Clinical trial NCT02778204
Conditions: HIV Infections
Keywords: Vertical HIV exposure Neonates Maraviroc
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2017-06-05; Completion date: 2019-11-20
Enrollment: 47 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study aimed to evaluate the safety, tolerability, and pharmacokinetics of maraviroc in infants at risk for mother-to-child HIV transmission, and to determine an appropriate dose of maraviroc during the first six weeks of life.

Detailed description:
Maraviroc is a C-C Chemokine Receptor 5 (CCR5) receptor antagonist used to treat HIV infection in adults. Adding maraviroc to a standard of care prophylaxis regimen may also reduce the risk of perinatal transmission of HIV. The purpose of this study was to evaluate the safety, tolerability, and pharmacokinetics of maraviroc in HIV-1-exposed infants at risk for mother-to-child HIV transmission. This study also aimed to determine an appropriate dose of maraviroc during the first six weeks of life.

The study allowed up to 72 mother-infant pairs in two cohorts to achieve a target of 36 evaluable infants receiving the final recommended dose of maraviroc. Because maraviroc interacts with the antiretroviral drug efavirenz (EFV) in adults, infants in this study were stratified within the cohorts based on their exposure to maternal EFV. Cohort 1 was stratified by in utero exposure to maternal EFV, with infants in both strata receiving a single dose of maraviroc solution within three days of birth and another single dose at Week 1 of life. Stratum 1A included infants without in utero exposure to maternal EFV during the eight weeks immediately before delivery. Stratum 1B included infants with in utero exposure to maternal EFV for a minimum of two weeks immediately before delivery.

Cohort 2 was stratified by exposure to maternal EFV after birth, with infants in both strata receiving maraviroc oral solution twice daily starting within three days of birth and continuing for up to 42 days. Based on evaluation of the Cohort 1 data, the initial daily dose of maraviroc oral solution to be administered in Cohort 2 was 8 mg/kg dose given twice daily. Stratum 2A included infants without any exposure to maternal EFV either in utero during the eight weeks immediately before delivery or while breastfeeding. Stratum 2B included breastfeeding infants with exposure to maternal EFV both in utero and after birth while breastfeeding, for a minimum of 2 weeks immediately before delivery and while breastfeeding.

Participants attended an entry visit within three days after the infant's birth. Participants attended five to six study visits through Week 16. Visits included medical history reviews, physical examinations, blood collection from the mother and/or infant, HIV testing, and adherence counseling.

Arms: arm 1: Infants in this cohort received a single dose of 8 mg/kg maraviroc solution within 3 days of birth and at Week 1 (7-14 days) of life; without in utero exposure to maternal efavirenz. arm 2: Infants in this cohort received a single dose of 8 mg/kg maraviroc solution within 3 days of birth and at Week 1 (7-14 days) of life; with in utero exposure to maternal efavirenz. arm 3: Infants in this cohort received 8 mg/kg maraviroc solution twice daily starting within 3 days of birth and continuing up to Week 6 (35-42) days of life; without in utero or breast milk exposure to maternal efavirenz. arm 4: Infants in this cohort received 8 mg/kg maraviroc solution twice daily starting within 3 days of birth and continuing up to Week 6 (35-42) days of life; with in utero and breast milk exposure to maternal efavirenz
Interventions: intervention 1: Maraviroc intervention 2: Maraviroc
Intervention descriptions: intervention 1: 8 mg/kg oral solution as a single dose. intervention 2: 8 mg/kg oral solution given twice daily.

Protocol documents:
ICF_000.pdf: 
IMPAACT 2007 Cohort 2 Sample Informed Consent Form 
 
Page 1 of 9 
 
 
21 May 2018 
Protocol Version 1.0 with Letters of Amendment #1 and #2 
Appendix III-B: Cohort 2 Sample Informed Consent Form for Study Participation 
 
IMPAACT 2007 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
VERSION 1.0, 13 April 2016 
 
 
You and your baby are being asked to participate in the research study named above. 
 
This form gives information about the study.  Please read it, or have it read to you, and ask any questions 
you may have.  We will take as much time as needed for you to fully understand the study.  We will ask 
you questions to see if we have explained the study clearly. 
 
After you understand the study, if you decide that you and your baby will participate, you will be asked to 
sign or make your mark on this form.  You will be offered a copy to keep. 
 
About the Study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [sites: 
insert site name] are doing this study to test an anti-HIV medicine (ARV) given to babies.  The medicine 
is called maraviroc. HIV is the virus that causes AIDS.   
 
You and your baby are being asked to participate in this study because you are infected with HIV and 
there is a risk that the infection may be passed onto your baby.  The transfer of HIV to newborn babies 
from HIV-infected mothers can occur at the time of birth.  
 
The study will include about 70 mothers who have HIV and their babies.  Your baby will receive the anti-
HIV medicine being tested.  Mothers will be in the study for up to 3 days and babies will be in the study 
for 4 months. 
 
The person in charge of the study at this clinic is [sites: insert name of Investigator of Record].  The 
United States National Institutes of Health is paying for this study.  
 
1. The study is being done to test the safety and blood levels of maraviroc in newborn babies 
 
Babies born to mothers who have HIV usually take ARVs to prevent infection of HIV after birth.  There 
are not many ARVs available for babies because many ARVs have not yet been tested in babies.  
 
Maraviroc is an ARV that is used in adults in the United States and other countries. This study will look 
at whether maraviroc causes any bad side effects when given to newborn babies.  It will also look at 
different doses of maraviroc to find what amount of maraviroc should be given to protect newborns.  
 
2. It is your decision whether or not to join the study. 
 
Deciding to join the study with your baby is voluntary.  You are free to join or not join.  If you join, you 
can change your mind and leave the study at any time.  Your decision will have no effect on the medical 
care that you and your baby receive at this clinic.  Your access to services and the benefits and rights you 
normally have will not be affected.  


IMPAACT 2007 Cohort 2 Sample Informed Consent Form 
 
Page 2 of 9 
 
 
21 May 2018 
Protocol Version 1.0 with Letters of Amendment #1 and #2 
 
Take your time and consider your decision carefully.  If you wish, you can talk to other people about 
allowing your baby to join the study.  You can bring other people here to learn about the study with you. 
 
No matter what you decide about the study, you must continue to take your anti-HIV medicines.  Your baby 
should also take anti-HIV medicine for 4-6 weeks after birth.  Taking these medicines is the best known way 
to maintain your health and avoid passing HIV to your baby while breastfeeding. 
 
3. Only mothers and their babies who qualify can participate in the study. 
 
If you decide to join the study with your baby, we will first do some tests to see if you and your baby 
qualify.  Some tests can be done while you are pregnant.  Other tests will be done after your baby is born. 
More information about the tests is given in #4 and #5. 
 
Finding out if you and your baby qualify 
 
4. We will ask questions and discuss the study requirements with you. 
 
To find out if you qualify for the study, we will:  
 
• 
Review your medical records. 
• 
Ask about your plans for feeding your baby and taking anti-HIV medicines after your baby is born. 
• 
Talk with you about the study requirements and if you are able to meet these requirements.   
• 
If needed, draw your blood (up to 10 mL or 2 teaspoons) for HIV testing. There are certain HIV tests 
that are required for mothers in this study. If the required tests are not in your medical records, we 
will do the tests that are needed.  
 
These procedures may be done while you are pregnant or within 3 days after your baby is born.  They will 
take 30-60 minutes. [sites: modify how much time this visit will take as needed].   
 
If these procedures show that you may qualify for the study, you will be given contact information for the 
study staff.  We will stay in contact as you get closer to your delivery date and ask you to contact us when 
your labor begins.  We will not be involved in the delivery of your baby but will arrange to see you soon 
after your baby is born.  You are welcome to contact us or return to the clinic at any time to talk about the 
study. 
 
5. After delivery, we will collect more information and examine your baby. 
 
To find out if your baby qualifies for the study, as soon as possible after your baby is born, we will: 
 
• 
Review your and your baby’s medical records. 
• 
Ask about your and your baby’s anti-HIV medicines. 
• 
Ask about your baby’s health and other medicines.  
• 
Ask about how you are feeding your baby. 
• 
Give your baby a physical examination 
• 
Draw your baby’s blood (about 4.5 mL or 1 teaspoon) for tests.  These tests include:  
o A test to look at your baby’s blood cells 
o A test to check how well your baby’s liver is working 
o An HIV test 


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o A portion of the blood will be stored for future HIV-related tests. The samples that will be tested 
will be chosen after the study is completed.  You or the site investigator will not be told of the 
results because the test is for investigation only and will be done after the study is completed. We 
will ask you about saving these samples in a separate form.  
 
These procedures will take about an hour [sites: modify how much time this visit will take as needed].  
The results of some of your baby’s blood tests will be available within a couple of days.  We will 
review the results and all other information to determine if you and your baby qualify for the study.   
 
• 
If you and your baby do not qualify, we will tell you this and give you information on where you and 
your baby can receive medical care and other services you may need. We will destroy any of your 
blood remaining after testing. 
 
• 
If you and your baby do qualify, we will ask you to confirm your decision for you and your baby to 
join the study.  With your confirmation, you and your baby will be entered into the study.   
 
Entering the study 
 
6. If you and your baby qualify, you and your baby will enter the study within 3 days after the baby’s birth.  
 
On the day when you and your baby enter the study, we will: 
 
• 
Draw your blood (14 mL or about 3 teaspoons) to test the amount of HIV in your blood and for future 
testing. 
• 
Ask about your health, anti-HIV medicines, and other medicines. 
 
These procedures may take up to 3 days [sites: modify how much time this visit will take as needed].   
 
Your baby will also receive his or her first dose of maraviroc during this visit.  We will show you how to 
give maraviroc to your baby.  It is very important that you give your baby maraviroc as instructed.  We 
will take as much time as needed for you to understand the instructions and identify strategies that will 
help you to give the study medicine to your baby as instructed. 
 
Being in the study 
 
7. After entering the study, your baby will have 5 scheduled visits over 4 months.    
 
Visits will be more frequent in the first 12 weeks.  During this time, your baby will have 4 visits, at 1, 4, 
6, and 12 weeks.  After that your baby will have 1 more visit at 4 months of age.    
 
Each visit will take about 1 to 2 hours [sites: modify how much time this visit will take as needed].  At 
these visits, we will:  
 
• 
Review your baby’s medical records and ask you about how your baby is doing and any side effects 
• 
Give your baby a physical examination 
• 
Draw your baby’s blood (1.5 mL - 4.5 mL or less than 1 teaspoon) for tests. These tests will check:  
o Your baby’s blood cells  
o How well your baby’s liver is working. 
o If your baby has HIV 


IMPAACT 2007 Cohort 2 Sample Informed Consent Form 
 
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o If you took efavirenz within 2 weeks before delivery, we will draw your baby’s blood (about 
0.5 mL or a few drops) to test the amount of efavirenz in your baby’s blood.  
 
These procedures will take about 1 to 2 hours [sites: modify how much time this visit will take as needed].  
Babies may have more visits if they are sick or if we need to do more tests to check on their health. 
 
8. Your baby will also participate in another study procedure.  This procedure will very closely measure the 
amount of maraviroc in their blood.   
 
Your baby will also have blood drawn to very closely measure the amount of maraviroc in his or her 
blood.  This is called a pharmacokinetic (PK) test.  There will be two of these tests.   
 
This collection will happen at the Week 1 and 4 visits. You must give your baby the medicine exactly as 
instructed and not miss but on the day of these visits, we will ask that you not give your baby maraviroc 
at home before coming to the clinic.  Your baby will be given maraviroc at the clinic, so that we know 
what time and the exact amount of maraviroc he or she took. This is called directly observed therapy. 
 
For the PK test, your baby will stay at the clinic for up to 13 hours after your baby takes maraviroc. If 
your baby is taking maraviroc only once a day, your baby will need to return to the clinic 20 - 24 hours 
after they took the medicine.  If your baby is taking maraviroc two times a day, your baby will not need to 
return to the clinic.  The study doctor will tell you how often your baby will take the medicine before the 
visit. 
 
[Sites: modify language as appropriate to indicate procedures for the intensive PK collection.  A small 
plastic tube (like a “drip”) will be placed in your baby’s arm to draw blood samples.  This tube is attached 
to a plastic needle so that we can draw blood several times.  We will not need to stick your baby with a 
needle each time.  The plastic tube will stay in place until all of the blood samples are drawn.]  
 
We will draw a few drops, about 0.5 mL of blood at 5 different time points at each PK test (a total of 2.5 
mL or ½ teaspoon).  We will look at the amount of study medicine in your baby’s blood at each of these 
times.   
 
At 6 weeks after birth your baby will also have one sample of blood drawn to measure the amount of 
maraviroc in his or her blood.  At this visit, it is important that you can tell study staff the exact time you 
gave the study medicine to your child. We will draw about 0.5 mL (a few drops of blood) for this test.  
 
9. Tests for how much of the study medicine is in your baby’s blood will be done at different laboratories. 
 
We will do most of the HIV tests and tests to check your baby’s blood here at our laboratory, but some of 
the blood tests will be done elsewhere.  We will give you the results of these tests at the next scheduled 
visit, or sooner, if necessary.  We will explain the results and give you counseling and referrals as needed.  
 
We will also draw blood for resistance and to check the amount of maraviroc in your baby’s blood here in 
the clinic.  These tests will be done at different laboratories in the United States.  Some tests may be done 
while the study is ongoing; others after the study is done.  We will try to give you the results of these tests 
when they have been tested during the study or after the study is over.   
 
10. We may stop your baby’s maraviroc.  
 
We may stop your baby’s study medicine if: 
 


IMPAACT 2007 Cohort 2 Sample Informed Consent Form 
 
Page 5 of 9 
 
 
21 May 2018 
Protocol Version 1.0 with Letters of Amendment #1 and #2 
• 
Your baby is not able to come to the study visits. 
• 
Your baby is not able to take the study medicine. 
• 
Your baby becomes infected with HIV. 
• 
Continuing maraviroc may be harmful to your baby. 
• 
You request to stop the maraviroc for your baby. 
 
Even if your baby stops the study medicine, your baby will stay in the study, with the same schedule of 
visits.   
 
If an HIV test that we do for the study shows that your baby has HIV infection, we will ask you to bring 
your baby to the clinic for another test. Your baby will not receive maraviroc and your baby will have 
additional blood drawn (8 mL or a little more than 1.5 teaspoons) for another HIV test to see if your baby 
truly is infected and to test for resistance to maraviroc.  If the second test confirms HIV infection, your 
baby will stay in the study, with the same schedule of visits, but will be taken off the study medicine. At 
these visits your baby will have all procedures done except HIV testing and testing for how much 
maraviroc is in his or her blood. The study cannot provide care and treatment for babies with HIV 
infection, but we will give information, counseling, and referrals to where your baby can get the care and 
treatment they need.   
 
11.  We may take you and your baby off the study if: 
 
• 
The study is stopped for any reason. 
• 
We determine that you and your baby cannot meet the study requirements (for example, if you move 
away and cannot come to the clinic). 
• 
We determine that staying in the study might harm you and your baby. 
 
12.  Please tell us if you wish you and your baby to leave the study. 
 
You and your baby are free to leave the study at any time for any reason.  The care that you and your 
baby receive at this clinic will not be affected, but it is important for us to know about your decision.  We 
will ask you to bring your baby to the clinic for one last visit.  At this visit we will ask questions about 
your baby’s health and medicines, give your baby a physical examination, and draw your baby’s blood 
(less than 1 teaspoon) for tests.  We will answer any questions you may have and give you information on 
how to contact us in the future, if you wish. 
 
Risks of the study 
 
13. There is little risk from the study procedures. 
 
Most procedures done in this study are routine medical procedures, with little risk to you and your baby.  
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted.  Rarely, 
drawing blood can cause fainting or infection. 
 
14. There are some risks from maraviroc.   
 
Maraviroc (MVC, Selzentry®) is like any other medication or drug and may have side effects.  Some of 
the most common or most serious effects are listed below.  The list does not include all of the possible 
side effects.  These lists include the more serious or common side effects with a known or possible 
relationship.  If you have questions about side effects not included in these lists, you can ask us.   
 


IMPAACT 2007 Cohort 2 Sample Informed Consent Form 
 
Page 6 of 9 
 
 
21 May 2018 
Protocol Version 1.0 with Letters of Amendment #1 and #2 
If your baby joins the study, we will tell you about the side effects of maraviroc that your baby will take.  
We will also check for any side effects during the visits and tell you what to do if your baby has any side 
effects. 
 
15. We will tell you about the most severe side effects first.  
 
First, you should know about the possible severe side effects.  These effects are rare, but they can cause 
serious health problems and can result in death: 
 
• 
Liver problems.  The liver is an organ near the stomach.  If your baby gets liver problems, he or she 
might have a rash on your baby’s body; yellowing of the skin or whites of the eyes; dark or tea 
colored urine; upset stomach or vomiting; or loss of appetite.  If your baby develops any of these 
symptoms, stop maraviroc and contact your baby’s doctor immediately.    
 
• 
Heart problems, including a heart attack.  
 
• 
Low blood pressure problems.  Low blood pressure may cause your baby to be dizzy or faint.  If your 
baby has kidney problems, he or she may be at an increased risk for low blood pressure.  The kidneys 
are organs near the middle of the back and there is one kidney on each site of the body.  Doctors 
usually find out about kidney problems from blood tests.   
 
16. There are also more common and not severe side effects from maraviroc.  
 
You should also know about the more common side effects.  These side effects are not severe.  There are 
many possible mild and moderate side effects.  The most common ones are listed below: 
 
Overall Body Effects 
• 
Swelling of parts of the body 
• 
Some infections, including herpes, colds, sore 
throat, flu and flu-like symptoms 
• 
Muscle aches, spasms and pain  
• 
Fever 
• 
Rash 
• 
Colds 
• 
Cough 
• 
Runny, congested nose 
Effects on Your Child’s Activity 
• 
Sleeping problems 
• 
Dizziness 
Effects on Your Child’s Belly 
• 
Stomach pain or bloating 
• 
Diarrhea 
Effects on Your Child’s Bladder 
• 
Problems with urination 
Effects on Your Child’s Blood 
• 
Low amounts of white blood cell counts 
(neutropenia), which could lead to risk of 
infection 
 
The list above is not a complete list of all side effects for maraviroc. As a reminder, if your baby joins the 
study, we will tell you about the side effects of maraviroc your baby will take. 
 
Note: Because of how maraviroc works in your baby’s body, there is a possible increased risk your baby 
may get other infections or cancer.  However, there is no evidence from clinical studies of an increase in 
serious infections or cancer. 
 


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Protocol Version 1.0 with Letters of Amendment #1 and #2 
Maraviroc contains soy lecithin.  If your baby has or develops an allergy to soy (soya or soybeans) or 
peanuts, your baby may develop an allergic reaction to maraviroc. If your baby is allergic to soy or 
peanuts, please tell your baby’s doctor immediately.  
 
17. There may be other possible risks of maraviroc. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain 
diseases may occur soon after starting combination ARVs but can also occur later.  Some of these 
symptoms may be life threatening.  If your baby starts having new symptoms, or if you notice that your 
baby’s existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 
 
The use of some strong ARV combinations may be related to unusual position of body fat and weight 
loss.  Some of the body changes may include body fat increasing around the abdomen, stomach area, 
chest or neck or body fat decreasing in the face, legs, or arms.  
 
Risk of resistance 
 
All ARVs can cause some resistance.  Resistance means that the ARVs may not work against HIV if it is 
taken again in the future.  To stop resistance, it is important that you give your baby the study medicine 
and ARVs as instructed, and do not miss any doses.   
 
18. There could be risks of disclosure of you and your baby’s information. 
 
We will make every effort to keep your baby’s information private and confidential.  Study records and 
specimens will be kept in secure locations.  All specimens and most records will be labeled only with a 
code number.  However, you and your baby’s names will be written on some records.  Despite our best 
efforts to keep you and your baby’s information private, it is possible that the information could be 
obtained by someone who should not have it.  If this were to happen, you and your baby could be treated 
badly or unfairly.  You could feel stress or embarrassment.   
 
[US sites, insert: To help us protect your privacy, we have obtained a Certificate of Confidentiality that 
protects us from being forced to release information that may identify you, such as by the courts or police. 
The certificate cannot be used in all situations, but it can be used to resist demands for information that 
would identify you. The certificate does not protect against requests for information from the US federal 
government or from the US Food and Drug Administration. Regardless of the certificate, you can release 
information about your participation in the study to others, if you wish.] 
 
 
Benefits of the study 
 
19. There may or may not be a benefit to your baby from being in the study. 
 
By joining the study, you and your baby will be part of the search for anti-HIV medicines that may be 
better for your baby.  There may or may not be a direct benefit to you or your baby by participating in this 
study. Your baby will have regular visits here and frequent checks on his or her health, including tests for 
HIV in your baby’s blood.  Information learned from this study may help other babies born to HIV-
infected mothers at risk of HIV infection. 
 


IMPAACT 2007 Cohort 2 Sample Informed Consent Form 
 
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21 May 2018 
Protocol Version 1.0 with Letters of Amendment #1 and #2 
Other information about the study 
 
20. There are no costs to you or your baby for being in the study. 
 
There are no costs to you or your baby for study visits, maraviroc, or procedures.  [Sites: insert 
information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits.  For each visit, you will be given (specify amount).] 
 
21. You and your baby’s study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include: 
• 
[insert name of site IRB/EC] 
• 
[insert name of other site drug entities that may review records] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Office for Human Research Protections 
• 
The US Food and Drug Administration 
• 
Other U.S., local, and international regulatory entities 
• 
The IMPAACT Network that is coordinating the study 
• 
The companies that make the study medicine (PHIVCO) 
 
Like the study staff, these groups are required to make efforts to keep study records private and 
confidential. 
 
The results of the study may be presented publicly or published.  However, no presentation or publication 
will use your baby’s name or identify your baby personally.  A description of this study will be available 
on ClinicalTrials.gov.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this website at any time. 
 
You and your baby’s study information may be disclosed to other authorities if required by law.  
 
22. If you or your baby gets sick or injured, contact us immediately. 
 
You and your baby’s health is important to us.  We will make every effort to protect you and your baby’s 
well-being and minimize risks to you and your baby.  It is possible, however, that your baby could have 
an illness or injury that is study-related.  This means that the illness or injury occurred as a direct result of 
the study procedures.   
 
If a study-related illness or injury occurs, we will treat your baby or tell you where you can get the 
treatment your baby needs.  The cost for this treatment may be charged to you or your insurance 
company.  There is no program for compensation either through this institution or the National Institutes 
of Health. 
 
Who to contact 
 
23. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study, contact:  
[sites: insert name and telephone number of investigator or other study staff] 
 


IMPAACT 2007 Cohort 2 Sample Informed Consent Form 
 
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21 May 2018 
Protocol Version 1.0 with Letters of Amendment #1 and #2 
• 
If you have questions about you and your baby’s rights as a research participant, or problems or 
concerns about how you and your baby are being treated in the study, contact:  
[sites: insert name and telephone number of IRB contact person or other appropriate 
person/organization] 
 
• 
If you or your baby has any health or other problems that may be related to his or her study 
participation, contact:  
[sites: insert name and telephone number of investigator or other study staff] 
 
• 
If you or your baby want to leave the study, contact:  
[sites: insert name and telephone number of investigator or other study staff] 
 
Signatures 
 
24. If you agree to participate in this study, and your baby, please sign or make your mark below. 
 
Before deciding whether to join this study with your baby, make sure you have read this form, or had it 
read to you, and that all of your questions have been answered.  You should feel that you understand the 
study, its risks and benefits, and what is expected of you and your baby if you decide to join.  
 
If you decide to allow your baby to join, we will tell you any new information from this study or other 
studies that may affect your willingness for your baby to stay in the study.  You are welcome to ask 
questions or request more information at any time.   
 
You do not give up any rights by signing this form. 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent’s Name (print) 
 
 
Parent’s Signature 
  
 
Date 
(Or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 
(As appropriate) 
 
 
 

SAP_002.pdf: 
 
 
 
Pharmacology Statistical Analysis Plan 
Version 3.0 
 
 
 
IMPAACT 2007 
 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants at 
Risk of Acquiring HIV-1 Infection 
 
 
CT.gov NCT Number: NCT02778204 
 
 
 
 
 
This is IMPAACT 2007 Pharmacology SAP Version 3.0 with names of authors redacted. 
 
 
 
 
January 24, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
 


IMPAACT 2007 PK SAP Version 3.0 
2 
 
Table of Contents 
1 
INTRODUCTION ..................................................................................................... 3 
2 
PK-RELATED STUDY BACKGROUND ................................................................. 3 
3 
PHARMACOKINETIC POPULATION ..................................................................... 3 
4 
PHARMACOKINETIC STUDY OBJECTIVES ......................................................... 4 
5 
NON-COMPARTMENTAL PHARMACOKINETIC ANALYSES .............................. 4 
5.1. BELOW THE LEVEL OF QUANTITATION ........................................................ 4 
5.2. TERMINAL SLOPE ESTIMATION ..................................................................... 4 
5.3. AUC VALUES .................................................................................................... 5 
6 
SUMMARY STATISTICS ........................................................................................ 5 
7 
PRESENTATION OF DATA .................................................................................... 5 
7.1. TABLES, LISTINGS AND FIGURES ................................................................. 6 
 
 
 


IMPAACT 2007 PK SAP Version 3.0 
3 
 
1. Introduction 
This Pharmacology Statistical Analysis Plan (PK SAP) is complementary to the 
IMPAACT 2007 Primary SAP (version 2.0), the IMPAACT 2007 Population 
Pharmacokinetic Reporting Analysis Plan (Population PK RAP, version 1.0), and the 
IMPAACT 2007 PK Data Management Plan (version 1.0). This document describes 
the non-compartmental pharmacokinetic (PK) analysis to be performed by the 
IMPAACT 2007 protocol pharmacologist(s) at the end of study on the completed 
study dataset and included in the Clinical Study Report (CSR, for regulatory 
submission) and study manuscript(s). 
 
2. PK-Related Study Background 
IMPAACT 2007 is a Phase I safety and pharmacokinetic study of maraviroc (MVC) 
in HIV-1 exposed infants at risk of acquiring HIV-1 infection. This study has two 
sequential dosing cohorts stratified by maternal use of efavirenz (EFV). Cohort 1 
infants receive two single doses of MVC – the first dose at study entry (days 0 – 3 of 
life) and the second dose at one week (7 – 14 days) of life, with PK evaluations 
around both single doses (refer to protocol sections 6.4.1 and 6.5.1 for sampling 
schedules). Once the dose is determined for each Cohort 1 Stratum, the 
corresponding Stratum will open to enrollment for Cohort 2. Infants enrolled in 
Cohort 2 will receive 6 weeks of daily MVC dosing (within day 3 of life up to day 42 
of life). In Cohort 2, PK evaluations are performed at weeks 1 and 4 (refer to protocol 
sections 6.5.3 and 6.7.2 for sampling schedules). In Cohort 2, both strata, single 
random sparse PK samples are also drawn at week 6. Additional single samples 
were collected in Stratum 1B and 2B infants to assess EFV concentrations in the 
infants (from maternal dosing). 
 
The starting dose for both strata in Cohort 1 is 8 mg/kg. Summary data were 
prepared to evaluate the dose in each Cohort 1 stratum after enrollment of at least 6 
infants per stratum to confirm appropriateness of dose, and to confirm dose(s) to be 
used in Cohort 2. Refer to protocol sections 9.2, 9.6.2, and 10.3 for the dose-finding 
algorithm. For the dose-finding interim PK analyses, non-compartmental 
pharmacokinetic analysis methods were used to generate PK parameters, followed 
by pharmacokinetic modeling as needed to generate Cavg estimates for the real-time 
PK assessments that were needed to make dosing decisions, as per protocol 
section 10.5. 
 
The MVC exposure target for this study is Cavg ≥ 75 ng/mL at both PK evaluations 
(entry and week 1 for Cohort 1, and weeks 1 and 4 for Cohort 2). 
 
