Clinical trial NCT03707977
Conditions: HIV Infection
Keywords: broadly neutralizing antibodies HIV suppression
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2019-06-17; Completion date: 2021-12-03
Enrollment: 30 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the impact of two broadly neutralizing antibodies, VRC01LS and 10-1074, on the maintenance of HIV suppression in a cohort of early-treated children in Botswana.

Detailed description:
This study will evaluate the impact of two broadly neutralizing antibodies, VRC01LS and 10-1074, on the maintenance of HIV suppression in a cohort of early-treated children in Botswana.

The primary objectives are as follows:

1. To conduct an interventional clinical trial to determine the safety, pharmacokinetics, dosing and antiviral efficacy of up to 24 weeks of maintenance VRC01LS and 10-1074 immunotherapy in early-treated HIV-1 infected children in Botswana.
2. To evaluate effects of treatment with VRC01LS and 10-1074 on the size and cellular composition of residual viral reservoirs.
3. To investigate the influence of VRC01LS and 10-1074 treatment on the magnitude and quality of antiviral innate and adaptive immune responses.

The study includes 4 steps: the pharmacokinetics (PK) Step, Step 1, Step 2, and Step 3. In the PK Step, antiretroviral treatment (ART) is continued and 12 study participants will undergo safety and PK testing, 6 for each bNAb used in the study (10-1074 and VRC01LS). In Step 1, ART is continued and dual bNAb treatment occurs, with PK confirmation of dual bNAb dosing for the first 6 participants in Step 1. In Step 2, ART is withdrawn and dual bNAb maintenance treatment occurs. In Step 3, dual bNAbs will be discontinued and participants will be re-started on ART.

Participants will be in the study for a minimum of 56 weeks, and a maximum of 98 weeks for those who start in the PK step and continue through the study.

Arms: arm 1: In the PK Step, participants will continue ART and receive VRC01LS at Weeks 0, 4, and 8 as a single intravenous (IV) dose (30 mg/kg load then 10 mg/kg maintenance). arm 2: In the PK Step, participants will continue ART and receive 10-1074 at Weeks 0, 4, and 8 as a single IV dose (30 mg/kg). arm 3: In Step 1, eligible participants will continue to receive ART and will receive both 10-1074 and VRC01LS at Weeks 0, 4, and 8. Following a recommendation from the study team and Safety Monitoring Committee (SMC) to increase the maintenance dosing based on the PK Step, a VRC01LS loading dose of 30 mg/kg will be given at the start of Step 1, followed by 15 mg/kg dosing at each 4-weekly visit, and 10-1074 dosing will be at 30 mg/kg at each 4-weekly visit. In Step 2, participants with ongoing viral suppression throughout Step 1 will undergo withdrawal of ART and will continue maintenance 10-1074 (30 mg/kg) and VRC01LS (15 mg/kg) treatment for up to 24 weeks. In Step 3, both 10-1074 and VRC01LS will be discontinued and ART will be re-started.
Interventions: intervention 1: ART intervention 2: VRC01LS intervention 3: 10-1074
Intervention descriptions: intervention 1: ART will not be provided by the study. Participants will continue to receive their ART regimen they were receiving prior to enrolling in the study. intervention 2: Administered by intravenous (IV) infusion intervention 3: Administered by intravenous (IV) infusion

Protocol documents:
ICF_002.pdf: 
Study Title: A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies 
VRC01LS and 10-1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated 
Children in Botswana 
 
NCT03707977 
 
Consent for PK Study of VRC01LS or 10-1074 version 2.0 dated December 20, 2018 
 
 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
1 
 
A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies VRC01LS and 
10-1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated Children in 
Botswana 
(Dual bNAb Treatment in Children) 
 
Consent for PK Study of VRC01LS or 10-1074 
 
1. INTRODUCTION 
 
• 
Your child is being invited to take part in a research study. This study is sponsored by 
the National Institutes of Health (NIH) in the United States and is being done together by 
researchers at the Harvard T.H. Chan School of Public Health and the Botswana 
Harvard AIDS Institute Partnership (BHP). The investigators in charge of this study are 
Dr. Roger Shapiro and Dr. Joseph Makhema. The first part of the study will check the 
safety and dosing of two experimental antibodies (called VRC01LS and 10-1074). 
VRC01LS has been given to children before; this study is the first time 10-1074 is being 
given to children. To decide whether or not you wish your child to take part in this study, 
you should understand its risks and benefits to make the best decision for you and your 
child. 
 
• 
This consent form gives information about the research study, which the study team will 
discuss with you. Once you understand the study, and if you agree to allow your child 
take part, we will ask you to sign this consent form and will offer you a copy to keep.  
 
• 
It is important that you understand the following: 
 
 Your decision for your child’s taking part in the study is completely voluntary. 
 You may refuse your child to take part in the study or leave it at any time without the 
loss of other benefits to you or your child. 
 Your decision to leave the study will not affect your/your child’s future medical care 
or your ability to take part in other studies. 
 
2. WHY IS THIS STUDY BEING DONE? 
• 
Most adults and most children who are HIV infected need to stay on HIV medicines for 
their whole life, but sometimes those medicines have side effects or are difficult to take 
every day.  
• 
This study is being done to see if children with very low levels of virus in their bodies 
might be able to safely receive the antibodies against HIV once each month instead of 
their other HIV medicines and remain with very low levels of HIV in their body.   
• 
The first part of the study—the part that this consent form is about—will be done to 
check the safety and dosing of these antibodies, while your child is also taking HIV 
medicines. This is called a “pharmacokinetics” or “PK study. Your child is invited to join 
the PK study now. Your child may be invited to join the second part of the study after 
completing the PK study. You will be given more information and asked to sign another 
consent form for the second part of the study if that happens. 
 
 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
2 
 
3. OVERVIEW OF THE PK STUDY 
 
• 
The PK study will enroll 12 children. All children in the study must have responded well 
to HIV medicines, with low viral levels in their cells and no recent viral rebound while 
taking HIV medicines. Viral rebound is when the level of HIV in the body is at a low level 
but then rises to a level where it can be picked up on a blood test. 
• 
Enrolled children continue their usual HIV medicines and will also receive one of the two 
antibodies in the study (VRC01LS or 10-1074). 
• 
The antibody will be given 3 times. This will occur once a month while your child is in the 
PK Study. 
• 
Your child will be monitored very closely during the PK study.   
 
4. WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
Enrollment / study entry 
 
• 
If you choose for your child to take part in this study, we will draw blood and most 
children will receive the antibodies at the first study visit. Your child will continue to take 
his/her usual HIV medicines. Your child will have a physical exam. 
• 
Your child will receive only one antibody during the PK Study (6 will receive VRC01LS, 
and 6 will receive 10-1074). Whether your child receives VRC01LS or 10-1074 depends 
on when he or she joins the study. You cannot choose the antibody your child receives. 
• 
Antibodies will be given to your child by an experienced study nurse and physician by an 
intravenous infusion (also called an IV drip). This means the antibodies will go directly 
into the vein using a needle and a tube. This will take about 30 minutes. The IV will be 
removed at the end of the treatment visit. We will ask you to stay at the clinic for 2-4 
hours after the first infusion to watch your child for any reaction. The first visit will take 
about 3-5 hours total. 
• 
Blood will be drawn to measure the amount of HIV in your child’s blood, called a viral 
load; the amount of the study antibodies in your child’s blood, the “PK tests;” the cells 
that fight infection, called the CD4; and to perform safety measurements, called “full 
blood count” (FBC) and chemistry. Some blood also will be stored to perform specialized 
tests on the virus and to study your child’s ability to fight the virus. Some of these tests 
may study your child’s genes. Genes contain information which is different for each 
person. This is done as a marker for your child’s ability to fight the virus. The total 
amount will be about 2 and a half teaspoons (up to 12 mL) from your child.  
• 
We will ask you some questions about your child’s household, and yourself. You don’t 
have to answer any questions you don’t want to answer. 
• 
If your child is already part of the EIT study, your child’s records will be available to the 
study team, and this will make sure that everything known about your child’s care in the 
EIT Study is also available for this research study.  
 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
3 
 
 
Study visits 
 
• 
The antibodies will be given 2 more times, at 4 weeks and 8 weeks after the first visit. 
Each time antibodies will be given by IV. Usually, the IV will be placed in a vein in your 
child’s arm, but could be in another place, like the leg, if necessary. This will take about 
30 minutes. We will watch your child for any reactions for about 60 minutes after these 
infusions.  
• 
Your child will have about 13 study visits. These will be the 3 visits when antibodies are 
given, and additional visits, one day, one week, and two weeks after the antibodies are 
given each time.  
• 
At most study visits, we will ask questions about your child’s health, and, we will ask 
whether he/she received every dose of the HIV medicines. We will also weigh your child 
and adjust the HIV medication doses as needed. We will also perform a physical exam 
at most visits. 
• 
The antibody visits will take about 2 hours. Other visits will take about 30-45 minutes. 
• 
You will receive transportation money and compensation for your time at each visit. If 
you request it, it may be possible to have some study visits at your home, but not when 
the antibody is given. The study team may check in with you about your child by 
telephone between visits. 
• 
At each visit, some blood will be drawn from your child to check levels of the antibody. 
Tests may also include FBC and chemistry, CD4, viral load, and stored blood for 
specialized tests to study your child’s ability to fight the virus, which may include tests of 
your child’s genes. Between about one-half and 2 and a half teaspoons of blood (2-12 
mL) will be drawn at these visits. When antibodies are given we may need to draw blood 
both before and after the infusion.  
 
Test results 
• 
Results of viral load, CD4, and other laboratory tests that check your child’s health will 
be given to you at scheduled visits as soon as they are available. If a lab test result 
suggests a health problem we will let you know sooner than your next scheduled visit. 
Results of other tests that do not affect your child’s clinical care will not be provided.  
 
Stored samples and future tests 
 
• 
If you agree (at the end of this consent form), some of your child’s blood taken as part of 
this study will be stored for up to 10 years after the end of this study, for approved HIV-
related research in the future. In most cases, we will use all of the blood drawn for the 
study tests. However, at some visits a small amount (generally less than half a 
teaspoon) of blood may be left over after testing occurs, and may be saved for future 
testing if needed. You can still take part in this study even if you decide to not allow your 
child's leftover samples to be stored for future approved research. No personal identifiers 
will be stored with the samples, so your child’s identity will be protected in the usual way 
(see Section 12, Confidentiality of Records). Some of these samples may be shipped 
outside of Botswana, but only for specialized testing that is not available in Botswana. 
You may ask that samples be destroyed if you later change your mind and do not want 
us to keep them. You can request this at any visit, or after the study by calling Dr. 
Joseph Makhema (Tel: 3902671, Cell 72100846). 
 
 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
4 
 
5. HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
• 
About 12 children will take part in the PK study. 
 
6. HOW LONG WILL MY CHILD BE IN THIS STUDY? 
• 
Your child will be in the PK study for 12 weeks.  
 
7. WHY WOULD THE STUDY INVESTIGATORS TAKE MY CHILD OFF THIS STUDY 
EARLY? 
The study doctor may need to take your child off the study early without your permission if: 
• 
the study is stopped or modified by the Botswana Ministry of Health, National Institutes 
of Health (NIH), the Food and Drug Administration (FDA), the United States Office of 
Human Research Protection (OHRP) and other government agencies, or the study 
Institutional Review Boards (IRBs).  An IRB is a committee that watches over the safety 
and rights of research participants. 
• 
the Study Monitoring Committee recommends that the study be stopped early. This 
committee, also known as the SMC, is made up of an outside group of experts who 
monitor the study.  
• 
you are not able to attend the study visits as required by the study. 
 
The study investigators may also need to take your child off of the study without your permission 
if: 
• 
continuing with the study is considered to be harmful to your child 
• 
your child is not able to follow the procedures of the study 
 
8. CAN MY CHILD LEAVE THE STUDY IF I CHANGE MY MIND?  
 
• 
You may have your child leave the study at any time for any reason, and your child will 
still be given medical care at the hospital or government clinic of your choice (we will 
help arrange this if you want). If you are willing, we would like to schedule a final study 
visit and blood draw before your child leaves the study. If you leave the study, the data 
collected until that date will remain part of the study database. 
 
9. WHAT ARE THE RISKS OF THE STUDY? 
 
RISKS OF VRC01LS and 10-1074  
• 
VRC01LS and 10-1074 are antibodies. Antibodies are made by the immune system to 
fight infection. Antibodies can also be made in laboratories. The antibodies used in the 
study are made in a laboratory. These antibodies are experimental. This means we do 
not know if they are safe to use in people. Both have been tested in animals and people, 
including in HIV-positive people. VRC01LS has also been used in children. These 
studies have had no safety concerns that were considered serious. Both antibodies are 
being tested in more research studies to learn more about them, and this study will help 
us learn about VRC01LS and 10-1074 in children who have HIV.  


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
5 
 
 
• 
VRC01LS 
As of April 2017, VRC01LS had been tested in more than 30 adults. So far, there 
have been no serious side effects seen in the adults who have received 
VRC01LS. VRC01LS is being studied in babies now in another study in the 
United States, South Africa, and Zimbabwe.   
 
VRC01LS is very similar to another experimental antibody called VCR01. As of 
January 2017, more than 800 HIV-negative and HIV-positive adults have 
received this very similar antibody 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 (rash) 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. 
 
Also as of January 2017, at least 33 babies born to mothers who have HIV have 
received VRC01 in a study being done in the United States, South Africa, and 
Zimbabwe. Some 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. 
 
• 
10-1074 
This study is the first time that 10-1074 is being given to children, but as of 
August 2017, 10-1074 had been tested in 76 adults at different doses. So far, 
there have been no serious side effects seen in the research participants who 
have received 10-1074. Some people had a headache, cold symptoms, or felt 
tired. A few people had dry eyes, dizziness, abdominal pain, nausea, itchiness, 
or mildly abnormal results on tests of their liver.  
 
• 
To watch for any possible reactions, children will be asked to stay in the clinic for 2-4 
hours after the first antibody injection, and at least 1 hour after later injections. During 
this time, study staff will check for reactions to the infusion.  
RESISTANCE TO VRC01LS and 10-1074 
• 
It is possible that children who receive VRC01LS and 10-1074 in this study could 
develop “resistance” to the antibodies. If resistance develops, the antibodies may not be 
effective in helping to control your child’s HIV. It isn’t known whether this will have any 
effect on your child’s health. This type of resistance has no impact on the ability of HIV 
medicines to control the virus. 
 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
6 
 
RISKS OF OTHER ANTIBODIES 
• 
Other antibodies that are different from VRC01LS and 10-1074 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, 
VRC01LS, or 10-1074. However, it is possible that children in this study could have 
these types of reactions. Children could also have other side effects or reactions that we 
do not yet know about. We will closely check on children in this study for side effects and 
reactions. Please contact the study staff immediately if any of these problems or any 
other problems occur. 
 
RISKS OF TAKING BLOOD and IV INFUSION 
• 
Taking blood may cause some discomfort, bleeding, or bruising where the needle pricks 
your child’s skin, and in rare cases, fainting/feeling lightheaded or infection.  A clot may form 
at the site of the needle prick.  
• 
We will follow the guidance of experts to make sure that we do not take too much blood from 
your child when we are checking the virus and the safety of the medicines and storing blood 
for research. However, there is a small possibility that drawing blood might make a low 
blood count even worse, and that this would lead to the need for a blood transfusion for your 
child. 
• 
VRC01LS and 10-1074 will be given as an infusion in to a vein. An IV infusion can cause 
stinging, itchiness, discomfort, pain, soreness, redness, bruising, swelling, or a small cut 
where the needle enters the skin. Rarely, needle sticks can cause infection.  
 
RISK OF STIGMA 
• 
We will try to protect the confidentiality of your/your child’s HIV status. We will visit your 
home only if you have granted permission for this (and you may change your mind about 
this at any time). In all cases, home visits will be by health workers in plain clothes and in 
unmarked vehicles or on foot. If your/your child’s HIV status were to become known or 
suspected because of your participation in this study, it is possible that the stigma of HIV 
could affect your personal relationships. This might cause you or your child stress. We will 
do everything possible to prevent this from happening, and confidential counseling also will 
be available to you through this clinic. You may feel uncomfortable answering study 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
7 
 
questions about yourself, your household, or income. You do not have to answer questions 
if you don’t want to. 
 
10. ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
We do not know if your child will benefit from being in this study. We do not know if the 
antibodies will affect your child’s health. It is possible that adding an antibody to your child’s HIV 
medicines will lower the level of virus in his/her body even further than the HIV medicines alone, 
and this could protect against future viral rebounds. However, we do not know whether this will 
occur. This study and other studies will help us learn more about the potential for this to occur. 
By joining the PK study, your child will be part of the search for new treatments for children who 
have HIV.  
 
• 
Your child will see a doctor at every study visit, and he/she will have access to frequent 
testing and monitoring to help treat his/her HIV infection, and to treat other childhood 
illnesses. This monitoring includes viral load testing and CD4 testing that will allow us to 
monitor your child’s health very closely. These extra visits with a doctor, and the extra 
monitoring, might improve your child’s health.  
• 
Knowledge gained from this study may help other children in the future. If children in this 
study are able to safely receive antibodies and we learn more about dosing, this will help 
make that option possible for other children in Botswana in the future.  
• 
A description of this clinical trial will be available on ClinicalTrials.gov. This website will not 
include information that can identify you/your child. At most, the website will include a 
summary of the results. You can search this website at any time. 
  
 
11. WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
Instead of being in this study you may choose not to allow your child to take part in the study 
and your child will be cared for either within the EIT study, or at a government clinic which 
provides HIV treatment and care. We will refer you to that clinic and make sure your child is 
seen there.  
 
12. WHAT ABOUT CONFIDENTIALITY? 
We will do everything we can to keep your and your child’s personal information confidential.  
We cannot guarantee complete confidentiality.  Your or your child’s personal information may be 
disclosed if required by law. 
• 
Your child’s medical records at this clinic or at a government clinic or hospital may be 
reviewed by the Botswana and Harvard T.H. Chan School of Public Health IRBs, the 
Botswana Ministry of Health, the U.S. National Institutes of Health (NIH); the U.S. Food 
and Drug Administration (FDA); the U.S. Office for Human Research Protections 
(OHRP); other local, U.S., and international regulatory entities; study staff, and study 
monitors. 
• 
Your child will be identified by a code number only known to you, the study team, or the 
health staff responsible for your child’s care. All information about your child and the 
information you give about yourself will be identified by this number. The code will be 
stored in a secure location. You and your child will not be identified by name in any 
publication or presentation from this study. 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
8 
 
• 
For purposes of the study, your child`s medical records may be photocopied when there 
is need. These copies will be kept safe and secure like other study records only accessed 
by authorized personnel. 
 
13. HOW WILL MY/MY CHILD’S SAFETY BE PROTECTED? 
• 
Your child will be followed throughout the study by the study staff. If any problems are 
found, VRC01LS and 10-1074 will be stopped if indicated to do so. 
• 
A safety monitoring committee will regularly review the safety of this study. 
• 
Counseling services will be available for you if needed throughout the study. 
 
14. WHAT ARE THE COSTS TO ME? 
• 
There is no cost to you or your child for the antibodies, clinic visits or laboratory tests 
related to this study. All other medical examinations or tests and medicines outside of 
this study will be given to you either through the study clinic or at a government clinic or 
hospital.  
 
15. WILL I RECEIVE ANY PAYMENT? 
• 
You will receive no money for your child’s participation in the study, but you will be given 
money for transportation costs to and from the clinic, and to compensate you for your 
time. Transportation costs will be discussed with you and provided as needed. The 
compensation for your time will be 150 Pula for each scheduled visit where antibody is 
given, and 100 Pula for other scheduled visits or for follow-up visits that are requested 
by the study staff. The amount is more for visits when antibody is given because these 
visits will take more time. 
 
16. WHAT HAPPENS IF MY CHILD IS INJURED? 
• 
Immediate, necessary care will be given to your child free of charge if he/she becomes 
injured due to taking part in this study. Our clinic has insurance to cover medical 
treatment in the case of a study-related injury. In rare cases the insurance funds may not 
be enough. The study sponsor (NIH) does not have a program to provide compensation 
for research related injury. 
 
• 
If you are injured because of this study, you should contact: 
 Dr. Joseph Makhema:   
 
Tel: 3902671  
Cell: 72100846 
 
17. WHAT ARE MY CHILD`S RIGHTS AS A RESEARCH PARTICIPANT? 
• 
Taking part in this study is completely voluntary. You may choose not to allow your child 
take part in this study or leave this study at any time.  No matter what you decide, we will 
help your child receive the best possible HIV treatment available at a government clinic 
or at another clinic if this is possible. 
• 
We will tell you about new information from this or other studies that may affect your 
child’s health, well-being, or willingness to stay in this study.  When the study ends, the 
results will be available from the study staff or clinic. 
 
18. WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
• 
If you have any questions about this study or your child`s rights as a participant, either 
while participating or after you have completed the study, you should contact: 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
9 
 
 
 Dr. Joseph Makhema (for study-related questions): Tel: 3902671 
Cell: 
72100846 
 The Chief Research Officer at Botswana Ministry of Health (for rights as a 
participant):    Tel: 3632775 
 
 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
10 
 
  
Overall Study Participation 
The purpose of the study, procedures to be followed, and risks and benefits have been 
explained to me.  By signing or placing my fingerprint below, I am agreeing for my child to 
participate in this study. I also understand that study staff will ask me some questions about my 
child’s household and about myself. I also give consent for Botswana Harvard Partnership study 
staff to access and use the information in my child’s medical records if needed for the purposes 
of the study, and all records from the EIT study (if applicable). I understand that this may involve 
photocopying any of my child’s medical records relevant to this study. I understand that I may 
withdraw my child’s participation at any time without affecting my rights or those of my child to 
receive medical care.  
 
 
Parent/guardian's name (first-last):______________________________________ 
Parent/guardian's Omang / Passport number:  
 OR Parent/guardian's Omang receipt number:  
 
 
Signature or thumbprint of the Parent/guardian : _____________________________ 
 
Date of Parent/guardian's signature:____/____/____ (dd/mm/yy) 
 
Time of Parent/guardian's signature: ___ ___: ___ ___ hours 
 
Consent for Storage and Use of Blood Specimens 
The purpose of storing and potentially using blood samples from my child has been explained to 
me.  I understand that remaining leftover samples of my child’s blood obtained in the course of 
this study may be stored for up to 10 years after the end of the study in the laboratories where 
the samples for the study were tested (in the Botswana Harvard Partnership laboratory 
whenever possible, or in Boston when specialized testing for the study was required). These 
samples may be used for HIV-related research in the future if such research is permitted by 
Botswana and Harvard ethical review boards. I understand that these specimens will contain no 
personal identifiers.  I also understand that I may ask for my child's stored samples to be 
destroyed, if I later change my mind, by notifying a staff member during any study visit or, if I 
change my mind after the end of the study, by contacting Dr. Joseph Makhema (Tel: 3902671, 
Cell 72100846). I understand that my child can still take part in this research even if I do not 
agree to store my child's leftover samples for future approved research. By signing below, I 
agree to store samples for future approved health research (note: if this is not signed, it 
indicates that permission was not given to store samples for this purpose). 
 
 
Signature or fingerprint of the Parent/guardian:______________________________ 
 
Date of Parent/guardian's signature:____/____/____ (dd/mm/yy) 
 


PK Step Consent Form v2.0, December 20, 2018 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0 December 20, 2018 
 
11 
 
Time of Parent/guardian's signature: ___ ___: ___ ___ hours 
 
Witness (for use if a Parent/guardianis illiterate, in addition to the Parent/guardian's 
thumbprint) 
The purpose of this study and the procedures, risks and benefits to her child have been 
explained to the parent/guardian. To the best of my knowledge she/he understands the 
purpose, procedure, risks and benefits to her/his child. 
 
 
Witness’s signature______________________________________ 
 
 
 
Witness’s name (first - last) _______________________________  
 
 
 
Date of signature ____/____/____ (dd/mm/yy) 
 
Time of signature: ___ ___: ___ ___ hours 
 
 
I have explained the purpose of the study to the participant’s parent/guardian.  To the best of my 
knowledge, she/he understands the purpose, procedures, risks and benefits to her/his child. 
 
 
Health officer's name: ____________________________________ 
 
 
 
Health officer's signature: _________________________________ 
 
 
 
Date of signature ____/____/____ (dd/mm/yy) 
 
Time of signature: ___ ___: ___ ___ hours 
 

ICF_003.pdf: 
Study Title: A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies 
VRC01LS and 10-1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated 
Children in Botswana 
 
NCT03707977 
 
Consent for Research Study of VRC01LS and 10-1074 to Maintain Viral Suppression 
version 3.0 dated May 19, 2020 
 
 
 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
1 
 
A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies VRC01LS and 
10-1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated Children in 
Botswana 
(Dual bNAb Treatment in Children) 
 
Consent for Research Study of VRC01LS and 10-1074 to Maintain Viral Suppression 
 
1. INTRODUCTION 
 
• 
Your child is being invited to take part in a research study. This study is sponsored by the 
National Institutes of Health (NIH) in the United States and is being done together by 
researchers at the Harvard T.H. Chan School of Public Health and the Botswana Harvard 
AIDS Institute Partnership (BHP). The investigators in charge of this study are Dr. Roger 
Shapiro and Dr. Joseph Makhema. The study will see if two experimental antibodies 
(called VRC01LS and 10-1074) can be given to your child to control the HIV virus without 
the need for other HIV medications for a limited period of time. VRC01LS has been given 
to children before; 10-1074 was given to 6 children in the first part of this study but has 
not yet been studied in other children. To decide whether or not you wish your child to take 
part in this study, you should understand its risks and benefits to make the best decision 
for you and your child. 
 
• 
This consent form gives information about the research study, which the study team will 
discuss with you. Once you understand the study, and if you agree to allow your child to 
take part, we will ask you to sign this consent form and will offer you a copy to keep.  
 
• 
It is important that you understand the following: 
 
 Your decision for your child’s taking part in the study is completely voluntary. 
 You may refuse your child to take part in the study or leave it at any time without the 
loss of other benefits to you or your child. 
 Your decision to leave the study will not affect your/your child’s future medical care or 
your ability to take part in other studies. 
 
2. WHY IS THIS STUDY BEING DONE? 
• 
Most adults and most children who are HIV infected need to stay on HIV medicines for 
their whole life, but sometimes those medicines have side effects or are difficult to take 
every day.  
• 
Your child started HIV medicines very early in life and has responded well to treatment 
with 3 HIV medicines. This treatment has reduced the virus to very low levels in his/her 
body. 
• 
This study is being done to see if children with very low levels of virus in their bodies might 
be able to safely receive the antibodies against HIV once each month instead of their other 
HIV medicines and remain with very low levels of HIV in their body.   
• 
This study is also being done to learn about the dosing and levels of the antibodies when 
given to children.  
 
 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
2 
 
3. OVERVIEW OF THE STUDY 
 
• 
The study will enroll up to 36 children from the Early Infant Treatment (EIT) Study. All 
children in the study must have responded well to HIV medicines, with low viral levels in 
their cells and no recent return of virus or viral rebound while taking HIV medicines. Viral 
rebound is when the level of HIV in the body is at a low level but then rises to a level where 
it can be picked up on a blood test. 
• 
Enrolled children will initially continue their usual HIV medicines and will also receive the 
2 antibodies (VRC01LS and 10-1074). After 8 weeks of receiving both antibodies, if levels 
of virus stay low, the other HIV medicines will be stopped and the 2 antibodies will continue 
to be given each month for 24 weeks.   
• 
Your child will be monitored very closely during the study, especially when receiving the 2 
antibodies alone without other HIV medicines. At every study visit, we will test the level of 
virus in your child’s blood, and we will re-start HIV medicines if the virus returns at a level 
above standard detection. We will monitor your child after re-starting the HIV medicines 
to be sure that the level goes down again to very low levels (below detection). 
• 
As long as the virus does not return while your child is on antibody treatment alone, the 
antibody treatment will continue for 24 weeks. After 24 weeks the antibodies will be 
stopped and your child will re-start his/her usual HIV medicines. If the virus returns sooner, 
your child will stop the antibodies and re-start their HIV medications at that time. 
• 
Additional study visits will occur through 56 weeks to make sure your child continues to 
do well and to continue to check the level of virus in his/her body.  
• 
The first 6 children enrolled will have some extra study visits. These first 6 children will be 
in this part of the study for a longer time (68 weeks to likely no more than 84 weeks). This 
is to do some extra tests and checks to learn more about the safety and dosing of the 
antibodies at the beginning of the study. 
 
4. WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
Enrollment / study entry 
 
• 
If you choose for your child to take part in this study, we will draw blood and your child will 
start 2 antibodies at the first study visit. Your child’s usual HIV medicines will still continue 
at that time, for 8 weeks.  
• 
Antibodies will be given to your child by an experienced study nurse and physician by an 
intravenous infusion (also called an IV drip). This means the antibodies will go directly into 
the vein using a needle and a tube. One antibody will be given at a time. This will take 
about 30 minutes for each antibody. The IV will be removed at the end of the treatment 
visit.  
• 
We will ask you to stay at the clinic for 2-4 hours after the first infusion to watch your child 
for any reaction. The first visit will take about 3-5 hours total. 
• 
Blood will be drawn to measure the amount of HIV in your child’s blood, called a viral load; 
the cells that fight infection, called the CD4; the amount of antibodies, and to perform 
safety measurements, called “full blood count” (FBC) and chemistry. Some blood also will 
be stored to perform specialized tests on the virus and to study your child’s ability to fight 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
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the virus. Some of these tests may study your child’s genes. Genes contain information 
which is different for each person. This is done as a marker for your child’s ability to fight 
the HIV virus.  
• 
The total amount will be between about 2 and a half teaspoons (up to 12 mL) from your 
child.  
• 
We may ask you some questions about your child’s household, and yourself. You don’t 
have to answer any questions you don’t want to answer. 
• 
Your child’s records from the EIT study will be available to the study team, and this will 
make sure that everything known about your child’s care in the EIT Study is also available 
for this research study.  
• 
Additional procedures for the first 6 children enrolled: at the first and second infusion visits, 
blood will be drawn before the infusions, at the end of infusions, one hour later, one day 
later, and one week afterward. This is to check how the amount of antibodies in your child’s 
blood changes over time.  
 
 
Study visits 
 
• 
At every study visit, we will ask questions about your child’s health, and while he/she is on 
HIV medicines, we will always ask whether he/she received every dose of the medicines. 
We will also weigh your child and adjust the medication doses as needed. We will also 
perform a physical exam at each visit (except if your child attends an extra visit 1 day after 
an infusion). 
• 
Study visits when antibodies are given will take about 2 hours, except for the first visit that 
takes about 3 hours. Other visits will take 30-45 minutes.  
• 
You will receive transportation money and compensation for your time at each visit. If you 
request it (or if it is necessary for public health reasons during a Covid-19 outbreak), it 
may be possible to have some study visits at your home, or at a different location than the 
study clinic, but not when the antibody is given. We will talk to you in advance about any 
change in location. If necessary, some study visits may also be done by phone, text, or 
email, whichever you prefer. The study team may check in with you about your child by 
telephone between visits. 
 
 
 
First 8 Weeks from the Start of Dual Antibody Therapy 
 
• 
Study visits will occur 1 week, 4 weeks, 5 weeks, and 8 weeks after your child starts the 
study. VRC01LS and 10-1074 antibodies will be given each month. HIV medicines will 
continue until 8 weeks after both antibodies are started. 
• 
At each visit, some blood will be drawn from your child to see if the antibodies have 
changed the levels of virus in the body. Tests include FBC and chemistry, CD4, viral load, 
tests to determine antibody levels, and stored blood for specialized tests to study your 
child’s ability to fight the virus, which may include tests of your child’s genes. Between 
about one-half and 2 and a half teaspoons of blood (2-12 mL) will be drawn at these visits.  
 
• 
Additional procedures for the first 6 children enrolled:  
 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
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o There will be additional blood drawn at the first two infusions visits (before the 
infusion, at the end of the infusions, and one hour later). There will be an extra visit 
and blood draw the day after the first 2 infusions. At the Week 1 and Week 5 visits 
a small amount of additional blood will be drawn to check antibody levels.  
o There will also be about 4 additional visits (possibly up to 12) while we check the 
results of the tests done so far. We will check for safety and dosing of the 
antibodies when given together during this time. These extra 4-12 visits will occur 
on a regular schedule, every 2 weeks until we have enough information to continue 
with the next step of the study.  
o Your child may receive infusions once a month during this time. If there are delays 
caused by Covid-19 (for example, if the lab tests cannot be done on time, or if it is 
necessary to avoid lengthy clinic visits, we may temporarily stop the infusions until 
we can get back on the regular schedule. If that happens, we will still ask you to 
come to the clinic at least once every 12 weeks for a physical exam, blood tests, 
and antiretroviral medication refills. Tests are the same as at other study visits, and 
include FBC and chemistry, CD4, viral load, tests to determine antibody levels, and 
stored blood for specialized tests to study your child’s ability to fight the virus. 
Between 1.5 to 2.5 teaspoons of blood (8-12mL) will be drawn at these clinic visits 
every 12 weeks. The other visits (every two weeks) can be done by phone if 
necessary. If your child’s infusions were temporarily stopped: when we restart 
giving antibody infusions, your child will be given the antibody infusions two times, 
4 weeks apart, before your child can move to or begin the next part of the study. 
 
 
Weeks 8-32 
 
• 
Study visits will occur every week for 4 weeks, then every two weeks for 24 weeks.  
• 
VRC01LS and 10-1074 antibodies will continue to be given each month during weeks 8-
32. Antibodies will usually be given by placing an IV in your child’s arm, but could be in 
another place, like the leg, if necessary. This will take about 60 minutes. We will watch 
your child for any reactions for about 60 minutes after the infusion. 
• 
Your child will stop taking other HIV medicines during this time. At each scheduled visit, 
some blood will be drawn from your child. These tests may include viral load, CD4, FBC 
and chemistry, drug and antibody levels, and stored blood for specialized tests to study 
the virus and your child’s ability to fight the virus, which may include tests of your child’s 
genes. About 1-2 teaspoons of blood (4-9 mL) will be drawn at these visits. 
• 
Your child’s usual HIV medicines will be re-started at the time of the last antibody treatment 
at the 32-week visit, or sooner if needed. 
 
Weeks 33-56 
 
• 
Your child will continue follow-up at the study clinic at 36, 48, and 56 weeks. At these 
visits, we will provide routine clinical care for your child. We may test viral load, CD4, FBC 
and chemistry and stored blood for specialized tests to study the virus and your child’s 
ability to fight the virus, which may include tests of your child’s genes. About 1.5-2 
teaspoons of blood (7-10 mL) will be drawn at these visits. 
 
Checking for return of virus (viral rebound) 
 
• 
During the first part of the study when your child is taking HIV medicines and receiving the 
antibodies, we will check for virus in your child’s blood once a month. If the level of virus 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
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has risen above 40 copies during this part of the study, your child will stop receiving the 
antibodies. Your child will have a follow-up visit like the visits scheduled for the first 8 
Weeks above, except no antibodies will be given. Then follow-up will occur at a new visit 
schedule with 3 more visits (one month, 3 months, and 6 months later). 
• 
During follow up from 8-32 weeks, we will check for virus in your child’s blood at every 
study visit by testing for viral load. The result of this test will not take more than a week to 
return, and in most cases it will be only a day or two. If the virus returns at a level where 
we think it will continue to rise (greater than or equal to 400 copies), your child will be 
asked to return so that HIV medicines can be re-started as soon as possible. If the virus 
returns at a low level (less than 400 copies, but at or above 40 copies), and we are not 
sure that it will continue to rise, we will have your child re-tested weekly; if this test is still 
positive at any level, we will re-start the HIV medicines.  
• 
If your child goes back on HIV medicines early, we will see him/her every week until the 
virus is no longer detectable, and then follow-up will occur at a new visit schedule with 3 
more visits (at Week 4, 12, and 24) after the virus is no longer detectable. 
• 
We may test viral load, CD4, FBC and chemistry and stored blood for specialized tests to 
study the virus and your child’s ability to fight the virus. About 1.5-2 teaspoons of blood 
(8-11 mL) will be drawn at these visits.  
  
 
Test results 
• 
Results of viral load, CD4, and other laboratory tests that check your child’s health will be 
given to you at scheduled visits as soon as they are available. If a lab test result suggests 
a health problem we will let you know sooner than your next scheduled visit. Results of 
other tests that do not affect your child’s clinical care will not be provided.  
 
Stored samples and future tests 
 
• 
If you agree (at the end of this consent form), some of your child’s blood taken as part of 
this study will be stored for up to 10 years after the end of this study, for approved HIV-
related research in the future. In most cases, we will use all of the blood drawn for the 
study tests. However, at some visits a small amount (generally less than half a teaspoon) 
of blood may be left over after testing occurs, and may be saved for future testing if 
needed. You can still take part in this study even if you decide to not allow your child's 
leftover samples to be stored for future approved research. No personal identifiers will be 
stored with the samples, so your child’s identity will be protected in the usual way (see 
Section 12, Confidentiality of Records). Some of these samples may be shipped outside 
of Botswana, but only for specialized testing that is not available in Botswana. You may 
ask that samples be destroyed if you later change your mind and do not want us to keep 
them. You can request this at any visit, or after the study by calling Dr. Joseph Makhema 
(Tel: 3902671, Cell 72100846). 
 
5. HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY?  
• 
Up to 36 children will take part in this study. 
 
6. HOW LONG WILL MY CHILD BE IN THIS STUDY? 
• 
Your child will be in this part of the study for up to 56 weeks (up to 84 weeks for the first 6 
participants).  


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
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7. WHY WOULD THE STUDY INVESTIGATORS TAKE MY CHILD OFF THIS STUDY EARLY? 
The study doctor may need to take your child off the study early without your permission if: 
• 
the study is stopped or modified by the Botswana Ministry of Health, National Institutes of 
Health (NIH), the Food and Drug Administration (FDA), the United States Office of Human 
Research Protection (OHRP) and other government agencies, or the study Institutional 
Review Boards (IRBs).  An IRB is a committee that watches over the safety and rights of 
research participants. 
• 
the Study Monitoring Committee recommends that the study be stopped early. This 
committee, also known as the SMC, is made up of an outside group of experts who monitor 
the study.  
• 
you are not able to attend the study visits as required by the study 
 
The study investigators may also need to take your child off of the study without your permission 
if: 
• 
continuing with the study is considered to be harmful to your child 
• 
your child is not able to follow the procedures of the study 
 
8. CAN MY CHILD LEAVE THE STUDY IF I CHANGE MY MIND?  
 
• 
You may have your child leave the study at any time for any reason, and your child will 
still be given medical care at the hospital or government clinic of your choice (we will help 
arrange this if you want). Your child will be restarted on their HIV medications if they were 
stopped at the time you wish to leave the study. If you are willing we would like to schedule 
a final study visit and blood draw before your child leaves the study. If you leave the study, 
the data collected until that date will remain part of the study database. 
 
9. WHAT ARE THE RISKS OF THE STUDY? 
 
RISKS OF VRC01LS and 10-1074  
• 
VRC01LS and 10-1074 are antibodies. Antibodies are made by the immune system to 
fight infection. Antibodies can also be made in laboratories. The antibodies used in the 
study are made in a laboratory. These antibodies are experimental. This means we do not 
know if they are safe to use in people. We also do not know if they are useful as treatment 
for HIV. Both have been tested in animals and people, including in HIV-positive people. 
We have given VRC01LS to 6 children and 10-1074 to 6 children in part of this study that 
has been completed. VRC01LS has also been used in children in other studies. The 
studies have had no safety concerns that were considered serious. The 6 children who 
received 10-1074 in the first part of this study did not have safety concerns that were 
considered serious, but there have not been other studies of 10-1074 in children yet. Both 
antibodies are being tested in more research studies to learn more about them, and this 
study will help us learn about VRC01LS and 10-1074 in children who have HIV.  
 
• 
VRC01LS 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
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As of April 2017 VRC01LS had been tested in more than 30 adults. So far, there 
have been no serious side effects seen in the adults who have received VRC01LS. 
VRC01LS is being studied in babies now in another study in the United States, 
South Africa, and Zimbabwe.   
 
VRC01LS is very similar to another experimental antibody called VCR01. As of 
January 2017, more than 800 HIV-negative and HIV-positive adults have received 
this very similar antibody 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 (rash) 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. 
 
Also, as of January 2017, at least 33 babies born to mothers who have HIV have 
received VRC01 in a study being done in the United States, South Africa, and 
Zimbabwe. Some 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. 
 
• 
10-1074 
This study is the first time that 10-1074 is being given to children, but as of August 
2017, 10-1074 had been tested in 76 adults at different doses. So far, there have 
been no serious side effects seen in the research participants who have received 
10-1074. Some people had a headache, cold symptoms, or felt tired. A few people 
had dry eyes, dizziness, abdominal pain, nausea, itchiness, or mildly abnormal 
results on tests of their liver.  
 
• 
To watch for any possible reactions, children will be asked to stay in the clinic for at least 
2 hours after the first antibody infusion, and at least 1 hour after later infusions. During this 
time, study staff will check for reactions to the infusion.  
RESISTANCE TO VRC01LS and 10-1074 
• 
It is possible that children who receive VRC01LS and 10-1074 in this study could develop 
“resistance” to the antibodies. If resistance develops, the antibodies may not be effective 
in helping to control your child’s HIV. It isn’t known whether this will have any effect on 
your child’s health. This type of resistance has no impact on the ability of HIV medicines 
to control the virus. 
RISKS OF OTHER ANTIBODIES 
• 
Other antibodies that are different from VRC01LS and 10-1074 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 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
8 
 
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, 
VRC01LS, or 10-1074. However, it is possible that children in this study could have these 
types of reactions. Children could also have other side effects or reactions that we do not 
yet know about. We will closely check on children in this study for side effects and 
reactions. Please contact the study staff immediately if any of these problems or any other 
problems occur. 
 
