symptoms, and diagnoses 
• 
Laboratory test results, signs, symptoms, and diagnoses that meet criteria for EAE reporting 
• 
Laboratory test results, signs, symptoms, and diagnoses that result in deferral or 
discontinuation of study product administration 
• 
Laboratory test results, signs, symptoms, and diagnoses that result in any change of cART 
regimen (including ARV holds, replacements, discontinuations, additions, and dose 
modifications) 
 
Through Week 16, the eCRFs referenced above must be entered within 48 hours of availability of 
the relevant clinical findings and laboratory test results at the site.  Thereafter, these eCRFs may 
be entered within standard timeframes for other eCRFs, unless otherwise requested by the CMC. 
 
7.3 
Expedited Adverse Event (EAE) Reporting 
 
 
EAEs will be reported only for infants randomized to Arm 1 of this study, as only these infants 
are exposed to study product (VRC01). 
 
7.3.1 
EAE Reporting to DAIDS 
 
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 
 
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. 
 
For questions about DAERS, please contact NIAID Clinical Research Management System 
Support via email at CRMSSupport@niaid.nih.gov. Questions may also be sent from within the 
DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office via email 
at DAIDSRSCSafetyOffice@tech-res.com.  
 


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7.3.2 
EAE Reporting Requirements for this Study 
 
EAEs will be reported only for infants in Arm 1 of this study, as only these infants will be 
exposed to study product (VRC01). 
 
The serious adverse event (SAE) reporting category, as defined in Version 2.0 of the DAIDS 
EAE Manual, will be used for this study.   
 
In addition to all SAEs, grade 3 or higher serum sickness, grade 3 or higher urticarial or other 
hypersensitivity reactions, and grade 4 injection site reactions must also be reported as EAEs in 
this study.  
 
The study product for which expedited reporting is required is VRC01.   
 
7.3.3 
Grading Severity of Events 
 
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 RSC website:   
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 
The only exceptions to the above apply to grading of axillary measured fever, injection site 
pain/tenderness, and malnutrition, which will be graded as follows:   
 
Axillary Measured Fever 
Grade 1 
37.4 to < 38.0o C 
Grade 2 
38.0 to < 38.7o C 
Grade 3 
38.7 to < 39.4o C 
Grade 4 
 39.4o C 
 
Injection Site Pain/Tenderness 
Grade 1 
Mild reaction to light touch with no or minimal limitation of movement of limb 
Grade 2 
Persistent crying (up to one hour) with no or light touch, or significant limitation of 
movement of limb 
Grade 3 
Persistent crying for more than one hour or interference with ability to sleep or eat 
Grade 4 
Inconsolable crying for more than two hours 
 
7.3.4 
EAE Reporting Period for this Study 
 
For infants randomized to Arm 1, the EAE reporting period begins at the time of first VRC01 
administration and continues through the protocol-specified end of follow-up (i.e., through the 
date of the Week 48 visit). 
 
After the above-specified period, only suspected, unexpected, serious adverse reactions 
(SUSARs), as defined in Version 2.0 of the DAIDS EAE Manual, will be reported if the study 
staff become aware of such events on a passive basis (e.g., from publicly available information). 
 
 


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8 
PARTICIPANT MANAGEMENT 
 
8.1 
Management of Adverse Events 
 
All adverse events identified in this study will be source documented consistent with the policies 
and procedures referenced in Section 11.  Among other details, source documentation will 
include the severity of each event (graded as described in Section 7.3.3).   
 
For infants in Arm 1, source documentation will also include the relationship of each event to 
study product, assessed as follows: 
 
Related 
There is a reasonable possibility that the event may be related to VRC01 
 
Not related 
There is not a reasonable possibility that the event may be related to VRC01 
 
Further standardized guidance on determining whether there is a reasonable possibility of a 
relationship is available in the DAIDS EAE Manual, referenced in Section 7.3.1 above. 
 
For infants in both study arms, all adverse events must be followed to resolution (return to 
baseline) or stabilization, with the frequency of repeat evaluations determined by the clinical 
significance of the event.  Grade 3 or 4 laboratory tests should be repeated for confirmation as 
soon as possible and within three working days.  Clinical management of all adverse events 
should be provided consistent with the best medical judgment of the site investigator and local 
clinical practice standards.  Additional evaluations beyond those indicated in Appendix I may be 
performed at the discretion of the site investigator to determine the etiology of an adverse event 
and/or further assess its severity or relationship to study product (if applicable). When applicable, 
management will include referral to non-study sources of further evaluation and treatment. 
 
Refer to Sections 8.1.1 and 8.1.2 for further guidance on management of adverse events. When 
management requires consultation with the CMC, the CMC should be contacted as soon as 
possible and within 72 hours of site awareness of the event.  Site investigators must notify the 
CMC of all of the following as soon as possible and within 72 hours of awareness:   
 
• 
Grade 1 or higher serum sickness 
• 
Grade 1 or higher urticarial or other hypersensitivity reaction 
• 
Any grade 3 or higher event assessed as related to study product 
• 
Any grade 3 or higher adverse events assessed as related to the infant’s cART regimen that 
persist for two weeks. 
 
Note:  Version 2.1 of the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events defines serum sickness as a disorder characterized by fever, arthralgia, myalgia, skin 
eruptions, lymphadenopathy, marked discomfort, and/or dyspnea.  Generally, it is expected that 
several of these signs and symptoms should be present to substantiate a diagnosis of serum 
sickness and ─ consistent with the instruction above to notify the CMC of all grade 1 or higher 
serum sickness ─ all diagnoses should be made in consultation with the CMC.  
 


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8.1.1 
General Adverse Event Management 
 
Adverse events other than those listed in Section 8.1.2 should be managed consistent with the 
following guidance:   
 
• 
Grade 1 or 2 clinical and laboratory events should be re-evaluated consistent with Section 6 
and the Schedule of Evaluations in Appendix I or additionally at the discretion of the site 
investigator. 
 
• 
Grade 3 or 4 clinical events, and confirmed grade 3 or 4 laboratory events should be re-
evaluated as follows:   
 
– For grade 3 or 4 events occurring from the time of randomization through Week 10, re-
evaluation should occur weekly until improvement to grade 2 or lower.  Thereafter, re-
evaluation should occur every two weeks until resolution (return to baseline, i.e., grade at 
study entry) or stabilization. 
 
– For grade 3 or 4 events occurring after Week 10, re-evaluation should occur no less 
frequently than every two weeks until resolution (return to baseline) or stabilization. 
 
For any grade 3 or 4 event that does not return to resolve (return to baseline) within four 
weeks after the date of onset of the event, the CMC should be consulted for further guidance 
on the frequency of re-evaluation and overall management of the event.  
 
Refer to Sections 8.2 and 8.3 for further information on deferral and discontinuation of study 
product administration, respectively.  
 
8.1.2 
Event-Specific Adverse Event Management 
 
The following types of adverse events should be managed consistent with the guidance provided 
in the event-specific tables in this section: 
 
• 
Injection site reaction  
• 
Urticaria or other hypersensitivity reaction 
• 
Serum sickness 
• 
Elevated ALT, total bilirubin, and creatinine values 
• 
Decreased absolute neutrophil counts 
 
 
 


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INJECTION SITE REACTION 
SEVERITY 
VRC01 MANAGEMENT  
FOLLOW-UP  
Grade 1 or 2  
Continue administration of VRC01 
doses.  Use alternate injection site 
until event resolves to less than 
Grade 1 
• Evaluate at subsequent visits per SoE.  
Grade 3, resolves 
within two hours 
Defer VRC01 until event reviewed 
with CMC.  
• Contact CMC within 72 hours.  
• If CMC and site investigator agree, 
may administer subsequent VRC01 
dose.  
Grade 3, persists 
longer than two 
hours  
Defer VRC01 until event reviewed 
with CMC.  
• Contact CMC within 72 hours.  
• Provide immediate clinical 
management per site investigator and 
subsequently in consultation with 
CMC. 
• If no alternative etiology is identified, 
permanently discontinue VRC01.  
• If alternative etiology identified and 
CMC agrees, may administer 
subsequent VRC01 dose.  If grade 3 
injection site reaction recurs, 
permanently discontinue VRC01. 
Grade 4 
Permanently discontinue VRC01.  
• Contact CMC within 72 hours.  
• Provide immediate clinical 
management per site investigator and 
subsequently in consultation with 
CMC. 
 
URTICARIA OR OTHER HYPERSENSTIVITY REACTION 
SEVERITY 
VRC01 MANAGEMENT  
FOLLOW-UP  
Grade 1, 2, 3, 4 
Stop VRC01 administration.  
Defer VRC01 until event reviewed 
with the CMC. 
• Contact CMC within 72 hours.  
• Assess for alternative cause; treat the 
underlying illness or remove the 
likely causative agent.  
• Provide immediate clinical 
management per site investigator (see 
study-specific MOP for guidance) and 
subsequently in consultation with 
CMC.  
• If diagnosis confirmed and assessed 
by either site investigator or CMC as 
related to VRC01, permanently 
discontinue VRC01. 
• If diagnosis not confirmed or definite 
alternative cause identified and event 
has resolved and CMC agrees, may 
administer subsequent VRC01 dose.  
If event recurs, permanently 
discontinue VRC01.   
 


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SERUM SICKNESS 
SEVERITY 
VRC01 MANAGEMENT  
FOLLOW-UP  
Grade 1  
Defer VRC01 until event reviewed 
with CMC. 
• Contact CMC within 72 hours.  
• Assess for alternative cause; treat the 
underlying illness or remove the likely 
causative agent.  
• Provide immediate clinical management 
per site investigator and subsequently in 
consultation with CMC.   
• If diagnosis confirmed and assessed by 
either site investigator or CMC as 
related to VRC01, permanently 
discontinue VRC01. 
• If diagnosis not confirmed or possible 
alternative cause identified and event 
has resolved and CMC agrees, may 
administer subsequent VRC01 dose.  If 
event recurs at any grade, permanently 
discontinue VRC01.   
Grade 2 
Defer VRC01 until event reviewed 
with CMC. 
• Contact CMC within 72 hours.  
• Assess for alternative cause. 
• Provide immediate clinical management 
per site investigator and subsequently in 
consultation with CMC.    
• If diagnosis confirmed and assessed by 
site investigator or CMC as related to 
VRC01, permanently discontinue 
VRC01. 
• If diagnosis not confirmed or probable 
alternative cause identified and has 
event has resolved and CMC agrees, 
may administer subsequent next 
VRC01 dose.  If event recurs at any 
grade, permanently discontinue VRC01.   
Grade 3 or 4 
Defer VRC01 until event reviewed 
with CMC. 
• Contact CMC within 72 hours.  
• Assess for alternative cause. 
• Provide immediate clinical management 
per site investigator and subsequently in 
consultation with CMC.    
• If diagnosis confirmed and assessed by 
site investigator or CMC as related to 
VRC01, permanently discontinue 
VRC01. 
• If diagnosis not confirmed or definite 
alternative cause identified and event 
has resolved and CMC agrees, may 
administer subsequent VRC01 dose. If 
event recurs at any grade, permanently 
discontinue VRC01.   
 
 
 


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ELEVATED ALT, TOTAL BILIRUBIN, OR CREATININE 
SEVERITY 
VRC01 MANAGEMENT  
FOLLOW-UP  
Grade 1 or 2 
Continue administration of VRC01 
doses.  
• Evaluate at subsequent visits per SoE 
or more frequently at the discretion of 
site investigator. 
Grade 3  
Defer VRC01 until event reviewed 
with CMC.  
• Contact CMC within 72 hours. 
• Repeat test within 3 working days.  
• If repeat test result is ≤ Grade 2, 
manage as per Grade 2.  
• Assess for alternative cause; treat the 
underlying illness or remove the 
likely causative agent.  
• If possible alternative cause identified 
and event has resolved to <Grade 3 
and CMC agrees, may administer 
subsequent VRC01 dose. If event 
recurs at Grade 3 or higher, 
permanently discontinue VRC01.   
• If no possible alternative cause 
identified, permanently discontinue 
VRC01.   
Grade 4 
Defer VRC01 until event reviewed 
with CMC.  
• Contact CMC within 72 hours. 
• Repeat test within 3 working days.  
• If repeat test result is ≤ Grade 2, 
manage as per Grade 2.  
• Assess for alternative cause; treat the 
underlying illness or remove the 
likely causative agent. 
• If probable alternative cause 
identified and event has resolved to 
<Grade 3 and CMC agrees, may 
administer the next VRC01 dose.  If 
event recurs at Grade 3 or higher, 
permanently discontinue VRC01.   
• If no probable alternative cause 
identified, permanently discontinue 
VRC01.   
 
 
 


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DECREASED ABSOLUTE NEUTROPHIL COUNT 
SEVERITY 
VRC01 MANAGEMENT  
FOLLOW-UP  
Grade 1 or 2  
Continue administration of VRC01 
doses. 
• Evaluate at subsequent visits per SoE 
or more frequently at the discretion of 
site investigator.  
Grade 3 
Defer VRC01 until event reviewed 
with CMC.  
• Contact CMC within 72 hours. 
• Repeat test within 3 working days.  
• If repeat test result is ≤ Grade 2, 
manage as per Grade 2.  
• Assess for alternative cause; treat the 
underlying illness or remove the 
likely causative agent.  
• If possible alternative cause identified 
and event has resolved to <Grade 3 
and CMC agrees, may administer 
subsequent VRC01 dose. If event 
recurs at Grade 3 or higher, 
permanently discontinue VRC01.   
• If no possible alternative cause 
identified, permanently discontinue 
VRC01.   
Grade 4  
Defer VRC01 until event reviewed 
with CMC.  
• Contact CMC within 72 hours. 
• Repeat test within 3 working days.  
• If repeat test result is ≤ Grade 2, 
manage as per Grade 2.  
• Assess for alternative cause; treat the 
underlying illness or remove the 
likely causative agent. 
• If probable alternative cause 
identified and event has resolved to 
<Grade 3 and CMC agrees, may 
administer the next VRC01 dose.  If 
event recurs at Grade 3 or higher, 
permanently discontinue VRC01.   
• If no probable alternative cause 
identified, permanently discontinue 
VRC01.   
 
 
 
 


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8.2 
Deferral of Study Product Administration 
 
The specifications of this section apply only to infants randomized to Arm 1.  
 
At each study product administration time point, the site investigator or designee must confirm 
infant eligibility to receive study product based on review of medical history, physical 
examination findings, and prior laboratory test results.   
 
For the types of adverse events listed in Section 8.1.2, study product administration must be 
deferred consistent with the guidance provided in the event-specific tables in that section.  
 
For all other types of adverse events, if any of the following are present on the scheduled day of 
study product administration, administration must be deferred, and the CMC should be consulted 
on next steps: 
 
• 
Any grade 3 or higher adverse event (sign, symptom, diagnosis, or laboratory test result)  
 
• 
Any other significant medical condition that, in the opinion of the investigator, would make it 
unsafe to administer study product or make it difficult to assess for subsequent product-
related adverse events  
 
Following required consultation with the CMC, and improvement or resolution of the 
exclusionary condition (if applicable), study product may be administered.  Whenever possible, 
infants should be re-scheduled to return to the clinic for product administration within the 
allowable visit window.  If the allowable window elapses, the site investigator should consult 
with the CMC, which may approve product administration after the allowable window.   
 
Infants who miss one or more scheduled administrations of study product will remain in follow-
up and will ideally complete all visits, subsequent study product administrations, and evaluations 
specified in Section 6 and Appendix I.   
 
8.3 
Discontinuation of Study Product Administration 
 
The specifications of this section apply only to infants randomized to Arm 1.  
 