3. Pharmacokinetic Population 
PK Dose-Finding Evaluable participants are infants whose PK results provide data 
on the primary PK parameter of interest (Cavg) and are included in the dose-finding 
evaluations (See Section 10.1 of the protocol for additional details).  Refer to the 
Primary SAP and the Analysis Implementation Manual for the Regulatory 
Submission (AIM) for a description of participants who are included for the dose-
finding purposes in this study (i.e., eligible participants who are PK and/or safety 


IMPAACT 2007 PK SAP Version 3.0 
4 
 
evaluable). The summary figures and tables and the listings will include all PK 
Dose-Finding Evaluable participants. Any infant who is not included in the PK 
Dose-Finding Evaluable group will be listed separately with a corresponding 
explanation or discussion of the reasons they are not included in the dose-finding 
group.   
 
4. Pharmacokinetic Study Objectives 
The primary PK objective for IMPAACT 2007 is to determine the pharmacokinetics 
of maraviroc solution during the first six weeks of life and to determine an 
appropriate dose over this time frame.  The secondary PK objective for IMPAACT 
2007 is to determine age-related changes in maraviroc pharmacokinetic parameters 
over the first six weeks of life. 
 
5. Non-Compartmental Pharmacokinetic Analyses 
The intensive PK sampling schedules are outlined in the IMPAACT 2007 protocol. 
Standard non-compartmental methods for PK parameter derivation will be performed 
using Phoenix (Certara USA, Inc). Where possible, the following PK parameters will 
be determined from maraviroc plasma concentrations following PK sampling: 
 
Parameter 
Definition 
Cmax 
Observed maximum plasma concentration 
tmax 
Time of maximum plasma concentration 
AUC(0-∞), pred 
For Cohort 1: Area under the concentration-time curve from time zero 
to infinity 
AUC(0-τ), pred 
For Cohort 2: Area under the concentration-time curve from time zero 
to the end of the dose interval  
CL/F 
Apparent oral clearance  
Vz/F 
Apparent volume of distribution calculated as CL/λz 
λz 
Terminal elimination rate constant 
t1/2 
Terminal half-life calculated as ln(2)/λz 
Cτ 
Concentration at the end of the dose interval 
Cavg 
Average concentration calculated as AUC/τ 
 
Additional PK parameters may be determined where appropriate. Pharmacokinetic 
analysis will be carried out using actual sampling times. Concentrations for PK 
analyses will be used as supplied by the analytical laboratory. 
 
5.1. 
Below the Level of Quantitation 
MVC concentration values that are below the level of quantification (BLQ), < 5 
ng/mL, will be set to zero. If an entire concentration-time profile is BLQ, the 
profile will be excluded from the PK analysis. If a pre-dose concentration is 
below the limit of assay detection, this value is set to zero. Any embedded 
BLQ value (BLQ value occurring between two quantifiable concentrations) in 


IMPAACT 2007 PK SAP Version 3.0 
5 
 
a profile will be set to missing for the purposes of PK analysis. For regulatory 
submission purposes, in the analysis of the log transformed values of the PK 
parameter and concentration data, log (BLQ) was replaced with the value of 
0. 
 
5.2. 
Terminal Slope Estimation 
The default settings for the analysis software will only estimate an elimination 
rate constant when the PK profile has three or more declining concentrations 
after the peak concentration in a non-compartmental analysis. For the infants 
in Cohort 2 whose peak concentration was at the 3 – 5 hour time point, only 
two more samples were drawn after the peak, and the default settings would 
not estimate the elimination rate constant in those infants. In those cases, the 
program was directed to calculate the elimination rate constant from the last 
two observed concentrations (the 6 – 8 hour concentration and the 11 – 13 
hour concentration). Those infants whose elimination rate constants were 
calculated from only two points (instead of the three points used in the 
remaining infants) are indicted in the output tables. 
 
5.3. 
AUC Values 
AUC is calculated by the linear trapezoidal rule. For Cohort 1, predicted AUC(0-
∞) is used. For Cohort 2, predicted AUC(0-τ) is used. Because the trough values 
are drawn over a range of times (either 11 – 13 hours post dose for twice daily 
dosing, or 20 – 24 hours post dose for once daily dosing) rather than right at 
the trough time post dose, the predicted AUC(0-τ) to the exact proposed trough 
time (12 or 24 hours) will be reported, and used to calculate Cavg. For Cohort 
1, if predicted AUC(0-∞) is missing because the terminal elimination rate 
constant could not be estimated, then AUC(ALL) will be used. AUC(ALL) is the 
observed AUC through the time of the last sample. For Cohort 1 at Week 1 
specifically, the limited sampling schedule and high number of BLQ MVC 
concentrations precluded the estimation of AUC (and hence Cavg) by non-
compartmental methods. Therefore, the Tables/Figures/Listings (TFLs) 
summarizing this end-of-study non-compartmental analysis do not include Cavg 
values for Cohort 1 at Week 1. Results from the end-of-study Population PK 
analysis will be reported separately (see Population PK RAP). For Cohort 2, if 
predicted AUC(0-τ) is missing (because terminal elimination rate constant could 
not be estimated), then AUC(ALL) will be used. 
 
6. Summary Statistics 
All individual concentrations and all pharmacokinetic parameters will be summarized 
using descriptive statistics. These will include the number of observations available, 


IMPAACT 2007 PK SAP Version 3.0 
6 
 
geometric mean, geometric coefficient of variation (CV), geometric 95% confidence 
intervals, arithmetic mean, standard deviation (SD), CV, median, minimum, and 
maximum. For dissemination, selected descriptive statistics will be used as 
appropriate for the data distribution. Typically, this includes using geometric means 
to summarize the log-transformed parameters, such as AUC, Cmax, Cavg, Vz/F, CL/F; 
median for tmax and arithmetic mean for t1/2. PK parameters will be summarized by 
strata, cohort and study visit as listed in section 7.1 below. 
 
7. Presentation of Data 
Concentration time profiles (for individual infants, strata, and/or cohorts) will be 
presented graphically. For summary statistics and median/mean plots by sampling 
time, the nominal PK sampling time will be used. For individual subject plots by time, 
the actual PK sampling time will be used. The tables, listings and figures to be 
included in the CSR are listed below. The summary figures and tables will include all 
participants who are included in the PK Dose-Finding Evaluable population. MVC 
concentrations and PK parameters will be listed out separately for any participant 
not included in the PK Dose-Finding Evaluable population. 
 
7.1. 
Tables/Listings 
• Plasma Maraviroc Concentration (ng/mL) versus Time Summary (Descriptive 
Statistics), By Visit, Strata and Cohort 
o Entry, Stratum 1A 
o Week 1, Stratum 1A 
o Entry, Stratum 1B 
o Week 1, Stratum 1B 
o Entry, pooled Cohort 1 
o Week 1, pooled Cohort 1 
o Week 1, Stratum 2A 
o Week 4, Stratum 2A 
o Week 6, Stratum 2A 
o Week 1, Stratum 2B 
o Week 4, Stratum 2B 
o Week 6, Stratum 2B 
o Week 1, pooled Cohort 2 
o Week 4, pooled Cohort 2 
o Week 6, pooled Cohort 2 
 These tables include all participants who were included in the 
PK Dose-Finding Evaluable population. 
• Maraviroc Concentration versus Time Listing, By Cohort 
o Cohort 1, Stratum 1A listings for each participant 


IMPAACT 2007 PK SAP Version 3.0 
7 
 
o Cohort 1, Stratum 1B listings for each participant 
o Cohort 2, Stratum 2A listings for each participant 
o Cohort 2, Stratum 2B listings for each participant 
 These tables include all participants who were included in the 
PK Dose-Finding Evaluable population. 
• Listing and Descriptive Summary of Maraviroc PK Parameters, By Visit, 
Strata and Cohort) 
o Entry, Stratum 1A 
o Week 1, Stratum 1A 
o Entry, Stratum 1B 
o Week 1, Stratum 1B 
o Entry, pooled Cohort 1 
o Week 1, pooled Cohort 1 
o Week 1, Stratum 2A 
o Week 4, Stratum 2A 
o Week 1, Stratum 2B 
o Week 4, Stratum 2B 
o Week 1, pooled Cohort 2 
o Week 4, pooled Cohort 2 
 In Cohort 2, include Week 1: Week 4 Cavg Ratio, and a Yes/No 
Column for Cavg Target met (Cavg for both Week 1 and Week 4 ≥ 
75 ng/mL), in addition to PK parameters noted in section 5.  
 Notate in these tables the PK profiles for which only two 
concentrations (instead of three) were used for estimation of the 
terminal elimination rate constant. 
 The tables above include all participants who were included in 
the PK Dose-Finding Evaluable population.  
• Concentration versus time listing, and PK parameters listing, by Visit, Strata 
and Cohort 
o For each participant who was not included in the PK Dose-Finding 
Evaluable population. 
 
Figures 
• Mean Plasma Maraviroc Concentration-Time Plot (Linear and Semi-Log), By 
Visit, Strata and Cohort 
o Entry Stratum 1A, Week 1 Stratum 1A, Entry Stratum 1B, Week 1 
Stratum 1B, Entry Pooled for Cohort 1, Week 1 Pooled for Cohort 1 
o Week 1 Stratum 2A, Week 4 Stratum 2A, Week 1 Stratum 2B, Week 4 
Stratum 2B, Week 1 Pooled for Cohort 2, Week 4 Pooled for Cohort 2 
 These figures will include all participants who were included in 


IMPAACT 2007 PK SAP Version 3.0 
8 
 
the PK Dose-Finding Evaluable population. 
• Median Plasma Maraviroc Concentration-Time Plot (Linear and Semi-Log), 
By Visit, Strata and Cohort 
o Entry Stratum 1A, Week 1 Stratum 1A, Entry Stratum 1B, Week 1 
Stratum 1B, Entry Pooled for Cohort 1, Week 1 Pooled for Cohort 1 
o Week 1 Stratum 2A, Week 4 Stratum 2A, Week 1 Stratum 2B, Week 4 
Stratum 2B, Week 1 Pooled for Cohort 2, Week 4 Pooled for Cohort 2 
 These figures will include all participants who were included in 
the PK Dose-Finding Evaluable population. 
• Summary Plasma Maraviroc Cavg, By Visit, Strata, and Cohort 
o Entry Stratum 1A, Week 1 Stratum 1A, Entry Stratum 1B, Week 1 
Stratum 1B, Entry Pooled for Cohort 1, Week 1 Pooled for Cohort 1 
o Week 1 Stratum 2A, Week 4 Stratum 2A, Week 1 Stratum 2B, Week 4 
Stratum 2B, Week 1 Pooled for Cohort 2, Week 4 Pooled for Cohort 2 
o Include reference line at 75 ng/mL 
 These figures will include all participants who were included in 
the PK Dose-Finding Evaluable population. 
• Maraviroc Concentration-Time Plot (Linear), By Visit and Strata 
o Include all individual profiles in one summary figure for each Visit 
o Entry Stratum 1A and 1B 
o Week 1 Stratum 1A and 1B 
o Week 1 Stratum 2A and 2B 
o Week 4 Stratum 2A and 2B 
 These figures will include all participants who were included in 
the PK Dose-Finding Evaluable population. 
• Maraviroc Concentration-Time Plot (Semi-Log), By Visit and Strata 
o Include all individual profiles in one summary figure for each 
Visit/Stratum 
o Entry Stratum 1A and 1B 
o Week 1 Stratum 1A and 1B 
o Week 1 Stratum 2A and 2B 
o Week 4 Stratum 2A and 2B 
 These figures will include all participants who were included in 
the PK Dose-Finding Evaluable population. 
 
Additional tables, listings or figures may be prepared upon request. 

Prot_003.pdf: 
IMPAACT 2007 
 
 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-
Exposed Infants at Risk of Acquiring HIV-1 Infection 
 
 
 
A Study of the International Maternal Pediatric Adolescent  
AIDS Clinical Trials Network 
 
 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases 
Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
National Institute of Mental Health 
 
 
Pharmaceutical Support Provided by: 
PHIVCO 
 
DAIDS ES # 20734 
IND # [TBA]   
 
 
 
Protocol Chair: 
Mark Mirochnick, MD  
 
NIAID Medical Officer:  
Elizabeth Smith, MD  
 
NICHD Medical Officer: 
Nahida Chakhtoura, MD, MsGH 
 
Clinical Trials Specialists: 
Kathleen George, MPH  
 
Sarah Bradford, MPH 
 
 
 
 
                                                                                                                                    
Final Version 1.0  
13 April 2016 
 
 


IMPAACT 2007, Version 1.0 
 
Page 1 of 93 
 
 
13 April 2016 
IMPAACT 2007 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
 
TABLE OF CONTENTS 
 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 4 
PROTOCOL TEAM ROSTER .................................................................................................... 6 
SCHEMA ..................................................................................................................................11 
Figure 1A: IMPAACT 2007 Overview of Study Design – Cohort 1 .......................................13 
Figure 1B: IMPAACT 2007 Overview of Study Design - Cohort 2 ........................................14 
1 
INTRODUCTION ...........................................................................................................15 
1.1 
Background ..................................................................................................................................... 15 
1.2 
Maraviroc Pharmacokinetics and Safety in Adults ........................................................................... 16 
1.3 
Maraviroc in Infants and Children .................................................................................................... 17 
1.4 
Rationale ......................................................................................................................................... 18 
1.5 
Hypotheses ..................................................................................................................................... 19 
2 
OBJECTIVES ................................................................................................................19 
2.1 
Primary Objectives .......................................................................................................................... 19 
2.2 
Secondary Objectives ...................................................................................................................... 19 
3 
STUDY DESIGN ...........................................................................................................20 
4 
STUDY POPULATION ..................................................................................................21 
4.1 
Inclusion Criteria .............................................................................................................................. 21 
4.2 
Exclusion Criteria............................................................................................................................. 23 
4.3 
Co-Enrollment Considerations ......................................................................................................... 23 
4.4 
Recruitment, Screening, and Enrollment Process ........................................................................... 24 
4.5 
Participant Retention ....................................................................................................................... 25 
4.6 
Participant Withdrawal or Termination from the Study .................................................................... 25 
5 
STUDY DRUG CONSIDERATIONS ..............................................................................26 
5.1 
Study Drug ...................................................................................................................................... 26 
5.2 
Study Drug Formulation ................................................................................................................... 26 
5.3 
Study Drug Regimens ..................................................................................................................... 26 
5.4 
Study Drug Preparation ................................................................................................................... 27 
5.5 
Study Drug Administration ............................................................................................................... 28 
5.6 
Study Drug Acquisition .................................................................................................................... 28 
5.7 
Study Drug Storage ......................................................................................................................... 28 
5.8 
Study Drug Accountability ............................................................................................................... 29 
5.9 
Final Disposition of Study Drug ....................................................................................................... 29 
5.10 
Concomitant Medications ................................................................................................................ 29 
5.11 
Disallowed Medications for Infants and Breastfeeding Mothers ...................................................... 29 
6 
STUDY VISITS AND PROCEDURES ...........................................................................30 
6.1 
Mother Screening Visit .................................................................................................................... 30 
6.2 
Mother Entry Visit ............................................................................................................................ 31 


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6.3 
Infant Screening Visit ....................................................................................................................... 31 
6.4 
Infant Entry Visit (Cohorts 1 and 2)/PK Sampling (Cohort 1) ........................................................... 32 
6.5 
Week 1 Visit/PK Sampling (Cohorts 1 and 2) .................................................................................. 33 
6.6 
7-Day Post Dose Safety Visit (Cohort 1 only) .................................................................................. 34 
6.7 
Week 4/PK Sampling (Cohort 2 only) .............................................................................................. 35 
6.8 
Week 6 Visit (Cohorts 1 and 2) ........................................................................................................ 36 
6.9 
Week 12 Visit (Cohort 2 only) .......................................................................................................... 36 
6.10 
Week 16 Visit (Cohorts 1 and 2) ...................................................................................................... 37 
6.11 
Procedures for Infants with Positive HIV NAT Results .................................................................... 37 
6.12 
Procedures for Infants who Prematurely Discontinue Study Participation ....................................... 38 
6.13 
Maternal Medical and Medications History ...................................................................................... 38 
6.14 
Infant Physical Examinations ........................................................................................................... 38 
6.15 
Additional Considerations for Laboratory Procedures ..................................................................... 39 
7 
SAFETY MONITORING, ASSESSMENT AND REPORTING .......................................40 
7.1 
Safety-Related Roles and Responsibilities ...................................................................................... 40 
7.2 
Safety-Related Recording on Case Report Forms .......................................................................... 41 
7.3 
Expedited Adverse Event (EAE) Reporting ..................................................................................... 41 
8 
PARTICIPANT MANAGEMENT ....................................................................................43 
8.1 
Management of Adverse Events ..................................................................................................... 43 
8.2 
General Management ...................................................................................................................... 43 
8.3 
Criteria for Premature Discontinuation of Study Drug ...................................................................... 44 
9 
STATISTICAL CONSIDERATIONS ..............................................................................45 
9.1 
General Design Issues .................................................................................................................... 45 
9.2 
Dose-Finding Algorithm ................................................................................................................... 46 
9.3 
Endpoints and Outcome Measures ................................................................................................. 47 
9.4 
Randomization and Stratification ..................................................................................................... 48 
9.5 
Sample Size and Accrual ................................................................................................................ 48 
9.6 
Monitoring ........................................................................................................................................ 48 
9.7 
Analyses .......................................................................................................................................... 53 
10 
PHARMACOLOGY PLAN .............................................................................................54 
10.1 
Pharmacology Overview and Objectives ......................................................................................... 55 
10.2 
Methods and Timing for Collections, Processing, Handling, and Storage ....................................... 55 
10.3 
Starting Dose, PK Guidelines for Dose Adjustment and Interim Analyses ...................................... 56 
10.4 
Laboratory Performing the Assays .................................................................................................. 57 
10.5 
Primary and Secondary Data Analysis Plan .................................................................................... 58 
10.6 
Anticipated Outcomes ..................................................................................................................... 58 
11 
DATA HANDLING AND RECORD KEEPING ...............................................................58 
11.1 
Data Management Responsibilities ................................................................................................. 58 
11.2 
Essential and Source Documents and Access to Source Data ....................................................... 59 
11.3 
Expectations for Data Usage ........................................................................................................... 59 
11.4 
Quality Control and Quality Assurance ............................................................................................ 60 
12 
CLINICAL SITE MONITORING .....................................................................................60 
13 
HUMAN SUBJECTS PROTECTIONS...........................................................................60 
13.1 
Institutional Review Board/Ethics Committee Review and Approval ............................................... 60 


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13 April 2016 
13.2 
Vulnerable Participants .................................................................................................................... 60 
13.3 
Informed Consent ............................................................................................................................ 61 
13.4 
Potential Benefits............................................................................................................................. 62 
13.5 
Potential Risks ................................................................................................................................. 62 
13.6 
Potential Social Impacts .................................................................................................................. 62 
13.7 
Reimbursement/Compensation ....................................................................................................... 63 
13.8 
Privacy and Confidentiality .............................................................................................................. 63 
13.9 
Communicable Disease Reporting .................................................................................................. 63 
13.10 
Management of Incidental Findings ................................................................................................. 63 
13.11 
Management of New Information Pertinent to Study Participation .................................................. 64 
13.12 
Post-Trial Access to Study Drug ...................................................................................................... 64 
14 
ADMINISTRATIVE PROCEDURES ..............................................................................64 
14.1 
Regulatory Oversight ....................................................................................................................... 64 
14.2 
Protocol Registration ....................................................................................................................... 64 
14.3 
Study Implementation ...................................................................................................................... 65 
14.4 
Protocol Deviation Reporting ........................................................................................................... 65 
14.5 
Critical Event Reporting ................................................................................................................... 65 
14.6 
ClinicalTrials.gov ............................................................................................................................. 66 
15 
PUBLICATIONS ...........................................................................................................66 
16 
REFERENCES ..............................................................................................................67 
APPENDICES...........................................................................................................................68 
IA:  
Maternal Schedule of Evaluations ..............................................................................68 
IB:  
Cohort 1 (Stratum 1A and 1B) – Infant Schedule of Evaluations .............................69 
IC:  
Cohort 2 (Stratum 2A and 2B) – Infant Schedule of Evaluations .............................70 
II:  
Maraviroc Weight Band Dosing Tables For Solution ................................................71 
III-A:  Cohort 1 Sample Informed Consent Form for Study Participation ..........................73 
III-B:  Cohort 2 Sample Informed Consent Form for Study Participation ..........................82 
IV:  
Sample Informed Consent Form for Specimen Storage and Future Use ................91 
 
 


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IMPAACT 2007 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
 
ABBREVIATIONS AND ACRONYMS 
 
3TC 
Lamivudine 
AE 
Adverse Event  
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Transaminase 
ARV 
Antiretroviral 
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CNS 
Central nervous system 
CRF  
Case Report Form 
CRPMC 
Clinical Research Products Management Center 
D4T 
Stavudine 
DAIDS 
Division of AIDS  
DAIDS PRO 
DAIDS Protocol Registration Office 
DAERS 
DAIDS Adverse Event Reporting System 
DBS 
Dried Blood Spot 
DMC 
Data Management Center 
DNA 
Deoxyribonucleic Acid 
EAE 
Expedited Adverse Event 
EC 
Ethics Committee 
EFV 
Efavirenz 
EIA 
Enzyme Immunoassay 
FDA 
(US) Food and Drug Administration 
FSTRF 
Frontier Science and Technology Research Foundation 
FTC 
Emtricitabine 
GCLP 
Good Clinical Laboratory Practice 
HAART 
Highly Active Antiretroviral Therapy 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IRB  
Institutional Review Board 
IND 
Investigational New Drug 
IoR 
Investigator of Record  
LDMS 
Laboratory Data Management System 
LPC 
Laboratory Processing Chart 
LPV/r 
Lopinavir/ritonavir 
MVC 
Maraviroc 
MOP 
Manual of Procedures 
NFV 
Nelfinavir 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
National Institute of Child Health and Development 


IMPAACT 2007, Version 1.0 
 
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13 April 2016 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NRTI 
Nucleoside Reverse Transcriptase Inhibitor 
NNRTI 
Non-Nucleoside Reverse Transcriptase Inhibitor 
NVP 
Nevirapine 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase Chain Reaction 
PIBA 
Press-in-bottle Adaptor 
PID 
Participant Identification Number 
PK 
Pharmacokinetics 
PMTCT 
Prevention of Mother To Child Transmission 
PoR 
Pharmacist of Record 
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SDMC 
Statistical and Data Management Center 
SES 
Subject Enrollment System 
SID 
Study Identification Number 
SMC 
Study Monitoring Committee 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAE 
Treatment Emergent Adverse Event 
US 
United States 
WBC 
White Blood Cell 
WHO 
World Health Organization 
X4/DM 
X4/dual-mixed tropic 
ZDV 
Zidovudine 
 
 
 


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IMPAACT 2007 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
PROTOCOL TEAM ROSTER 
 
Protocol Chair 
Mark Mirochnick, MD 
Boston University School of Medicine/Boston 
Medical Center 
771 Albany Street, Room 4111 
Boston, MA 02118 
Phone: (617) 414-3754 
Email: markm@bu.edu 
 
Protocol Vice Chair  
Ellen Chadwick, MD 
Professor of Pediatrics, Northwestern  
University Feinberg School of Medicine 
Division of Infectious Diseases,  
Ann & Robert H. Lurie Children’s  
Hospital of Chicago  
225 E. Chicago Ave, 
Chicago, IL 60611 
Phone: (312) 227-4080 
Email egchadwick@luriechildrens.org  
 
Protocol Vice Chair  
and Protocol Pharmacologist 
Brookie Best, PharmD, MAS 
Univ of California San Diego 
9500 Gilman Drive, MC 0657 
La Jolla, CA 92093-0657 
Phone: (858) 822-5550 
Email: brookie@ucsd.edu 
 
Clinical Trials Specialists 
Kathleen George, MPH  
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040 x11150 
Email: kgeorge@fhi360.org 
 
Sarah Bradford, MPH  
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040 x11685 
Email: sbradford@fhi360.org 
 
NIAID Medical Officer 
Elizabeth Smith, MD  
Maternal Adolescent and Pediatric Research 
Branch 
Prevention Sciences Program 
Division of AIDS 
NIAID, NIH, 8B48 
5601 Fishers Lane 
Rockville, MD 20852 
Phone: (240) 292-4788 
Email: betsysmith@niaid.nih.gov 
 
NICHD Medical Officer 
Nahida Chakhtoura, MD, MsGH 
Maternal and Pediatric Infectious Disease 
Branch 
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
(NICHD) 
National Institutes of Health 
6100 Executive Blvd., Room 4B11 
Bethesda, MD 20892-7510 
Phone: (301) 435-6872 
Email: nahida.chakhtoura@nih.gov 
 
 


IMPAACT 2007, Version 1.0 
 
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13 April 2016 
Protocol Pharmacist 
Bijal Patel, Pharm. D, BCPS 
Pharmacist, HJF Contractor 
Pharmaceutical Affairs Branch 
DAIDS, OCSO 
5601 Fishers Lane 
Rockville, MD 20852 
Phone: (240) 421-8445 
Fax: (240) 627-3112 
E-mail: Bijal.patel@nih.gov 
 
Protocol Statisticians 
Pearl Samson, MS 
Center for Biostatistics in AIDS Research 
(CBAR), Harvard T.H. Chan School of Public 
Health/Frontier Science & Technology Research 
Foundation (FSTRF) 
900 Commonwealth Ave, 2nd Floor 
Boston, MA 02215-6017 
Phone: (617) 632-2000 x4030 
Email: psamson@sdac.harvard.edu 
 
Terence Fenton, EdD 
Statistical & Data Analysis Center  
Harvard T.H. Chan School of Public Health 
651 Huntington Avenue  
Boston, MA 02115 
Phone: (617) 432-3027 
Email: fenton@sdac.harvard.edu 
 
Kevin Butler, MS 
Statistical & Data Analysis Center  
Harvard T.H. Chan School of Public Health 
651 Huntington Avenue  
Boston, MA 02115 
Phone: (617) 432-3026 
Email: kbutler@sdac.harvard.edu  
 
Pharmaceutical Representatives 
Rebecca Zhang Roper MD, MSc, PhD  
Director (Physician), Global Clinical Safety and 
Pharmacovigilance 
GlaxoSmithKline 
Stockley Park, Uxbridge, UB11 1BT, 
Middlesex, UK 
Phone:  +440 20 8990 4199 
E-mail: rebecca.y.zhang-roper@gsk.com 
Katy Hayward, MD 
Global Medical Leader Kivexa/Epzicom 
ViiV Healthcare 
980 Great West Road 
Brentford 
Middlesex, UK 
Phone: +44 7825116112 
Email: katy.j.hayward@viivhealthcare.com 
 
Protocol Data Managers 
Michael Basar, BA 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900 x7271 
Fax: (716) 834-8675 
Email: basar.michael@fstrf.org 
 
Aaron Atlas, BS  
Protocol Data Manager 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226-1056 
Phone: (716) 834-0900  
Fax: (716) 834-8432 
Email: atlas@fstrf.org 
 
Protocol Laboratory Data Manager 
Rachael Henderson, BS 
Frontier Science & Technology Research 
Foundation 
4033 Maple Road 
Amherst, NY 14226 USA 
Phone: (716) 834-0900 Ext. 7331 
Email: henderso@fstrf.org  
 


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13 April 2016 
Laboratory Center Representative 
William Murtaugh, MPH 
IMPAACT Laboratory Center 
Children's Hospital of Los Angeles 
4650 Sunset Blvd., MS #51 
Los Angeles, CA 90027 
Phone: (323) 361-6224 
E-mail: wmurtaugh@impaactlabcenter.org 
 
Protocol Laboratory Technologist 
Bernadette Malunda, HBS, DMLS 
Harare Family Care Clinic 
Parirenyatwa, Harare 
Zimbabwe 
Phone 011 263 772 807 167 
Email bmalunda@uzcrc.co.zw 
 
Westat Clinical Research Associate  
Rita Patel, MS  
Westat  
1441 W. Montgomery Ave 
Rockville, MD 20850  
Phone:  (240) 453-2693  
Fax:  (301) 294-4494  
Email:  ritapatel@westat.com 
 
Community Program Manager 
Jontraye Davis, MHA 
IMPAACT Operations Center 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040 x11715 
Email: jodavis@fhi360.org 


IMPAACT 2007, Version 1.0 
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13 April 2016   
SITE ROSTER 
 
Site 4001, Lurie Children’s Memorial Hospital 
Ram Yogev, MD 
Lurie Children’s Hospital 
225 East Chicago Ave., Box 155 
Chicago, IL 60611-2605 
Phone: (212) 227-6280 
Email: ryogev@luriechildrens.org 
 
Site 4601, University of California, San Diego 
Stephen A. Spector, MD 
Director, Mother-Child-Adolescent HIV 
Program 
University of California, San Diego 
La Jolla, CA 92093-0672 
Phone: (858) 534-7055 
Email: saspector@ucsd.edu 
 
Site 5011, Boston Medical Center 
Ellen R. Cooper, MD 
Boston Medical Center 
670 Albany St. 
Boston, MA 02118 
Phone: 617-414-5588 
Email: ercooper@bu.edu 
 
Site 5048, University of Southern California 
James Homans, MD 
Maternal Child and Adolescent/Adult Center for 
Infectious Diseases and Virology 
1640 Marengo Street, Suite 300 
Los Angeles, CA 90033 
Phone: (323) 865-1585 
Email: homans@usc.edu 
 
Site 5052, University of Colorado 
Elizabeth McFarland, MD 
CHIP Clinic 
B055 
Children’s Hospital Colorado 
13123 East 16th Ave. 
Aurora, CO 80045 
Phone: 720-777-1966 
Email: Betsy.McFarland@ucdenver.edu 
 
Site 5083, Rush/Cook County 
Mariam Aziz, MD 
600 S. Paulina, Suite 140 
Chicago, IL 60612 
Phone: (312) 942-4265 
Email: mariam.aziz@rush.edu 
 
Site 5115, Siriraj Hospital Mahidol University 
Kulkanya Chokephaibulkit, MD 
Pediatric Infectious Diseases Unit, 
Department of Pediatrics,  
Siriraj Hospital Mahidol University 
2 Prannok Road, Bangkoknoi,  
Bangkok, Thailand 10700 
Phone: +6624195671 
Email: kulkanya.cho@mahidol.ac.th 
 
Site 5121, KEMRI 
Isaac Tsikhutsu, MBCHB, MMED, FPCCM 
Kenya Medical Research Institute/Walter Reed 
Project  
Hospital Road 
P.O. Box 1357-20200  
Kericho, Kenya 
Phone 254 729 110 124 
Email: Isaac.tsikhutsu@usamru-k.org 
 
Site 6501, St. Jude Children’s Research Hospital 
Katherine Knapp, MD 
262 Danny Thomas Place, MS 600 
Memphis, TN 38105 
Phone: (901) 595-4645 
Email: katherine.knapp@stjude.org 
 
Site 8052, Perinatal HIV Research Unit 
Sisinyana Ruth Mathiba, MBCHB 
Perinatal HIV Research Unit 
New Nurses Home 
Chris Hani Baragwanath Academic Hospital 
Chris Hani Road 
Soweto, 1862, Gauteng 
South Africa 
Phone: 011989 974661 
Email: mathibas@phru.co.za 
 


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13 April 2016 
Site 30293, MUJHU Research Collaboration 
Jesca Nakibuka, MBChB 
Upper Mulago Hill Raod 
Box 23491 
Kampala, Uganda 
Phone: 256 44 541044 
Email: jnakibuka@mujhu.org 
 
Site 30300, CAPRISA Umlazi Clinical Research 
Site 
Sherika Hanley, MBChB, MFamMed, FCFP 
CAPRISA - Umlazi Clinical Research Site 
Nelson R. Mandela School of Medicine 
Durban 4051 
South Africa 
Phone: 27 31 2604685 
Email: hanley@ukzn.ac.za 
 
 
 
 
 


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13 April 2016 
IMPAACT 2007 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
SCHEMA 
 
Purpose: 
To determine an appropriate dose of maraviroc solution during the first six weeks 
of life for infants born to HIV-1 infected mothers.    
 