RISKS OF STOPPING HIV MEDICINES 
• 
We think that some children (up to half) may have return of virus at some point after the HIV 
medicines are stopped, between week 8 and week 32. If virus does return, there is the risk 
that your child might become sick with fever, rash, and general weakness. However, we think 
this is unlikely as long as we re-start the HIV medicines as soon as virus is detectable. It is 
therefore important for you to bring your child to the clinic for each study visit while your child 
is off HIV medicines. You should bring your child to the clinic between study visits if he/she 
has fever, rash, or weakness while off his/her HIV medicines. 
• 
If the virus returns, there is a small chance that the medicines your child was taking will no 
longer work when they are re-started. This would occur if the virus has become resistant to 
one or more of the medicines. Because we will re-start the medicines very quickly, we think 
the risk of resistance is very low. In the unlikely chance that resistance is detected or 
suspected, we will give your child other medicines approved by the Botswana National 
program instead. 
• 
There is a small chance that a long period of viral rebound (the virus returning) could increase 
the amount of virus that is hidden in different parts of your child’s body. We don’t know if this 
could have an effect on treatment in the future of not. To prevent a long period of viral rebound, 
we will check your child’s blood frequently. 
 
RISKS OF TAKING BLOOD and IV INFUSION 
• 
Taking blood may cause some discomfort, bleeding, or bruising where the needle pricks your 
child’s skin, and in rare cases, fainting/feeling lightheaded or infection.  A clot may form at the 
site of the needle prick.  
• 
We will follow the guidance of experts to make sure that we do not take too much blood from 
your child when we are checking the virus and the safety of the medicines and storing blood 
for research. However, there is a small possibility that drawing blood might make a low blood 
count even worse, and that this would lead to the need for a blood transfusion for your child. 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
9 
 
• 
VRC01LS and 10-1074 will be given as an infusion in to a vein. An IV infusion can cause 
stinging, itchiness, discomfort, pain, soreness, redness, bruising, swelling, or a small cut 
where the needle enters the skin. Rarely, needle sticks can cause infection.  
 
RISK OF STIGMA 
• 
We will try to protect the confidentiality of your/your child’s HIV status. We will visit your home 
only if you have granted permission for this (and you may change your mind about this at any 
time). In all cases, home visits will be by health workers in plain clothes and in unmarked 
vehicles or on foot. If your/your child’s HIV status were to become known or suspected 
because of your participation in this study, it is possible that the stigma of HIV could affect 
your personal relationships. This might cause you or your child stress. We will do everything 
possible to prevent this from happening, and confidential counseling also will be available to 
you through this clinic. You may feel uncomfortable answering study questions about yourself, 
your household, or income. You do not have to answer questions if you don’t want to. 
 
10. ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
We are doing this study to learn whether the antibodies being tested will work to keep your child’s 
HIV levels low during the time off HIV medicines. This study will also learn whether and how the 
antibodies may affect your child’s health. It is possible your child will benefit from some of the 
following things. 
 
CARE IN THE STUDY 
• 
Your child will see a doctor at every study visit, and he/she will have access to frequent testing 
and monitoring to help treat his/her HIV infection, and to treat other childhood illnesses. This 
monitoring includes viral load testing and CD4 testing that will allow us to monitor your child’s 
health very closely, and to make medication adjustments very quickly if these are needed. 
These extra visits with a doctor, and the extra monitoring, might improve your child’s health.  
 
MONTHLY DOSING OF ANTIBODIES 
• 
It may be easier for your child to receive monthly treatment rather than having to take 3 drugs 
every day. This may also be easier for you and other caregivers. However, this will only 
happen if your child’s HIV levels stay low when the daily HIV medicines are stopped. Your 
child will need to re-start the HIV medicines and stop the monthly antibodies if his/her virus 
levels test high.  
 
REDUCED TOXICITIES 
• 
HIV medicines can have long-term toxicities. Long-term toxicities from HIV medicines can 
include effects on growth, bones, body shape, blood cells, kidney function, heart and blood 
vessels, and possibly brain development. If your child is able to remain off these medicines 
for up to 24 weeks, your child may experience fewer toxicities from HIV medicines, but we do 
not know if that will happen. Although this study cannot measure changes in most of these 
things, we will monitor your child’s growth to see if it improves when off HIV medicines.  
 
IMPROVED IMMUNE RESPONSE TO HIV 


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Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
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• 
It is possible that the anti-HIV antibodies being tested will help your child’s immune system 
recognize HIV, and it may allow your child to fight HIV better. This might be important if your 
child stops taking HIV medicines in the future, because the HIV level might not get as high in 
the body. However, we do not know yet whether this will occur. This study and other studies 
will help us learn more about the potential for this to occur. 
 
 
SCIENTIFIC KNOWLEDGE 
• 
Knowledge gained from this study may help other children in the future. If children in this study 
are able to safely remain off HIV medicines, this may help make that option possible for other 
children in Botswana in the future. 
• 
 A description of this clinical trial will be available on ClinicalTrials.gov. This website will not 
include information that can identify you/your child. At most, the website will include a 
summary of the results. You can search this website at any time. 
 
 
11. WHAT OTHER CHOICES DO I HAVE BESIDES THIS STUDY? 
Instead of being in this study you may choose not to allow your child take part in the study and 
your child will be cared for either within the EIT study, or at a government clinic which provides 
HIV treatment and care. We will refer you to that clinic and make sure your child is seen there.  
 
12. WHAT ABOUT CONFIDENTIALITY? 
We will do everything we can to keep your and your child’s personal information confidential.  We 
cannot guarantee complete confidentiality.  Your or your child’s personal information may be 
disclosed if required by law. 
• 
Your child’s medical records at this clinic or at a government clinic or hospital may be 
reviewed by the Botswana and Harvard T.H. Chan School of Public Health IRBs, the 
Botswana Ministry of Health, the U.S. National Institutes of Health (NIH); the U.S. Food 
and Drug Administration (FDA); the U.S. Office for Human Research Protections (OHRP); 
other local U.S. and international regulatory entities; study staff, and study monitors.  
• 
Your child will be identified by a code number only known to you, the study team, or the 
health staff responsible for your child’s care. All information about your child and the 
information you give about yourself will be identified by this number. The code will be 
stored in a secure location. You and your child will not be identified by name in any 
publication or presentation from this study.  
• 
For purposes of the study, your child`s medical records may be photocopied when there 
is need. These copies will be kept safe and secure like other study records only accessed 
by authorized personnel. 
 
13. HOW WILL MY/MY CHILD’S SAFETY BE PROTECTED? 
• 
Your child will be followed throughout the study by the study staff. If any problems are 
found, VRC01LS and 10-1074 will be stopped if indicated to do so. 
• 
A safety monitoring board will regularly review the safety of this study. 
• 
Counseling services will be available for you if needed throughout the study. 
 
14. WHAT ARE THE COSTS TO ME? 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
11 
 
• 
There is no cost to you or your child for the antibodies, clinic visits or laboratory tests 
related to this study. All other medical examinations or tests and medicines outside of this 
study will be given to you either through the study clinic or at a government clinic or 
hospital.  
 
15. WILL I RECEIVE ANY PAYMENT? 
• 
You will receive no money for your child’s participation in the study, but you will be given 
money for transportation costs to and from the clinic, and to compensate you for your time. 
Transportation costs will be discussed with you and provided as needed. The 
compensation for your time will be 150 Pula for each scheduled visit where antibody is 
given, and 100 Pula for other scheduled visits or for follow-up visits that are requested by 
the study staff. The amount is more for visits when antibody is given because these visits 
will take more time. 
 
 
16. WHAT HAPPENS IF MY CHILD IS INJURED? 
• 
Immediate, necessary care will be given to your child free of charge if he/she becomes 
injured due to taking part in this study. Our clinic has insurance to cover medical treatment 
in the case of a study-related injury. In rare cases the insurance funds may not be enough.  
The study sponsor (NIH) does not have a program to provide compensation for research 
related injury. 
 
• 
If you are injured because of this study, you should contact: 
 Dr. Joseph Makhema:   
 
Tel: 3902671  
Cell: 72100846 
 
17. WHAT ARE MY CHILD`S RIGHTS AS A RESEARCH PARTICIPANT? 
• 
Taking part in this study is completely voluntary. You may choose not to allow your child 
take part in this study or leave this study at any time.  No matter what you decide, we will 
help your child receive the best possible HIV treatment available at a government clinic or 
at another clinic if this is possible. 
• 
We will tell you about new information from this or other studies that may affect your child’s 
health, well-being, or willingness to stay in this study.  When the study ends, the results 
will be available from the study staff or clinic. 
 
18. WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
• 
If you have any questions about this study or your child`s rights as a participant, either 
while participating or after you have completed the study, you should contact: 
 
 Dr. Joseph Makhema (for study-related questions): Tel: 3902671 
Cell: 
72100846 
 The Chief Research Officer at Botswana Ministry of Health (for rights as a participant):    
Tel: 3632775 
 
 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
12 
 
  
Overall Study Participation 
The purpose of the study, procedures to be followed, and risks and benefits have been explained 
to me.  By signing or placing my fingerprint below, I am agreeing for my child to participate in this 
study. I also understand that study staff may ask me some questions about my child’s household 
and about myself. I also give consent for Botswana Harvard Partnership study staff to access and 
use the information in my child’s medical records if needed for the purposes of the study, and all 
records from the EIT study. I understand that this may involve photocopying any of my child’s 
medical records relevant to this study. I understand that I may withdraw my child’s participation 
at any time without affecting my rights or those of my child to receive medical care.  
 
 
Parent/guardian's name (first-last):______________________________________ 
Parent/guardian's Omang / Passport number:  
 OR Parent/guardian's Omang receipt number:  
 
 
Signature or thumbprint of the Parent/guardian: _____________________________ 
 
Date of Parent/guardian's signature:____/____/____ (dd/mm/yy) 
 
Time of Parent/guardian's signature: ___ ___ : ___ ___ hours 
 
Consent for Storage and Use of Blood Specimens 
The purpose of storing and potentially using blood samples from my child has been explained to 
me.  I understand that remaining leftover samples of my child’s blood obtained in the course of 
this study may be stored for up to 10 years after the end of the study in the laboratories where 
the samples for the study were tested (in the Botswana Harvard Partnership laboratory whenever 
possible, or in Boston when specialized testing for the study was required). These samples may 
be used for HIV-related research in the future if such research is permitted by Botswana and 
Harvard ethical review boards. I understand that these specimens will contain no personal 
identifiers.  I also understand that I may ask for my child's stored samples to be destroyed, if I 
later change my mind, by notifying a staff member during any study visit or, if I change my mind 
after the end of the study, by contacting Dr. Joseph Makhema (Tel: 3902671, Cell 72100846). I 
understand that my child can still take part in this research even if I do not agree to store my 
child's leftover samples for future approved research. By signing below, I agree to store samples 
for future approved health research (note: if this is not signed, it indicates that permission was not 
given to store samples for this purpose). 
 
 
 
Signature or fingerprint of the Parent/guardian:______________________________ 
 


Steps 1-3 Consent Form v3.0, May 19, 2020 
Protocol: VRC01LS and 10-1074 in Early Treated Children v2.0, December 20, 2018 
 
13 
 
 
Date of Parent/guardian's signature:____/____/____ (dd/mm/yy) 
 
Time of Parent/guardian's signature: ___ ___ : ___ ___ hours 
 
Witness (for use if a Parent/guardian is illiterate, in addition to the Parent/guardian's 
thumbprint) 
The purpose of this study and the procedures, risks and benefits to her child have been explained 
to the parent/guardian. To the best of my knowledge she/he understands the purpose, procedure, 
risks and benefits to her/his child. 
 
 
 
Witness’s signature______________________________________ 
 
 
 
Witness’s name (first - last) _______________________________  
 
 
 
Date of signature ____/____/____ (dd/mm/yy) 
 
Time of signature: ___ ___ : ___ ___ hours 
 
 
I have explained the purpose of the study to the participant’s parent/guardian.  To the best of my 
knowledge, she/he understands the purpose, procedures, risks and benefits to her/his child. 
 
 
Study Staff name: ____________________________________ 
 
 
 
Study Staff signature: _________________________________ 
 
 
 
Date of signature ____/____/____ (dd/mm/yy) 
 
Time of signature: ___ ___ : ___ ___ hours 
 

Prot_000.pdf: 
A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies VRC01LS and 
10-1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated Children in
Botswana 
(Dual bNAb Treatment in Children) 
Phase I/II 
A Collaboration of: 
The Harvard School of Public Health AIDS Initiative 
The Brigham and Women’s Hospital 
The Ragon Institute at Massachusetts General Hospital 
The Ministry of Health of Botswana 
DAIDS-ES 38551 
NCT03707977
This file contains the current Dual bNAb Treatment in Children protocol, comprising the 
following documents, presented in reverse chronological order: 
Clarification Memo #3, dated July 19, 2021 
Letter of Amendment #3, dated May 19, 2020 
Clarification Memo #2, dated April 9, 2020 
Letter of Amendment #2, dated January 2, 2020 
Letter of Amendment #1, dated October 4, 2019 
Clarification Memo #1, dated April 1, 2019 
Protocol version 2.0, dated December 20, 2018 


DAIDS ES-38551, Tatelo (Dual bNAb Treatment in Children), Version 2.0, Clarification Memo #3 (19 July 
2021) 
Page 1 of 1 
 
CLARIFICATION MEMO #3 
 
DATE: July 19, 2021 
TO: Tatelo Co-Principal Investigators, CRS Leaders, and CRS Coordinators 
FROM: Tatelo Protocol Team 
SUBJECT: Clarification Memo #3 to the Tatelo Protocol (DAIDS ES-38551), Version 2.0 dated 
December 20, 2018 entitled “A Clinical Trial to Evaluate the Impact of Broadly Neutralizing 
Antibodies VRC01LS and 10-1074 on Maintenance of HIV Suppression in a Cohort of Early-
Treated Children in Botswana” 
 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your Institutional 
Review Board (IRB)/Ethics Committee (EC); however, as always you must follow your 
IRB/EC policies and procedures. If IRB/EC review of clarification memos is required at 
your site, please submit this document for review. 
Each site should file a copy of this clarification memo with the protocol for reference. 
The protocol clarifications contained in this memo will be included in the next version of 
the Tatelo (DAIDS-ES 38551) protocol if it is amended at a future date. 
 
The following clarifications to the Tatelo protocol (DAIDS-ES 38551), Version 2.0, dated 
December 20, 2018 have been made: 
1. Analysis of HIV-1-specific neutralizing antibody responses will be completed in 
collaboration with Monogram Biosciences, Inc. instead of Beth Israel Deaconess Medical 
Center. Specifically, specimens for these analyses already described in the IRB-
approved protocol will be shipped from the Kuritzkes laboratory at Brigham and 
Women’s Hospital in Boston, MA to Monogram Biosciences in South San Francisco, 
California for protocol-indicated testing. There are no changes required to the processing 
or shipping procedures in Botswana, or to the Botswana-Harvard Partnership Laboratory 
Processing Chart. 
 


Page 1 of 11 
A Clinical Trial to Evaluate the Impact of Broadly Neutralizing 
Antibodies VRC01LS and 10-1074 on Maintenance of HIV Suppression 
in a Cohort of Early-Treated Children in Botswana 
(Dual bNAb Treatment in Children) 
DAIDS-ES 38551 
Protocol Version 2.0, Dated December 20, 2018 
Letter of Amendment #3, dated May 19, 2020 
PROTOCOL SIGNATURE PAGE 
I will conduct the 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 U.S. 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 signed: ____/____/____ (dd/mm/yy) 
Name of Investigator of Record (printed):  
_____________________________________________ 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 2 of 11 
  
 
 
Date: May 19, 2020 
 
RE:  
LETTER OF AMENDMENT #3 FOR DUAL BNAB TREATMENT IN CHILDREN 
Version 2.0, dated December 20, 2018 
 
“A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies VRC01LS and 
10-1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated Children in 
Botswana” 
 
DAIDS-ES #38551 
 
TO: Study Coordinators at Sites Participating in Dual BNAb Treatment in Children 
 
FROM: Roger Shapiro, MD, MPH (Corresponding Principal Investigator) 
 
 
The following information impacts the Dual BNAb Treatment in Children Study (DAIDS-
ES#38551) and must be forwarded to your Institutional Review Board (IRB)/Ethics Committee 
(EC) as soon as possible for their information and review. This must be approved by your 
IRB/EC before implementation.   
 
The following information may also impact the sample informed consent. Your IRB/EC will be 
responsible for determining the process of informing subjects of the contents of this letter of 
amendment. 
 
Upon receiving final IRB/EC and any other applicable Regulatory Entity (RE) approval(s) for this 
LoA, sites should implement the LoA immediately. Sites are still required to submit a LoA 
registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory Support 
Center (RSC).  Sites will receive a registration notification for the LoA once the DAIDS PRO 
verifies that all the required LoA registration documents have been received and are complete. 
A LoA registration notification from the DAIDS PRO is not required prior to implementing the 
LoA. A copy of the LoA registration notification along with this letter and any IRB/EC 
correspondence should be retained in the site’s regulatory files. 
 
 
The purpose of this LOA is to 1) provide operational flexibility for conducting study visits and 
procedures in the context of circulating severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) and the associated coronavirus disease (COVID-19) pandemic; 2) correct the frequency 
of safety and accrual reporting to the IRBs. Safety and accrual reports are submitted to IRBs per 
their reporting criteria and requirements. This study also uses the SAE Reporting Category for 
Expedited Adverse Event reporting to DAIDS; EAE reports are also submitted to IRBs at the time 
of reporting to DAIDS; 3) to incorporate relevant revisions described in Clarification Memos #1 
dated April 1, 2019 and #2 dated April 9, 2020); and 4) to incorporate relevant revisions made to 
the Investigator’s Brochure for VRC01LS version 4.0 dated December 27, 2019. 
 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 3 of 11 
  
These changes will affect the following sections of the protocol. Additions to text are shown in 
bold. Deletions are shown in strikethrough. 
 
1. Study Team Roster: The contact information for Rachel Bowman has been updated to 
include an email address. 
 
Laboratory Data Manager 
Rachel Bowman, PhD 
Frontier Science and Technology Research Foundation, Inc.  
4033 Maple Road  
Amherst, NY 14226  
Phone: (716) 834-0900 x7375 
Email: bowman@fstrf.org 
 
2. Section 1.7. Study Intervention: The following subsections have been revised to read: 
 
Step 1 (first 6 participants)  
 
All Step 1-3 participants must be from the EIT Study. After approval, Step 1 will begin for a 
maximum of 6 participants, all of whom will have participated in the PK Step (3 from each PK 
Step group), and all of whom will have been >12 weeks from last bNAb dosing. ART is 
continued throughout Step 1, and all participants receive both 10-1074 and VRC01LS. 
Following a recommendation from the study team and SMC to increase the maintenance 
dosing based on the PK Step, a VRC01LS loading dose of 30 mg/kg will be given at the start 
of Step 1, followed by 15mg/kg dosing at each 4-weekly visit, and 10-1074 dosing will be at 
30mg/kg at each 4-weekly visit. At Week 0, Week 4, and Week 8 doses of Step 1, PK testing 
for both bNAbs will occur prior to infusion, and at Weeks 0 and 4 only at end of infusion, 1 
hour post-infusion, 1 day post-infusion, and 1 week post-infusion. Post-infusion PK blood 
draws will occur at the end of and 1-hour after the completion of both infusions, if both are 
administered on the same day. HIV-1 RNA will be checked every 4 weeks in Step 1. The first 
6 participants in Step 1 will continue in this Step, receiving both oral ART and dual bNAb 
infusions, until the second study team/SMC review occurs. This review of safety and PK data 
will occur within 8-10 weeks of the 6th participant’s Week 8 PK sampling (or as soon as is 
feasible in the event of Covid-19 related delays).  
 
In the event that disruptions due to Covid-19 affect the Step 1 timeline, the first 6 
participants in Step 1 will temporarily discontinue bNAbs and remain in Step 1, 
receiving at a minimum oral ART and safety monitoring every 12 weeks. These first 6 
participants in Step 1 will resume dual bNAb infusions when the protocol team deems 
it is safe and feasible to do so. BNAb infusions are planned to occur throughout Step 
1, but may resume later in the extended Step 1 schedule in the event of missed or 
discontinued infusions. If a child has missed more than 2 dual bNAb infusions, then 
dosing will be given as at the start of Step 1 upon resuming bNAbs: a VRC01LS loading 
dose of 30mg/kg and a 10-1074 dose of 30mg/kg will be given at the first resumed 
infusion visit. Maintenance dosing will follow as per protocol with VRC01LS given at 
15mg/kg and 10-1074 given at 30mg/kg at each 4-weekly visit. BNAbs will be resumed 
at the next scheduled bNAb administration visit on the extended Step 1 schedule (i.e., 
at Week 12, 16, 20, 24, 28, 32, 36, etc.) and participants may enter Step 2 (if open) on 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 4 of 11 
  
the day of the 3rd resumed bNAb infusion visit or later (8 weeks or later after resuming 
monthly bNAb infusions). 
 
SMC Review of Safety and PK Data from Step 1 (first 6 participants) 
 
Safety, PK, and viral suppression data for the first 6 participants from Step 1 will be reviewed 
within 8-10 weeks (or as soon as is feasible in the event of Covid-19 related delays) by 
the study team, sponsor, and SMC. (No changes to the remainder of this subsection.) 
 
Step 2 (all participants) 
 
Following a successful Step 1 review, Step 2 may begin. Step 2 will begin after a participant 
has spent at least 8 weeks in Step 1 (and has completed at least 2 consecutive dual bNAb 
infusion visits with the third or later dual bNAb infusion scheduled for the Step 2 entry 
visit). (No changes to the remainder of this paragraph.)  
 
3. Section 4. Study Design: The following subsections have been revised to read: 
 
All Step 1-3 participants must be from the EIT Study. After approval, Step 1 will begin for a 
maximum of 6 participants, all of whom will have participated in the PK Step (3 from each PK 
Step group), and all of whom will have been >12 weeks from last bNAb dosing. ART is 
continued throughout Step 1, and all participants receive both 10-1074 and VRC01LS. 
Following a recommendation from the study team and the SMC to increase the maintenance 
dosing based on the PK Step, a VRC01LS loading dose of 30 mg/kg will be given at the start 
of Step 1, followed by 15mg/kg dosing at each 4-weekly visit, and 10-1074 dosing will be at 
30mg/kg at each 4-weekly visit. At Week 0, Week 4, and Week 8 doses of Step 1, PK testing 
for both bNAbs will occur prior to infusion, and at Weeks 0 and 4 only at end of infusion, 1 
hour post-infusion, 1 day post-infusion, and 1 week post-infusion. HIV-1 RNA will be checked 
every 4 weeks in Step 1. The first 6 participants in Step 1 will continue in this Step, receiving 
both oral ART and dual bNAb infusions, until the second study team/SMC review occurs. This 
review of safety and PK data will occur within 8-10 weeks (or as soon as is feasible in the 
event of Covid-19 related delays) of the 6th participant’s Week 8 PK sampling.  
 
In the event that disruptions due to Covid-19 affect the Step 1 timeline, the first 6 
participants in Step 1 will temporarily discontinue bNAbs and remain in Step 1, 
receiving at a minimum oral ART and safety monitoring every 12 weeks. These first 6 
participants in Step 1 will resume dual bNAb infusions when the protocol team deems 
it is safe and feasible to do so. BNAb infusions are planned to occur throughout Step 
1, but may resume later in the extended Step 1 schedule in the event of missed or 
discontinued infusions. If a child has missed more than 2 dual bNAb infusions, then 
dosing will be given as at the start of Step 1 upon resuming bNAbs: a VRC01LS loading 
dose of 30mg/kg and a 10-1074 dose of 30mg/kg will be given at the first resumed 
infusion visit. Maintenance dosing will follow as per protocol with VRC01LS given at 
15mg/kg and 10-1074 given at 30mg/kg at each 4-weekly visit. BNAbs will be resumed 
at the next scheduled bNAb administration visit on the extended Step 1 schedule (i.e., 
at Week 12, 16, 20, 24, 28, 32, 36, etc.) and participants may enter Step 2 (if open) on 
the day of the 3rd resumed bNAb infusion visit or later (8 weeks or later after resuming 
monthly bNAb infusions). 
 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 5 of 11 
  
SMC Review of Safety and PK Data from Step 1 (first 6 participants) 
 
Safety, PK, and viral suppression data for the first 6 Step 1 participants will be reviewed within 
8-10 weeks (or as soon as is feasible in the event of Covid-19 related delays) by the study 
team, sponsor, and SMC. (No changes to the remainder of this paragraph.)  
 
Step 2 (all participants) 
 
Following a successful Step 1 review, Step 2 may begin. Step 2 will begin after a participant 
has spent at least 8 weeks in Step 1 (and has completed at least 2 consecutive dual bNAb 
infusion visits with the third or later dual bNAb infusion scheduled for the Step 2 entry 
visit). (No changes to the remainder of this subsection.) 
 
4. Section 6.2. 10-1074 Description, Supply, and Storage. The second sentence in the second 
paragraph has been revised to read: 
 
10-1074 is supplied as single-use 20 mg/mL solution for IV injection in a 5ml or 30ml volume 
of buffered solution composed of sodium phosphate, potassium phosphate, potassium 
chloride, sodium chloride and polysorbate 80 with a pH of 7.0. 
 
5. Section 6.3. Schedule of Intervention and Dosing. New text has been added after the second 
paragraph: 
 
In the event that a) the PK testing for the SMC review cannot be completed on schedule 
(due to Covid-19 related disruptions), and there is not a clear path forward to 
completing the review without a delay of less than 6-8 weeks, or b) the study leadership 
determines that it is necessary to avoid regular in-person clinic visits for a period of 
time due to a Covid-19 outbreak, the study leadership team may choose to pause the 
bNAb infusions for the first 6 children in Step 1, while allowing children to remain in 
Step 1 and on ART. If such a pause in bNAb administration occurs, the study team may 
consider conducting visits in the extended schedule for the first 6 participants (Week 
10 and beyond) by remote contact and prioritizing in-person clinic visits every 12 weeks 
for physical assessments and all laboratories normally collected at the Week 0 visit of 
Step 1 (with the exception of ADA testing and proviral genome sequencing). These 
laboratory tests are indicated in brackets [X] in Table 4 at Visits 20 and 32. Provision of 
antiretroviral medications will occur at the 12-week visit intervals, and also as required 
between these visits (preferably by home drop-off). Remote contact should also be 
performed whenever it becomes necessary to further reduce in-person clinic visits for 
staff or participant safety. Any missed procedures, including bNAb infusions will be 
recorded.  
 
Once the Step 1 bNAb administration pause is ended by the study leadership team 
(when PK testing is imminent or completed and the study team has determined that it 
is feasible and safe to conduct infusion visits at the clinics), the 6 participants in Step 
1 may resume dual bNAbs. If a child has missed more than 2 infusion visits, then dosing 
will be given as at the start of Step 1 upon resuming bNAbs: a VRC01LS loading dose 
of 30mg/kg and a 10-1074 dose of 30mg/kg will be given at the first resumed infusion 
visit. Maintenance dosing will follow as per protocol with VRC01LS given at 15mg/kg 
and 10-1074 given at 30mg/kg at each 4-weekly visit. BNAbs will be resumed at the next 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 6 of 11 
  
scheduled bNAb administration visit on the extended Step 1 schedule (i.e., at Week 12, 
16, 20, 24, 28, 32, 36, etc.) and participants may enter Step 2 (if open) on the day of the 
3rd resumed bNAb infusion visit or later (8 weeks or later after resuming monthly bNAb 
infusions).  
 
Additional enrollments to Step 1 will not occur until approval is granted. If the PK data are in 
range and no dosing changes for the bNAbs are required, the dosing used in Step 1 will 
continue to be used for the remainder of the study unless new data emerges requiring 
additional review. 
 
After approval is granted from this second review, the first 6 Step 1 participants will enter Step 
2 and discontinue ART, provided they have been in Step 1 for at least 8 weeks; have 
completed at least 2 consecutive dual bNAb infusion visits with the third or later dual 
bNAb infusion scheduled for the Step 2 entry visit; and have remained with viral 
suppression <40 copies/mL (Table 5). Additional participants will also enroll in Step 1 at this 
time (both those who previously participated in the PK Step, and new participants). These 
participants may also proceed to Step 2 and discontinue ART after 8 weeks in Step 1, if they 
remain with viral suppression <40 copies/mL. A participant who experiences a confirmed viral 
rebound ≥40 copies/mL in Step 1 will discontinue bNAbs, complete visit procedures equivalent 
to those outlined for Step 1 Week 8, and enter Step 3. (No changes to the remainder of this 
subsection.) 
 
6. Section 6.3.1. VRC01LS Dose Calculation Instructions. The first paragraph has been 
revised to read:  
 
VRC01LS will be dosed at 30mg/kg at the first infusion visit, followed by 10mg/kg maintenance 
at subsequent infusion visits in the PK Step. Following a recommendation to increase the 
maintenance dosing of VRC01LS based on review of data from the PK Step, VRC01LS will 
be dosed at 30mg/kg at the first Step 1 infusion visit, followed by 15mg/kg maintenance at 
subsequent Step 1 infusion visits. If a child misses more than 2 doses in Step 1, then 
VRC01LS will be reinitiated as a loading dose of 30mg/kg IV at the first resumed 
infusion visit followed by 15mg/kg IV every 4 weeks. 
 
7. Section 6.4.1. Preparation of VRC01LS IV Solution. This section has been revised to read: 
 
To prepare VRC01LS IV infusion, the pharmacist will calculate the weight-based dose as in 
section 6.3.1 and remove the total number of vials needed as well as a 100 mL IV bag of 
Sodium Chloride for Injection USP, 0.9% from storage. Do not use Dextrose 5% Water or 
other fluids to prepare VRC01LS IV infusions. The pharmacist, using aseptic technique, 
will add the appropriate amount of VRC01LS to the 100 mL IV bag of Sodium Chloride for 
Injection USP, 0.9%. Typically 50–100mL of additional volume may be added to a 100mL bag 
of normal saline. Each pharmacist should test the capacity of the brand of saline bags that will 
be used at the site to confirm the capacity to add additional volume. The pharmacist will label 
the infusion bag including a Beyond Use Date and time. 
 
VRC01LS is a highly concentrated protein solution and may develop white, opaque to 
translucent particles after thawing. When particles are observed, they may disappear after a 
few hours at room temperature or storage at 2°C to 8°C. 
 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 7 of 11 
  
The following instructions apply to thawing VRC01LS vialed product:  
1. Thaw vials for a minimum of 1 hour at controlled room temperature (maximum 27°C) after 
removing from freezer.  
 
2. Keep the material at controlled room temperature (maximum 27°C) during the entire 
preparation period, up to the maximum storage times described in the Section 6.1.  
 
3. Prior to preparation for administration, vials should be swirled for 30 seconds with sufficient 
force to resuspend any visible particles, yet avoiding foaming. DO NOT SHAKE THE VIALS.  
a) Visually inspect the vials; if 10 or fewer visible particles are present, the vial 
may be used for product preparation. 
b) If more than 10 particles are observed, return the vials to 2°C to 8°C storage. If 
the particles redissolve or if 10 or fewer visible particles are present within the 
maximum storage times described in Section 6.1, the vials may be used for product 
preparation.  
c) If particles continue to be observed, do not use the vialed product for IV 
administration. Refrigerated product must be equilibrated at controlled room 
temperature (maximum 27°C) for a minimum of 30 minutes before preparation and 
must be used within 8 hours of any subsequent return to room temperature.  
 
4. If the thawed material is not administered within 24 hours of thaw, follow the storage 
information provided in Section 6.1.  
 
The following instructions apply to VRC01LS Prepared Product (IV Bag and Syringe): 
After product preparation in IV bags, the prepared VRC01LS may be stored at 2°C to 8°C up 
to 24 hours or at room temperature (maximum 2730°C) for a maximum of 48 hours total 
including the infusion time. Product may not be stored in direct sunlight. If stored at 2°C to 
8°C, prepared product must be equilibrated at room temperature (maximum 2730°C) for a 
minimum of 30 minutes prior to product administration. 
 
8. Section 6.6. Concomitant Medications: ART Management. A new subsection on “ART Drug 
Supply” has been added to the end of this section as follows: 
 
ART Drug Supply 
 
To avoid gaps in antiretroviral drug supply in the event of missed or cancelled study 
visits, study staff may dispense up to three months’ supply of study drug, ensuring 
safety monitoring and addressing potential needs for dose modification due to weight 
gain. Further considerations are as follows:  
o Participants who have been dispensed an extra supply of antiretroviral 
medication should still come for their scheduled visits, if possible.  
o If a participant is expected to grow into a higher weight band requiring a 
dose increase soon, sites should ensure accurate contact information with 
the family; if an in-person visit is not possible, study drug dose 
modifications may be implemented with dosing instructions provided to 
the participant’s caregiver by telephone based on weight reported by the 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 8 of 11 
  
caregiver. Any such instruction should be source documented in the 
participant’s study chart.  
o In the event of a public health emergency, such as Covid-19, requiring 
reduced in-person contact, where feasible, sites are encouraged to 
implement antiretroviral drug delivery options involving outdoor pick-up or 
drop-off. In such cases, sites are encouraged to provide ART adherence 
assessment, counseling, and support remotely (e.g., by telephone). 
 
9. Section 7.1. Clinical Evaluations and Procedures. If a pause in bNAb administration occurs 
for the first 6 participants in Step 1, the study team may consider conducting visits in the 
extended schedule for the first 6 participants (Week 10 and beyond) by remote contact and 
prioritized procedures for in-person clinic visits every 12 weeks for physical assessments 
and all laboratories normally collected at the Week 0 visit of Step 1 (with the exception of 
ADA testing and proviral genome sequencing). Table 4 has been revised to indicate these 
laboratory tests in brackets [X] at Visits 20 and 32 with updated blood volumes and 
explanatory footnotes.  
 
Table 1: Follow-up and laboratory testing for Step 1 (all participants) 
 
Step 1:  
ART + dual bNAbs 
Possible additional visits for first 6 participants in Step 1$ 
Study week 
0 
0+
1& 1 
4 
4+
1& 5 8$ 
10* 12* 14* 16* 18* 20* 
22* 24* 26* 28* 30* 32* 
VRC01LS  
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
10-1074 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Exam 
X 
 
X 
X 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Baseline 
Characteristics/
Demographics/ 
SES (if required) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adherence 
Assessment 
 
X 
 
X 
X 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability 
Assessment 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV RNA҂ 
X∞  
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC^ 
X 
 
X 
 
 
X  
X 
 
X 
 
X 
[X] 
X 
 
X 
 
X 
[X] 
CD4/CD8 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
[X] 
X 
 
X 
 
X 
[X] 
Chem / LFTs^ 
X 
 
X#  
 
X#  
X#  
X#  
X# [X#] 
X#  
X#  
X# [X#] 
Stored Plasma 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Stored PBMC 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
HIV-1 Qualitative 
DNA 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Proviral  
Genome 
Sequencing** 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 9 of 11 
  
 
SES, socioeconomic status 
Laboratory test time-points are optional when marked in parentheses: (X). 
҂ If a participant has a confirmed viral load result ≥40 copies/mL during Step 1, he/she will discontinue 
bNAbs, complete visit procedures equivalent to those outlined for Step 1 Week 8 and enter Step 3. 
∞ May be drawn up to 4 weeks prior to Week 0 visit. 
&  For first 6 participants, PK draws will occur pre-infusion at Week 0, and also for both bNAbs at end 
of infusion at Week 0, 1 hour post-infusion at Week 0, Week 0 + 1 day after infusion, Week 1, Week 
4 pre-infusion, at end of infusion at Week 4, 1 hour post-infusion at Week 4, Week 4 + 1 day after 
infusion, and Week 5. All subsequent PK testing will be pre-dose trough testing only. Other 
participants will not have PK on Day 0 or Week 1 or Week 5, but will have pre-dose trough testing at 
the visits noted beginning at 4 weeks. 
$  Step 2 testing schedule for “Step 2 Week 0” supersedes Step 1 schedule on the day of entry into 
Step 2. 
* Additional Step 1 visits may be required only for the first 6 participants while awaiting SMC review 
of safety and PK data. In the unlikely event that a participant reaches the Week 32 Step 1 visit prior 
to the conclusion/recommendation of the SMC review or the opening of Step 2, Week 30 and Week 
32 visit procedures will be repeated alternately every two weeks, if feasible, until a decision on Step 
2 is reached. 
** In the event of plasma rebound ≥400 copies/mL, viral sequencing from plasma samples will also 
be considered. 
% CD4 T cell subsets will be considered if sufficient PBMC volume available. 
^ CBC includes: hemoglobin (g/dl), Hematocrit (%), RBC (million/mm3), MCV (microns), WBC (103/ 
cu mm), differential WBC, absolute neutrophil count (ANC), Platelets (103/cu mm). Chemistry 
includes: electrolytes, BUN, creatinine, glucose, albumin. LFTs include ALT, AST, total and direct 
bilirubin. Any draw that includes electrolytes should be performed with a butterfly needle when 
possible, to reduce the chances of hemolysis; specimens considered hemolyzed should be repeated 
at the next regularly scheduled visit. If clinical concern for hyperkalemia exists, hemolyzed specimens 
should be repeated as soon as possible. 
# LFTs only 
≠ADA testing will not be done on the first 6 participants in Step 1 who had this testing during the PK 
Step. 
[X] indicate added laboratory tests to be done in the event that in-person clinic visits are 
reduced to 12-weekly on the extended Step 1 schedule for the first 6 participants. 
 
(No changes to the remainder of this subsection.) 
 
10. Section 7.7.1. Evaluations in the Setting of Maintained Viral Suppression. The following text 
has been added to the end of the subsection on Step 1: 
 
Step 1 Week 8-32 Visits (if remaining in Step 1 with reduced in-person visits due to 
Covid-19 related disruptions). Visits may be completed in full or in part, off-site, or by 
HIV-1 gag DNA 
Analysis by 
ddPCR% 
X 
 
 
 
 
 
X 
 
 
 
X 
 
[X] 
 
X 
 
 
 
X 
Immune Profiling (X)  
 
(X)  
 
X 
 
 
 
X 
 
(X) 
 
X 
 
 
 
X 
ELISA 
X 
 
 
 
 
 
X 
 
 
 
X 
 
[X] 
 
X 
 
 
 
X 
PK Testing& 
X& X& X& X& X& X& X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
ADA Testing≠ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Volume 
(mL) 
12 
2 4 
9 
2 4 11 4 
8 
4 
9 
4 
8[-12] 4 
9 
4 
8 
4 
9[-
12] 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 10 of 11 
  
phone, text message, email, or other electronic means. Any missed procedures will be 
documented. 
• 
Perform physical exam 
• 
Adherence Assessment 
• 
Acceptability Assessment (at Week 8) 
• 
Continue ART while remaining in Step 1 
• 
VRC01LS and 10-1074 administration (scheduled for Weeks 8, 12, 16, 20, 24, 28, 
32) must be completed at the study clinics and will therefore be completed only 
when local circumstances allow for in-person to be conducted safely. Missed 
infusions will be documented. If a child misses more than 2 doses of dual bNAbs 
in Step 1, then VRC01LS will be reinitiated as a loading dose of 30mg/kg IV at 
the first resumed infusion visit followed by 15mg/kg IV every 4 weeks.  
• 
Samples obtained for: HIV-1 RNA monthly (at Weeks 8, 12, 16, 20, 24, 28, 32); 
hematology, CD4/CD8, and LFTs (at Weeks 10, 14, 18, 22, 26, and 30); stored 
PBMC/plasma monthly (at Weeks 8, 12, 16, 20, 24, 28, and 32), qualitative HIV 
DNA PCR monthly (at Weeks 8, 12, 16, 20, 24, 28, and 32), whole genome 
sequencing (Week 8), quantitative HIV DNA PCR from stored PBMC every 8 
weeks (at Weeks 8, 16, 24, and 32), immune profiling (at Weeks 8, 16, 20 
(optional), 24, and 32), ELISA (at Weeks 8, 16, 24, and 32), PK testing (at Weeks 
8, 12, 16, 20, 24, 28, and 32). Missed evaluations will be documented. 
If limiting in person clinic visits to 12-weekly, add CBC, CD4/CD8, LFT to Week 20 and 
Week 32 evaluations. Add quantitative HIV DNA PCR from stored PBMC and ELISA to 
Week 20 evaluations. 
 
 
11. Section 7.9. Timing and method of evaluations. The title of this subsection has been revised 
as shown. The second paragraph under Scheduled evaluations has been revised to read: 
 
Visits will occur at the weeks indicated whenever possible. A visit may be counted as 
completed if attendance is either early (if performed no sooner than halfway between the 
previous visit target date and the target date for the upcoming scheduled visit) or late (no later 
than halfway between the target date for the scheduled visit and the target date for the next 
scheduled visit). Thus, a child is always eligible for a scheduled visit when seen in the clinic. 
However, the clinic staff may use their discretion to either perform visits as “unscheduled” if 
far from the target date and a reliable participant, or to count a visit as “scheduled” and 
perform all required tasks (see “Ill visits” below). Unless paused due to Covid-19 related 
disruptions, Iinfusion visits that are not completed within 14 days of the scheduled visit will 
trigger review by the protocol team and, if in Step 2, weekly HIV RNA testing will occur. 
 
Administration of bNAbs must be completed at the study clinics, and will therefore be 
completed only when local circumstances allow for in-person clinic visits to be 
conducted safely.  
Sites may conduct study visits, in full or in part, off-site if permitted by applicable 
government, health authority, and institutional polices. If an off-site visit is planned, 
site staff should communicate with the parent/legal guardian to determine in advance 
where and when such visits will take place, with adequate protections for safety, 
privacy, and confidentiality. Staff will make arrangements for adequate biohazard 
containment, and specimen and data chain of custody.  


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 11 of 11 
  
Clinic visits for data collection and procedures other than bNAb administration 
(scheduled and ad hoc) may be conducted by phone, text message, email, or other 
electronic means.  
If adverse events requiring further evaluation or management are identified during a 
remote contact, staff conducting the remote visit should arrange for appropriate 
clinical management, in consultation with the IoR or designee as needed. 
 
The paragraph under Premature discontinuation of study treatment has been revised to read: 
 
Premature discontinuation of study treatment 
If the single bNAb needs to be discontinued during the PK Step the child will go off Step after 
completing the visit procedures equivalent to Week 12 of the PK Step. If the participant is 
permanently discontinuing study treatment in the PK Step he/she will go off-study. In general 
during participation in Step 1 or Step 2, if a child needs to discontinue study treatment for any 
reason, he/she will complete final visit evaluations for the Step and enroll to Step 3. However, 
if the study leadership chooses to temporarily discontinue study treatment for the first 
6 children in Step 1 as a result of the Covid-19 outbreak, these participants may resume 
dual bNAbs in Step 1 on the extended schedule when it is deemed feasible and safe to 
resume in-person clinic operations. 
 