Administration of study product will be permanently discontinued in the event that: 
 
• 
The infant’s parent or legal guardian refuses further study product administration or 
evaluations required to monitor safety following study product administration 
 
• 
The infant does not receive the study Entry (Week 0) dose of VRC01 within 14 days after 
initiation of cART. 
 
• 
The infant experiences an adverse event requiring permanent discontinuation of study product 
per the event-specific tables in Section 8.1.2.   
 
• 
The infant experiences a grade 3 or higher adverse event that is assessed as related to study 
product and, in consultation with the CMC, is determined to require discontinuation of study 
product administration. 
 


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• 
The site investigator determines that further administration of study product would not be in 
the best interest of the infant (consultation with the CMC is encouraged but not required prior 
to final determination) 
 
Note:  For infants who experience a grade 3 or higher adverse event, and for whom study product 
administration is approved to continue following improvement/resolution of the event, if the same 
grade 3 or higher adverse event recurs after subsequent study product administration, no further 
study product will be administered, unless there is an alternative explanation for the recurrence 
of the event and the CMC approves further study product administration. 
 
Infants who are permanently discontinued from administration of study product will remain in 
follow-up and will complete all visits and evaluations specified in Section 6 and Appendix I. 
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
This is a Phase I/II, multisite, two-arm, randomized, controlled, open-label study to evaluate the 
safety and antiviral activity of VRC01 among HIV-1-infected infants initiating cART within 12 
weeks of birth.  A total of 68 infants are expected to be enrolled at study sites located in 
Botswana, Brazil, Haiti, Malawi, South Africa, Zimbabwe, and the US.  Enrolled infants will be 
randomly assigned in a 1:1 ratio to either receive VRC01 (Arm 1) or to not receive VRC01 (Arm 
2).  Infants assigned to receive VRC01 will be administered subcutaneous injections (40 mg/kg) 
at study Entry (Week 0) and Weeks 2, 6, and 10.  Enrolled infants will be followed for 48 weeks 
with safety, pharmacokinetic, and antiviral activity evaluations performed throughout the duration 
of follow-up as specified in Section 6 and Appendix I. 
 
Infants’ mothers may optionally enroll in this study for purposes of one-time blood collection at 
the time of infant study entry, but mothers will not receive VRC01, will not undergo any other 
study evaluations, and will not be followed after blood collection at study entry. 
 
As this is a relatively small study, only relatively large differences in safety and efficacy will be 
detectable between arms. 
 
9.2 
Outcome Measures 
 
Note:  The numbering of outcome measures in this section corresponds to the numbering of the 
study objectives in Section 2.  Additional exploratory outcome measures will be defined after 
completion of the primary, secondary, and other analyses described in Section 9.6. 
 
The primary and secondary outcome measures listed in Section 9.2.1 and 9.2.2 below will be 
addressed in the study’s primary statistical analysis plan, which will define the content of the 
primary analysis report. This report will form the basis for the primary study publication and 
results reporting to ClinicalTrials.gov. Outcomes of interest for other objectives (intended for 
subsequent publications) are listed as other outcome measures in Section 9.2.3. 
 
 


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9.2.1 
Primary Outcome Measures 
9.2.1.1 
• Grade 3 or higher adverse events including reactogenicity outcomes, 
abnormal laboratory test results, signs, symptoms, and diagnoses occurring 
from randomization through Week 14 
9.2.1.2 
• Change of HIV-1 DNA concentration in PBMCs from baseline (Week 0) to 
Week 14 
9.2.2 
Secondary Outcome Measures 
9.2.2.1 
• Pharmacokinetic parameters of VRC01 in the plasma at Weeks 2, 6, 10, 14, 
and 16 (Arm 1 only; see Section 10 for more details) 
9.2.3 
Other Outcome Measures 
9.2.3.1 
• Grade 3 or higher adverse events including reactogenicity outcomes, 
abnormal laboratory test results, signs, symptoms, and diagnoses occurring 
from randomization through Week 48  
9.2.3.2 
• Detection of antibodies against VRC01 at Weeks 14, 24, and 48 (binary 
outcome, Arm 1 only) 
9.2.3.3 
• Time from study entry to first plasma HIV-1 RNA below 40 copies/mL 
9.2.3.4 
• Change of HIV-1 DNA concentration in PBMCs from baseline (Week 0) to 
Weeks 24 and 48  
• Change of HIV-1 RNA concentration in PBMCs (multiply-spliced and 
unspliced) from baseline (Week 0) to Weeks 14, 24, and 48  
• Concentration in PBMCs of inducible HIV-1 RNA measured by TILDA at 
Weeks 24 and 48 
9.2.3.5 
• ADCC activity against viral isolates (expressed as antibody titers) at Weeks 
14, 24, and 48  
• Neutralization against viral isolates (expressed as antibody titers) at Weeks 
14, 24, and 48  
 
9.3 
Randomization 
 
Infants will be randomized in a 1:1 ratio to the two study arms using the permuted block method 
and stratified by whether the infant’s initial cART regimen included an integrase inhibitor.  In the 
event that twins (or other multiplets) are enrolled, both (all) infants will be randomized to the 
same arm.  Randomization will not be balanced within each site, as some sites may have small 
numbers of participants. 
 
9.4 
Sample Size and Accrual 
 
Sixty-eight infants are planned to be enrolled, with approximately 34 in Arm 1 and 34 in Arm 2, 
in order to have at least 20 infants per arm who are evaluable for the primary antiviral activity 
outcome at Week 14.  Infants will be considered evaluable for this analysis based on an as-treated 
population who receive at least the first scheduled dose of VRC01 dose (Arm 1) and do not 
interrupt cART for more than three consecutive days prior to the Week 14 visit (Arm 1 and Arm 
2).  Infants who are not considered evaluable will not be replaced.   
 
All enrolled infants will be included in safety analyses.  
 
Enrollment is anticipated to be completed within one year after the first infant is enrolled in the 
study. 


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9.4.1 
Safety 
 
For the primary safety objective, Table 5 summarizes the probability of observing at least one 
adverse event (AE, as defined in Section 9.2.1) with 10, 20, 25, 34, and 40 participants and a 
variety of hypothetical event probabilities.  For example, assuming the hypothetical probability of 
an adverse event in the Arm 1 is 0.05, with a sample size of 34, the probability of observing at 
least one participant with an adverse event will be 0.83. 
 
Table 5 
Probability of Observing at Least One Adverse Event with Sample Sizes of  
10, 20, 25, 34, and 40 Infants within an Arm and Hypothetical Adverse Event Probabilities 
Sample Size 
True Probability of an AE 
Probability of Observing at Least One AE 
10 
0.01 
0.10 
0.03 
0.26 
0.05 
0.40 
0.07 
0.52 
0.09 
0.61 
 
20 
0.01 
0.18 
0.03 
0.46 
0.05 
0.64 
0.07 
0.77 
0.09 
0.85 
 
25* 
0.01 
0.22 
0.03 
0.53 
0.05 
0.72 
0.07 
0.84 
0.09 
0.91 
 
34* 
0.01 
0.29 
0.03 
0.64 
0.05 
0.83 
0.07 
0.92 
0.09 
0.96 
 
40 
0.01 
0.33 
0.03 
0.70 
0.05 
0.87 
0.07 
0.95 
0.09 
0.98 
*Sample sizes of 25 and 34 are used to power the study for the primary objective of antiviral activity 
(please see section on antiviral activity below) 
 
 
 
 


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Table 6 provides 95% confidence intervals (CIs), based on the Wilson Score method, on the 
adverse event probability for various observed adverse event numbers across sample sizes of 10, 
20, 25, 34, and 40 infants.  For example, if an adverse event is observed in 5 out of 34 infants, 
based on the 95% CI, these data are consistent with an adverse event occurring with a probability 
between 0.10 and 0.36.  The resulting CI is also relevant if no adverse events are observed.  
Notably, observing no events among 34 infants is consistent with a probability of an adverse 
event of 0 to 0.10.   
 
Table 6 
95% Confidence Intervals for the Probability of an Adverse Event with Sample Sizes 
(and Adverse Event Numbers) of 10, 20, 25, 34, and 40 infants within an Arm 
Sample Size 
Number  
of Events 
Proportion with 
an Event 
95% CI  
Lower Bound 
95% CI  
Upper Bound 
Width 
10 
0 
0 
0.00 
0.28 
0.28 
 
1 
0.1 
0.02 
0.40 
0.39 
 
2 
0.2 
0.06 
0.51 
0.45 
 
3 
0.3 
0.11 
0.60 
0.50 
 
4 
0.4 
0.17 
0.69 
0.52 
 
5 
0.5 
0.24 
0.76 
0.53 
 
20 
0 
0 
0.00 
0.16 
0.16 
 
2 
0.1 
0.03 
0.30 
0.27 
 
4 
0.2 
0.08 
0.42 
0.34 
 
6 
0.3 
0.15 
0.52 
0.37 
 
8 
0.4 
0.22 
0.61 
0.39 
 
10 
0.5 
0.30 
0.70 
0.40 
 
25* 
0 
0 
0.00 
0.13 
0.13 
 
2 
0.1 
0.03 
0.28 
0.24 
 
4 
0.2 
0.09 
0.39 
0.30 
 
5 
0.2 
0.09 
0.39 
0.30 
 
10 
0.4 
0.23 
0.59 
0.36 
 
15 
0.6 
0.41 
0.77 
0.36 
 
34* 
0 
0 
0.00 
0.10 
0.10 
 
4 
0.1 
0.04 
0.24 
0.21 
 
5 
0.2 
0.10 
0.36 
0.26 
 
10 
0.3 
0.17 
0.47 
0.29 
 
15 
0.5 
0.34 
0.66 
0.32 
 
40 
0 
0 
0.00 
0.09 
0.09 
 
4 
0.1 
0.04 
0.23 
0.19 
 
10 
0.25 
0.14 
0.40 
0.26 
 
15 
0.4 
0.26 
0.55 
0.29 
 
20 
0.5 
0.35 
0.65 
0.30 
*Sample sizes of 25 and 34 are used to power the study for the primary objective of antiviral activity 
(please see section on antiviral activity below) 
 
 
 


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9.4.2 
Antiviral Activity 
 
The antiviral activity analysis is powered on the primary assessment of an average change from 
baseline (Week 0) to Week 14 in HIV-1 DNA concentration in PBMCs (log10 HIV-1 DNA copies 
per million PBMCs) between arms.   
 
Data from the IMPAACT P1030 study [9] were reviewed to provide an estimate of the mean and 
standard deviation (SD) in the change from baseline to Week 14 in log10 HIV-1 DNA copies per 
million PBMCs (referred to as log10 HIV-1 DNA copies) for the sample size and power 
calculations for detecting a difference in the mean change between arms.  
 
P1030 was a multicenter, phase I/II, open-label, single arm trial of LPV/r for treatment of 31 
HIV-1-infected infants in which the pharmacokinetic properties of LPV/r were established.  HIV-
1 DNA data were available on 24, 20, 20, and 16 participants at Week 0 (baseline) and 24, 48, 
and 96 weeks, respectively, after cART initiation.  In P1030, HIV-1 DNA measurements were not 
assayed during the weeks between baseline and Week 24, so there are no data for Week 14, the 
primary evaluation time point for this study.  Therefore, these calculations are based on data from 
20 participants with available HIV-1 DNA copies per million PBMC measurements both at 
baseline and data at the nearest available time point (Week 24).   
 
In P1030, the mean (SD) log10 HIV-1 DNA copies measurements at baseline was 3.16 log10 (0.7 
log10) HIV-1 DNA copies, and all infants had detectable HIV-1 DNA copies.  The mean (SD) 
log10 HIV-1 DNA copies change from baseline to Week 24 was 0.88 (0.34) log10 HIV-1 DNA 
copies for the 20 participants with data both at baseline and week 24. 
 
Based on these estimates, sample size and power calculations for this study consider a range of 
possible differences of mean changes between two arms from baseline to Week 14 of 0.75, 1.0, 
and 1.5 and SD of change of 0.5 to 2.0 log10 HIV-1 DNA copies.  Evaluable sample sizes of 10, 
20, 30, and 40 participants per arm (20, 40, 60, 80 total for two arms) were considered to power 
the study.  Calculations are based on the two-sided t-test with pooled variances for the primary 
outcome of antiviral activity comparison between arms with a 5% significance level (Table 7).  
Assuming a SD of 1.0, the study would have 87% power to detect a difference in mean change of 
HIV-1 DNA of 1.0 log10 copies between two arms with a sample size of 20 analyzed participants 
per arm (40 total for two arms).  A difference of 1.0 log10 would be considered a meaningful 
difference. 
 
Incorporating a non-parametric adjustment to use the Wilcoxon rank sum test, the necessary 
sample size per arm is 21 (using a relative efficiency ratio of 0.95).  Adjusting for 20% missing 
data at baseline and/or at Week 14 due to VRC01 or cART discontinuation, loss-to-follow-up, 
missed visits or potential problems with the samples, the sample size per arm should be 25 infants 
per arm (50 total for two arms).   
 
Furthermore, data on the effect of VRC01 on viremia in HIV-1-infected adults [12], indicate that 
a proportion of the viremic adults treated with VRC01 had virus that resisted neutralization by 
VRC01. An additional analysis will restrict the comparison between arms to infants with 
susceptible (not resistant) virus, as identified through testing planned to be performed after study 
completion.  To provide adequate statistical power for this analysis, and assuming that up to 25% 
of infants may be identified with virus that is resistant to VRC01 neutralization at entry, the final 
selected sample size of 34 infants per arm represents a 25% increase from the 25 per arm noted 
above (25/0.75).      


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Table 7 
Power to Detect a Difference Between Arms in  
Mean Change of Log10 HIV-1 DNA Copies per Million PBMCs at Week 14 
Standard  
Deviation 
Mean 
Difference 
Sample Size  
per Arm 
Power 
0.50 
0.75 
10 
0.89 
20 
>0.99 
30 
>0.99 
40 
>0.99 
1.00 
10 
0.99 
20 
>0.99 
30 
>0.99 
40 
>0.99 
1.50 
10 
>0.99 
20 
>0.99 
30 
>0.99 
40 
>0.99 
2.00 
10 
>0.99 
20 
>0.99 
30 
>0.99 
40 
>0.99 
1.00 
0.75 
10 
0.36 
20 
0.64 
30 
0.81 
40 
0.91 
1.00 
10 
0.56 
20 
0.87 
30 
0.97 
40 
0.99 
1.50 
10 
0.89 
20 
>0.99 
30 
>0.99 
40 
>0.99 
2.00 
10 
0.99 
20 
>0.99 
30 
>0.99 
40 
>0.99 
1.50 
0.75 
10 
0.19 
20 
0.34 
30 
0.48 
40 
0.60 
1.00 
10 
0.29 
20 
0.54 
30 
0.72 
40 
0.84 
1.50 
10 
0.56 
20 
0.87 
30 
0.97 
40 
0.99 
2.00 
10 
0.80 
20 
0.98 
30 
>0.99 
40 
>0.99 


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Table 7 
Power to Detect a Difference Between Arms in  
Mean Change of Log10 HIV-1 DNA Copies per Million PBMCs at Week 14 
Standard  
Deviation 
Mean 
Difference 
Sample Size  
per Arm 
Power 
2.00 
0.75 
10 
0.12 
20 
0.21 
30 
0.30 
40 
0.38 
1.00 
10 
0.19 
20 
0.34 
30 
0.48 
40 
0.60 
1.50 
10 
0.36 
20 
0.64 
30 
0.81 
40 
0.91 
2.00 
10 
0.56 
20 
0.87 
30 
0.97 
40 
0.99 
 
9.5 
Monitoring 
 
Implementation of this study will be monitored at multiple levels, consistent with standard 
procedures described in the IMPAACT Manual of Procedures.  Included in these standard 
procedures is monthly review of participant accrual and retention by the IMPAACT Management 
Oversight Group.  A study monitoring plan that details monitoring roles and responsibilities and 
data to be reviewed at each level will be prepared before the study opens to accrual.  Sections 11 
and 12 provide more information on on-site monitoring and quality management at the site level.  
Further information on monitoring of study progress, quality of study conduct, participant safety, 
pharmacokinetics, and antiviral activity across sites is provided below. 
 