Design: 
Phase I safety and pharmacokinetics (PK) study with two sequential dosing 
cohorts stratified by maternal use of efavirenz (EFV). 
 
Study Population: 
Infants born to HIV-1 infected mothers and are receiving a single or combination 
antiretroviral (ARV) regimen for prevention of perinatal HIV transmission that 
does not include a potent cytochrome P450 CYP3A4 inhibitor or inducer 
(mothers will also be enrolled in the study but will not receive study drug).  
 
Sample Size: 
Up to 72 mother-infant pairs to achieve a target of 36 evaluable infants receiving 
the final recommended dose of maraviroc.  
 
Cohort 1:  Stratified by infant in utero exposure to maternal EFV, with 
concurrent enrollment of both strata.  Breastfeeding and formula feeding infants 
are eligible for this cohort; infant exposure to maternal EFV after birth is not 
relevant to eligibility or stratum assignment. 
 
Up to 36 mother-infant pairs to achieve a target of 12 evaluable infants (6 in each 
stratum) receiving the dose of maraviroc that passes safety and PK guidelines for 
the relevant stratum and is recommended for Cohort 2.   
 
Stratum 1A: 
n = 6-18 infants without in utero exposure to maternal EFV (no 
EFV exposure during the eight weeks immediately prior to 
delivery).   
 
Stratum 1B: 
n = 6-18 infants with in utero exposure to maternal EFV (EFV 
exposure for a minimum of two weeks immediately prior to 
delivery).  
 
Cohort 2:  Stratified by infant exposure to maternal EFV after birth, with 
enrollment of each stratum opening upon dose selection from the corresponding 
stratum in Cohort 1.  Breastfeeding and formula feeding infants are eligible for 
Stratum 2A; only breastfeeding infants are eligible for Stratum 2B.  
 
Up to 36 mother-infant pairs to achieve a target of 24 evaluable infants (12 in 
each stratum) receiving the final recommended dose of maraviroc that passes 
safety and PK guidelines for the relevant stratum.   
 
Stratum 2A:  
n = 12-18 infants without any exposure to maternal EFV either 
in utero (no EFV exposure during the eight weeks immediately 
prior to delivery) and if breastfeeding while breastfeeding. 
 


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13 April 2016 
Stratum 2B:  
n = 12-18 breastfeeding infants with exposure to maternal EFV 
both in utero and after birth while breastfeeding (EFV exposure 
for a minimum of two weeks immediately prior to delivery and 
while breastfeeding).  
 
Study Drug:   
Cohort 1: Single doses of maraviroc solution at two time points: within 3 days of 
life and at one week (7-14 days) of life.  The initial starting dose for this cohort 
will be 8 mg/kg; dose adjustment may occur as needed based on experience 
within the cohort. 
 
Cohort 2: Daily dosing of maraviroc solution starting within 3 days of life and 
continuing up to 42 days of life. The initial starting dose for this cohort will be 
determined based on experience in Cohort 1.  Dose adjustments for the cohort 
may occur as needed based on experience within the cohort.  
 
Study Duration: 
Approximately 28 months total.  Accrual is expected to require approximately 24 
months and enrolled infants will be followed for four months. 
 
Primary Objectives 
 
• 
To evaluate the safety and tolerability of maraviroc solution, during the first six weeks of life, when 
administered with ARV prophylaxis to HIV-1 exposed infants at risk of acquiring HIV-1 infection 
with and without exposure to maternal EFV.  
 
• 
To evaluate the pharmacokinetics of maraviroc solution, during the first six weeks of life, when 
administered with ARV prophylaxis to HIV-1 exposed infants at risk of acquiring HIV-1 infection 
with and without exposure to maternal EFV.  
 
• 
To determine an appropriate dose of maraviroc solution during the first six weeks of life.  
 
Secondary Objectives 
 
• 
To assess safety through 16 weeks of life following administration of maraviroc solution during the 
first six weeks of life. 
 
• 
To determine age-related changes in maraviroc pharmacokinetic parameters during the first six weeks 
of life. 
 
• 
To explore the impact of maraviroc treatment on viral tropism in the event of perinatal transmission 
of an X4/dual-mixed tropic strain of HIV.   
 
 


IMPAACT 2007, Version 1.0 
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13 April 2016 
IMPAACT 2007 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
Figure 1A: IMPAACT 2007 Overview of Study Design – Cohort 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cohort 1:  Stratum 1A and 1B – open concurrently.  
The following will apply to each stratum, independently. 
Initial (n=6) infants 
 
Maraviroc Regimen: Single doses of maraviroc solution at two time points:  
Birth (within 3 days of birth) and Week 1 (7-14 days of life)   
  
Intensive PK Evaluation: Birth and Week 1 
Safety Evaluation: through 7-days Post Last Dose 
 Follow-Up: through 16 weeks of life 
  
Guidelines met for evaluating the dose (n=6) 
 
Safety: Dose is safe and well tolerated 
 
PK: Cavg ≥ 75ng/mL  
Yes 
No 
Cohort 2: 
corresponding 
stratum opens with 
dose meeting 
guidelines. 
Core Protocol Team will evaluate to either: 
1. Adjust the current dose, enroll new infants 
(n=6), and evaluate safety and PK on the 
adjusted dose OR 
2. Continue current dose OR 
3. Stop study 
  


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13 April 2016 
Figure 1B: IMPAACT 2007 Overview of Study Design - Cohort 2 
 
 
 
 
 
 
 
 
 
No 
Initial (n=6) infants 
Maraviroc Regimen: Dose determined from corresponding stratum in Cohort 1. 
Daily dosing of maraviroc solution starting within 3 days of birth and continued 
through Week 6 (35-42 days of life) 
  
Intensive PK Evaluation: Week 1 and Week 4 
Safety Evaluation: through Week 6 
Follow-up: through 16 weeks of life 
  
Guidelines met for evaluating the dose (n=6) 
 
Safety: Dose is safe and well tolerated 
 
PK: Cavg ≥ 75ng/mL  
Yes 
• 
Enroll additional infants 
(n=6): treat at dose meeting 
guidelines to complete full 
cohort (n=12) 
• 
Evaluate safety and PK on 
full cohort 
Core Protocol Team will evaluate 
to either: 
1. Adjust the current dose, enroll 
new infants (n=6), and evaluate 
safety and PK on the adjusted 
dose OR 
2. Continue current dose OR 
3. Stop study 
Guidelines met for evaluating  
the dose (n=12) 
No 
Yes
Dose established for stratum 
Cohort 2:  Stratum 2A or 2B – will open once the dose is established in 
the corresponding stratum from Cohort 1. 
 The following will apply to each stratum, independently. 


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13 April 2016   
1 
INTRODUCTION 
 
1.1 
Background  
 
While there is a critical need for ARVs for use as prophylaxis and treatment of neonates, neonatal 
safety and dosing information are not available for most ARVs. Of the nucleoside reverse 
transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitor (NNRTIs), only 
zidovudine (ZDV), lamivudine (3TC), emtricitabine (FTC), stavudine (d4T), and nevirapine 
(NVP) are approved for use in neonates less than 14 days of age. Of the protease inhibitors, only 
nelfinavir (NFV) has pharmacokinetic (PK) data available for neonates, but these data 
demonstrate highly variable plasma concentrations and the optimal dosing regimen remains 
uncertain.[1, 2]  The powder formulation of NFV that was studied in neonates is no longer 
commercially available and NFV is not approved in children less than two years old. 
Lopinavir/ritonavir (LPV/r), is available as a pediatric solution, but its dosing is uncertain in the 
first weeks of life and its use is not recommended in neonates less than two weeks old and 42 
weeks post-menstrual age after several cases of life-threatening toxicities, including 
bradyarrhythmias, cardiac dysfunction, metabolic acidosis and CNS disturbances, were reported 
in neonates.[3, 4]  No neonatal safety or PK data following neonatal dosing are available for any 
of the integrase inhibitors, so these drugs are not approved for use in neonates.  The three-drug 
ARV regimen with the greatest experience in neonates is ZDV/3TC/NVP, and alternative agents 
for use in this population are urgently needed. 
 
Maraviroc is a CCR5 receptor antagonist used in the treatment of HIV-1 infection.  The safety 
and efficacy of maraviroc have been confirmed in Phase II-IV clinical trials.  Maraviroc works as 
an entry inhibitor, blocking entry of HIV into vulnerable host lymphocytes.  It was approved to 
treat CCR5 tropic HIV-1 infected adults in 2007.  Current United States (US) guidelines 
recommend maraviroc for use in HIV-1 infected adults as second line therapy, due to lack of 
virologic benefit when compared with other recommended regimens and the need for twice daily 
dosing. [5]  
 
Postnatal prophylaxis with multiple antiretroviral agents is currently recommended for HIV-
exposed neonates at high risk for acquiring HIV infection.  Due to the lack of adequate neonatal 
safety and PK data, the ARV options are limited to several NRTI’s and the NNRTI nevirapine, as 
indicated above, that can be safely used in neonates.  Maraviroc, as an HIV entry inhibitor, has a 
different mechanism of action from the NRTIs and NNRTIs, making it attractive as a potential 
component of neonatal prophylaxis regimens.  Maraviroc’s novel mechanism of action might be 
especially valuable for infants born to mothers with HIV strains resistant to the more commonly 
used ARV classes.    
 
Turn-around time for diagnostic tests of HIV-1 infection has improved in recent years, and HIV-1 
infected neonates are now routinely identified in the first days and weeks of life. Strategies for 
early treatment of HIV-1 infected newborns with intensive four drug regimens have been 
proposed, with a goal of either improving outcome or limiting the size of the latent reservoir to 
achieve long-term remission, but the drugs available for use in neonates are limited.  Maraviroc 
may also prove to be of value for early treatment of those infants who fail prophylaxis and are 
diagnosed with HIV-1 infection, although this protocol will be limited to the study of maraviroc 
as prophylaxis in the first six weeks of life. 
 
Because over 90% of HIV-1 infected neonates are infected with CCR5 tropic virus alone, 
maraviroc, as a CCR5 receptor antagonist, has the potential to play an important role in infant 


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13 April 2016 
prophylaxis.[6]  Before maraviroc can be studied as part of a prophylaxis regimen to prevent 
perinatal HIV transmission, a Phase I study to investigate safety and PK in neonates is needed. 
 
1.2 
Maraviroc Pharmacokinetics and Safety in Adults 
 
Based on data from healthy adult volunteers, maraviroc is well absorbed following oral dosing 
with Cmax typically occurring 0.5-4 hours after dosing.  The in vitro protein-adjusted IC90 for 
maraviroc against wild-type virus is 2.1 ng/mL.  The oral PK of maraviroc are not dose 
proportional, although the non-proportionality is most marked at doses below 100 mg. This dose 
non-proportionality is thought to result from absorption (P-glycoprotein and other transporters) 
rather than elimination.  Maraviroc was dosed in initial clinical pharmacology studies as an oral 
solution and in later clinical studies as research and commercial tablet formulations. A 
comparison of the PK of the oral solution to the research tablet demonstrated that maraviroc 
exposure following the solution dose was moderately higher (12%) than that following the tablet 
in the fasting state. The overall PK profile of the solution doses was similar to that of the research 
tablet (75 mg).[7] 
 
Maraviroc is primarily metabolized by CYP3A4 with renal clearance contributing approximately 
23% of total clearance (in the absence of metabolic inhibitors). Maraviroc does not inhibit any of 
the major cytochrome P450 enzymes (CYP 1A2, 2B6, 2C9, 2C19, 2D6, and 3A4) in vitro at 
clinically relevant concentrations. Therefore, maraviroc is unlikely to inhibit the metabolism of 
co-administered drugs that are metabolized by cytochrome P450 enzymes. Since maraviroc is a 
CYP3A4 substrate, the concentration of maraviroc is increased by CYP3A4 inhibitors (including 
HIV protease inhibitors [PI]; except tipranavir/ritonavir) and decreased by CYP3A4 inducers 
(such as rifampin, etravirine, and efavirenz). In adults, maraviroc dose adjustments are 
recommended if it is to be co-administered with such agents, including efavirenz.[8] 
 
The safety and efficacy of oral maraviroc for treatment of HIV-1 infection have been confirmed 
in Phase II, Phase III, and Phase IV clinical trials.  Cumulatively, the safety and tolerability of 
maraviroc has been evaluated in >4,600 participants (patients and healthy volunteers) in over 50 
clinical studies during the clinical development program.  Cumulative post-marketing exposure to 
maraviroc up to 31st March 2014 is estimated to be 56,769 patient-years.[7]  
 
Based upon the pooled data from the Phase III treatment-experienced studies, A4001027 and 
A4001028, the most common (>10% incidence in any treatment group) treatment-related 
treatment emergent adverse events (TEAEs) in the maraviroc treatment group were diarrhea, 
nausea, and headache.  Similarly, data from the Phase III treatment naïve study A4001026 
reported the most frequently reported treatment-related TEAEs (>10% incidence in any treatment 
group) in the maraviroc treatment group were nausea and headache.[8]  
 
Safety concerns raised by pre-clinical models and the Phase I/IIa studies of maraviroc include 
postural hypotension.  Theoretical concerns based on the drug’s mechanism of action include an 
increased risk for infection and the development of malignancy.  However, the Phase IIb/III 
studies that administered maraviroc in adults at a dose equivalent of 300mg (QD or BID) did not 
show any increased frequency relative to placebo of symptomatic postural hypotension, QTc 
interval prolongation, infections or malignancy.  Postural hypotension is recognized to be the 
dose-limiting toxicity of maraviroc but at recommended doses, the effect is not clinically 
significant. When maraviroc was administered to healthy volunteers at doses higher than the 
recommended dose, symptomatic postural hypotension was seen at a greater frequency than in 
placebo. However, when maraviroc was given at the recommended dose in HIV-1 infected 


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13 April 2016 
participants in Phase III trials, symptomatic postural hypotension was seen at a rate similar to 
placebo (approximately 0.5%).[8] 
 
Review of post-marketing and clinical trial data has identified the occurrence of very rare reports 
of hepatotoxicity and hepatic failure with allergic features in patients taking maraviroc. In these 
cases, hepatotoxicity has occurred in association with rash and/or other features of 
hypersensitivity, such as fever and eosinophilia, shortly after starting maraviroc (typically within 
1 month). These cases are confounded by co-suspect medications which make it difficult to 
determine causality, however, it is possible that maraviroc may play a role in the development of 
drug-induced hypersensitivity.[8] 
 
1.3 
Maraviroc in Infants and Children 
 
To begin to assess the potential for use of maraviroc in pediatric populations, PHIVCO conducted 
a pediatric study (Study A4001031) to determine maraviroc PK, safety and efficacy in 
combination with optimized background therapy in antiretroviral-experienced children 2 to <18 
years of age.  The maraviroc dose in this study was based on the participant’s body surface area 
and adjusted for concomitant medication if participants were receiving potent CYP3A4 inhibitors 
and/or inducers. Participants demonstrated good virologic response if they achieved the target 
concentration of Cavg ≥100 ng/mL, the exposure associated with near-maximal efficacy in 
treatment-experienced adults, and no new toxicities in children were observed. In addition, 
preliminary analyses suggest that maraviroc dosing in children two to less than 18 years of age 
could also be determined by weight bands, which may be preferable in resource sparse areas. 
 
Safety results from Study A4001031 suggest that, in HIV-1-infected, treatment-experienced 
children aged two to <18 years maraviroc (administered twice-daily, in addition to OBT) was 
generally well-tolerated. Overall, 285 all causality TEAEs were reported for 74 (71.8%) 
participants up to Week 48. The proportion of participants with TEAEs in the four cohorts ranged 
from 64.5% to 79.1%. The TEAEs reported were predominantly Grade 1 in severity followed by 
Grade 2. The most commonly (>10% of participants) reported TEAEs, were diarrhea (17 [16.5%] 
participants), vomiting (17 [16.5%] participants), and upper respiratory tract infection (14 
[13.6%] subjects). Six participants had Grade 3 or 4 TEAEs, none of which were considered to 
be related to maraviroc by the investigator. 
 
A total of 12 (11.7%) participants experienced 15 SAEs up to Week 48: two participants each in 
Cohorts 1, 2, and 3; and six participants in Cohort 4. The majority of SAEs reported were 
infections.  No SAEs were attributed to maraviroc by the investigator. No deaths occurred in the 
48 Week reporting period. 
 
No new safety concerns were identified regarding the occurrence of serious hypersensitivity 
reactions, hepatotoxicity, malignancies, infections, autoimmune diseases, rhabdomyolysis 
/muscle toxicity or other AE of special interest in subjects receiving maraviroc. Treatment - 
emergent Category C events (Grade 1 pulmonary tuberculosis and Grade 1 recurrent 
pneumonia) were reported in two participants in Cohort 4 and considered not related to study 
drug. Grade 3 and 4 laboratory abnormalities were reported in 14% of participants up to the 48-
week study period. The most common laboratory abnormality was Grade 3 decreases in absolute 
neutrophil count experienced by 8 participants (1 each in Cohort 1 and 3, and 3 each in Cohort 2 
and 4). There was no Grade 4 neutropenia. 
 
To date, maraviroc plus other background therapy appears to be well-tolerated and effective, with 
a manageable safety profile in children.  


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13 April 2016 
 
Since childhood growth and maturation are most prominent during infancy, from a clinical 
pharmacology perspective, maraviroc absorption, distribution, metabolism and elimination are 
constantly changing during childhood. Due to these developmental changes in immature body 
organs, a PK and safety study from birth to 2 years of age has been requested by regulatory 
authorities.  However, maraviroc’s recommended use in only second line regimens limits its 
relevance to older infants and toddlers on initial HIV treatment regimens, who have other 
effective options for combination antiretroviral regimens, making a PK and safety study in HIV-1 
infected older infants up to age 2 years impractical at this time.  However, as discussed above, 
maraviroc may have a role as a component of neonatal prophylactic regimens. 
 
An important safety consideration is whether the use of maraviroc in newborns could lead to 
selective transmission of X4/dual-mixed tropic (DM) strains or lead to inferior outcomes among 
neonates who are born having been infected in utero with X4/DM virus.  While some data 
suggest that infants born to mothers with DM virus may be at elevated risk of becoming infected 
with X4/DM strains, most infants are born with R5 virus, and even viral populations that are 
initially X4/DM generally shift to CCR5 as the infant ages.[9-12] It is not expected that use of 
maraviroc by neonates would significantly alter the risk of transmission of X4/DM virus because 
maraviroc will only be given in addition to the standard of care prophylaxis regimen, and should 
thus only add to prophylactic efficacy.  For infants already HIV-1 infected at birth, the brief 
exposure to maraviroc that would occur while the infant was receiving other antiretrovirals as 
prophylaxis would likewise not be expected to alter outcomes. In fact, while maraviroc is 
recommended for patients with R5 virus, two recent studies demonstrated that adults with non-R5 
virus treated with maraviroc did not have a decline in CD4 count despite the absence of viral 
suppression.[8, 13] 
 
Maraviroc is metabolized by CYP3A4 and its clearance is induced when administered with 
efavirenz, an agonist of CYP3A4 activity.  As a result, the recommended maraviroc dose is 
doubled in adults receiving both maraviroc and efavirenz.[8]  In many areas of the world with 
high prevalence of HIV, efavirenz is part of the ARV combination regimen most commonly used 
during pregnancy.  Efavirenz is readily transferred during pregnancy from mother to fetus infant 
across the placenta and after birth from mother to infant via breast milk.[14, 15]  Transplacental 
and breast milk transfer of efavirenz may result in accumulation of biologically active plasma 
efavirenz concentrations in neonates with the potential to induce neonatal CYP3A4 maraviroc 
clearance.  This study will separate neonates into two strata, with and without exposure to 
maternal efavirenz, so that the impact of maternal efavirenz use during pregnancy and 
breastfeeding can be evaluated and the need for different maraviroc dosing in efavirenz exposed 
neonates can be determined. 
 
1.4 
Rationale 
 
While maraviroc has promise for use as part of regimens to prevent or treat neonatal HIV 
infection, its efficacy cannot be studied until its safety and PK have been established in this 
population. Addition of maraviroc to a standard of care prophylaxis regimen might benefit infants 
by reducing the risk of perinatal transmission. This Phase I study will evaluate the safety and PK 
of maraviroc in infants whose mothers are HIV-1 infected and are at risk for perinatal HIV 
transmission. Due to the significant drug-drug PK interaction between maraviroc and efavirenz in 
adults, study infants will be stratified by exposure to maternal efavirenz.  The maraviroc exposure 
target will be a Cavg of ≥ 75 ng/mL, which is the exposure associated with near-maximal efficacy 
in the treatment-naïve adult study (MERIT) of maraviroc given with ZDV/3TC. [16] 
 


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13 April 2016 
Although it is expected that the majority of infants enrolling in the study will not be born with 
HIV infection, it will be important to assess for potential switch of virus tropism after exposure to 
maraviroc among the few, if any infected infants. Maternal HIV RNA levels will be collected to 
correlate with perinatal transmission risk, and a sample for maternal viral tropism will be stored 
to be run in the event that the infant is found to be HIV-1 infected.  In addition, since 
understanding of the pathogenesis of HIV transmission continues to evolve, with the consent of 
the mother, any blood sample that is not used will be stored for future testing if new 
methodologies are developed to better elucidate mechanisms of perinatal HIV transmission from 
mother to child. 
 
The protocol team has been working in cooperation with ViiV Healthcare to create this study 
with the intention of producing data for fulfillment of a pediatric written request pursuant to the 
Best Pharmaceutical’s for Children’s Act and for labelling changes for the Company’s product.   
 
1.5 
Hypotheses 
 
Maraviroc will be well tolerated in full-term infants and can be safely administered to achieve 
usual drug exposure targets (Cavg ≥75 ng/mL) as in adults treated with maraviroc.   
 
Note: The maraviroc exposure target of Cavg ≥ 75 ng/mL was selected because this is the exposure 
associated with near-maximal efficacy in the treatment-naïve adult study (MERIT) of maraviroc 
given with ZDV/3TC. [16] 
 
2 
OBJECTIVES 
 
2.1 
Primary Objectives 
 
The primary objectives of this study are to:  
 
2.1.1 
To evaluate the safety and tolerability of maraviroc solution, during the first six weeks of 
life, when administered with ARV prophylaxis to HIV-1 exposed infants at risk of 
acquiring HIV-1 infection with and without exposure to maternal EFV.  
 
2.1.2 
To evaluate the pharmacokinetics of maraviroc solution, during the first six weeks of life, 
when administered with ARV prophylaxis to HIV-1 exposed infants at risk of acquiring 
HIV-1 infection with and without exposure to maternal EFV.  
 
2.1.3 
To determine an appropriate dose of maraviroc solution during the first six weeks of life.  
 
2.2 
Secondary Objectives 
 
The secondary objectives of this study are to:  
 
2.2.1 
To assess safety through 16 weeks of life following administration of maraviroc solution 
during the first six weeks of life. 
 
2.2.2 
To determine age-related changes in maraviroc pharmacokinetic parameters during the 
first six weeks of life.  
 
2.2.3 
To explore the impact of maraviroc treatment on viral tropism in the event of perinatal 
transmission of an X4/dual-mixed tropic strain of HIV.   


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3 
STUDY DESIGN 
 
This is a Phase I, multi-center, open label, intensive PK study to evaluate the safety and PK of 
maraviroc solution when administered with a single or combination ARV regimen for prevention 
of perinatal HIV transmission to HIV-1 exposed infants at risk of infection. Refer to Figures 1A 
and 1B for an overview of the study design, to Sections 4.1-4.2 for the study eligibility criteria, 
and to Section 4.4 for a description of the study recruitment, screening, and enrollment process.  
Study sites will be located in Kenya, South Africa, Thailand, Uganda, and the United States. 
 
The protocol will enroll two sequential dosing cohorts.  Cohort 1 will be stratified by in utero 
exposure to maternal EFV and Cohort 2 will be stratified by exposure to maternal EFV during 
breastfeeding, as follows:      
 
Cohort 1:  HIV-exposed infants stratified by infant in utero exposure to maternal EFV, with 
concurrent enrollment of both strata. Breastfeeding and formula feeding infants are eligible; 
infant exposure to EFV after birth is not relevant to eligibility or stratum assignment. 
 