New text on “Documentation” has been added to the end of this subsection as follows: 
 
Documentation 
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  
• 
Use of alternate laboratories or alternate laboratory assays  
• 
Alternate provision of study drug  
• 
Dose modifications implemented remotely 
 
12. Section 13.8.1. Quarterly Reporting and SMC Triggers for Safety or Stopping Criteria. The 
first sentence in the first paragraph has been revised to read: Monthly safety and accrual 
monitoring by the protocol team will occur throughout the study. Reports will be provided to 
the study sponsor and IRBs quarterly. 
 
The above information will be incorporated into the next protocol version as necessary if the 
protocol is amended. 
 
The following changes affect the informed consent form for Steps 1-3. Additions to text are 
shown in bold. Deletions are shown in strikethrough. 


Letter of Amendment #3, May 19, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 12 of 11 
  
 
Section 4. “What do I have to do if I am in this study?” 
 
Study visits (third bullet) 
 
• 
You will receive transportation money and compensation for your time at each visit. If 
you request it (or if it is necessary for public health reasons during a Covid-19 
outbreak), it may be possible to have some study visits at your home, or at a different 
location than the study clinic, but not when the antibody is given. We will talk to you 
in advance about any change in location. If necessary, some study visits may also 
be done by phone, text, or email, whichever you prefer. The study team may check 
in with you about your child by telephone between visits. 
 
First 8 Weeks from the Start of Dual Antibody Therapy (third bullet, subsection on 
“Additional procedures for the first 6 children enrolled”) 
 
• 
Additional procedures for the first 6 children enrolled:  
o There will be additional blood drawn at the first two infusions visits (before the 
infusion, at the end of the infusions, and one hour later). There will be an extra 
visit and blood draw the day after the first 2 infusions. At the Week 1 and Week 5 
visits a small amount of additional blood will be drawn to check antibody levels.  
o There will also be about 4 additional visits (possibly up to 12) while we check the 
results of the tests done so far. We will check for safety and dosing of the 
antibodies when given together during this time. These extra 4-12 visits will 
occur on a regular schedule, every 2 weeks, with infusions once a month until we 
have enough information to continue with the next step of the study.  
o Your child may receive infusions once a month during this time. If there are 
delays caused by Covid-19 (for example, if the lab tests cannot be done on 
time, or if it is necessary to avoid lengthy clinic visits, we may temporarily 
stop the infusions until we can get back on the regular schedule. If that 
happens, we will still ask you to come to the clinic at least once every 12 
weeks for a physical exam, blood tests, and antiretroviral medication refills. 
Tests are the same as at other study visits, and include FBC and chemistry, 
CD4, viral load, tests to determine antibody levels, and stored blood for 
specialized tests to study your child’s ability to fight the virus. Between 1.5 
to 2.5 teaspoons of blood (8-12mL) will be drawn at these clinic visits every 
12 weeks. The other visits (every two weeks) can be done by phone if 
necessary. If your child’s infusions were temporarily stopped: when we 
restart giving antibody infusions, your child will be given the antibody 
infusions two times, 4 weeks apart, before your child can move to or begin 
the next part of the study. 
 


DAIDS ES-38551, Tatelo (Dual bNAb Treatment in Children), Version 2.0, Clarification Memo #2 
(9 April 2020) 
Page 1 of 3 
 
CLARIFICATION MEMO #2 
 
DATE: April 9, 2020 
TO: Tatelo Co-Principal Investigators, CRS Leaders, and CRS Coordinators 
FROM: Tatelo (Dual bNAb Treatment in Children) Protocol Team 
SUBJECT: Clarification Memorandum #2 to the Tatelo Protocol (DAIDS ES-38551), Version 2.0 
dated December 20, 2018 entitled “A Clinical Trial to Evaluate the Impact of Broadly 
Neutralizing Antibodies VRC01LS and 10-1074 on Maintenance of HIV Suppression in a Cohort 
of Early-Treated Children in Botswana” 
 
This clarification memorandum (CM) does not result in a change in the protocol informed 
consent document. The Division of AIDS does not require you to forward it to your 
Institutional Review Board (IRB)/Ethics Committee (EC); however, as always you must 
follow your IRB/EC policies and procedures. If IRB/EC review of clarification memos is 
required at your site, please submit this document for review. 
Each site should file a copy of this clarification memo with the protocol for reference.The 
protocol clarifications contained in this memo will be included in the next version of the 
Tatelo (DAIDS-ES 38551) protocol if it is amended at a future date. 
 
This CM is being issued to safeguard the health and well-being of Tatelo study participants in 
the context of circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 
the associated coronavirus disease (COVID-19) pandemic. The purpose of this CM is to provide 
operational flexibility for conducting study visits and procedures. Implementation of this CM is 
expected to be time-limited in relation to the COVID-19 pandemic. In consultation with the study 
Sponsor, the Tatelo 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.  
 
Prioritization of Study Visit Procedures 
• 
Administration of bNAbs must be completed at the study clinics, and will therefore be 
completed only when local circumstances allow for in-person clinic visits to be conducted 
safely.  
• 
Sites may conduct study visits, in full or in part, off-site if permitted by applicable 
government, health authority, and institutional polices. The protocol currently states that 
home visits may be performed for procedures other than bNAb administration. If an off-
site visit is planned, site staff should communicate with the parent/legal guardian to 
determine in advance where and when such visits will take place, with adequate 
protections for safety, privacy, and confidentiality. Staff will make arrangements for 
adequate biohazard containment, and specimen and data chain of custody.  


DAIDS ES-38551, Tatelo (Dual bNAb Treatment in Children), Version 2.0, Clarification Memo #2 
(9 April 2020) 
Page 2 of 3 
• 
Clinic visits for data collection and procedures other than bNAb administration 
(scheduled and ad hoc) may be conducted by phone, text message, email, or other 
electronic means.  
• 
If adverse events requiring further evaluation or management are identified during a 
remote contact, staff conducting the contact should arrange for appropriate clinical 
management, in consultation with the IoR or designee as needed. 
• 
Six participants have been enrolled in Step 1. The protocol currently requires that safety, 
PK, and viral suppression data for these first 6 participants be reviewed by the Safety 
Monitoring Committee (SMC) within 8-10 weeks of the 6th participant completing the 
Step 1 Week 8 visit. Per the current protocol, the first 6 participants in Step 1 are to 
continue in Step 1 with bNAb infusions every 4 weeks until the SMC review occurs and 
approval to move forward to Step 2 is obtained. No additional children are to be enrolled 
to Step 1 until this SMC review occurs and approval to proceed is granted. In the event 
that the PK testing for the SMC review cannot be completed on schedule (due to Covid-
19 related disruptions), and if there is not a clear path forward to completing the review 
without a delay of less than 6-8 weeks, the study leadership team may choose to pause 
the bNAb infusions for these 6 children, while allowing children to remain in Step 1 and 
on ART. If such a pause occurs, the study team may consider conducting visits in the 
extended schedule for the first 6 participants (Week 10 and beyond) by remote contact 
and prioritizing in-person clinic visits every 12 weeks for physical assessments and all 
laboratories normally collected at the Week 0 visit of Step 1 (with the exception of ADA 
testing). Provision of antiretroviral medications will occur at the 12-week visit intervals, 
and also as required between these visits (preferably by home drop-off). Remote contact 
should also be performed as described above whenever it becomes necessary to further 
reduce in-person clinic visits for staff or participant safety. Once the Step 1 bNAb 
administration pause is ended by the study leadership team (when PK testing is 
imminent or completed and the study team has determined that it is feasible and safe to 
conduct infusion visits at the clinics), the 6 participants in Step 1 may resume dual 
bNAbs. If a child has missed more than 2 infusion visits, then dosing will be given as at 
the start of Step 1 upon resuming bNAbs: a VRC01LS loading dose of 30mg/kg and a 
10-1074 dose of 30mg/kg will be given at the first resumed infusion visit. Maintenance 
dosing will follow as per protocol with VRC01LS given at 15mg/kg and 10-1074 given at 
30mg/kg at each 4-weekly visit. BNAbs will be resumed at the next scheduled bNAb 
administration visit on the extended Step 1 schedule (i.e., at Week 12, 16, 20, 24, 28, 
32, 36, etc.) and participants may enter Step 2 (if open) on the day of the 3rd resumed 
bNAb infusion visit or later (8 weeks or later after resuming monthly bNAb infusions).   
 
Antiretroviral Drug Supply 
• 
Tatelo participants may obtain antiretroviral medication refills at scheduled bNAb 
administration visits at the clinic (monthly). However, to avoid gaps in drug supply in the 
event of missed or cancelled visits, sites may dispense up to three months’ supply of 
study drug, ensuring safety monitoring and addressing potential needs for dose 
modification due to weight gain. Further considerations are as follows:  
o Participants who have been dispensed an extra supply of antiretroviral 
medication should still come for their scheduled visits, if possible.  
o If a participant is expected to grow into a higher weight band requiring a dose 
increase soon, sites should ensure accurate contact information with the family; if 


DAIDS ES-38551, Tatelo (Dual bNAb Treatment in Children), Version 2.0, Clarification Memo #2 
(9 April 2020) 
Page 3 of 3 
an in-person visit is not possible, study drug dose modifications may be 
implemented with dosing instructions provided to the participant’s caregiver by 
telephone based on weight reported by the caregiver. Any such instruction 
should be source documented in the participant’s study chart.  
o Where feasible, sites are encouraged to implement antiretroviral drug delivery 
options involving outdoor pick-up or drop-off.  
o Sites are encouraged to provide adherence assessment, counseling, and support 
remotely (e.g., by telephone).  
 
Documentation  
• 
Site-specific contingency plans, and the implementation thereof, should be 
documented in essential document files for Tatelo.  
• 
Documentation should be entered in participant study charts in real-time should any 
of the following occur:  
o Missed visits  
o Out-of-window visits  
o Off-site visits (document the location of the visit)  
o Incomplete or partial visits (document which procedures were performed and 
which were not)  
o Remote contacts performed in lieu of in-person visits (document method used 
to complete the contact and which procedures were performed)  
o Any other participant contacts  
o Use of alternate laboratories or alternate laboratory assays  
o Alternate provision of study drug  
o Dose modifications implemented remotely 
 
 


Page 1 of 10 
 
A Clinical Trial to Evaluate the Impact of Broadly Neutralizing 
Antibodies VRC01LS and 10-1074 on Maintenance of HIV Suppression 
in a Cohort of Early-Treated Children in Botswana 
(Dual bNAb Treatment in Children) 
 
 
DAIDS-ES 38551 
 
 
Protocol Version 2.0, Dated December 20, 2018 
Letter of Amendment #2, dated January 2, 2020 
 
PROTOCOL SIGNATURE PAGE 
 
I will conduct the 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 U.S. 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 signed: ____/____/____ (dd/mm/yy) 
 
 
Name of Investigator of Record (printed):  
 
_____________________________________________ 
 
 


Letter of Amendment #2, January 2, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 2 of 10 
  
 
 
Date: January 2, 2020 
 
RE:  
LETTER OF AMENDMENT #2 FOR DUAL BNAB TREATMENT IN CHILDREN 
Version 2.0, dated December 20, 2018 
 
“A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies VRC01LS and 
10-1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated Children in 
Botswana” 
 
DAIDS-ES #38551 
 
TO: Study Coordinators at Sites Participating in Dual BNAb Treatment in Children 
 
FROM: Roger Shapiro, MD, MPH (Corresponding Principal Investigator) 
 
 
The following information impacts the Dual BNAb Treatment in Children Study (DAIDS-
ES#38551) and must be forwarded to your Institutional Review Board (IRB)/Ethics Committee 
(EC) as soon as possible for their information and review. This must be approved by your 
IRB/EC before implementation.   
 
The following information may also impact the sample informed consent. Your IRB/EC will be 
responsible for determining the process of informing subjects of the contents of this letter of 
amendment. 
 
Upon receiving final IRB/EC and any other applicable Regulatory Entity (RE) approval(s) for this 
LoA, sites should implement the LoA immediately. Sites are still required to submit a LoA 
registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory Support 
Center (RSC).  Sites will receive a registration notification for the LoA once the DAIDS PRO 
verifies that all the required LoA registration documents have been received and are complete. 
A LoA registration notification from the DAIDS PRO is not required prior to implementing the 
LoA. A copy of the LoA registration notification along with this letter and any IRB/EC 
correspondence should be retained in the site’s regulatory files. 
 
 
The purpose of this LOA is to 1) incorporate recommendations of the study team and Safety 
Monitoring Committee (SMC) following review of data from the PK Step of this trial, specifically a) 
to increase the maintenance dose of VRC01LS from 10mg/kg to 15 mg/kg every 4 weeks in Step 
1 and for the remainder of the study if targets are met, and to provide data from the PK Step 
supporting this recommendation, b) to maintain the same dose of 10-1074 at 30mg/kg every 4 
weeks and to provide data from the PK Step supporting this recommendation, and c) to clarify 
that the first 6 participants in Step 1 will be selected without consideration of individual results 
from the PK Step; 2) to extend the time between the first 6 participants completion of Step 1 and 
the Safety Monitoring Committee (SMC) review of Step 1 data from 8 weeks to 8-10 weeks to 
allow for adequate time to review; and 3) to update the in-use storage conditions for the prepared 


Letter of Amendment #2, January 2, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 3 of 10 
  
10-1074 in IV bags following the release of the revised Investigator’s Brochure version 6.0, dated 
September 1, 2019.  
 
These changes will affect the following sections of the protocol. Additions to text are shown in 
bold. Deletions are shown in strikethrough. 
 
1. Section 1.7. Study Intervention: The following subsections have been revised to read: 
 
Step 1 (first 6 participants)  
 
All Step 1-3 participants must be from the EIT Study. After approval, Step 1 will begin for a 
maximum of 6 participants, all of whom will have participated in the PK Step (3 from each PK 
Step group), and all of whom will have been >12 weeks from last bNAb dosing. ART is 
continued throughout Step 1, and all participants receive both 10-1074 and VRC01LS. If 
Following a recommendation from the study team and SMC to increase the 
maintenance dosing recommendations do not change based on the PK Step, a VRC01LS 
loading dose of 30 mg/kg will be given at the start of Step 1, followed by 150mg/kg dosing at 
each 4-weekly visit, and 10-1074 dosing will be at 30mg/kg at each 4-weekly visit. At Week 
0, Week 4, and Week 8 doses of Step 1, PK testing for both bNAbs will occur prior to infusion, 
and at Weeks 0 and 4 only at end of infusion, 1 hour post-infusion, 1 day post-infusion, and 1 
week post-infusion. Post-infusion PK blood draws will occur at the end of and 1-hour after the 
completion of both infusions, if both are administered on the same day. HIV-1 RNA will be 
checked every 4 weeks in Step 1. The first 6 participants in Step 1 will continue in this Step, 
receiving both oral ART and dual bNAb infusions, until the second study team/SMC review 
occurs. This review of safety and PK data will occur within 8-10 weeks of the 6th participant’s 
Week 8 PK sampling.  
 
SMC Review of Safety and PK Data from Step 1 (first 6 participants) 
 
Safety, PK, and viral suppression data for the first 6 Step 1 participants from Step 1 will be 
reviewed within 8-10 weeks by the study team, sponsor, and SMC. All PK data will be 
assessed by the study team based on pre-specified PK trough targets which are the same as 
those used in the PK Step for 10-1074 (7.5 mcg/mL) at Day 56, and revised for VRC01LS 
based on data from the PK Step (160 mcg/mL at Day 56). The review will confirm that PK 
targets are met for the updated VRC01LS dosing and during dual bNAb administration. (No 
changes to the remainder of this paragraph.) 
 
Step 2 (all participants) 
 
Following a successful Step 1 review, Step 2 may begin. Step 2 will begin after a participant 
has spent at least 8 weeks in Step 1. For the first 6 participants, Step 2 will begin at a 
scheduled bNAb dosing visit (i.e. 4 weeks from last Step 1 bNAb dosing), and for all 
subsequent participants it will begin at the 8 Week visit date for Step 1 (which becomes the 
Week 0 Step 2 visit). Participants with ongoing viral suppression throughout Step 1 will 
undergo withdrawal of ART and will continue maintenance 10-1074 (30mg/kg) and VRC01LS 
(150mg/kg) treatment for up to 24 weeks in Step 2. HIV-1 RNA will be checked at all visits in 
Step 2, which occur weekly from Weeks 1-4 in Step 2, and every 2 weeks thereafter. (No 
changes to the remainder of this paragraph.) 
 


Letter of Amendment #2, January 2, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 4 of 10 
  
2. Section 2.1.8.1. The subheading title is revised as follows: Initial PK Considerations for 
VRC01LS in the PK Step.  
 
The second paragraph has been revised to read: 
 
These PK and safety data for VRC01, coupled with results from adult studies of VRC01LS 
(VRC 606), allow for dosing estimation for children in the current study. In addition, VRC01LS 
dosing considerations have been described for children in IMPAACT P1112 [43]. VRC01LS 
differs by 2 amino acids from VRC01, and is expected to have a similar peak level with a 
longer half-life and improved concentration at mucosal surfaces. VRC01LS population PK 
parameters can bewere obtained from a PK analysis of study VRC606 in healthy volunteers 
[45] to generate a typical profile for a two-year-old given VRC01LS 30mg/kg loading dose IV 
followed 
by 
two 
maintenance 
doses 
of 
10mg/kg 
(Figure 
2).  
 
The first sentence of the third paragraph has been revised to read: 
 
Following administration of the 30mg/kg loading dose, the Cmax and troughs wereare not 
expected to accumulate much with repeat 10 mg/kg dosing, with the expected steady-state 
trough concentrations with 10mg/kg IV greater than 400 µg/mL. (No changes to the remainder 
of this paragraph.) 
 
3. Section 2.1.8.1.1. Pharmacokinetic Targets for VRC01LS: A new subsection heading 
2.1.8.1.1.1 VRC01LS target for the PK Step: has been added to the first paragraph to clarify 
this subsection pertains to the PK Step only. (No changes to the remainder of this paragraph.) 
 
4. A new subsection 2.1.8.1.1.2. Updated PK Considerations for VRC01LS in Step 1: has 
been added as follows:  
 
2.1.8.1.1.2. Updated PK Considerations for VRC01LS in Step 1: Following the PK Step 
completion and PK data review, updated considerations for VRC01LS dosing in Step 1 
are as below: 
 
Participants in the VRC01LS arm received 30 mg/kg on Day 1, then 10mg/kg on Day 28 
and 10mg/kg on Day 56 of the PK Step. The median (range) Cmax after the first dose of 
30 mg/kg was 710.7 mcg/mL (559.2—798.8 mcg/mL).  The median Cmax value fell to 
429.2 mcg/mL and 453.5 mcg/mL after the second and third doses of 10 mg/kg.  The 
median pre-dose (28 days post previous dose) concentrations were 223.3 mcg/mL 
(157.9-253.3 mcg/mL), 180.7 mcg/mL (164.9-227.1 mcg/mL) and 156.9 mcg/mL (125.8-
201.4 mcg/mL) at Days 28, 56 and 84, respectively.  Four of the six (67%) participants 
had VRC01LS concentrations above 200 mcg/mL at Day 28 while one had a 
concentration >200 mcg/mL at Days 56 or 84.  However, all VRC01LS participants 
maintained VRC01LS concentrations above 125 mcg/mL throughout the study.  The 
median AUC following the first dose (AUC0-28) and across all three doses (AUC0-84) were 
7,983 mcg*d/mL (6,878-9,850 mcg*d/mL) and 22,247 mcg*d/mL (18,491-22,552 
mcg*d/mL), respectively.  All participants exhibited average concentrations (AUC 
divided by the collection duration) that exceeded 200 mcg/mL through Days 28 and 84 
(Weeks 4 and 12) (Table 1).  
 


Letter of Amendment #2, January 2, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 5 of 10 
  
Table 1. Median VRC01LS Concentrations for 6 Participants in the PK Step 
CmaxDose1 
(mcg/mL) 
CmaxDose2 
(mcg/mL) 
CmaxDose3 
(mcg/mL) 
Pre-DoseC28D 
(mcg/mL) 
Pre-DoseC56D 
(mcg/mL) 
Pre-DoseC84D 
(mcg/mL) 
AUC0-84D 
(mcg*d/mL) 
710.7 
429.2 
453.5 
223.3 
180.7 
156.9 
22,247 
 
In summary, the VRC01LS troughs were somewhat lower than expected, and lower than 
the protocol-specified target trough concentration of 200 mcg/mL at 84 days. However, 
the peaks were adequate and there were no outlier values below the pre-specified value 
of 115 mcg/mL, and the average concentrations exceeded 200 mcg/mL through Days 
28 and 84.  
 
Following SMC review of these data on December 12, 2019, a recommendation was 
made to increase the maintenance dose of VRC01LS from 10mg/kg to 15 mg/kg to 
better match the adult values (Figure 4; Figure 5). Therefore, in Step 1, VRC01LS will 
be initiated as a loading dose of 30mg/kg IV followed by 15mg/kg IV every 4 weeks.   
 
The VRC01LS concentration 28 days after the second dose (one loading dose of 
30mg/kg and one maintenance dose of 15mg/kg), called the Concentration at Day 56 
(C56D), will be used to assess adequacy of the dosing regimen. Specifically, if the 
median C56D of VRC01LS is above 160 mcg/mL (~80% of the original PK Step threshold 
of 200 mcg/mL accounting for 10-20% accumulation expected with continued dosing) 
then VRC01LS dosing will be deemed adequate from a PK perspective. If the PK data 
are above 160 mcg/mL and no dosing changes for VRC01LS are required, the dosing 
used in Step 1 will continue to be used for the remainder of the study unless new data 
emerges requiring additional review. 
 


Letter of Amendment #2, January 2, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 6 of 10 
  
Figure 4. VRC01LS Concentrations in Children in the PK Step compared to Adult 
Values (Adult simulation data from VRC606) 
 
 
Figure 5. Predicted VRC01LS Concentrations using Updated Maintenance Dose of 
15mg/kg every 4 weeks 
 
 
 
5. Section 2.1.8.2 PK Considerations for 10-1074: A new subsection heading Initial Dosing 
Considerations for the PK Step for 10-1074: has been added to the first paragraph to clarify 
0
2
4
6
8
10
12
14
Time (Wks)
10
100
1000
5000
VRC01LS Conc (mcg/mL)
0
4
8
12
16
20
Time (Weeks)
10
100
1000
5000
VRC01LS Conc (mcg/mL)
- - -P95 
–––P50 
- - -P05 
- - - Adult P95 
––– Adult P50 
- - - Adult P05 
    Children 


Letter of Amendment #2, January 2, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 7 of 10 
  
this subsection pertains to the PK Step only. (No changes to the remainder of this subsection.) 
 
6. Section 2.1.8.2.1. Pharmacokinetic Targets for VRC01LS: A new subsection heading 
2.1.8.2.1.1. 10-1074 target for the PK Step: has been added to the first paragraph to clarify 
this subsection pertains to the PK Step only. (No changes to the remainder of this paragraph.) 
 
7. A new subsection 2.1.8.2.1.2. Updated PK Considerations for 10-1074 in Step 1: has been 
added as follows:  
 
Following the PK Step completion and PK data review by the SMC, updated 
considerations for 10-1074 dosing in Step 1 are as below: 
 
Participants in the 10-1074 arm received 30 mg/kg on Days 1, 28 and 56. The median 
(range) Cmax after the first dose was 1,632.5 mcg/mL (1,174.0-1,998.6 mcg/mL). The 
median Cmaxs were in the same range after the second and third doses (1,484.6 
and 2,063.6 mcg/mL).  The median pre-dose (28 days post previous dose) 
concentrations were 155.2 mcg/mL (91.3-318.6 mcg/mL), 232.0 mcg/mL (113.6-328.5 
mcg/mL) and 258.3 mcg/mL (122.4-467.3 mcg/mL) at Days 28, 56 and 84, 
respectively.  All six participants had 10-1074 concentrations that greatly exceeded 
7.5 mcg/mL throughout the study.  The median AUC following the first dose (AUC0-
28) and across all three doses (AUC0-84) were 11,461 mcg*d/mL (8,222-16,937 
mcg*d/mL) and 37,505 mcg*d/mL (32,485-66,034 mcg*d/mL), respectively. All 
participants exhibited average concentrations that exceeded 250 and 350 mcg/mL 
through Days 28 and 84 (Weeks 4 and 12) (Table 2; Figure 8). 
Table 2: Median 10-1074 Concentrations for 6 Participants in the PK Step 
CmaxDose1 
(mcg/mL) 
CmaxDose2 
(mcg/mL) 
CmaxDose3 
(mcg/mL) 
Pre-DoseC28D 
(mcg/mL) 
Pre-DoseC56D 
(mcg/mL) 
Pre-DoseC84D 
(mcg/mL) 
AUC0-84D 
(mcg*d/mL) 
1,632.5  
1,484.6 
2,063.6 
155.2 
232.0 
258.3 
37,505 
 
Following SMC review of these data on December 12, 2019, a recommendation was 
made to keep the 10-1074 dose the same at 30 mg/kg every 4 weeks for the 
remainder of the study.  


Letter of Amendment #2, January 2, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 8 of 10 
  
Figure 8. 10-1074 Concentrations in Children in the PK Step compared to Adult 
Values (10-1074 adult percentiles from the Nussenzweig 584/MCA-906 study) 
 
8. Section 2.3.1. Specific Aim 1 has been revised to read: VRC01LS and 10-1074 will not be 
associated with serious adverse events, and median trough concentrations at the doses 
used will be above established target values of 200 mcg/mL and 7.5 mcg/mL respectively. 
 
9. Section 4. Study Design: The following subsections have been revised to read: 
 
Step 1 (first 6 participants)  
 
All Step 1-3 participants must be from the EIT Study. After approval, Step 1 will begin for a 
maximum of 6 participants, all of whom will have participated in the PK Step (3 from each PK 
Step group), and all of whom will have been >12 weeks from last bNAb dosing. ART is 
continued throughout Step 1, and all participants receive both 10-1074 and VRC01LS. If 
Following a recommendation from the study team and SMC to increase the 
maintenance dosing recommendations do not change based on the PK Step, a VRC01LS 
loading dose of 30 mg/kg will be given at the start of Step 1, followed by 150mg/kg dosing at 
each 4-weekly visit, and 10-1074 dosing will be at 30mg/kg at each 4-weekly visit. At Week 
0, Week 4, and Week 8 doses of Step 1, PK testing for both bNAbs will occur prior to infusion, 
and at Weeks 0 and 4 only at end of infusion, 1 hour post-infusion, 1 day post-infusion, and 1 
week post-infusion. HIV-1 RNA will be checked every 4 weeks in Step 1. The first 6 
participants in Step 1 will continue in this Step, receiving both oral ART and dual bNAb 
infusions, until the second study team/SMC review occurs. This review of safety and PK data 
will occur within 8-10 weeks of the 6th participant’s Week 8 PK sampling.  
 
SMC Review of Safety and PK Data from Step 1 (first 6 participants) 
 
Safety, PK, and viral suppression data for the first 6 Step 1 participants will be reviewed within 
0
2
4
6
8
10
12
14
Time (Wks)
10
100
1000
5000
10-1074 Conc (mcg/mL)
- - - Adult P95 
––– Adult P50 
- - - Adult P05 
    Children 


Letter of Amendment #2, January 2, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 9 of 10 
  
8-10 weeks by the study team, sponsor, and SMC. All PK data will be assessed by the study 
team based on pre-specified PK trough targets which are the same as those used in the PK 
Step for 10-1074 (7.5 mcg/mL) at Day 56, and revised for VRC01LS based on data from 
the PK Step (160 mcg/mL at Day 56). (No changes to the remainder of this subsection.) 
 
10. Section 5.5. The following sentence has been added to the end of this section. The first 6 
participants in Step 1 will be selected without consideration of individual results from 
the PK Step.  
 
11. Section 6.3. Schedule of Intervention and Dosing. The second paragraph has been revised 
to read: 
 
After approval is granted to begin Step 1, 6 of the first 12 PK Step participants will begin 
dual bNAb treatment per the dosing and follow-up schedule in Table 24. The first 6 Step 1 
participants will include 3 participants from each group in the PK Step; these participants 
may be the first 6 PK Step participants, but this is not required. In Step 1 dosing for 
VRC01LS is 30mg/kg load followed by 15mg/kg maintenance, and for 10-1074 
30mg/kg. These Step 1 participants will receive enhanced PK testing for both bNAbs at the 
Week 0 and Week 4 visits, with pre-infusion testing, testing at end of infusion, 1 hour post-
infusion, 1 day post-infusion and 1 week post-infusion (all other PK testing for these 
participants will be trough pre-dose testing). A review of the safety and PK data for the first 2 
dual bNAb doses will occur for these 6 participants. While awaiting this review (see Section 
13.8), all 6 participants will remain in Step 1 per follow-up outlined in Table 24, with 4-weekly 
dual bNAb treatment and ongoing oral ART. Additional enrollments will not occur until 
approval is granted. If the PK data are in range and no dosing changes for the bNAbs 
are required, the dosing used in Step 1 will continue to be used for the remainder of 
the study unless new data emerges requiring additional review. 
 
12. Section 6.3.1. VRC01LS Dose Calculation Instructions. The first paragraph has been 
revised to read: VRC01LS will be dosed at 30mg/kg at the first infusion visit, followed by 
10mg/kg maintenance at subsequent infusion visits in the PK Step. Following a 
recommendation to increase the maintenance dosing of VRC01LS based on review of 
data from the PK Step, VRC01LS will be dosed at 30mg/kg at the first Step 1 infusion 
visit, followed by 15mg/kg maintenance at subsequent Step 1 infusion visits. 
 
13. Section 6.4.2. Preparation of 10-1074 IV Solution. This section has been revised to read:  
 
To prepare 10-1074 IV infusion, the pharmacist will calculate the weight-based dose as in 
section 6.3.2 and remove the total number of vials needed as well as a 100 mL IV bag of 
Sodium Chloride for Injection USP, 0.9% from storage. The pharmacist, using aseptic 
technique, will add the appropriate amount of 10-1074 to the 100 mL IV bag of Sodium 
Chloride for Injection USP, 0.9%. After product preparation in IV bags, the prepared 10-1074 
may be stored at 2°C to 8°C for up to 6 hours up to 24 hours or at controlled room 
temperature (maximum 20°C to 3025°C) for a maximum of 8up to 4 hours. total including 
tThe infusion timeof study product must be completed within the storage timeframe 
specified for the respective storage conditions. Product may not be stored in direct 
sunlight. If stored at 2°C to 8°C, prepared product must be equilibrated at room temperature 
(maximum 30°C) for a minimum of 30 minutes prior to product administration. The pharmacist 
will label the infusion bag including a Beyond Use Date and time. 


Letter of Amendment #2, January 2, 2020 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 10 of 10 
  
 
14. Section 13.8.1. Quarterly Reporting and SMC Triggers for Safety or Stopping Criteria. The 
following subsection has been revised to read: 
 
Review of Safety and PK Data from Step 1 (first 6 participants) 
 
Safety, PK, and viral suppression data for the first 6 Step 1 participants will be reviewed within 
8-10 weeks by the study team including its sponsor representatives, and SMC. All PK data 
will be assessed by the study team based on pre-specified PK trough targets which are the 
same as those used in the PK Step for 10-1074 (7.5 mcg/mL) at Day 56, and revised for 
VRC01LS based on data from the PK Step (160 mcg/mL at Day 56). The review will confirm 
that PK targets are met for the updated VRC01LS dosing and during dual bNAb 
administration. (No changes to the remainder of this paragraph.) 
 
15. New Tables and Figures (Table 1, Figure 4 and Figure 5 in Section 2.1.8.1.1.2.; Table 2 and 
Figure 8 in Section 2.1.8.2.1.2) have been included in the protocol and the subsequent Table 
and Figure numbers in the protocol document have been updated accordingly. 
 
The above information will be incorporated into the next protocol version as necessary if the 
protocol is amended. 
 


Letter of Amendment #1, October 4, 2019 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 1 of 2 
 
 
Date: October 4, 2019 
 
RE:  
LETTER OF AMENDMENT #1 FOR DUAL BNAB TREATMENT IN CHILDREN 
Version 2.0, dated December 20, 2018 
 
“A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies VRC01LS and 
10-1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated Children in 
Botswana” 
 
DAIDS-ES #38551 
 
TO: Study Coordinators at Sites Participating in Dual BNAb Treatment in Children 
 
FROM: Roger Shapiro, MD, MPH (Corresponding Principal Investigator) 
 
 
The following information impacts the Dual BNAb Treatment in Children Study (DAIDS-
ES#38551) and must be forwarded to your Institutional Review Board (IRB)/Ethics Committee 
(EC) as soon as possible for their information and review. This must be approved by your 
IRB/EC before implementation.   
 
The following information may also impact the sample informed consent. Your IRB/EC will be 
responsible for determining the process of informing subjects of the contents of this letter of 
amendment. 
 
Upon receiving final IRB/EC and any other applicable Regulatory Entity (RE) approval(s) for this 
LoA, sites should implement the LoA immediately. Sites are still required to submit a LoA 
registration packet to the DAIDS Protocol Registration Office (PRO) at the Regulatory Support 
Center (RSC).  Sites will receive a registration notification for the LoA once the DAIDS PRO 
verifies that all the required LoA registration documents have been received and are complete. 
A LoA registration notification from the DAIDS PRO is not required prior to implementing the 
LoA. A copy of the LoA registration notification along with this letter and any IRB/EC 
correspondence should be retained in the site’s regulatory files. 
 
 
After a review of the study timeline, the study team is proposing to implement the following 
change: 
 
1. Increase the upper age limit of eligibility for enrollment to Step 1 from 5 years to 7 years 
old. 
 
This change will affect the following sections of the protocol. Additions are shown in bold. 
Deletions are shown in strikethrough. 
 
Section 5.4.1: 
 


Letter of Amendment #1, October 4, 2019 
Dual bNAb Treatment in Children v2.0 dated December 20, 2018 
IND#140909 
Page 2 of 2 
Inclusion Criteria for Entry into Step 1 (followed by participation in Steps 2-3): 
1) EIT Study participant 
2)  On ART for at least 96 weeks 
3) ≥96 weeks and <57 years of age at enrollment 
4) HIV RNA <40 copies/mL for at least 24 weeks prior to entry** 
5) Ability to remain in close study follow-up for at least 56 weeks 
6) Willingness to receive IV infusions of bNAbs 
7) Willingness to provide signed informed consent (by the parent/guardian) 
 
Section 7.9. Timing of evaluations 
 
Enrollment should occur at or after 96 weeks on ART, with an upper age limit of 5 years for 
the PK Step (7 years for Step 1).  
 


DAIDS ES-38551, Tatelo (Dual bNAb Treatment in Children), Version 2.0, Clarification Memo #1 (1 April 
2019) 
Page 1 of 1 
 
CLARIFICATION MEMO #1 
 
DATE: April 1, 2019 
TO: Tatelo Co-Principal Investigators, CRS Leaders, and CRS Coordinators 
FROM: Tatelo Protocol Team 
SUBJECT: Clarification Memo #1 to the Tatelo Protocol (DAIDS ES-38551), Version 2.0 dated 
December 20, 2018 entitled “A Clinical Trial to Evaluate the Impact of Broadly Neutralizing 
Antibodies VRC01LS and 10-1074 on Maintenance of HIV Suppression in a Cohort of Early-
Treated Children in Botswana” 
 
This clarification memo does not result in a change in the protocol informed consent 
document. The Division of AIDS does not require you to forward it to your Institutional 
Review Board (IRB)/Ethics Committee (EC); however, as always you must follow your 
IRB/EC policies and procedures. If IRB/EC review of clarification memos is required at 
your site, please submit this document for review. 
Each site should file a copy of this clarification memo with the protocol for reference. 
The protocol clarifications contained in this memo will be included in the next version of 
the Tatelo (DAIDS-ES 38551) protocol if it is amended at a future date. 
 
The following clarifications to the Tatelo protocol (DAIDS-ES 38551), Version 2.0, dated 
December 20, 2018 have been made: 
1. 10-1074 is now available in a 30ml vial, in addition to the 5ml vial indicated in Section 
6.2 of the protocol. Either size vial may be used in the study, depending on availability.  
 