9.5.1 
Monitoring by the Protocol Team 
 
Study Progress and Quality of Study Conduct 
 
The Protocol Team is responsible for continuous monitoring of study progress, including timely 
achievement of key milestones and quality of study conduct.   
 
The Protocol Team will closely monitor participant accrual based on reports that will be 
generated at least monthly by the SDMC.  The team has developed a study accrual plan that 
includes site-specific and total enrollment projections over the course of the accrual period, and 
actual accrual will be monitored relative to these projections.  The team will monitor the timing 
of site-specific study activation, which will determine when each site will begin accruing 
participants, and actual accrual following activation.  For any site that is delayed in completing 
the study activation process or that falls short of its accrual projections, the team will 
communicate with the site to identify the barriers the site has encountered and the operational 
strategies and action plans to address these.   
 


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The Protocol Team will monitor participant retention in a manner similar to participant accrual.  
On behalf of the Protocol Team, the CMC will monitor adherence to study product regimen and 
other key indicators of the quality of study conduct (e.g., data quality, data and specimen 
completeness) based on reports generated by the SDMC and will take action with study sites as 
needed to ensure high quality study conduct throughout the period of study implementation.  
 
Participant Safety 
 
On behalf of the Protocol Team, the CMC will closely monitor participant safety through routine 
review of safety data reports generated by the SDMC.  These reports will provide information on 
adverse events reported in the eCRF database for Arm 1 and Arm 2, including abnormal 
laboratory test results, signs, symptoms, and diagnoses.  For infants in Arm 1, local injection site 
reactions will also be listed.  The CMC will review data at the infant level, and data listings will 
include information on receipt of VRC01 and cART.  Therefore, the CMC will be unblinded to 
participant random assignments.   
 
The CMC will review safety data reports via conference call or other meeting at least monthly 
and — in addition to the site investigator — will assess the relationship of reported adverse 
events to the study product according to the categories of attribution provided in Section 8.1.  In 
addition to individual adverse event listings, data reports will include the cumulative number and 
frequency of grade 2 or higher adverse events assessed as related to VRC01.  At the time of each 
review, the DAIDS Medical Officer will also review any EAEs reported for infants in Arm 1 
(defined in Section 7.3) reported to the DAIDS Safety Office that are not yet reflected in the 
eCRF database.  The CMC will continually evaluate the pattern and frequency of reported events 
and assess for any individual occurrences or trends of concern.  
 
The CMC will also monitor whether any of the safety-related triggers for SMC review specified 
in Section 9.5.2 are met.  If so, the CMC will rapidly review the triggering events and notify the 
SMC that an ad hoc review is required.  The CMC will likewise request SMC review of any other 
safety concerns that may be identified throughout the course of the study.     
 
In addition to the routine reviews described above, given that the VRC01 dosing regimen 
specified for this study has not previously been administered to infants, an interim safety analysis 
will be performed when the first five infants in Arm 1 have completed their Week 3 visits.  This 
analysis will include all adverse events for all infants enrolled in the study at the time of the 
analysis.  The CMC will review these data prior to SMC review; participant accrual will continue 
pending the SMC’s review unless a safety-related trigger for SMC review (see Section 9.5.2) is 
met.  
 
Pharmacokinetics 
 
The regimen of VRC01 administered in this study is expected to maintain targeted concentrations 
of VRC01.  To confirm that targeted concentrations are being achieved, an interim analysis will 
be performed when six infants randomized to Arm 1 have received the first two scheduled doses 
of VRC01 and have specimens available for PK analysis through Week 6.  The CMC will review 
the dose evaluation data as soon as available and provide the data — along with a 
recommendation as to whether dose adjustment appears to be indicated — for independent review 
by the SMC.  See Section 9.5.2 for further information about this SMC review and Section 10 for 
further information on the clinical pharmacology plan.   
 


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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.   
 
9.5.2 
Monitoring by the SMC  
 
An independent IMPAACT Study Monitoring Committee (SMC) will review this study regularly, 
following policies described in the IMPAACT Manual of Procedures.  The composition of the 
SMC will include the SMC Chair; IMPAACT Chair or Vice Chair; IMPAACT Cure Scientific 
Committee Chair or Vice Chair; representatives of the IMPAACT Operations Center, Statistical 
and Data Management Center, and Laboratory Center; and representatives of NIAID and NICHD.  
 
The first SMC review of this study is expected at the time of the interim safety analysis, which 
will be performed when the first five infants in Arm 1 have completed their Week 3 visits.  The 
first regularly scheduled SMC review will occur after the first 50% of participants are enrolled or 
at 12 months after the first site is activated to initiate the study (whichever comes first); regular 
reviews will then be scheduled annually.  SMC reviews may also occur on a more frequent or ad 
hoc basis if any issues or concerns arise, or if requested by the SMC.  Based on any of its 
reviews, the SMC may recommend that the study proceed as currently designed, proceed with 
design modifications, or be discontinued.  The SMC may also provide operational 
recommendations to help address any study implementation challenges that may be identified 
during their reviews.   
 
Reports prepared for the SMC will present data by blinded study arm; codes will also be provided 
to permit unblinding at the discretion of the SMC.   
 
Study Progress and Quality of Study Conduct 
 
The SMC will monitor study progress and the quality of study conduct through review of the 
same types of data reports as the Protocol Team and CMC.  As noted above, however, reports 
prepared for the SMC will present data by blinded study arm.   
 
Participant Safety 
 
The SMC will monitor participant safety through review of the same types of safety data reports 
as the CMC; however, data will be made available to the SMC by blinded study arm when 
possible (data on local injection site reactions will not be blinded).  For ad hoc or triggered safety 
reviews, more limited data may be provided, focusing on the events that triggered the reviews.   
 
As indicated above, the SMC will review an interim safety analysis when the first five infants in 
Arm 1 have completed their Week 3 visits.  This analysis will include all adverse events for all 
infants enrolled in the study at the time of the analysis; the SMC will additionally focus on safety-
related trigger events (listed below).  If trigger 1 or trigger 2 is met, or if other safety-related 
concerns warranting a change of study design are identified, accrual into the study and 
administration of study product will be paused. 
 


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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 
 
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 will be counted in scenario (3). 
 
If either scenario (1) or scenario (2) 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 (3) 
occurs, accrual into the study and administration of study product will not be paused, and an SMC 
review will take place within seven days. 
 
In the event of any other event or trend of concern identified by the CMC, an SMC review may 
be requested, and the CMC may choose to pause participant accrual and administration of study 
product pending the outcome of the SMC review. 
 
Following any pause, participant accrual and administration of study product may be resumed if 
recommended by the SMC.  If resumption is not recommended, no further participants will be 
enrolled and no further study product will be administered, but all enrolled participants will 
continue follow-up per protocol, unless otherwise advised by the SMC. 
 
Given the relatively small study sample size, the information available for safety decisions will be 
imperfect.  Two types of sampling errors are possible:  
 
1. In a group where the true rate of adverse events is too high to warrant increased exposure to 
VRC01, the sample data may pass the safety guidelines;  
2. In a group where the true rate of adverse events is low enough that further exposure to 
VRC01 is warranted the sample data may fail the guidelines.   
 
The extent to which the safety guidelines protect against the errors described above can be 
assessed by examining various hypothetical "true adverse events" rates that could occur if the 
study product were used extensively among the participant population.  The hypothetical 
situations presented in Table 8 range from conditions under which VRC01 would cause a high 
incidence of severe and life threatening adverse events to conditions under which severe adverse 
events would be relatively rare and would not be life threatening.  For each of these hypothetical 
situations, it is assumed that a sample of 25 infants is drawn from the participant population, 
receives VRC01, and that the safety guidelines specified above are followed.    
 
For example, Table 8 shows that there is an 86% chance of meeting the safety review trigger for 
the SMC under conditions in which the true rate of Grade 4 adverse events or deaths is 5% and 
the rate of Grade 3 adverse events is 10%, and a 92% chance if the true rate of Grade 4 adverse 
events or deaths is 7% and the rate of Grade 3 adverse events is 10%.  Assuming that VRC01 is 
associated with this extent of severe adverse events would be unacceptable, the 14% and 8% 
chance of not triggering an SMC safety review under these conditions, respectively, would 
represent sampling error. 


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The true rate of Grade 3 events would have to be over 10% to provide a strong probability of 
pausing the study when there are no Grade 4 events or deaths in Arm 1.  This is considered 
acceptable, since a larger sample size would be needed to increase the probability of pausing the 
study at lower rates of Grade 3 events, and this would entail exposing greater numbers of children 
to VRC01, which may be either toxic or sub-therapeutic.  (Accordingly, the probability of 
meeting study pausing guideline for SMC review would be lower for smaller sample sizes than 
the sample size of 25). 
 
Table 8  
Probability of Failing Safety Criteria (n = 25) 
True Adverse Event Rates 
 
Grade 3 AE related to 
VRC01 
Grade 4 or death related 
to VRC01 
Probability of meeting study 
pausing guideline for SMC 
review 
0.50 
0.00 
>0.99 
0.50 
0.01 
>0.99 
0.50 
0.02 
>0.99 
0.50 
0.05 
>0.99 
0.50 
0.07 
>0.99 
 
0.25 
0.00 
0.97 
0.25 
0.01 
0.98 
0.25 
0.02 
0.98 
0.25 
0.05 
0.99 
0.25 
0.07 
>0.99 
 
 
 
0.15 
0.00 
0.75 
0.15 
0.01 
0.81 
0.15 
0.02 
0.85 
0.15 
0.05 
0.94 
0.15 
0.07 
0.97 
 
0.10 
0.00 
0.46 
0.10 
0.01 
0.59 
0.10 
0.02 
0.68 
0.10 
0.05 
0.86 
0.10 
0.07 
0.92 
 
0.05 
0.00 
0.13 
0.05 
0.01 
0.32 
0.05 
0.02 
0.48 
0.05 
0.05 
0.76 
0.05 
0.07 
0.86 
 
0.01 
0.00 
<0.01 
0.01 
0.01 
0.22 
0.01 
0.02 
0.40 
0.01 
0.05 
0.72 
0.01 
0.07 
0.84 


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True Adverse Event Rates 
 
Grade 3 AE related to 
VRC01 
Grade 4 or death related 
to VRC01 
Probability of meeting study 
pausing guideline for SMC 
review 
 
0.00 
0.01 
0.22 
0.00 
0.02 
0.40 
0.00 
0.05 
0.72 
0.00 
0.07 
0.84 
 
Pharmacokinetics 
 
The regimen of VRC01 administered in this study is expected to maintain targeted concentrations 
of VRC01.  To confirm that targeted concentrations are being achieved, an interim analysis will 
be performed when six infants randomized to Arm 1 have received the first two scheduled doses 
of VRC01 and have specimens available for PK analysis through Week 6.  The CMC will review 
the dose evaluation data as soon as available and provide the data — along with the CMC’s 
interpretation of the data and recommendation as to whether dose adjustment appears to be 
indicated — for review by the SMC.  If these data are available at the time of a routinely 
scheduled SMC review, they will be provided to the SMC at the time of that review; otherwise, 
they will be provided to the SMC with a request for an ad hoc review. 
 
Antiviral Activity 
 
When approximately 50% of participants have reached Week 14, the SMC will review data on 
plasma HIV-1 RNA levels as a measure of antiviral activity.  The SDMC will first generate 
plasma HIV-1 RNA profiles for each infant and descriptive summary statistics for the change 
from randomization (Week 0) for each arm (blinded) for review by the SMC.  If the SMC has 
concerns of lack of antiviral activity, prior to recommending changes to the study accrual plan or 
design, available specimens will be tested for (i) ARV drug concentrations, (ii) virus 
susceptibility to VRC01, and (iii) HIV-1 DNA concentrations in PBMCs.  These results will be 
provided to the SMC for further consultation regarding continuing participant accrual or stopping 
accrual early. 
 
If the above-described data are available at the time of a routinely scheduled SMC review, they 
will be provided to the SMC at the time of that review; otherwise, they will be provided to the 
SMC for an ad hoc review.  
  
9.6 
Analyses 
 
A detailed statistical analysis plan will be developed and finalized before the first distribution of 
safety data for CMC review.  
 
All statistical tests will be two-sided with a nominal significance level of 0.05.   
 
In the event that twins or other multiplets are enrolled in the study, one of the multiplets will be 
randomly selected to be included in the analyses. Sensitivity analyses will be performed in which 
the selected infant will be replaced by the other sibling(s) to ensure that any choice would support 
the same overall results. Line listings will provide individual data from all infants. 
 


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9.6.1 
Primary Analyses 
 
 
Safety 
 
All enrolled infants will be included in safety analyses.   
 
For the primary safety analysis, Grade 3 or higher adverse events occurring after randomization 
cumulatively through Week 14 will be summarized.  Descriptive analyses will consist of 
frequency distributions by type of event.  For each infant, the worst grade of adverse event 
experienced will be summarized.  Separate summaries and listings of deaths will also be 
provided.  Estimates of Grade 3 or higher adverse event rates will be computed separately for 
each arm and bounded by 95% CIs, reflecting the precision of the estimates using the Wilson 
Score method.  Death rates will also be computed separately for each arm and bounded by 95% 
CI.   
 
 
Antiviral Activity 
 
The primary analysis of antiviral activity will be an as-treated analysis, limited to evaluable 
infants who do not interrupt cART for more than three consecutive days prior to the Week 14 
visit and, if randomized to Arm 1, who receive at least the first scheduled dose of VRC01.  
 
Log-transformations will be applied to the primary antiviral activity outcome of HIV-1 DNA 
concentration in PBMCs.  For values below the assay detection limit, a value of one half the 
lower assay limit will be imputed.  The proportion of values below the assay limit will be 
summarized at each time point, if any. 
   
The values and changes from baseline (Week 0) of HIV-1 DNA concentration in PBMCs will be 
tabulated and summarized graphically at each scheduled study visit by calculating 95% CI around 
the mean.   
 
The primary analysis will compare the change in HIV-1 DNA concentrations in PBMCs from 
baseline to Week 14 between the two randomized arms, testing the null hypothesis of no 
difference in the distribution of change from baseline between the two arms, using a Wilcoxon 
rank sum test at a 5% significance level.  
 
Infants will not be tested at screening to determine if their virus is resistant to neutralization by 
VRC01.  However, an additional analysis of the primary outcome will exclude infants whose 
baseline virus is resistant to VRC01 neutralization, as identified at the time when HIV-1 DNA 
concentrations are determined. 
 
Sensitivity analyses will be conducted using the last available time point before Week 14 if 
HIV-1 DNA concentration in PBMCs is missing at Week 14.      
 
9.6.2 
Secondary Analyses 
 
Refer to Section 10 for a detailed description of the planned analyses of the PK of VRC01. 
 
 
 
 


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9.6.3 
Other Analyses 
 
 
Safety 
 
Analyses of the safety outcome through Week 48 will parallel the analysis approach of the 
primary safety outcome.   
 
The same summaries for the safety outcome for Arm 1 will also be provided for Arm 2.  
Additional analyses will compare the adverse event probabilities by arm with Fisher’s exact test 
with the mid-p option (as-treated and intent-to-treat analyses).  Injection reactions will be 
excluded when comparing safety between arms.  In another safety analysis, Grade 3 or higher 
adverse events that are judged by the CMC to be related to study product at any time 
cumulatively through Week 14 will also be summarized for Arm 1.   
 