Up to 36 mother-infant pairs will be enrolled in this cohort to achieve a target of 12 evaluable 
infants (6 in each stratum) receiving the dose of maraviroc that passes safety and PK guidelines 
for each stratum and is recommended for Cohort 2.   
 
Stratum 1A: 
n = 6-18 infants without in utero exposure to maternal EFV (no EFV exposure 
during the eight weeks immediately prior to delivery).   
 
Stratum 1B: 
n = 6-18 infants with in utero exposure to maternal EFV (EFV exposure for a 
minimum of two weeks immediately prior to delivery).  
 
Cohort 2:  HIV-exposed infants stratified by infant exposure to maternal EFV after birth, with 
enrollment of each stratum opening upon dose selection from the corresponding stratum in  
Cohort 1.  Breastfeeding and formula feeding infants are eligible for Stratum 2A; only 
breastfeeding infants are eligible for Stratum 2B.  
 
Up to 36 mother-infant pairs to achieve a target of 24 evaluable infants (12 in each stratum) 
receiving the final recommended dose of maraviroc that passes safety and PK criteria for each 
stratum.   
 
Stratum 2A:  n = 12-18 infants without any exposure to maternal EFV either in utero (no EFV 
exposure during the eight weeks immediately prior to delivery) and if 
breastfeeding while breastfeeding. 
 
Stratum 2B:  n = 12-18 breastfeeding infants with exposure to maternal EFV both in utero and 
after birth while breastfeeding. (EFV exposure for a minimum of two weeks 
immediately prior to delivery and while breastfeeding).  
 
The study will implement a dose-finding algorithm based on real time safety and PK data as 
described in Section 9.2.  
 
Mothers-infant pairs will be enrolled within three days of infant birth and infants will receive 
their first dose of maraviroc solution at entry. Infants enrolled in Cohort 1 will receive a second 
dose of maraviroc solution one week (7-14 days) after birth.  Infants enrolled in Cohort 2 will 


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receive daily dosing of maraviroc solution through six weeks (35-42 days) of life.  Intensive PK 
sampling will be performed in both cohorts per the schedule described in Section 6.0.    
 
Infants will be followed for 16 weeks (112-140 days) of life, with clinical and laboratory 
evaluations as shown in the Schedules of Evaluations in Appendix IB (Cohort 1) or IC (Cohort 
2). Mothers will have evaluations performed at screening and entry only as shown in Appendix 
IA.   
 
4 
STUDY POPULATION 
 
This study will be conducted in full-term infants up to 3 days old, born to HIV-1 infected 
mothers.  Infants will be enrolled in pairs with their mothers, although only infants will receive 
study drug. Mother-infant pairs will be selected for the study according to the criteria in Sections 
4.1 and 4.2 and the guidelines in Section 4.3.  The study-specific approach to recruitment, 
screening, and enrollment is described in Section 4.4.  Considerations related to participant 
retention and withdrawal/termination from the study are provided in Sections 4.5 and 4.6, 
respectively. 
 
4.1 
Inclusion Criteria 
 
All of the following criteria must be met in order for mother-infant pairs to be included in this 
study: 
 
4.1.1 
Mother is of legal age to provide independent informed consent for research participation 
and is willing and able to provide written informed consent for her and her infant’s 
participation in this study. 
 
4.1.2 
Mother has confirmed HIV-1 infection based on testing of two samples collected at 
different time points:  
 
• 
Sample #1 may be tested using any of the following: 
o Two rapid antibody tests from different manufacturers or based on different 
principles and epitopes 
o One enzyme immunoassay (EIA) OR Western Blot OR immunofluorescence 
OR chemiluminescence 
o One HIV DNA PCR 
o One quantitative HIV RNA PCR (above the limit of detection of the assay) 
o One qualitative HIV RNA PCR 
o One HIV total nucleic acid test 
 
• 
Sample #2 may be tested using any of the following: 
o Rapid antibody test. If this option is used in combination with two rapid tests 
for Sample #1, at least one of the three rapid tests must be FDA-approved, 
and the third rapid test must be from a third manufacturer or based on a third 
principle or epitope. 
o One EIA OR Western Blot  OR immunofluorescence OR chemiluminescence 
o One HIV DNA PCR 
o One quantitative HIV RNA PCR (above the limit of detection of the assay) 
o One qualitative HIV RNA PCR 
o One HIV total nucleic acid test 


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All samples tested must be whole blood, serum, or plasma.  If both samples are tested 
using antibody tests, at least one of the samples must be tested in a laboratory that 
operates according to Good Clinical Laboratory Practice (GCLP) guidelines and 
participates in an appropriate external quality assurance program.  If nucleic acid testing 
is used, at least one test must be performed in a CLIA-certified (US sites) or VQA-
certified (non-US certified) laboratory.  For tests performed in other (non-GCLP-
compliant or non-VQA-certified) settings, adequate source documentation including the 
date of specimen collection, date of testing, test performed, and test result must be 
available. 
 
4.1.3   At entry, infant meets EFV exposure requirements, based on mother’s report and 
confirmed by medical records if available, as follows: 
 
For Cohort 1, Stratum 1A 
4.1.3.1 Infant born to a mother who did not receive EFV during the eight weeks 
immediately prior to delivery.   
 
Note:  Breastfeeding and formula feeding infants are eligible for this stratum.  
 
For Cohort 1, Stratum 1B 
4.1.3.2 Infant born to a mother who received EFV for a minimum of two weeks 
immediately prior to delivery.  
 
Note:  Breastfeeding and formula feeding infants are eligible for this stratum.  
 
For Cohort 2, Stratum 2A 
4.1.3.3 Infants born to a mother who did not receive EFV during the eight weeks 
immediately prior to delivery and if breastfeeding, mother is not receiving 
maternal EFV.   
 
Note:  Breastfeeding and formula feeding infants are eligible for this stratum. 
 
For Cohort 2, Stratum 2B 
4.1.3.4 Breastfeeding infants born to a mother who received EFV for a minimum of two 
weeks immediately prior to delivery, intends to breastfeed for a minimum of six 
weeks and will continue to receive maternal EFV while breastfeeding.  
 
Note:  Only breastfeeding infants are eligible for this stratum. 
 
4.1.4 
At birth, infant’s estimated gestational age was at least 37 weeks. 
 
Note:  If gestational age at birth is not documented in the infant’s available birth records, 
study staff may assess gestational age at the earliest possible opportunity during the 
screening period and use this assessment for purposes of eligibility determination. 
 


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4.1.5 
At birth, infant’s weight was at least 2 kg. 
 
Note:  If weight at birth is not documented in the infant’s available birth records, study 
staff may assess infant weight at the earliest possible opportunity during the screening 
period and use this assessment for purposes of eligibility determination. 
 
4.1.6 
At entry, infant is less than or equal to 3 days old. 
 
4.1.7 
At entry, infant has ≤ Grade 2 AST, ALT, total bilirubin, hemoglobin, white blood cell 
counts, and platelet counts. 
 
4.1.8 
At entry, infant has initiated antiretroviral prophylaxis that does not include a potent 
CYP3A4 inhibitor or inducer. (See Section 5.11).   
 
4.1.9 
At entry, infant is assessed by the site investigator or designee as generally healthy based 
on review of available medical records, other available medical history information, and 
physical examination findings. 
 
4.1.10 Born after singleton delivery (not after multiple birth). 
4.2 
Exclusion Criteria 
 
Mother-infant pairs must be excluded from the study if any of the following are identified at any 
time during screening:  
  
4.2.1 
Infant has any other condition that, in the opinion of the site investigator or designee, 
would make participation in the study unsafe, complicate interpretation of study outcome 
data, or otherwise interfere with achieving the study objectives; for example, severe 
congenital malformation, other medical condition, or clinically significant finding from 
physical examination.  
 
4.2.2 
At entry, any positive infant HIV nucleic acid test result (results are not required to be 
available prior to entry but any positive results obtained prior to entry are exclusionary).  
 
4.2.3 
At entry, infant or breastfeeding mother is receiving any disallowed medication listed in 
Section 5.11. 
 
4.2.4 
Mother received maraviroc during pregnancy. 
 
 
4.3 
Co-Enrollment Considerations 
 
Co-enrollment in A Phase IV Randomized Trial to Evaluate the Virologic Response and 
Pharmacokinetics of Two Different Potent Regiments in HIV Infected Women Initiating Triple 
Antiretroviral Regiments between 28 and 36 Weeks of Pregnancy for the Prevention of Mother-
to-Child Transmission: NICHD P1081 is allowed.  Co-enrollment in other studies is not 
precluded but requires approval from the protocol teams of both studies. 
 


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4.4 
Recruitment, Screening, and Enrollment Process 
 
Although mother-infant pairs will not be enrolled in this study until after delivery, recruitment 
will typically begin with provision of information about the study to HIV-1 infected pregnant 
women attending antenatal and/or Prevention of Mother to Child Transmission (PMTCT) clinics.  
The study-specific informed consent process will typically be conducted during the second or 
third trimester of pregnancy; however, the process may be conducted, in whole or in part, after 
infant birth.  
 
It is generally expected that the informed consent process will take place over the course of more 
than one session, and women will be invited to bring their partners or other persons of their 
choosing to these sessions, if they wish.  The informed consent process will include detailed 
review of the study informed consent form (ICF), time to address any questions or concerns each 
woman may have, and an assessment of each woman’s understanding before proceeding to her 
informed consent decision.  The process will be fully documented and only women who are able 
to demonstrate understanding will be asked to provide written informed consent for themselves 
and their infants to take part in the study.   
 
Eligibility screening will be initiated after written informed consent is provided.  Maternal 
screening will include confirmatory HIV-1 testing (if needed) and assessment of other maternal 
eligibility requirements. If at any time it is determined that a woman is not eligible for the study, 
or that study participation may not be feasible or in the best interest of a given woman or infant, 
the eligibility screening process will be discontinued.  
 
Study staff will remain in contact with potentially eligible women as they approach their expected 
dates of delivery, with instructions provided to inform study staff upon onset of labor.  Study staff 
will arrange to see each woman as soon as possible after delivery to discuss the study again and 
confirm continued consent for study participation.  Infant screening — including review of 
medical records and other available medical history information, physical examination, and 
specimen collection for laboratory testing — may occur prior to confirmation of continued 
consent but final eligibility determination and next steps toward enrollment will only proceed 
after confirmation of continued consent. 
 
Each site must establish standard operating procedures (SOPs) for eligibility determination that 
describe where and when screening procedures will be performed; roles and responsibilities for 
performing the required procedures; roles and responsibilities for assessing and confirming 
eligibility; and procedures for documenting the process, taking into consideration the required 
timing of enrollment and the cohorts open for enrollment.  Mother-infant pairs who are found to 
meet the study eligibility criteria will be enrolled and infants will receive their first dose of 
maraviroc solution within 3 days of life.  Screening procedures may be performed on the day of 
enrollment; however, the mother’s HIV test results and the infant’s hematology and chemistry 
test results must be available for eligibility determination prior to enrollment. 
 


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The IMPAACT Data Management Center (DMC) Subject Enrollment System (SES) will be used 
to assist with tracking the screening and enrollment process.  When informed consent is obtained, 
participant identification numbers (PIDs) will be assigned to the mother and infant.  For pairs 
found to be eligible, enrollment will occur upon successful entry of required eligibility data into 
the SES.  Successful entry into the SES will generate a study identification number (SID) and 
prescribing information for the cohort in which the infant has been enrolled.  For pairs who are 
found to be ineligible for the study, or who do not enroll in the study for any reason, a case report 
form (CRF) will be completed to record the screening outcome.  Refer to Section 9.6 for more 
information on monitoring participant accrual in this study.  
 
4.5 
Participant Retention 
 
Once a mother-infant pair is enrolled in this study, study staff will make every effort to assist 
them with full adherence and to retain them for the protocol-specified duration of follow-up and 
thereby minimize potential biases associated with loss-to-follow-up.  Refer to Sections 9.6.1 and 
9.6.3 for more information on monitoring participant accrual in this study. 
 
4.6 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant, retention procedures referenced above, mothers may voluntarily 
withdraw from the study at any time.  Participants may also be terminated from the study by the 
site investigator or designee under the following circumstances: 
 
• 
Infant is not administered initial dose of study drug within 3 days of birth.  
• 
Infant re-locates away from the study site or is otherwise determined to be lost-to-follow-up. 
• 
Investigator or designee determines that continued participation in the study would be unsafe 
or otherwise not in the best interest of the infant participant, after consultation with the Core 
Protocol Team.   
• 
The study is stopped or canceled by the sponsors, government or regulatory authorities, site 
IRBs/ECs, the US Food and Drug Administration (FDA), NIAID or the Office for Human 
Research Protections (OHRP). 
 
Should the mother of an enrolled infant die, no longer have custody, or no longer be available for 
any reason, no further study drug should be administered and no further study-specific 
evaluations should be performed until informed consent for continued study participation is 
obtained from an authorized guardian, as defined locally.  Study sites may continue to provide 
care for the infant as needed and appropriate (outside of the study) consistent with the local 
standard of care but no study-specific procedures may be performed.  If an authorized guardian 
cannot be identified, or if the authorized guardian does not consent to continued infant study 
participation, the infant must be terminated from the study.  Refer to Section 13.3 for further 
guidance on guardian consent for study participation. 
 
For any infant who is withdrawn or terminated from the study prior to scheduled completion of 
follow-up, study staff will document the reason for the withdrawal or termination in detail and 
will make every effort to complete final evaluations as described in Section 6.12.  In the event 
that the circumstances that led to an infant’s withdrawal or termination change (e.g., the family 
returns to the study site area after having re-located previously), the site investigator or designee 
should contact the Core Protocol Team to discuss options for resumption of follow-up. 
 
 


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5 
STUDY DRUG CONSIDERATIONS  
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for standard pharmacy operations.  Refer to Figures 1A and 1B for an overview 
of the study design and to the Investigator’s Brochure (IB) for further information about the study 
drug. 
 
5.1 
Study Drug 
 
Study drug is defined as maraviroc 20 mg/mL oral solution.    
 
5.2 
Study Drug Formulation  
 
Maraviroc will be supplied as 20 mg/mL oral solution. The solution will be supplied, ready to 
use, in a 250 mL white high-density polyethylene (HDPE) bottle, with a polypropylene (PP) 
closure. Each bottle contains 235 mL of solution. Each bottle requires insertion of a press-in-
bottle adaptor (PIBA) prior to the first dose administration; this PIBA will be provided separately 
from the bottle.   
 
5.3 
Study Drug Regimens 
 
5.3.1 
Study Drug Regimen for Cohort 1 
 
Infants in Stratum 1A and Stratum 1B will receive two single doses of maraviroc solution as 
follows:  
   
First single dose: 
Maraviroc 8mg/kg* oral solution as a single dose within 3 days of birth.  
 
Second single dose: 
Maraviroc 8mg/kg* oral solution as a single dose at Week 1 (Day 7-14) of life.   
 
For each dose, refer to Table D in Appendix II, Maraviroc Weight Based Dosing Table for Oral 
Solution, and use the infant’s current weight at the visit to determine the dose. A new study drug 
prescription will be required in order for the site pharmacist to dispense the new dose. 
 
*If a dose adjustment is required for Cohort 1 (Stratum 1A or Stratum 1B), the selected table in 
Appendix II will be communicated to study sites via a protocol Clarification Memorandum.   
 
Note:  If the Core Protocol Team determines that a stratum dose or dosing schedule adjustment is 
required and the appropriate dose is not included in Appendix II, an updated dosing table will be 
provided through an appropriate mechanism. 
 
Any infants in Cohort 1 with an indication of HIV-1 infection prior to the second single dose will 
have study drug permanently discontinued (i.e., the second dose will not be administered), see 
Section 6.11.   


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5.3.2 
Study Drug Regimen for Cohort 2 
 
Infants in Stratum 2A will receive daily doses of maraviroc solution as follows: 
 
• 
Maraviroc oral solution once or twice daily at the dose and frequency determined from 
Stratum 1A* will be administered within 3 days of birth and continued for up to 42 (35 to 42 
days) of life.  Refer to the selected Table in Appendix II, Maraviroc Weight Based Dosing 
Table for Oral Solution, and use the infant’s current weight at the visit to determine the dose.  
 
Infants in Stratum 2B will receive daily doses of maraviroc solution as follows: 
 
• 
Maraviroc oral solution once or twice daily at the dose and frequency determined from 
Stratum 1B* will be administered within 3 days of birth and continued for up to 42 (35 to 42) 
days of life. Refer to the selected Table in Appendix II, Maraviroc Weight Based Dosing 
Table for Oral Solution and use the infant’s current weight at the visit to determine the dose.  
 
*The initial dose size and frequency selected in Appendix II for Cohort 2 (Stratum 2A or Stratum 
2B) and any dose adjustments required will be communicated to study sites via a protocol 
Clarification Memorandum. A new study drug prescription will be required in order for the site 
pharmacist to dispense the new dose.  
 
Note:  If the Core Protocol Team determines that a stratum dose or dosing schedule adjustment is 
required and the appropriate dose is not included in Appendix II, Maraviroc Weight Based 
Dosing Table for Oral Solution, an updated dosing table will be provided through an appropriate 
mechanism. 
 
 
Any infants with confirmed HIV-1 infection identified within the six-week dosing period will 
have study drug permanently discontinued (study drug should be held upon first indication of 
infection and pending confirmation of initial positive test, see Section 6.11). 
 
5.4 
Study Drug Preparation 
 
Bottle preparation:  
The PIBA must be inserted to the maraviroc oral solution bottle and the bottle must be labelled 
with the date and time of opening and the 60 days expiration date. Ensure that the work area is 
clean and only the materials necessary are present.  
 
Dose preparation: 
An oral dosing syringe consisting of a polypropylene barrel & HDPE Plunger will be required for 
dose preparation. Syringe gradations should be appropriate for the dose required. The syringes 
must be suitable for use with the PIBA system. 
 
The required volume of the maraviroc oral solution must be withdrawn from the prepared bottle 
using the appropriate size syringe. Syringes may be re-used during take home dosing.  All 
syringes should be cleaned and dried after use.  Cleaning is performed by rinsing the plunger and 
barrel with water, and allowing to air dry. Inspect the dosing syringe prior to each dose 
withdrawal and administration to ensure the syringe is clean and dry.   
 
Polypropylene syringe cap may be used to transport the study drug containing syringe from the 
pharmacy to the clinic. 


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Each dose should be prepared and administered following detailed instructions that will be 
provide in the study-specific Manual of Procedures.    
 
5.5 
Study Drug Administration  
 
Cohort 1 
The first single dose administered within 3 days of birth and the second single dose administered 
at one week (day 7-14) of life, will be prepared by the site pharmacist and administered orally by 
study staff.  Administration will occur in the context of PK specimen collection as described in 
Sections 6 and 10.  If the participant vomits most or all of the dose within the first 30 minutes 
after administration, the dose should not be repeated.  The PK sampling should not be completed, 
and the infant should be followed for toxicity. An additional infant should be enrolled for PK 
evaluation.   
 
Cohort 2  
The first dose administered within 3 days of birth, will be prepared by the site pharmacist and 
administered orally by the study staff.  The Week 1 and Week 4 doses will be administered orally 
by the parent or caregiver or study staff and directly observed in the clinic as described in Section 
6 and 10 (the parent or caregiver will be instructed not to administer the dose in the home on the 
days of the PK visits). The parent or caregiver will administer all other doses orally.   
 
Site staff will instruct the parent or caregiver how to properly prepare and administer each dose 
following instructions that will be provided in the study-specific Manual of Procedures.  
If the infant vomits most or all of the dose within the first 30 minutes after administration, the 
dose should be repeated. If the infant vomits within 30 minutes after administration on a PK 
sampling day, the PK sampling should be rescheduled within 1-2 days when the infant can 
receive another study drug dose.  
 
Infants’ parents or caregivers will be counseled as needed throughout the study to help ensure 
adherence.  Site staff will confirm full adherence with dosing three days prior to scheduling the 
PK visit for Cohort 2.   
 
5.6 
Study Drug Acquisition  
 
Maraviroc 20 mg/mL oral solution will be supplied by PHIVCO (Pfizer/ViiV).  Maraviroc oral 
solution will be available through the Clinical Research Products Management Center (CRPMC).  
Comar 1 mL oral syringes, Comar 5 mL oral syringes and Polypropylene (PP) syringe caps will 
be available through the CPRMC for study drug preparation and administration.  
 
The other components of the antiretroviral (ARV) regimen will not be supplied by the study. 
Upon successful completion of protocol registration procedures, the site pharmacist can obtain 
the study drug and oral syringes for this study by following the instructions in the manual 
Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 
 
5.7 
Study Drug Storage 
 
Unopened bottles of maraviroc oral solution should be stored at 15 to 30°C (59 to 86°F). Bottles 
should be maintained in an upright orientation. 
 


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Once the bottle of maraviroc oral solution is opened, it should be stored at 15 to 30°C (59 to 
86°F), and maintained in an upright orientation. Once opened, the shelf life of maraviroc oral 
solution stored at 15 to 30°C (59 to 86°F) is 60 days. Once the maraviroc oral solution bottle is 
opened, label the drug with date opened and the expiration date.   
 
Maraviroc oral solution held within a dosing syringe for administration is stable for 24 hours at 
15°C to 30°C. 
 
5.8 
Study Drug Accountability 
 
 
The site pharmacist is required to maintain complete records of all study products received from 
the NIAID CRPMC and subsequently dispensed. All unused study product must be returned to 
the NIAID CRPMC (or as otherwise directed by the sponsor) after the study is completed or 
terminated. The procedures to be followed are provided in the manual Pharmacy Guidelines and 
Instructions for DAIDS Clinical Trials Networks in the section Study Product Management 
Responsibilities. 
 
 
5.9 
Final Disposition of Study Drug  
 
 
Any unused study drug remaining at US sites after the study is completed or terminated must be 
returned to the CRPMC.  At non-US sites, any remaining study drug will be destroyed. Site 
pharmacists will follow the relevant instructions for return or destruction of unused study drug 
provided in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 
 
5.10 
Concomitant Medications  
 
5.10.1 Antiretroviral Concomitant Medications 
 
ARVs taken by each infant’s mother to which the infant may have been exposed in-utero and all 
ARVs taken by enrolled infants will be source documented and recorded on CRFs as part of the 
ARV exposure history obtained at each visit. In addition, for breastfeeding infants while 
receiving maraviroc all ARVs taken by the infant’s mother, to which the infant may have been 
exposed through breastmilk will be source documented and recorded on CRFs.  As needed, 
mothers will be counseled on the importance of adherence to antiretroviral regimens both for their 
own health and for prevention of HIV transmission to their infants.  
 
 
5.10.2 Other Concomitant Medications  
 
In addition to the ARV medications described above, while the infant is receiving maraviroc all 
other concomitant medications received by infants and medications taken by breastfeeding 
mothers to which a breastfeeding infant may have been exposed through breastmilk, must be 
source documented and recorded on CRFs.  
 
5.11 
Disallowed Medications for Infants and Breastfeeding Mothers 
 
Any infant exposed to any of the following medications (either directly or through breastfeeding) 
considered prohibited while on study drug must have the study drug permanently discontinued 
but will remain in follow-up for safety.  
 


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Potent CYP3A inhibitors such as:  
– atazanavir, darunavir, fosamprenavir, lopinavir, ritonavir, saquinavir, cobicistat 
– boceprevir, telaprevir 
– elvitegravir  
– ketoconazole, itraconazole, clarithromycin 
 
Potent CYP3A inducers such as:  
– efavirenz (Strata 1A and 2A only), etravirine 
– rifampin 
– St. John’s Wort 
– carbamazepine, phenobarbital, and phenytoin 
 
Other: 
– isoniazid 
 
In the event that a need for one or more of the above-listed medications is identified, the site 
investigator or designee should notify the Core Protocol Team. 
 
 
6 
STUDY VISITS AND PROCEDURES 
 
Refer to Section 4.4 for a description of the study recruitment, screening, and enrollment process.  
An overview of the study visits and evaluation schedules including blood draw volumes are 
provided in Appendix I as follows: Appendix IA-Mothers; Appendix-IB Cohort 1 Infants; and 
Appendix-IC Cohort 2 Infants.  Presented in this section is additional information on visit-
specific study procedures. As indicated in Appendix IA, maternal evaluations are required only at 
Screening and Entry.  
 
All visits and procedures must be performed at the clinical research site or associated facilities 
identified in the site’s approved Study Implementation Plan and must be documented in 
accordance with the NIAID Division of AIDS (DAIDS) policies for source documentation; refer 
to Section 11 for more information on documentation requirements and completion of CRFs.  
Refer to Section 7 for information on expedited adverse event (EAE) reporting, which may be 
required at any time during follow-up.  All procedures specified to be performed at scheduled 
visits should ideally be performed on the same day.  However, if this is not possible (e.g., if a 
participant must leave the clinical research site before all procedures can be performed), visits 
may be split, with procedures performed on more than one day within the allowable visit window. 
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks consistent with site SOPs, including but not limited to collecting, reviewing, and 
updating demographic and locator information; reviewing elements of informed consent; 
scheduling telephone contacts and visits; providing instructions for contacting study staff between 
visits; providing visit reminders; and following up on missed visits.  All such tasks should be 
documented consistent with site SOPs.  Study staff should inform mothers (or other authorized 
guardians if applicable) of clinically meaningful physical exam findings and laboratory test 
results when available. 
6.1 
Mother Screening Visit 
 
The Screening Visit may be performed during pregnancy or within 3 days after delivery. Multiple 
visits may be conducted within this timeframe to complete all required procedures, if necessary. 


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Written informed consent must be obtained before any study-specific screening procedures are 
performed. For potential participants who do not meet the eligibility criteria, screening may be 
discontinued once ineligibility is determined. Ineligible women may rescreen for study 
participation at a later time.  
 
Mother Screening Visit Procedures (During pregnancy or within 3 days of delivery)   
Administrative 
and Regulatory 
• Obtain written informed consent 
• Obtain screening number from SES 
• Assign PIDs to mother and infant 
• Assess eligibility 
Clinical 
• Obtain available medical record documentation of mother’s 
HIV infection status  
• Obtain available medical records and medical and 
medications history 
Laboratory 
 
Collect blood for: 
• HIV-1 test (confirmatory tests as needed)  
 
6.2 
Mother Entry Visit 
 
The mother and her infant are enrolled as a pair, therefore final eligibility determination for both 
the mother and infant must be completed prior to enrollment. In the event that a woman is found 
to be ineligible on the day of enrollment, enrollment should not occur. 
 
Note:  No further maternal evaluations are performed following completion of the Entry Visit; for 
administrative and data collection purposes, mothers are therefore considered “off study” upon 
completion of the Entry Visit. 
 
Maternal Entry Visit Procedures (within 0 - 3 days of delivery)   
Administrative 
and Regulatory 
Immediately prior to Entry: 
• Review elements of informed consent and confirm mother’s continued 
consent for study participation* 
Clinical 
• Obtain available medical records and update medical and medications 
history since screening.  
Laboratory 
 
Collect blood for: 
• HIV-1 RNA 
• Storage (tropism testing)  
*Perform prior to enrollment 
 
6.3 
Infant Screening Visit 
 
Infant screening procedures are to be done within 3 days after birth. Multiple visits may be 
conducted within this timeframe to complete all required procedures, if necessary. Written 
informed consent must be obtained before any study-specific screening procedures are performed. 
For potential participants who do not meet the eligibility criteria, screening may be discontinued 
once ineligibility is determined.  
 
 


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Refer to Section 4.4 for a description of the study recruitment, screening, and enrollment process.   
 