2. Rachel Bowman’s email address was inadvertently omitted from the study team roster 
contact details. Her email address is bowman@fstrf.org. 
 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 1 of 75 
 
A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies VRC01LS and 10-
1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated Children in Botswana 
(Dual bNAb Treatment in Children) 
 
Phase I/II 
 
A Collaboration of: 
The Harvard School of Public Health AIDS Initiative 
 
The Brigham and Women’s Hospital 
 
The Ragon Institute at Massachusetts General Hospital 
The Ministry of Health of Botswana 
 
IND#: 140909 
DAIDS-ES 38551 
 
Coordinating Centre: 
Botswana-Harvard School of Public Health Partnership for HIV Research and Education 
Princess Marina Hospital 
Private Bag BO 320, Bontleng 
Gaborone, Botswana 
Tel: +267-390-2671, Fax: +267-390-1284 
 
Funded by: 
The National Institute of Allergy and Infectious Diseases (NIAID) 
 
Co-Principal Investigators: 
 
Roger Shapiro (corresponding) 
Daniel Kuritzkes 
Mathias Lichterfeld 
 
 
 
 
 
 
Co-Investigators: 
 
 
Kara Bennett 
Edmund Capparelli 
 
 
 
 
 
Marina Caskey 
 
 
 
 
 
Ajibola Gbolahan 
 
 
 
 
 
Molly Pretorius Holme 
 
 
 
 
 
Michael Hughes 
Shahin Lockman 
Joseph Makhema 
Kenneth Maswabi 
Mogomotsi Matshaba 
Sikhulile Moyo 
Kathleen Powis 
Xu Yu 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 2 of 75 
 
A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies 
VRC01LS and 10-1074 on Maintenance of HIV Suppression in a Cohort of 
Early-Treated Children in Botswana 
(Dual bNAb Treatment in Children) 
 
 
DAIDS-ES 38551 
 
 
Version 2.0 
Dated December 20, 2018 
 
PROTOCOL SIGNATURE PAGE 
 
I will conduct the 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 U.S. 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 signed: ____/____/____ (dd/mm/yy) 
 
 
Name of Investigator of Record (printed): _____________________________________________ 
 
 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 3 of 75 
 
TABLE OF CONTENTS 
 
 
 
 
 
 
 
List of Figures and Tables ..................................................................................................... 6 
Study Team Roster .............................................................................................................. 7 
Glossary .......................................................................................................................... 12 
1. PROTOCOL SUMMARY .................................................................................................... 13 
2. INTRODUCTION ............................................................................................................. 16 
2.1. Background .............................................................................................................................................. 16 
2.2. Rationale .................................................................................................................................................. 25 
2.3. Study Hypotheses ................................................................................................................................... 26 
3. PRIMARY OBJECTIVES ................................................................................................... 26 
4. STUDY DESIGN .............................................................................................................. 27 
5. STUDY SITES AND STUDY POPULATION ............................................................................ 29 
5.1. Clinical Sites ............................................................................................................................................ 29 
5.2. Laboratory Sites ...................................................................................................................................... 29 
5.3. Potential Study Participants .................................................................................................................. 31 
5.4. Inclusion / Exclusion Criteria ................................................................................................................. 31 
5.5. Recruitment Process .............................................................................................................................. 33 
5.6. Study Consent ......................................................................................................................................... 33 
5.7. Reimbursement ....................................................................................................................................... 34 
5.8. Participant Retention, Missed Visits, Study Withdrawal ................................................................... 34 
6. STUDY PRODUCT AND INTERVENTIONS ............................................................................ 34 
6.1. VRC01LS Description, Supply, and Storage ...................................................................................... 34 
6.2. 10-1074 Description, Supply, and Storage ......................................................................................... 35 
6.3. Schedule of Intervention and Dosing ................................................................................................... 35 
6.4. Preparation of Study Product Intravenous (IV) Solution ................................................................... 37 
6.5. Study Product Administration ............................................................................................................... 38 
6.6. Concomitant Medications: ART Management .................................................................................... 38 
7. STUDY PROCEDURES AND EVALUATIONS ......................................................................... 39 
7.1. Clinical Evaluations and Procedures ................................................................................................... 39 
7.2. Monitoring during Step 2 ....................................................................................................................... 43 
7.3. Participant Sampling .............................................................................................................................. 43 
7.4. Specimen Management ......................................................................................................................... 43 
7.5. Biohazard Containment ......................................................................................................................... 44 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 4 of 75 
 
7.6. Blood Volumes ........................................................................................................................................ 44 
7.7. Schedule of Evaluations ........................................................................................................................ 44 
7.8. End of Study Follow-Up ......................................................................................................................... 49 
7.9. Timing of evaluations ............................................................................................................................. 49 
7.10. Laboratory Testing Panels in Botswana ........................................................................................... 50 
7.11. Clinical Evaluations and Reporting Requirements .......................................................................... 52 
7.12. Medical Care and Referrals ................................................................................................................ 52 
7.13. Laboratory Procedures in Boston ...................................................................................................... 52 
8. ASSESSMENT OF SAFETY ............................................................................................... 52 
8.1. Serious Adverse Events (SAEs) ........................................................................................................... 52 
8.2. Adverse Event Reporting ....................................................................................................................... 53 
9. CLINICAL MANAGEMENT ................................................................................................ 54 
9.1. Toxicity Management ............................................................................................................................. 54 
9.2. Participants Lost to Follow-up ............................................................................................................... 56 
9.3. Child Death .............................................................................................................................................. 56 
9.4. Criteria for Study Discontinuation ......................................................................................................... 56 
10. STATISTICAL CONSIDERATIONS ..................................................................................... 57 
10.1. Statistical Considerations for Aim 1 ................................................................................................... 57 
10.2. Data Analysis and Statistical Considerations for Specific Aim 2 ................................................... 58 
10.3. Data analysis and interpretation for Specific Aim 3......................................................................... 59 
11. DATA HANDLING AND RECORD KEEPING ......................................................................... 59 
11.1. Data Management Responsibilities ................................................................................................... 59 
11.2. Source Documents ............................................................................................................................... 60 
11.3. Quality Control and Assurance ........................................................................................................... 60 
12. CLINICAL SITE MONITORING .......................................................................................... 61 
13. HUMAN SUBJECTS PROTECTIONS .................................................................................. 61 
13.1. Characteristics of study population .................................................................................................... 61 
13.2. Sources of Research Material ............................................................................................................ 61 
13.3. Participant Recruitment and Study Consent .................................................................................... 62 
13.4. Risks and Benefits ................................................................................................................................ 62 
13.5. Adherence to Human Subjects Requirements ................................................................................. 65 
13.6. Procedures for Minimizing Potential Risks ....................................................................................... 66 
13.7. Participation of Children, Women and Minorities ............................................................................ 67 


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13.8. Monitoring and Interim Analyses ........................................................................................................ 67 
13.9. Biohazard Containment ....................................................................................................................... 69 
13.10. Vertebrate Animals ............................................................................................................................. 69 
14. ADMINISTRATIVE PROCEDURES ..................................................................................... 69 
14.1. Protocol Registration ............................................................................................................................ 69 
14.2. Regulatory Oversight ........................................................................................................................... 70 
14.3. Study Implementation .......................................................................................................................... 70 
14.4. ClinicalTrials.gov ................................................................................................................................... 70 
15. REFERENCES .............................................................................................................. 71 
 
 
 
 


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List of Figures and Tables 
 
Figure 1: Study Schematic ................................................................................................................................ 13 
Figure 2: VRC01LS Simulations - 2 year old ................................................................................................. 21 
Figure 3: VRC01LS Troughs, Cmax, and Cave by Body Weight .................................................................... 22 
Figure 4: 10-1074 Simulations - 2 year old .................................................................................................... 23 
Figure 5: 10-1074 Troughs, Cmax, and Cave by body weight ......................................................................... 24 
 
Table 1: Follow-up and laboratory testing for the PK Step (first 12 participants) ..................................... 40 
Table 2: Follow-up and laboratory testing for Step 1 (all participants) ....................................................... 41 
Table 3: Follow-up and laboratory testing for Step 2 and Step 3 (all participants) .................................. 42 
 
 
 
 


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Study Team Roster 
 
Co-Principal Investigators: 
 
Roger Shapiro, MD, MPH (corresponding co-PI) 
Department of Immunology and Infectious Disease 
Harvard T.H. Chan School of Public Health 
651 Huntington Ave, FXB 305AA 
Boston, MA 02115 
Phone: 617-771-0040 (cell)  
Fax:  617-739-8348 
Email: rshapiro@hsph.harvard.edu 
 
Daniel Kuritzkes, MD 
Chief, Division of Infectious Disease 
Brigham and Women's Hospital  
75 Francis Street 
Boston, MA  02115 
Phone: 617-768-8371 
Fax: 617-768-8738 
Email: dkuritzkes@partners.org 
 
Mathias Lichterfeld, MD, PhD 
Infectious Disease Division 
Brigham and Women’s Hospital/Massachusetts General Hospital 
65 Landsdowne Street 
Cambridge, MA 02139 
Phone: 617-768-8399 
Fax: 617-726-5411 
E-mail: mlichterfeld@partners.org 
 
Co-Investigators: 
 
Kara Bennett, MS 
Bennett Statistical Consulting, Inc. 
21 Nolan Road 
Ballston Lake, NY 12019 
Phone: 518-727-1399 
Email: karabstat@gmail.com 
 
Edmund Capparelli, PharmD 
Division of Clinical Pharmacology and Developmental Therapeutics 
University of California, San Diego, San Diego, CA 
Phone: 858-246-0009 
Fax: 858-246-0025 
Email: ecapparelli@ucsd.edu 
 


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                        December 20, 2018 
 
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Marina Caskey, MD 
Rockefeller University 
1230 York Avenue 
New York, NY 10065 
Phone: 646-962-8747 
Email: mcaskey@mail.rockefeller.edu 
 
Ajibola Gbolahan, MD  
Botswana-Harvard Partnership, Gaborone, Botswana 
Phone: 267-3902671 
Fax: 267-3901284 
Email: gajibola@bhp.org.bw 
 
Molly Pretorius Holme, MSc 
Department of Immunology and Infectious Disease 
Harvard T.H. Chan School of Public Health 
651 Huntington Ave, FXB 406a 
Boston, MA 02115 
Phone: 617-432-4377 
Fax: 617-739-8348 
Email: mpretori@hsph.harvard.edu 
 
Michael Hughes, PHD 
Director, Center for Biostatistics in AIDS Research 
Department of Biostatistics 
655 Huntington Avenue 
Building II Room 439A 
Boston, Massachusetts 02115 
Phone: 617-432-2815 
Fax: 617-739-1781 
Email: mhughes@sdac.harvard.edu 
 
Shahin Lockman, MD, MS 
Brigham and Women’s Hospital, Boston 
Harvard T.H. Chan School of Public Health, Boston 
Phone: 617-771-8780 (cell) 
Fax: 617-739-8348 
Email: slockman@hsph.harvard.edu 
 
Joseph Makhema, MD 
Botswana-Harvard Partnership, Gaborone, Botswana 
Phone: +267-3902671 
Fax: +267-3901284 
Email: jmakhema@bhp.org.bw 
 
Kenneth Maswabi, MD 
Botswana-Harvard Partnership, Gaborone, Botswana 
Phone: 267-3902671 
Fax: 267-3901284 
Email: kmaswabi@bhp.org.bw 
 


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Mogomotsi Matshaba, MD 
The Botswana-Baylor Children’s Clinical Center of Excellence 
Princess Marina Hospital, Gaborone, Botswana 
Tel: +267 3190083 
Email: matshaba@bcm.edu 
 
Sikhulile Moyo, MPH, PhD 
Botswana-Harvard Partnership, Gaborone, Botswana 
Phone: +267-3902671 
Cell phone: +267 72113640 
Email: smoyo@bhp.org.bw 
 
Kathleen Powis, MD, MPH 
Massachusetts General Hospital 
Botswana-Harvard Partnership, Gaborone, Botswana 
Phone: +267-74300105 / 617-947-9150 (cell) 
Email: kpowis@mgh.harvard.edu 
 
Xu Yu, MD, MSc 
Ragon Institute of MGH, MIT and Harvard 
400 Technology Square 
Cambridge, MA 02139 
Phone: 857-268-7004 
E-mail: xyu@partners.org 
 
Product Developer Representative 
Lucio Gama, MS, PhD 
Vaccine Research Center 
National Institutes of Health 
40 Convent Drive, Room 5502 
Phone: 301-761-7580 
Email: lucio.gama@nih.gov 
 
Protocol Data Manager 
Christina Reding, MPH 
Frontier Science and Technology Research 
Foundation, Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x7339 
Email: reding@fstrf.org 
 
Laboratory Data Manager 
Rachel Bowman, PhD 
Frontier Science and Technology Research Foundation, Inc.  
4033 Maple Road  
Amherst, NY 14226  
Phone: (716) 834-0900 x7375 
 


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Data Operations and IT 
Coulson Kgathi 
Botswana-Harvard Partnership, Gaborone, Botswana 
Phone: +267-390-2671 
Email: ckgathi@bhp.org.bw 
 
Pharmacists: 
 
Pharmacist 
Tshepho Frank, BPharm 
Botswana-Harvard Partnership, Gaborone, Botswana 
Phone: +267-390-2671 
Email: tfrank@bhp.org.bw 
 
DAIDS Protocol Pharmacist 
Lynette Purdue, PharmD 
Division of AIDS 
5601 Fishers Lane 
Rockville, MD 20852 
Phone: 240-627-3061 
Email: lpurdue@niaid.nih.gov 
 
Project Administrator 
Ria Madison 
Botswana-Harvard Partnership, Gaborone, Botswana 
Phone: 267-3902671 
Cell phone: 267-72109025 
Fax: 267-3901284 
Email: rmadison@bhp.org.bw 
 
Study Funder 
National Institutes of Health  
National Institutes of Allergy and Infectious Diseases 
 
Medical Officer 
Patrick Jean-Philippe, MD 
National Institute of Allergy and Infectious Diseases 
5601 Fishers Lane, 8B21,  
Rockville, MD 20852, United States 
Phone: 240-292-4790 
Fax: 240-627-3465 
Email: jeanphilippep@niaid.nih.gov 
 
Program Officer 
Judi Miller 
National Institute of Allergy and Infectious Diseases 
5601 Fishers Lane, 8C21,  
Rockville, MD 20852, United States 
Phone:  1-240-292-4801 
Email:  jmillera@niaid.nih.gov 


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Study Management 
All questions concerning this protocol, including issues regarding: 
Clinical medical management, toxicity management, concomitant medications, laboratory tests, 
and/or forms development should be sent via e-mail to rshapiro@hsph.harvard.edu. 
 


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Glossary 
 
ADA 
 
anti-drug antibody testing 
ADCC  
antibody-dependent cell-mediated cytotoxicity 
AE 
 
adverse events 
ART 
 
antiretroviral therapy or treatment 
ATI 
 
analytic treatment interruption 
AUC 
 
area under the curve 
BHP 
 
Botswana-Harvard AIDS Institute Partnership 
BHHRL 
Botswana-Harvard HIV Reference Laboratory 
bNAb  
Broadly neutralizing monoclonal antibody 
CBV 
 
Combivir 
CHO  
Chinese hamster ovary 
CNS 
 
central nervous system 
CRF 
 
case report form 
CRPMC 
Clinical Research Products Management Center 
CTL 
 
cytotoxic T-lymphocyte 
DAIDS  
Division of AIDS, National Institutes of Health 
DBS 
 
dried blood spot 
ddPCR 
digital droplet polymerase chain reaction 
EAE 
 
Expedited adverse event (reporting) 
EFV 
 
efavirenz 
EIT 
 
Early Infant Treatment Study 
FDA 
 
Food and Drug Administration 
IRB 
 
institutional review board 
IV 
 
intravenous 
3TC 
 
lamivudine 
LFT 
 
liver function test 
LPV 
 
lopinavir 
LPV/r  
lopinavir/ritonavir 
MTB 
 
Mycobacterium tuberculosis 
MTCT  
mother-to-child transmission 
NIAID  
US National Institute of Allergy and Infectious Diseases 
NIH  
 
US National Institutes of Health 
NNRTI  
nonnucleoside reverse transcriptase inhibitor 
NRTI  
nucleoside reverse transcriptase inhibitor 
NVP 
 
nevirapine 
OHRP  
US Office of Human Research Protection 
PBMC  
peripheral blood mononuclear cells 
PCR 
 
polymerase chain reaction 
PI 
 
protease inhibitor or Principal Investigator 
PK 
 
pharmacokinetics 
PMTCT 
prevention of MTCT 
RT 
 
reverse transcriptase 
SES 
 
socioeconomic status 
SMC  
Safety Monitoring Committee 
TDF 
 
tenofovir disoproxil fumarate 
ZDV 
 
zidovudine 
 
 


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1. PROTOCOL SUMMARY 
 
1.1. Title: A Clinical Trial to Evaluate the Impact of Broadly Neutralizing Antibodies VRC01LS and 10-
1074 on Maintenance of HIV Suppression in a Cohort of Early-Treated Children in Botswana  
 
1.1.1. Short title: Dual bNAb Treatment in Children 
 
1.2. Sample Size: Up to 40 children 
 
1.3. Study Population:  
• 
HIV-infected children enrolled in the Early Infant Treatment (EIT) Study who are at 
least 96 weeks of life and meet entry criteria; 
• 
In the PK Step only, HIV-infected children who are not enrolled in the EIT Study who 
are at least 96 weeks of life and meet entry criteria 
 
1.4. Participating Sites: Gaborone CRS #31833 and Francistown CRS #31891 
 
1.5. Study Design: This study will be a phase I/II, multi-site clinical trial of dual treatment with two 
broadly neutralizing monoclonal antibodies (bNAbs), VRC01LS and 10-1074, offered to HIV-1 infected 
virally suppressed children. There will be 4 Steps in the protocol: PK Step, Step 1, Step 2, and Step 3. 
In the PK Step, antiretroviral treatment (ART) is continued and 12 study participants will undergo 
safety and PK testing, 6 for each bNAb used in the study (10-1074 and VRC01LS). In Step 1, ART is 
continued and dual bNAb treatment occurs, with PK confirmation of dual bNAb dosing for the first 6 
participants in Step 1. In Step 2, ART is withdrawn and dual bNAb maintenance treatment occurs. In 
Step 3, dual bNAbs will be discontinued and participants will be re-started on ART.  
 
 
Figure 1: Study Schematic 
 


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1.6. Study Duration: 56-98 weeks 
 
1.7. Study Intervention:  
 
PK Step 
 
The first 12 participants in the study will undergo the PK Step, to allow for detailed safety and PK 
assessment of each bNAb alone. In the PK Step, while continuing ART, participants 1, 3, 5, 7, 9, 11 
will receive VRC01LS at Week 0, Week 4, and Week 8 as a single intravenous (IV) dose (30 mg/kg 
load, then 10mg/kg maintenance); safety and PK measurements will occur at end of infusion, 1 hour 
post-infusion, 1 day post-infusion, 1 week post-infusion, 2 weeks post-infusion, and 4 weeks post-
infusion. Participants 2, 4, 6, 8, 10, 12 will receive 10-1074 at Week 0, Week 4, and Week 8 as a 
single IV dose (30mg/kg), and safety and PK measurements will also occur at end of infusion, 1 hour 
post-infusion, 1 day post-infusion, 1 week post-infusion, 2 weeks post-infusion, and 4 weeks post-
infusion. In the PK Step, it is anticipated that all 12 participants will be from the Early Infant Treatment 
(EIT) Study; however, in the event that 12 participants from EIT are not available at the time the PK 
Step begins, participants 9-12 may be recruited from other virally suppressed HIV-infected children. 
These additional, non-EIT children would not be eligible for further study steps after completing the 
PK Step. In the event that a participant discontinues bNAb during the PK Step, the participant may be 
replaced to allow for PK data to be obtained from 12 participants total. 
 
SMC Review of Safety and PK Data from PK Step 
 
After all 12 PK Step participants complete the PK Step, safety, PK, and viral suppression data will be 
reviewed within 8 weeks by the study team, sponsor, and SMC (earlier review by the SMC may be 
triggered based on pre-specified safety parameters). Participants will not continue to be dosed with 
bNAbs while awaiting SMC review, but will continue ART. All PK data from the PK Step will be 
assessed based on pre-specified PK trough targets; peak values will be assessed, but primary 
guidance for peak values will be based on toxicity. The study team will determine if the pre-specified 
trough targets have been achieved, and present this information to the SMC. The SMC will review 
safety data utilizing pre-defined safety criteria. If safety criteria are met, and if the PK data are in the 
pre-specified range, approval to begin Step 1 may be granted by the SMC. If the dosing and 
frequency of bNAbs established in the PK Step is acceptable, it will continue to be used for the first 6 
participants in Step 1 (see additional safety review below). If a change in dosing is recommended by 
experts on the study team (or by the SMC, if it does not accept the team’s recommendation), 
adjustments will occur and IRB and study sponsor approval will be sought regarding required protocol 
changes prior to starting Step 1. The recommendations by the study team or by the SMC may include 
early termination of the study, if warranted by the safety/PK data, or a re-design of the study as 
approved by the study sponsors and regulatory boards. 
 
Step 1 (first 6 participants)  
 
All Step 1-3 participants must be from the EIT Study. After approval, Step 1 will begin for a maximum 
of 6 participants, all of whom will have participated in the PK Step (3 from each PK Step group), and 
all of whom will have been >12 weeks from last bNAb dosing. ART is continued throughout Step 1, 
and all participants receive both 10-1074 and VRC01LS. If dosing recommendations do not change 
based on the PK Step, a VRC01LS loading dose of 30 mg/kg will be given at the start of Step 1, 
followed by 10mg/kg dosing at each 4-weekly visit, and 10-1074 dosing will be at 30mg/kg at each 4-
weekly visit. At Week 0, Week 4, and Week 8 doses of Step 1, PK testing for both bNAbs will occur 
prior to infusion, and at Weeks 0 and 4 only at end of infusion, 1 hour post-infusion, 1 day post-
infusion, and 1 week post-infusion. Post-infusion PK blood draws will occur at the end of and 1-hour 


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Page 15 of 75 
 
after the completion of both infusions, if both are administered on the same day. HIV-1 RNA will be 
checked every 4 weeks in Step 1. The first 6 participants in Step 1 will continue in this Step, receiving 
both oral ART and dual bNAb infusions, until the second study team/SMC review occurs. This review 
of safety and PK data will occur within 8 weeks of the 6th participant’s Week 8 PK sampling.  
 
SMC Review of Safety and PK Data from Step 1 (first 6 participants) 
 
Safety, PK, and viral suppression data for the first 6 Step 1 participants will be reviewed within 8 
weeks by the study team, sponsor, and SMC. All PK data will be assessed by the study team based 
on pre-specified PK trough targets which are the same as those used in the PK Step. The review will 
confirm that PK targets are met during dual bNAb administration. Safety criteria will be reviewed by 
the SMC, also using the same criteria as for the PK Step. If safety criteria are met, and if the PK data 
for both bNAbs are in the pre-specified range, the SMC may approve entry into Step 2 for the first 6 
participants and enrollment of additional participants into Step 1. If the PK data are in range and no 
dosing changes for the bNAbs are required, the dosing will continue to be used for the remainder of 
the study unless new data emerges requiring additional review. If a change in dosing is recommended 
by experts on the study team (or by the SMC, if it does not accept the team’s recommendation), IRB 
and study sponsor approval will be sought regarding required protocol changes. The 
recommendations by the study team or by the SMC may include early termination of the study, if 
warranted by the safety/PK data, or a re-design of the study as approved by the study sponsors and 
regulatory boards. 
 
Step 1 (all subsequent participants) 
 
After approval to proceed is obtained by the SMC, additional participants will enroll directly into Step 1 
and receive dual bNAbs and ART for 8 weeks. All study visits and follow-up will be the same as for 
the first 6 Step 1 participants, with the exception of PK testing; only trough PK testing will be required 
for these participants, beginning at Week 4 of Step 1. 
 
Step 2 (all participants) 
 
Following a successful Step 1 review, Step 2 may begin. Step 2 will begin after a participant has spent 
at least 8 weeks in Step 1. For the first 6 participants, Step 2 will begin at a scheduled bNAb dosing 
visit (i.e. 4 weeks from last Step 1 bNAb dosing), and for all subsequent participants it will begin at the 
8 Week visit date for Step 1 (which becomes the Week 0 Step 2 visit). Participants with ongoing viral 
suppression throughout Step 1 will undergo withdrawal of ART and will continue maintenance 10-
1074 (30mg/kg) and VRC01LS (10mg/kg) treatment for up to 24 weeks in Step 2. HIV-1 RNA will be 
checked at all visits in Step 2, which occur weekly from Weeks 1-4 in Step 2, and every 2 weeks 
thereafter. Qualitative HIV DNA will be checked at each visit by DBS. If a participant experiences a 
single viral rebound >400 copies/mL in Step 2, ART will be re-started (and VRC01LS and 10-1074 will 
be discontinued). A single viral rebound is defined as an HIV RNA result ≥400 copies/mL at any Step 
2 visit, without need for confirmation. If HIV RNA becomes ≥400 copies/mL prior to the end of Step 2, 
all evaluations ordinarily scheduled at “Week 24” will be performed immediately prior to ART re-
initiation.  If HIV-1 RNA is ≥40 copies/mL but <400 copies/mL, or if Qualitative DNA turns from 
negative to positive, virologic monitoring tests will be repeated weekly. Clinical examination will occur 
at each study visit.  
 
Step 3 (all participants) 
 
All participants will end Step 2 after 24 weeks, and enter Step 3. In Step 3, both 10-1074 and 
VRC01LS will be discontinued, and ART will be re-started. Follow-up visits in Step 3 will occur at 4, 


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12, and 24 weeks.     
 
1.8. Primary Objectives 
• 
Specific Aim 1: To conduct an interventional clinical trial to determine the safety, 
pharmacokinetics, dosing and antiviral efficacy of up to 24 weeks of maintenance VRC01LS 
and 10-1074 immunotherapy in early-treated HIV-1 infected children in Botswana. 
• 
Specific Aim 2: To evaluate effects of treatment with VRC01LS and 10-1074 on the size and 
cellular composition of residual viral reservoirs.  
• 
Specific Aim 3: To investigate the influence of VRC01LS and 10-1074 treatment on the 
magnitude and quality of antiviral innate and adaptive immune responses. 
 
1.9. Primary Endpoints and Analyses 
Aim 1: The primary endpoints will be (1) the frequency and severity of treatment-associated adverse 
events, and (2) the proportion of children who maintain HIV-1 plasma RNA <400 copies/mL (and <40 
copies/mL), after initiating VRC01LS and 10-1074 infusions (24 weeks after withdrawal of standard 
ART). Secondary endpoints will include pharmacokinetic profiles of all children who receive VRC01LS 
and 10-1074 and growth characteristics (height and weight z-scores) of virally suppressed children 
receiving bNAbs. 
 
Aim 2: Viral reservoirs during treatment with VCR01LS and 10-1074 will be evaluated in blood 
samples (PBMCs) using a novel single-template, near full-length viral sequencing assay that provides 
information on the complete spectrum of HIV-1 DNA copies integrated into host chromosomes. This 
approach will allow us to evaluate defective vs. intact HIV-1 genomes, antiretroviral drug and cytotoxic 
T-lymphocyte (CTL) escape variants and longitudinal viral sequence evolution in total CD4 T cells as 
well as in phenotypically-complex subsets of CD4 T cells known to be critical for viral reservoir 
stabilization. Cell-associated HIV-1 RNA and plasma RNA will be simultaneously analyzed and 
sequenced. If rebound occurs during analytic treatment interruption (ATI), viral reservoir parameters 
will be correlated to viral rebound kinetics, to pharmacokinetic measurements of bNAbs, and to 
antiviral immune parameters determined in Specific Aim 3. 
 
Aim 3: We will use comprehensive phenotypic and functional assays to profile effects of VRC01LS 
and 10-1074 treatment on biomarkers of immune activation and on innate cellular immune responses, 
coupled with RNA-Seq-based gene expression studies in selected immune cell subsets. In addition, 
the evolution of neutralizing antibody breadth and the frequency and functionality of HIV-1-specific T 
cells will be analyzed, and combined with viral sequencing data (generated in specific aim 2) to 
identify viral immune escape.  
 
2. INTRODUCTION 
 
2.1. Background 
 
2.1.1. Non-ART viral suppression strategies are a priority for children. Long-term viral 
suppression with ART is difficult to maintain over the course of a lifetime, and significant toxicities to 
ART may accumulate with time. Novel strategies that maintain HIV viral suppression while allowing 
time off 3-drug ART are needed, and proof-of-concept studies to demonstrate the feasibility of such a 
strategy – and to study its impact on viral reservoir, immune responses, and clinical outcomes – are of 
high priority. The practical benefits of an ART-sparing intervention may reduce direct ART toxicities 
during critical periods of growth and development [1]. Long-term side effects and toxicities from 3-drug 


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ART are only beginning to be understood, particularly in areas of Africa where many children who 
received ART in childhood are now reaching adolescence. Even with newer and more tolerable ART 
regimens, toxicities that might be ameliorated by an ART-sparing strategy include impaired growth 
and endocrine effects [2, 3], lipodystrophy [4], hematologic toxicities [5], renal toxicity [6, 7], bone 
density effects [8-10], cardiovascular disease [11-13], and possible neurodevelopmental effects [14]. 
Finally, strategies that allow time off ART are highly desirable for many patients and caregivers for 
reasons related to treatment fatigue, travel, stigma, or other factors [15]. 
 
2.1.2. Viral reservoir suppression may be possible with broadly neutralizing monoclonal 
antibodies (bNAbs). Broadly neutralizing monoclonal antibodies can suppress HIV-1 RNA and may 
help to deplete residual viral reservoirs [16-19]. VRC01, a recombinant human immunoglobulin G1 
(IgG1) monoclonal antibody produced in a Chinese Hamster Ovary (CHO) cell line that targets the 
CD4 binding site of gp120, has demonstrated activity in reducing plasma viremia among ART-
untreated individuals [16], and delaying viral rebound after periods of ART interruption compared with 
historical controls in chronically infected adults [20, 21]. The long-acting VRC01LS formulation 
improves tissue levels and may improve efficacy [22]. The bNAb 10-1074 targets the V3 glycan 
supersite on the HIV-1 envelope (Env) protein, which is a different Env binding site from VRC01. This 
potent monoclonal antibody has achieved 1.52 log HIV RNA reductions when used in chronically 
infected adults [23]. Combination use of two separate bNAbs which act at different binding sites has 
not been previously evaluated in a cohort of low-reservoir, early-treated children, and – like combined 
potent ART – has a high probability of successful maintenance of viral suppression.  
Although chronically-infected adults receiving either VRC01 or 10-1074 did not achieve long-term viral 
suppression off ART, there are important differences between these prior studies and the proposed 
combination study in early-treated children, including: 1) previous trials did not use a combined 
approach to prevent the development of resistance to each bNAb, which is widely regarded to be 
critical for suppressive treatment with bNAbs (as has been established with ART) [24, 25], and which 
is supported by some non-human primate data [26]; 2) viral reservoir burden is higher in chronically 
infected adults than in very early treated children; 3) chronically infected adults have pre-existing 
resistance to VRC01 and 10-1074 (from prior immune responses to the virus) which allow for escape 
[20, 21], and this viral resistance would not be expected in early-treated children; 4) the prior studies 
employed only minimal overlap of bNAbs and ART, and a longer overlap period may reduce viral 
reservoir sufficiently to allow for a longer period off ART, and 5) immune effects of bNAbs in children 
with a developing immune system may be different than in adults, and may  facilitate induction of 
more potent autologous cellular and humoral immune responses against HIV-1. Other monoclonal 
antibodies targeting HIV co-receptors have demonstrated the ability to maintain viral suppression in a 
majority of adult participants for over a year [27] or during the period of antibody administration [28].  
 
2.1.3. Viral reservoirs can be reduced with bNAbs. bNAbs have been associated with reduction in 
viral reservoirs, particularly when used in combination with ART. In non-human primates, combination 
bNAb treatment has led to 4- to 10-fold reduction in HIV copies in PBMCs, lymph nodes, and the GI 
tract [29]. The bNAb 3BNC117, which also targets the CD4 binding site, was shown to accelerate 
clearance of infected cells in animal models [19]. Although one study of VRC01 administered to adults 
on suppressive ART did not alter markers of viral reservoir [30], that study administered only two 
doses of VRC01 to participants on long-term suppressive ART, and detectable changes in markers for 
the latent reservoir would not be expected. Data using VRC01LS in non-human primates 
demonstrated improved protection against HIV infection during rectal challenge, perhaps mediated by 
enhanced mucosal localization and more robust antibody-dependent cell-mediated cytotoxicity 
(ADCC) [22]. It is plausible that viral reservoir dynamics of early treated children differ sufficiently from 
adults with chronic infection prior to treatment, and that the design of the proposed study also differs 
sufficiently, to hypothesize potential viral reservoir reduction as measured in blood samples from the 


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combination of VRC01LS and 10-1074 in early treated children.  
 
2.1.4. VRC01LS and 10-1074 resistance may be limited in early treated children. Among 
perinatally HIV-infected children, founder viruses have been susceptible to VRC01 [31, 32] because 
VRC01 binds a highly conserved epitope (the CD4 binding site) [33][27]. The likelihood of viral 
susceptibility within this restricted reservoir is a critical difference between the study population and 
adults with chronic infection, and will be further evaluated in this study. No data are currently available 
regarding resistance to 10-1074 in a pediatric population with early ART; this study will provide the 
first data for this population. Preliminary viral sequencing data from the EIT study children (who will be 
the same children eligible for this intervention) have demonstrated no concerning mutations for 10-
1074 at positions 324, 326, 327 (M. Lichterfeld, unpublished data, 2018). Viral reservoir size is 
another consideration for resistance in children, and has been closely linked to age at ART initiation. 
IMPAACT P1030, which evaluated viral reservoir following ART initiation between 4 weeks and 6 
months of age, demonstrated that after 2 years of viral suppression proviral HIV DNA remained 
detectable in all children but was correlated with the time to viral treatment/suppression [34]. Recent 
data support conservation of founder virus and lack of viral diversification with early-ART treatment 
[35]. Our preliminary data from the EIT Study in Botswana supports and extends these findings. 
Preliminary results from the first children in this study who started ART in the first week of life shows 
lack of HIV DNA detectability to a limit of 5 copies/million cells for the majority of children. 
 
2.1.5. bNAbs may enhance immune responses. Unlike ART, bNAbs have the potential to engage 
host immune cells in viral defense. bNAbs have demonstrated the ability to enhance and broaden 
autologous humoral immune responses, possibly through stimulation of B cells or dendritic cells by 
viral antigen-antibody complexes [36, 37]; this may allow for children to develop improved antiviral 
immune responses that help control or limit viral rebound upon withdrawal of ART. ART from infancy 
limits the infant HIV-1 antibody response, and most early treated children lack long-lasting HIV-1-
specific antibodies [38]. Thus, immune modulation using bNAbs may benefit children who started 
treatment early and for that reason have very limited autologous immune responses to HIV-1. This 
immunologic benefit may be more long-lasting than the bNAb treatment itself (potentially restricting 
viral rebound during periods of non-adherence to ART later in life). bNAbs may also enhance 
clearance of viral reservoir cells through antibody-dependent cellular cytotoxicity (ADCC) [22], which 
may contribute to natural viral control or delay viral rebound following ART interruption [29]. Finally, 
emerging data from experimental animal models with non-human primates suggest that bNabs may 
facilitate the development of more functional HIV-1-specific cellular immune responses, and support 
the development of an improved antiviral immune profile.  
 
2.1.6. Early childhood may be the ideal time period for immunologic interventions directed 
against the HIV-1 reservoir. Our proposed intervention will occur after at least 96 weeks on ART in 
children who began ART within days after birth. In addition to the advantage of a long period on ART 
to maximally reduce viral reservoir by attrition of infected cells of the early infant immune system, this 
is a period of immune quiescence in children. This period of life has been called a “honeymoon 
period” [39, 40] when the immune system is well-adapted to control a variety of infections – possibly 
including HIV – without immunopathology. ADCC may be supported by the use of a bNAb among 
children in this age range, whereas it may not be sufficiently developed in younger infants. 
 
2.1.7. Safety considerations for VRC01 and 10-1074: Passive polyclonal antibody products have 
been used for treatment and prophylaxis with excellent safety profiles over many decades. These 
agents include hepatitis B immunoglobulin (HBIG), Respigam®, Cytogam®, HIVIg, and IVIG.  In a 
large study of IVIG to prevent infection in preterm infants published in 2011, adverse events were rare 
and did not differ between IVIG and placebo [41]. 
 
 


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VRC01 has an extensive safety record when used in adult clinical trials (N=over 840 participants) [16, 
21, 30, 42], and adverse events leading to VRC01 or placebo discontinuation have been limited to 
one participant with chest discomfort and one with rash. VRC01 has been used in pediatric clinical 
trials [43, 44], and there have been no safety concerns reported. IMPAACT P1112 is a Phase I trial 
enrolling HIV-1-exposed infants at birth at high risk of transmission. It is determining the PK and 
safety of a single dose of VRC01 to reduce HIV-1 transmission to infants. VRC01 has been well 
tolerated at 20mg/kg (N=13) and 40mg/kg subcutaneously (SC) (N=13). There have been eight grade 
3 or higher events, all from causes that were not attributed to VRC01 (neutropenia, elevated total 
bilirubin, elevated creatinine, abdominal distension, and episodes of bronchiolitis). No systemic 
reactions were attributed to VRC01. Local infusion-related reactions (mild or moderate erythema, 
induration or edema) did occur in 15 infants; none were serious and almost all resolved within four 
hours of injection. Pain (grade 1) at the injection site was reported in only two infants. There have 
been no other adverse events attributed to VRC01. VRC01LS differs by 2 amino acids from VRC01 
(which modifies binding characteristics and extends the half-life), and it is currently also being used in 
children in IMPAACT P1112. In preclinical non-human primate experiments, VRC01LS administered 
IV at doses from 0.02 to 20 mg/kg (n=26), or SC at a dose of 10 mg/mL (n=6), had no indication of 
local reactogenicity, anaphylactoid reaction, or any systemic disease [22]. In human studies, 39 adults 
have received VRC01LS at different doses delivered intravenously or subcutaneously in clinical 
studies, and there have been no serious adverse events reported [45].  
 
 
A tissue cross-reactivity study for VRC01LS was performed by Charles River Laboratories, Frederick, 
MD, to determine the potential cross-reactivity of VRC01LS with cryosections of selected neonatal 
human tissues. No VRC01LS cross-reactivity was observed in any of the neonatal human tissues 
examined. Similarly, no tissue cross-reactivity of toxicologic relevance was identified for VRC01LS in 
adult tissues [46].  
In pre-clinical studies of 10-1074, twice weekly IV administration of 10-1074 at doses of 4, 15, and 
60mg/kg/injection as well as the combination IV dose of 10-1074 and 3BNC117 (each 60mg/kg once 
weekly), and twice weekly doses of 10-1074 at 60 mg/kg/injection via the subcutaneous route, for a 
25-day dosing period were considered well-tolerated in male and female Sprague Dawley rats. Test 
item-related findings were consistent with an immune response to repeated administration of a foreign 
protein primarily in subcutaneously-dosed animals, as evidenced by hindpaw swelling, liver and 
spleen organ weight changes; as well as microscopic liver and spleen changes including mononuclear 
cell infiltrate and sinusoid histiocytosis/dilatation in the liver, and lymphoid hypercellularity, sinusoid 
histiocytosis and extramedullary hematopoiesis of the spleen, in all dose groups. These changes were 
either fully or nearly completely recovered by the end of the 45-day recovery period [47]. 
The bNAb 10-1074 has been used in adults with a reassuring safety profile. No grade 3 or 4 or 
serious treatment-related adverse events, or notable laboratory abnormalities, occurred during a total 
of 5,447 patient days of follow-up [23]. As of August 2017, 10-1074 had been administered to 76 
research participants, at doses ranging from 3 mg/kg to 30 mg/kg; 44 of these participants were HIV 
infected. Protocol MCA-885 was an open label, dose-escalation, Phase 1 study to evaluate safety, 
pharmacokinetics and antiretroviral activity of 10-1074 in 33 HIV-uninfected and HIV- infected 
individuals. No grade 3, 4 or serious adverse events considered possibly related to 10-1074 were 
reported, and no clinically significant treatment-related changes in laboratory parameters occurred 
during study follow up. Of 11 infusion-related events that were considered at least possibly related 
adverse events (AEs), no related grade 3 or 4 events were observed. The most common adverse 
event reported under protocol MCA-885 was headache (N=5/33). One participant experienced 
malaise/fatigue, and one had elevated bilirubin.  
A tissue cross-reactivity study for 10-1074 was performed on a full panel of tissues from humans and 


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                        December 20, 2018 
 
Page 20 of 75 
 
rats. Although 10-1074 showed cytoplasmic binding in some tissues, this finding was considered of 
little to no toxicologic significance [48]. No specific tissue cross-reactivity studies have been 
performed for 10-1074 to monitor for off-target events in pediatric tissues. However, the study 
procedures and monitoring in place for this study will be sufficient to identify almost all issues of 
clinical concern, in the unlikely event of differences between adult and pediatric tissue cross-reactivity.  
IV administration will occur rather than SC because the SC volume would exceed the safety limits for 
children over ~ 10 kg given the current VRC01LS formulation of 100mg/ml. IV administration will also 
occur for 10-1074, which has not been used SC. IV formulations take longer to administer, but may be 
associated with fewer injection site reactions than SC administration. 
 
2.1.7.1. Safety considerations for combination of bNAbs:  There are no indications to date for any 
safety considerations related to the combination of 2 different bNAbs. Data from at least 5 primate 
studies using combinations of bNAbs had no concerning safety signals from dual bNAb use [24, 49]. 
Two recent studies in HIV-infected and HIV-uninfected adults have evaluated 10-1074 in combination 
with 3BNC117 (which uses a similar CD4 binding site as VRC01), and there were no safety concerns 
using this combination when administering the antibodies in sequence. These studies have enrolled 
25 HIV-infected and  24 HIV-uninfected participants, and in total there have been 9 AEs at least 
possibly related to the infusions, and no serious AEs have been reported to date in either protocol 
(Rockefeller University, unpublished data, 2018) [50].  
 
 
2.1.8. VRC01LS and 10-1074 PK and dosing considerations:  
 
2.1.8.1. PK Considerations for VRC01LS. For VRC01LS, target plasma levels for this study are 
based on preclinical studies of VRC01 that demonstrate over 91% of viral isolates tested across 
clades are neutralized at an ID50 of 50 µg/ml. VRC01 PK results in HIV-infected and uninfected 
patients have been published [16, 30], and a 40 mg/kg dose has been chosen for adults to maintain 
levels >50 µg/ml for 4 weeks, which leads to an overall median value closer to 100 µg/mL. VRC01LS 
has similar activity to VRC01, and these well-tolerated target concentrations can therefore be 
extrapolated. In HIV-infected adults receiving 40 mg/kg IV of VRC01, mean maximum serum 
concentrations were 1600 µg/ml ± standard deviation 230 µg/ml (n=5) after the first infusion, and 1500 
µg/ml ±400 µg/ml after the second dose 28 days later. Mean 28-day trough serum concentrations 
were 57 µg/ml ±19 µg/ml (n=5) after the first dose, and 89 µg/ml ±40 µg/ml after the second dose (~ 
day 56). Similar results were reported for HIV-uninfected participants.  
 
These PK and safety data for VRC01, coupled with results from adult studies of VRC01LS (VRC 606), 
allow for dosing estimation for children in the current study. In addition, VRC01LS dosing 
considerations have been described for children in IMPAACT P1112 [43]. VRC01LS differs by 2 
amino acids from VRC01, and is expected to have a similar peak level with a longer half-life and 
improved concentration at mucosal surfaces. VRC01LS population PK parameters can be obtained 
from a PK analysis of study VRC606 [45] to generate a typical profile for a two-year-old given 
VRC01LS 30mg/kg loading dose IV followed by two maintenance doses of 10mg/kg (Figure 2).  
  


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Figure 2: VRC01LS Simulations - 2 year old 
0
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VRC01LS Conc (mcg/mL)
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Conc: concentration; SS: steady state 
 
Following administration of the 30mg/kg loading dose, the Cmax and troughs are not expected to 
accumulate much with repeat 10 mg/kg dosing, with the expected steady-state trough concentrations 
with 10mg/kg IV greater than 400 µg/mL. We expect significantly higher initial VRC01LS 
concentrations than will be seen in infants from P1112 (40mg/kg SC), due to the lower slow and 
incomplete absorption following SC administration but the Cmax with 10mg/kg every 4 weeks is still 
expected to be below the Cmax of ~2200 µg/mL seen after 40mg/kg IV from VRC606 in 
adults.  Additional data from P1112 is expected in 2018, and may be used to guide dosing further if 
needed. 
 
The impact of weight on bNAb exposure metrics (Ctrough, Cmax, Cave) is modest over the range of 
participant weights expected in the proposed study (Figure 3). Differences in exposure metrics at the 
weight extremes are about 20% or less for VRC01LS. The VRC01LS Cmax modeled after the first dose 
(30mg/kg) is greater than at steady-state on 10mg/kg q4 weeks, but within the range seen in adults. 
Therefore, no stratification of dose, based on age or weight, is necessary for the current study. 
 
 
 
 
 
 
 
 
 
 


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                        December 20, 2018 
 
Page 22 of 75 
 
Figure 3: VRC01LS Troughs, Cmax, and Cave by Body Weight 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.1.8.1.1. Pharmacokinetic Targets for VRC01LS 
 
The VRC01LS target, 3rd dose trough (C84D), is derived from the multiple-dose PK results from adults 
in VRC606 incorporating expected PK differences due to age and weight in the study population [45, 
50, 51]. Adult trough concentrations following multiple doses of 20mg/kg every 12 weeks are 150-300 
mcg/mL and predicted adult average steady-state concentrations are 400-550 mcg/mL. The target for 
acceptable C84D trough concentrations for this study corresponds to achieving C84D that are greater 
than adults following 20mg/kg IV every 12 weeks and which also corresponds to the majority of 
subjects having average VRC01LS concentrations at or slightly above those seen in the adults.  The 
pediatric dose of 10mg/kg every 4 weeks is predicted to achieve similar average steady-state 
concentrations to adults (20mg/kg every 12 weeks) of about 500-650 mcg/mL. With more frequent 
every-4-week dosing, pediatric peak-trough fluctuation will be reduced.  Thus steady-state troughs are 
expected to be 50% higher and Cmaxs lower than adults receiving VRC01LS 20mg/kg every 12 weeks. 
With VRC01LS’s very long half-life, it would take at least 6 months of “maintenance” dosing to reach 
steady-state and steady-state will not be achieved in the PK Step of this study. Therefore, VRC01LS 
will be initiated as a loading dose of 30mg/kg IV followed by 10mg/kg IV every 4 weeks to rapidly 
achieve concentrations near predicted steady-state.  The VRC01LS concentration 28 days after the 
third dose (second 10mg/kg dose), C84D, will be used to assess adequacy of the dosing regimen. 
Specifically, if the median C84D VRC01LS concentration is above 200 mcg/mL (~80% of the 
predicted adult steady-state trough), then VRC01LS dosing will be deemed adequate from a PK 
perspective. 
 