VRC01 tolerability will be summarized by the number of participants who prematurely 
discontinue the study product along with the reasons for discontinuation.  Probabilities and 95% 
CIs will be estimated.   
 
 
Antiviral Activity 
 
Analyses of the antiviral activity outcomes — changes at Week 24 and Week 48 — will parallel 
the analysis approach of the primary antiviral activity outcome.  For analyses of inducible HIV-1 
RNA at Weeks 24 and 48, in the event that specimen collection volumes at baseline do not permit 
evaluation of changes from baseline to Week 24 or Week 48, TILDA results for the two 
randomized arms will be compared at each time point (rather than comparing changes from 
baseline). 
 
Time to event outcomes (e.g., time to viral load <40 copies/mL) for both arms will be estimated 
using the method of Kaplan-Meier. Time-to-event distributions will be compared with log-rank 
tests, and differences between arms will be assessed by the Cox proportional hazards model. 
 
Other analyses will additionally include sensitivity analyses of the primary outcomes, in 
particular restricting the VRC01 analysis set to those who received all four injections; intent-to-
treat analyses; and analyses with alternative censoring and imputation methods. 
 
An analysis of within-participant change will be evaluated by comparing post-VRC01 
measurements with pre-VRC01 measurements in all participants who received at least one 
infusion of VRC01 using a Wilcoxon signed rank test at 5% significance level. 
 
 
Other Outcomes 
 
The estimated probabilities of participants with a measurable level of antibody to VRC01 will be 
presented along with an exact 95% CI.   
 
The absolute values and changes of laboratory test results for different measures of HIV-1 
reservoir size, ADCC activity, and virus neutralization will be summarized graphically at each 
scheduled visit by calculating 95% CI around the mean. 
  
Analyses will parallel the analysis approach of the antiviral activity outcomes.  
 
 


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10  
CLINICAL PHARMACOLOGY PLAN 
 
10.1 
Pharmacology Objective 
 
The pharmacology objective of this study is to determine the pharmacokinetics (PK) of a regimen 
of four doses of VRC01 (40 mg/kg per dose) administered subcutaneously to HIV-1-infected 
infants initiating cART within 12 weeks of birth. 
 
10.2 
Pharmacology Data 
 
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) 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. 
 
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.  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 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. 
 
10.3 
Pharmacology Study Design, Modeling, and Data Analysis 
 
PK samples will be collected from all infants randomized to Arm 1 at the time points listed 
above.  At each time point, 1-2 mL of whole blood will be collected to yield 0.4-1.0 mL of 
plasma. 
 
VRC01 concentrations will be presented for each time point and the frequency of achieving 
trough concentrations greater than 20 and 50 mcg/mL at Week 2, 6, 10 and 14 will be calculated.  
The median, mean, and standard deviation of the concentrations will also be calculated from 
evaluable samples at each time point.  Evaluable samples are defined as those with adequate 


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volume and integrity to yield accurate concentration results, with associated accurate dosing and 
sample time data.   
 
It is expected that the VRC01 pharmacokinetic parameters and their variability observed in this 
study will be similar to those observed in IMPAACT P1112.  The observed VRC01 
concentrations will be compared to those observed in P1112 as well as those observed in adults.  
Specifically, the geometric mean and 90% CI for the Week 6 concentrations, which are expected 
to be the lowest observed concentrations in this study, will be generated.  Based on currently 
available data from infants and adults, the Week 6 concentrations are predicted to fall within the 
range of 20-70 mcg/mL, as shown in Figure 2. 
 
Figure 2 
Predicted VRC01 Concentrations:  
Median and 5th-95th Percentile 
  
0
28
56
84
112
Time Days
0
100
200
300
400
500
600
700
VRC01 Conc (mcg/mL)
Predicted VRC01 Conc (40mg/kg)
VRC01 PK M DL203 - 08JUN16
 
10.4 
Pharmacokinetic Analysis 
 
Given the sparse nature of the PK data being collected, non-compartmental pharmacokinetic 
analysis will not be performed.  However, population pharmacokinetic analyses using the 
computer program NONMEM will be conducted on the VRC01 pharmacokinetic data to 
determine VRC01 apparent clearance (CL/F).  Other compartmental PK parameters will be 
estimated to the extent possible.  Both one and two compartment pharmacokinetic models with 
first order absorption will be assessed based on existing pharmacokinetic studies of 
subcutaneously administered VRC01. Prior analysis in adults suggests a two compartment model 
will be needed to characterize the VRC01 pharmacokinetics in infants.  However, due to the 
limited early sampling in this study, the absorption rate constant (KA) and distribution parameters 
(V1/F and Q/F) may be leveraged with infant PK parameter estimates from IMPAACT P1112 to 
enhance estimation of CL/F in this study.   
 


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The population analysis will generate estimates for apparent volumes of distribution (V1/F and 
V2/F), inter-compartmental clearance (Q/F), CL/F and absorption rate constant KA.  Given the 
small number of infants in this study, the population pharmacokinetic analysis will not include an 
exploratory covariate analysis to assess clinical factors as fixed effects associated with VRC01 
pharmacokinetic parameters, except for study (P1112 versus 2008). Infant size will be included 
using standard allometric scaling. 
 
The population analysis will be used to quantify unexplained between-infant PK variability.  
Final model selection will be based on changes in the objective function and graphically by 
goodness of fit plots.  The final population model parameters will be assessed using bootstrapping 
to generate 95% CIs for parameter estimates.   Post-hoc empiric Bayesian estimates of individual 
infant pharmacokinetic parameters will be generated.  The final population PK model and the 
study dosing regimen (40 mg/kg subcutaneously administered x 4) will be used to assess the 
ability of the regimen to achieve and maintain target VRC01 concentrations through Monte Carlo 
simulations with at least 5000 virtual infants. 
 
This study is not powered for a stand-alone population PK analysis that can generate a complete 
set of PK parameters.  However, the PK variability in pre-dose VRC01 concentrations following 
subcutaneous administration in studies 601 and 602 was approximately 40%.  Assuming similar 
variability in this study, and with 34 infants receiving VRC01 in this study, the precision of the 
pre-dose concentration in this study is expected to generate a 95% CI of ± 15% of the observed 
mean.  While population PK studies do not lend themselves to classical power calculations, based 
on PK studies of similar size, the 238 PK samples collected from 34 infants in this study are 
expected to yield precise estimates of the population estimate for VRC01 CL/F. 
 
10.5 
Anticipated Outcomes 
 
It is expected that VRC01 exposure (Week 6 concentrations) will be consistently above 20 
mcg/mL and frequently above 50 mcg/ml, as shown in Figure 3. 
 
Figure 3 
Expected VRC01 Concentrations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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11 
DATA HANDLING AND RECORD KEEPING 
 
11.1 
Data Management Responsibilities 
 
As described in Section 4.5, data on screening and enrollment in this study will be collected using 
the DMC SES.   
 
Study sites must maintain adequate and accurate research records containing all information 
pertinent to the study for all screened and enrolled mother-infant pairs, including paper-based 
CRFs (if used), eCRFs, and supporting source data.  In maintaining these records, sites must 
comply with the standards of source documentation specified in the DAIDS policy on 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials 
(available on the website referenced in Section 11.2). 
 
eCRFs and an eCRF completion guide will be made available to study sites by the DMC.  Study 
site staff will enter required data into eCRFs, with system checks applied and data queries 
generated immediately upon saving the entered data.  Data must be entered within timeframes 
specified by the DMC; queries must also be resolved in a timely manner.  Selected laboratory 
data will be transferred electronically to the DMC through the LDMS.   
 
Further information on eCRFs and IMPAACT data management procedures will be provided by 
the DMC.  A User Manual for the Subject Enrollment System is available on the DMC portal at  
www.frontierscience.org.   
 
11.2 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures 
 
Study sites must comply with DAIDS policies on Requirements for Essential Documents at 
Clinical Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials and 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials.  In 
its policy on Requirements for Manual of Operational Procedures, DAIDS requires sites to 
establish SOPs for maintaining essential and source documents in compliance with these policies.  
Site SOPs should be updated and/or supplemented as needed to describe roles, responsibilities, 
and procedures for this study, and site SOPs should be followed throughout the study.  
 
Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must 
be stored in a manner that ensures privacy, confidentiality, security, and accessibility during the 
conduct of the study and after the study is completed.  Records must be retained for a minimum 
of three years after the completion of the study.  Per 21 CFR 312.62, records must be maintained 
for two years after the date a marketing application is approved for one or more of the study 
products for the indication for which it is evaluated in this study; or, if no application is filed, or if 
the application is not approved for this indication, records must be retained two years after the 
study is discontinued and the FDA is notified. 
 
 
 
 


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All study records must be accessible for inspection, monitoring, and/or auditing during and after 
the conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, the VRC, the US Food and Drug Administration, site drug regulatory 
authorities, site IRBs/ECs, OHRP, and other applicable regulatory entities.  Records must be kept 
on site throughout the period of study implementation; thereafter, instructions for off-site storage 
may be provided by NIAID of NICHD.  No study records may be removed to an off-site location 
or destroyed prior to receiving approval from NIAID or NICHD.   
 
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 
 
 
12 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records including consent forms, paper-based CRFs (if used), eCRFs 
medical records, laboratory records, and pharmacy records, to ensure protection of study 
participants, compliance with the IRB/EC approved protocol, and accuracy and completeness of 
records.  The monitors also will review essential document files to ensure compliance with all 
applicable regulatory requirements.  Site investigators will make study facilities and documents 
available for inspection by the monitors. 
   
 
13 
HUMAN SUBJECTS PROTECTIONS 
 
13.1 
IRB/EC Review and Approval  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this 
protocol and site-specific ICFs in accordance with 45 CFR 46; subsequent to initial review and 
approval, IRBs/ECs must review the study at least annually.  Site investigators must also 
promptly report to the IRB/EC any changes in the study and any unanticipated problems 
involving risks to participants or others.    
 
All IRB/EC policies and procedures must be followed, and complete documentation of all 
correspondence to and from the IRBs/ECs must be maintained in site essential document files.  
Sites must submit documentation of both initial review and approval and continuing review to the 
DAIDS Protocol Registration Office (PRO) in accordance with the DAIDS Protocol Registration 
Manual (see also Section 14.2). 
 
13.2 
Vulnerable Participants 
 
Study sites must comply with the requirements of the DAIDS policy on Enrolling Children 
(including Adolescents) in Clinical Research, which is available at: 
www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 


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Infants enrolled in this study are considered vulnerable participants per 45 CFR 46 Subpart D.  
Site IRBs/ECs must consider the potential benefits, risks, and discomforts of the study to children 
and assess the justification for their inclusion in the study.  As part of this assessment, IRBs/ECs 
must determine the level of risk to children in the categories specified in 45 CFR 46.404-407. 
Documentation of this determination is required to complete the DAIDS protocol registration 
process described in Section 14.2 and the risk category assigned by the IRB/EC determines the 
parental informed consent requirements for the study at each site.  Per 45 CFR 46.408 (b), the 
IRB/EC may find that the consent of one parent is sufficient for research to be conducted under 
46.404 or 46.405.  If the IRB/EC finds that the research is covered by 46.406 or 46.407, both 
parents must give their consent, unless one parent is deceased, unknown, incompetent, or not 
reasonably available or when only one parent has legal responsibility for the care and custody of 
the child (as determined locally).  IRBs/ECs must document their risk determination, and study 
sites should adapt the signature pages of their site-specific ICFs as needed to accommodate the 
parental consent requirements associated with the IRB/EC determination. 
 
13.3 
Informed Consent 
 
Refer to Section 4.5 and the study-specific MOP for further information on informed consent 
procedures for this study.  Refer to Appendices II-V for sample informed consent forms. 
 
Written informed consent for infant study participation will be obtained from each infant’s 
mother or legal guardian before any study-specific procedures are performed.  The informed 
consent process will include information exchange, detailed discussion, and assessment of 
understanding of all required elements of informed consent, including the potential risks, benefits, 
and alternatives to study participation.  The process will emphasize the randomized nature of the 
study design and the unproven efficacy of VRC01.  Regardless of random assignment, mothers or 
legal guardians will be extensively counseled on the importance of adherence to the infant’s 
cART regimen for viral suppression and other long-term treatment goals. 
  
As part of the informed consent process, mothers (or legal guardians) will be asked whether they 
agree to collection of infant blood specimens for primary, secondary, other, and exploratory 
evaluations.  Mothers or legal guardians must agree to this in order for infants to participate in the 
study; however, genetic testing of these specimens may be declined.  Similarly, collection of 
residual CSF for exploratory evaluations may be declined.  
 
The mothers of enrolled infants will also be asked to consent to collection of their own blood for 
exploratory evaluations.  This consent is optional; it is not required for infant study participation.  
In addition, genetic testing of maternal specimens may be declined.   
 
Separately, mothers (or legal guardians) will be asked whether they agree to storage and future 
research testing of specimens remaining after all protocol-specified primary, secondary, other, 
and exploratory testing has been completed.  Future research testing of residual specimens may 
be declined with no impact on other aspects of infant study participation.  This informed consent 
process should ideally be conducted at study screening or entry visits; however, if this is not 
possible logistically, or if more time is needed for a mother (or legal guardian) to decide whether 
to provide or decline consent for future research testing, this process may be completed at any 
time up until the Week 6 visit. 
 


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As indicated above, it is generally expected that the consent of one parent (or legal guardian) will 
be sufficient for infant participation in this study.  However, consenting requirements at each site 
will depend on the IRB/EC risk determination described in Section 13.2; all IRB/EC requirements 
will be followed.   
 
Should the consenting parent (or legal guardian) of an enrolled infant die or no longer be 
available for any reason, all applicable IRB/EC policies and procedures should be followed; 
however, no further study product should be administered (if applicable) and no further study-
specific evaluations should be performed until informed consent for continued study participation 
is obtained from the infant’s authorized guardian, as defined locally.  Study sites may continue to 
provide care for the infant as needed and appropriate (outside of the study) consistent with the 
local standard of care, but no study-specific procedures (outside of the standard of care) may be 
performed.  If an authorized guardian cannot be identified, or if the authorized guardian does not 
consent to continued infant study participation, the infant must be terminated from the study.  In 
accordance with the DAIDS policy on Enrolling Children (including Adolescents) in Clinical 
Research (available at the website referenced in Section 13.2), all sites must establish and 
maintain written procedures describing the standards that will be followed to identify who may 
serve as guardian for an enrolled infant, reflective of applicable IRB/EC guidance for conduct of 
human subjects research within the context of available local law, regulation, or government 
policy. 
 
13.4 
Potential Benefits 
 
Administration of VRC01 transiently reduced plasma HIV levels in adults when given without 
cART [12] and thus may reduce plasma HIV levels when given in combination with initiation of 
cART.  Although it is hypothesized that administration of VRC01 may attenuate HIV reservoir 
formation and lead to lower concentrations of HIV-infected cells in peripheral blood, there may 
be no direct benefit to infants who take part in their study.  Likewise, there may be no benefit to 
mothers who take part in this study.  Information learned in this study may, however, be of 
benefit to infants born to HIV-infected mothers in the future. 
 
 
 
 
13.5 
Potential Risks  
 
The potential risks of participation in this study include risks associated with study procedures 
and risks associated with receipt of VRC01.   
 
Most study procedures are routine medical procedures that are associated with minimal to no risk 
in participants.  Blood collection may cause pain, bruising, swelling, and (rarely) infection at the 
site where the needle is inserted.   
 