Infant Screening Visit Procedures (within 3 days of birth) 
Administrative 
and Regulatory 
• Assess eligibility  
Clinical 
• Obtain infant history information (since birth) 
- 
Medical/medications 
- 
ARV exposure 
- 
Infant feeding status 
• Perform complete infant physical exam (also assess gestational age if not 
documented in available medical records)  
Laboratory 
 
 
Collect blood for: 
• HIV NAT  
• CBC with differential and platelets  
• AST, ALT, total bilirubin, creatinine 
• Plasma storage 
• DBS storage 
 
 
 
The result of the HIV NAT performed at this visit is not required prior to entry; however, infants 
with any positive HIV NAT result available prior to entry are not eligible for enrollment for this 
study and should not be enrolled.  In the event that the result of the HIV NAT performed at this 
visit is positive, the infant should return to the clinic as soon as possible for confirmatory testing.  
 
6.4 
Infant Entry Visit (Cohorts 1 and 2)/PK Sampling (Cohort 1) 
 
In the event that a mother-infant pair is found to be ineligible on the day of enrollment, 
enrollment should not occur.  
 
For Cohort 1, the Entry Visit may be conducted over multiple days as a split visit. The 
administrative and regulatory procedures should be conducted on the first day of the split visit; 
procedures that may provide information relevant to eligibility for the study should be performed 
first, prior to final eligibility determination. 
 
 
Infant Entry Visit Procedures (within 3 days of birth) 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the mother-infant pair, print and file a copy of the confirmation file 
Study Drug 
• Prescribe study drug  
• Administer initial dose within 3 days of birth (for Cohort 1, administer dose 
within 1 hour after collection of pre-dose PK sample) 
• Dispense study drug for home administration (Cohort 2 only) 
• Provide instructions and adherence counseling for home administration of 
study drug (Cohort 2 only) 
Laboratory 
 
 
• EFV level (Cohort 1, Stratum 1B only), see Section 6.4.1 
• PK sample collection (Cohort 1 only), see Section 6.4.1 
 
*Perform prior to enrollment 
 


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6.4.1 
Cohort 1 Intensive PK 
PK sampling for maraviroc must be initiated on the same day as the first dose of maraviroc 
(within 3 days of birth), and conducted over the course of up to 72 hours according to the 
following time points: pre-dose (< 1 hour before dosing), then post dose 1 – 2 hours, 4 - 8 hours, 
11 – 13 hours, 20 – 24 hours, and 48 – 72 hours after the observed dose.  Depending on site 
capacity, mothers and their infants may stay at the clinical research facility overnight for PK 
sampling. The same procedure can be followed for obtaining the PK samples 48  ̶  72 hours after 
dosing. 
 
For infants in Stratum 1B only, an additional sample for analysis of EFV levels should also be 
drawn at any time on the same day the first maraviroc dose is given. 
 
6.5 
Week 1 Visit/PK Sampling (Cohorts 1 and 2) 
 
The Week 1 Visit is targeted to take place on Day 7, counted from the date of birth as Day 0, with 
an allowable visit window of +7 days.  
 
Week 1 Visit Procedures (Day 7 to Day 14)   
Administrative 
and Regulatory 
• None  
Clinical 
• Update infant history information  
– Medical/medications 
– Feeding Status 
– ARV exposure  
• Review screening HIV NAT result, if available (if positive; see Section 6.11) 
• Perform targeted physical exam 
• Identify/review/update adverse events (abnormal lab values, signs, symptoms, 
diagnoses) 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult Core Protocol Team if indicated) 
Study Drug 
• Administer study drug within 1 hour after collection of pre-dose PK sample  
• Prescribe and dispense study drug for home administration as needed (Cohort 
2 only) 
• Provide instructions and adherence counseling as needed for home 
administration of study drug (Cohort 2 only) 
Laboratory 
 
Collect blood for: 
• CBC with differential and platelets 
• AST, ALT, total bilirubin, creatinine 
• EFV level (Stratum 1B and 2B only) 
• PK sample collection, see Section 6.5.1 – 6.5.3 
 
6.5.1 
Cohort 1 Limited PK  
PK sampling for maraviroc must be initiated on the same day as the dose of maraviroc and 
conducted over the course of up to 26 hours according to the following time points: pre-dose (<1 
hour before dosing), then post dose 1- 2 hours and 22 – 26 hours after the observed dose. 
 
For infants in Stratum 1B only, an additional sample for analysis of EFV levels should also be 
drawn at any time during the Week 1 visit. 
 


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6.5.2 
Cohort 2 Intensive PK with Once Daily dosing 
Maraviroc samples should be drawn according to the following time points: pre-dose (< 1 hour 
before dosing), post dose 1 – 2 hours, 4 - 8 hours, 11 – 13 hours, 20 – 24 hours after the observed 
dose. Further operational details are found in Section 10.2.2. 
 
For infants in Stratum 2B only, an additional sample for analysis of EFV levels should also be 
drawn at any time during the Week 1 visit.   
 
6.5.3 
Cohort 2 Intensive PK with Twice Daily dosing 
Maraviroc samples should be drawn according to the following time points: pre-dose (< 1 hour 
before dosing), post dose 1 – 2 hours, 3 - 5 hours, 6 – 8 hours, and 11 – 13 hours after the 
observed dose. Further operational details are found in Section 10.2.3. 
 
For infants in Stratum 2B only, an additional sample for analysis of EFV levels should also be 
drawn at any time during the Week 1 visit.   
 
6.6 
7-Day Post Dose Safety Visit (Cohort 1 only) 
 
This visit is targeted to take place seven days after the Week 1 visit (7 days after receiving the last 
dose of study drug), with an allowable window of ± 3 days.   
 
7 Day Post Dose Safety Visit (7 days after Week 1 visit ± 3 days) (Cohort 1 only)  
Administrative 
and Regulatory 
• None  
Clinical 
• Update infant history information  
– Medical/medications 
– Feeding status 
– ARV exposure  
• Perform targeted physical exam 
• Identify/review/update adverse events (abnormal lab values, signs, symptoms, 
diagnoses) 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult Core Protocol Team if indicated) 
Laboratory 
 
Collect blood for: 
• CBC with differential and platelets 
• AST, ALT, total bilirubin, creatinine 
 
 
 


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6.7 
Week 4/PK Sampling (Cohort 2 only)  
 
The Week 4 Visit is targeted to take place on Day 28, counted from the date of birth as Day 0, 
with an allowable window of -7 to +3 days.  
 
Week 4 Visit Procedures (Day 21 to Day 31) (Cohort 2 only) 
Administrative 
and Regulatory 
• None  
Clinical 
• Update infant history information  
– Medical/medications  
– Feeding status 
– ARV exposure  
• Perform targeted physical exam 
• Review/update adverse events (perform evaluations as needed per Section 8.0) 
Study Drug 
• Administer study drug (< 1 hour prior to PK sampling)  
• Prescribe and dispense study drug for home administration as needed. Provide 
instructions and adherence counseling as needed for home administration of study 
drug. 
Laboratory 
 
Collect blood for: 
• CBC with differential and platelets 
• AST, ALT, total bilirubin, creatinine 
• EFV level (Stratum 2B only) 
• PK sample collection, see Section 6.7.1 – 6.7.2  
 
6.7.1 
Cohort 2 Intensive PK with Once Daily dosing 
Maraviroc samples should be drawn pre-dose (< 1 hour before dosing), post dose 1 – 2 hours, 4 - 
8 hours, 11 – 13 hours, and 20 – 24 hours after the observed dose. Further operational details are 
found in Section 10.2.2. 
 
For Stratum 2B only, an additional sample for analysis of EFV levels should also be drawn at any 
time during this study visit. 
 
6.7.2 
Cohort 2 Intensive PK with Twice Daily dosing 
Maraviroc samples should be drawn pre-dose (< 1 hour before dosing), post dose 1 – 2 hours, 4 - 
8 hours, and 11 – 13 hours after the observed dose.  Further operational details are found in 
Section 10.2.3. 
For Stratum 2B only, a single EFV sample should be drawn at any time during this study visit. 
 
 


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6.8 
Week 6 Visit (Cohorts 1 and 2)   
 
The Week 6 Visit is targeted to take place on Day 35, counted from the date of birth as Day 0, 
with an allowable window of +7 days.  
 
Week 6 Visit Procedures (Day 35 to Day 42)   
Administrative 
and Regulatory 
• None  
Clinical 
• Update infant history information  
– Medical/medications  
– Feeding status 
– ARV exposure (if breastfeeding) 
• Perform targeted physical exam 
• Review prior HIV NAT results, if available 
• Review/update adverse events (perform evaluations as needed per Section 8.0) 
Study Product 
• Collect any remaining study drug (Cohort 2 only) 
Laboratory 
 
Collect blood for: 
• HIV NAT  
• CBC with differential and platelets 
• AST, ALT, total bilirubin, creatinine 
• DBS storage  
• EFV level (Stratum 2B only) 
• Population PK sample collection (Cohort 2 only, see Section 6.8.1 )  
  
In the event that the result of the HIV NAT performed at this visit is positive, the infant should 
return to the clinic as soon as possible for confirmatory testing per Section 6.11. 
 
6.8.1 
Cohort 2 Population PK with Once or Twice Daily Dosing 
A single random maraviroc sample should be drawn at any time during this study visit.  
 
6.9 
Week 12 Visit (Cohort 2 only) 
 
The Week 12 Visit is targeted to take place on Day 84, counted from the date of birth as Day 0, 
with an allowable window of ±7 days.  
 
Week 12 Visit Procedures (Day 77 to Day 91) (Cohort 2 only)  
Administrative 
and Regulatory 
• None  
Clinical 
• Update infant history information (since last visit) 
– Medical/medications 
– Feeding status 
– ARV exposure  
• Perform targeted physical exam 
• Review/update adverse events (perform evaluations as needed per Section 8.0) 
Laboratory 
 
Collect blood for: 
• CBC with differential and platelets 
• AST, ALT, total bilirubin, creatinine 
 
 
 


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6.10 
Week 16 Visit (Cohorts 1 and 2)   
 
The Week 16 Visit is targeted to take place on Day 112, counted from the date of birth as Day 0, 
with an allowable window of +28 days.  
 
Week 16 ( Day 112 to Day 140) and Early Study Discontinuation Visit Procedures  
Administrative 
and Regulatory 
• None  
Clinical 
• Update infant history information  
– Medical/medications 
– Feeding status 
– ARV exposure (if breastfeeding) 
• Perform targeted physical exam 
• Identify/review/update adverse events (abnormal lab values, signs, symptoms, 
diagnoses) 
• Perform additional evaluations per Section 8 and/or if clinically indicated (consult 
Protocol Team if indicated) 
Laboratory 
 
Collect blood for: 
• HIV NAT  
• CBC with differential and platelets  
• AST, ALT, total bilirubin, creatinine 
• DBS storage  
 
At this visit, mothers will be informed of how to contact study staff with any post-study questions 
and arrangements should be made to provide the infant’s mother with clinically meaningful test 
results from the final evaluations. In the event that the result of the HIV NAT performed at this 
visit is positive, the infant will be recalled to the clinic as soon as possible for confirmatory 
testing and referrals per Section 6.11.  For all infants, referrals will be provided as needed to 
ensure transition to non-study sources of routine child health care.  
 
6.11 
Procedures for Infants with Positive HIV NAT Results 
 
After enrollment, any infant with a positive HIV NAT test result should be recalled to the clinic 
as soon as possible for confirmatory testing; administration of maraviroc must be held pending 
receipt of the result of the confirmatory test. At the time of specimen collection for the 
confirmatory test, a sample for tropism testing and resistance testing should also be collected per 
Appendix IB or IC and the Laboratory Processing Chart (LPC).  If HIV infection is confirmed, 
maraviroc will be permanently discontinued.  However, the infant will remain in follow-up with 
visits and procedures performed per the relevant Schedule of Evaluations through Week 16, 
except that no further HIV testing and no further PK sampling will be performed.   
 
All infants identified with HIV infection will be actively referred to non-study sources of HIV 
care and treatment. 
 


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6.12 
Procedures for Infants who Prematurely Discontinue Study Participation 
 
Refer to Section 4.6 for criteria for infant withdrawal or termination from the study.  For any 
infant who discontinues study participation prior to completion of follow-up at Week 16, every 
effort should be made to complete a final series of study evaluations if possible.  In general, the 
Week 16 Visit procedures should be performed, and arrangements should be made to provide the 
infant’s mother with clinically meaningful test results from the final evaluations.  The parent or 
guardian should also be provided information and referrals, as applicable, to non-study sources of 
care and treatment for the infant. 
 
6.13 
Maternal Medical and Medications History  
 
At Screening and Entry visits, the following should be recorded on CRFs: 
   
• 
All ARVs taken during the current pregnancy and any other medications within 30 days prior 
to study entry 
• 
Any diagnoses that were new or ongoing during the current pregnancy 
• 
Any signs or symptoms within 30 days prior to study Entry 
 
6.14 
Infant Physical Examinations 
 
A physical examination is required at scheduled visits as indicated in Appendix IB and IC. 
Complete exams are required at the Screening Visits; targeted exams are required at all other 
scheduled visits.   
 
Complete exams should include the following: 
• 
Length measurement 
• 
Weight measurement 
• 
Auscultation of chest 
• 
Examination of skin, head, mouth, neck, abdomen, extremities 
 
Note:  Inclusion criteria 4.1.4 and 4.1.5 permit study staff to assess infant gestational age and 
weight if these outcomes were not documented in medical records at birth.  When applicable, 
these assessments should be performed at the earliest possible opportunity as part of the 
screening physical exam. 
 
Targeted exams should include the following: 
 
• 
Length measurement 
• 
Weight measurement 
• 
Auscultation of chest 
• 
Examination of body systems driven by prior and new signs, symptoms, and diagnoses 
 
At all visits, additional assessments may be performed at the discretion of the examining site 
investigator.  Also at all visits, the measurements listed above should be charted on standard 
infant growth charts and weight-for-age assessed in relation to WHO Growth Standards.   
 


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6.15 
Additional Considerations for Laboratory Procedures 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, which 
is available at: 
 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/Laboratories.aspx 
 
HIV NAT performed following the entry visit for diagnosis of infant infection must be performed 
in a laboratory that is CLIA-certified (for US sites) or DAIDS-VQA certified (for non-US sites) 
(refer to Section 4.1.2 for maternal HIV testing requirements). All samples tested must be whole 
blood, serum, or plasma. 
 
6.15.1 Specimen Collection 
 
Specimens will be collected for this study as indicated in the Schedule of Evaluations and per 
detailed guidance provided in the LPC, which will be available on the IMPAACT website.   
 
NIH recommendations for maximum pediatric and adult blood draw volumes will be followed in 
this study. For women, the volume of blood drawn shall not exceed 10.5 mL/kg or 550 mL, 
whichever is smaller, over any eight week period. For infants, the volume of blood drawn at any 
study visit should not exceed 5 mL/kg in a single day or 9.5 mL/kg over any eight-week period. 
In the event that infant blood collection must be limited, available specimens will be prioritized 
for use in the following order: (1) safety (chemistries, CBC), (2) HIV Nucleic Acid Test, (3) PK, 
and (4) stored DBS. 
 
6.15.2 Specimen Preparation, Testing, Storage, and Shipping 
 
All specimens collected for this study will be labeled, transported, processed, tested, stored and/or 
shipped in accordance with the DAIDS policy referenced in Section 6.15, site and local 
laboratory SOPs, and the LPC.  The frequency of specimen collection and testing will be directed 
by the Schedule of Evaluations and specifications for clinical management provided in Section 8.  
The Laboratory Data Management System (LDMS) will be used to document specimen 
collection, testing, storage, and shipping as specified in the LPC.   
 
Specimens collected, processed, and stored at site laboratories for PK evaluations are expected to 
be shipped to the designated testing laboratory as follows. For each infant in Strata 1A and 1B, 
PK samples from the Entry and Week 1 visits may be shipped together immediately after 
completion of the Week 1 visit.  For each infant in Strata 2A and 2B, Week 1 and Week 4 
samples should be shipped immediately after completion of each visit; Week 6 PK samples may 
be stored and shipped in batches monthly.  
 
After all protocol-specified laboratory testing has been performed, residual specimens may be of 
interest for future research use.  Infants’ mothers (or other authorized guardians if applicable) will 
be asked to provide written informed consent for future research use of these specimens, if 
permitted by site IRBs/ECs and other applicable review bodies.  Mothers may choose to provide 
or to decline informed consent for future research use of residual specimens with no impact on 
other aspects of infant participation in the study.  
 


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6.15.3 Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as currently recommended by the US Centers for Disease Control and 
Prevention, NIH, and other applicable agencies.  All specimens will be shipped using packaging 
that meets requirements specified by the International Air Transport Association Dangerous 
Goods Regulations for UN 3373, Biological Substance, Category B, and Packing Instruction 650.  
Culture isolates, if obtained in this study, are to be shipped as specified for UN 2814 Category A 
Infectious Substances. 
 
 
7 
SAFETY MONITORING, ASSESSMENT AND REPORTING 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study.  Sections 7.1-7.3 describe safety-related roles, responsibilities, and 
procedures for site investigators.  The safety monitoring roles of the Core Protocol Team and the 
IMPAACT Study Monitoring Committee (SMC) are briefly referenced in Section 7.1 and 
described in greater detail in Section 9.6. 
 
7.1 
Safety-Related Roles and Responsibilities 
 
7.1.1 
Site Investigators 
 
Site investigators are responsible for continuous monitoring of all study participants and for 
alerting the Core Protocol Team if unexpected concerns arise.  Site investigators will record 
safety-related events on CRFs as indicated in Section 7.2 and complete expedited adverse event 
(EAE) reporting as indicated in Section 7.3.  Site investigators are also responsible for prompt 
reporting to their IRBs/ECs and other applicable review bodies of any unanticipated problems 
involving risks to participants or others. 
 
Site investigators should notify the Core Protocol Team by e-mail within three business days of 
site awareness of any Grade 3 or higher adverse event regardless of relationship to maraviroc 
occurring throughout follow-up.  This notification should include the diagnoses or symptom, 
grade, and relationship assessment.    
 
7.1.2 
Core Protocol Team 
 
The Core Protocol Team is comprised of the Protocol Chair and Vice Chairs, Medical Officers, 
Statistician, Data Manager, Pharmacologist, Clinical Trials Specialist, and representatives from 
ViiV.  The Core Protocol Team will provide guidance as needed to site investigators regarding all 
aspects of participant management, including but not limited to questions of participant 
eligibility, study drug administration, and management of adverse events. Refer to Section 8 for 
more information on participant management. 
 
On behalf of the full Protocol Team, the Core Protocol Team will monitor participant safety 
through routine review of study data reports as described in Section 9.6. 
 


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7.1.3 
Study Monitoring Committee 
 
An independent IMPAACT SMC may contribute to monitoring participant safety in this study if 
needed. Refer to Section 9.6.3 for more information on the composition and role of the SMC in 
monitoring this study. 
 
7.2 
Safety-Related Recording on Case Report Forms 
 
Note: This section refers to recording requirements on Case Report Forms for infant adverse 
events and pre-existing conditions.  For information on severity grading and criteria for EAE 
reporting, refer to sections 7.3.3 and 7.3.2, respectively.  
 
Consistent with international good clinical practice guidelines, the term adverse event is used in 
this protocol to refer to any untoward medical occurrence identified in an enrolled infant who is 
administered study drug, which does not necessarily have a causal relationship with study 
drug.  An adverse event can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or diagnosis temporally associated with administration of 
study drug, whether or not related to study drug. This definition of adverse event will be applied 
to all infants in this study, beginning at the time of first dose of maraviroc. Any untoward medical 
occurrences identified between the time of infant birth and the time of the first dose of maraviroc 
solution will be considered pre-existing conditions.  
 
All pre-existing conditions and adverse events identified in this study will be source documented 
in infant research records, consistent with the policies and procedures referenced in Section 
11.  Among other details, source documentation will include the date of onset and severity of 
each pre-existing condition and adverse event, with severity graded as described in Section 
7.3.3.  Source documentation for each adverse event will also include relationship to study drug,  
assessed according to the categories and definitions specified in Section 8.1. 
 
All pre-existing conditions and adverse events will be recorded on the relevant adverse event case 
report form, regardless of severity grade and relationship to study drug.  All laboratory test results 
will also be recorded on the relevant laboratory case report form. 
 
CRFs used to record the above listed safety outcomes must be keyed into the study database 
within 48 hours of availability of the relevant clinical findings and laboratory test results at the 
site. 
 
7.3 
Expedited Adverse Event (EAE) Reporting 
 
EAEs will be reported only for infants in this study.  
 
7.3.1 
Adverse Event Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of adverse events (AEs) are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC website at 
http://rsc.tech-res.com/safetyandpharmacovigilance. 
 
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 


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about DAERS, please contact NIAID Clinical Research Management System at 
CRMSsupport@niaid.nih.gov.  Questions 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: 
http://rsc.tech-res.com/safetyandpharmacovigilance/.  For questions about expedited reporting, 
please contact DAIDS RSC (DAIDSRSCSafetyOffice@tech-res.com). 
 
7.3.2 
Reporting Requirements for this Study 
 
The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS 
EAE Manual, will be used for this study.  The study agent for which expedited reporting is 
required is maraviroc solution.  With respect to the relationship categories specified for purposes 
of participant and toxicity management in Section 8.1, the categories of definitely related, 
probably related, and possibly related will correspond to an assessment of “related” for EAE 
reporting; the categories of probably not related and not related will correspond to an assessment 
of “not related” for EAE reporting.  
 
7.3.3 
Grading Severity of Events 
 
Adverse events identified in this study will graded according to the Division of AIDS Table for 
Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), Version 
2.0, dated November 2014, which is available on the RSC website:   
http://rsc.tech-res.com/safetyandpharmacovigilance/ 
 
In addition, grading of infant malnutrition will follow the table below:   
 
 
 
Grade 1 
Mild 
 
Grade 2 
Moderate 
 
Grade 3 
Severe 
Grade 4 
Potentially  
Life-Threatening 
Infant 
malnutrition 
WHO weight-for-
length  
Z score <-1 to >-2 
WHO weight-for-
length  
Z score <-2 to ≥-3 
WHO weight-for-
length  
Z score <-3 
WHO weight-for-
length  
Z score <-3  
with life-threatening 
consequences 
 
 
7.3.4 
Expedited AE Reporting Period 
 
• 
EAEs will be reported only for infants in this study. For each enrolled infant, the EAE 
reporting period begins at the time of administering the first dose of study drug and continues 
through the protocol-specified end of follow-up.   
 
• 
After the protocol-defined AE reporting period, only suspected, unexpected, serious adverse 
reactions (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). 
 
 


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8 
PARTICIPANT MANAGEMENT 
 
8.1 
Management of Adverse Events 
 
Relationship categories for Adverse Events are as follows: 
 
 
Definitely related 
The event and administration of study drug are related in time, and a 
direct association can be demonstrated. 
 
Probably related 
The event and administration of study drug are reasonably related in time 
and the event is more likely explained by study drug than other causes. 
 
Possibly related 
The event and administration of study drug are reasonably related in time 
and the event can be explained equally well by causes other than study 
drug. 
 
Probably not related A potential relationship between the event and study drug could exist 
(i.e., the possibility cannot be excluded), but the event is most likely 
explained by causes other than study drug. 
 
Not related 
The event is clearly explained by another cause not related to study drug.  
 
As described in greater detail below, adverse events identified in enrolled infants will be managed 
based on their severity and assessed relationship to study drug.  For grade 3 and higher events that 
may affect administration of study drug (as described in Sections 8.2), relationship to study drug 
will be assessed by site investigators as well as the Core Protocol Team.   
 
All adverse events must be followed to resolution (return to baseline) or stabilization, with the 
frequency of repeat evaluations determined by the clinical significance of each event. Grade 3 or 
higher laboratory tests should be repeated as soon as possible (within one business day) and all 
grade 3 or higher adverse events should be re-evaluated in consultation with Core Protocol Team 
until improvement to grade 2 or lower.  Additional evaluations beyond those listed in Appendix I 
may be performed at the discretion of the site investigator to determine the etiology of a given 
event and/or further assess its severity or relationship to study drug.  Clinical management of all 
adverse events should be provided consistent with the best medical judgment of the site 
investigator and local clinical practice standards. 
 
8.2 
General Management  
 
The following general guidelines (by grade) apply to management of maraviroc in response to 
adverse events.  Any infants who discontinue administration of maraviroc will remain in follow-
up and per the relevant Schedule of Evaluations in Appendix I with the exception that no further 
PK sampling will be done.  
 
8.2.1 
Cohort 1  
 
Grade 1 - The second maraviroc dose can be administered; routine monitoring.  


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Grade 2 - The second maraviroc dose can be administered; monitor closely; as per site 
investigator and work-up to exclude other causes. 
Grade 3 – If the adverse event is a grade 3 laboratory value, the second maraviroc dose should be 
withheld while awaiting confirmatory results.  For confirmed grade 3 laboratory values, and 
grade 3 clinical events, contact the Core Protocol Team and hold the second maraviroc dose until 
improvement to grade 2 or lower.  If repeat assessment is Grade 2 or lower, manage per the grade 
of the repeat assessment.  Alternatively, if the site investigator assesses the event as not related or 
probably not related to maraviroc, with approval from the Core Protocol Team, the second 
maraviroc dose may be administered.  
Grade 4 - If the adverse event is a grade 4 laboratory value, the second maraviroc dose should be 
withheld while awaiting confirmatory results.  For confirmed grade 4 laboratory values and grade 
4 clinical events assessed as not related to maraviroc, the site investigator should contact the Core 
Protocol Team to determine if and when the second maraviroc dose should be administered. 
Otherwise, the second maraviroc dose should not be administered and the site investigator should 
contact the Core Protocol Team for further instructions.   
 
8.2.2 
Cohort 2   
 
Grade 1 - Continue maraviroc; routine monitoring.  
Grade 2 - Continue maraviroc; monitor closely; as per the site investigator, work-up to exclude 
other causes. 
Grade 3 – The maraviroc dose should be withheld awaiting results of the confirmatory test.  If 
Grade 3 abnormalities are confirmed, contact the Core Protocol Team, and the maraviroc should 
continue to be withheld until the abnormalities are Grade 2 or below unless the site investigator, 
with the approval of the Core Protocol Team, assesses the event as not related or probably not 
related to maraviroc administration and maraviroc should be continued. If the event is Grade 2 or 
lower, manage per the grade of the repeat assessment.   
Grade 4 – The maraviroc dose should be withheld awaiting results of the confirmatory test.   
For Grade 4 adverse events determined to be at least possibly related to study drug, maraviroc 
should be permanently discontinued.  For Grade 4 adverse events that are determined to be 
probably not related or not related to study drug, the investigator should contact the Core Protocol 
Team for further instructions. 
 
Note:  In the event of discontinuation of study drug, participants will be asked to continue to be 
followed until the 16 week visit. 
 
8.2.3 
Non- Maraviroc Antiretroviral Drug-related Toxicity  
 
Toxicities resulting from components of a PMTCT regimen will be managed by the site 
investigator, according to best clinical practice; consultation with the Core Protocol Team is 
available but not required.  
 
8.3 
Criteria for Premature Discontinuation of Study Drug  
 
Administration of maraviroc will be permanently discontinued in the event that: 
 


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8.3.1 
The infant is determined to be HIV-1 infected (confirmed with two diagnostic tests), or  
 
8.3.2 
The infant experiences an adverse event that requires discontinuation as defined in 
Section 8.2, or 
 
8.3.3 
The infant requires isoniazid, rifampin, or any other disallowed medication listed in 
Section 5.11, or  
 
8.3.4 
The site investigator determines that further administration of maraviroc would be 
detrimental to the infant’s health or well-being. 
 
8.3.5 
New data become available that indicate maraviroc should be discontinued as 
determined by the Core Protocol Team.  
 
8.3.6 
A Cohort 2B infant whose mother stops breastfeeding.   
 
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues   
 
This is a Phase I study whose primary objectives are to evaluate the safety, tolerability and PK of 
maraviroc in infants. The ultimate objective is to determine an appropriate dose of maraviroc 
solution when administered to HIV-1 exposed infants at risk of HIV infection, along with 
standard PMTCT ARV prophylaxis, during the first 6 weeks of life. Both mother and infant will 
be enrolled, with the mother only having study visits at screening and entry and the infant 
followed through 16 weeks of life. 
 