 
2.1.8.2. PK Considerations for 10-1074.  
10-1074 has an average IC50 of 0.37 mcg/ml among 182 sensitive strains tested. For 10-1074, target 
plasma levels for this study are based on adult data presented by Caskey et al. [23]. This open-label 
phase 1 clinical trial was performed among 14 HIV-uninfected and 19 HIV-infected individuals who 
received a single IV infusion of 10-1074 at doses of 3, 10 or 30 mg/kg. 10-1074 serum levels were 
0
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VRC01LS Troughs - Mean + SD (mgc/mL)
Predicted VRC01LS Steady-State Troughs
Every 4 Wk (Pediatric) vs. 12 Wk (Adult) Dosing
Pediatric
10mg/kg q 4wk
Adult
10mg/kg q 12wk
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Every 4 Wk (Pediatric) vs 12 Wk (Adult) Dosing
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10mg/kg q 12wk
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First Dose (30mg/kg) vs Steady-State at 10mg/kg q 4 Wk
Pediatric
Dose 1 30mg/kg
Pediatric
SS on 10mg/kg q 4 Wk
Adult
SS 20mg/kg q 12 Wk
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VRC01LS Cave - Mean + SD  (mcg/mL)
Predicted VRC01LS Steady-State Cave
Every 4 Wk (Pediatric) vs. 12 Wk (Adult) Dosing
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10mg/kg q 4wk
Adult
10mg/kg q 12wk
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20mg/kg q 12wk
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                        December 20, 2018 
 
Page 23 of 75 
 
determined by TZM.bl neutralization assay, and the dose of 30 mg/kg was associated with the 
maximal drop in HIV RNA of 1.52 log copies/mL. Viral nadir was reached at an average of 10.3 days 
(range 7-25 days). Serum half-life of 10-1074 was significantly different for individuals with and 
without HIV-1: for HIV-infected viremic participants, the half-life was 12.8 days, and for HIV-uninfected 
participants it was 24 days. It is expected that HIV-infected participants with complete HIV RNA 
suppression such as the children eligible for the proposed study will have serum half-life similar to 
those who are HIV-uninfected, and therefore dosing considerations for this study are based on the 
longer reported half-life of 24 days (and will also be evaluated in detail). It is also notable that pre-
established mutations at V3-loop positions were associated with more rapid viral rebound, and that 
individuals lacking such mutations had longer time until rebound and low concentrations of 10-1074 
(as low as 6.5µg/mL) at the time of rebound. Children in our proposed study do not have evidence of 
V3 loop mutations in archived virus, in sequencing performed to date (M. Lichterfeld, unpublished 
data, 2018). 
Based on the data from Caskey et al., using extracted raw 10-1074 concentration data from the 
supplement files allows a population- PK analysis. This analysis reveals a similar elimination half-life 
to the published values from the non-compartmental analysis, with more rapid elimination in HIV-
infected than HIV-uninfected subjects and a modest dose effect on elimination. In addition, this model 
can generate predicted profiles based on the proposed dosing regimen using a 2-year-old, 12.5 kg 
subject for the simulations, incorporating allometric scaling for size effects on PK parameters. This 
modeling is shown in Figure 4. 
Figure 4: 10-1074 Simulations - 2 year old 
0
4
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Time (weeks)
10
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Median 10-1074 Conc (mcg/mL)
y
10-1074 HIV+
30mg/kg
10-1074 HIV-
30 mg/kg
 
Assuming no PK change with repeat dosing, the typical troughs after 2 doses in HIV-infected viremic 
subjects are ~30 µg/mL while those in HIV-uninfected are slightly over 100 µg/mL. Slight 
accumulation is expected after the second dose but the PK after 2 doses will be near steady-state.    


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                        December 20, 2018 
 
Page 24 of 75 
 
The impact of weight on bNAb exposure metrics (Ctrough, Cmax, Cave) are modest over the range of 
participant weights expected in the proposed study (Figure 5).  Differences in exposure metrics at the 
weight extremes are about 30% or less for 10-1074. The impact of body weight modeled is greater for 
10-1074 than VRC01LS and most pronounced on Ctrough, as expected due to the shorter t1/2 for 10-
1074. However, expected bNAb exposure metrics are within the range of those seen or currently 
being studied in adults. Therefore, no stratification of dose, based on age or weight, is necessary for 
the current study. 
 
Figure 5: 10-1074 Troughs, Cmax, and Cave by body weight  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.1.8.2.1 Pharmacokinetic Targets for 10-1074 
 
The 10-1074 target for this study will also be based on the trough after the 3rd dose, C84D.  Based on 
analysis of the PK data from Caskey et al., the expected average concentrations in HIV infected 
adults with 30mg/kg at steady-state are 150-300 mcg/mL. Single doses of 30 mg/kg and 10 mg/kg in 
adults exhibited good safety and short-term virologic activity–greater than 1 log HIVRNA reduction.  
Using a 30 mg/kg dose in young children is expected to be safe and result in 10-1074 concentrations 
that are about 25% lower than in adults. However, the pediatric concentrations are still expected to 
exceed those seen in adults following 10mg/kg by several fold. Since 10-1074 has a much shorter 
half-life than VRC01LS, no “loading” dose is needed to accelerate achievement of steady-state 
concentrations. Based on safety and tolerability following 30mg/kg in adults, 30mg/kg will be the 
pediatric dosage used in the current study. Pediatric 10-1074 third dose troughs, C84D, with this 
dosage are anticipated to be lower at steady-state than expected in adults on 30mg/kg but higher than 
in adults on 10mg/kg. Therefore, the acceptable target for C84D 10-1074 in this study will be a 
median that exceeds that expected from 10mg/kg in adults (7.5mcg/mL). The pediatric 30mg/kg dose 
is expected to result in nearly all of the participants maintaining trough concentrations above the 
target of 7.5 mcg/mL. 
0
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Weight (kg)
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10-1074 Troughs -Mean + SD (mcg/mL)
Predicted 10-1074 Steady-State Troughs with q 4 Wk Dosing
Pediatric 30mg/kg
HIV (-)
Pediatric 30mg/kg
HIV (+) viremic
Adult 30mg/kg
HIV (-)
Adult 30mg/kg
HIV (+) viremic
Adult 10mg/kg
HIV (-)
Adult 10mg/kg
HIV (+) viremic
0
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10-1074 Cmax - Mean + SD (mcg/mL)
Predicted 10-1074 Steady-State Cmax with q 4 Wk Dosing
Pediatric 30mg/kg
HIV (-)
Pediatric 30mg/kg
HIV (+) viremic
Adult 30mg/kg
HIV (-)
Adult 30mg/kg
HIV (+) viremic
Adult 10mg/kg
HIV (-)
Adult 10mg/kg
HIV (+) viremic
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10-1074 Cave - Mean + SD  (mcg/mL)
Predicted 10-1074 Steady-State Cave with q 4 Wk Dosing
Pediatric 30mg/kg
HIV (-)
Pediatric 30mg/kg
HIV (+) viremic
Adult 30mg/kg
HIV (-)
Adult 30mg/kg
HIV (+) viremic
Adult 10mg/kg
HIV (-)
Adult 10mg/kg
HIV (+) viremic


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                        December 20, 2018 
 
Page 25 of 75 
 
2.1.8.3. Co-administration. Regarding PK considerations for the co-administration of VRC01LS and 
10-1074 (in a serial manner), animal data and initial human data suggest no PK concerns when using 
dual bNAbs. In data recently presented by Cohen et al. at CROI 2018 [50], PK results for the 
combination of 10-1074 and 3BNC117 were nearly identical to those found when each product was 
administered alone. This combination closely resembles our combination of 10-1074 with VRC01LS, 
and provides good assurance that no dosing adjustments will be required when using combination 
therapy. Step 1 of our study will also closely evaluate for any PK changes with dual bNAb 
administration in the first 6 participants who receive dual bNAb treatment. Despite the low suspicion 
that dual bNAb administration will alter PK parameters, the study team and SMC will evaluate for 
changes from the pre-specified PK targets (as listed above) for both VRC01LS and 10-1074 in these 
6 participants to make a decision regarding further enrollment into Step 1 and starting Step 2. Trough 
PK values will be collected in all subsequent participants and will be stored for later analysis. 
2.2. Rationale 
 
2.2.1. Proof of Concept: The EIT cohort provides an ideal low-reservoir pediatric population in which 
to test whether viral suppression can be maintained for up to 24 weeks with dual bNAb therapy. 
Children in this cohort will have received at least 96 weeks of ART from very early in life, and will 
receive 8 weeks of overlapping ART plus VRC01LS/10-1074 prior to stopping ART for up to 24 
weeks. Our design is practical in its approach, aiming to demonstrate as a proof-of concept that in a 
low-reservoir pediatric population dual bNAb therapy alone may be sufficient to maintain viral 
suppression for 24 weeks. If at least 30% of participants remain virally suppressed after 6 months of 
dual bNAb treatment following ART cessation, this will be a significant difference from prior cohorts 
such as the CHER Study where <6% of children treated in the first year of life remained virally 
suppressed by 6 months off ART in the absence of an intervention [52]. Our study design also allows 
for detailed study of viral reservoir changes as measured in blood samples during the addition of 
bNAbs to ART and following transition to bNAb maintenance; it accounts for ethical concerns by 
offering all participants a potentially effective intervention in a highly controlled manner to maintain 
viral suppression, while still ensuring interpretable study endpoints; and it is affordable and efficient 
because of the existing EIT study cohort. 
 
2.2.2. Characterizing the Impact of VRC01LS and 10-1074 on the Infant Virologic Reservoir: We 
will apply state-of-the art virologic studies to quantify and characterize the viral reservoir in study 
participants; blood samples. These assays include quantitative digital droplet PCR (ddPCR) 
measurement of integrated (proviral) HIV-1 DNA, cell-associated HIV-1 RNA, and plasma HIV-1 RNA 
measured by a highly sensitive single-copy assay [53]. In addition, we will quantify the number of 
intact proviruses by use of a novel single-genome amplification strategy that combines limiting dilution 
PCR of near-full-length genomes with next-gen (Illumina) sequencing of the clonal amplicons. This 
approach will allow us to identify phylogenetic associations between viral sequences longitudinally 
collected during the proposed study, and is highly informative for characterizing viral sequence 
evolution and escape mutations in response to bNabs, autologous cellular immune responses or 
antiretroviral agents. In addition, this assay is more feasible than performing virus outgrowth assays 
for identifying genome-intact and replication-competent virus, given limitations on blood volume that 
can be obtained from young children, and helps to track clonal expansion of virally infected cells 
based on complete sequence identity of viral DNA products generated from discrete cells.   
 
2.2.3. Unique Opportunity for Immunologic Evaluation: A major innovative component of this 
study is the ability to evaluate immunomodulatory effects of bNAbs on innate and adaptive immune 
responses in a group of pediatric HIV-1 patients specifically selected to have minimal residual viral 
reservoirs. So far, investigations of immune effects mediated by bNAbs have been restricted to animal 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 26 of 75 
 
models or adult HIV-1 patients [36, 37]. While these studies suggested that bNAbs may be able to 
affect the breadth, magnitude and potency of antiviral humoral and cellular immune responses, 
immunological effects of bNAbs in the context of a developing immune system in children, specifically 
in those with an extremely low reservoir of virally infected cells, at present remain entirely unknown. 
We hypothesize that controlled exposure to low-level viremia during bNAb treatment (in the absence 
of ART) will support the evolution of highly functional autologous antiviral immune responses that 
may, in conjunction with direct antiviral effects of the bNAbs, allow for viral control to be maintained for 
a prolonged time period off conventional ART. In addition, our studies will, for the first time in pediatric 
patients, allow for detailed profiling of associations between antiviral immune responses and the size 
and cellular composition of viral reservoir cells in the setting of bNAb treatment. 
 
2.3. Study Hypotheses 
 
2.3.1. Specific Aim 1: VRC01LS and 10-1074 will not be associated with serious adverse events, 
and median trough concentrations at the doses used will be above established target values of 200 
mcg/mL and 7.5 mcg/mL respectively. At least 70% of early-treated low-reservoir children will remain 
with HIV-1 RNA <400 copies/mL after 24 weeks of receiving VRC01LS and 10-1074 maintenance.  
 
2.3.2. Specific Aim 2: Measurable decline in viral reservoir as measured in blood samples will occur 
in some children with the addition of dual bNAb therapy to ART. Viral reservoir size prior to receiving 
ART and prior to receiving VRC01LS and 10-1074, as determined by cell associated HIV-1 DNA and 
other assays, is inversely correlated to viral rebound kinetics (if rebound occurs on bNAb 
maintenance). If present, viral rebound will not exceed 1,000 copies/mL prior to re-initiation of ART 
(and acute retroviral syndrome will not occur). Delayed HIV-1 RNA and DNA suppression patterns in 
early life will correlate with viral rebound during the ATI. Baseline HIV from most children will be 
sensitive to VRC01LS and 10-1074, and a decrease in sensitivity will be detectable among children 
who experience viral rebound. 
 
2.3.3. Specific Aim 3: The breadth of humoral immune responses to HIV-infection will increase 
following VRC01LS and 10-1074 use. Markers of cellular immune activation may increase on bNAb 
maintenance. Cell-mediated immune responses to HIV-1 will be preferentially detectable among 
children with viral rebound. 
 
3. PRIMARY OBJECTIVES 
 
Specific Aim 1: To conduct an interventional clinical trial to determine the safety, 
pharmacokinetics, dosing and antiviral efficacy of up to 24 weeks of maintenance VRC01LS 
and 10-1074 immunotherapy in early-treated HIV-1 infected children in Botswana. This 
uncontrolled, open-label clinical trial will be conducted at two sites in Botswana, using established 
clinical research infrastructure provided by the Botswana-Harvard Partnership (BHP). The primary 
endpoints of this study will be the frequency and severity of treatment-associated serious adverse 
events, and the proportion of children who maintain HIV-1 plasma RNA <400 copies/mL (and <40 
copies/mL) 32 weeks after initiating dual bNAb treatment (24 weeks after withdrawal of standard 
ART). Secondary endpoints will include pharmacokinetic profiles of all children who receive VRC01LS 
and 10-1074 and growth characteristics of virally suppressed children receiving bNAbs.  
 
Specific Aim 2: To evaluate effects of treatment with VRC01LS and 10-1074 on the size and 
cellular composition of residual viral reservoirs. Viral reservoirs during treatment with bNAbs will 
be evaluated in blood samples using a novel single-template, near full-length viral sequencing assay 


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that provides information on the complete spectrum of HIV-1 DNA copies integrated into host 
chromosomes. This approach will allow for evaluation of defective vs. intact HIV-1 genomes, 
antiretroviral drug and CTL escape variants and longitudinal viral sequence evolution in total CD4 T 
cells as well as in phenotypically-complex subsets of CD4 T cells known to be critical for viral 
reservoir stabilization. Cell-associated HIV-1 RNA and plasma RNA will be simultaneously analyzed 
and sequenced. Viral reservoir parameters will be correlated to viral rebound kinetics during ATI, to 
pharmacokinetic measurements of VRC01LS and 10-1074, and to antiviral immune parameters 
determined in Specific Aim 3. 
 
Specific Aim 3: To investigate the influence of VRC01LS and 10-1074 treatment on the 
magnitude and quality of antiviral innate and adaptive immune responses. Data from clinical 
trials in HIV-1-infected adults show that bNAbs can profoundly influence autologous HIV-1 immune 
responses. We will use comprehensive phenotypic and functional assays to profile effects of bNAb 
treatment on biomarkers of immune activation and on innate cellular immune responses, coupled with 
RNA-Seq-based gene expression studies in selected immune cell subsets. In addition, the evolution 
of neutralizing antibody breadth and the frequency and functionality of HIV-1-specific T cells will be 
analyzed, and combined with viral sequencing data (generated in Specific Aim 2) to identify viral 
immune escape.  
 
4. STUDY DESIGN 
 
PK Step 
 
The first 12 participants in the study will undergo the PK Step, to allow for detailed safety and PK 
assessment of each bNAb alone. In the PK Step, while continuing ART, participants 1, 3, 5, 7, 9, 11 
will receive VRC01LS at Week 0, Week 4, and Week 8 as a single intravenous (IV) dose (30 mg/kg 
load, then 10mg/kg maintenance); safety and PK measurements will occur at end of infusion, 1 hour 
post-infusion, 1 day post-infusion, 1 week post-infusion, 2 weeks post-infusion, and 4 weeks post-
infusion. Participants 2, 4, 6, 8, 10, 12 will receive 10-1074 at Week 0, Week 4, and Week 8 as a 
single IV dose (30mg/kg), and safety and PK measurements will also occur at end of infusion, 1 hour 
post-infusion, 1 day post-infusion, 1 week post-infusion, 2 weeks post-infusion, and 4 weeks post-
infusion. In the PK Step, it is anticipated that all 12 participants will be from the EIT Study; however, in 
the event that 12 participants from EIT are not available at the time the PK Step begins, participants 
9-12 may be recruited from other virally suppressed HIV-infected children. These additional, non-EIT 
children would not be eligible for further study steps after completing the PK Step. In the event that a 
participant discontinues bNAb during the PK Step, the participant may be replaced to allow for PK 
data to be obtained from 12 participants total. 
 
SMC Review of Safety and PK Data from PK Step 
 
After all 12 PK Step participants complete the PK Step, safety, PK, and viral suppression data will be 
reviewed within 8 weeks by the study team, sponsor, and SMC (earlier review by the SMC may be 
triggered based on pre-specified safety parameters). All PK data from the PK Step will be assessed 
based on pre-specified PK trough targets; peak values will be assessed, but primary guidance for 
peak values will be based on toxicity. The study team will determine if median trough concentrations 
are above the pre-specified targets (see Section 2.1.8), and present this information in a written report 
to the SMC. In addition, outlier concentrations will be presented and reviewed; the study team expects 
no more than 2 participants to have trough concentrations below 115 mcg/mL for VRC01LS and no 
more than 2 participants to have trough concentrations below 5mcg/mL for 10-1074. The SMC and 


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the study team will review any cases of outlier PK concentrations and make individual 
recommendations about whether a child with these levels should proceed to Steps 1-3. The SMC will 
review safety data utilizing pre-defined safety criteria defined in the protocol (see Section 13.8). If 
safety criteria are met, and if the PK data are in the pre-specified range, approval to begin Step 1 may 
be granted by the SMC. If the dosing and frequency of bNAbs established in the PK Step is 
acceptable, it will continue to be used for the first 6 participants in Step 1 (see additional safety review 
below). If a change in dosing is recommended by experts on the study team (or by the SMC, if it does 
not accept the team’s recommendation), adjustments will occur and IRB and study sponsor approval 
will be sought regarding required protocol changes prior to starting Step 1. The recommendations by 
the study team or by the SMC may include early termination of the study, if warranted by the 
safety/PK data, or a re-design of the study as approved by the study sponsors and regulatory boards. 
 
Step 1 (first 6 participants)  
 
All Step 1-3 participants must be from the EIT Study. After approval, Step 1 will begin for a maximum 
of 6 participants, all of whom will have participated in the PK Step (3 from each PK Step group), and 
all of whom will have been >12 weeks from last bNAb dosing. ART is continued throughout Step 1, 
and all participants receive both 10-1074 and VRC01LS. If dosing recommendations do not change 
based on the PK Step, a VRC01LS loading dose of 30 mg/kg will be given at the start of Step 1, 
followed by 10mg/kg dosing at each 4-weekly visit, and 10-1074 dosing will be at 30mg/kg at each 4-
weekly visit. At Week 0, Week 4, and Week 8 doses of Step 1, PK testing for both bNAbs will occur 
prior to infusion, and at Weeks 0 and 4 only at end of infusion, 1 hour post-infusion, 1 day post-
infusion, and 1 week post-infusion. HIV-1 RNA will be checked every 4 weeks in Step 1. The first 6 
participants in Step 1 will continue in this Step, receiving both oral ART and dual bNAb infusions, until 
the second study team/SMC review occurs. This review of safety and PK data will occur within 8 
weeks of the 6th participant’s Week 8 PK sampling.  
 
SMC Review of Safety and PK Data from Step 1 (first 6 participants) 
 
Safety, PK, and viral suppression data for the first 6 Step 1 participants will be reviewed within 8 
weeks by the study team, sponsor, and SMC. All PK data will be assessed by the study team based 
on pre-specified PK trough targets which are the same as those used in the PK Step. The review will 
confirm that PK targets are met during dual bNAb administration. Safety criteria for the Step 1 data 
will be reviewed by the SMC, using similar criteria as for the PK Step (see Section 13.8). If safety 
criteria are met, and if the PK data for both bNAbs are in the pre-specified range, the SMC may 
approve entry into Step 2 for the first 6 participants and enrollment of additional participants into Step 
1. If the PK data are in range and no dosing changes for the bNAbs are required, the dosing will 
continue to be used for the remainder of the study unless new data emerges requiring additional 
review. If a change in dosing is recommended by experts on the study team (or by the SMC, if it does 
not accept the team’s recommendation), IRB and study sponsor approval will be sought regarding 
required protocol changes. The recommendations by the study team or by the SMC may include early 
termination of the study, if warranted by the safety/PK data, or a re-design of the study as approved 
by the study sponsors and regulatory boards. 
 
Step 1 (all subsequent participants) 
 
After approval to proceed is obtained by the SMC, additional participants will enroll directly into Step 1 
and receive dual bNAbs and ART for 8 weeks. All study visits and follow-up will be the same as for 
the first 6 Step 1 participants, with the exception of PK testing; only trough PK testing will be required 
for these participants, beginning at Week 4 of Step 1. 
 


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Step 2 (all participants) 
 
Following a successful Step 1 review, Step 2 may begin. Step 2 will begin after a participant has spent 
at least 8 weeks in Step 1. For the first 6 participants, Step 2 will begin at a scheduled bNAb dosing 
visit (i.e. 4 weeks from last Step 1 bNAb dosing), and for all subsequent participants it will begin at the 
8 Week visit date for Step 1 (which becomes the Week 0 Step 2 visit). Participants with ongoing viral 
suppression throughout Step 1 will undergo withdrawal of ART and will continue maintenance 10-
1074 (30mg/kg) and VRC01LS (10mg/kg) treatment for up to 24 weeks in Step 2. HIV-1 RNA will be 
checked weekly from Weeks 1-4 in Step 2, and every 2 weeks thereafter. Qualitative HIV DNA will be 
checked at each visit by DBS. If a participant experiences a single viral rebound >400 copies/mL in 
Step 2, ART will be re-started (and VRC01LS and 10-1074 will be discontinued). A single viral 
rebound is defined as an HIV RNA result ≥400 copies/mL at any Step 2 visit, without need for 
confirmation. If HIV RNA becomes ≥400 copies/mL prior to the end of Step 2, all evaluations ordinarily 
scheduled at “Week 24” will be performed immediately prior to ART re-initiation. If HIV-1 RNA is ≥40 
copies/mL but <400 copies/mL, or if Qualitative DNA turns from negative to positive, virologic 
monitoring tests will be repeated weekly. Clinical examination will occur at each study visit.  
 
Step 3 (all participants) 
 
All participants will end Step 2 after 24 weeks, and enter Step 3. In Step 3, both 10-1074 and 
VRC01LS will be discontinued, and ART will be re-started. Follow-up visits in Step 3 will occur at 4, 
12, and 24 weeks.     
 
5. STUDY SITES AND STUDY POPULATION 
 
5.1. Clinical Sites 
  
This protocol will be implemented at two NIAID-approved BHP clinical research sites in Botswana: 
Gaborone (CRS #31833) and Francistown (CRS #31891). The Botswana-Harvard School of Public 
Health AIDS Initiative Partnership (BHP) was established in 1996 as a signed agreement between the 
Ministry of Health (MOH) of Botswana and the Harvard School of Public Health AIDS Initiative. BHP 
now maintains one of the largest research laboratories for HIV/AIDS-related work in Africa. Multiple 
studies enrolling more than 7,000 participants have been conducted at BHP, including HIV vaccine, 
prevention of mother-to-child transmission (PMTCT), ART trials (Phase I through Phase III), as well as 
observational studies; most of these studies have been NIH-funded. In 2006, BHP was selected as a 
Division of AIDS (DAIDS) “Clinical Trials Unit” (CTU) for the AIDS Clinical Trials Group (ACTG) and 
the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) group, and has 
enrolled to three studies of the HIV Prevention Trials Network (HPTN). BHP works in close 
collaboration with the MOH in the conduct of clinical trials.  
 
5.2. Laboratory Sites  
Laboratory techniques will be performed according to the most current approved protocols at each 
reference laboratory. 


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5.2.1. Botswana  
 
Testing of samples collected at Gaborone: 
 
HIV DNA PCR, hematology, chemistries, CD4+ cell counts, HIV-1 RNA measurements, and 
plasma/cell separation will be carried out at the Botswana-Harvard HIV Reference Laboratory 
(BHHRL), adjacent to Princess Marina Hospital in Gaborone.  
 
Testing of samples collected at Francistown: 
 
Samples will be processed at the National HIV Reference Laboratory in Francistown and either 
shipped to BHHRL in real-time, or run in real-time in Francistown, or stored at -70ºC for later 
shipment to BHHRL.  
 
Testing of samples at collaborating institutions: 
 
Samples may occasionally be sent between BHP sites or to designated DAIDS-approved back-up 
laboratory sites. For assays that cannot be performed at BHHRL, samples from Gaborone and 
Francistown will be processed and stored at -70ºC and later shipped to either Brigham and Women’s 
Hospital in Boston, Massachusetts General Hospital / Ragon Institute in Boston, or to another 
designated facility for specialized testing. PK and anti-drug antibody (ADA) testing will be performed 
at the Vaccine Research Center in Bethesda, Maryland, at Duke University in Durham, North 
Carolina, and at Dartmouth University in Hanover, New Hampshire.  
 
5.2.2. Brigham and Women’s Hospital, Boston: The Kuritzkes Laboratory at Brigham and 
Women’s Hospital is a research and diagnostic virology laboratory. The laboratory conforms to 
Good Laboratory Practices for the performance of research assays applied to samples from 
clinical trials.  
 
5.2.3. Massachusetts General Hospital / Ragon Institute, Boston: The Ragon Institute at 
Massachusetts General Hospital (MGH), Massachusetts Institute of Technology (MIT) and 
Harvard is located in Cambridge, MA. The Center includes laboratory-based clinical investigators, 
clinic-based clinical researchers, and fellows who are conducting research in HIV virology, 
immunology, vaccine development, antiviral drug resistance, antiviral therapy, opportunistic 
infections, immunotherapy, AIDS-related malignancies and HIV epidemiology. There are several 
BL2+ containment rooms with a total of 80 laminar flow hoods and a vantage FACS cell sorter in 
large FLOW Cytometry CORE facility. There are adequate hoods, incubators, freezers, 
centrifuges, and other equipment necessary to conduct work with HIV positive specimens and to 
grow viral stocks and perform work on BL2+ level. To assess HIV-1 specific neutralizing antibody 
responses, additional immunologic testing of the samples shipped to MGH will be performed by 
the laboratory of Dr. Michael Seaman at Beth Israel Deaconess Medical Center in Boston. 
 
5.2.4. PK Testing and ADA Testing for VRC01LS and 10-1074  
5.2.4.1. Vaccine Research Center at NIH will perform PK testing and ADA testing for the VRC01LS. 
VRC01LS concentration in participant plasma samples will be quantified using the murine anti-VRC01 
monoclonal antibody 5C9 as previously described [30]. Quantification of VRC01LS concentrations will 
be performed in 96-well plates on a Beckman Biomek-based automation platform (Beckman Coulter, 
Brea, CA, USA) utilizing the monoclonal antibody 5C9 for VRC01LS detection. If PK testing is 
required to confirm low/undetectable levels of standard ART during Step 2, it will be requested for 
selected specimens based on clinical responses, using the existing PK specimens sent to VRC. 


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5.2.4.2. The lab of Georgia Tomaras at Duke University will perform the PK testing for the 10-1074. 
Levels of 10-1074 will be determined by a validated sandwich ELISA, as previously described [54]. 
The serum concentration of 10-1074 will be calculated from the standard curve of 10-1074 run on the 
same plate using a 5-PL curve fitting algorithm.  
5.2.4.3. The lab of Margaret Ackerman at Dartmouth University will perform the ADA testing for the 
10-1074. The Ackerman laboratory has developed high throughput tools to evaluate antibody 
response to aid in therapeutic antibody and vaccine design and development. The ADA 
characterization assays are performed using a tiered testing approach to identify and define ADA 
responses that may arise during clinical trials.  In short, drug products are conjugated with either biotin 
or a Sulfo-Tag label. Biotinylated and Sulfo-Tagged drug are then mixed with serum and if ADAs are 
present, they will act as a bridge between labeled forms of the drug. Biotinylated drug bridged to 
Sulfo-tagged drug can then be measured using the Meso Scale Diagnostics™ platform and a pre-
established cut-point can be used to define positivity (Tier 1). If a sample is Tier 1 positive, a 
competition assay (Tier 2) with free drug is used to determine if the interaction between the drug and 
sample components is specific according to a reduction threshold determined during assay 
development.  Finally, Tier 1 and Tier 2 positive samples will be titered to determine the relative 
magnitude of the ADA response.  
5.3. Potential Study Participants 
 
All participants receiving dual bNAb treatment will be recruited from the EIT Study. EIT is an ongoing 
NIAID-funded (U01AI114235) clinical trial of early infant diagnosis and treatment performed at BHP by 
the same investigative team (Multiple PIs Drs. Shapiro, Kuritzkes, and Lichterfeld). The study 
successfully launched in 2015, and has accrued 40 antepartum infected participants. In utero HIV 
infection has been identified in ~ 0.5% of infants screened at government maternity wards [55]. HIV-
infected infants are offered enrollment in the study, and ART is started within 7 days of life (usually 
within 48 hours) if antenatal infection is identified, or before 57 days of life if intrapartum infection is 
identified. ART is provided through the Botswana government, and the initial ART regimen is 
nevirapine (NVP)/zidovudine (ZDV)/ lamivudine (3TC) for infants <2 weeks/40 weeks gestational age 
equivalent; thereafter the regimen is changed to lopinavir/ritonavir/ZDV/3TC. The aims of the study 
are to demonstrate that ART with NVP, ZDV, and 3TC can be safely initiated very early in life after 
diagnosis of HIV infection and will result in rapid viral decay in most infants, and to evaluate virologic 
and immunologic outcomes of very early ART in infancy.  
 
A small number of children who are not enrolled in EIT may participate in the PK Step only of this 
study, if additional participants are needed to complete the PK step with 12 participants in a timely 
fashion. These children will go off-study after the PK Step and will not be eligible to participate in 
Steps 1-3. 
 
5.4. Inclusion / Exclusion Criteria  
 
We plan to enroll only children on long-term (for at least 96 weeks) suppressive ART initiated within 7 
days of birth (or those with peripartum infection who initiated ART within 57 days of life), i.e. EIT 
cohort participants, in Steps 1-3; non-EIT children may participate in the PK Step only. Specific criteria 
are as follows:  
 


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5.4.1. Inclusion Criteria  
 
Inclusion Criteria for PK Step*: 
1) On ART for at least 96 weeks 
2) > 96 weeks and <5 years of age at enrollment 
3) HIV RNA <40 copies/mL** for at least 24 weeks prior to entry 
4) Ability to remain in close study follow-up for at least 12 weeks 
5) Willingness to receive IV infusions of bNAbs 
6) Willingness to provide signed informed consent (by the parent/guardian) 
 
*It is anticipated that all children in PK Step will be from EIT Study; however, up to 4 HIV+ 
children outside the PK Study (age range 2-5 years) may participate in the PK Step if 
otherwise eligible and if EIT children are unavailable. 
** All EIT children have HIV RNA drawn at least every 12 weeks. For non-EIT children or in the 
event of missing values, minimum HIV RNA criteria include lack of known detectable HIV RNA 
≥40 copies/mL in past 36 weeks (note: viral suppression confirmed from tests with <400 
copies/mL as threshold does not constitute “known detectable HIV RNA”), plus documented 
suppression to <40 copies/mL within 4 weeks of PK Step entry.  
 
Inclusion Criteria for Entry into Step 1 (followed by participation in Steps 2-3): 
1) EIT Study participant 
2) On ART for at least 96 weeks 
3) ≥96 weeks and <5 years of age at enrollment 
4) HIV RNA <40 copies/mL for at least 24 weeks prior to entry** 
5) Ability to remain in close study follow-up for at least 56 weeks 
6) Willingness to receive IV infusions of bNAbs 
7) Willingness to provide signed informed consent (by the parent/guardian) 
 
** All EIT children have HIV RNA drawn at least every 12 weeks. In the event of missing 
values, minimum HIV RNA criteria include lack of known detectable HIV RNA ≥40 copies/mL 
in past 36 weeks, plus documented suppression to <40 copies/mL within 4 weeks of Step 1 
entry.  
 
5.4.2. Exclusion Criteria: 
 
1) Medical condition making survival for at least 32 weeks unlikely  
 
2) Active tuberculosis or malignancy 
 
3) Actively breastfeeding 
4) Previous receipt of VRC01/VRC01LS or 10-1074 (except during the PK Step) 
 
It is anticipated that this group of participants will have a limited viral reservoir, based on previous 
work showing that early infant treatment limits, but does not prevent, establishment of the HIV 
reservoir [56].  We hypothesize that a smaller viral reservoir in these children will improve the chances 
for maintaining viral suppression with dual bNAbs. We believe that adding additional inclusion criteria 
based on immunologic parameters or a lower HIV-1 RNA or DNA threshold may limit participation in 
the study without clear data suggesting that stricter parameters are required for a successful 
intervention. Stricter criteria, especially those based on non-standard tests available only in 
specialized laboratories, might unnecessarily restrict the applicability and interpretability of data 
generated from this intervention. In addition, preliminary data from the first 10 children in the EIT study 
suggest that similar low viral reservoir (median ~ 5 copies/million PBMCs) occurred at 84-96 weeks 
even among children with brief periods of viral rebound (BHP, unpublished data, 2018).  
 


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5.5. Recruitment Process 
 
Children who enrolled in the EIT study and have reached at least 96 weeks of life and meet entry 
criteria are eligible for the intervention (and 4 additional children outside of the EIT Study may be 
eligible for the PK Step only). All children enrolled in the EIT Study will be eligible for screening for the 
proposed intervention after 84 weeks of ART (and may enter the intervention at or after 96 weeks of 
ART). Screening evaluation and testing will be performed as part of the routine visits in the EIT Study. 
By definition, all participants in the EIT Study meet certain baseline criteria to be part of the EIT Study. 
For in utero infected children, this includes being HIV DNA PCR positive within 96 hours of life and 
starting ART before 7 days of life. For intrapartum infected children, it includes being HIV DNA PCR 
negative by 96 hours of life, but HIV positive and on ART before 57 days of life.  
 
To allow for careful monitoring of participant safety, no more than two children will enroll per week for 
the entire study (regardless of site of enrollment). We anticipate that mothers/caregivers for almost all 
eligible children (90-100%) will choose to have their children participate in the intervention study. We 
anticipate this high acceptability based on their current engagement in the EIT study, the potential 
future benefits to HIV-infected children if the intervention is effective, and the interest expressed by 
mothers/caregivers in potential alternatives to daily ART dosing. We therefore anticipate a sample 
size of 20-36 EIT children for the intervention study (if 35-40 children are available at or after 96 
weeks from EIT, 0-5 mothers/caregivers decline, and 4-10 are ineligible). An additional 4 non-EIT 
children may participate in the PK Step in the event that fewer than 12 EIT children are immediately 
available for this study step at the time it is enrolling (i.e., if fewer than 12 EIT children have reached 
the 96 week eligibility window at the time the PK Step is enrolling, or if a greater number than 
anticipated are ineligible or do not consent). Thus, the total possible number of participants in all study 
steps is 36 if all PK Step participants are from EIT, but may be as high as 40 if 4 non-EIT participants 
are enrolled in the PK Step. 
 
To enroll non-EIT children in the PK Step, study staff will liaise with staff at local pediatric HIV clinics 
to identify potentially eligible children. The parent/guardian will be given information about the study, 
and if interested, study staff will meet with the parent/guardian to provide further education about the 
study and to obtain informed consent.  
 
5.6. Study Consent 
 
Consent will be obtained from the parent/guardian. Assent of the children involved in this study will not 
be sought because they are too young to be capable of providing assent. The protocol-specific 
consent forms describe the study products to be used and all aspects of protocol participation (See 
Section 15). Elements of informed consent are included as described in Title 45, CFR Part 46 and 
Title 21 CFR, Part 50, and in the International Conference on Harmonisation (ICH) E6, Good Clinical 
Practice: Consolidated Guidance 4.8. In addition to IRBs and all regulatory agencies with oversight of 
the study, a BHP Community Advisory Board will review the consent forms before they are finalized. 
This review will include issues of cultural competence, local language considerations, and the level of 
understandability.  
 
The consent process will begin at or after the 84-week EIT study visit at the EIT Study Clinic. 
Separate consent forms will be used for the PK Step and for the intervention study (Steps 1-3). EIT 
participants enrolled in the PK Step will remain in the EIT Study (EIT visits will be performed at the 
time of PK Step visits, if required). EIT participants enrolled in Steps 1-3 will permanently exit the EIT 
Study at the time of Step 1 entry. However, in all cases this will be a seamless transition for the 


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participants. Care will be provided by the same study team, and consent will be obtained to share all 
data and records as needed between the two studies.  
 
5.7. Reimbursement 
 
We will offer reimbursement for participant transport (or will provide patient transport), and 100-150 
Botswana Pula (approximately $11.00-16.50) per attended scheduled visit to compensate for 
participant time commitment. We will also offer reimbursement for unscheduled visits that are 
requested of the participant for follow-up tests. This compensation rate is slightly higher than other 
BHP studies because of the intensity of follow-up for each child, the need for a blood draw at most 
visits, the need for IV infusion, and because of the critical importance of maintaining close contact 
with each participant. 
 
5.8. Participant Retention, Missed Visits, Study Withdrawal 
 
We anticipate 100% of children enrolled will be retained in the cohort, as has been the case for the 
EIT Study. Resources will be devoted to cohort retention, transport provided as needed, and care 
providers will be compensated fairly for their time at a rate approved by the Botswana IRB. Most 
women who enroll infants in BHP studies have a cell phone number or a family member with a cell 
phone number. We will perform home visits if requested (for visits other than bNAb administration) 
and will perform calls and home visits for any missed study visit. If bNAb administration is not possible 
within a study visit window, ART will be re-started. Likewise, if a parent/guardian requests withdrawal 
from the intervention during the bNAb-only phase, ART will be re-started.  
 
6. STUDY PRODUCT AND INTERVENTIONS 
 
6.1. VRC01LS Description, Supply, and Storage 
 
VRC01LS is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody produced in a 
CHO cell line that binds to the CD4 binding site of gp120. The antibody was originally isolated from an 
adult infected with HIV-1 who maintained viral control without ART. Investigators at the Vaccine 
Research Center (VRC) isolated and screened memory B lymphocytes from peripheral blood 
mononuclear cells (PBMC) of HIV-1-infected donors to identify this antibody clone. VRC01 was found 
to neutralize more than 90% of genetically diverse heterologous strains of HIV-1 at a concentration of 
50 mcg/mL, and more than 70% at a concentration of 1 μg/mL. VRC01LS is modified by 2 amino 
acids to have longer half-life than VRC01.  
 
VRC01LS is manufactured under cGMP using a stably transfected CHO cell line, purified, and the 
drug product vials filled and labeled at the VRC, Vaccine Clinical Material Program operated by 
Leidos Biomedical Research, Inc., Frederick, MD. VRC01LS will be shipped from the NIAID Clinical 
Research Products Management Center (CRPMC). VRC01LS is a sterile, aqueous buffered solution 
filled into 10 or 3 mL single-dose glass vials. Each vial contains a volume of 6.25 ± 0.1 mL or 2.25 ± 
0.1 mL at a concentration of 100 ± 10 mg/mL VRC01LS in formulation buffer containing 25 mM 
Sodium Citrate, 50 mM Sodium Chloride, and 150 mM LArginine Hydrochloride at pH 5.8. 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 


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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.  
 
At the CRPMC, VRC01LS is to be stored in a freezer at -35⁰C to -15⁰C. In study site pharmacies, 
VRC01LS is to be stored in a freezer with a temperature range of -45°C to -10°C (-49°F to 14°F). 
Following thaw, VRC01LS vials 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. Product may not be stored in direct sunlight. If 
stored at 2°C to 8°C, vials must be equilibrated at 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.  
 
Sodium Chloride for Injection USP, 0.9% will be purchased by BHP pharmacists from pharmaceutical 
suppliers.  
 
Any empty vials, unused portion of entered vials, or unused IV solution that contains study product will 
be discarded in a biohazard containment bag and incinerated or autoclaved in accordance with 
institutional or pharmacy policy.  
 
6.2. 10-1074 Description, Supply, and Storage 
 
10-1074 is a recombinant, fully human IgG1 bNAb targeting the V3 loop and surrounding glycans on 
the HIV-1 envelope. It was cloned from a patient infected with HIV-1 clade A virus. 10-1074 is 
expressed in CHO cells and purified using standard methods.  
 
The 10-1074 to be used for this study was manufactured by Mass Bio under contract to the NIAID and 
will be provided for the study by DAIDS. 10-1074 will be shipped from the NIAID CRPMC. 10-1074 is 
supplied as single-use 20 mg/mL solution for IV injection in a 5ml volume of buffered solution 
composed of sodium phosphate, potassium phosphate, potassium chloride, sodium chloride and 
polysorbate 80 with a pH of 7.0. Sodium Chloride for Injection USP, 0.9% will be purchased by BHP 
pharmacists from pharmaceutical suppliers.  
 
Vials of 10-1074 must be stored or shipped at 2-8°C.  
 
Any empty vials, unused portion of entered vials, or unused IV solution that contains study product will 
be discarded in a biohazard containment bag and incinerated or autoclaved in accordance with 
institutional or pharmacy policy. 
 
6.3. Schedule of Intervention and Dosing 
 
The first 12 eligible and consenting participants will receive 3 doses of a single bNAb (participants 1, 
3, 5, 7, 9, 11 receive VRC01LS, and 2, 4, 6, 8, 10, 12 receive 10-1074); dosing for VRC01LS is 
30mg/kg load followed by 10mg/kg maintenance, and for 10-1074 30mg/kg. Oral ART will continue 
during the PK Step. For the PK Step, PK measurements will occur at end of infusion, 1 hour post-
infusion, 1 day post-infusion, 1 week post-infusion, 2 weeks post-infusion, and 4 weeks post-infusion 
(Table 1). Pre-infusion PK testing will also occur at Weeks 4 and 8. After the PK Step, monitoring will 
occur as outlined in 13.8.  
 
After approval is granted to begin Step 1, 6 of the first 12 PK Step participants will begin dual bNAb 
treatment per the dosing and follow-up schedule in Table 2. The first 6 Step 1 participants will include 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 36 of 75 
 
3 participants from each group in the PK Step; these participants may be the first 6 PK Step 
participants, but this is not required. These Step 1 participants will receive enhanced PK testing for 
both bNAbs at the Week 0 and Week 4 visits, with pre-infusion testing, testing at end of infusion, 1 
hour post-infusion, 1 day post-infusion and 1 week post-infusion (all other PK testing for these 
participants will be trough pre-dose testing). A review of the safety and PK data for the first 2 dual 
bNAb doses will occur for these 6 participants. While awaiting this review (see Section 13.8), all 6 
participants will remain in Step 1 per follow-up outlined in Table 2, with 4-weekly dual bNAb treatment 
and ongoing oral ART. Additional enrollments will not occur until approval is granted.  
 