VRC01 has not previously been administered to HIV-infected infants, but has been administered 
to both HIV-infected and HIV-uninfected adults.  It also has been administered to newborn HIV-
exposed infants.  As indicated in Section 1.2, VRC01 has generally been well-tolerated by all 
study populations to date.  Among infants, only mild to moderate local reactions following 
subcutaneous administration of VRC01 have been observed to date, and no other adverse events 
attributable to VRC01 have been identified.  Experience with VRC01 in adults also indicates a 
generally mild risk profile, with few and mild to moderate local reactions at the site of 
administration and mild systemic reactions including malaise, myalgia, fatigue, headache, and 
nausea observed in some study participants.  In addition, mild to severe urticarial reactions have 
been observed rarely. 


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In general, administration of mAb may have a risk of immune reactions such as acute 
anaphylaxis, serum sickness, and the generation of antibodies; however, these reactions are rare 
and more often associated with mAb targeted to human proteins or with the use of murine 
monoclonal antibodies. In this regard, as VRC01 is targeted to a viral antigen and is a human 
monoclonal antibody, it is expected to have a low risk of such side effects. Typically, the side 
effects of mAbs are mild but may include fever, chills, rigors, nausea, vomiting, pain, headache, 
dizziness, shortness of breath, bronchospasm, hypotension, hypertension, pruritus, rash, urticaria, 
angioedema, diarrhea, tachycardia or chest pain. There are several FDA-licensed mAbs for which 
reactions related to the rate of infusion have been described. Some symptoms may be treated by 
slowing or stopping the infusion. Supportive treatment may also be indicated for some signs and 
symptoms. 
 
There is a theoretical risk that receiving VRC01 might affect sensitivity to ARVs that work 
through entry or fusion inhibition; however, these are third-line ARVs that are not approved for 
use in infants or young children.  There is also a theoretical risk that receipt of VRC01 could lead 
to viral resistance to VRC01, thereby limiting its use in the future for a given infant, and possibly 
also conferring cross-resistance to other antibodies that target the CD4 binding site. This risk is 
minimized, however, through the use of VRC01 in combination with cART. 
 
These types of reactions may be observed in infants in this study, and there may be other risks 
that are not currently known.  
 
13.6 
Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be reimbursed for costs associated with completing 
study visits (e.g., transport costs).  Reimbursement amounts will be specified in site-specific ICFs 
or other materials if applicable per IRC/EC policies and procedures.  
 
13.7 
Privacy and Confidentiality 
 
All study procedures will be conducted in private, and every effort will be made to protect 
participant privacy and confidentiality to the extent possible.  Participant information will not be 
released without written permission to do so except as necessary for review, monitoring, and/or 
auditing as described in Section 11.2.  If any photographs of observed reactions are taken, 
standard precautions will be followed to ensure that participant privacy and confidentiality are 
protected.   
 
All study-related information will be stored securely.  Participant research records will be stored 
in locked areas with access limited to study staff.  All laboratory specimens, CRFs, and other 
documents that may be transmitted off-site (e.g., EAE report forms, photographs of observed 
reactions) will be identified by PID only.  Likewise, communications between study staff and 
Protocol Team members regarding individual participants will identify participants by PID only.   
 
Study sites are encouraged but not required by DAIDS policies to store study records that bear 
participant names or other personal identifiers separately from records identified by PID.  All 
local databases must be secured with password-protected access systems.  Lists, logbooks, 
appointment books, and any other documents that link PID numbers to personal identifying 
information should be stored in a separate, locked location in an area with limited access.   
 


IMPAACT 2008, FINAL Version 2.0 
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In addition to the above, a Certificate of Confidentiality has been obtained for this study from the 
US Department of Health and Human Services.  This certificate protects study staff from being 
compelled to disclose study-related information by any US federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings.  It thus serves to protect the identity and privacy 
of study participants.  Because the certificate cannot be enforced outside of the US, however, it 
applies only to US sites and participants.  
 
13.8 
Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases including HIV 
infection identified among study participants to health authorities. Participants will be made 
aware of all applicable reporting requirements as part of the study informed consent process. 
 
13.9 
Management of Incidental Findings 
 
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. When applicable, site clinicians will provide 
referrals to non-study sources of medical care for further evaluation and/or treatment of these 
findings.  
 
The results of protocol-specified pharmacokinetic, virologic, and immunologic assays are not 
planned to be provided to infants’ parents or guardians, as these are considered research tests that 
are not expected to be relevant to clinical care and management.  If, however, new information 
becomes available during the course of the study indicating that the results of any of these assays 
are of clinical relevance, the results of these assays will be provided.  Additional results 
disclosure may also occur if determined to be in the best interest of study participants based on 
the outcome of SMC reviews as described in Section 9.5.2. 
 
13.10 Management of New Information Pertinent to Study Participation 
 
Infants’ parents or legal guardians will be provided any new information learned over the course 
of the study that may affect their willingness to allow their infants to continue receive VRC01 (if 
in Arm 1) or to remain in follow-up in the study.   
 
13.11 Post-Trial Access to Study Product 
 
This Phase I/II study will provide information on the safety and antiviral activity of VRC01 for 
HIV-1-infected infants initiating cART.  Based on the results of this study, other studies may be 
conducted in the future to further characterize the safety and efficacy of VRC01 for this 
population.  Before such studies are completed, the efficacy of VRC01 and its risk-to-benefit ratio 
for this population remain unknown; therefore, VRC01 will not be immediately available after 
this study is completed.  Should future studies demonstrate clinical benefit from use of VRC01, 
the VRC intends to develop the product so that it can be made available for appropriate 
indications. 
  
 


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14 
ADMINISTRATIVE PROCEDURES 
 
14.1 
Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), 
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), 
and National Institute of Mental Health (NIMH), which are part of the United States National 
Institutes of Health (NIH).  The study product, VRC01, is provided by the NIAID Vaccine 
Research Center (VRC); however, the VRC is not involved in sponsorship or regulatory oversight 
of this study.   
 
The Division of AIDS (DAIDS) within the NIAID is responsible for regulatory oversight of this 
study.  DAIDS will distribute safety-related information pertaining to the study products prior to 
and during the conduct of the study, in accordance with its sponsor obligations.   
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be 
conducted.  Each institute contracts with independent clinical site monitors who will perform 
monitoring visits as described in Section 12.  As part of these visits, monitors will inspect study-
related documentation to ensure compliance with all applicable US and local regulatory 
requirements. 
 
14.2 
Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol ICFs approved, as appropriate, by their local IRB/EC, 
local IBC, and any other applicable regulatory entity.  Upon receiving final approval, sites will 
submit all required protocol registration documents to the DAIDS PRO at the RSC.  The DAIDS 
PRO will review the submitted protocol registration packet to ensure that all of the required 
documents have been received.   
 
Site-specific ICFs will be reviewed and approved by the DAIDS PRO, and sites will receive an 
Initial Registration Notification from the DAIDS PRO that indicates successful completion of the 
protocol registration process.  A copy of the Initial Registration Notification should be retained in 
the site's regulatory files. 
 
For any future protocol amendments, upon receiving final IRB/EC and any other applicable 
regulatory entity approvals, sites should implement the amendment immediately.  Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the RSC.  The 
DAIDS PRO will review the submitted protocol registration packet to ensure that all the required 
documents have been received.  Site-specific ICFs will not be reviewed and approved by the 
DAIDS PRO, and sites will receive an Amendment Registration Notification when the DAIDS 
PRO receives a complete registration packet.  A copy of the Amendment Registration 
Notification should be retained in the site's regulatory files. 
 
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 on the RSC website:  
http://rsc.tech-res.com/clinical-research-sites/protocol-registration/policy-manual 
 


IMPAACT 2008, FINAL Version 2.0 
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14.3 
Study Implementation  
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US, and non-US country and local regulations.  Study 
implementation will also be guided by the IMPAACT Manual of Procedures, study-specific 
MOP, LPC, and other study implementation materials, which will be available on the IMPAACT 
web site:  www.impaactnetwork.org. 
 
Study implementation at each site will also be guided site-specific SOPs.  The DAIDS policy on 
Requirements for Manual of Operational specifies the minimum set of SOPs that must be 
established at sites conducting DAIDS funded and/or sponsored clinical trials (available on the 
website referenced in Section 11.2).  These SOPs should be updated and/or supplemented as 
needed to describe roles, responsibilities, and procedures for this study. 
  
14.4 
Protocol Deviation Reporting 
 
Per the policy for Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials (available at the website referenced in Section 11.2), all protocol deviations must 
be documented in participant research records.  Reasons for the deviations and corrective and 
preventive actions taken in response to the deviations should also be documented.  
 
Deviations should be reported to site IRBs/ECs and other applicable review bodies in accordance 
with the policies and procedures of these review bodies.  Serious deviations that are associated 
with increased risk to one or more study participants and/or significant impacts on the integrity of 
study data must also be reported within IMPAACT, following procedures specified in the 
IMPAACT Manual of Procedures. 
 
14.5 
Critical Event Reporting 
 
Per the DAIDS policy on Identification and Classification of Critical Events, a critical event is 
defined as an unanticipated study-related incident that is likely to cause harm or increase the risk 
of harm to participants or others or has a significant adverse impact on study outcomes or 
integrity.  All such events must be reported following procedures specified in the DAIDS Critical 
Events Manual, which is available at: 
www.niaid.nih.gov/research/daids-clinical-research-event-reporting-safety-monitoring 
 
14.6 
ClinicalTrials.gov 
 
This protocol is subject to the United States Food and Drug Administration Amendments Act of 
2007 (FDAAA), including registration in ClinicalTrials.gov. 
 
 
15 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT 
policies, which are available in the IMPAACT Manual of Procedures.  
 
 


IMPAACT 2008, FINAL Version 2.0 
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16 
REFERENCES 
 
1. 
UNAIDS. Children and HIV fact sheet. 2016  [cited 2016 October 18]. 
2. 
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Engl J Med, 2015. 372(8): p. 786-8. 
3. 
Persaud, D., et al., Influence of age at virologic control on peripheral blood human 
immunodeficiency virus reservoir size and serostatus in perinatally infected adolescents. JAMA 
Pediatr, 2014. 168(12): p. 1138-46. 
4. 
Martinez-Bonet, M., et al., Establishment and Replenishment of the Viral Reservoir in Perinatally 
HIV-1-infected Children Initiating Very Early Antiretroviral Therapy. Clin Infect Dis, 2015. 
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5. 
Williams, J.P., et al., HIV-1 DNA predicts disease progression and post-treatment virological 
control. Elife, 2014. 3: p. e03821. 
6. 
Persaud, D., et al., Absence of detectable HIV-1 viremia after treatment cessation in an infant. N 
Engl J Med, 2013. 369(19): p. 1828-35. 
7. 
Violari, A., et al., Early antiretroviral therapy and mortality among HIV-infected infants. N Engl 
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8. 
UNAIDS, The Gap Report. 2014. 
9. 
Uprety, P., et al., Cell-Associated HIV-1 DNA and RNA Decay Dynamics During Early 
Combination Antiretroviral Therapy in HIV-1-Infected Infants. Clin Infect Dis, 2015. 61(12): p. 
1862-70. 
10. 
Chadwick, E.G., et al., Pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less 
than 6 months of age: 24 week results. AIDS, 2008. 22(2): p. 249-55. 
11. 
Kwong, P.D. and J.R. Mascola, Human antibodies that neutralize HIV-1: identification, 
structures, and B cell ontogenies. Immunity, 2012. 37(3): p. 412-25. 
12. 
Lynch, R.M., et al., Virologic effects of broadly neutralizing antibody VRC01 administration 
during chronic HIV-1 infection. Sci Transl Med, 2015. 7(319): p. 319ra206. 
13. 
Caskey, M., et al., Viraemia suppressed in HIV-1-infected humans by broadly neutralizing 
antibody 3BNC117. Nature, 2015. 
14. 
Ko, S.Y., et al., Enhanced neonatal Fc receptor function improves protection against primate 
SHIV infection. Nature, 2014. 514(7524): p. 642-5. 
15. 
Barouch, D.H., et al., Therapeutic efficacy of potent neutralizing HIV-1-specific monoclonal 
antibodies in SHIV-infected rhesus monkeys. Nature, 2013. 503(7475): p. 224-8. 
16. 
Chadwick, E.G., et al., Early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: 
pharmacokinetics and 24-week safety and efficacy. Pediatr Infect Dis J, 2009. 28(3): p. 215-9. 
17. 
Persaud, D., et al., Dynamics of the resting CD4(+) T-cell latent HIV reservoir in infants 
initiating HAART less than 6 months of age. AIDS, 2012. 26(12): p. 1483-90. 
18. 
Horwitz, J.A., et al., HIV-1 suppression and durable control by combining single broadly 
neutralizing antibodies and antiretroviral drugs in humanized mice. Proc Natl Acad Sci U S A, 
2013. 110(41): p. 16538-43. 
19. 
Shingai, M., et al., Antibody-mediated immunotherapy of macaques chronically infected with 
SHIV suppresses viraemia. Nature, 2013. 503(7475): p. 277-80. 
20. 
Bolton, D.L., et al., Human Immunodeficiency Virus Type 1 Monoclonal Antibodies Suppress 
Acute Simian-Human Immunodeficiency Virus Viremia and Limit Seeding of Cell-Associated 
Viral Reservoirs. J Virol, 2015. 90(3): p. 1321-32. 
21. 
Barouch, D.H., Broadly Neutralizing Antibody for HIV-1 Eradication Strategies, in Conference 
on Retroviruses and Opportunistic Infections (CROI). 2015: Seattle, WA. 
22. 
Hessell, A.J., et al., Early short-term treatment with neutralizing human monoclonal antibodies 
halts SHIV infection in infant macaques. Nat Med, 2016. 
23. 
Perelson, A.S., et al., Decay characteristics of HIV-1-infected compartments during combination 
therapy. Nature, 1997. 387(6629): p. 188-191. 