Infants will be stratified by maternal EFV-exposure, see Section 3.0, and will be enrolled into 2 
sequential dosing cohorts defined as follows:  
 
Cohort 1: divided into 2 strata, 1A and 1B, which will accrue concurrently. 
 
Stratum 1A  
(Infants NOT exposed to maternal EFV in utero): n=6-18  
 
Stratum 1B 
(Infants exposed to maternal EFV in utero): n=6-18  
 
Cohort 2: divided into 2 strata, 2A and 2B, which will begin accrual pending dose determination 
from the corresponding stratum from Cohort 1  
 
Stratum 2A  
(Infants NOT exposed to maternal EFV in utero or while breastfeeding) n=12-18  
 
Stratum 2B  
(Breastfeeding infants exposed to maternal EFV in utero and while 
breastfeeding) n=12-18  
 
A minimum of 12 and 24 infants (and their mothers) in Cohorts 1 and 2, respectively, will be 
accrued to the study. If an infant has unevaluable PK data, which reflects uncertainty about 
appropriate exposure to the study drug, then the infant will be replaced and will be excluded from 
both the PK and safety analyses during the dose-evaluation. However, the infant may be allowed 
to continue on-study drug and will be followed through week 16. It may be necessary to perform 


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sensitivity analyses on the final data to test whether the results of the final safety analysis are 
consistent with and without this infant's data. 
 
The final enrollment target is 6 evaluable infants each from Stratum 1A and Stratum 1B, and 12 
evaluable infants each from Stratum 2A and Stratum 2B, treated at the final dose recommended 
for each stratum. 
 
9.2 
Dose-Finding Algorithm 
 
Cohort 1 
Each strata (Stratum 1A and Stratum 1B) will enroll an initial group of 6 evaluable infants and 
their safety and PK data will be evaluated independently as follows. 
 
The study will implement a dose-finding algorithm applied to each stratum based on real time PK 
data and safety through the 7 Day Post Dose Safety Visit from an initial group of 6 infants from 
Stratum 1A and Stratum 1B. If these 6 infants meet both safety and PK guidelines (specified in 
Section10.3), then the starting dose for the corresponding Cohort 2 stratum will be established, 
and that stratum will begin to accrue. If the infants receiving the initial Cohort 1 dose for the 
stratum do not meet either the safety or the PK guidelines, then the Core Protocol Team will 
evaluate whether to adjust the dose upwards or downwards.  Individual dose adjustments will not 
be made. If the dose is changed, six new infants will be enrolled at the adjusted dose, and the 
evaluation of real time safety and PK will be repeated on these infants.  If this second group of 
infants were to not meet the safety and/or PK guidelines, the Core Protocol Team would evaluate 
whether to adjust the dose.  If the dose is adjusted, a third group receiving a second dose 
modification would be enrolled.  The goal is to enroll six infants at a dose in each stratum in 
Cohort 1 who meet both safety and PK guidelines, providing adequate data to establish a starting 
dose for the corresponding Cohort 2 stratum. 
 
Cohort 2 
 
Each stratum (2A and 2B) will begin to enroll as soon as the starting dose is established from the 
corresponding Cohort 1 stratum, and will be evaluated independently as follows: 
 
The same algorithm will apply to each stratum in Cohort 2 (2A and 2B) starting with six infants 
per stratum, except that the dose-finding algorithm applied to each stratum will be based on PK 
and safety data through the Week 6 Visit.  If each stratum meets both safety and PK guidelines at 
a given dose (guidelines specified in Sections 9.6.2 and 10.3.2), then an additional six infants will 
be accrued and administered this dose to complete a full stratum of n=12 infants.  Safety and PK 
will then be assessed on the full stratum. If safety and PK guidelines are met, then the dose is 
established for the stratum.  Otherwise, the dose may be adjusted, a new group of six infants will 
be enrolled at the adjusted dose, and the evaluation procedures described above will be repeated.  
This will proceed until a full stratum of 12 infants administered a given dose has met both safety 
and PK guidelines.  
 
Note: No more than 2 additional mother-infant pairs will be allowed to enroll to each stratum 
before the preliminary evaluation of PK and safety data on 6 initial participants has been 
completed. Please see detailed note in Section 9.6.2.1.    
 


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9.3 
Endpoints and Outcome Measures 
 
In the following sections, the words “Endpoint” and “Outcome” refer to dependent variables on 
which objectives will be evaluated.  “Endpoint” refers to whether a specific criterion has been 
met, while “Outcome” refers to a continuous or categorical variable which is relevant to protocol 
objectives, but does not reflect a specific criterion. 
 
9.3.1 
Primary Endpoints (from the initial maraviroc dose through week 6 of life) 
 
Safety  
• 
For dose finding purposes: Adverse events of Grade 3 or higher or that result in 
discontinuation of study drug, judged by the Core Protocol Team to be at least possibly 
related to study drug.  (Cohort 1: through 7 Day Post Dose Visit; Cohort 2: through Week 6 
Visit).   
 
• 
For analysis purposes: All adverse events of grade 3 or higher or that result in discontinuation 
of study drug.  
 
PK 
• 
Failure to meet PK target of Cavg ≥ 75 ng/mL. Cavg represents the area under the curve (AUC) 
divided by the duration of the dosing interval used to determine AUC. 
 
9.3.2 
Primary Outcome Variables (from the initial maraviroc dose through week 6 of life) 
 
Safety 
• 
All adverse events (all severity grades). 
 
PK 
• 
PK parameters: Cmax, Tmax, AUC, Cavg, and for Cohort 2, also Ctrough 
 
9.3.3 
Secondary Endpoints (from the initial maraviroc dose through week 16 of life) 
 
Safety 
• 
For dose finding purposes: Adverse events of Grade 3 or higher or that result in 
discontinuation of study drug, judged by the Core Protocol Team to be at least possibly 
related to the study drug. 
 
• 
For analysis purposes: All adverse events of Grade 3 or higher or that result in 
discontinuation of study drug due to toxicity. 
 
9.3.4 
Secondary Outcome Variables (from the initial maraviroc dose through week 16 of life) 
 
Safety 
• 
All adverse events (all severity grades). 
 
PK 
• 
Changes in maraviroc PK parameters over first 6 weeks of life (Cohort 2 only) 
 


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Tropism 
• 
Infant’s viral tropism after exposure to maraviroc (infants who are HIV-1 infected only) 
• 
Viral tropism at entry (mothers of infants who are HIV-1 infected only) 
 
9.4 
Randomization and Stratification 
 
There will be no randomization. For each cohort, infants will be stratified, based on EFV-
maternal exposure as follows: 
 
Cohort 1: Infants to receive single doses of maraviroc solution between 0 and 3 days and day 7-
14 of life. 
 
• 
Stratum 1A: Infants NOT exposed to maternal EFV in utero  
• 
Stratum 1B: Infants exposed to maternal EFV in utero 
 
Cohort 2: Infants to receive daily dosing, starting within 3 days from birth and continuing through 
6 weeks of life, with maraviroc solution at a dose determined on the basis of corresponding 
Stratum 1A or Stratum 1B data.  
 
• 
Stratum 2A: Infants NOT exposed to maternal EFV in utero or through breastfeeding.  
• 
Stratum 2B: Breastfeeding Infants exposed to maternal EFV in utero and while breastfeeding. 
 
9.5 
Sample Size and Accrual 
 
Total accrual will depend upon the number of participants who must be enrolled to yield: 
 
• 
12 infants in Cohort 1 (6 for each stratum 1A, 1B) treated at the dose which has met safety 
and PK guidelines and is recommended for Cohort 2, and  
 
• 
24 infants in Cohort 2 (12 for each stratum 2A, 2B) treated at the final recommended dose for 
each stratum. 
 
Note: No more than 2 additional mother-infant pairs will be allowed to enroll to each stratum 
before the preliminary evaluation of PK and safety data on 6 initial participants has been 
completed. Please see detailed note in Section 9.6.2.1    
 
9.6 
Monitoring 
 
Implementation of this study will be monitored at multiple levels, consistent with standard 
IMPAACT procedures.  A study monitoring plan that details monitoring roles and responsibilities 
and data to be reviewed at each level will be prepared before the study opens to accrual.  Sections 
11 and 12 provide more information on on-site monitoring and quality management at the site 
level.  Further information on monitoring of study progress, quality of study conduct, and 
participant safety across sites is provided below. 
 


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9.6.1 
Monitoring by the Protocol Team 
 
Study Progress and Quality of Study Conduct 
 
The Protocol Team is responsible for continuous monitoring of study progress, including timely 
achievement of key milestones, and the quality of study conduct.  The team will closely monitor 
participant accrual and retention based on reports that will be generated at least monthly by the 
SDMC.  The team has developed a study accrual plan that includes site-specific and total 
enrollment projections over the course of the accrual period, and actual accrual will be monitored 
relative to these projections.  The team will monitor the timing of site-specific study activation, 
which will determine when each site will begin accruing participants, and accrual performance 
following activation.  Accrual performance will be reported by the SDMC, by site and across 
sites, and the team will review and discuss performance at least monthly.   For any site that is 
delayed in completing the study activation process, or that falls short of its accrual projections, 
the team will communicate with the site to identify the barriers the site has encountered and the 
operational strategies and action plans to address these.   
 
The Protocol Team will similarly review participant retention and other key indicators of the 
quality of study conduct (e.g. adherence to study drug regimen, data quality, and data and 
specimen completeness) based on reports generated by the SDMC and take action with study sites 
as needed to ensure high quality study conduct throughout the period of study implementation.  
 
The IMPAACT Management Oversight Group will be provided monthly updates on participant 
accrual and retention. 
 
Infant Safety 
 
On behalf of the full Protocol Team, the Core Protocol Team will closely monitor infant safety 
through routine review of safety reports generated by the SDMC.  These reports will provide 
tabulations of adverse events (defined in Section 7.2) identified in enrolled infants, including 
abnormal laboratory test results, signs, symptoms, and diagnoses.  The Core Protocol Team will 
review these reports via conference call or other meeting at least monthly until the last participant 
enrolled has completed follow-up.  At the time of each call, the DAIDS Medical Officer will also 
review any EAEs (defined in Section 7.3) reported to the DAIDS Safety Office that are not yet 
reflected in the data reports.   
 
The Core Protocol Team will continually evaluate the pattern and frequency of reported events 
and assess for any individual occurrences or trends of concern.  The Core Protocol Team will also 
monitor safety and take action as needed according to the following guidelines:   
 
(1) 
In the event of any adverse event that is life-threatening or results in death, the Core 
Protocol Team will review the event as soon as possible (ideally within three working days) 
and assess its relationship to study drug.  
 
Note:  The term life-threatening refers to an event in which the participant 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. 
 
• 
If either the site investigator or the Core Protocol Team assesses the event as possibly, 
probably or definitely related to study drug, participant accrual and administration of 


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study drug will immediately be paused to the stratum in which the triggering event had 
occurred and the Core Protocol Team will discuss how the study should proceed. 
 
• 
If the site investigator and the Core Protocol Team assess the event as probably not or 
not related to study drug, participant accrual and administration of study drug will 
continue.   
 
(2) 
In the event of any unresolvable disagreement within the Core Protocol Team on an issue 
which would impact decision making; or if the Core Protocol Team encounters any other 
event or trend of concern an SMC review of the relevant data will be requested.   The 
Core Protocol Team may choose to pause participant accrual and/or administration of study 
drug, pending the outcome of the SMC review.  
 
Dose Finding 
 
During the dose finding stages of this study, the Core Protocol Team will also review the 
pharmacokinetic data, with the aim of determining the recommended dose for each cohort while 
protecting infant safety.  The Core Protocol Team will review PK data reports at least monthly 
and take action as needed according to the guidelines in Section 9.6.2.  
 
Following any pause, participant accrual and/or administration of study drug may be resumed if 
resumption is recommended by the Core Protocol Team or SMC.   
 
9.6.2 
Safety Guidelines for Evaluating the Dose   
9.6.2.1 Safety Guidelines for groups of n=6 participants from each stratum in a given Cohort: Cohort 1 (1A, 
1B) and 2 (2A, 2B) Started at a Given Dose Level 
For each stratum in a given Cohort (Cohort 1 (1A and 1B) and Cohort 2 (2A and 2B), the 
frequency of adverse events at the starting dose of the study drug will be evaluated on the first 6 
participants.  The data will extend through the Day 7 Post Last Dose Safety Visit for Cohort 1and 
through the Week 6 Visit for Cohort 2.   
  
If any of the following conditions occur, then the group of n=6 infants would not meet the safety 
guidelines:  
 
• 
A life threatening adverse event or death  assessed as at least possibly related to the study 
drug, or 
 
Note:  The term life-threatening refers to an event in which the participant 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. 
 
• 
A Grade 4 event that is assessed as probably or definitely related to the study drug.  
 
• 
Three or more infants experienced a Grade 3 or higher adverse event assessed as at least 
possibly related to study drug or are discontinued from study drug due to an adverse event 
assessed as at least possibly related study drug. 
 
If none of these conditions has been met, then the safety guidelines have been met. 


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Given the small sample sizes in each stratum within a cohort, the information available for safety 
decisions will be imperfect. Two types of sampling errors are possible: 1) in a stratum within a 
cohort where the true rate of toxicity is too high to warrant exposure to the current dose of study 
drug, the sample data may pass the safety guidelines; and 2) in a stratum within a cohort where 
the true rate of toxicity is low enough that further exposure to the current dose is warranted, the 
sample data may fail the guidelines.  
 
The extent to which the safety guidelines protect against the errors described above can be 
assessed by examining various hypothetical rates of "true toxicity" which could occur, if the 
study drug were used extensively among the participant population at the dose level under 
question. The hypothetical situations presented in Table (1) range from conditions under which a 
given dose level would cause a high incidence of severe and life threatening adverse events to 
conditions under which severe adverse events would be relatively rare and would not be life 
threatening.  For each of these hypothetical situations, we assume that a sample of 6 infants is 
drawn from the participant population and that the safety guidelines, summarized above, are 
followed.  
 
Table (1) uses a multinomial response model to assess the probability of failing the safety 
guidelines under each of these hypothetical situations. The calculations are performed as follows:  
Each of the 6 participants represents a trial, which may have 1 of 3 mutually exclusive outcomes: 
(1) a death or life threatening adverse event judged to be at least possibly related to study drug or 
a grade 4 event judged to be probably or definitely related to study drug; (2) a Grade 3+ event or 
treatment termination, not satisfying the guidelines set forth in #1, immediately above, but judged 
to be at least possibly related to study drug; and (3) a relatively benign outcome, satisfying 
neither the criteria in #1 nor #2, immediately above.  
 
There are 3 sets of results under which this set of 6 trials would meet the safety guidelines:  
• 
First set: all participants would fall under outcome #3, immediately above, or 
• 
Second set: 5 participants would fall under outcome #3 and 1 participant would fall under 
outcome #2, with none falling under outcome #1, or 
• 
Third set: 4 participants would fall under outcome #3 and 2 would fall under outcome #2, 
with none falling under outcome #1,  
 
Thus, the probability of passing the safety criteria represents the sum of the probabilities of these 
sets of results, and “1 minus the probability of passing the safety guidelines” represents the 
probability of failing them. The “True Toxicity Rates” presented in Table (1) below, along with 
the true rate of having neither of the types of toxicity represented by the true toxicity rates (which 
is 1 - the sum of the true toxicity rates), provide the probabilities for the outcomes which are used 
in the multinomial calculations for each of the hypothetical situations evaluated below. 
 
As examples of how to read Table (1): this table shows that there is a 78% chance of failing the 
safety guidelines under conditions in which the true rate of life-threatening toxicity is 5% and the 
rate of non-life threatening Grade 3+ adverse event is 50%. Assuming that it would be 
undesirable to open a new group (stratum within a cohort) or accrue additional infants at a dose 
that had these true rates of adverse events, the 22% chance of NOT failing the safety guidelines 
would represent the probability of error. The table also shows that there is a 0.2 % chance of 
failing, when the true rate of non-life threatening Grade 3+ adverse event is only 5% and the true 
rate of life threatening adverse event is zero. Assuming that the potential benefits associated with 
exposing additional infants to this dose of the drug would outweigh the risks associated with this 


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relatively low rate of toxicity, failing the safety guidelines under these conditions would be an 
error. 
 
Note: Once 6 mother-infant pairs have been accrued for the preliminary evaluation of the dose for 
each cohort-EFV stratum, the study will allow no more than 2 additional mother-infant pairs to 
enroll to that stratum before the preliminary evaluation of PK and safety data on these 6 initial 
participants has been completed.  The PK and safety guidelines will determine decisions based on 
the first n=6 infants. If extra (up to 2) infants have been accrued and have evaluable data, then 
this additional information will be taken into account in decision making, such that: (1) if at least 
one infant experiences a life-threatening toxicity (including death) that is at least possibly related 
to the study drug, or a grade 4 toxicity that is  probably or definitely related to the study drug or 
(2) the extra participants exhibit toxicities (grade 3+ or treatment termination that are at least 
possibly study drug related) that cause the percentage of toxicity in the total accrual for that 
cohort-stratum to exceed 33%, then the team will re-evaluate the dose and determine whether it is 
safe proceed. Note that, due to uncertainty as to whether any extra participants will actually have 
been accrued and evaluated prior to decision making based on the first 6 participants, Table 1 
does not take account of the possibility that data from the extra participants may change decisions 
based on evaluation of date from the first 6. Since the extra participants provide additional 
potential for safety failure, the probability of failing safety guidelines, based on data from the first 
6 participants plus up to 2 additional participants, is somewhat greater than that presented in 
Table 1.  
 
Table 1: Probability that the First 6 Participants will Fail Safety Guidelines Under Potential Rates 
of True Toxicity 
 
True Toxicity Rates 
Probability of 
Failing Safety 
Guidelines 
Grade 3+ events or study 
treatment termination deemed at 
least possibly due to study drug,  
excluding Grade 4 events 
probably or definitely 
attributable to study drug 
Life threatening adverse 
events (including death) 
deemed to be at least possibly 
attributable to study drug, or 
Grade 4 events probably or 
definitely attributable to study 
drug 
.50 
.00 
.66 
.50 
.05 
.78 
.50 
.25 
.98 
.25 
.00 
.17 
.25 
.05 
.41 
.25 
.25 
.88 
.05 
.00 
.002 
.05 
.05 
.27 
.05 
.25 
.82 
.00 
.05 
.26 
.00 
.25 
.82 
 


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9.6.2.2 Safety Guidelines for the n=12 participants of each stratum in a given Cohort: Cohort 2 (2A, 2B) 
Started at a Given Dose Level 
 
For each stratum in Cohort 2, if the group of n= 6 infants meets both the safety and PK guidelines 
(see Section 10.3), then an additional 6 more infants will be accrued to complete the full cohort.  
The safety and PK results of the full-cohort of 12 infants will be evaluated.  The final safety 
guidelines applied to a given starting dose of the study drug for the full cohort will make use of 
data from all infants started at that dose. The data will extend to the Week 6 visit.   
 
If any of the following conditions occur, then a full cohort of 12 infants would not meet the safety 
guidelines: 
 
• 
A life threatening adverse event assessed as at least possibly related to the study drug, or  
• 
A Grade 4 event assessed as probably or definitely related to study drug, or  
• 
More than 25% of the infants experience a Grade 3+ adverse event assessed as at least 
possibly related to study drug or are discontinued from study drug due to an adverse event 
assessed as at least possibly related. 
 
If none of these conditions has occurred, then the safety guidelines have been met. 
 
9.6.3 
Monitoring by the SMC  
 
An independent IMPAACT SMC will review this study regularly, following policies described in 
the IMPAACT Network Manual of Procedures.   
 
SMC reviews will occur annually and focus on participant accrual, retention, study conduct, and 
safety (i.e., listing of Grade 3 and 4 events with corresponding treatment attributions). Additional 
SMC reviews focused on safety may also occur if requested by the Core Protocol Team as 
indicated in Section 9.6.1.  Based on any of its reviews, the SMC may recommend that the study 
proceed as currently designed, proceed with design modifications, or be discontinued.  The SMC 
may also provide operational recommendations to help address any study implementation 
challenges identified during their reviews.   
 
9.7 
Analyses 
 
The safety analysis will consist of descriptive statistics summarizing outcomes by strata within 
cohorts. See pharmacology Section 10 for description of PK analyses. 
 
Summary of Dose Finding Data 
 
The analysis of dose finding data will consist of descriptive statistics summarizing the safety data 
from the dose-finding phase of the study.  The data will be presented by stratum within each 
cohort and will include the results of the safety evaluations applied to each starting dose tested, 
including information indicating which starting doses have passed or failed the safety guidelines.  
For each starting dose within each stratum, every grade 3 or higher adverse event will be listed, 
along with participant demographics, the dose prescribed to the participant at the time of the 
event and the protocol team’s assessment of the probability that this event was due to the study 
drug. 
 


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Analysis of Data Representing Exposure to the Doses Selected for Each Stratum within a Cohort 
 
The primary analyses will be conducted for each stratum based on infants who were exposed to 
the final selected dose and will be restricted to data through week 6 of life.  Secondary analyses 
will include all infants, in subgroups for each dose received, and will include data through Week 
16. 
 
Each participant’s safety data will be summarized as: the worst grade of adverse event 
experienced at these time points and the worst grade of adverse event assessed as at least possibly 
related to study drug.   Frequency distributions of these safety outcomes will be presented.  
Listings of all Grade 3 or higher events will be provided. 
 
The proportions of participants experiencing grade 3 or higher adverse events, bounded by exact 
95% confidence intervals, will be presented.  Similar analyses will present the proportions of 
participants with Grade 3 or higher events assessed as at least possibly related to study drug, 
again bounded by exact 95% confidence intervals. Table 2 presents the upper and lower limits of 
confidence intervals around potential results observed in the groups of n=6 and full cohorts of 
n=12 of the strata with and without maternal EFV. 
 
Table 2: Percent of Participants Experiencing ≥ Grade 3 Adverse Events (or ≥ Grade 3 Adverse 
Events Attributed to the Study Medication) with Exact 95% Confidence Intervals 
 
N* 
n (%)  With ≥ Grade 3 
Adverse Events 
95% C.I. 
6 
0 (0%) 
0% -- 46% 
12 
0 (0%) 
0% -- 27% 
 
 
 
6 
1 (17%) 
.4% -- 64% 
12 
2 (17%) 
2% -- 49% 
 
 
 
6 
2 (33%) 
4%  -- 78% 
12 
4 (33%) 
10% -- 65% 
 
 
The proportions of infants who have become HIV-1 infected will be presented, bounded by 95% 
confidence intervals.  The upper and lower limits of the confidence intervals around selected, 
potential proportions occurring in the groups of n=6 and full cohorts will be similar to those 
presented in Table 2. The results will be presented separately for the EFV vs. non-EFV strata. 
 
Additional Secondary Analysis on Tropism 
  
Note that the study team expects only few infants (if any) to become HIV-1 infected during the 
study. Exploratory analysis will be performed in infants who become HIV-1 infected: (1) to 
determine the infant’s viral tropism after exposure to maraviroc; and (2) to assess if the infant’s 
viral tropism matches the mother's. 
  
 
10 
PHARMACOLOGY PLAN  
 
The design and analysis plans for objectives 2.1.2, 2.1.3, and 2.2.2 are described in this section. 


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10.1 
Pharmacology Overview and Objectives 
 
This study is designed to assess the PK and safety of maraviroc solution in infants during the first 
six weeks of life. Cohort 1 infants will receive a single dose of maraviroc after enrollment and 
within 3 days of life and again at Week 1. PK samples will be drawn around each of these doses. 
Cohort 2 infants will receive daily dosing of maraviroc after enrollment and within 3 days of life 
through 6 weeks of life at a dose determined in Cohort 1. Cohort 2 infants will have intensive PK 
evaluations at Weeks 1 and 4, and an additional sparse PK sample at Week 6. Both cohorts will 
be stratified by maternal use of efavirenz, see Section 3.0 for stratification.    
 
PK evaluable infants are those whose PK results provide data on the primary PK parameters of 
interest. Unevaluable infants will be replaced. See Section 9.1. Unevaluable infants would include 
infants taken off maraviroc due to HIV-1 infection, infants of breastfeeding mothers who stop 
taking EFV (Stratum 2B), infants who vomit within 30 minutes of maraviroc administration 
(Cohort 1), and any other reasons for which the protocol team may determine that the infant 
would be unevaluable. 
 
 
10.2 
Methods and Timing for Collections, Processing, Handling, and Storage 
 
PK sample collection methods, processing, storage and shipping instructions are detailed in the 
LPC. 
 
10.2.1 PK collections: Cohort 1 
 
 
Entry (birth to 3 days)  
The PK sampling for maraviroc must be initiated on the same day as the first dose of maraviroc 
(within 3 days of life) per Section 6.4.  As mentioned in Section 6.4, the Entry Visit may be 
conducted as a split visit.    
 
For infants in Stratum 1B only, an additional sample for analysis of EFV levels should also be 
drawn at any time on the same day the first maraviroc dose is given. 
  
Week 1 (7 to 14 days) 
Intensive PK sampling for maraviroc must be initiated on the same day as the dose of maraviroc 
and conducted as per Section 6.5.1   
 
For infants in Stratum 1B only, an additional sample for analysis of EFV levels should also be 
drawn at any time during the Week 1 visit. 
 
10.2.2 Intensive PK collections: Cohort 2 with Once Daily Dosing 
 
Intensive PK sampling should be scheduled so that the observed dosing of maraviroc is as close 
as possible to 24 hours (generally 22-26 hours) after the previous dosing.  Infants should take 
study drug for 3 days prior to the intensive PK visit; otherwise, the intensive PK visit should be 
re-scheduled. 
 
Week 1 (7 to 14 days) 
The Intensive PK sampling for maraviroc should be conducted as per Section 6.5.2  
 


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For infants in Stratum 2B only, an additional sample for analysis of EFV levels should also be 
drawn at any time during the Week 1 visit.   
 
Week 4 (21 to 31 days) 
The Intensive PK sampling for maraviroc should be conducted as per Section 6.7.1  
 
For infants in Stratum 2B only, an additional sample for analysis of EFV levels should also be 
drawn at any time during the Week 4 visit.    
 
10.2.3 Intensive PK collections: Cohort 2 with Twice Daily Dosing 
 
Intensive PK sampling should be scheduled so that the observed dosing of maraviroc is as close 
as possible to 12 hours (generally 11-13 hours) after the previous dosing.  Infants should have 
taken study drug for 3 days prior to the intensive PK visit; otherwise the intensive PK visit should 
be re-scheduled. 
 
Week 1 (7 to 14 days) 
 
The Intensive PK sampling for maraviroc should be conducted as per Section 6.5.3. For Stratum 
2B only, an additional sample for analysis of EFV levels should also be drawn at any time during 
the Week 1 visit. 
 
Week 4 (21 to 31 days) 
The Intensive PK sampling for maraviroc should be conducted as per Section 6.7.2.  For Stratum 
2B only, an additional sample for analysis of EFV levels should also be drawn at any time during 
this study visit. 
 
10.2.4 Population PK collection: Cohort 2 with Once or Twice Daily Dosing 
 
Week 6 (35 to 42 days) 
A single random sample for maraviroc population PK should be drawn at any time during the 
Week 6 visit. 
 
For Stratum 2B only, an additional sample for analysis of EFV levels should also be drawn at any 
time during the Week 6 visit.  
 
10.3 
Starting Dose, PK Guidelines for Dose Adjustment and Interim Analyses 
 
10.3.1 Starting Dose 
 
The initial single doses for the first six infants enrolled into Strata 1A and 1B will be 8 mg/kg, 
based on extrapolation from adult and adolescent data, and expected differences in ontogeny of 
drug disposition in infants.  
 
For Stratum 1B, in which infants may be exposed to efavirenz in utero or through breastfeeding, 
higher doses of maraviroc might be needed, IF efavirenz causes a clinically significant interaction 
with infant use of maraviroc. Whether such an interaction will occur is unknown for the following 
reasons. The efavirenz “dose”, or the systemic exposure which each infant will receive from 
maternal transfer, is unknown and expected to be low at birth and lower during breastfeeding, and 
may be highly variable between infants. Further, the activity of CYP 3A4 is lower at birth than in 


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older infants and children, and the ability of efavirenz to induce the activity of this immature 
enzyme system (and the extent to which this immature enzyme system may be induced) in infants 
is unknown. Because of the uncertainties surrounding whether low passive exposure to efavirenz 
in infants will cause a clinically significant decrease in maraviroc exposure, and our lack of safety 
data for maraviroc use in infants at the outset of this study, infants in Stratum 1B will begin with 
the same 8 mg/kg single doses as infants in Stratum 1A. 
 