After approval is granted from this second review, the first 6 Step 1 participants will enter Step 2 and 
discontinue ART, provided they have been in Step 1 for at least 8 weeks and have remained with viral 
suppression <40 copies/mL (Table 3). Additional participants will also enroll in Step 1 at this time 
(both those who previously participated in the PK Step, and new participants). These participants may 
also proceed to Step 2 and discontinue ART after 8 weeks in Step 1, if they remain with viral 
suppression <40 copies/mL. A participant who experiences a confirmed viral rebound ≥40 copies/mL 
in Step 1 will discontinue bNAbs, complete visit procedures equivalent to those outlined for Step 1 
Week 8, and enter Step 3.  
 
All participants in Step 2 will continue with monthly dual bNAb maintenance for up to 24 weeks. HIV-1 
RNA will be checked at least every 4 weeks while on ART in Step 1, and at every visit in Step 2 
(weekly from Weeks 0-4 of Step 2, and every 2 weeks from Week 6-24 of Step 2). Qualitative HIV 
DNA will be checked at each Step 2 and Step 3 visit by dried blood spot (DBS). Clinical examination 
will occur at each study visit, except for the 1-day post-infusion PK visits. If participants experience a 
single viral rebound >400 copies/mL in Step 2, ART will be re-started (and VRC01LS and 10-1074 will 
be discontinued) without need for confirmation. If HIV RNA becomes ≥400 copies/mL in Step 2 prior 
to the Week 24 visit, all “Week 24” evaluations will be performed immediately prior to ART re-initiation. 
If HIV-1 RNA is ≥40 copies/mL but <400 copies/mL, or if qualitative DNA turns from negative to 
positive, virologic monitoring tests will be repeated weekly. After 24 weeks in Step 2, or if HIV RNA 
≥400 copies/mL, participants will discontinue bNAbs, re-start ART and enter Step 3 (Table 3). 
Participants who enter Step 3 early due to viral rebound will have additional weekly visits until HIV 
RNA returns to <40 copies/mL. Routine Step 3 study visits will occur at weeks 4, 12, and 24.  
 
6.3.1. VRC01LS Dose Calculation Instructions: 
 
VRC01LS will be dosed at 30mg/kg at the first infusion visit, followed by 10mg/kg maintenance at 
subsequent infusion visits.  
 
Prior to preparation of the first infusion (enrollment and Step 1 entry visit), a new prescription for 
VRC01LS will be sent to the pharmacy. The prescription must contain the participant’s weight based 
upon the participant’s weight at the most recent visit where weight was measured. Subsequent visit 
weights (based upon the participant’s weight at the most recent visit where weight was measured) 
must be communicated to the pharmacy in writing prior to the day of the infusion visit. Any changes in 
weight of more than 10% (between the prior weight and the weight on the day of the infusion visit) will 
require an updated visit weight communication to the pharmacy in writing so that product can be 
prepared based on that weight change. 
 
6.3.2. 10-1074 Dose Calculation Instructions: 
 
10-1074 will be dosed at 30mg/kg. Prior to preparation of the first infusion (enrollment and Step 1 
entry visit), a new prescription for 10-1074 will be sent to the pharmacy. The prescription must contain 
the participant’s weight based upon the participant’s weight at the most recent visit where weight was 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 37 of 75 
 
measured. Subsequent visit weights (based upon the participant’s weight at the most recent visit 
where weight was measured) must be communicated to the pharmacy in writing prior to the day of the 
infusion visit. Any changes in weight of more than 10% (between the prior weight and the weight on 
the day of the infusion visit) will require an updated visit weight communication to the pharmacy in 
writing so that product can be prepared based on that weight change. 
 
6.4. Preparation of Study Product Intravenous (IV) Solution  
 
IV infusion will be used for this study because the product formulations and volumes required for 
children over ~ 10 kg are not practical for subcutaneous (SC) injection.  
 
6.4.1. Preparation of VRC01LS IV Solution: To prepare VRC01LS IV infusion, the pharmacist will 
calculate the weight-based dose as in section 6.3.1 and remove the total number of vials needed as 
well as a 100 mL IV bag of Sodium Chloride for Injection USP, 0.9% from storage. The pharmacist, 
using aseptic technique, will add the appropriate amount of VRC01LS to the 100 mL IV bag of Sodium 
Chloride for Injection USP, 0.9%. Typically 50–100mL of additional volume may be added to a 100mL 
bag of normal saline. Each pharmacist should test the capacity of the brand of saline bags that will be 
used at the site to confirm the capacity to add additional volume. The pharmacist will label the infusion 
bag including a Beyond Use Date and time. 
 
VRC01LS is a highly concentrated protein solution and may develop white, opaque to translucent 
particles after thawing. When particles are observed, they may disappear after a few hours at room 
temperature or storage at 2°C to 8°C. 
 
The following instructions apply to thawing VRC01LS vialed product:  
1. Thaw vials for a minimum of 1 hour at controlled room temperature (maximum 27°C) after removing 
from freezer.  
 
2. Keep the material at controlled room temperature (maximum 27°C) during the entire preparation 
period, up to the maximum storage times described in the Section 6.1.  
 
3. Prior to preparation for administration, vials should be swirled for 30 seconds with sufficient force to 
resuspend any visible particles, yet avoiding foaming. DO NOT SHAKE THE VIALS. If particles are 
observed, return the vials to 2°C to 8°C storage. If the particles redissolve within the maximum 
storage times described in Section 6.1, the vials may be used for product preparation. If particles 
continue to be observed, do not use the vialed product for IV administration. Refrigerated 
product must be equilibrated at controlled room temperature (maximum 27°C) for a minimum of 30 
minutes before preparation and must be used within 8 hours of any subsequent return to room 
temperature.  
 
4. If the thawed material is not administered within 24 hours of thaw, follow the storage information 
provided in Section 6.1.  
 
The following instructions apply to VRC01LS Prepared Product (IV Bag and Syringe): 
After product preparation in IV bags, the prepared VRC01LS may be stored at 2°C to 8°C up to 24 
hours or at room temperature (maximum 30°C) for a maximum of 8 hours total including the infusion 
time. Product may not be stored in direct sunlight. If stored at 2°C to 8°C, prepared product must be 
equilibrated at room temperature (maximum 30°C) for a minimum of 30 minutes prior to product 
administration. 
 


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                        December 20, 2018 
 
Page 38 of 75 
 
6.4.2. Preparation of 10-1074 IV Solution: To prepare 10-1074 IV infusion, the pharmacist will 
calculate the weight-based dose as in section 6.3.2 and remove the total number of vials needed as 
well as a 100 mL IV bag of Sodium Chloride for Injection USP, 0.9% from storage. The pharmacist, 
using aseptic technique, will add the appropriate amount of 10-1074 to the 100 mL IV bag of Sodium 
Chloride for Injection USP, 0.9%. After product preparation in IV bags, the prepared 10-1074 may be 
stored at 2°C to 8°C up to 24 hours or at room temperature (maximum 30°C) for a maximum of 8 
hours total including the infusion time. Product may not be stored in direct sunlight. If stored at 2°C to 
8°C, prepared product must be equilibrated at room temperature (maximum 30°C) for a minimum of 
30 minutes prior to product administration. The pharmacist will label the infusion bag including a 
Beyond Use Date and time. 
 
6.5. Study Product Administration 
 
At all infusion visits during dual bNAb treatment in Step 1 and Step 2, the designated order for bNAb 
administration will be 10-1074 first and VRC01LS second. When both study products are 
administered there will be a gap of approximately 10-15 minutes (longer if necessary) during which 
the second infusion will be set up and vital signs will be measured. 
 
6.5.1. 10-1074 Administration: The solution will typically be administered IV over about 30 minutes. 
The total time needed to administer the dose maybe longer based on factors such as participant 
tolerance.  
 
The clinician responsible for administration will check the IV bag label and confirm that the participant 
identifier is correct, that the weight on the bag label is within 10% of the participant’s current actual 
weight, and that the beyond use date/time has not been reached prior to administration. 
 
A 0.2 or 0.22 micron in-line filter infusion set must be used for IV administration (see SOP for Infusion 
instructions). 
 
6.5.2. VRC01LS Administration: The solution will typically be administered IV over about 30 
minutes. The total time needed to administer the dose may be longer based on factors such as 
participant tolerance.  
The clinician responsible for administration will check the IV bag label and confirm that the participant 
identifier is correct, that the weight on the bag label is within 10% of the participant’s current actual 
weight, and that the beyond use date/time has not been reached prior to administration. 
 
An in-line filter infusion set must be used for IV administration (see SOP for Infusion instructions). In-
line filters must comply with the following specifications: 1.2 micron PES (polyethersulfone) filter 
membrane, DEHP-free, latex-free (equivalent to Braun #473994 filter extension set). When the in-line 
filter is added to the tubing, prime the administration set. Flush the administration set with about 30 
mL or appropriate volume of normal saline at the end of product administration. 
 
6.6. Concomitant Medications: ART Management 
 
During the PK Step, Step 1, and Step 3, ART will be provided as part of the Botswana ART program 
(Masa Program), but may be dispensed by study staff as per prior agreements between BHP and the 
Botswana Ministry of Health. ART is standard of care for HIV-infected children in Botswana and will 
not be considered study drug. At the time of enrollment, all children in this study will continue the ART 
regimen being provided through the EIT Study, and will re-start ART with that same regimen in Step 3 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 39 of 75 
 
as long as there is no clinical contraindication. During the PK Step, Step 1, and Step 3, the ART 
regimen may be changed if required. All ART management decisions will be per Botswana ART 
guidelines and/or by study physicians made with guidance from specialists.  
 
7. STUDY PROCEDURES AND EVALUATIONS  
 
7.1. Clinical Evaluations and Procedures 
 
Study enrollment and follow-up for participants will be performed at the study clinic when possible, or 
at home visits if requested by caregivers for some visits (other than for bNAb administration). Children 
will be followed as outlined below in Table 1, Table 2, and Table 3.  
 
Table 1 refers to special procedures for the PK Step to evaluate single bNAb administration. Table 2 
describes Step 1 (the start of dual bNAb therapy) for the first 6 participants and for all additional 
participants. Table 3 outlines procedures for Step 2 when participants receive dual bNAb therapy 
without ART for 24 weeks, and procedures for the period of follow-up after dual bNAb therapy is 
discontinued and ART is re-started (Step 3).  
 
 
 


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                        December 20, 2018 
 
Page 40 of 75 
 
Table 1: Follow-up and laboratory testing for the PK Step (first 12 participants) 
 
SES, socioeconomic status 
Laboratory test time-points are optional when marked in parentheses: (X). 
҂ Participants will be weighed at least monthly, and at each visit preceding an infusion visit. 
$ Participants 1, 3, 5, 7, 9, and 11 will receive VRC01LS only (30mg/kg at Week 0, then 10 mg/kg at Week 4 and 
8), and participants 2, 4, 6, 8, 10, and 12 will receive 10-1074 only (30mg/kg). 
∞ May be drawn up to 4 weeks prior to Week 0 visit. 
^ CBC includes: hemoglobin (g/dl), Hematocrit (%), RBC (million/mm3), MCV (microns), WBC (103/ cu mm), 
differential WBC, absolute neutrophil count (ANC), Platelets (103/cu mm). Chemistry includes: electrolytes, BUN, 
creatinine, glucose, albumin. LFTs include ALT, AST, total and direct bilirubin. Any draw that includes 
electrolytes should be performed with a butterfly needle when possible, to reduce the chances of hemolysis; 
specimens considered hemolyzed should be repeated at the next regularly scheduled visit. If clinical concern for 
hyperkalemia exists, hemolyzed specimens should be repeated as soon as possible. 
# LFTs only  
% CD4 T cell subsets will be considered if sufficient PBMC volume available. 
* PK testing will occur pre-infusion (at Weeks 4 and 8), at the end of infusion and again 1 hour post-infusion on 
the day of administration. 
 
 
 
 
PK Step 
Study week 
0 
0+1 
day 1wk 2wks 4wks 4wks
+1day 5wks 
6wks 
8wks 8wks+
1 day 
9wks 10wks 12wks 
10-1074 
X$ / 0 
 
 
 
X$ / 0 
 
 
 
X$ / 0 
 
 
 
 
VRC01LS 
0 / X$ 
 
 
 
0 / X$ 
 
 
 
0 / X$ 
 
 
 
 
Exam҂ 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Baseline 
Characteristics/ 
Demographics/SES  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Adherence Assessment 
X 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
Acceptability 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV RNA∞ 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
CBC^ 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
CD4/CD8 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Chem / LFTs^ 
X 
 
X# 
 
 
 
X# 
 
 
 
X# 
 
X 
Stored Plasma 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Stored PBMC 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
HIV-1 Qualitative DNA 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
X 
Proviral Genome 
Sequencing 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
HIV-1 DNA Analysis by 
ddPCR% 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Immune Profiling 
(X) 
 
 
 
 
 
 
 
 
 
 
 
(X) 
ELISA 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
PK Testing 
X* 
X 
X 
X 
X* 
X 
X 
X 
X* 
X 
X 
X 
X 
ADA Testing 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood Volume (mL) 
12 
2 
4 
2 
10 
2 
4 
2 
10 
2 
3 
2 
12 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 41 of 75 
 
Table 2: Follow-up and laboratory testing for Step 1 (all participants) 
 
SES, socioeconomic status 
Laboratory test time-points are optional when marked in parentheses: (X). 
҂ If a participant has a confirmed viral load result ≥40 copies/mL during Step 1, he/she will discontinue 
bNAbs, complete visit procedures equivalent to those outlined for Step 1 Week 8 and enter Step 3. 
∞ May be drawn up to 4 weeks prior to Week 0 visit. 
&  For first 6 participants, PK draws will occur pre-infusion at Week 0, and also for both bNAbs at end of 
infusion at Week 0, 1 hour post-infusion at Week 0, Week 0 + 1 day after infusion, Week 1, Week 4 pre-
infusion, at end of infusion at Week 4, 1 hour post-infusion at Week 4, Week 4 + 1 day after infusion, and 
Week 5. All subsequent PK testing will be pre-dose trough testing only. Other participants will not have PK 
on Day 0 or Week 1 or Week 5, but will have pre-dose trough testing at the visits noted beginning at 4 
weeks. 
$  Step 2 testing schedule for “Step 2 Week 0” supersedes Step 1 schedule on the day of entry into Step 2. 
 
Step 1:  
ART + dual bNAbs 
Possible additional visits for first 6 participants in Step 1$ 
Study week 
0 
0+
1& 1 
4 
4+
1& 5 
8$ 
10* 
12* 14* 16* 18* 20* 22* 24* 26* 28* 30* 32* 
VRC01LS  
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
10-1074 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Exam 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Baseline 
Characteristics/
Demographics/ 
SES (if required) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adherence 
Assessment 
 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability 
Assessment 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV RNA҂ 
X∞  
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
CBC^ 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
CD4/CD8 
X 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Chem / LFTs^ 
X 
 
X#  
 
X# 
 
X# 
 
X# 
 
X# 
 
X#  
X#  
X#  
Stored Plasma 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Stored PBMC 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
HIV-1 
Qualitative DNA X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Proviral  
Genome 
Sequencing** 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 gag DNA 
Analysis by 
ddPCR% 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Immune Profiling (X)  
 
(X) 
 
 
X 
 
 
 
X 
 
(X) 
 
X 
 
 
 
X 
ELISA 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PK Testing& 
X& X& X& X& 
X& X& 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
ADA Testing≠ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Volume 
(mL) 
12 
2 4 
9 
2 4 
11 
4 
8 
4 
9 
4 
8 
4 
9 
4 
8 
4 
9 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 42 of 75 
 
* Additional Step 1 visits may be required only for the first 6 participants while awaiting SMC review of 
safety and PK data. In the unlikely event that a participant reaches the Week 32 Step 1 visit prior to the 
conclusion/recommendation of the SMC review, Week 30 and Week 32 visit procedures will be repeated 
alternately every two weeks, if feasible, until a decision on Step 2 is reached. 
** In the event of plasma rebound ≥400 copies/mL, viral sequencing from plasma samples will also be 
considered. 
% CD4 T cell subsets will be considered if sufficient PBMC volume available. 
^ CBC includes: hemoglobin (g/dl), Hematocrit (%), RBC (million/mm3), MCV (microns), WBC (103/ cu 
mm), differential WBC, absolute neutrophil count (ANC), Platelets (103/cu mm). Chemistry includes: 
electrolytes, BUN, creatinine, glucose, albumin. LFTs include ALT, AST, total and direct bilirubin. Any draw 
that includes electrolytes should be performed with a butterfly needle when possible, to reduce the 
chances of hemolysis; specimens considered hemolyzed should be repeated at the next regularly 
scheduled visit. If clinical concern for hyperkalemia exists, hemolyzed specimens should be repeated as 
soon as possible. 
# LFTs only 
≠ADA testing will not be done on the first 6 participants in Step 1 who had this testing during the PK Step. 
 
Table 3: Follow-up and laboratory testing for Step 2 and Step 3 (all participants) 
 
Step 2:  
Dual bNAbs alone 
Step 3: ART 
alone 
Study week 
0 
1 
2 
3 
4 
6 
8 
10 12 14 
16 18 20 22 24# 0҂ 4 
12 24 
VRC01LS  
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
10-1074 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Adherence 
Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Acceptability 
Assessment 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
HIV RNA* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
CBC^ 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
CD4/CD8 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
LFTs 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
Stored Plasma 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
Stored PBMC 
X 
 
X 
 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
HIV-1 Qualitative 
DNA* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
Proviral Genome 
Sequencing** 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
HIV-1 DNA 
Analysis  by 
ddPCR% 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Immune Profiling 
X 
 
(X) 
 
X 
 
 
 
(X) 
 
X 
 
(X) 
 
X 
 
 
 
X 
ELISA 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
PK Testing (pre-
dose trough) 
X 
 
 
 
X& 
 
X& 
 
X& 
 
X& 
 
X& 
 
X& 
 
 
 
 
ADA Testing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Discontinue ART 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re-start ART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Blood Volume 
(mL) 
10 
7 
8 
6 
9 
10 
9 
8 
8 
8 
9 
8 
8 
8 
12 
0 8 
8 
11 


VRC01LS and 10-1074 in Early Treated Children, BHP, v.2.0  
                        December 20, 2018 
 
Page 43 of 75 
 
Laboratory test time-points are optional when marked in parentheses: (X). 
* If HIV RNA remains <400 copies/mL; if HIV RNA becomes >400 copies/mL during the period of bNAbs alone, 
ART will be resumed, and follow-up schedule modified per protocol. If HIV RNA >40 copies/mL and <400 
copies/mL, or if qualitative DNA turns from negative to positive, HIV RNA will occur weekly. 
# If HIV RNA becomes ≥400 copies/mL prior to the Step 2 Week 24 visit, all “Week 24” evaluations will be 
performed (but bNAbs will not be administered) immediately prior to ART re-initiation. Follow-up will then occur 
weekly until HIV-1 RNA returns to <40 copies/mL, with testing that will include adherence assessment, exam, 
HIV-1 RNA, qualitative HIV DNA, stored plasma and stored PBMC.  Thereafter, visits will occur as routine Step 
3 visits at Weeks 4, 12, and 24 (as applicable depending on study week when re-suppression occurs), with 
events as per Table 3. If weekly follow-up during the period of re-suppression coincides with one of these 
scheduled visits, the testing protocol for that visit week will be observed.  
** Genome sequencing will be performed from PBMC. In the event of plasma rebound ≥400 copies/mL, viral 
sequencing from plasma samples will also be considered. 
% CD4 T cell subsets will be considered if sufficient PBMC volume available. 
^ CBC includes: hemoglobin (g/dl), Hematocrit (%), RBC (million/mm3), MCV (microns), WBC (103/ cu mm), 
differential WBC, absolute neutrophil count (ANC), Platelets (103/cu mm).  
& May include PK testing for the presence of drugs from the participant’s prior Step 1 ART regimen, for a 
subset of HIV-1 RNA-suppressed children. 
҂ Participants will enter Step 3 on the same day as completing the Step 2 Week 24 visit. 
 
7.2. Monitoring during Step 2  
 
Transition to treatment with VRC01LS and 10-1074 alone (Step 2) will be performed in a closely 
monitored setting with frequent visits and HIV RNA testing to ensure that ART is re-started within days 
of viral rebound and that HIV-1 RNA is quickly re-suppressed after ART re-start (see also Sections 
7.7.2 and 13.8.1). There will be minimal risk of loss-to-follow-up during this critical period, as we have 
extensive experience finding/retaining these same participants in the EIT Study.  
 
7.3. Participant Sampling 
 
Samples will be obtained as outlined in Table 1, Table 2, and Table 3. No maternal samples will be 
requested (but are available from EIT study). Please see below discussion of blood volume limits. 
 
7.4. Specimen Management  
 
All specimens will be sent to the BHP Laboratory in Gaborone or to the National HIV Reference 
Laboratory in Francistown. Complete blood counts, chemistries, HIV RNA, Qualitative HIV DNA and 
CD4 cell counts will be performed at these or at BHP/NIAID designated back-up laboratories. HIV 
RNA testing will be performed with expedited testing and reporting (<7 days). Validated laboratory 
values will be entered at the BHP Data Center or directly uploaded from the laboratory to the Data 
Center.  
 
Stored specimens will be shipped periodically to Dr. Kuritzkes’ and Dr. Lichterfeld’s lab in Boston. 
Samples for VRC01LS PK/ADA testing will be sent to the Vaccine Research Center in Bethesda. 
Samples for 10-1074 PK testing will be sent to Dr. Tomaras’ lab at Duke University, and samples for 
10-1074 ADA testing will be sent to Dr. Ackerman’s laboratory at Dartmouth University.  
 
Initial laboratory data review will evaluate data completeness, data checks against the clinical 
database (e.g., dates of samples/results), assessment for outliers and interaction with the testing 


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                        December 20, 2018 
 
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laboratories regarding assay limits of detection and the potential impact of low blood volumes and low 
event counts (especially immune cell subsets) on the testing, results and analyses.  
 
7.5. Biohazard Containment  
 
Transmission of HIV and other blood borne pathogens can occur through contact with contaminated 
needles, blood, and blood products. Respiratory pathogens such as Mycobacterium tuberculosis 
(MTB) are transmitted by inhalation of droplet nuclei. Appropriate blood, secretion, and respiratory 
precautions will be employed by all personnel in the administration of IV infusion, collection of clinical 
samples and the shipping and handling of all clinical samples and isolates for this study, as currently 
recommended by the Centers for Disease Control and Prevention in the United States, the WHO 
internationally and the National Institutes of Health.  
 
All protocol 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. 
 
7.6. Blood Volumes  
 
Blood volumes are an important consideration for this protocol, and will be minimized to the greatest 
extent possible at every visit. We will follow NIH Clinical Center guidance for maximal allowed blood 
volumes allowed in research. The NIH recommends a limit of 5 mL/kg per single blood draw and a 
limit of 9.5 mL/kg in any 8-week period. We will draw no more than 12 mL at any draw during the 
study and <12 mL at most visits. If additional clinical blood draws occur, study staff will account for 
these draws and make adjustments in the volume drawn for the study if needed. However, given that 
all children will be at least 96 weeks of age, we expect them to be over 10 kg (which is ~ 5th 
percentile). By NIH Clinical Center guidance, a 10 kg child would be able to have up to 50 mL of blood 
per draw (we will only draw 12 mL maximum), and up to 95 mL in an 8-week period (the maximum in 
this study would be far lower). Thus, we believe that the blood draw volumes for the study are well-
within safety parameters, even if a child is at 5th percentile or lower in weight.  
 
7.7. Schedule of Evaluations 
 
7.7.1. Evaluations in the Setting of Maintained Viral Suppression: 
 
All visits will assess for diagnoses, signs and symptoms of any Grade. 
 
Adherence to ART during the PK Step, Step 1, and Step 3 will be monitored through an Adherence 
Assessment form, on which information such as date of last dose of ARV, any missed doses of ARVs, 
and reasons for missed doses will be recorded.  
 
Acceptability of the infusions will be assessed by asking questions about tolerability and willingness to 
opt for procedures involving infusions in the future.  
  
PK Step Week 0 Visit  
• 
Confirmation of signed and dated PK Step consent form 
• 
Perform physical exam 


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                        December 20, 2018 
 
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• 
Continue ART 
• 
Baseline Characteristics/Demographics/Socioeconomic Status (SES) Data Collection 
• 
Adherence/Acceptability Assessments  
• 
10-1074 or VRC01LS given 
• 
Samples obtained for: HIV-1 RNA, hematology, CD4/CD8, chemistry/LFTs, stored plasma 
and PBMCs for HIV proviral DNA quantification (including by ddPCR), qualitative HIV DNA 
PCR, whole genome sequencing, immune profiling (optional), ELISA, PK testing (at end of 
infusion and 1-hour post-infusion), ADA testing. 
• 
Set up visit for next day for “Week 0 + 1 day” post-dose PK testing  
 
PK Step Week 0 + 1 day post-single bNAb infusion Visit  
• 
Continue ART 
• 
Samples obtained for: PK testing 
 
PK Step Week 1 Visit  
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment 
• 
Samples obtained for: hematology, LFTs, qualitative HIV DNA PCR, PK testing 
 
PK Step Week 2 Visit  
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment 
• 
Samples obtained for: PK testing 
 
PK Step Week 4 Visit  
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment  
• 
10-1074 or VRC01LS given 
• 
Samples obtained for: HIV-1 RNA, CD4/CD8, stored plasma and PBMCs for HIV proviral 
DNA quantification (including by ddPCR), qualitative HIV DNA PCR, PK testing (pre-
infusion, at end of infusion and 1-hour post-infusion) 
• 
Set up visit for next day for “Week 4 + 1 day” post-dose PK testing  
 
PK Step Week 4 + 1 day post-single bNAb infusion Visit  
• 
Continue ART 
• 
Samples obtained for: PK testing 
 
PK Step Week 5 Visit  
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment 
• 
Samples obtained for: hematology, LFTs, qualitative HIV DNA PCR, PK testing 
 


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PK Step Week 6 Visit 
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment 
• 
Samples obtained for: PK testing 
 
PK Step Week 8 Visit  
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment  
• 
10-1074 or VRC01LS given 
• 
Samples obtained for: HIV-1 RNA, CD4/CD8, stored plasma and PBMCs for HIV proviral 
DNA quantification (including by ddPCR), qualitative HIV DNA PCR, PK testing (pre-
infusion, at end of infusion and 1-hour post-infusion) 
• 
Set up visit for next day for “Week 4 + 1 day” post-dose PK testing 
 
PK Step Week 8+1 Visit 
• 
Continue ART 
• 
Samples obtained for: PK testing 
 
PK Step Week 9 Visit 
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment 
• 
Samples obtained for: hematology, LFTs, PK testing 
 
PK Step Week 10 Visit 
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment 
Samples obtained for: PK testing  
 
PK Step Week 12 Visit 
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence/Acceptability Assessments  
• 
Samples obtained for: HIV-1 RNA, hematology, CD4/CD8, chemistry/LFTs, stored plasma 
and PBMCs for HIV proviral DNA quantification (including by ddPCR), qualitative HIV DNA 
PCR, whole genome sequencing, immune profiling (optional), ELISA, PK testing, ADA 
testing 
__________________________________________________________________________ 
 
Step 1 Week 0 Visit  
• 
Confirmation of signed and dated consent form (for enrollment to Steps 1-3) 
• 
Perform physical exam 
• 
Continue ART 
• 
Baseline Characteristics/Demographics/SES Data Collection (if required) 
• 
Adherence/Acceptability Assessments 
• 
VRC01LS and 10-1074 given 


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• 
Samples obtained for: HIV-1 RNA, hematology, CD4/CD8, chemistry/LFTs, stored plasma 
and PBMCs for HIV proviral DNA quantification (including by ddPCR), qualitative HIV DNA 
PCR, whole genome sequencing, immune profiling (optional), ELISA; for the first 6 
participants only PK testing pre-infusion, at end of infusion and 1-hour post infusion; ADA 
testing  
• 
Set up visit for next day for “Day 1 post- dual dose” PK testing (first 6 participants only)  
 
Step 1 Week 0 + 1 day post-bNAb infusion visit (first 6 only) 
• 
Continue ART 
• 
Samples obtained for: PK testing 
 
Step 1 Week 1 Visit 
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment 
• 
Samples obtained for: hematology, LFTs, PK testing  
 
Step 1 Week 4 Visit 
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment 
• 
VRC01LS and 10-1074 given 
• 
Samples obtained for: HIV-1 RNA, stored plasma, stored PBMC for immune profiling 
(optional), qualitative HIV DNA PCR, PK testing 
 
Step 1 Week 4 + 1 day Visit (first 6 only) 
• 
Continue ART 
• 
Samples obtained for: PK testing 
 
Step 1 Week 5 Visit  
• 
Perform physical exam 
• 
Continue ART 
• 
Adherence Assessment 
• 
Samples obtained for: hematology, LFTs, PK testing 
 
Step 1 Week 8-32 Visits (if remaining in Step 1) 
• 
Perform physical exam 
• 
Adherence Assessment 
• 
Acceptability Assessment (at Week 8) 
• 
Continue ART while remaining in Step 1 
• 
VRC01LS and 10-1074 given at  Weeks 8, 12, 16, 20, 24, 28, 32 
• 
Samples obtained for: HIV-1 RNA monthly (at Weeks 8, 12, 16, 20, 24, 28, 32); 
hematology, CD4/CD8, and LFTs (at Weeks 10, 14, 18, 22, 26, and 30); stored 
PBMC/plasma monthly (at Weeks 8, 12, 16, 20, 24, 28, and 32), qualitative HIV DNA PCR 
monthly (at Weeks 8, 12, 16, 20, 24, 28, and 32), whole genome sequencing (Week 8), 
quantitative HIV DNA PCR from stored PBMC every 8 weeks (at Weeks 8, 16, 24, and 32), 
immune profiling (at Weeks 8, 16, 20 (optional), 24, and 32), ELISA (at Weeks 8, 16, 24, 
and 32), PK testing (at Weeks 8, 12, 16, 20, 24, 28, and 32). 
 


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___________________________________________________________________ 
 
Step 2 Week 0 (must coincide with a Step 1 Week 8, 12, 16, 20, 24, 28, or 32 Visit) 
• 
Perform physical exam 
• 
Discontinue ART 
• 
Adherence Assessment 
• 
Acceptability Assessment 
• 
VRC01LS and 10-1074 given  
• 
Samples obtained for: HIV-1 RNA, CD4/CD8, stored plasma/PBMC, qualitative DNA PCR, 
whole genome sequencing, quantitative HIV DNA PCR from stored PBMC, immune 
profiling, ELISA and PK testing 
 
Step 2 Non-infusion Visits (Weeks 1, 2, 3, 6, 10, 14, 18, 22) 
• 
Perform physical exam (all visits) 
• 
Samples obtained for: HIV-1 RNA (all visits), hematology (at Weeks 6, 10, 14, 18, and 22), 
CD4/CD8 (at Weeks 6, 10, 14, 18, and 22), LFTs (at Weeks 1, 6, 10, 14, 18, and 22), 
stored plasma/PBMC (only at non-infusion visits at Weeks 2 and 6), qualitative DNA PCR 
(all visits), immune profiling (optional at Week 2)  
 
Step 2 Infusion Visits (Weeks 4, 8, 12, 16, 20) 
• 
Perform physical exam (all visits) 
• 
Acceptability Assessment (Week 12) 
• 
VRC01LS and 10-1074 given  
• 
Samples obtained for: HIV-1 RNA (all visits),  stored plasma/PBMC (all visits), qualitative 
DNA PCR (all visits), quantitative HIV DNA PCR from stored PBMC (at Weeks 4, 8, 16), 
immune profiling (at Weeks 4, and 16, optional at Weeks 12 and 20), ELISA (at Weeks 4, 
8, 16), PK testing (at Weeks 4, 8, 12, 16, 20) 
 
Step 2 Week 24 Visit (or last visit off ART) 
• 
Perform physical exam 
• 
Acceptability Assessment 
• 
VRC01LS and 10-1074 given (if visit at 24 weeks, but not if last Step 2 visit for rebound) 
• 
Samples obtained for: HIV-1 RNA, CD4/CD8, stored plasma/PBMC, qualitative DNA PCR, 
whole genome sequencing, quantitative HIV DNA PCR from stored PBMC, immune 
profiling, ELISA, PK testing 
• 
Enter Step 3 (Step 3 Week 0 = Day of ART re-start) 
 
____________________________________________________________________ 
 
Step 3 Week 0 (occurs the same day as completion of Step 2 Week 24 evaluations) 
• 
Re-start ART 
 
Step 3 additional weekly visits for participants who enter Step 3 with HIV RNA ≥400 
copies/mL; repeat weekly until HIV RNA returns to <40 copies/mL, also complete Routine Step 3 
Visits) 
• 
Perform physical exam 
• 
Adherence Assessments 
• 
Samples obtained for: HIV-1 RNA, Qualitative DNA PCR, plasma and stored PBMC 
 


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Step 3 Weeks 4, 12, 24 (Routine) 
• 
Perform physical exam  
• 
Adherence Assessment 
• 
Acceptability Assessment (Week 24) 
• 
Labs: HIV-1 RNA, hematology (at Weeks 4 and 24 only), CD4/CD8 (all visits), LFTs (at 
Week 4 only), stored plasma/PBMC (at Weeks 12 and 24 only), qualitative DNA PCR, 
whole genome sequencing (at Week 24 only), quantitative HIV DNA PCR, and immune 
profiling (at Week 24 only), CD4/CD8 (all visits), ELISA at Week 24, ADA testing at Week 
24. 
 
7.7.2. Evaluations in the Event of Viral Rebound: If viral rebound ≥400 copies/mL occurs and 
ART is re-started per protocol, the “Step 2 Week 24” visit schedule will occur (except without 
bNAb administration), and the participant enters Step 3. Follow-up will then occur with additional 
weekly visits in Step 3 until HIV-1 RNA returns to <40 copies/mL, with testing that will include 
exam, adherence assessment, HIV-1 RNA, Qual DNA PCR, stored plasma and stored PBMC (8 
mL blood draws). Thereafter, follow-up will continue with routine Step 3 visits at Weeks 4, 12, and 
24 (as applicable depending on study week when re-suppression occurs). Laboratory collections 
for these visits will be as per Table 3. The scheduled visit laboratory schedule will be followed 
when it coincides with weekly follow-up visits to monitor viral re-suppression. HIV resistance 
testing will be performed for clinical purposes if viral suppression has not been achieved 12 weeks 
following ART re-initiation. 
 
7.8. End of Study Follow-Up  
 
Children will be followed up for a minimum of 56 weeks, and a maximum of 98 weeks for those 
who start in the PK step and continue (or longer in unlikely event that Step 1 is extended beyond 
16 weeks for the first 6 participants). 
 
7.9. Timing of evaluations 
 
Enrollment should occur at or after 96 weeks on ART, with an upper age limit of 5 years.  
 
Scheduled evaluations  
Every attempt should be made to conduct the visit as close as possible to the target visit date, and 
barring that, within the target visit window. Visit windows remain open until the mid-way point to the 
next scheduled evaluation, at which point the visit is marked as missed and a contact would be 
counted as the next scheduled evaluation. However, if a visit window is missed, every effort should 
still be made to conduct the laboratory evaluations and clinical evaluations that were required at the 
missed visit at the time of the next clinical contact, even if this falls outside of the specified visit 
window, with the exception of PK testing. The study team may check on participants by telephone 
between visits. 
 
Visits will occur at the weeks indicated whenever possible. A visit may be counted as completed if 
attendance is either early (if performed no sooner than halfway between the previous visit target date 
and the target date for the upcoming scheduled visit) or late (no later than halfway between the target 
date for the scheduled visit and the target date for the next scheduled visit). Thus, a child is always 
eligible for a scheduled visit when seen in the clinic. However, the clinic staff may use their discretion 
to either perform visits as “unscheduled” if far from the target date and a reliable participant, or to 
count a visit as “scheduled” and perform all required tasks (see “Ill visits” below). Infusion visits that 


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are not completed within 14 days of the scheduled visit will trigger review by the protocol team and, if 
in Step 2, weekly HIV RNA testing will occur. 
 
Missed visits  
If a scheduled visit is missed then the next attended visit should include major monitoring parameters 
from the missed visit (within allowable blood draw ranges). If a visit is missed, the schedule of visits 
should not be “reset” but should remain as if the visit were not missed. 
 
Ill visits  
If an ill visit occurs and the participant will not be able to attend the next scheduled visit, the ill visit 
can substitute for the scheduled visit at the discretion of the study physician. In such a case, all 
information/tests scheduled for the routine visit should be obtained and reported.   
 
If an ill visit is not considered a scheduled visit, clinical events that meet reporting criteria for the study 
should be noted in the patient medical record (non-source document) and also recorded on an 
unscheduled contact CRF, and other applicable CRFs. The participant should be reminded to attend 
the next regularly scheduled study visit. Should the ill visit constitute a serious adverse event that 
requires expedited adverse event (EAE) reporting, the EAE form should be completed and submitted 
to the Data Centre within the specified time frame.   
 
Premature discontinuation of study treatment 
If the single bNAb needs to be discontinued during the PK Step the child will go off Step after 
completing the visit procedures equivalent to Week 12 of the PK Step. If the participant is 
permanently discontinuing study treatment in the PK Step he/she will go off-study. In general during 
participation in Step 1 or Step 2, if a child needs to discontinue study treatment for any reason, 
he/she will complete final visit evaluations for the Step and enroll to Step 3. 
 
 
7.10. Laboratory Testing Panels in Botswana 
 
Samples will be stored for up to 10 years after the study is closed with IRBs of record, if consent 
for this is granted. 
 
Plasma HIV-1 RNA 
All evaluations are to be done using approved viral load assays at the BHP study laboratory in 
Gaborone or at the HIV Reference Laboratory in Francistown. Testing may occur by approved 
laboratory techniques, and may occur in conjunction with the Botswana Masa Program using the 
Roche Taqman platform. If the approved method for HIV RNA detection in Botswana is modified, the 
study may utilize newly approved platforms (including point-of-care testing) but will also continue with 
the “gold standard” testing throughout the study. 
 
Hematology 
Hemoglobin, hematocrit, red blood cells (RBC), mean corpuscular volume (MCV), white blood cell 
count (WBC), differential WBC (neutrophils, lymphocytes, eosinophils, monocytes, and basophils), 
absolute neutrophil count (ANC), and platelets. 
 
Blood Chemistries / LFTs 
Sodium, potassium, chloride, glucose, bicarbonate, BUN, creatinine, ALT, AST, and bilirubin (total 
and direct).   
 


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CD4+/CD8+ 
Determinations of CD4+ and CD8+ cell counts and subset percentage evaluations should be 
performed at the approved BHP laboratories in Gaborone or Francistown, throughout the course of 
the study. All CD4+ and CD8+ cell count results will be recorded on the CRFs. 
 
Stored Plasma/Cells 
Stored plasma will be performed per laboratory SOP, either from the PBMC separation process or 
upon direct processing of whole blood for HIV RNA testing. When PBMC processing is not 
performed, cells will be stored separately after processing for plasma. Stored plasma will be used for 
analysis of ADA at designated laboratories (VRC, Duke).   
 
Stored PBMC 
Whole blood will be processed for PBMCs per standard laboratory protocols. PBMCs will be 
separated into 2 equal aliquots and frozen until shipped to Boston. Plasma remaining from PBMC 
separation will be used for HIV RNA testing and ELISA testing when applicable, and the remainder 
will be stored. 
 
HIV-1 DNA PCR (Qualitative) 
For Qualitative DNA PCR, whole blood will be obtained by dried blood spot (DBS). Testing may occur 
by approved laboratory techniques, including the Roche Taqman platform. Selected Qual DNA PCR 
tests may occur at the BHP laboratory on PBMC samples (of approximately 1 million PBMCs), if 
volume permits. The Cepheid platform for rapid HIV DNA testing may also be utilized for DBS or 
whole blood testing as an adjunct to the Taqman platform. 
 
Proviral Genome Sequencing 
The number of intact proviruses will be quantified using a novel single-genome amplification strategy 
that combines limiting dilution PCR of near-full-length genomes with next-gen (Illumina) sequencing 
of the clonal amplicons, as described in our previous work [57]. Briefly, proviral DNA diluted to single 
genomes will be amplified with primers spanning near full-length HIV-1 clade C, followed by Illumina 
MySeq next-generation sequencing. Resulting contigs will be de novo assembled; subsequently, an 
analysis pipeline written in R coding language will be used to identify large deletions, hypermutations, 
premature stop codons and defects in the 5-LTR region. Sequences without detectable defects will be 
classified as “genome-intact”. Genome sequencing will be performed from PBMC. In the event of 
plasma rebound ≥400 copies/ml, viral sequencing from plasma samples will also be considered. 
 
HIV DNA PCR (Quantitative) 
Quantitative DNA PCR will occur by approved laboratory techniques from stored PBMCs, at the 
Kuritzkes laboratory in Boston. These assays include quantitative digital droplet PCR (ddPCR) 
measurement of integrated (proviral) HIV-1 DNA, cell-associated HIV-1 RNA, and plasma HIV-1 RNA 
measured by a highly sensitive single-copy assay. 
 
Immune Profiling 
Immune profiling assays performed at MGH/Ragon, and neutralization assays at BIDMC, are 
listed in 7.13.  
 
HIV ELISA 
HIV ELISA will be performed on plasma using test kits approved as part of the Botswana Masa 
Program, run at the BHP study laboratory.  
 
PK Testing / ADA Testing  


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Vaccine Research Center at NIH will perform PK testing and ADA testing for the VRC01LS. VRC01 
concentration in participant plasma samples will be quantified using the murine anti-VRC01 
monoclonal antibody 5C9 for VRC01LS detection. The lab of Georgia Tomaras at Duke University will 
perform the PK testing for the 10-1074. Levels of 10-1074 will be determined by a validated 
sandwich ELISA. The lab of Margaret Ackerman at Dartmouth University will perform the ADA 
testing for the 10-1074 using a tiered testing approach. 
 
7.11. Clinical Evaluations and Reporting Requirements 
 
Children will undergo an examination at every study visit (except the 1-day post-infusion PK visits). 
Length and weight will be recorded at least monthly. All prior clinical and laboratory information from 
the EIT Study will be available for clinical and study purposes. All diagnoses, signs/symptoms will be 
recorded on CRF, as will WHO Stage III/IV HIV-related illnesses. Vaccinations, hospitalizations, and 
relevant concomitant medications (from a targeted list included in the electronic data capture system) 
are recorded at each follow-up visit. Adherence to and modifications of ART are recorded at each visit 
while participants are on ART. These are assessed with specific questions in the CRFs. 
 