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Bar, K.J., et al., Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption. N 
Engl J Med, 2016. 375(21): p. 2037-2050. 
25. 
Ananworanich, J., B. McSteen, and M.L. Robb, Broadly neutralizing antibody and the HIV 
reservoir in acute HIV infection: a strategy toward HIV remission? Curr Opin HIV AIDS, 2015. 
10(3): p. 198-206. 
26. 
Ackerman, M.E. and G. Alter, Opportunities to exploit non-neutralizing HIV-specific antibody 
activity. Curr HIV Res, 2013. 11(5): p. 365-77. 
27. 
Kwong, P.D., J.R. Mascola, and G.J. Nabel, Broadly neutralizing antibodies and the search for 
an HIV-1 vaccine: the end of the beginning. Nat Rev Immunol, 2013. 13(9): p. 693-701. 
28. 
Archin, N.M., et al., Immediate antiviral therapy appears to restrict resting CD4+ cell HIV-1 
infection without accelerating the decay of latent infection. Proc Natl Acad Sci U S A, 2012. 
109(24): p. 9523-8. 
29. 
Fouda, G.G., et al., Postnatally-transmitted HIV-1 Envelope variants have similar neutralization-
sensitivity and function to that of nontransmitted breast milk variants. Retrovirology, 2013. 10: p. 
3. 
30. 
Nakamura, K.J., et al., Coverage of primary mother-to-child HIV transmission isolates by second-
generation broadly neutralizing antibodies. AIDS, 2013. 27(3): p. 337-346. 
31. 
Wu, X., et al., Rational design of envelope identifies broadly neutralizing human monoclonal 
antibodies to HIV-1. Science, 2010. 329(5993): p. 856-61. 
32. 
Milligan, C., et al., Passively acquired antibody-dependent cellular cytotoxicity (ADCC) activity 
in HIV-infected infants is associated with reduced mortality. Cell Host Microbe, 2015. 17(4): p. 
500-6. 
33. 
Goo, L., et al., Early development of broadly neutralizing antibodies in HIV-1-infected infants. 
Nat Med, 2014. 20(6): p. 655-8. 
34. 
Luzuriaga, K., et al., Early therapy of vertical human immunodeficiency virus type 1 (HIV-1) 
infection: control of viral replication and absence of persistent HIV-1-specific immune responses. 
J Virol, 2000. 74(15): p. 6984-91. 
35. 
Wu, X., et al., Focused evolution of HIV-1 neutralizing antibodies revealed by structures and 
deep sequencing. Science, 2011. 333(6049): p. 1593-602. 
36. 
Zhou, T., et al., Structural basis for broad and potent neutralization of HIV-1 by antibody 
VRC01. Science, 2010. 329(5993): p. 811-7. 
37. 
Ferrari, G., et al., An HIV-1 gp120 envelope human monoclonal antibody that recognizes a C1 
conformational epitope mediates potent antibody-dependent cellular cytotoxicity (ADCC) activity 
and defines a common ADCC epitope in human HIV-1 serum. J Virol, 2011. 85(14): p. 7029-36. 
38. 
Ledgerwood, J.E., et al., Safety, pharmacokinetics and neutralization of the broadly neutralizing 
HIV-1 human monoclonal antibody VRC01 in healthy adults. Clin Exp Immunol, 2015. 182(3): p. 
289-301. 
39. 
Mayer, K.H., et al., Clinical Safety and Pharmacokinetics of IV and SC VRC01, a Broadly 
Neutralizing mAb, in Conference on Retroviruses and Opportunistic Infections (CROI). 2016: 
Boston, MA. 
40. 
Cunningham, C.K., et al., Safety and pharmacokinetics of the monoclonal antibody, VRC01, in 
HIV-exposed newborns, in Conference on Retroviruses and Opportunistic Infections (CROI). 
2017: Seattle, WA. 
41. 
Riddler, S.A., et al., VRC01 infusion has no effect on HIV-1 persistance in ART-suppressed 
chronic infection, in Conference on Retroviruses and Opportunistic Infections (CROI). 2017: 
Seattle, WA. 
42. 
Bar, K.J., et al., ACTG 5340: The Effect of VRC01 on Viral Kinetics After Analytic Treatment 
Interruption, in Conference on Retroviruses and Opportunistic Infections (CROI). 2016: Boston, 
MA. 


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43. 
Chun, T.W., et al., Effect of Infusion of Broadly Neutralizing Antibody VRC01 on HIV Plasma 
Rebound, in Conference on Retroviruses and Opportunistic Infections (CROI). 2016: Boston, 
MA. 
44. 
Procopio, F.A., et al., A Novel Assay to Measure the Magnitude of the Inducible Viral Reservoir 
in HIV-infected Individuals. EBioMedicine, 2015. 2(8): p. 874-83. 
45. 
Ng, C.T., et al., Passive neutralizing antibody controls SHIV viremia and enhances B cell 
responses in infant macaques. Nat Med, 2010. 16(10): p. 1117-9. 
46. 
Hellmuth, J., V. Valcour, and S. Spudich, CNS reservoirs for HIV: implications for eradication. J 
Virus Erad, 2015. 1(2): p. 67-71. 
47. 
Pels, H., et al., Intraventricular and intravenous treatment of a patient with refractory primary 
CNS lymphoma using rituximab. J Neurooncol, 2002. 59(3): p. 213-6. 
48. 
Osuga, T., et al., Transfer of specific IgG and IgG subclasses to herpes simplex virus across the 
blood-brain barrier and placenta in preterm and term newborns. Acta Paediatr, 1992. 81(10): p. 
792-6. 
 
 
 


 
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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 
14 
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 d 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Maternal Evaluations (for mothers of enrolled infants who consent to blood collection) 
 
 
 
 
 
 
 
Stored plasma and PBMCs 
for exploratory evaluations 
 
10 mL 
 
 
 
 
 
 
 
 
 
 
 
 
Stored serum for 
exploratory evaluations 
 
10 mL 
 
 
 
 
 
 
 
 
 
 
 
 
Infant Evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-related testing history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medications history 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
ARV history 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Immunization history 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Feeding history 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
cART adherence assessment 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Physical examination 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
VRC01 administration1 
(Arm 1 only) 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Reactogenicity assessment2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Confirmatory HIV nucleic 
acid test (if needed) 
0-3 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete blood count with 
differential and platelets 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
1 mL 
ALT, AST, ALP, creatinine 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
1 mL 
CD4 and CD8 cell count 
and percentage3 
1 mL 
 
 
 
 
 
 
 
 
 
 
 
 
1 mL 
HIV-1 RNA in plasma4 
(real time) 
 
1 mL4 
 
3 mL4 
 
 
 
3 mL4 
 
 
3 mL4 
 
 
3 mL4 
Urinalysis 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 


 
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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 
14 
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 d 
Infant Evaluations (continued) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Stored plasma and PBMCs 
for primary, secondary, and 
other evaluations 
 
3-5 mL5 
 
 
1 mL 
 
 
1 mL 
 
 
1 mL 
 
 
5 mL 
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 
 
 
 
 
 
 
 
 
 
 
 
 
ADCC  
(plasma) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
ARV levels  
(plasma, adherence) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Stored serum for 
neutralization assay 
 
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 
 
 
 


 
IMPAACT 2008, FINAL Version 2.0 
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Appendix I 
IMPAACT 2008 Schedule of Evaluations:  Week 16 through Week 48 
Study Visit 
Week  
16 
Week  
20 
Week  
24 
Week  
36 
Week  
48 
Early  
D/C7 
CSF 
Collection8 
Visit Window 
±7 d 
±14 d 
±14 d 
±14 d 
±14 d 
NA 
NA 
Informed consent 
 
 
 
 
 
 
 
 
Maternal Evaluations (for mothers of enrolled infants who consent to specimen collection) 
Stored plasma and PBMCs 
for exploratory evaluations 
 
 
 
 
 
 
 
Stored serum for 
exploratory evaluations 
 
 
 
 
 
 
 
Infant Evaluations 
 
 
 
 
 
 
 
HIV-related testing history 
 
 
 
 
 
 
 
Medical/medications history 
X 
X 
X 
X 
X 
X 
X8 
ARV history 
X 
X 
X 
X 
X 
X 
 
Immunization history 
X 
X 
X 
X 
X 
X 
 
Feeding history 
X 
X 
X 
X 
X 
X 
 
cART adherence assessment 
X 
X 
X 
X 
X 
X 
 
Physical examination 
X 
X 
X 
X 
X 
X 
 
VRC01 administration 
(Arm 1 only) 
 
 
 
 
 
 
 
Reactogenicity assessment 
 
 
 
 
 
 
 
Confirmatory HIV nucleic 
acid test (if needed) 
 
 
 
 
 
 
 
Complete blood count with 
differential and platelets 
 
1 mL 
1 mL 
0-1 mL3 
0-1 mL3 
1 mL7 
 
ALT, AST, ALP, creatinine 
 
1 mL 
1 mL 
 
 
 
 
CD4 and CD8 cell count 
and percentage3 
 
 
1 mL 
1 mL3 
1 mL3 
1 mL7 
 
HIV-1 RNA in plasma4 
(real time) 
3 mL4 
 
3 mL4 
3 mL4 
3 mL4 
3 mL4,7 
 
Urinalysis 
 
 
X 
 
 
[X]7 
 


 
IMPAACT 2008, FINAL Version 2.0 
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Appendix I 
IMPAACT 2008 Schedule of Evaluations:  Week 16 through Week 48 
Study Visit 
Week  
16 
Week  
20 
Week  
24 
Week  
36 
Week  
48 
Early  
D/C7 
CSF 
Collection8 
Visit Window 
±7 d 
±14 d 
±14 d 
±14 d 
±14 d 
NA 
NA 
Infant Evaluations (continued) 
 
 
 
 
 
 
Stored plasma and PBMCs 
for primary, secondary, and 
other evaluations 
1 mL 
 
7 mL 
 
7 mL 
5-7 mL7 
 
VRC01 level  
(plasma) 
X 
 
 
 
 
X 
 
Anti-VRC01 antibodies 
(plasma) 
 
 
X 
 
X 
X 
 
HIV-1 DNA  
(PBMC) 
 
 
X 
 
X 
X 
 
HIV-1 RNA (spliced/ 
unspliced; PBMC) 
 
 
X 
 
X 
X 
 
HIV-1 RNA (inducible; 
PBMC) 
 
 
X 
 
X 
 
 
ADCC 
(plasma) 
 
 
X 
 
X 
X 
 
ARV levels  
(plasma, adherence) 
 
 
X 
 
X 
X 
 
Stored serum for 
neutralization assay 
 
 
1 mL 
 
1 mL 
1 mL7 
 
Stored plasma and PBMCs 
for exploratory evaluations6 
X6 
 
2 mL 
5 mL 
7 mL 
2 mL7 
2 mL8 
Cerebral spinal fluid storage 
for exploratory evaluations 
 
 
 
 
 
 
X8 
Total Infant Blood Volume 
4 mL 
2 mL 
16 mL 
9-10 mL 
19-20 mL 
13-15 mL 
2 mL 
 
 
 
 


 
IMPAACT 2008, FINAL Version 2.0 
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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.  


 
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Appendix II 
Sample Informed Consent Form for Infant Study Participation 
 
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 
 
 
Your baby is being asked to participate in the research study named above.  
 
This form gives information about the study.  Please read it, or have it read to you, and ask any questions 
you may have.  We will take as much time as you need to fully understand the study.  We will ask you 
questions to see if we have explained the study clearly.  
 
After you understand the study, if you decide to have your baby participate, you will be asked to sign or 
make your mark on this form. You will be offered a copy to keep. 
 
About the study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [insert 
site name] are doing this study. The study is testing an experimental injection called VRC01 in babies 
who have HIV.  HIV is the virus that causes AIDS.   
 
The study will include about 68 babies who are less than 12 weeks old from Botswana, Brazil, Haiti, 
Malawi, South Africa, Zimbabwe, and the United States.  Babies will be in the study for about one year.   
 
The person in charge of the study at [insert site name] is [insert name of IoR].  The United States National 
Institutes of Health are paying for the study. 
 
1. The study is testing VRC01 in babies who have HIV.  
 
The study will test the safety of VRC01 when given to babies who are starting treatment for HIV.  It will 
also test the effect of VRC01 on the amount of HIV that can be found in babies’ blood and blood cells.   
 
VRC01 is an antibody against HIV.  Antibodies are made by the immune system to fight infection.  
Antibodies can also be made in laboratories.  VRC01 is made in a laboratory.   
 
VRC01 has been tested in laboratory experiments and in animals and people.  It has been tested in HIV-
negative adults, HIV-positive adults, and babies born to HIV-positive mothers.  Laboratory experiments 
have shown that VRC01 could help decrease the amount of HIV in the body.  However, we are still in the 
early stages of testing VRC01 to find out what its effects may be.  This will be the first study of VRC01 
in babies who have HIV. 
 


 
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2. We do not know if VRC01 may be a useful treatment for HIV. 
 
The study is a first step in testing VRC01 in babies who have HIV.  All babies in the study will be taking 
anti-HIV medicines (ARVs).  We do not know if VRC01 may be a useful treatment when given in 
addition to ARVs.  The study will help us learn about that.  While we are learning about VRC01, it is very 
important that babies keep taking ARVs.  Taking ARVs is the best known way for people who have HIV to 
stay healthy. 
 
3. Only babies who qualify can participate in the study. 
 
If you decide to have your baby join the study, we will first do some tests to see if your baby qualifies.  
More information about the tests is given in #5 (see below).  If your baby qualifies, he or she will be 
entered in the study.  If your baby does not qualify, he or she cannot be entered in the study. 
 
4. It is your decision whether to join the study. 
 
Deciding to have your baby join the study is voluntary (your choice).  You are free to have your baby join 
or not join.  If you decide to have your baby join, you can change your mind and take your baby off the 
study.  Your decisions will have no effect on the medical care that your baby receives at this clinic.  Your 
baby’s access to services, and the benefits and rights he or she normally has, will not be affected.  
 
Take your time and consider your decisions carefully.  If you wish, you can talk to other people about the 
study before you decide.  You can bring other people here to learn about the study with you.   
 
No matter what you decide about the study, your baby should continue to receive standard medical care 
outside of the study.  This includes childhood immunizations, ARVs, and other standard care and 
treatment for children with HIV.  We will tell you where your baby can receive this care if needed.  
 
Finding out if you and your baby qualify 
 
5. We will ask questions, examine your baby, and test your baby’s blood.  
 
To find out if your baby qualifies for the study, we will:  
 
• 
Review your baby’s medical records. 
• 
Ask about your baby’s health and how you are feeding your baby. 
• 
Ask about the ARVs and other medicines you (the baby’s mother) and your baby have taken. 
• 
Give your baby a physical examination. 
• 
Draw your baby’s blood (up to 6 mL or about 1 teaspoon) for tests.  The tests will:  
– Check your baby’s blood cells, liver, and kidneys. 
– Check your baby’s CD4 and CD8 cells.  These cells are part of the immune system, which is the 
part of the body that fights infections.  HIV attacks CD4 cells, so it is important to check the 
number of these cells that can be found in the blood.  
– Confirm that your baby has HIV.  There are certain HIV tests that are required for this study.  If 
the required tests are not in your baby’s medical records, we will do the tests that are needed. 
• 
Talk with you about the study requirements and if your baby will be able to meet these requirements.   
 


 
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These procedures will take about 2 hours.  The results of your baby’s blood tests will then be available 
within several days.  We will review the results and all other information to determine if your baby 
qualifies for the study.  We will schedule your baby to come back to the clinic when the results are 
available. 
 
• 
If your baby does not qualify, we will tell you this. Your baby will not be entered in the study and we 
will tell you where your baby can go for any medical care or other services your baby may need.  
 
• 
If your baby does qualify, he or she will be entered in the study.   
 
Entering the study 
 
6. If your baby qualifies, he or she will enter the study within a specified timeframe.  
 
There are certain timeframes for when babies can enter the study.  For example, babies must be less than 
12 weeks old when they enter.  We will explain the timeframes to you so you know what to expect.  
 
On the day your baby enters the study, we will:  
 
• 
Review your baby’s medical records and ask about: 
– Your (the baby’s mother’s) and your baby’s ARVs. 
– Your baby’s health and other medicines. 
– How you are feeding your baby. 
• 
Give your baby a physical examination. 
• 
Collect your baby’s urine for tests to check his or her kidneys. 
• 
Draw your baby’s blood (up to 9 mL or about 2 teaspoons) for tests including:  
– A test of the amount of HIV in your baby’s blood.  This is called your baby’s “viral load.”  The 
viral load should decrease over time as your baby takes ARVs.  
– Tests of the effects of VRC01. 
 
7. Babies will be placed in 1 of 2 groups on the day they enter the study.    
 
Babies placed in one group will be given VRC01.  Babies placed in the other group will not be given 
VRC01.  To test the effects of VRC01, babies given VRC01 will be compared to babies not given 
VRC01.  
 
Each baby will be placed a group at random, [like flipping a coin; sites may insert a different example if 
preferred].  Each baby has a 1-in-2 or 50% chance of being placed in the group that is given VRC01.  The 
study staff cannot choose which group each baby is placed in.  Babies’ parents also cannot choose.  
 
8. Babies in the VRC01 group will be given 4 injections. 
 
Babies in the VRC01 group will be given the first injection of VRC01 when they enter the study.  The 
other injections will be given 2, 6, and 10 weeks later.  The injections will be given in the skin of the 
thigh.  The amount of VRC01 given will depend on the baby’s weight.  The largest amount given will be 
about 4 mL (less than 1 teaspoon).  If the full amount of VRC01 cannot be given in one injection, two 
injections will be given.  Each injection is expected to take about 10-15 minutes. 
 