10.3.2 PK Guidelines for Dose Adjustment 
 
The study will implement a dose-finding algorithm (see Section 9.2) based on the review of real-
time PK and safety data from Strata 1A and 1B separately, with an initial group of 6 infants in 
each of these strata with evaluable PK data.  The maraviroc exposure target will be a Cavg of ≥ 75 
ng/mL, which is the exposure associated with near-maximal efficacy in the treatment naïve adult 
study (MERIT) of maraviroc when dosed in combination with ZDV/3TC. [15] If the maraviroc 
exposure target (Cavg ≥75 ng/mL) is not met in 2 or more of the 6 infants at the Entry visit and the 
Week 1 visits, the Core Protocol Team will evaluate the PK and safety data and decide whether to 
adjust the dose, continue with the current dose, or stop the study. Enrollment of additional groups 
of six infants receiving adjusted doses (increased or decreased doses) will be allowed.  If the 
safety and PK guidelines are met in Stratum 1A or 1B, then the corresponding Stratum 2A or 2B 
will open with n=6 infants in each stratum receiving daily dosing, with a dose size and frequency 
(once or twice daily) to be determined based on the Stratum 1A or 1B data. Strata 2A and 2B PK 
data from n=6 will be checked prior to the full accrual of n=12 for each stratum.  Strata 2A and 
2B will allow further dose adjustment for PK or safety as needed (see Section 9.2 for the Dose 
Adjustment algorithm based on both safety and PK guidelines).  Final enrollment target is 12 
infants in Stratum 2A and 12 infants in Stratum 2B with evaluable PK data on the final dose.  If 3 
or more of the 12 infants in Stratum 2A or 2B do not meet the maraviroc exposure target at both 
PK assessments (Weeks 1 and 4), the Core Protocol Team will evaluate the PK and safety data, 
and decide whether to change the dose, continue with the same dose, or stop the study. 
Enrollment of additional groups of 6 infants receiving adjusted doses (increased or decreased 
doses) will be allowed, and the process above will be repeated.   
 
10.3.3 Timing of Interim Analyses   
 
The PK data will be analyzed for each individual infant enrolled in this study in real-time. The 
individual PK analyses will be reviewed by the Core Team as soon as the results are available for 
each infant. A summary of the PK data will be prepared at the following times:  
 
1. After the real-time PK analyses have been completed for the first 6 infants enrolled in any 
stratum at a given dose level. 
2. In Stratum 1A or 1B at a given dose level: After two infants do not meet the PK guidelines. 
3. In Stratum 2A or 2B at a given dose level: After two infants (at n=6) and three infants (at 
n=12) do not meet the PK guidelines. 
4.   The Core Protocol Team deems it important to assess the current dose.  
 
10.4 
Laboratory Performing the Assays 
 
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10.5 
Primary and Secondary Data Analysis Plan 
 
The primary PK endpoint for all participants is whether or not maraviroc Cavg ≥ 75 ng/mL at all 
PK assessments. The primary PK outcome variables are Cavg, AUC, and Cmax for Strata 1A and 
1B. Ctrough is an additional primary PK outcome variable for Strata 2A and 2B. Other standard PK 
parameter estimates will also be calculated (half-life, elimination rate constant, oral clearance). 
 
Cmax and Ctrough will be observed from the concentration versus time curve for each participant.  
Noncompartmental analyses of the intensive PK data will initially provide rough estimates of the 
AUC and Cavg in each participant in real-time.  Compartmental modeling methods (using one or 
two compartment models in the software program, WinNonlin) may be explored and utilized if 
necessary for the real-time PK assessments to calculate the Cavg. 
 
For interim analyses, population PK models will be constructed in NONMEM and simulations 
will be used to estimate appropriate doses. Both intensive and sparse PK data from the studies in 
both adults and children may be utilized, along with all of the data generated in each of the strata 
in this study, to maximize the available information and provide a rich and diverse dataset.  
 
To determine maraviroc PK over the first six weeks of life, all available information regarding the 
evolution of maraviroc clearance, possibly interacting drugs and CYP 3A4 ontogeny with age 
will be included in the population modeling. Covariates of interest will be explored. The model 
can be used to simulate an optimal dosing scheme (with dose and/or frequency adjustments at 
appropriate times) to meet the PK targets throughout the course of dosing. 
 
10.6 
Anticipated Outcomes   
 
The goal of this study is to gain an understanding of maraviroc PK in young infants, the ontogeny 
of maraviroc metabolism, the potential effect of maternal efavirenz use on infant maraviroc PK, 
and to have defined the dose(s) and dosing interval that achieve the desired systemic exposure in 
this population. 
 
 
11 
DATA HANDLING AND RECORD KEEPING 
 
11.1 
Data Management Responsibilities 
 
As described in Section 4.4, data on screening and enrollment in this study will be collected using 
the DMC SES.   
 
Study sites must maintain adequate and accurate research records containing all information 
pertinent to the study for all screened and enrolled mother-infant pairs, including CRFs and 
supporting source data.  In maintaining these records, sites must comply with the standards of 
source documentation specified in the DAIDS policy on Requirements for Source Documentation 
in DAIDS Funded and/or Sponsored Clinical Trials (available on the website referenced in 
Section 11.2). 
 
CRFs are completed by study site staff and, following quality control and quality assurance 
reviews, are keyed using a remote data entry system designated by the DMC and transferred 


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electronically to the DMC.  Selected laboratory data are transferred electronically to the DMC 
through the LDMS.   
 
At the DMC, computerized checks are applied to the transferred data and, when required, data 
queries are issued for resolution by study site staff.  All data must be transferred to the DMC 
within timeframes specified in the forms instructions; queries must also be resolved in a timely 
manner.  
 
Further information on the study CRFs and IMPAACT data management procedures, including a 
Forms Manual: Policies and Procedures for Forms Completion for DAIDS-Sponsored Clinical 
Trials, a comprehensive Computing Manual, and a User Manual for the SES, are available on the 
DMC portal at www.fstrf.org.   
 
11.2 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/ClinicalSite.aspx  
 
Study sites must comply with DAIDS policies on Requirements for Essential Documents at 
Clinical Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials and 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials.  In 
its policy on Requirements for Manual of Operational Procedures, DAIDS requires sites to 
establish SOPs for maintaining essential and source documents in compliance with these policies.  
Site SOPs should be updated and/or supplemented as needed to describe roles, responsibilities, 
and procedures for this study, and site SOPs should be followed throughout the study.  
 
Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must 
be stored in a manner that ensures privacy, confidentiality, security, and accessibility during the 
conduct of the study and after the study is completed.  Records must be retained for a minimum 
of three years after the completion of the study.  Per 21 CFR 312.62, records must be maintained 
for two years after the date a marketing application is approved for one or more of the study drugs 
for the indication for which it is evaluated in this study; or, if no application is filed, or if the 
application is not approved for this indication, records must be retained two years after the study 
is discontinued and the FDA is notified.  
 
All study records must be accessible for inspection, monitoring, and/or auditing during and after 
the conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, the US Food and Drug Administration, site drug regulatory authorities, site 
IRBs/ECs, the US Office for Human Research Protections, and other applicable regulatory 
entities.  Records must be kept on-site throughout the period of study implementation; thereafter, 
instructions for off-site storage may be provided by NIAID or NICHD.  No study records may be 
removed to an off-site location or destroyed prior to receiving approval from NIAID or NICHD.  
 
11.3 
Expectations for Data Usage  
 
DAIDS acknowledges ViiV’s intention to use the data from this Clinical Trial for the fulfillment 
of a pediatric written request pursuant to the Best Pharmaceuticals for Children’s Act and for 
labeling changes for the Company’s products.  
 
 


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11.4 
Quality Control and Quality Assurance 
 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the DAIDS policy on 
Requirements for Clinical Quality Management Plans, which is available at: 
 
www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/ClinicalSite.aspx  
 
 
12 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records including consent forms, CRFs, medical records, laboratory 
records, and pharmacy records, to ensure protection of study participants, compliance with the 
IRB/EC approved protocol, and accuracy and completeness of records.  The monitors also will 
review essential document files to ensure compliance with all applicable regulatory requirements.  
Site investigators will make study facilities and documents available for inspection by the 
monitors.   
 
13 
HUMAN SUBJECTS PROTECTIONS 
 
13.1 
Institutional Review Board/Ethics Committee Review and Approval  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this 
protocol and site-specific ICFs in accordance with 45 CRF 46; subsequent to initial review and 
approval, IRBs/ECs must review the study at least annually.  Site investigators must also 
promptly report to the IRB/EC any changes in the study and any unanticipated problems 
involving risks to participants or others. 
 
All IRB/EC policies and procedures must be followed and complete documentation of all 
correspondence to and from the IRBs/ECs must be maintained in site essential document files.  
Sites must submit documentation of both initial review and approval and continuing review to the 
DAIDS Protocol Registration Office (PRO) in accordance with the DAIDS Protocol Registration 
Manual (see also Section 14.2). 
 
13.2 
Vulnerable Participants 
 
The NIH is mandated by law to ensure that pregnant women and children be included in clinical 
research when appropriate. [17, 18] This study responds to that mandate and will provide clinical 
research data to inform maraviroc safety and dosing in full-term infants.  The infants who take 
part in this study are considered vulnerable participants per the US Code of Federal Regulations, 
and site IRBs/ECs must consider the potential risks and benefits to infant participants as 
described in 45 CFR 46 Subpart B (for pregnant women, fetuses, and neonates) and 45 CFR 46 
Subpart D (for children). 
 
With respect to 45 CFR 46 Subpart B, the specifications of 45 CFR 46.204 (d) are considered to 
apply; therefore, maternal participants will be asked to provide written informed consent for their 
own and their infant’s study participation. 
 


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With respect to 45 CFR 46 Subpart D, IRBs/ECs must determine the level of risk to children in 
the categories specified in 45 CFR 46.404-407.  Documentation of this determination is required 
to complete the DAIDS protocol registration process described in Section 14.2, and the risk 
category assigned by the IRB/EC further determines the parental informed consent requirements 
for the study at each site.  Per 45 CFR 46.408 (b), the IRB/EC may find that the consent of one 
parent is sufficient for research to be conducted under 46.404 or 46.405.  If the IRB/EC finds that 
the research is covered by 46.406 or 46.407, both parents must give their consent, unless one 
parent is deceased, unknown, incompetent, or not reasonably available or when only one parent 
has legal responsibility for the care and custody of the child (as determined locally).  IRBs/ECs 
must document their risk determination, and study sites should adapt the signature pages of their 
site-specific ICFs as needed to accommodate the parental consent requirements associated with 
the IRB/EC determination. 
 
Study sites must comply with the requirements of the DAIDS policy on Enrolling Children in 
Clinical Research, which is available at:  
 
www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/Pages/ClinicalSite.aspx 
 
13.3 
Informed Consent 
 
Written informed consent for maternal and infant study participation will be obtained before any 
study-specific procedures are performed.  The informed consent process may be conducted 
during pregnancy or, in whole or in part, after infant birth.  If informed consent is obtained during 
pregnancy, the study will be discussed again with the mother after delivery and her prior consent 
decision will be confirmed at that time.  If the mother changes her mind and withdraws her 
consent at that time, the mother-infant pair will not be enrolled in the study and no further study-
specific procedures will be performed. 
 
The informed consent process will include information exchange, detailed discussion, and 
assessment of understanding of all required elements of informed consent, including the potential 
risks, benefits, and alternatives to study participation.  The process will emphasize the unproven 
efficacy of the study drug for prevention of mother to child transmission and mothers will be 
extensively counseled on the importance of adherence to their standard of care ARV regimen for 
perinatal transmission and adherence to the infants ARV regimen.    
  
As indicated above, it is generally expected that mothers will provide informed consent for their 
own and their infant’s participation in this study.  However, parental consenting requirements at 
each site will depend on the IRB/EC risk determination described in Section 13.2; all IRB/EC 
requirements will be followed.   
 
As part of the informed consent process, mothers will be asked whether they agree to storage and 
future research testing of biological specimens, remaining after all protocol-specified testing has 
been completed.  Future research testing of residual specimens may be declined with no impact 
on other aspects of infant study participation.   
 
Should the mother of an enrolled infant die or no longer be available for any reason, no further 
study drug may be administered and no study-specific visits or procedures may be performed 
until informed consent for continued study participation is obtained from a locally authorized 
guardian.  In accordance with the DAIDS policy on Enrolling Children (including Adolescents) in 
Clinical Research (available at the website referenced in Section 12.2), all study sites must 
establish and maintain written procedures describing the standards that will be followed to 


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identify who may serve as guardian for an enrolled infant, reflective of applicable IRB/EC 
guidance for conduct of human subjects research within the context of available local law, 
regulation, or government policy.  
 
13.4 
Potential Benefits 
 
There may be no direct benefit to mothers or infants who take part in this study.  The infants in 
Cohort 1 only receive two single doses of maraviroc (in addition to standard of care ARVs) and 
should therefore not expect any benefit. The infants in Cohort 2 will receive daily doses of 
maraviroc for up to 42 days and while there is no established benefit, this may provide some 
prophylactic benefit (in addition to standard of care ARVs). Information learned in this study may 
be of benefit to infants born to HIV-1 infected mothers in the future, and mothers may appreciate 
the opportunity for themselves and their infants to contribute to HIV-related research. 
 
13.5 
Potential Risks  
 
The potential risks of participation in this study include risks associated with study procedures 
and risks associated with receipt of maraviroc.  Most study procedures are routine medical 
procedures that are associated with minimal to no risk in participants.  Blood collection may 
cause pain, bruising, swelling, and (rarely) infection at the site where the needle is inserted. 
 
Maraviroc has been used widely in adults as second line treatment, see Section 1.2. A pediatric 
study was completed, to determine the safety and efficacy in combination with optimized 
background therapy in HIV-1 infected children 2 to <18 years of age, see Section 1.3.  To date, 
maraviroc plus other background therapy appears to be well tolerated and effective, with a 
manageable safety profile in adult and pediatric populations.  The most common treatment related 
adverse events seen in adults receiving maraviroc were diarrhea, nausea and headache.  The most 
common treatment related adverse events seen in the pediatric study of children ages 2 to <18 
years were gastrointestinal disorders.  Two subjects in the 12-18 year old cohort met initial 
biochemical criteria of Hy's law but in final analysis, these liver toxicities were considered 
unlikely to be related to maraviroc.  These subjects are described in detail in Section 1.3.  For 
subjects in the 2-6 year old cohort, there were a few cases of grade 1 ALT/AST elevation but no 
higher grade liver toxicity was observed. 
 
There may be other risks to study participants that are not currently known. 
 
13.6 
Potential Social Impacts 
 
Participation in clinical research includes the risk of loss of confidentiality. Although study sites 
make every effort to protect participant privacy and confidentiality, it is possible that participants' 
involvement in the study could become known to others, and that social harms may result (e.g., 
because participants could become known as having HIV).  For example, participants could be 
treated unfairly or discriminated against or could have problems being accepted by their families 
and/or communities.  
 


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13.7 
Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be reimbursed for costs associated with completing 
study visits (e.g., transport costs).  Reimbursement amounts will be specified in site-specific ICFs 
or other materials if applicable per IRC/EC policies and procedures.  
 
13.8 
Privacy and Confidentiality 
 
All study procedures will be conducted in private and every effort will be made to protect 
participant privacy and confidentiality to the extent possible.  Participant information will not be 
released without written permission to do so except as necessary for review, monitoring, and/or 
auditing as described in Section 11.2. 
 
All study-related information will be stored securely.  Participant research records will be stored 
in locked areas with access limited to study staff.  All laboratory specimens, CRFs, and other 
documents that may be transmitted off-site (e.g., EAE report forms) will be identified by PID 
only.  Likewise, communications between study staff and protocol team members regarding 
individual participants will identify participants by PID only.   
 
Study sites are encouraged but not required by DAIDS policies to store study records that bear 
participant names or other personal identifiers separately from records identified by PID.  All 
local databases must be secured with password protected access systems.  Lists, logbooks, 
appointment books, and any other documents that link PID numbers to personal identifying 
information should be stored in a separate, locked location in an area with limited access.   
 
In addition to the above, a Certificate of Confidentiality has been obtained for this study from the 
US Department of Health and Human Services.  This certificate protects study staff from being 
compelled to disclose study-related information by any US Federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings.  It thus serves to protect the identity and privacy 
of study participants.  Because the certificate cannot be enforced outside of the US, however, it 
applies only to US sites and participants. 
 
13.9 
Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases including HIV 
infection identified among study participants to health authorities.  Participants will be made 
aware of all applicable reporting requirements as part of the study informed consent process. 
 
13.10 Management of Incidental Findings 
 
Site investigators will inform mothers (or other authorized guardians if applicable) of all 
clinically meaningful physical exam findings and laboratory test results, including results of HIV 
tests and hematology and chemistry tests. Mothers will not routinely receive infant PK test results 
in this study.  When applicable, site investigators will provide referrals to non-study sources of 
medical care for further evaluation and/or treatment of these findings.  
 


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13.11 Management of New Information Pertinent to Study Participation 
 
Infants’ mothers (or other authorized guardians if applicable) will be provided any new 
information learned over the course of the study that may affect their willingness to allow their 
infants to continue receiving study drug and/or remain in follow-up in the study.   
 
13.12 Post-Trial Access to Study Drug 
 
Participants will complete the study drug regimen prior to exiting the study. Therefore, post-study 
access to study drug is not applicable. 
 
 
14 
ADMINISTRATIVE PROCEDURES 
 
14.1 
Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), 
Eunice Kennedy Shriver National Institute of Child Health and Development (NICHD), and 
National Institute of Mental Health (NIMH), which are part of the United States National 
Institutes of Health (NIH).  The study drug maraviroc is provided by PHIVCO; however, these 
organizations are not involved in sponsorship or regulatory oversight of this study.   
 
The Division of AIDS (DAIDS) within the NIAID is responsible for regulatory oversight of this 
study.  DAIDS will distribute safety-related information pertaining to the study drugs prior to and 
during the conduct of the study, in accordance with its sponsor obligations.  
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be 
conducted.  Each institute contracts with independent clinical site monitors who will perform 
monitoring visits as described in Section 12.  As part of these visits, monitors will inspect study-
related documentation to ensure compliance with all applicable US and local regulatory 
requirements. 
 
14.2 
Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol ICFs approved, as appropriate, by their local IRB/EC and 
any other applicable regulatory entity.  Upon receiving final approval, sites will submit all 
required protocol registration documents to the DAIDS PRO at the RSC.  The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all of the required documents 
have been received.   
 
Site-specific ICFs will be reviewed and approved by the DAIDS PRO and sites will receive an 
Initial Registration Notification from the DAIDS PRO that indicates successful completion of the 
protocol registration process.  A copy of the Initial Registration Notification should be retained in 
the site's regulatory files. 
 
For any future protocol amendments, upon receiving final IRB/EC and any other applicable 
regulatory entity approvals, sites should implement the amendment immediately.  Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the RSC.  The 
DAIDS PRO will review the submitted protocol registration packet to ensure that all the required 


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documents have been received.  Site-specific ICFs will not be reviewed and approved by the 
DAIDS PRO and sites will receive an Amendment Registration Notification when the DAIDS 
PRO receives a complete registration packet.  A copy of the Amendment Registration 
Notification should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual, which is available on the RSC website:  
 
http://rsc.tech-res.com/protocolregistration/ 
 
14.3 
Study Implementation 
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US and local regulations.  Study implementation will also be guided 
by the IMPAACT MOP, study-specific MOP, LPC, and other study implementation materials, 
which will be available on the IMPAACT website:  www.impaactnetwork.org. 
 
Study implementation at each site will also be guided site-specific SOPs.  The DAIDS policy on 
Requirements for Manual of Operations specifies the minimum set of SOPs that must be 
established at sites conducting DAIDS funded and/or sponsored clinical trials (available on the 
website referenced in Section 11.2).  These SOPs should be updated and/or supplemented as 
needed to describe roles, responsibilities, and procedures for this study. 
 
14.4 
Protocol Deviation Reporting 
 
Per the policy for Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials (available at the website referenced in Section 11.2), all protocol deviations must 
be documented in participant research records.  Reasons for the deviations and corrective and 
preventive actions taken in response to the deviations should also be documented.  
 
Deviations should be reported to site IRBs/ECs and other applicable review bodies in accordance 
with the policies and procedures of these review bodies.  Serious deviations that are associated 
with increased risk to one or more study participants and/or significant impacts on the integrity of 
study data must also be reported within IMPAACT, following procedures specified in the 
IMPAACT Manual of Procedures. 
 
14.5 
Critical Event Reporting 
 
Per the DAIDS policy on Identification and Classification of Critical Events, a critical event is 
defined as an unanticipated study-related incident that is likely to cause harm or increase the risk 
of harm to participants or others or has a significant adverse impact on study outcomes or 
integrity.  All such events must be reported following procedures specified in the DAIDS Critical 
Events Manual, which is available at: 
 
www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Pages/Safety.aspx  
 


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14.6 
ClinicalTrials.gov 
 
This protocol is not subject to the Food and Drug Administration Amendments Act of 2007 
(FDAAA).  However, it will be registered in ClinicalTrials.gov to meet International Committee 
of Medical Journal Editors requirements. 
 
15 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT 
policies, which are available in the IMPAACT Manual of Procedures.  
 
 


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16 
REFERENCES 
 
1. 
Hirt, D., et al., Age-related effects on nelfinavir and M8 pharmacokinetics: a population study 
with 182 children. Antimicrob.Agents Chemother., 2006. 50(3): p. 910-916. 
2. 
Mirochnick, M., et al., Nelfinavir and Lamivudine pharmacokinetics during the first two weeks of 
life. Pediatr.Infect.Dis.J., 2011. 30(9): p. 769-772. 
3. 
Lopriore, E., et al., Twins with cardiomyopathy and complete heart block born to an HIV-infected 
mother treated with HAART. AIDS, 2007. 21(18): p. 2564-5. 
4. 
McArthur, M.A., et al., Twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir 
therapy. Pediatr.Infect.Dis.J., 2009. 28(12): p. 1127-1129. 
5. 
US Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and 
Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and 
adolescents. Drug Interactions Between NRTIs and Other Drugs (including antiretroviral 
agents), Table 15c, 145. 2011. 01-10-2011. 2011. 
6. 
Church, J.D., et al., Analysis of HIV tropism in Ugandan infants. Curr HIV Res, 2010. 8(7): p. 
498-503. 
7. 
ViiV Healthcare, Maraviroc (UK-427857) Investigator’s Brochure. January 2016. 
8. 
ViiV Healthcare, Maraviroc package insert. April 2015. 
9. 
Casper, C.H., et al., Link between the X4 phenotype in human immunodeficiency virus type 1-
infected mothers and their children, despite the early presence of R5 in the child. J Infect Dis, 
2002. 186(7): p. 914-21. 
10. 
Church, J.D., et al., HIV-1 tropism and survival in vertically infected Ugandan infants. J Infect 
Dis, 2008. 197(10): p. 1382-8. 
11. 
Crudeli, C.M., et al., Relevance of early detection of HIV type 1 SI/CXCR4-using viruses in 
vertically infected children. AIDS Res Hum Retroviruses, 2012. 28(7): p. 685-92. 
12. 
Salvatori, F. and G. Scarlatti, HIV type 1 chemokine receptor usage in mother-to-child 
transmission. AIDS Res Hum Retroviruses, 2001. 17(10): p. 925-35. 
13. 
Saag, M., et al., A double-blind, placebo-controlled trial of maraviroc in treatment-experienced 
patients infected with non-R5 HIV-1. J Infect Dis, 2009. 199(11): p. 1638-47. 
14. 
McCormack, S.A. and B.M. Best, Protecting the Fetus Against HIV Infection: A Systematic 
Review of Placental Transfer of Antiretrovirals. Clinical pharmacokinetics, 2014. 53(11): p. 989-
1004. 
15. 
Olagunju, A., et al., Breast milk pharmacokinetics of efavirenz and breastfed infants' exposure in 
genetically-defined subgroups of mother-infant pairs: an observational study. Clinical Infectious 
Diseases, 2015: p. civ317. 
16. 
McFadyen, L., et al. Maraviroc exposure-efficacy (<50 copies/mL) analysis in HIV-1-infected 
treatment-naive subjects - ITT population (MERIT study). in 17th International AIDS Conference. 
2008. Mexico City, Mexico. 
17. 
National Institutes of Health, Guidelines for the Inclusion of Women and Minorities as Subjects in 
Clinical Research. Federal Register. 1994. 
18. 
National Institutes of Health, NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects. 1998. 
 
 


IMPAACT 2007, Version 1.0 
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13 April 2016 
APPENDICES 
 
Appendix IA: Maternal Schedule of Evaluations 
 
 
Study Visit 
Screen 
Entry 
Visit Window 
During pregnancy 
through 0 – 3 days  
0 – 3 days  
Informed Consent 
X 
 
HIV-1 Testing (if needed) 
 [3- 10 mL] 
 
Medical/Medication History 
X 
X 
HIV-1 RNA 
 
6 mL 
Blood Storage (tropism testing) 
 
8 mL 
Total Maximum Blood Volume 
10 mL 
14 mL 
 
Day 0 is defined as the date of delivery (infant date of birth). Screening and enrollment (all evaluations 
shown above) must occur within 3 days of delivery.  
 
 


IMPAACT 2007, Version 1.0 
 
 
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13 April 2016 
Appendix IB: Cohort 1 (Stratum 1A and 1B) – Infant Schedule of Evaluations 
 
Study Visit 
 
Screen  
 
 
Entry 
 
 
Week 1 
 
 
7 Days Post 
Dose Safety  
Week 6  
 
Week 16 or 
Early Study 
Discontinuation 
Visit Window 
0 – 3 days  
0 – 3 days 
7 – 14 days  
+/- 3days 
35 – 42 days 
112 – 140 days 
Clinical 
 
 
 
 
 
 
History 
X 
 
X 
X 
X 
X 
Physical Exam 
X 
 
X 
X 
X 
X 
Laboratory 
 
 
 
 
 
 
HIV Nucleic Acid Test (NAT) 
2 mL 
 
  
 
2 mL  
2 mL  
CBC with differential and platelets 
0.5 mL  
 
0.5  mL 
0.5 mL 
0.5 mL 
0.5 mL 
AST, ALT, total bilirubin, creatinine  
1 mL 
 
1 mL 
1 mL 
1 mL 
1 mL 
Plasma Storage 
1 mL 
 
 
 
 
 
Dried blood spot storage 
From NAT 
 
 
 
From NAT 
From NAT 
HIV Confirmatory Testing  
 
If the initial HIV NAT is positive, confirm as soon as possible with a repeat HIV NAT on a 
second sample drawn on a different day and collect an additional 6 mL for tropism and 
resistance testing, per the LPC. See Section 6.11 for further instructions. Note: 6 mL does 
not appear in totals below since this will be a sample drawn on an unscheduled visit.  
Pharmacokinetics 
 
 
 
 
 
 
Intensive PK Sampling 
 
3 mL  
(0.5 mL per 
sample)  
1.5 mL  
(0.5 mL per 
sample) 
 
 
 
EFV level (Stratum 1B only)  
 
0.5 mL 
0.5 mL  
 
 
 
Total Maximum Blood Volume 
4.5 mL 
3.5 mL 
3.5 mL 
1.5 mL 
3.5 mL 
3.5 mL 
Day 0 is defined as the infant’s date of birth and all follow-up visits are scheduled from this date with the exception of the 7 Days Post Dose Safety Visit 
which is scheduled for 7 days (+/- 3 days) from the day of administration of the Week 1 dose of study drug. Screening and enrollment must occur within three 
days of birth. 