7.12. Medical Care and Referrals 
 
General medical care of children should be provided through the study clinics. Vaccinations may be 
provided either at the study clinic or at government clinics. Children requiring hospitalization will be 
referred appropriately, and clinical decisions during hospitalization will be made by hospital staff. 
However, study staff will follow hospitalized children, and advise regarding ART decisions (and 
possibly other medical decisions) as appropriate. 
 
7.13. Laboratory Procedures in Boston 
 
Please reference the Laboratory Testing Documents for all virology research laboratory testing 
details. The following immunologic research assays will be conducted, according to standard 
protocols: 
• 
Immune phenotyping of different leukocyte subsets, using flow cytometry or Cytometry by 
time-of-flight (CYTOF) 
• 
Analysis of HIV-1-specific T cell responses and NK cells using cytokine secretion, proliferation 
and cytotoxicity assays 
• 
Interferon-γ elispot assays for characterizing HIV-1-specific cytotoxic T cell responses 
• 
Gene expression profiling assays in isolated T cells, using gene microarrays or RNA-Seq 
assays (if sufficient PBMC samples available) 
• 
Immunogenetic assessments of HLA class I alleles 
• 
Analysis of HIV-1-specific neutralizing antibody responses (in collaboration with Dr. Michael 
Seaman, BIDMC) 
• 
HIV-1 DNA analysis and viral sequencing assays 
 
 
8. ASSESSMENT OF SAFETY 
 
8.1. Serious Adverse Events (SAEs) 
 
SAEs are defined as an AE following any exposure to the study agent that: 
• Results in death 


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• Is life-threatening (the term “life-threatening” refers to an event in which the patient was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe.)  
• Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization itself is 
not an AE, but is an outcome of the event). The following types of hospitalization do not require 
expedited reporting to DAIDS:  
• 
Any admission unrelated to an AE   
•   Admission for diagnosis or therapy of a condition that existed before receipt of study 
agent(s) and has not increased in severity or frequency as judged by the clinical 
investigator.  
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect, or 
• Is an important medical event that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the patient or may require intervention to prevent one of the 
other outcomes listed in the definition above.  
 
Guidelines for reporting SAE’s that require expedited reporting (EAE’s) are summarized in an EAE 
SOP. 
 
8.2. Adverse Event Reporting 
 
All adverse events (Grade 1 or higher), including all infusion reactions, will be recorded on an Adverse 
Event Log. Potential infusion reactions will also be described on the Infusion Reaction form. 
 
8.2.1. Expedited Adverse Event Reporting to DAIDS: Requirements, definitions and methods for 
expedited reporting of AEs are outlined in Version 2.0 of the DAIDS EAE Manual, which is available 
on the RSC website at 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 expedited AE reporting to DAIDS. In the event of system outages or technical 
difficulties, expedited AEs may be submitted via the DAIDS EAE Form. For questions about 
DAERS, please contact NIAID CRMS Support at CRMSSupport@niaid.nih.gov. Site queries may 
also be sent from within the DAERS application itself. 
 
Where DAERS has not been implemented, sites will submit expedited AEs by documenting the 
information on the current DAIDS EAE Form. This form is available on the RSC website: 
https://rsc.niaid.nih.gov/clinical-research-sites/paper-eae-reporting. For questions about expedited 
reporting, please contact DAIDS RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
8.2.2. Reporting Requirements for this Study: The SAE Reporting Category, as defined in Version 
2.0 of the DAIDS EAE Manual, will be used for this study. 
 
VRC01LS and 10-1074 are the only study agents for which expedited reporting is required for SAEs. 
The Suspected Unexpected Serious Adverse Reactions (SUSAR) reporting category will be used in 
all other circumstances, until 30 days after study completion for each participant.  
 
In addition to all SAEs meeting the above criteria, all 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.  


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8.2.3. Grading Severity of Events: The most current Division of AIDS Table for Grading the Severity 
of Adult and Pediatric Adverse Events (DAIDS AE Grading Table) at the time that the study opens will 
be used, and is available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-
adverse-event-grading-tables. 
 
8.2.4. Expedited AE Reporting Period: The expedited AE reporting period for this study is for 30 
days following the final dose of VRC01LS and 10-1074. 
 
After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs as defined in 
Version 2.0 of the EAE Manual will be reported to DAIDS if the study staff become aware of the 
events on a passive basis (from publicly available information).  
 
9. CLINICAL MANAGEMENT 
 
9.1. Toxicity Management  
 
VRC01LS and 10-1074 are monoclonal antibodies and unlikely to lead to toxicities other than 
possible local injection site reactions (See Section 2.1.7). 
 
However, AEs of interest to be monitored for include: 
 
• 
Constitutional symptoms, such as fever, changes in blood pressure, rigors/chills; 
• 
Injection site reaction/extravasation changes, pruritus, urticaria, erythema, desquamation, 
ulceration; 
• 
Serum sickness like syndromes as evidenced by fever, rash, arthralgia, arthritis, nephritis; 
• 
Deposition of immune complexes in the kidneys leading to renal insufficiency; 
• 
Anaphylaxis; Acute Respiratory Distress Syndrome, bronchospasm/wheezing, facial flushing; 
• 
Cytokine release syndrome. 
 
The most current Division of AIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events (DAIDS AE Grading Table) should be used to report adverse events and is 
available on the RSC website at https://rsc.niaid.nih.gov/clinical-research-sites/daids-adverse-
event-grading-tables. 
 
This Toxicity Management section refers to management of toxicities that occur among children 
receiving VRC01LS and 10-1074. Additional details are provided in study-specific SOPs. Please also 
refer to specific SOPs and to Botswana ART guidelines for management of toxicities related to ART, 
which is used according to best standard of care in Botswana.  
 
For the 12 PK Step participants, toxicity may be attributed to either bNAb alone in the PK Step. If the 
single bNAb needs to be discontinued during the PK Step the child will go off Step. In Steps 1 and 2, 
toxicity management should generally group both bNAbs together in assessment of relationship to 
the event, with the exception of reactions specific to each infusion. 
 
9.1.1. Dosage Modification Instructions: VRC01LS and 10-1074 will not be dose-adjusted because 
of toxicity.  
 


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9.1.2. Management for Rashes, Urticaria and Hypersensitivity Reactions: All rashes are graded 
based on the DAIDS toxicity table (Corrected Version 2.1, July 2017). 
 
Grade 1 or 2 rashes or urticaria 
VRC01LS and 10-1074 may be continued with close observation, at the discretion of the study 
clinician. If an isolated Grade 1 or 2 rash does not resolve within 14 days of onset, further 
management should be discussed with the study team. Other potential causes of rash/urticaria 
should be investigated and treated, and potential causative agents (such as lotions/creams/soaps) 
should be discontinued. 
 
Grade 3 rash with no definitive alternative explanation (Grade 3 rash should have vesicles or limited 
number of bullae or superficial ulcerations of mucous membrane): 
Any products or non-essential medicines that could be causing the rash should be discontinued. ALT 
and FBC with differential should be drawn, and the child should be evaluated clinically approximately 
weekly, until the rash resolves to Grade 1 or lower. If the Grade 3 rash was ultimately deemed very 
likely due to another diagnosis or drug, then VRC01LS and 10-1074 may be continued, in 
consultation with a study PI/designee. However, if VRC01LS and 10-1074 were paused for possible 
hypersensitivity and no other explanation is apparent, they should be permanently discontinued and 
ART re-started (if paused).  
 
Grade 4 rash (with mucosal involvement, or suspected hypersensitivity): 
Immediately modify or hold VRC01LS and 10-1074 and refer to the hospital for further clinical 
care/management, including clinical management of ART resumption if paused, and seek guidance 
from a study PI/designee. If VRC01LS and 10-1074 were paused for possible hypersensitivity and no 
other explanation is apparent, they should not be re-started. 
 
9.1.3. Guidelines for Managing Local Reactions / Infusion Site Reactions 
Infusion site reactions should be managed as follows: 
 
Grade 1-2: Continue administration of VRC01LS and 10-1074. Use alternate infusion site until event 
resolves to less than Grade 1. 
 
Grade 3: Defer further VRC01LS and 10-1074 administration until event reviewed by the study team. 
Contact protocol team within 72 hours. Participant should be followed approximately weekly until 
resolution to Grade ≤1 or until stabilized and no longer in need of frequent monitoring, as determined 
by the site investigator.  
 
Grade 4: Provide immediate clinical management and consult with protocol team. Permanently 
discontinue VRC01LS and 10-1074. Participant should be followed approximately weekly until 
resolution to Grade ≤1 or until stabilized and no longer in need of frequent monitoring, as determined 
by the site investigator.  
 
9.1.4. Guidelines for Other Toxicities  
 
In general, VRC01LS and 10-1074 may be continued for other toxicities that are Grade 1 or 2. 
 
For Grade 3 toxicities, VRC01LS and 10-1074 may be continued or held, depending on the toxicity 
and potential relatedness to study drug. 
 


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Children who develop a symptomatic Grade 4 adverse event or toxicity felt to be related to VRC01LS 
and 10-1074 will have VRC01LS and 10-1074 discontinued with ART resumption, if it had been 
paused.   
 
Children experiencing adverse events requiring permanent discontinuation of study treatment should 
be followed approximately weekly until resolution of the adverse event to Grade ≤1 or until stabilized 
and no longer in need of such frequent monitoring, as determined by the site investigator. 
 
In cases in which VRC01LS and 10-1074 are held due to a toxicity, they may be resumed (with 
careful monitoring) when that toxicity has resolved to Grade 2 or lower if there is an alternate 
explanation for the event. 
 
Any toxicity leading to non-receipt of either study product that extends beyond 14 days of the 
expected infusion visit will trigger review by the protocol team and, if in Step 2, weekly HIV-1 
RNA testing will occur. 
 
9.2. Participants Lost to Follow-up 
 
Collecting any intention to move or change of address during each visit will minimize the loss of 
contact with participants. In case of absence at a scheduled visit, a study nurse or counselor will 
attempt to locate the parent/guardian and child by phone or home visit.  Efforts will be made to keep 
all participants in study follow-up. In the event that consent is withdrawn by the parent/guardian, a 
final study visit / blood draw will be requested for the child at this time, and ART resumed (if paused) 
with appropriate referral for care.   
 
9.3. Child Death  
 
In the case of a child’s death, a Death Form should be completed within 3 business days of the study 
team becoming aware of the death. If a child dies in a health facility, events prior to and at the time of 
death will be collected from hospital records and a verbal autopsy CRF will be completed. If death 
occurs outside the hospital setting, a verbal autopsy CRF will be completed upon interview of the 
parent or guardian. If the parent of a participant dies participant follow-up will continue throughout the 
study period if possible. The purpose of the study will be explained to the guardian of the child. During 
screening, study staff will ask the parent/guardian, where possible, to identify an individual with whom 
she would like the study team to share information about her baby’s health in the event of her 
absence. This information will be documented on the locator form. Additional support may be sought 
from social services.  
 
9.4. Criteria for Study Discontinuation 
 
• Request by the parent/guardian to withdraw. 
• The child’s parent/guardian is judged by the investigator to be at significant risk of failing to 
comply with the provisions of the protocol as to cause harm to the child or to interfere with the 
validity of the study results. This may include the child missing 2 consecutive study visits (despite 
attempts to locate), at the investigator’s discretion. 
• At the discretion of the NIH or local Ministry of Health. 
• At the recommendation of the SMC. 


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• The study may be discontinued at any time by NIH, the FDA, the IRB/ECs, Office of Human 
Research Protection (OHRP), Botswana Government or other government agencies as part of 
their duties to ensure that research participants are protected.  
 
10. STATISTICAL CONSIDERATIONS 
 
10.1. Statistical Considerations for Aim 1  
 
10.1.1. Safety and PK evaluations: The first objective of Aim 1 is to determine the safety and PK 
parameters for VRC01LS and 10-1074. We will describe the cumulative proportion of children 
experiencing serious adverse events during follow-up, and the proportion of potentially bNAb-related 
events. We will describe the PK parameters in detail for participants in the PK Step, the first 6 
participants in Step 1, and the proportion of children with trough VRC01LS and 10-1074 
concentrations below defined trough ranges at Step 1 Weeks 4, and 8, and monthly during Step 2. 
We will also perform exploratory analyses correlating trough concentrations in plasma with HIV-1 RNA 
levels and other viral reservoir parameters.   
 
10.1.2. Proportion Remaining Virally Suppressed: The next objective of Aim 1 is to evaluate the 
proportion of children in whom HIV RNA remains <400 copies/mL after 32 weeks of dual bNAb 
treatment (24 weeks off ART). With a sample size of 20 children (the minimum number expected), 
safety and PK evaluations will be descriptive, and there will be reasonable precision to estimate the 
proportion with HIV viral suppression. For example, if the observed proportion with HIV RNA <400 
copies/mL is 70%, then this includes 46% to 88% with 95% confidence (based on exact confidence 
limits) and so there would be evidence that HIV RNA can be maintained suppressed in 46% or more 
of children. If the observed proportion is lower than 70%, this study will have value as proof-of-
concept but is less likely to be of importance as an alternative treatment to ART. Based on data from 
the CHER Study [52] and from a randomized treatment interruption trial in Kenya [58], <6% of children 
treated in the first year of life are expected to remain virally suppressed by 6 months off ART. Thus, 
we believe that demonstrating at least 30% success at 6 months is of scientific interest for this proof-
of-concept trial. If the observed proportion is 30% suppressed with an N=20, then a 95% confidence 
interval will be from 12% to 54% (based on exact confidence limits), and would indicate a biologic 
effect of the intervention. Thus, for an observed proportion of 30%, we will reasonably be able to rule 
out low true proportions (e.g. <12%) or high proportions (e.g. >54) and conclude that this strategy 
achieves suppression in a subset of individuals (even if it is not be useful for most treatment 
purposes). Accordingly, we have based study stopping criteria on the probability of achieving 30% 
success (see Section 13.8.1). This approach provides a balance between maximizing the scientific 
benefits of the study, while not allowing an excessive number of participants to experience viral 
rebound in the event that there is little treatment benefit from the dual bNAb strategy.   
 
 
Although this proof-of-concept Phase I/II study will not have a control group, an observed proportion 
of at least 30% suppression on dual bNAb therapy would provide reasonable evidence of a positive 
effect of VRC01LS + 10-1074 in maintaining virologic suppression, as maintenance of HIV-1 RNA 
<400 copies/mL is unlikely in the absence ART, even for early-treated children. As noted above, data 
from children treated in the first year of life in CHER [52] and in Kenya [58] showed that few children 
remain suppressed to a threshold of <400 copies/mL at 6 months off ART. In CHER, only 2 of 183 
children were suppressed to <400 copies/mL at 6 months (one of whom has remained suppressed for 
> 9 years, and the other rebounded at ~ 8 months). Additional data from Aims 2 and 3 that correlate 
viral reservoir (pre-ART, and pre- and post-bNAbs) and maintenance of viral suppression, and 


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associations between immune responses and viral control, will bolster interpretation of the specific 
effect of VRC01LS + 10-1074 on maintenance of viral suppression.  
 
10.1.3. Dynamics of viral decay and rebound: Based on frequent HIV RNA monitoring after ART 
withdrawal, the kinetics of viral rebound (if rebound occurs) will be summarized descriptively. 
Analyses will assess viral suppression off-ART (yes vs. no) and time to HIV RNA ≥400 (and ≥40) 
copies/mL, and will evaluate associations of these metrics with pre-ART and on-ART virologic and 
immunologic measures including immune activation and anti-HIV immune responses (binary 
regression; rank correlations analyzing infants with sustained undetectable HIV RNA off-ART as the 
lowest rank).   
 
10.1.4. Growth assessments: Child weight and height will be measured at least every month, and 
WHO standardized Z-scores will be evaluated for changes over time (beginning with pre-intervention 
data from the EIT study), and compared with data from prior studies for children on continuous ART. 
Although neurodevelopmental assessments would be of interest, the small number of children in this 
cohort and lack of an appropriate comparator group would preclude meaningful information from 
being obtained from standard neurodevelopmental testing. 
 
10.2. Data Analysis and Statistical Considerations for Specific Aim 2  
 
10.2.1. Virologic Assays: Results of virologic assays will be expressed as copies/mL, copies/million 
PBMC or copies/million CD4+ cells, or full-length genome-equivalents, as appropriate.  Assay limits of 
detection will be calculated based on the volume of plasma or the number of cells tested. For 
phylogenetic studies, we will perform sequence alignments using MUSCLE [59]. Phylogenetic 
distances between sequences will be examined using ClustalX-generated neighbor joining algorithms 
[60]. Genome-intact viral sequences will be evaluated for the presence of viral escape mutations to 
antiretroviral agents, to HIV-1-specific CD8 T cell-mediated immune pressure (based on CTL epitope 
mapping data conducted in SA3) and to VCR01LS and 10-1074-mediated immune activity. For 
calculation of HIV-1 DNA changes in CD4 T cell populations, Tobit regression for censored data [61] 
will be applied using a standard Markov-Chain Monte Carlo Method as described in [62], applying 
non-informative normally distributed priors. Differences in HIV-1 DNA content between different CD4 
cell populations within the same study persons will be analyzed using the Wilcoxon signed rank test 
for paired data. Biomarkers of viral reservoir size will be correlated with PK levels (trough levels and 
AUC levels) of VRC01LS and 10-1074, and with viral rebound kinetics after discontinuation of 
standard antiretroviral therapy.    
 
10.2.2. Potential pitfalls and alternative approaches: Each of the virologic techniques described 
above are well established in our laboratory and should not pose technical problems. The major 
challenges that may arise include limited assay sensitivity due to limited recovery of CD4 T cells or 
plasma due to limitations on sampling in small children, and the possibility that very early treatment 
initiation may have reduced reservoir size to undetectable levels. Another potential limitation is that 
sampling of plasma and circulating CD4+ T cells may not reflect the reservoir in lymphoid tissues.  
Although negative results in these assays do not imply absence of any residual tissue reservoir, as 
illustrated by the “Mississippi baby” [63, 64] and the “Boston patients” [65], absence of detectable 
measures of the reservoir will still be informative if they remain negative during the period of 
maintenance therapy with VRC01LS and 10-1074 alone.  Likewise, a detectable change in any one of 
the several reservoir measures during the period of bNAb maintenance therapy will be highly 
informative. 
 


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10.3. Data analysis and interpretation for Specific Aim 3  
 
10.3.1. Analysis of flow cytometry/CyTOF data: Mass spectrometry and flow cytometry data will be 
stored as FSC files, and analyzed according to standard protocols, using FlowJo software or using 
“Spanning tree progression analysis of density normalized events” (SPADE), a computational 
algorithm specifically developed to analyze and visualize high-dimensional mass spectrometry data 
generated by multidimensional CyTOF and flow cytometry data [66]. CyTOF and flow cytometry data 
will be analyzed and visualized using dot plots, histograms, heatmaps, principal component analysis 
(PCA) or as consensus tree structures reflecting cellular hierarchies based on immunophenotypic 
characteristics. 
 
10.3.2. Analysis of functional immunological assays: Mean and standard deviation of functional 
immune parameters will be calculated, as previously demonstrated in the investigators’ work [67-69]. 
We will consider paired T- tests or nonparametric Wilcoxon tests for comparison between baseline 
and on-study immunological results.  
 
10.3.3. Analysis of gene expression profiles: Differences in gene expression intensity among 
baseline (prior to study treatment) and subsequent timepoints will be detected using the empirical 
Bayes (eBayes) adjusted t-test, as implemented in the LIMMA package of R. Detection of p-values 
will be corrected for multiple hypothesis testing using calculation of false discovery rates (FDR). For 
further analysis, principal component analysis, hierarchical clustering or gene set enrichment analysis 
(GSEA) will be performed, as described in our previous work [70].  
 
10.3.4. Analysis of neutralizing breadth: Viral neutralization titers (50% inhibitory dose [ID50]) 
against tier 1-3 viruses in the presence of patient plasma will be calculated as the plasma dilution at 
which relative light units (RLU) are reduced by 50% compared to the number of RLU in virus control 
wells after subtraction of background RLU counts in cell control wells. ID50 levels will be longitudinally 
compared between baseline and on-study timepoints.  
 
10.3.5. Associations between immune parameters and clinical/virological characteristics: 
Correlations will be calculated between biomarkers of HIV reservoir size (total HIV DNA, genome-
intact HIV DNA,  plasma RNA) and (i) proportions of individual leukocyte and CD4 memory T cell 
subsets, (ii) phenotypic markers of T, B, NK cell and dendritic/monocyte cell markers, (iii) proportions 
and functions of HIV-specific CD4 and CD8 T cells, NK cells, and neutralizing antibody breadth and 
(iv) gene expression patterns in specific immune cell subsets. Correlations will be cross-sectionally 
determined at pre-bNAb infusions and at selected timepoints during the subsequent study, using 
Spearman correlations. In addition, correlations between immunological and virological parameters 
across multiple timepoints will also be calculated, using generalized estimated equations for repeated 
measures (GEEs). Associations between changes of specific HIV-1 reservoir biomarkers during given 
time intervals and corresponding changes in immunologic measures will also be analyzed. In addition, 
possible associations between immune responses and viral rebound kinetics after antiretroviral 
treatment interruption will also be explored.   
 
11. DATA HANDLING AND RECORD KEEPING 
 
11.1. Data Management Responsibilities  
 
Data will be entered by clinical study staff onto standardized case report forms (either paper or 
electronic) at the sites. Electronic data capture will occur using Medidata Rave, supported by Frontier 


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Science (please see Human Subjects Protections Section 13 for a description of data storage and 
access plans, and security of the data). A data manager will incorporate basic error checking 
capability to minimize data entry errors and to allow rapid querying of the sites for illogical or missing 
data. The data manager will generate monthly accrual reports as well as periodic reports 
(approximately 3-monthly) that will summarize basic demographic data and reported aggregate 
diagnoses, to allow real-time review of enrollment/data. 
 
11.2. Source Documents  
 
The following data items will be considered source documents: 
• 
Signed Consent Form 
• 
Certified Copies of Clinical records: photocopies of clinical records, including hospitalization 
notes (where necessary) will be made at every visit and all copies will be certified as true 
copies of the original by the person making the photocopy. This will be documented by signing 
and dating a “certification of copy” stamp on the photocopy and those copies will be filed in the 
study participant’s file at the site. 
• 
For any death of a study participant while on study. 
o Copies of death certificate when available. 
o Copies of hospital inpatient or outpatient/clinic records with information thought by the 
Study Physician to be directly related to the participant’s death. 
o Copy of the completed verbal autopsy form. 
o Any laboratory or other clinical investigation/procedure report containing information 
directly related to the participant’s death. 
 
11.3. Quality Control and Assurance 
  
1. The study physician will review all completed CRFs. 
2. Study nurses and study physician will be responsible for the following: 
a. Weekly internal audits of participants’ files 
b. Create checklist and follow-up logs 
3. Administrative assistants are responsible for: 
a. Updating follow-up logs and appointment book 
b. Confirming the availability of checklist in the files. The checklist should include: 
i. Locator form filled and signed 
ii. Enrolment consent signed with time and date of consent 
iii. Laboratory information  
iv. Pharmacy information 
Keyed data will be reviewed by a second person (either a study physician or study nurse) whenever 
feasible, to improve quality control.  
If an error, inconsistency or incomplete data is identified, the CRF will be tagged “unverified” until the 
error is resolved. If the original staff member is not available to make corrections, the study physician 
or other research nurse will make corrections or completions on his/her behalf provided they have 
access to the correct information.  
There are additional levels of quality control, which will occur at the Data Manager level (Frontier 
Science). Error checking is part of the RAVE data entry program and assists the keyer in identifying 
problems. The keyer is notified by the program feature of a logic check function that gives a detailed 


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explanation of the incomplete or inconsistent data. This allows for potential errors to be resolved prior 
to CRF completion.   
 
12. CLINICAL SITE MONITORING 
 
Site monitors under contract to the National Institute of Allergy and Infectious Diseases (NIAID) will 
visit participating clinical research sites to review participants records, including consent forms, CRFs, 
medical records (e.g., physicians’ progress notes, nurses’ notes, individual’s hospital charts), and 
laboratory records to ensure protection of study participants, compliance with the EC/IRB approved 
protocol/amendments, and accuracy and completeness of records. The monitors will inspect sites’ 
regulatory files to ensure that local regulatory requirements, in addition to U.S. Federal regulations, 
are being followed. They will also inspect sites’ pharmacies to review product storage and 
management. 
 
The site investigator will make study documents (e.g. consent forms, drug distribution forms, eCRFs) 
and pertinent hospital or clinic records readily available for inspection by the local IRB and the 
Harvard T.H. Chan School of Public Health IRB, the Botswana Ministry of Health, the site monitors, 
the FDA, the NIAID, the OHRP, and other local, U.S. or international regulatory entities for 
confirmation of the study data. 
 
13. HUMAN SUBJECTS PROTECTIONS 
 
Human subjects will be enrolled in this study. HIV-infected children who are study eligible will 
represent the population enrolled in this study. The health status of HIV-infected children participating 
in this study is expected to reflect that of optimally-treated HIV-infected children in Botswana.  HIV-
infected pediatric participants will receive the standard-of-care in accordance with Botswana National 
HIV treatment guidelines for at least 8 weeks from the date of bNAb treatment initiation, in addition to 
the bNAb intervention. Study participants will then undergo ART treatment interruption in Step 2 and 
will continue ongoing VRC01LS and 10-1074 infusions with close monitoring for up to 24 weeks. If 
viral load rebounds, ART will immediately be re-started. If there is no viral rebound, ART will be 
restarted after the final VRC01LS and 10-1074 infusions of the Step 2 Week 24 Visit (at Week 0 of 
Step 3).  
 
Inclusion criteria for this study make it likely that only children with very low viral reservoir will undergo 
the dual bNAb intervention. All children will have started ART within the EIT study, with the majority 
from the antenatal cohort and having started <7 days of life, and all required to have maintained viral 
suppression <40 copies/mL for 24 weeks prior to enrollment.  
 
13.1. Characteristics of study population 
 
The study population will consist of HIV-infected children ≥96 weeks of life.  
 
13.2. Sources of Research Material 
 
Research material will consist of data obtained from questionnaires and from blood draws. 
 


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13.3. Participant Recruitment and Study Consent 
 
Participants will be recruited from the EIT study as outlined above. For eligible HIV-infected children 
whose parents/guardians wish to enroll, written informed consent for the study will be obtained by 
study physicians or study nurses. Consent forms will be written in both Setswana and English and will 
be reviewed verbally with the parent/guardian by the study team. The consent process will describe 
the purpose of the study, the nature and duration of study follow-up, and the risks and benefits of 
participation, and will highlight the parent/guardian’s freedom to decline or withdraw participation at 
any point without compromising her infant’s future medical care. Up to 4 additional children from 
outside the EIT study may be recruited for the PK Step only, in the event that EIT children are not 
available for recruitment. These children may be recruited from Botswana government ART clinics or 
other treatment clinics in Botswana including the Botswana-Baylor Children’s Clinical Center for 
Excellence. 
 
Study investigators will prioritize optimizing participant education and informed consent procedures for 
the study. Participant understanding of scientific information, research methods, and human subjects 
rights can be enhanced through the following: 1) full, standardized disclosure of study-related 
information in both written and verbal formats, 2) minimizing the reading level and enhancing the 
visual display of written documents, 3) providing adequate time and opportunity for participants to 
read/hear about, reflect upon, ask questions about, and discuss the research.  
 
13.4. Risks and Benefits 
 
VRC01LS and 10-1074 are expected to be safe for children, and antibody-related adverse events 
other than possible injection site reactions or infiltrations are not anticipated. Risks also include the 
potential for viral rebound, and possibly acute retroviral syndrome. Increased seeding of the viral 
reservoir is also a possibility, although the clinical consequences of this are not known. Frequent viral 
load monitoring and early re-start of ART will minimize the potential risks of viral rebound and 
reservoir seeding to a very low level. The potential benefit for children in this study who remain virally 
suppressed during treatment with dual bNAbs is an extended period off ART with the potential for 
increased patient/caregiver satisfaction and reduced long-term toxicities, and the theoretical benefit of 
a broader immune response to HIV. There is also substantial scientific benefit from the knowledge 
gained, including benefit for other children in Botswana.  
 
13.4.1. Risks 
 
13.4.1.1 Stigma / Confidentiality / Coercion: Some parents/guardians of children enrolled in the 
study, or the children participants themselves might be subject to stigma or the perception of stigma if 
they participate in the study, especially regarding HIV status disclosure. However, most participants 
are already being followed in the EIT study and we are not aware of issues or concern about stigma 
from study clinic visits. The ability to remain off daily ART may reduce stigma in the household or 
community by moving all HIV-related treatment to the study clinic during the period of dual bNAb 
therapy. Measures to protect confidentiality of data are in place that include computer encryption and 
use of subject identifiers instead of personal identifiers, with limited/encrypted access to the linkage 
between subject and personal identifiers. 
 
Coercion to enroll in the study will be avoided by the balanced consent process and the limited 
amount of travel and time reimbursement which is set at a level approved by the ethical review 
boards.  
 


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13.4.1.2. Blood Draws: Blood volumes are an important consideration for this protocol, and will be 
minimized to the greatest extent possible at every visit. A summary for multiple guidelines on this 
topic, published by WHO in the WHO Bulletin, is as follows: “Existing guidelines for blood sample 
volume limits (ranging from 1–5% of total blood volume within 24 hours and up to 10% of total blood 
volume over 8 weeks) are consistent with the limited evidence available on “minimal risk” to children.  
Lower limits for sick children are advisable, and a maximum of 3 ml/kg post-neonatally within 24 
hours (3.8% of total blood volume), in line with United States policy, seems to be a reasonable 
guideline, although each study must be judged on its own merits and greater caution may be needed 
in children with illnesses that impair the replenishment of blood volume or hemoglobin [71].” The NIH 
Clinical Center also provides guidance for maximal allowed blood volumes allowed in research. The 
NIH recommends a limit of 5 mL/kg per single blood draw and a limit of 9.5 mL/kg in any 8-week 
period.  
 
We will draw no more than 12 mL at any draw during the study, and less at most visits. If additional 
clinical blood draws occur, study staff will account for these draws and make adjustments in the 
volume drawn for the study if needed. However, given that all children will be at least 96 weeks of 
age, we expect them to be over 10 kg (which is ~ 5th percentile). By established limits above, a 10 kg 
child would be able to have up to 50 mL of blood per draw (we will only draw 12 mL), and up to 95 mL 
in an 8 week period (the maximum in this study would be much less). Thus, we believe that the blood 
draw volumes for the study are well-within safety parameters, even if a child is at 5th percentile or 
lower in weight.  
 
13.4.1.3. VRC01LS and 10-1074: Passive polyclonal antibody products have been used for treatment 
and prophylaxis with excellent safety profiles over many decades. These agents include hepatitis B 
immunoglobulin (HBIG), Respigam®, Cytogam®, HIVIg, and IVIG.  In a large study of IVIG to prevent 
infection in preterm infants published in 2011, adverse events were rare and did not differ between 
IVIG and placebo [41]. However, few children have received VRC01LS and none have received 10-
1074, and while safety and PK data are available from children/adults, there are unknowns. Among 
children and adults who have participated in prior studies, only minor safety concerns were identified 
with these agents. Children will be closely monitored for these events. Review of detailed safety and 
PK testing will occur for all children enrolled in the PK Step and the first 6 children in Step 1 (see 
below Section 13.8). 
 
13.4.1.4. Antiretroviral treatment interruption: Standard ART will be paused during this study after 
at least 8 weeks of overlap between standard ART and dual bNAb therapy. The BHP laboratory use 
the sensitive Roche Taqman assay, which has limit of quantification to <40 copies/mL to monitor HIV 
RNA in this period, and will also use Qualitative HIV DNA for those who are negative at study entry as 
a potentially more sensitive measure for viral rebound. Although a lower limit of detection is possible 
when large blood volumes are obtained (a limiting factor when treating children), the lower limit for 
clinically defining children who have reservoirs low enough to participate in this trial is unknown and 
we believe that using clinically available and interpretable cut-off of <40 copies/mL is appropriate. The 
goal of this study is to prevent viral rebound using VRC01LS and 10-1074 (i.e., these agents will 
serve as effective alternate therapy). However, even if viral rebound occurs, the risk is expected to be 
small. Analytic treatment interruptions have been performed safely in HIV-positive patients, and have 
been helpful in determining the extent of viremia, viral rebound and changes in immune function 
following initiation of a treatment modality, such as ART. Analytical treatment interruption (interruption 
until plasma viremia returns followed by re-initiation of ART, or re-initiation of ART shortly after return 
of plasma viremia) is different from structured treatment interruptions that have been studied as 
potential ART sparing treatment strategies. Episodic antiretroviral therapy guided by CD4+ counts in 
such structured treatment interruptions often involve intermittent and repeating cessation of therapy in 
viremic individuals for months at a time, and may be associated with increased risk of opportunistic 


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disease or death from any cause. We are not planning on sustained or episodic treatment 
interruptions in the setting of plasma viremia. Although studies in adults such as SMART [72] and 
Trivican [73] have led to concerns regarding treatment interruption, there are 2 reasons why the 
proposed strategy is expected to be safe if viral rebound does occur: 1) frequent monitoring of viral 
rebound, and 2) unique characteristics of children and safety of previous treatment interruption trials 
among children. In SMART, unchecked viremia for long periods of time lead to a pro-inflammatory 
state and immune dysregulation. By contrast, in the proposed study ART will be resumed upon 
confirmed detection of viremia, thus limiting the risk of uncontrolled viral replication. Interruption 
studies in children have not replicated concerning findings in adults [74-76], including the Bana Study 
performed in Botswana (personal communication, E. Lowenthal, 2016). Although drug resistance may 
be a concern with repeated interruption of NNRTI-based ART, resistance is not anticipated with a 
single interruption and resumption of PI-based ART [77], especially given the expectation that if viral 
rebound occurs in this population it will do so after all ART levels are undetectable. Finally, preliminary 
data from the first 10 children in the EIT study suggests that even those children who experience 
occasional viral rebound have low viral reservoir (median ~ 5 copies/million cells) at 84-96 weeks of 
life, suggesting that brief plasma rebounds may not impact viral reservoir to a large extent (BHP, 
unpublished data, January 2018). 
 
The VRC01LS and 10-1074 maintenance in this study will be performed in a carefully monitored 
manner. ART withdrawal will be followed by weekly viral load monitoring for 4 weeks, and 2-weekly 
monitoring thereafter (however, if HIV RNA is 40-400 copies/mL, or if there is a newly positive 
qualitative DNA PCR, weekly HIV RNA monitoring will continue). Children will be restarted on ART 
(the same regimen as prior to interruption) if they have a single viral load ≥400 copies/mL. If patients 
experience viral rebound, they will be followed with viral load testing until they achieve viral 
suppression (<40 copies mL), at which time, routine clinical monitoring will be continued.  
 
The risk of developing antiretroviral resistance after analytic treatment interruption is small, and similar 
to continuous therapy groups in large trial populations [78]. Although this study proposes a much 
more limited analytical treatment interruption, HIV resistance testing will be performed if viral 
suppression has not been achieved 12 weeks following ART re-initiation.  
 
Children who rebound in the setting of VRC01LS and 10-1074 may exhibit resistance to these bNAbs, 
which usually occurs by selection for pre-existing resistance mutations (and is felt to be less likely in 
early-treated low reservoir children). If resistance occurs to one or both bNAbs, it would indicate that 
there is limited utility in using the same bNAb agent in future studies or treatment settings for the child. 
 
13.4.2. Benefits: Results from this study may provide a proof-of-concept that may benefit other 
children in Botswana in the future, including those who may be unable to take ART or to remain 
suppressed on ART. There are no known individual benefits to study participants. However, it is 
possible that some may indirectly benefit from the potential to remain off ART for an extended period 
of time while viral suppression is closely monitored and maintained, with potential medical and 
psycho-social benefits that accompany this break from daily ART. It is also plausible that participants 
could potentially have improved immunologic responses to HIV if viral rebound does occur later in life 
at a time of non-adherence. 
 
13.4.2.1. Time off ART: Given the unique characteristics of children in this study and the possibility 
that up to 70% might remain without viral rebound for up to 24 weeks, the potential advantages of 
identifying children who may remain off ART for long periods of time (and avoid potential ART 
toxicities) are substantial. Benefits of remaining off ART include patient preferences (including 
potential reduced stigma of taking daily medication), and the avoidance of possible long-term ART 
toxicities that include impaired growth and endocrine effects [2, 3], lipodystrophy [4], hematologic 


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toxicities [5], renal toxicity [6, 7], bone density effects [8-10], cardiovascular disease [11-13], and 
possible neurodevelopmental effects [14]. In addition, strategies that allow time off ART are highly 
desirable for many patients and caregivers for reasons related to treatment fatigue, travel, stigma, or 
other factors [15]. 
 
13.4.2.2. Immune Responses: Another potential benefit of bNAb use in children is the potential for 
immunologic recognition of HIV and avoidance of acute retroviral syndrome in the event that viral 
rebound occurs either during the study or at a later period in life. It is expected that early treated 
children will have almost no immune recognition of HIV, and therefore, at a future period in life where 
viral rebound occurs it may do so with high viral load and accompanying antiretroviral syndrome. 
VRC01LS and 10-1074 may enhance immune responses to HIV, and may therefore mitigate the 
possibility of antiretroviral syndrome for participants in this study. 
 
13.4.2.3. Proof of Concept: Dual bNAb therapy with VRC01LS and 10-1074 may will help answer 
critically important questions for HIV curative research, including whether early-treated children can 
remain virally suppressed with dual bNAb therapy; what markers predict ongoing suppression or 
delayed viral rebound; and modification of immune responses by bNAbs. As bNAb research 
progresses, and as longer-acting agents are developed, bNAbs may become a viable strategy for viral 
suppression and for allowing time off ART for patients in Botswana and elsewhere. Such a strategy 
may be particularly important for children during times of growth and development, and during times 
when adherence to daily ART is challenging. For some children who cannot receive daily ART or who 
fail to suppress viral load on standard ART, a bNAb-based strategy may serve as a viable future 
alternative. 
 
13.4.3. Risks/Benefits: The risks of the study are mitigated by the close monitoring that will occur. 
While there may be no direct benefit to individual participants in the study, there are several potential 
benefits for those who are able to maintain viral suppression during the dual bNAb therapy. There are 
several benefits associated with the proof-of-concept that may benefit HIV-infected children in the 
future. 
 
 
13.5. Adherence to Human Subjects Requirements 
 
Study participants will be recruited, enrolled, and followed in Botswana. Adherence to human subjects 
regulations will primarily be the responsibility of both Harvard T.H. Chan School of Public Health and 
Botswana staff. The BHP team will adhere with all requirements by:  
 
• 
Developing a study protocol that is able to meet its stated research objectives, and thus reflect 
adequate risk-benefit ratios for human subjects. 
• 
Specifying study procedures in the protocols that protect the rights and safety of human 
subjects. 
• 
Developing an informed consent form that includes all elements of informed consent required 
by Federal regulations and accurately represents study requirements, risks, and benefits in 
language that is understandable to study participants. 
• 
Including human subjects considerations and requirements in study training sessions. 
• 
Monitoring adherence to protocol specifications and human subjects requirements. 
 
This proposal will be submitted to the Institutional Review Boards (IRB) of the Botswana Ministry of 
Health (the Health Research and Development Committee, or HRDC, and to the Harvard T.H. Chan 
School of Public Health.  


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13.6. Procedures for Minimizing Potential Risks 
 
1) Identification and disclosure of HIV Status: Children participating in our study (or their parents) may 
experience stigma from being thought to be HIV-infected.  We have spent several years working to 
reduce the stigma concerns among participants in previous studies (including the EIT study, from 
which most participants will be drawn), and have had success in these efforts. We have dedicated 
health educators at each site, and we provide extensive counseling during the screening process and 
at all subsequent visits, as needed.  We invite parents/guardians of participants to bring family 
members or significant others to the clinic if they wish to do so, for joint counseling.  We have also 
helped to develop support groups in the community for HIV-infected individuals.  
 
Any information provided by the participant and/or the participant’s parent/guardian, including and 
especially their HIV status, will be subject to strict confidentiality. Special care will be exercised in all 
interactions with the participant and his/her parent/guardian to ensure that participation or non-
participation in the study does not cause release of information.  
 
The protection of information given in interviews is standard procedure. The identity of the participants 
will be only kept at the clinic sites in a locked facility, and in an encrypted database. Identifying 
information will be stored in separate locked file cabinets, and a numeric code will be assigned to the 
completed questionnaires.  
 
2) Recruitment and Informed Consent: A parent/guardian will undergo an informed consent process 
and sign a written informed consent for their child’s participation in this study. The study informed 
consent form will contain all of the required elements as outlined by 45 CFR, 46.116. Informed 
consent forms for BHP studies are translated into Setswana, and back-translated into English. These 
translations are approved by both IRBs at Harvard School of Public Health and at the Botswana 
Ministry of Health (the HRDC). In general, Setswana-speaking nurses conduct the informed consent 
process with the potential participant’s parent/guardian, and physicians will review and discuss the 
process and answer questions after the nurse goes through the consent form. In a private setting, the 
nurse verbally reviews the contents of the entire informed consent form with the child’s parent or legal 
guardian (regardless of literacy level). For more complicated studies, this process can take 1-2 hours, 
allowing sufficient time for the parent/guardian to ask questions. Schematics/diagrams are used when 
possible. Sometimes, informed consent occurs over two separate visits. At the end of the discussion 
regarding the study (and full review of the informed consent form), the parent/guardian is given the 
opportunity to read the form, to ask questions, etc. Then, the nurse and study physician usually review 
the parent/guardian’s understanding of study purpose, procedures, risks, benefits, etc.—the most 
important elements of the study from a human subjects perspective—to ensure that the 
parent/guardian understands these prior to the parent/guardian and the study staff member who 
conducted the informed consent process signing the form. 
 
3) Safety and toxicity and PK monitoring plans outlined in the protocol, and approved by IRBs, SMC 
and study sponsor, will ensure the early identification of events and safe resolution of any possible 
toxicities. Post-infusion monitoring for 2-4 hours will occur following the first infusion (4 hours for the 
first cohort receiving 10-1074 in the PK Step). If initial doses are tolerated 1-hour post-infusion 
monitoring will occur with subsequent infusions. 
 