 
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Although babies in the VRC01 group are expected to be given 4 injections, we may not give injections to 
babies who are sick when injections are scheduled to be given.  We may stop giving injections to any 
baby if we determine that more injections might be harmful.  Babies who miss any injections will still 
stay in the study. 
 
9. Babies in the VRC01 group will be checked for reactions to the injections. 
 
After the first injection of VRC01, babies must stay in the clinic for at least 2 hours.  During this time, 
study staff will check for reactions to the injection.  After the other injections, babies must stay in the 
clinic for at least one hour.   
 
[Here and in #19, sites may modify text regarding photographs if IRBs/ECs mandate a separate form for 
obtaining informed consent for photographs.]  If your baby has any reactions to VRC01, such as redness 
where VRC01 in injected, we may take a photo of the reaction.  The photo will help the doctors working 
on the study assess the reaction.  
 
10. All babies will have 13 scheduled visits over 1 year.  
 
Starting 1 week after entering the study, babies will have 11 visits over 6 months. After that, babies will 
have 2 more visits, about 3 months apart.  Each visit will take about 2 hours.  At these visits, we will:  
 
• 
Review your baby’s medical records and ask about: 
– Your (the baby’s mother’s) and your baby’s ARVs. 
– Your baby’s health and other medicines. 
– How you are feeding your baby. 
• 
Give your baby a physical examination. 
• 
Collect your baby’s urine for tests to check his or her kidneys.  
• 
Draw your baby’s blood for tests. The amount drawn will be up to 5 mL (about 1 teaspoon) while the 
baby is less than 3 months old, and up to 20 mL (about 4 teaspoons) as the baby ages to 6 and 12 
months.  At different visits, the tests will check your baby’s: 
– Blood cells, liver, and kidneys. 
– CD4 and CD8 cells. 
– HIV viral load. 
Tests will also check the amount of VRC01 in the blood and the effects of VRC01. 
 
Babies may have more visits if they are sick or need more tests to check on their health.  Additional blood 
or urine may be drawn at these visits if needed. 
 
11. Mothers or caregivers are asked to check on their babies.  
 
After 4 of the study visits, you will be asked to take your baby’s temperature and write down how your 
baby is doing.  You will be asked to do this for 7 days after the visit when your baby enters the study, and 
for 7 days after the visits 2, 6, and 10 weeks later.  For babies in the VRC01 group, these are the visits 
when VRC01 is given, but you will be asked to do this even if your baby is not given VRC01.   
 
We will show you how to write down the information about your baby.  After 3 days, we will telephone 
you to ask for the information you have written down. You can also come to the clinic with your baby or 
have a study staff member come to your home instead of having the telephone call.  If your baby has any 
problems, you will be asked to bring him or her to the clinic.  
 


 
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12. If babies need a lumbar puncture, we will save spinal fluid for the study.  
[here and below, sites may use locally appropriate terminology (e.g., “spinal tap”) to refer to lumbar 
puncture] 
 
A procedure called “lumbar puncture” is sometimes done when babies are sick.  This procedure uses a 
needle to collect fluid from the baby’s spine.  The fluid is then tested to find out what may be causing the 
baby to be sick.  No lumbar punctures will be done for this study.  However, if your baby has a lumbar 
puncture outside of the study, we would like to save any spinal fluid that may be left over for tests.  If you 
agree to this, the tests will look for HIV in the fluid.  The tests may also look for other factors related to 
HIV and the immune system in the fluid.   
 
If your baby has a lumbar puncture, and you agree to have the spinal fluid saved, we will ask you to bring 
your baby to the clinic. At this visit, we will: 
 
• 
Review your baby’s medical records 
• 
Ask about your baby’s health and medicines. 
• 
Draw your baby’s blood (2 mL or about half a teaspoon) for tests. The tests may look for HIV in the 
blood and blood cells.  The tests may also look for other factors related to HIV and the immune 
system. 
 
13. Different tests will be done at different laboratories.  
 
We will do tests of your baby’s urine, blood cells, liver, kidneys, CD4 and CD8 cells, and HIV viral load 
here at our laboratory.  We will give you the results of these tests at the next scheduled visit or sooner if 
necessary.  We will explain the results and give you counseling and referrals as needed.   
 
Tests of the amount of VRC01 in the blood and of the effects of VRC01 will be done at different 
laboratories in the United States.  Tests of spinal fluid will also be done in the United States.  Some tests 
may be done while the study is ongoing, others after the study is completed.  The results of these tests are 
for research purposes only.  This means they are not expected to give any information relevant to your 
baby’s health.  The results will not be given to the study staff or to you. 
 
If you agree, some of your baby’s blood will be used for tests of his or her genes.  Genes are passed to 
children from their birth parents.  They affect how people look and how their bodies work.  Differences in 
people’s genes can help explain why some people get a disease while others do not.  For this study, only 
genes related to HIV, the immune system, and the effects of VRC01 will be tested.  The results of these 
tests are for research purposes only and will not be given to the study staff or to you. 
 
14. We may take your baby off the study early. 
 
Babies are expected to stay in the study for about 1 year.  However, we may take your baby off the study 
if: 
 
• 
The study is stopped for any reason. 
• 
We determine that your baby cannot meet the study requirements (for example, if you move away and 
cannot come to the clinic). 
• 
We determine that staying in the study might harm your baby. 
 


 
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15. Please tell us if you wish to take your baby off the study. 
 
You are free to take your baby off the study at any time for any reason.  The care that your baby receives 
at this clinic will not be affected, but it is important that we know your decision.  We will ask you to bring 
your baby to the clinic for one last visit.  At this visit we will: 
 
• 
Ask about your (the baby’s mother’s) and your baby’s ARVs. 
• 
Ask about your baby’s health and other medicines. 
• 
Ask about how you are feeding your baby. 
• 
Give your baby a physical examination. 
• 
Draw your baby’s blood (about 15 mL or 3 teaspoons) for tests.  The tests will check: 
– The baby’s blood cells 
– The baby’s CD4 and CD8 cells 
– The baby’s HIV viral load  
– The effects of VRC01 
 
If your baby has been in the study for less than six months, we will also collect urine for tests to check his 
or her kidneys. 
 
We will answer any questions you may have and tell you how to contact us in the future, if you wish. 
 
Risks of the study 
 
16. There is little risk from the study procedures.  
 
Most procedures done in this study are routine medical procedures, with little risk to your baby.  Drawing 
blood can cause pain, swelling, bruising, or bleeding where the needle is inserted.  Rarely, drawing blood 
can cause fainting or infection.  
 
17. VRC01 is experimental.  
 
This means we do not know if VRC01 is safe to use in people.  We also do not know if VRC01 is useful 
as a treatment for HIV.  VRC01 is being tested in research studies to learn more about it, and this study 
will help us learn about VRC01 in babies who have HIV.   
 
VRC01 will be given as an injection in the skin.  This kind of injection can cause stinging, itchiness, 
discomfort, pain, soreness, redness, bruising, swelling, or a small cut where the needle enters the skin.  
Rarely, this kind of injection can cause infection.  
 
As of January 2017, more than 800 HIV-negative and HIV-positive adults have received VRC01 in 
research studies in the United States, Botswana, Malawi, South Africa, Zimbabwe, and other countries.  
Some people had mild or moderate reactions like itchiness, redness, or swelling where VRC01 was 
injected.  Some people felt tired or had mild body discomfort, muscle or joint pain, headache, chills, or 
nausea after receiving injections.  Some people had hives while VRC01 was being given or soon after 
VRC01 was given. In some cases, the hives were severe. One person had chest discomfort and one 
fainted. Some people had abnormal results on tests of their blood cells, liver, or kidneys. These came back 
to normal after a few days or weeks.   
 


 
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As of January 2017, 40 babies born to mothers who have HIV have received VRC01 in a research study 
being done by the IMPAACT network in the United States, South Africa, and Zimbabwe. Most of these 
babies had redness, swelling, or a small bruise where VRC01 was injected, which lasted for a short 
time.  No other effects thought to be caused by VRC01 have been seen, and no serious health problems 
have occurred. 
 
It is possible that babies who receive VRC01 in this study could develop “resistance” to VRC01 or other 
antibodies like VRC01.  If resistance develops, the antibodies may not be effective in helping to control 
the baby’s HIV.  In this study, the risk of resistance is minimized by giving VRC01 with ARVs. 
 
18. Other antibodies have caused other side effects.  
 
Other antibodies that are different from VRC01 have been given to people for other illnesses. With those 
antibodies, most side effects happen within the first 24 hours including fever, chills, shaking, nausea, 
vomiting, pain, headache, dizziness, trouble breathing, high or low blood pressure, itchiness, rash, hives, 
lip or face swelling, diarrhea, racing heartbeat or chest pain.  Rarely, some antibodies have caused serious 
reactions that may be life-threatening.  
 
One type of serious reaction may occur soon after getting an antibody.  It includes difficulty breathing 
possibly leading to low blood oxygen, low blood pressure, hives or rash, and swelling in the mouth and 
face.  A second type of serious reaction may occur several days to 3 weeks after getting an antibody.  It 
includes hives or a rash, fever, big lymph nodes, muscle and joint pains, kidney problems, chest 
discomfort and shortness of breath. Rarely, antibodies used to treat other diseases have been linked to a 
blood disorder that interferes with blood clotting, cancer, damage to the heart muscle, and to the body’s 
immune system attacking healthy cells.  
 
These rare side effects and reactions have not been seen in other studies of VRC01.  However, it is 
possible that babies in this study could have these types of reactions.  Babies could also have other side 
effects or reactions that we do not yet know about.  
 
We will closely check on babies in this study for side effects and reactions.  Please contact the study staff 
if any of these problems or any other problems occur. 
 
19. There could be risks of disclosure of your baby’s information. 
 
We will make every effort to keep your baby’s information private and confidential.  Study records and 
specimens will be kept in secure locations.  All specimens and most records will be labeled only with a 
code number.  However, your baby’s name will be written on some records.  Despite our best efforts to 
keep your baby’s information private, it is possible that your baby’s information, including information 
about your baby’s genes, could be obtained by someone who should not have it.  If this were to happen, 
your baby could be treated badly or unfairly.   
 
[Sites may modify this paragraph if IRBs/ECs mandate a separate form for obtaining informed consent 
for photographs.]  If we take photos of any reactions to VRC01, we will not photograph your baby’s face.  
Photos will be labeled only with a code number (not with your or your baby’s name).  Photos will be kept 
securely with other information collected for the study.  Photos also may be shared with other doctors 
working on the study.  The other doctors may be here at [site name] or in other countries.  These doctors 
will not be given your or your baby’s name, and they will be required to keep the photos private and 
confidential.  When the study is completed, the photos will be destroyed.  
 


 
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[US sites, insert: To help us protect your privacy, we have obtained a Certificate of Confidentiality that 
protects us from being forced to release information that may identify your baby, such as by the courts or 
police. The certificate cannot be used in all situations, but it can be used to resist demands for information 
that would identify your baby. The certificate does not protect against requests for information from the 
US federal government or from the US Food and Drug Administration. Regardless of the certificate, you 
can release information about your baby’s participation in the study to others, if you wish.] 
 
Benefits of the study 
 
20. There may be no benefit from being in the study.  
 
By joining the study, your baby will be part of the search for new treatments for babies who have HIV.  
However, being in the study may not benefit your baby in any way.   
 
Your baby will have regular visits here and frequent checks on his or her health.  It is possible that the 
examinations and tests done in the study may help your baby stay healthy.  If these procedures show that 
your baby may need medical care that cannot be provided through the study, we will tell you where you 
can go for the care your baby needs.  
 
Other information about the study 
 
21. There are no costs to you or your baby. 
 
There are no costs to you or your baby for the study visits, injections, or procedures.   
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits. For each visit, you will be given (specify amount).] 
 
22. Your baby’s study records may be reviewed by study staff and groups that oversee the study.  
 
Groups that oversee the study include:   
 
• 
[insert name of site IRBs/ECs] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site drug entities that may review records] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
The IMPAACT Network that is coordinating the study 
 
The study staff and these groups are required to make every effort to keep study records private and 
confidential.  Your baby’s study information may be disclosed to other authorities if required by law.  
The results of the study may be presented publicly or published.  However, no presentation or publication 
will use your baby’s name or identify your baby personally.   
 
A description of this study will be available on www.ClinicalTrials.gov as required by United States Law.  
This website will not include any information that can identify your baby.  At most, the website will 
include a summary of the results of the study.  You can search this website at any time. 
 


 
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23. If your baby gets sick or injured, contact us right away. 
 
Your baby’s health is important to us.  We will make every effort to minimize risks and protect your 
baby’s well-being.  It is possible, however, that your baby could have an illness or injury that is study-
related.  This means that the illness or injury occurred as a direct result of the study injections or other 
study procedures.   
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.]  If a study-
related illness or injury occurs, we will treat your baby or tell you where you can you can get the 
treatment your baby needs.  The cost for this treatment may be charged to you or your health insurance.  
There is no program to pay money or give other forms of compensation for study-related illness or injury 
through [site name or] the United States National Institutes of Health.  
 
Who to contact 
 
24. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your baby’s rights as a research participant or concerns about how your 
baby is being treated in the study:  
[insert name and telephone number of IRB contact person or other appropriate person/organization].  
 
• 
If your baby has health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you want to take your baby off the study:  
[insert name and telephone number of investigator or other study staff]. 
 
 
 


 
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Signatures 
 
25. If you decide to have your baby join this study, please sign or make your mark below.  
 
Before deciding whether to have your baby join this study, make sure you have read this form, or had it 
read to you, and that all of your questions have been answered.  You should feel that you understand the 
study, its risks and benefits, and what is expected if you decide to have your baby join.  
 
We will tell you any new information from this study or other studies that may affect your willingness to 
keep your baby in the study.  You can ask questions or request more information at any time.   
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies. Separate consent decisions must 
be documented for storage of residual CSF and for genetic testing]. 
 
 
 


 
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Please write your initials or make your mark next to your choices:  
 
 
__________ 
I agree to have my baby join this study 
 
 
 
 
For storage of leftover spinal fluid:  
 
 
 
__________ 
I agree to storage of leftover spinal fluid (if my baby has a lumbar 
puncture outside of the study)  
 
__________ 
I do not agree to storage of leftover spinal fluid (if my baby has a lumbar 
puncture outside of the study)  
 
 
 
 
 
 
For genetic testing:   
 
 
__________ 
I agree to testing of my baby’s genes related to HIV, VRC01, and the 
immune system 
 
__________ 
I do not agree to testing of my baby’s genes  
 
 
 
 
 
 
 
 
 
 
Name of Infant 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Mother 
 
 
Signature of Mother 
  
 
Date 
(or Legal Guardian; print) 
 
(or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
 
(if applicable; print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Consent Process (print) 
 
 


 
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Appendix III 
Sample Informed Consent Form for Maternal Blood Collection and Testing 
 
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 
 
 
You are being asked to give blood for the research study named above.  
 
This form gives information about giving blood for the study.  Please read it, or have it read to you, and 
ask any questions you may have.  We will take as much time as you need to fully understand the 
information.  We will ask you questions to see if we have explained the information clearly.  
 
After you understand the information, if you decide to give blood for the study, you will be asked to sign 
or make your mark on this form. You will be offered a copy to keep. 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [insert 
site name] are doing this study to test an experimental injection called VRC01 in babies. Because your 
baby is participating in the study, you are being asked to give blood for the study.   
 
The person in charge of the study at this clinic is [insert name of IoR].  The United States National 
Institutes of Health are paying for the study. 
 