4) Blood Draws: The study will follow research criteria established by NIH for safe volumes of blood 
drawn in children. Study physicians will carefully review all clinical history and weights to be sure that 
established safe blood volumes drawn at each visit or over time are not exceeded and prioritize blood 


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draws, as needed, if limits are being approached based upon a child’s weight. Physicians will monitor 
for signs and symptoms of anemia, including pallor, tachycardia, and scheduled full blood count. 
Close clinical monitoring for anemia will occur in all children. 
 
13.7. Participation of Children, Women and Minorities 
 
Children are included in this research plan and will comprise 100% of those enrolled in the study. BHP 
study sites are accessible to individuals drawn from different ethnic groups, all of whom have access 
to government clinics and who are offered HIV testing by the National Program to prevent MTCT and 
ART, if HIV-infected.  
 
13.8. Monitoring and Interim Analyses 
 
An independent, external Safety Monitoring Committee (SMC) will be established for this study, 
consisting of approximately 5 members, and approved by the study sponsor. Committee members will 
include those with expertise in HIV treatment trials and pediatrics.  The primary role of the SMC is to 
help protect the safety of participants in the study. The reviews of interim data by the SMC will be 
triggered by criteria described below, but will occur at least every six months unless otherwise 
recommended by the SMC.  The SMC will make recommendations to the study team and to the study 
sponsor. Following SMC reviews, the sponsor and study team will communicate and discuss the 
findings. A response plan will be developed by the study team, and sign off by the sponsor will be 
required to implement the response. 
 
13.8.1. Quarterly Reporting and SMC Triggers for Safety or Stopping Criteria. Monthly safety and 
accrual monitoring by the protocol team will occur throughout the study. Reports will be provided to 
the study sponsor and IRBs quarterly. Regularly scheduled conference calls will occur between 
members of the study team (including 1 or more PIs) and the Medical Officer at least quarterly. 
Serious adverse events that are EAEs may trigger an early review by the SMC (SAE-category EAE 
reporting will be used for most of the study). The occurrence of any EAE will prompt immediate review 
by the PIs and Medical Officer. The attribution of relationship of an EAE to study product will be 
discussed and the relationship will be determined by the study team, taking into account the site and 
the Medical Officer’s assessment of the event. Interpretation of 10-1074 or VRC01LS relationship to 
adverse events will be based on the type of event, the relationship of the event to the time of 
immunization, the known biology of the monoclonal antibody and the investigators’ medical judgment. 
Gradation of relationship will use the following terminology: “not related”, and “related.” The 
occurrence of 2 EAEs determined to be related to study product will trigger an SMC review. This may 
lead to a recommendation for study discontinuation in consultation with the study team and sponsor. 
Due to the fact that Grade 3 neutropenia and anemia are common in children on ARVs, and the fact 
that hemolyzed specimens may falsely lead to Grade 3 hyperkalemia values, these toxicities will not 
be counted in the real-time safety review algorithm.  
 
NOTE: If at any time during the study the triggers for SMC review are met, the study will be paused to 
new accruals and an SMC review performed within 7 days. The SMC will decide what additional data 
they would like to see and advise the study team on how to proceed.  
 
Review of Data from PK Step 
 
After all 12 PK Step participants complete the PK Step, safety, PK, and viral suppression data will be 
reviewed within 8 weeks by the study team including its sponsor representatives, and SMC. All PK 


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data from the PK Step will be assessed based on pre-specified PK trough targets; the study team will 
determine if median trough concentrations are above the pre-specified targets (see Section 2.8.1) and 
present this information in a written report to the SMC. In addition, outlier concentrations will be 
presented and reviewed; the study team expects no more than 2 participants to have trough 
concentrations below 115 mcg/mL for VRC01LS and no more than 2 participants to have trough 
concentrations below 5mcg/mL for 10-1074. The SMC and the study team will review any cases of 
outlier PK concentrations and make individual recommendations about whether a child with these 
levels should proceed to Steps 1-3.  The SMC will review safety data utilizing pre-defined safety 
criteria defined as follows: 0 EAEs support study continuation; 1-2 EAEs related to study product but 
for different events warrant concern; >2 EAEs, or 2 of the same EAEs that are related to study product 
may lead to a recommendation for study discontinuation. If safety criteria are met, and if the PK data 
are in the pre-specified range (see Section 2.1.8), Step 1 will begin unless otherwise recommended 
by the SMC. If the dosing and frequency of bNAbs established in the PK Step is accepted, it will 
continue to be used for the first 6 participants in Step 1 (see additional safety review below). If a 
change in dosing is recommended by experts on the study team (or by the SMC, if it does not accept 
the team’s recommendation), adjustments will occur and IRB and study sponsor approval will be 
sought regarding required protocol changes prior to starting Step 1. The recommendations by the 
study team or by the SMC may include early termination of the study, if warranted by the safety/PK 
data, or a re-design of the study as approved by the study sponsors and regulatory agencies. 
 
 
Review of Safety and PK Data from Step 1 (first 6 participants) 
 
Safety, PK, and viral suppression data for the first 6 Step 1 participants will be reviewed within 8 
weeks by the study team including its sponsor representatives, and SMC. All PK data will be 
assessed by the study team based on pre-specified PK trough targets which are the same as those 
used in the PK Step. The review will confirm that PK targets are met during dual bNAb administration. 
Safety criteria for the Step 1 data will be reviewed by the SMC, using similar criteria as for the PK 
Step: 0 EAEs support study continuation; 1-2 EAEs related to study product but for different events 
warrant concern; >2 EAEs, or 2 of the same EAEs that are related to study product may lead to a 
recommendation for study discontinuation. If safety criteria are met, and if the PK data are in the pre-
specified range (see Section 2.1.8), unless otherwise recommended by the SMC, the first 6 
participants will enter Step 2 and enrollment of additional participants into Step 1 will continue. If the 
PK data are in range and no dosing changes for the bNAbs are required, the dosing will continue to 
be used for the remainder of the study unless new data emerges requiring additional review. If a 
change in dosing is recommended by experts on the study team (or by the SMC, if it does not accept 
the team’s recommendation), IRB and study sponsor approval will be sought regarding required 
protocol changes. The recommendations by the study team or by the SMC may include early 
termination of the study, if warranted by the safety/PK data, or a re-design of the study as approved 
by the study sponsors and regulatory boards. 
 
Review for Early Stopping Criteria in Step 2 
 
The SMC will review safety and virologic outcome data every six months after the first participant 
enters Step 2 or on a frequency recommended by the SMC, but at least annually.  During Step 2, as 
well as a possible early review triggered by the occurrence of EAEs as outlined above, early review by 
the SMC will be triggered if 2 participants are unable to achieve re-suppression of HIV-1 RNA to <40 
copies/mL within 12 weeks after re-starting ART. Otherwise, time to re-suppression will be reported to 
the SMC as part of their regular reviews. 
 


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Earlier reviews will also be triggered if all seven of the first seven participants in Step 2 experience 
viral rebound or if 13 of the first 14 participants in Step 2 experience viral rebound during the 24 week 
period of ART interruption. As a guideline for evaluating the proportion of participants experiencing 
viral rebound, if a true success rate (i.e. no rebound within 24 weeks) of 30% seems unlikely, then the 
study team feels that termination of further enrollment to Step 2 and restart of ART among participants 
already enrolled would be appropriate.  Specifically, if all of the first seven participants in Step 2 
experience viral rebound before or at week 24 (so no successes), or 13 or more of the first 14 
participants (so no or only one success), then termination of further enrollment to Step 2 and restart of 
ART among participants already enrolled may be appropriate. These criteria have been chosen on the 
basis that the observed rates would be unlikely (probability 0.10) if the true success rate is 30%.  
Conversely, observed rates meeting these criteria would be likely (probability 0.88) if the true success 
rate is 5% (a value chosen based on what was observed in the CHER [52] and Kenya studies [58]).  
Note, however, that the SMC will be presented with all available virologic outcome data for all 
participants who have been enrolled at the time that either of these triggers are met in order to inform 
their recommendations. No additional enrollments will occur during this period of SMC review. 
 
Routine reports to the SMC will occur every 6 months unless otherwise recommended by the SMC. 
Built-in safety measures for the study include a plan to enroll slowly, with no more than two children 
enrolling per week. Additional reviews or an altered schedule of review or trigger for early review may 
be instituted at the discretion of the SMC. The SMC will make recommendations for the study team 
and Sponsor at each of these reviews regarding whether the study should continue as originally 
designed. Statistical analyses will be prepared in advance of each SMC meeting.  
 
13.9. 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, infusing antibodies, and shipping and handling of 
all specimens for this study, as currently recommended by the Centers for Disease Control and 
Prevention. 
All infectious specimens will be sent using the ISS-1 SAF-T-PAK or equivalent package that is 
compliant to the International Air Transport Association Dangerous Goods Regulations Packing 
Instruction 602.  Please refer to individual carrier guidelines (for example: Federal Express, Airborne, 
etc.) for additional specific instructions. Appropriate shipping permits will be obtained. 
 
13.10. Vertebrate Animals 
 
This project does not involve vertebrate animals. 
 
14. ADMINISTRATIVE PROCEDURES  
 
14.1. Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, the protocol 
and the protocol informed consent forms will be approved by the IRBs in Botswana and in Boston, 
and any other applicable regulatory entity. Upon receiving final approval, investigators will submit all 
required protocol registration documents to the DAIDS Protocol Registration Office (PRO) at the 


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DAIDS Regulatory Support Center (RSC). The DAIDS PRO will review the submitted protocol 
registration packet to ensure that all of the required documents have been received. Site-specific 
informed consent forms 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.  
 
Upon receiving final IRB/EC and any other applicable regulatory entity approval(s) for an amendment, 
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 ICF(s) 
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: https://rsc.niaid.nih.gov/clinical-research-sites/daids-
protocol-registration-policy-and-procedures-manual.  
 
14.2. Regulatory Oversight 
 
This study will be sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) which 
is part of the United States National Institutes of Health (NIH). The study product VRC01LS is 
provided by the NIAID Vaccine Research Center (VRC). The study product 10-1074 is provided by the 
Division of AIDS (DAIDS). DAIDS within the NIAID will be 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. 
 
An IND application to the Division of Antiviral Drug Research, Center for Drug Evaluation and 
Research (CDER), FDA, will be submitted. To support the IND application, the investigator 
brochure for VRC-HIVMAB080-00-AB (VRC01-LS) and 10-1074 will be submitted to the FDA. 
These documents include all relevant information on physical, chemical and pharmaceutical 
properties of the study drugs, summarize results from non-clinical and clinical studies and list all 
toxicology and safety data. Cross-reference to the existing IND for VRC01LS (held by DAIDS) and 
10-1074 (held by Rockefeller University) will also occur for the IND application of this clinical trial.   
 
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 SOPs. These SOPs will be updated and/or supplemented as needed to 
describe roles, responsibilities, and procedures for this study. 
 
14.4. ClinicalTrials.gov 
 
This protocol will be subject to the United States Food and Drug Administration Amendments Act of 
2007 (FDAAA), including registration in ClinicalTrials.gov.  
 
 
 


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VRC01 in healthy adults. Clin Exp Immunol 2015,182:289-301. 
31. 
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. 337-46. 
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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. 
33. 
Wu, X., et al., Rational design of envelope identifies broadly neutralizing human monoclonal 
antibodies to HIV-1. Science, 2010. 329(5993): p. 856-61. 
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Uprety, P., et al., Cell-Associated HIV-1 DNA and RNA Decay Dynamics During Early Combination 
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Rolland M, Sanders-Buell E, Bose M, et. al. Resurgence Of Hiv-1 Founder Viruses Following 
Antiretroviral Treatment Interruption. 24th Conference on Retroviruses and Opportunistic 
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Ackerman ME, Alter G. Opportunities to exploit non-neutralizing HIV-specific antibody activity. Curr 
HIV Res 2013,11:365-377. 
37. 
Bolton DL, Pegu A, Wang K, McGinnis K, Nason M, Foulds K, et al. Human Immunodeficiency Virus 
Type 1 Monoclonal Antibodies Suppress Acute Simian-Human Immunodeficiency Virus Viremia and 
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Goulder PJ, Lewin SR, Leitman EM. Paediatric HIV infection: the potential for cure. Nat Rev Immunol 
2016,16:259-271. 
40. 
Ahmed, R., Oldstone, M. B. & Palese, P. Protective immunity and susceptibility to infectious 
diseases: lessons from the 1918 influenza pandemic. Nat. Immunol. 8, 1188–1193 (2007). 
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Group IC, Brocklehurst P, Farrell B, King A, Juszczak E, Darlow B, et al. Treatment of neonatal sepsis 
with intravenous immune globulin. N Engl J Med 2011,365:1201-1211. 
42. 
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. 
43. 
IMPAACT P1112. Open-Label, Dose-Escalating, Phase I Study to Determine Safety and 
Pharmacokinetic Parameters of Subcutaneous (SC) VRC01 and VRC01LS, Potent Anti-HIV Neutralizing 
Monoclonal Antibodies, in HIV-1-Exposed Infants. 
http://impaactnetwork.org/DocFiles/P1112/V3/P1112_Protocol_V3.0_07APR2017_with_PSP_LoA1_
CM1_2OCT2017.pdf (Accessed 3Jan18). 
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Cunningham CK ME, Capparelli E, et al. Safety and Pharmacokinetics of the Monoclonal Antibody, 
VRC01, in HIV-Exposed Newborns. In: 24th Conference on Retroviruses and Opportunistic Infections. 
Seattle, WA; 2017. 
45. 
Gaudinski MR, Coates EE, Houser KV, Chen GL, Yamshchikov G, Saunders JG, et al. Safety and 
pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-
label clinical trial in healthy adults. PLoS Med 2018,15:e1002493. 
46. 
Investigator's Brochure: VRC01LS (VRC-HIVMAB080-00-AB) A Broadly Neutralizing HIV-1 Human 
Monoclonal Antibody. Version 3.0. Release Date August 21, 2017. 
47. 
Investigator's Brochure: 10-1074 A Broadly Neutralizing Human Monoclonal Antibody Targeting HIV-
1 gp120. Edition no. 3.0; Release date: August 10, 2017. The Rockefeller University. 
48. 
Rockefeller University. 10-1074 Original IND 123713. Section 2.6.6 Toxicology Written Summary. 
49. 
Nishimura Y, Martin MA. Of Mice, Macaques, and Men: Broadly Neutralizing Antibody 
Immunotherapy for HIV-1. Cell Host Microbe 2017,22:207-216. 
50. 
Cohen YZ, Butler A, Levin R, Millard K, Pack M, Belblidia SA, Dizon JP, Shimeliovich I,  Seaton K, Yates 
NL, Tomaras G, Zingg M, Seaman MS, Nussenzweig M, Caskey M. A Phase 1 Trial of the Combination 
of 3BNC117 and 10-1074 In HIV-Uninfected Adults. 25th Conference on Retroviruses and 
Opportunistic Infections. March 4–7, 2018, Boston, MA. Abstract Number: 1062. 
51. 
Deng R, Iyer S, Theil FP, Mortensen DL, Fielder PJ, Prabhu S.  Projecting human pharmacokinetics of 
therapeutic antibodies from nonclinical data What have we learned?  mAbs 3:1, 61-66; 
January/February 2011. 
52. 
Violari A, Chan M, Otwombe KN, Panchia R, Jean-Philippe P, Gibb D, Cotton M, Babiker A.  Time to 
viral rebound after stopping ART in children treated from infancy in CHER. 25th Conference on 
Retroviruses and Opportunistic Infections, Boston, MA. March 4-7, 2018. Abstract No. 137. . 
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Henrich TJ, Gallien S, Li JZ, Pereyra F, Kuritzkes DR. Low-level detection and quantitation of cellular 
HIV-1 DNA and 2-LTR circles using droplet digital PCR. J Virol Methods 2012,186:68-72. 
54. 
Mendoza P, Gruell H, Nogueira L, Pai JA, Butler AL, Millard K, et al. Combination therapy with anti-
HIV-1 antibodies maintains viral suppression. Nature 2018,561:479-484. 
55. 
Ibrahim MR, Maswabi K, Ajibola G, Moyo S, Hughes M, Auletta-Young C, Kuritzkes D, Lichterfeld M, 
Makhema J, Shapiro RL. Targeted HIV Screening at Birth Can Identify the Majority of In Utero 
Transmissions. 24th Conference on Retroviruses and Opportunistic Infections, Seattle, February 13–
16, 2017. Abstract 790. 


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56. 
Persaud D, Palumbo PE, Ziemniak C, Hughes MD, Alvero CG, Luzuriaga K, et al. Dynamics of the 
resting CD4(+) T-cell latent HIV reservoir in infants initiating HAART less than 6 months of age. Aids 
2012,26:1483-1490. 
57. 
Lee GQ, Orlova-Fink N, Einkauf K, Chowdhury FZ, Sun X, Harrington S, et al. Clonal expansion of 
genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells. J Clin Invest 2017,127:2689-2696. 
58. 
Wamalwa D, Benki-Nugent S, Langat A, Tapia K, Ngugi E, Moraa H, et al. Treatment interruption 
after 2-year antiretroviral treatment initiated during acute/early HIV in infancy. Aids 2016,30:2303-
2313. 
59. 
Edgar RC. MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic 
Acids Res 2004,32:1792-1797. 
60. 
Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, et al. Clustal W and 
Clustal X version 2.0. Bioinformatics 2007,23:2947-2948. 
61. 
Tobin J. Estimation of Relationships for Limited Dependent Variables. Econometrica 1958,1:24-36. 
62. 
Huang Y, Wu H, Acosta EP. Hierarchical Bayesian inference for HIV dynamic differential equation 
models incorporating multiple treatment factors. Biom J 2010,52:470-486. 
63. 
Luzuriaga K, Gay H, Ziemniak C, Sanborn KB, Somasundaran M, Rainwater-Lovett K, et al. Viremic 
relapse after HIV-1 remission in a perinatally infected child. N Engl J Med 2015,372:786-788. 
64. 
Persaud D, Luzuriaga K. Absence of HIV-1 after treatment cessation in an infant. N Engl J Med 
2014,370:678. 
65. 
Henrich TJ, Hanhauser E, Marty FM, Sirignano MN, Keating S, Lee TH, et al. Antiretroviral-free HIV-1 
remission and viral rebound after allogeneic stem cell transplantation: report of 2 cases. Ann Intern 
Med 2014,161:319-327. 
66. 
Bendall SC, Simonds EF, Qiu P, Amir el AD, Krutzik PO, Finck R, et al. Single-cell mass cytometry of 
differential immune and drug responses across a human hematopoietic continuum. Science 
2011,332:687-696. 
67. 
Lichterfeld M, Yu XG, Waring MT, Mui SK, Johnston MN, Cohen D, et al. HIV-1-specific cytotoxicity is 
preferentially mediated by a subset of CD8(+) T cells producing both interferon-gamma and tumor 
necrosis factor-alpha. Blood 2004,104:487-494. 
68. 
Lichterfeld M, Mou D, Cung TD, Williams KL, Waring MT, Huang J, et al. Telomerase activity of HIV-1-
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PD ligand 1 in progressors. Blood 2008,112:3679-3687. 
69. 
Lichterfeld M, Kaufmann DE, Yu XG, Mui SK, Addo MM, Johnston MN, et al. Loss of HIV-1-specific 
CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-
specific CD4+ T cells. J Exp Med 2004,200:701-712. 
70. 
Vigneault F, Woods M, Buzon MJ, Li C, Pereyra F, Crosby SD, et al. Transcriptional profiling of CD4 T 
cells identifies distinct subgroups of HIV-1 elite controllers. J Virol 2011,85:3015-3019. 
71. 
Howie S. Blood sample volumes in child health research: review of safe limits. Bulletin of the World 
Health Organization 2011;89:46-53. 
72. 
El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, Arduino RC, et al. CD4+ count-guided 
interruption of antiretroviral treatment. N Engl J Med 2006,355:2283-2296. 
73. 
Danel C, Moh R, Minga A, Anzian A, Ba-Gomis O, Kanga C, et al. CD4-guided structured antiretroviral 
treatment interruption strategy in HIV-infected adults in west Africa (Trivacan ANRS 1269 trial): a 
randomised trial. Lancet 2006,367:1981-1989. 
74. 
Bunupuradah T, Duong T, Compagnucci A, McMaster P, Bernardi S, Kanjanavanit S, et al. Outcomes 
after reinitiating antiretroviral therapy in children randomized to planned treatment interruptions. 
Aids 2013,27:579-589. 
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Green H, Gibb DM. Treatment interruption in children with HIV infection. Curr Opin HIV AIDS 
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76. 
Palacios GC, Sanchez LM, Briones E, Ramirez TJ, Castillo H, Rivera LG, et al. Structured interruptions 
of highly active antiretroviral therapy in cycles of 4 weeks off/12 weeks on therapy in children 
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Dis 2010,14:e34-40. 
77. 
Souda S, Gaseitsiwe S, Georgette N, Powis K, Moremedi D, Iketleng T, et al. No Clinically Significant 
Drug Resistance Mutations In HIV-1 subtype C Infected Women After Discontinuation Of NRTI-Based 
Or PI-Based HAART For PMTCT In Botswana. J Acquir Immune Defic Syndr 2013. 
78. 
Fox Z, Phillips A, Cohen C, Neuhaus J, Baxter J, Emery S, et al. Viral resuppression and detection of 
drug resistance following interruption of a suppressive non-nucleoside reverse transcriptase 
inhibitor-based regimen. Aids 2008,22:2279-2289. 
 
 

SAP_001.pdf: 
TATELO (BHP107) 
Statistical Analysis Plan for Steps 1 to 3 
Version 2.0 
A Clinical Trial to Evaluate the Impact of Broadly Neutralizing 
Antibodies VRC01LS and 10-1074 on Maintenance of HIV 
Suppression in a Cohort of Early-Treated Children in Botswana 
(Dual bNAb Treatment in Children) 
Protocol Version 2.0 (dated December 20, 2018) 
Including LOA #1, LOA #2 and LOA #3, and CM#1, CM#2 and 
CM#3 
ClinicalTrials.gov Identifier: NCT03707977 
DAIDS-ES 38551 
IND#: 140909  
September 27, 2022 
Created by: 
Bryan Nelson, SM and Michael Hughes, PhD 
Harvard T.H. Chan School of Public Health 


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Table of Contents 
 
TABLE OF CONTENTS ................................................................................................................... 1 
VERSION HISTORY ........................................................................................................................ 2 
1 
INTRODUCTION ........................................................................................................................ 2 
1.1 
Purpose ............................................................................................................................ 2 
1.2 
Version History ............................................................................................................... 2 
2 
STUDY OVERVIEW ................................................................................................................... 3 
2.1 
Study Design ................................................................................................................... 3 
2.2 
Study Objective Addressed in this SAP ....................................................................... 4 
2.2.1 
Primary Objective ................................................................................................. 4 
2.3 
Hypotheses ...................................................................................................................... 4 
2.3.1 
Specific Aim 1 ....................................................................................................... 4 
2.4 
Overview of Sample Size Considerations .................................................................... 5 
2.5 
Overview of Formal Interim Monitoring ........................................................................ 5 
3 
OUTCOME MEASURES ........................................................................................................... 5 
3.1 
Specific Aim 1 Primary Outcome Measures ................................................................. 5 
3.2 
Specific Aim 1 Secondary Outcome Measures............................................................ 5 
4 
STATISTICAL PRINCIPLES ..................................................................................................... 5 
4.1 
General Considerations ................................................................................................. 5 
4.1.1 
Defining baseline .................................................................................................. 5 
4.1.2 
Analysis populations ............................................................................................ 5 
4.1.3 
Visit windows and schedule ................................................................................. 6 
4.1.4 
Adjustment for multiple comparisons ................................................................... 7 
4.1.5 
Summarizing continuous variables ...................................................................... 7 
4.1.6 
Missing data ......................................................................................................... 7 
4.1.7 
Defining SAEs ...................................................................................................... 7 
4.2 
Analysis Approaches ..................................................................................................... 7 
4.2.1.  
Baseline Characteristics ...................................................................................... 7 
4.2.2. 
Primary outcomes ................................................................................................ 7 
4.2.3. 
Secondary outcomes ........................................................................................... 8 
4.3. Exploratory objectives ................................................................................................... 9 
5. REPORT CONTENTS ............................................................................................................. 10 
6. ASSOCIATED DOCUMENTS ................................................................................................. 11 
 
 
 


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Version History 
 
Version 
Changes Made 
Date Finalized 
1 
Original Version 
10/27/2021 
2 
• 
Clarified primary safety outcome as occurring through 30 
days after the last study visit (this aligns with the intended 
outcome measure as posted on clinicaltrials.gov). 
• 
Revised plans for exploratory analysis evaluating 
characteristics of participants who experienced virologic 
rebound during Step 2 versus participants who did not 
experience rebound. 
• 
Edits for clarification.  
09/27/2022 
 
1 
Introduction 
1.1 
Purpose 
This Statistical Analysis Plan (SAP) describes primary and secondary outcome measures of the 
Tatelo study that will be included in the primary manuscript(s), and which address, at a minimum, 
the primary objective of the study for Steps 1, 2 and 3 (see study design section below for 
description of the Steps). This SAP outlines the general statistical approaches that will be used in 
the analysis of these Steps of the study. 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 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 for the Analysis Report will be 
included in the Analysis Implementation Plan (AIP).  
Analyses will be finalized once the last participant has completed the Week 24 study visit of Step 
3 and any relevant queries have been resolved.  Analyses addressing the pharmacokinetic (PK) 
component of the primary objective of the study using PK data collected in the PK Step and in 
Step 1a have been undertaken previously based on a PK Step SAP. 
1.2 
Version History 
Version 2.0 of the SAP includes the following changes compared with the previous version: 
• 
Clarified primary safety outcome as including adverse events occurring through 30 days 
after the last study visit (this aligns with the intended outcome measure as posted on 
clinicaltrials.gov).   


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• 
Revised plans for exploratory analysis evaluating characteristics of participants who 
experienced virologic rebound during Step 2 versus participants who did not experience 
rebound.  
• 
 Minor edits for clarification. 
2 
Study Overview 
2.1 
Study Design 
This study is a phase I/II, multi-site clinical trial of dual treatment with two broadly neutralizing 
monoclonal antibodies (bNAbs), VRC01LS and 10-1074, offered to HIV-1 infected virally 
suppressed children. The study planned to enroll up to 40 children from two participating sites in 
Botswana (Gaborone and Francistown).  Participants eligible for Tatelo were children with HIV who 
were enrolled in the Early Infant Treatment (EIT) Study (and started antiretroviral treatment [ART] 
shortly after birth), were at least 96 weeks old, received ART for at least 96 weeks, had HIV RNA 
<40 copies/mL for at least 24 weeks prior to entry, were willing to receive infusions of bNAbs, and 
met all other entry criteria.   
There are 4 Steps in the protocol: PK Step, Step 1, Step 2, and Step 3. In the PK Step, ART was 
continued and 6 study participants underwent safety evaluations and PK testing following a single 
dose of VRC01LS (administered at Week 0, Week 4, and Week 8), and 6 study participants 
underwent safety evaluations and PK testing following a single dose of 10-1074 (administered at 
Week 0, Week 4, and Week 8).                                                                                                                                           
Additional participants were eligible to be enrolled in Step 1 and were followed through Steps 1, 2 
and 3. In Step 1, ART was continued and dual bNAb treatment was given. In Step 2, ART was 
withdrawn and dual bNAb maintenance treatment continued. In Step 3, dual bNAbs were 
discontinued and participants re-started ART. Figure 1 provides a schematic of the study. Note 
that the first six participants enrolled in Step 1 participated in an additional PK component of the 
study to confirm dual bNAb dosing. This is referred to as Step 1a; PK data from this step have 
been analyzed previously. All participants were monitored for both safety and viral rebound 
throughout the study. 


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Figure 1: Study Schematic 
 
2.2 
Study Objective Addressed in this SAP 
This SAP addresses the following primary objective listed in the study protocol for Specific Aim 1 
(other than the PK component of the objective for the PK Step and Step 1a which has been 
addressed previously), which includes the major outcomes for evaluating the effect of the study 
treatment. Other study objectives in the protocol will be addressed separately.  
Analysis of the study objectives below will be analyzed under a proof-of-concept framework.  This 
study does not have a control arm; however, 95% confidence intervals will be reported.  
 
2.2.1 
Primary Objective 
2.2.1.1 
Specific Aim 1  
To conduct an interventional clinical trial to determine the safety, pharmacokinetics, dosing and 
antiviral efficacy of up to 24 weeks of maintenance VRC01LS and 10-1074 immunotherapy in 
early-treated HIV-1 infected children in Botswana. 
2.3 
Hypotheses 
2.3.1 
Specific Aim 1 
VRC01LS and 10-1074 will not be associated with serious adverse events (SAEs), and median 
trough concentrations at the doses used will be above established target values of 200 mcg/mL 
and 7.5 mcg/mL respectively [note, Letter of Amendment (LOA) #2 revised PK trough target for 
VRC01LS to 160mcg/mL at Day 56 of Step 1]. At least 70% of early-treated low-reservoir children 
will remain with HIV-1 RNA <400 copies/mL after 24 weeks of receiving VRC01LS and 10-1074 
maintenance. 


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2.4 
Overview of Sample Size Considerations 
Sample size considerations and estimated precision given in version 2.0 of the protocol are in 
relation to follow-up through the end of Step 2 of at least 20 children.  With a sample size of 20 
children (the minimum number expected), safety and PK evaluations will be descriptive, and there 
will be reasonable precision to estimate the proportion with HIV viral suppression. 
2.5 
Overview of Formal Interim Monitoring 
An independent and external Safety Monitoring Committee (SMC) was established to review 
interim study data, including safety, PK and viral load.  These reviews occurred at the end of the 
PK step, after the first 6 participants have completed at least 8 weeks of follow-up under Step 1 
and then at least every 6 months, and as recommended by the SMC.  Details are provided in 
section 13 of version 2.0 of the protocol and in LOA #3. 
3 
Outcome Measures 
3.1 
Specific Aim 1 Primary Outcome Measures  
• 
AEs graded for severity according to Division of AIDS Table for Grading the Severity of 
Adult and Pediatric Adverse Events (DAIDS AE Grading Table), assessed for association 
with treatment, and measured through 30 days after last study visit. Clinical Research 
Site staff make an initial assessment of association with treatment, followed by team 
review. In the event of any discordance, team assessment will be used.   
• 
HIV-1 RNA in plasma through week 24 of Step 2. 
3.2 
Specific Aim 1 Secondary Outcome Measures  
• 
VRC01LS and 10-1074 concentrations in serum measured through week 32 following 
Step 1 entry 
• 
Growth characteristics (sex-specific WHO standardized Z-scores for height for age and 
weight for age) measured at least monthly, including growth trajectories.  
4 
Statistical Principles 
4.1 
General Considerations 
4.1.1 
Defining baseline  
Baseline is the date of initiating dual bNAbs in Step 1 (labeled as Day 0 of Step 1).   
4.1.2 
Analysis populations 
The main analysis population is the population of children that receive any infusions in Step 1.  
Any children that enroll to the study but do not receive any infusions in Step 1 will be included in 
screening, accrual and eligibility summaries only.   


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4.1.3 
Visit windows and schedule 
The baseline visit, as defined above, is considered day 0. Baseline measurements are the last 
available measurement for a given parameter obtained prior to administration of this first infusion.  
The visit schedule is based on this day 0. 
Per protocol, the scheduled visit window begins at the midpoint from the previous visit and 
extends to the midpoint with the next visit.  During participation in Step 1 or Step 2, if a child 
needed to discontinue study treatment for any reason, he/she would complete final visit 
evaluations for the Step and enroll to Step 3.  
Children enrolled to Step 1a (first 6 participants) had initial visits at Day 0, Day 1, Week 1, Week 
4, Week 4 + 1 day, Week 5 and Week 8.  Infusions occurred at Day 0, Week 4 and Week 8.  
Single PK draws were made at all non-infusion visits and at Week 8, while more intensive PK 
draws occurred on Day 0 (pre-infusion, end of infusion and 1 hour post-infusion) and Week 4 
(pre-infusion, end of infusion and 1 hour post infusion at Week 4).  The Step 1a follow-up 
extended beyond Week 8 at 2 week intervals until Week 32 (which also served as Step 2 Week 
0), with infusion and single PK draws every 4 weeks.  SMC review and approval of Step 1a 
results was required prior to starting Step 2 
Step 1b (for participants enrolled after the first six participants in Step 1/SMC review) visits were 
scheduled at Day 0, Week 1, Week 4, Week 5 and Week 8 (Step 2 Week 0). Dual bNAbs were 
administered at Day 0, Week 4 and Week 8; PK measures were limited to pre-dose trough at 
Week 4 and Week 8 (which also served as Step 2 Week 0).  
If a participant had a confirmed viral load result ≥40 copies/mL during Step 1 (either 1a or 1b), 
he/she would discontinue bNAbs, complete visit procedures equivalent to those outlined for Step 
1 Week 8, and enter Step 3 (and not participate in Step 2). 
Step 2 visits occurred every week for the first 4 weeks, then every 2 weeks through Step 2, Week 
24, with dual bNAbs administered and PK trough draws every 4 weeks.  
If a participant experienced a single viral rebound ≥400 copies/mL in Step 2, ART was re-started 
(and bNAbs discontinued). If HIV-1 RNA was ≥400 copies/mL prior to the end of Step 2, all 
evaluations ordinarily scheduled at Week 24 were performed immediately prior to ART re-
initiation. If HIV-1 RNA was ≥40 copies/mL but <400 copies/mL, or if qualitative DNA turned from 
negative to positive, virologic monitoring tests were repeated weekly.  All participants who did not 
experience viral rebound prior to week 24 entered Step 3 at the same visit as Step 2 Week 24. 
In Step 3 visits were scheduled at 4 weeks from Step 3, Day 0 (which was the same visit as Step 
2 Week 24), 12 weeks, and 24 weeks. Participants who entered Step 3 due to viral rebound prior 
to Week 24 of Step 2 were followed for virologic monitoring visits weekly in Step 3 until HIV-1 
RNA returned to <40 copies. There were no bNAbs administered or PK draws done in Step 3. 


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4.1.4 
Adjustment for multiple comparisons 
The analyses for the Steps 1-3 are descriptive and exploratory and no adjustment for multiple 
comparisons (e.g. across outcome measures) will be undertaken. 
4.1.5 
Summarizing continuous variables 
Continuous variables will be summarized using minimum, lower quartile (Q1), median, upper 
quartile (Q3) and maximum, along with mean and standard deviation. 
4.1.6 
Missing data 
Participants in this study have been successfully followed with demonstrated high adherence to 
study evaluations for at least 96 weeks before entering this study, so missing data are expected 
to be minimal.  Missing data will be documented and the potential impact of missing data on the 
interpretation of results will be considered along with taking into account the specific reasons for 
missingness.  
4.1.7 
Defining SAEs 
For this study a SAE, as defined by the International Conference on Harmonisation (ICH), is an 
AE following an infusion of a bNAb that: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect or 
• 
Is an important medical event that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the child or may require intervention to 
prevent one of the other outcomes listed in the definition above. 
4.2 
Analysis Approaches  
4.2.1.  Baseline Characteristics 
Baseline characteristics will be summarized using data obtained at EIT Study entry (and 
subsequently entered into the Tatelo Study database), as well as data collected at Tatelo 
Study entry on the demographics form (primarily SES information, which may have 
changed from the prior EIT Study collection), and also age at Tatelo entry. Data from EIT 
will include: maternal ART regimen at delivery; birth weight and gestational age; baseline 
plasma HIV RNA and PBMC DNA prior to ART start; age at EIT entry; whether the child 
ever rebounded after 24 weeks on ART (and length of prior virologic rebound on ART if 
any). 
4.2.2. 
Primary outcomes 
1. AEs will be summarized generally (any graded event) and specifically (any SAE, defined 
above, or any AE determined by the study team to be related to one or both bNAb 


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infusion).  Summaries will include listings by child of all graded events and summaries by 
frequency of AEs by event (including all graded events and focusing on SAEs and bNAb-
related AEs).   
 
2. Cumulative proportion of children experiencing SAEs during follow-up (until 30 days after 
last study visit for each participant) and proportion of potentially bNAb-related events.  In 
particular, proportions of children experiencing the following events will be summarized 
along with 95% exact confidence intervals (based on the Clopper-Pearson method).  The 
denominators for the following are all participants who received at least one infusion of a 
bNAb in Step 1.   
a. At least one graded AE (of any grade) 
b. At least one grade 3 or higher AE 
c. At least one SAE (as defined above) 
d. At least one potentially bNAb-related AE of any grade 
e. At least one potentially bNAb-related AE grade 3 or higher 
f. 
At least one potentially bNAb-related SAE 
 
 
3. Proportion of children, among those receiving at least one infusion of a bNAb in Step 1, 
who maintain HIV-1 RNA in plasma less than 400 copies/mL at least 32 weeks after 
initiating dual bNAb treatment (i.e., 24 weeks after withdrawal of standard ART, which is 
through week 24 of Step 2) will be calculated along with a 95% confidence interval 
(based on exact Clopper-Pearson confidence limits).  
 
4. Repeat #3 but considering only those children who enter Step 2 and discontinue ART.  
 
5. Repeat #3 and #4 but considering the maintenance of less than 40 copies/mL (rather 
than 400 copies/mL). 
 
6. Time from Step 2, Day 0 to HIV-1 RNA ≥ 400 copies/mL will be analyzed using Kaplan-
Meier methods, with censoring at last available HIV-1 RNA measurement in Step 2 if lost 
to follow-up or administratively at Step 2, Week 24.  This will be done among all 
participants receiving at least one infusion of a bNAb, and among those who entered 
Step 2 and discontinued ART. 
 
7. Repeat #6 but considering time to HIV-1 RNA ≥ 40 copies/mL.  
 
8. Time to re-suppression to < 40 copies/mL (and < 400 copies/mL) will be analyzed using 
Kaplan-Meier methods among those who entered Step 3 because of virologic failure in 
Step 2; time will be measured from the day of re-starting ART in Step 3 (Step 3 Day 0).  
4.2.3. 
Secondary outcomes 
1. Summarize continuous measures of VRC01LS and 10-1074 trough concentrations in 
serum at Step 1, Week 4 and Week 8, and monthly during Step 2 through 24 weeks of 


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follow-up. Median values overall will be reported, and stratified by successes and failures 
in Step 2.  
 
2. Proportion of children with trough VRC01LS and 10-1074 concentrations below defined 
trough values at Step 1 Week 4 and Week 8, and monthly during Step 2 through 24 
weeks of follow-up (including exact confidence limits). 
 
3. Monthly height measurements will be standardized using WHO Z-scores (for age and 
sex) and described at each scheduled measurement time from Step 1, Day 0 through 
Week 24 of Step 3.  Mean changes (with 95% confidence intervals) will be obtained from 
Step 1, Day 0 to Step 2, Day 0 (representing change during the period of dual bNAbs + 
ART), from Step 2, Day 0 to Step 3, Day 0 (representing change during the period of dual 
bNAbs without ART), and from Step 1, Day 0 to Step 3, Week 24 (the period of complete 
follow-up). 
 
4. The previous analysis will be repeated for monthly Z-score weight measurements. 
 
5. Summarize anti-drug antibody (ADA) results for each bNAb; if warranted based on initial 
assessment, summarize by successes and failures in Step 2. 
4.3. Exploratory objectives 
1. Compare trough VRC01LS and 10-1074 levels at Step 2 entry between children who 
ultimately remained suppressed (<400 through Step 2) versus those who rebound to 
>=400 during Step 2 (restricting to children who start Step 2). Sub-analysis of levels for 
children who were in Step 1a (first six children) will be performed (as these six children 
received bNAbs in addition to ART for 32 weeks whereas subsequent children received 
bNAbs in addition to ART for 8 weeks). 
 
2. Compare trough levels at end of Step 2 for children suppressed (<400 through Step 2) to 
levels at time of rebound to >=400 for children who rebound during Step 2 (restricting to 
children who start Step 2). 
 
3. Correlate trough levels at Step 2 entry with time of rebound >=400 with censoring at 32 
weeks (restricting to children who start Step 2). 
 
4. Correlate trough levels at end of Step 2 for children suppressed (<400 through Step 2) 
and trough levels at time of rebound to >=400 for children who rebound during Step 2 
with time to rebound (censoring at 32 weeks).   
 
5. Evaluation of potential risk factors for viral rebound to >=400 copies/mL at/before 24 weeks 
in Step 2 (yes/no) (restricting to children who start Step 2).  Risk factors may include 
demographic variables, HLA type, baseline plasma HIV RNA and PBMC DNA prior to ART 
(from the EIT study), PMBC DNA at Step 1 and Step 2 entry, history of prior virologic 
rebound on ART, duration of dual bNAb treatment (extended >8 weeks for participants in 


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Step 1a versus 8 weeks for other participants), trough PK values for each bNAb during 
Step 2 (time dependent variable), and presence of pre-defined HIV envelope sequences 
associated with resistance to either bNAb (earliest available in life, closest available prior 
to rebound, and at rebound).   The extent of risk factors considered will be dependent on 
availability of results for these factors at the time of analysis.  Analyses will compare 
characteristics of participants who experience rebound versus those who do not 
experience rebound using Fisher’s Exact Test for categorical variables and Wilcoxon’s Test 
for continuous variables). 
5. 
Report Contents 
Detailed descriptions of the content of each of the following sections will be given in the report.   
1. Step 1 entry 
a. Screening (describing children from EIT by eligibility status and among those 
who were eligible, enrollment status) 
b. Enrollment 
c. Eligibility violations  
2. Baseline characteristics 
3. Protocol deviations 
4. Study status  
5. Study treatment (VRC01LS and 10-1074) status 
6. Changes/interruptions to antiretroviral regimen during study follow-up 
7. PK and ADA 
8. Safety: 
a. All AEs (and potential relation to bNAbs) 
b. Grade 3+ AEs (and potential relation to bNAbs) 
c. All SAEs (and potential relation to bNAbs) 
d. Infusion reactions 
e. Deaths 
9. HIV-1 RNA during study follow-up 
10. Growth assessments 
11. Associations of PK and virologic outcomes 
12. Comparison of characteristics of participants who experience rebound during Step 2 
versus those who do not experience rebound. 
 
 
 
 


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6. 
Associated Documents 
 
6.2.2.1.1.1.1.1. Writing Team Roster 
To be determined by study team.  
6.2.2.1.1.1.1.2. Timetable for primary analysis and manuscript preparation 
To be determined by study team.