1. The study is being done to test VRC01 in babies.  
 
The study will test the effects of VRC01 when given to babies who have HIV.  In the study, we will do 
laboratory tests of babies’ blood to learn about these effects.  We would also like to test the blood of 
babies’ mothers to learn more about the effects of VRC01 in babies.  For example, mothers have 
antibodies and other substances in their blood that are passed to their babies.  It is possible that these 
substances could have an impact on the effects of VRC01 in their babies.   
 
2. It is your decision whether to give your blood for the study. 
 
Deciding to give blood for the study is voluntary.  You are free to give blood or not.  If you decide to give 
blood, you can change your mind at any time.  Your decision will have no effect on your baby’s 
participation in the study.  Your decision will also have no effect on the medical care that you or your 
baby receive at this clinic.  Your access to services and the benefits and rights you normally have will not 
be affected.  
 
3. Mothers’ blood will be collected on the day babies enter the study.  
 
If you decide to give blood for the study, we will collect 20 mL (4 teaspoons) from your arm. The blood 
will be collected on the day your baby enters the study or within the next 7 days, if necessary. 
 


 
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4. Mothers’ blood will tested at different laboratories.  
 
Mothers’ blood will be tested after all babies have completed the study.  Different tests will be done at 
different laboratories in the United States.  The results of these tests are for research purposes only.  This 
means they are not expected to give any information relevant to your or your baby’s health.  The results 
will not be given to the study staff or to you. 
 
If you agree, the blood that you give for this study could be used for tests of your genes.  Your genes are 
passed to you from your birth parents.  They affect how you look and how your body works.  Differences 
in people’s genes can help explain why some people get a disease while others do not.  For this study, 
only genes related to HIV, the immune system, and the effects of VRC01 will be tested.   
 
5. There is little risk from giving blood.  
 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted.  Rarely, 
drawing blood can cause fainting or infection.   
 
6. There could be risks of disclosure of your information. 
 
We will make every effort to keep your information private and confidential.  Study records and blood 
samples will be kept in secure locations.  All blood samples and most records will be labeled only with a 
code number.  Your name will be written on some records but the results of your blood tests will not be 
kept with these records.  Therefore, it is unlikely that anyone could find out the results of your tests linked 
to your name.  Despite these efforts, it is possible that your information, including information about your 
genes, could be obtained by someone who should not have it.  If this were to happen, you could be treated 
badly or unfairly.  You could also feel stress or embarrassment.   
 
[US sites, insert: To help us protect your privacy, we have obtained a Certificate of Confidentiality that 
protects us from being forced to release information that may identify you, such as by the courts or police. 
The certificate cannot be used in all situations, but it can be used to resist demands for information that 
would identify you. The certificate does not protect against requests for information from the US federal 
government or from the US Food and Drug Administration. Regardless of the certificate, you can release 
information about your participation in the study to others, if you wish.] 
 
7. There may be no benefit from giving blood.  
 
By giving blood, you will be part of the search for new treatments for babies who have HIV.  However, 
giving blood is not expected to directly benefit you or your baby in any way.  
 
8. There are no costs to you. 
 
There are no costs to you for giving blood for this study.  
 
9. Your records may be reviewed by study staff and groups that oversee the study.  
 
Groups that oversee the study include:   
 
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site drug entities that may review records] 


 
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• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
The IMPAACT Network that is coordinating the study 
 
Like the study staff, these groups are required to make efforts to keep study records private and 
confidential.  Your study information may be disclosed to other authorities if required by law.  
 
The results of the study may be presented publicly or published.  However, no presentation or publication 
will use your name or identify you personally.   
 
A description of this study will be available on www.ClinicalTrials.gov as required by United States Law.  
This website will not include any information that can identify you.  At most, the website will include a 
summary of the results of the study.  You can search this website at any time. 
 
10. Please tell us if you change your mind about giving blood.  
 
If you decide to give blood, and then change your mind, please tell us.  We will destroy any of your blood 
that has not yet been tested.  
 
11. If you are ill or injured, contact us right away. 
 
Your health is important to us.  We will make every effort to minimize risks and protect your well-being.  
It is possible, however, that you could have an illness or injury that is study-related.  This means that the 
illness or injury occurred as a direct result of giving samples for the study.   
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.]  If a study-
related illness or injury occurs, we will treat you or tell you where you can you can get the treatment you 
need.  The cost for this treatment may be charged to you or your health insurance.  There is no program to 
pay money or give other forms of compensation for study-related illness or injury through [site name or] 
the United States National Institutes of Health.    
 
12. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your rights as a research participant or concerns about how you are being 
treated in the study:  
[insert name and telephone number of IRB contact person or other appropriate person/organization].  
 
• 
If you have health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you want to change your mind about giving samples for the study:  
[insert name and telephone number of investigator or other study staff]. 
 
 


 
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Signatures 
 
13. If you decide to give blood for this study, please sign or make your mark below.  
 
Before deciding whether to give blood for study, make sure you have read this form, or had it read to you, 
and that all of your questions have been answered.  You should feel that you understand the study, its 
risks and benefits, and what is expected of you. 
 
We will tell you any new information from this study or other studies that may affect your willingness to 
have your blood tested for the study.  You are welcome to ask questions or request more information at 
any time.   
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies. Separate consent decisions must 
be documented for genetic testing]. 
 
Please write your initials or make your mark next to your choice:  
 
 
__________ 
I agree to give blood for this study and I agree to testing of my genes related to HIV, 
VRC01, and the immune system. 
 
__________ 
I agree to give blood for this study but I do not agree to testing of my genes.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Mother 
 
 
Signature of Mother 
  
 
Date 
(print)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
 
(if applicable; (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Consent Process (print) 
 
 


 
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Appendix IV 
Sample Informed Consent Form for Specimen Storage and Future Use: Infants 
 
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 
 
 
You have decided to have your baby join the study named above.  As part of the study, your baby will 
have blood drawn.  Your baby also may have spinal fluid collected.  After your baby’s samples are tested 
for the study, some samples may be left over.  We call these extra samples.  The IMPAACT Network 
would like to keep these extra samples and use them for other research in the future. 
 
This form gives information about use of extra samples.  Please read it, or have it read to you, and ask any 
questions you may have.  After we discuss the information with you, you will record your decisions on 
use of extra samples at the end of the form.  
 
1. It is your decision whether to allow extra samples to be used.  
 
You are free to say yes or no, or to change your mind at any time.  Your decision will not affect your or 
your baby’s participation in the study.  If you say no, all extra samples will be destroyed.  
 
2. If you agree, your baby’s extra samples will be kept in a repository.  
 
[Sites should insert one of the two options show below. Choose/adapt the second option if local 
regulations do not permit storage of samples for future research use in the United States.] 
 
A repository is a secure facility that is used to store samples.  The IMPAACT Network repository is in the 
United States.  If you agree to have extra samples stored, the samples will be kept in this repository.  
There is no limit on how long the samples will be kept [sites may insert time limits here if required by 
local authorities]. 
 
A repository is a secure facility that is used to store samples.  The IMPAACT Network has repository in 
the United States.  However, our local regulations require that extra samples be stored in our country.  
Therefore, we will keep the samples in a repository here at our laboratory. There is no limit on how long 
the samples will be kept [sites may insert time limits here if required by local authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, VRC01, the immune system, and other diseases.  The 
research may be done in the United States or in other locations.  
 
If you agree, the extra samples could also be used for research that looks at your baby’s genes.  Genes are 
passed to children from their birth parents.  They affect how people look and how their bodies work. 
Differences in people’s genes can help explain why some people get a disease while others do not.  Your 
baby’s extra samples would only be used to look at genes related to HIV and the immune system.   
 


 
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Any research done with the extra samples must be reviewed and approved by the IMPAACT Network.  
The research must also be approved by an ethics committee. The role of an ethics committee is to review 
the research plan and protect the rights and well-being of the people whose samples will be used.   
 
The research done with extra samples is not expected to give any information relevant to your baby’s 
health.  Therefore, the results will not be given to the study staff or to you. The results also will not be 
placed in your baby’s study records.  
 
4. There is little risk to your baby.  
 
When extra samples are used for research, they are labeled with a code number only.  To protect your 
baby’s privacy, no names are used.  However, information such as age, gender, HIV status, and other 
health information may be linked to the samples.  Information on whether your baby received VRC01 and 
the results of other tests related to VRC01 may also be linked to the samples.  
 
There may be risks from tests of your baby’s genes.  If others found out the results of these tests, they 
could treat your baby badly or unfairly.  However, this is almost impossible because the results will not 
be given to the study staff or to you, and will not be in your baby’s study records. 
 
5.  There may be no benefit to your baby.  
 
By allowing your baby’s extra samples to be used for research, your baby will be part of the search for 
new information that may benefit people with HIV in the future.  However, the research done with the 
extra samples is not expected to directly benefit you or your baby in any way.  
 
6.  You will not be paid for use of your baby’s samples. 
 
There is no cost to you for use of your baby’s extra samples.  The samples will not be sold and you will 
not be paid for use of the samples.  It is possible that research done with the samples could lead to a new 
discovery or a new product.  If this happens, there is no plan to share any money with you.  
 
7.  Information from research using extra samples may be reviewed by groups that oversee the research. 
 
These groups include:   
 
• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
 
The people who do research with the extra samples and the groups listed above are required to make 
efforts to keep information private and confidential. 
 
The results of the research done with extra samples may be presented publicly or published.  However, no 
presentation or publication will use your baby’s name or identify your baby personally.   
 


 
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8. If you have any questions, concerns, or problems related to your baby’s extra samples, use these 
contacts. 
 
• 
If you have questions about use of your baby’s extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you later change your mind about use of your baby’s extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your baby’s rights as a research participant or concerns about how your 
baby is being treated in the study:  
[insert name and telephone number of IRB contact person or other appropriate person/organization].  
 
Signatures 
 
Before deciding whether to allow your baby’s extra samples to be used for research, make sure you have 
read this form, or had it read to you, and that all of your questions have been answered.  You should feel 
that you understand your options and the possible risks and benefits before making your decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies. Separate consent decisions must 
be documented for genetic testing]. 
 
 
 


 
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29 May 2017 
Please write your initials or make your mark next to your choice:  
 
 
__________ 
I allow my baby’s extra samples to be used for research on HIV, VRC01, the immune 
system, and other diseases.  I also allow my baby’s samples to be used for tests of his or 
her genes.   
 
 
__________ 
I allow my baby’s extra samples to be used for research on HIV, VRC01, the immune 
system, and other diseases.  I do not allow my baby’s samples to be used for tests of his 
or her genes.   
 
 
__________ 
I do not allow my baby’s extra samples to be used for any research.   
 
 
 
 
 
 
 
 
 
Name of Infant 
(print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Mother 
 
 
Signature of Mother 
  
 
Date 
(or Legal Guardian; print) 
 
(or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
 
(if applicable; print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Consent Process (print) 
 


 
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29 May 2017 
Appendix V 
Sample Informed Consent Form for Specimen Storage and Future Use: Mothers 
 
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 
 
 
You have decided to have your blood drawn for the study named above with your baby.  After your blood 
samples are tested for the study, some samples may be left over.  We call these extra samples.  The 
IMPAACT Network would like to keep these extra samples and use them for other research in the future. 
 
This form gives information about use of extra samples.  Please read it, or have it read to you, and ask any 
questions you may have.  After we discuss the information with you, you will record your decisions on 
use of extra samples at the end of the form.  
 
1. It is your decision whether to allow extra samples to be used.  
 
You are free to say yes or no, or to change your mind at any time.  Your decision will not affect your or 
your baby’s participation in the study.  If you say no, all extra samples will be destroyed.  
 
2. 
If you agree, your extra samples will be kept in a repository.  
 
[Sites should insert one of the two options show below. Choose/adapt the second option if local 
regulations do not permit storage of samples for future research use in the United States.] 
 
A repository is a secure facility that is used to store samples.  The IMPAACT Network repository is in the 
United States.  If you agree to have extra samples stored, the samples will be kept in this repository.   
There is no limit on how long the samples will be kept [sites may insert time limits here if required by 
local authorities]. 
 
A repository is a secure facility that is used to store samples.  The IMPAACT Network has repository in 
the United States.  However, our local regulations require that extra samples be stored in our country.  
Therefore, we will keep the samples in a repository here at our laboratory. There is no limit on how long 
the samples will be kept [sites may insert time limits here if required by local authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, VRC01, the immune system, and other diseases.  The 
research may be done in the United States or in other locations.  
 
If you agree, the extra samples could also be used for research that looks at your genes.  Genes are passed 
to children from their birth parents.  They affect how people look and how their bodies work. Differences 
in people’s genes can help explain why some people get a disease while others do not.  Your extra 
samples would only be used to look at genes related to HIV and the immune system.   
 


 
IMPAACT 2008, FINAL Version 2.0 
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29 May 2017 
Any research done with the extra samples must be reviewed and approved by the IMPAACT Network.  
The research must also be approved by an ethics committee. The role of an ethics committee is to review 
the research plan and protect the rights and well-being of the people whose samples will be used.   
 
The research done with extra samples is not expected to give any information relevant to your health.  
Therefore, the results will not be given to the study staff or to you. The results also will not be placed in 
your study records.  
 
4. There is little risk to you.  
 
When extra samples are used for research, they are labeled with a code number only.  To protect your 
privacy, no names are used.  However, information such as age, gender, HIV status, and other health 
information may be linked to the samples.  Information on whether your baby received VRC01 and the 
results of other tests related to VRC01 may also be linked to the samples.  
 
There may be some risks from tests of your genes.  If others found out the results of these tests, they 
could treat you badly or unfairly.  However, this is almost impossible because the results will not be given 
to study staff or to you, and will not be in your study records. 
 
5.  There may be no benefit to you.  
 
By allowing your extra samples to be used for research, you will be part of the search for new information 
that may benefit people with HIV in the future.  However, the research done with the extra samples is not 
expected to directly benefit you or your baby in any way.  
 
6.  You will not be paid for use of your samples. 
 
There is no cost to you for use of your extra samples.  The samples will not be sold and you will not be 
paid for use of the samples.  It is possible that research done with the samples could lead to a new 
discovery or a new product.  If this happens, there is no plan to share any money with you.  
 
7.  Information from research using extra samples may be reviewed by groups that oversee the research. 
 
These groups include:   
 
• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
 
The people who do research with the extra samples and the groups listed above are required to make 
efforts to information private and confidential. 
 
The results of research done with extra samples may be presented publicly or published.  However, no 
presentation or publication will use your name or identify you personally.   
 


 
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8. If you have any questions, concerns, or problems related to your extra samples, use these contacts. 
 
• 
If you have questions about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you later change your mind about use of your extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your rights as a research participant or concerns about how you are being 
treated in the study:  
[insert name and telephone number of IRB contact person or other appropriate person/organization].  
 
Signatures 
 
Before deciding whether to allow your extra samples to be used for research, make sure you have read 
this form, or had it read to you, and that all of your questions have been answered.  You should feel that 
you understand your options and the possible risks and benefits before making your decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies. Separate consent decisions must 
be documented for genetic testing]. 
 
Please write your initials or make your mark next to your choice:  
 
 
__________ 
I allow my extra samples to be used for research on HIV, VRC01, the immune system, 
and other diseases.  I also allow my samples to be used for tests of my genes.   
 
__________ 
I allow my extra samples to be used for research on HIV, VRC01, the immune system, 
and other diseases.  I do not allow my samples to be used for tests of my genes.   
 
__________ 
I do not allow my extra samples to be used for any research.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Mother 
 
 
Signature of Mother 
  
 
Date 
(print)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Witness 
 
 
Signature of Witness 
 
 
Date 
 
(if applicable; print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Name of Study Staff Conducting 
Signature of Study Staff  
 
Date 
Consent Process (print)