IMPAACT 2007, Version 1.0 
 
 
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13 April 2016 
Appendix IC: Cohort 2 (Stratum 2A and 2B) – Infant Schedule of Evaluations 
 
Study Visit  
 
Screen/Entry 
 
 
Week 1 
 
 
Week 4  
 
 
 
Week 6 
 
 
 
Week 12   
 
 
Week 16 or 
Early Study 
Discontinuation  
 
Visit Window  
0 –  3 days  
7 – 14 days 
21 – 31 days 
35 – 42 days 
77 –  91 days 
112 – 140 days  
Clinical 
 
 
 
 
 
 
Medical History  
X 
X 
X 
X 
X 
X 
Physical Exam 
X 
X 
X 
X 
X 
X 
Laboratory 
 
 
 
 
 
 
HIV Nucleic Acid Test 
2 mL 
 
 
 2 mL 
 
 2 mL  
CBC with differential and platelet 
0.5mL 
0.5 mL 
0.5 mL 
0.5 mL 
0.5 mL 
0.5 mL 
AST, ALT, total bilirubin, creatinine  
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
Plasma Storage 
1 mL 
 
 
 
 
 
Dried blood spot storage 
From NAT 
 
 
From NAT 
 
From NAT 
HIV Confirmatory Testing 
 
If the initial HIV NAT is positive, confirm as soon as possible with a repeat HIV NAT on 
a second sample drawn on a different day and collect an additional 6 mL for tropism and 
resistance testing, per the LPC. See Section 6.11 for further instructions. Note: 6 mL 
does not appear in totals below since this will be a sample drawn on an unscheduled 
visit. 
Pharmacokinetics 
 
 
 
 
 
 
Intensive PK Sampling 
   
2.5 mL (0.5 
mL per 
sample) 
2.0 - 2.5 mL 
(0.5 mL per 
sample) 
 
 
 
Population PK Sampling  
 
 
 
0.5 mL 
 
 
EFV level (Stratum 2B only) 
 
0.5 mL 
0.5 mL 
0.5 mL 
 
 
Total Maximum Blood Volume 
4.5 mL 
4.5 mL 
4.5 mL 
4.5 mL 
1.5 mL 
3.5 mL 
Day 0 is defined as the infant’s date of birth and all follow-up visits are scheduled from this date.  
 


IMPAACT 2007, Version 1.0 
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13 April 2016 
 
Appendix II: Maraviroc Weight Band Dosing Tables For Solution 
(Solution Concentration is 20 mg/mL) 
 
Note:  The tables listed below show unit doses of each maraviroc dose, which may or may not equal the 
total daily dose, depending on the dose frequency. Sections 5.3.1 and 5.3.2 include the dosing regimen for 
Cohort 1 (Stratum 2A or Stratum 2B) and Cohort 2 (Stratum 2A or Stratum 2B), respectively.  The 
selected table for any stratum dose adjustments for Cohort 1 and the dose and frequency for Cohort 2 
(Stratum 1A and Stratum 2B) will be communicated to study sites via a protocol Clarification 
Memorandum. If the Core Protocol Team determines that a stratum dose or dosing schedule adjustment is 
required and the appropriate dose is not included in the tables below, an updated dosing table will be 
provided through an appropriate mechanism. 
 
Table A – Dose of 2 mg/kg 
Weight Band (kg) 
2 mg/kg 
Volume (mL)  
 
Dose in (mg) 
Volume to Administer 
2.0-2.4 
5 mg 
0.25 mL 
2.5-3.4 
6 mg 
0.3 mL 
3.5-4.4 
8 mg 
0.4 mL 
4.5-5.4 
10 mg 
0.5 mL 
5.5-6.4 
12 mg 
0.6 mL 
 
Table B – Dose of 4 mg/kg 
Weight Band (kg) 
4 mg/kg 
Volume (mL) 
 
Dose in (mg) 
Volume to Administer 
2.0-2.4 
8 mg 
0.4 mL 
2.5-2.7 
10 mg 
0.5 mL 
2.8-3.1 
12 mg 
0.6 mL 
3.2-3.6 
14 mg 
0.7 mL 
3.7-4.1 
16 mg 
0.8 mL 
4.2-5.4 
20 mg 
1 mL 
5.5-6.0 
25 mg 
1.25 mL  (1/4 tsp) 
 
Table C – Dose of 6 mg/kg 
Weight Band (kg) 
6 mg/kg 
Volume (mL)  
 
Dose in (mg) 
Volume to Administer 
2.0-2.4 
14 mg 
0.7 mL 
2.5-2.9 
16 mg 
0.8 mL 
3.0-3.4 
20 mg 
1 mL 
3.5-3.9 
25 mg 
1.25 mL (1/4 tsp) 
4.0-4.9 
30 mg 
1.5 mL  
5.0-6.0 
40 mg 
2 mL 
 
Table D – Dose of 8 mg/kg 
Weight Band (kg) 
8 mg/kg 
Volume (mL)  
 
Dose in (mg) 
Volume to Administer 
2.0-2.5 
20 mg 
1 mL 
2.6-3.1 
25 mg 
1.25 mL (1/4 tsp) 
3.2-3.8 
30 mg 
1.5 mL 
3.9-5.0 
40 mg 
2 mL 
5.1-6.0 
50 mg 
2.5 mL (1/2 tsp) 
 


IMPAACT 2007, Version 1.0 
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13 April 2016  
Table E – Dose of 10 mg/kg 
Weight Band (kg) 
10 mg/kg 
Volume (mL)  
 
Dose in (mg) 
Volume to Administer 
2.0-2.4 
25 mg 
1.25 mL (1/4 tsp) 
2.5-2.9 
30 mg 
1.5 mL 
3.0-3.9 
40 mg 
2 mL 
4.0-4.9 
50 mg 
2.5 mL (1/2 tsp) 
5.0-6.0 
60 mg 
3 mL 
 
Table F – Dose of 12 mg/kg 
Weight Band (kg) 
12 mg/kg 
Volume (mL)  
 
Dose in (mg) 
Volume to Administer 
2.0-2.4 
30 mg 
1.5 mL 
2.5-3.3 
40 mg 
2 mL 
3.4-4.1 
50 mg 
2.5 mL (1/2 tsp) 
4.2-4.9 
60 mg 
3 mL 
5.0-6.0 
80 mg 
4 mL 
 
Table G – Dose of 14 mg/kg 
Weight Band (kg) 
14 mg/kg 
Volume (mL) 
 
Dose in (mg) 
Volume to Administer 
2.0-2.8 
40 mg 
2 mL 
2.9-3.5 
50 mg 
2.5 mL (1/2 tsp) 
3.6-4.2 
60 mg 
3 mL 
4.3-5.7 
80 mg 
4 mL 
5.8-6.0 
100 mg 
5 mL (1 tsp) 
 
Table H – Dose of 16 mg/kg 
Weight Band (kg) 
16 mg/kg 
Volume (mL)  
 
Dose in (mg) 
Volume to Administer 
2.0-2.4 
40 mg 
2 mL 
2.5-3.1 
50 mg 
2.5 mL (1/2 tsp) 
3.2-3.7 
60 mg 
3 mL 
3.8-4.9 
80 mg 
4 mL 
5.0-6.0 
100 mg 
5 mL (1 tsp) 
 
Table I – Dose of 18 mg/kg 
Weight Band (kg) 
18 mg/kg 
Volume (mL)  
 
Dose in (mg) 
Volume to Administer 
2.0-2.7 
50 mg 
2.5 mL (1/2 tsp) 
2.8-3.3 
60 mg 
3 mL 
3.4-4.4 
80 mg 
4 mL 
4.5-5.5 
100 mg 
5 mL (1 tsp) 
5.6-6.0 
120 mg 
6 mL 
 
Table J – Dose of 20 mg/kg 
Weight Band (kg) 
16 mg/kg 
Volume (mL)  
 
Dose in (mg) 
Volume to Administer 
2.0-2.4 
50 mg 
2.5 mL (1/2 tsp) 
2.5-2.9 
60 mg 
3 mL 
3.0-3.9 
80 mg 
4 mL 
4.0-4.9 
100 mg 
5 mL (1 tsp) 
5.0-6.0 
120 mg 
6 mL 


IMPAACT 2007, Version 1.0 
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13 April 2016  
Appendix III-A: Cohort 1 Sample Informed Consent Form for Study Participation 
 
IMPAACT 2007 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
VERSION 1.0, 13 April 2016  
 
You and your baby are being asked to participate in the research study named above. 
 
This form gives information about the study.  Please read it, or have it read to you, and ask any questions 
you may have.  We will take as much time as needed for you to fully understand the study.  We will ask 
you questions to see if we have explained the study clearly. 
 
After you understand the study, if you decide that you and your baby will participate, you will be asked to 
sign or make your mark on this form.  You will be offered a copy to keep. 
 
About the Study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [sites: 
insert site name] are doing this study to test an anti-HIV medicine (ARV) given to babies.   The medicine 
is called maraviroc. HIV is the virus that causes AIDS.   
 
You and your baby are being asked to participate in this study because you are infected with HIV and 
there is a risk that the infection may be passed onto your baby.  The transfer of HIV to newborn babies 
from HIV-infected mothers can occur at the time of birth.  
 
The study will include about 70 mothers who have HIV and their babies. Mothers will be in the study for 
up to 3 days and babies will be in the study for 4 months.  
 
The person in charge of the study at this clinic is [sites: insert name of Investigator of Record].  The 
United States National Institutes of Health is paying for the study. 
 
1. The study is being done to test the safety and blood levels of maraviroc in newborn babies. 
 
Babies born to mothers who have HIV usually take ARVs to prevent infection of HIV after birth.  There 
are not many ARVs available for babies because many ARVs have not yet been tested in babies. 
 
Maraviroc is an ARV that is used in adults in the United States and other countries. This study will look 
at whether maraviroc causes any bad side effects when given to newborn babies.  It will also look at 
different doses of maraviroc to find what amount of maraviroc should be given to protect newborns.  
 
2. It is your decision whether or not to join the study. 
 
Deciding to join the study with your baby is voluntary.  You are free to join or not join.  If you join, you 
can change your mind and leave the study at any time.  Your decision will have no effect on the medical 
care that you and your baby receive at this clinic.  Your access to services and the benefits and rights you 
normally have will not be affected.  
 
Take your time and consider your decision carefully.  If you wish, you can talk to other people about 
allowing your baby to join the study.  You can bring other people here to learn about the study with you. 


IMPAACT 2007, Version 1.0 
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13 April 2016  
 
No matter what you decide about the study, you must continue to take your anti-HIV medicines.  Your baby 
should also take anti-HIV medicine for 4-6 weeks after birth.  Taking these medicines is the best known way 
to maintain your health and avoid passing HIV to your baby while breastfeeding. 
 
3. Only mothers and their babies who qualify can participate in the study. 
 
If you decide to join the study with your baby, we will first do some tests to see if you and your baby 
qualify.  Some tests can be done while you are pregnant.  Other tests will be done after your baby is born. 
More information about the tests is given in #4 and #5. 
 
Finding out if you and your baby qualify 
 
4. We will ask questions and discuss the study requirements with you. 
 
To find out if you qualify for the study, we will:  
 
• 
Review your medical records. 
• 
Ask about your plans for feeding your baby and taking anti-HIV medicines after your baby is born. 
• 
Talk with you about the study requirements and if you are able to meet these requirements.   
• 
If needed, draw your blood (up to 10 mL or less than 2 teaspoons) for HIV testing. There are certain 
HIV tests that are required for mothers in this study. If the required tests are not in your medical 
records, we will do the tests that are needed.  
 
These procedures may be done while you are pregnant or within 3 days after your baby is born.   They 
will take 30-60 minutes [sites: modify how much time this visit will take as needed].   
 
If these procedures show that you may qualify for the study, you will be given contact information for the 
study staff.  We will stay in contact as you get closer to your delivery date and ask you to contact us when 
your labor begins.  We will not be involved in the delivery of your baby but will arrange to see you soon 
after your baby is born.  You are welcome to contact us or return to the clinic at any time to talk about the 
study. 
 
5. After delivery, we will collect more information and examine your baby. 
 
To find out if your baby qualifies for the study, as soon as possible after your baby is born, we will: 
 
• 
Review your and your baby’s medical records. 
• 
Ask about your and your baby’s anti-HIV medicines. 
• 
Ask about your baby’s health and other medicines.  
• 
Ask about how you are feeding your baby. 
• 
Give your baby a physical examination 
• 
Draw your baby’s blood (about 4.5 mL or 1 teaspoon).  These tests include:   
o A test to look at your baby’s blood cells. 
o A test to check  how well your baby’s liver is working 
o An HIV test.   
o A portion of the blood will be stored for future HIV-related tests. The samples that will be tested 
will be chosen after the study is completed.  You or the site investigator will not be told of the 
results because the test is for investigation only and will be done after the study is completed. We 
will ask you about saving these samples in a separate form.  
 


IMPAACT 2007, Version 1.0 
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13 April 2016  
These procedures will take about an hour. [sites: modify how much time this visit will take as needed].  
The results of some of your baby’s blood tests will be available within a couple of days.  We will 
review the results and all other information to determine if you and your baby qualify for the study.   
 
• 
If you and your baby do not qualify, we will tell you this and give you information on where you and 
your baby can receive medical care and other services you may need. We will destroy any of your 
blood remaining after testing. 
 
• 
If you and your baby do qualify, we will ask you to confirm your decision for you and your baby to 
join the study.  With your confirmation, you and your baby will be entered into the study.   
 
Entering the study 
 
6. If you and your baby qualify, you and your baby will enter the study within 3 days after the baby’s birth.  
 
On the day when you and your baby enter the study, we will: 
 
• 
Draw your blood (14 mL or about 3 teaspoons) to test the amount of HIV in your blood and for future 
HIV-related testing. 
• 
Ask about your health, anti-HIV medicines, and other medicines. 
• 
If you took the ARV called efavirenz within 2 weeks before your delivery, we will draw your baby’s 
blood (about 0.5 mL or a few drops) to test the amount of efavirenz in your baby’s blood.  
 
These procedures may take up to 3 days [sites: modify how much time this visit will take as needed].   
 
Your baby will receive his or her first dose of maraviroc and then have blood drawn to test the amount of 
maraviroc in the blood over the next 3 days. More information is given in #8 below.  
 
Being in the study 
 
7. After entering the study, your baby will have 4 scheduled visits over 4 months.    
 
Visits will be more frequent in the first 6 weeks.  During this time, your baby will have 3 visits, at 1, 
between 2 and 3, and 6 weeks.  After that your baby will have 1 more visit, at 4 months of age.    
 
Each visit will take about 1 to 2 hours [sites: modify how much time this visit will take as needed].  At 
these visits, we will:  
 
• 
Review your baby’s medical records and ask you about how your baby is doing and any side effects 
• 
Give your baby a physical examination 
• 
Draw your baby’s blood (2- 4 mL or less than 1 teaspoon) for tests.  These tests will check  
o Your baby’s blood cells  
o How well your baby’s liver is working. 
o If your baby has HIV 
o At one visit, if you took efavirenz within 2 weeks before delivery, we will draw your baby’s 
blood (about 0.5 mL or a few drops) to test the amount of efavirenz in your baby’s blood.  
 
These procedures will take about 1 to 2 hours [sites: modify how much time this visit will take as needed].  
Babies may have more visits if they are sick or if we need to do more tests to check on their health. 
 
8. Your baby will get 2 doses of maraviroc and participate in another study procedure.  This procedure will 
very closely measure the amount of maraviroc in their blood.   


IMPAACT 2007, Version 1.0 
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13 April 2016  
 
Your baby will also have blood drawn to very closely measure the amount of maraviroc in his or her 
blood.  This is called a pharmacokinetic (PK) test.  Your baby will only get two doses of maraviroc, one 
with each PK test. 
 
This PK test will happen within 3 days of your baby’s birth and at the Week 1 visit.  At these visits, you 
will bring your baby to the clinic and the study staff will give your baby maraviroc so that we know what 
time maraviroc was given.  This is called directly observed therapy. 
 
The first PK test (within 3 days of your baby’s birth) will require a clinic visit for 3 days.  Your baby will 
stay at the clinic for up to 13 hours after your baby takes maraviroc.  Then your baby will need to return 
to the clinic 2 more times at 20 - 24 and 48-72 hours after they took maraviroc.  [sites: modify If the study 
clinic is able, you may be allowed to stay at the clinic the night before and during your first PK visit.] 
 
The second PK test will happen at the Week 1 visit and take 2 separate days in a row.  Your baby will get 
a dose of maraviroc on the first day and a PK test will be started and the next day the PK test will be 
finished.  Your baby will need to return to the clinic 22 to 26 hours after they took maraviroc.  
 
[Sites: modify language as appropriate to indicate procedures for the intensive PK collection.  A small 
plastic tube (like a “drip”) will be placed in your baby’s arm to draw blood samples.  This tube is attached 
to a plastic needle so that we can draw blood several times.  We will not need to stick your baby with a 
needle each time.  The plastic tube will stay in place until all of the blood samples are drawn.]  
 
We will draw a few drops or about 0.5 mL of blood at 6 different time points during the first day for the 
PK test (a total of 3.0 mL or ½ teaspoon) and at 3 time points during the second part of the PK test (a total 
of about 1.5 mL or less than ½ teaspoon).  We will look at the amount of maraviroc in your baby’s blood 
at each of these times.   
 
9. Tests for how much maraviroc is in your baby’s blood will be done at different laboratories. 
 
We will do most of the HIV tests and tests to check your baby’s blood here at our laboratory, but some of 
the blood tests will be done elsewhere.  We will give you the results of these tests at the next scheduled 
visit, or sooner, if necessary.  We will explain the results and give you counseling and referrals as needed.  
 
The test to check the amount of maraviroc in your baby’s blood will be done at laboratories in the United 
States or in other countries.  Some tests may be done while the study is ongoing; others after the study is 
done.  
 
10. We may stop your baby’s maraviroc doses, one or both.  
 
We may stop giving your baby maraviroc if: 
 
• 
Your baby is not able to come to the study visits. 
• 
Your baby is not able to take maraviroc.  
• 
Your baby becomes infected with HIV. 
• 
Continuing maraviroc may be harmful to your baby. 
• 
You request to stop the maraviroc for your baby. 
 
Even if your baby stops taking maraviroc, your baby will stay in the study, with the same schedule of 
visits.   
 


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13 April 2016  
If an HIV test that we do for the study shows that your baby has HIV infection, we will ask you to bring 
your baby to the clinic for another test.  Your baby will not receive maraviroc and your baby will have 
additional blood drawn (6 mL or a little more than 1 teaspoon) for another HIV test to see if your baby 
truly is infected and to test for resistance to the study medicine.  If the second test confirms HIV infection, 
your baby will stay in the study, with the same schedule of visits, but will be taken off maraviroc. At 
these visits your baby will have all procedures done except HIV testing and testing for how much 
maraviroc is in his/her blood.  The study cannot provide care and treatment for babies with HIV infection, 
but we will give information, counseling, and referrals to where your baby can get the care and treatment 
they need.  
 
11. We may take you and your baby off the study if: 
 
• 
The study is stopped for any reason. 
• 
We determine that you and your baby cannot meet the study requirements (for example, if you move 
away and cannot come to the clinic). 
• 
We determine that staying in the study might harm you and your baby. 
 
12.  Please tell us if you wish you and your baby to leave the study. 
 
You and your baby are free to leave the study at any time for any reason.  The care that you and your 
baby receive at this clinic will not be affected, but it is important for us to know about your decision.  We 
will ask you to bring your baby to the clinic for one last visit.  At this visit, we will ask questions about 
your baby’s health and medicines, give your baby a physical examination, and draw your baby’s blood 
(less than 1 teaspoon) for tests.  We will answer any questions you may have and give you information on 
how to contact us in the future, if you wish. 
 
Risks of the study 
 
13. There is little risk from the study procedures. 
 
Most procedures done in this study are routine medical procedures, with little risk to you and your baby.  
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted.  Rarely, 
drawing blood can cause fainting or infection. 
 
14. There are some risks from maraviroc.    
 
Maraviroc (MVC, Selzentry®) is like any other medication or drug and may have side effects.  Some of 
the most common or most serious effects are listed below.  The list does not include all of the possible 
side effects.  These lists include the more serious or common side effects with a known or possible 
relationship.  If you have questions about side effects not included in these lists, you can ask us.   
 
If your baby joins the study, we will tell you about the side effects of maraviroc that your baby will take.  
We will also check for any side effects during the visits and tell you what to do if your baby has any side 
effects. 
 
15. We will tell you about the most severe side effects first.  
 
First, you should know about the possible severe side effects.  These effects are rare, but they can cause 
serious health problems and can result in death: 
 
• 
Liver problems.  The liver is an organ near the stomach.  If your baby gets liver problems, he or she 
might have a rash on your baby’s body; yellowing of the skin or whites of the eyes; dark or tea 


IMPAACT 2007, Version 1.0 
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13 April 2016  
colored urine; upset stomach or vomiting; or loss of appetite.  If your baby develops any of these 
symptoms, stop maraviroc and contact your baby’s doctor immediately.    
 
• 
Heart problems, including a heart attack.  
 
• 
Low blood pressure problems.  Low blood pressure may cause your baby to be dizzy or faint.  If your 
baby has kidney problems, he or she may be at an increased risk for low blood pressure.  The kidneys 
are organs near the middle of the back and there is one kidney on each site of the body.  Doctors 
usually find out about kidney problems from blood tests.   
 
• 
Stroke 
 
16. There are also more common and not severe side effects from maraviroc.   
 
You should also know about the more common side effects.  These side effects are not severe.  There are 
many possible mild and moderate side effects.  The most common ones are listed below: 
 
Overall Body Effects 
• 
Swelling of parts of the body 
• 
Some infections, including herpes, colds, sore 
throat, flu and flu-like symptoms 
• 
Muscle aches, spasms and pain  
• 
Fever 
• 
Rash 
• 
Colds 
• 
Cough 
• 
Runny, congested nose 
Effects on Your Child’s Activity 
• 
Sleeping problems 
• 
Dizziness 
Effects on Your Child’s Belly 
• 
Stomach pain or bloating 
• 
Diarrhea 
Effects on Your Child’s Bladder 
• 
Problems with urination 
Effects on Your Child’s Blood 
• 
Low amounts of white blood cell counts 
(neutropenia), which could lead to risk of 
infection 
 
The list above is not a complete list of all side effects for maraviroc.  As a reminder, if your baby joins the 
study, we will tell you about the side effects of maraviroc your baby will take. 
 
Note: Because of how maraviroc works in your baby’s body, there is a possible increased risk your baby 
may get other infections or cancer.  However, there is no evidence from clinical studies of an increase in 
serious infections or cancer. 
 
Maraviroc contains soy lecithin.  If your baby has or develops an allergy to soy (soya or soybeans) or 
peanuts, your baby may develop an allergic reaction to maraviroc. If your baby is allergic to soy or 
peanuts, please tell your baby’s doctor immediately.  
 
17. There may be other possible risks from maraviroc.  
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain 
diseases may occur soon after starting combination ARVs but can also occur later.  Some of these 
symptoms may be life threatening.  If your baby starts having new symptoms, or if you notice that your 
baby’s existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 


IMPAACT 2007, Version 1.0 
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13 April 2016  
 
The use of some strong ARV combinations may be related to unusual position of body fat and weight 
loss.  Some of the body changes may include body fat increasing around the abdomen, stomach area, 
chest or neck or body fat decreasing in the face, legs, or arms.  
 
Risk of resistance 
 
All ARVs can cause some resistance.  Resistance means that the ARVs may not work against HIV if it is 
taken again in the future.  To stop resistance, it is important that you give your baby the study medicine 
and ARVs as instructed, and do not miss any doses.   
 
18. There could be risks of disclosure of you and your baby’s information. 
 
We will make every effort to keep your baby’s information private and confidential.  Study records and 
specimens will be kept in secure locations.  All specimens and most records will be labeled only with a 
code number.  However, you and your baby’s names will be written on some records.  Despite our best 
efforts to keep you and your baby’s information private, it is possible that the information could be 
obtained by someone who should not have it.  If this were to happen, you and your baby could be treated 
badly or unfairly.  You could feel stress or embarrassment.   
 
[US sites, insert: To help us protect your privacy, we have obtained a Certificate of Confidentiality that 
protects us from being forced to release information that may identify you, such as by the courts or police. 
The certificate cannot be used in all situations, but it can be used to resist demands for information that 
would identify you. The certificate does not protect against requests for information from the US federal 
government or from the US Food and Drug Administration. Regardless of the certificate, you can release 
information about your participation in the study to others, if you wish.] 
 
Benefits of the study 
 
19. There may or may not be a benefit to your baby from being in the study. 
 
By joining the study, you and your baby will be part of the search for anti-HIV medicines that may be 
better for your baby.  There may or may not be a direct benefit to you or your baby by participating in this 
study. Your baby will have regular visits here and frequent checks on his or her health, including tests for 
HIV in your baby’s blood.  Information learned from this study may help other babies born to HIV-
infected mothers at risk of HIV infection. 
 
Other information about the study 
 
20. There are no costs to you or your baby for being in the study. 
 
There are no costs to you or your baby for study visits, maraviroc, or procedures.  [Sites: insert 
information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits.  For each visit, you will be given (specify amount).] 
 
21. You and your baby’s study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include: 
• 
[insert name of site IRB/EC] 
• 
[insert name of other site drug entities that may review records] 


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13 April 2016  
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Office for Human Research Protections 
• 
The US Food and Drug Administration 
• 
The IMPAACT Network that is coordinating the study 
• 
The companies that make maraviroc (PHIVCO) 
 
Like the study staff, these groups are required to make efforts to keep study records private and 
confidential. 
 
The results of the study may be presented publicly or published.  However, no presentation or publication 
will use your baby’s name or identify your baby personally.  A description of this study will be available 
on ClinicalTrials.gov.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this website at any time. 
 
You and your baby’s study information may be disclosed to other authorities if required by law.  
22. If you or your baby gets sick or injured, contact us immediately. 
 
You and your baby’s health is important to us.  We will make every effort to protect you and your baby’s 
well-being and minimize risks to you and your baby.  It is possible, however, that your baby could have 
an illness or injury that is study-related.  This means that the illness or injury occurred as a direct result of 
the study procedures.   
 
If a study-related illness or injury occurs, we will treat your baby or tell you where you can get the 
treatment your baby needs.  The cost for this treatment may be charged to you or your insurance 
company.  There is no program for compensation either through this institution or the National Institutes 
of Health. 
 
Who to contact 
 
23. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study, contact:  
[sites: insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about you and your baby’s rights as a research participant, or problems or 
concerns about how you and your baby are being treated in the study, contact:  
[sites: insert name and telephone number of IRB contact person or other appropriate 
person/organization] 
 
• 
If you or your baby has any health or other problems that may be related to his or her study 
participation, contact:  
[sites: insert name and telephone number of investigator or other study staff] 
 
• 
If you or your baby want to leave the study, contact:  
[sites: insert name and telephone number of investigator or other study staff] 
 
 
 
 
 
 
 


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13 April 2016  
Signatures 
 
24. If you agree to participate in this study, and your baby, please sign or make your mark below. 
 
Before deciding whether to join this study with your baby, make sure you have read this form, or had it 
read to you, and that all of your questions have been answered.  You should feel that you understand the 
study, its risks and benefits, and what is expected of you and your baby if you decide to join.  
 
If you decide to allow your baby to join, we will tell you any new information from this study or other 
studies that may affect your willingness for your baby to stay in the study.  You are welcome to ask 
questions or request more information at any time.   
 
You do not give up any rights by signing this form. 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent’s Name (print) 
 
 
Parent’s Signature 
  
 
Date 
(Or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 
(As appropriate) 
 
 
 


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Appendix III-B: Cohort 2 Sample Informed Consent Form for Study Participation 
 
IMPAACT 2007 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
VERSION 1.0, 13 April 2016 
 
 
You and your baby are being asked to participate in the research study named above. 
 
This form gives information about the study.  Please read it, or have it read to you, and ask any questions 
you may have.  We will take as much time as needed for you to fully understand the study.  We will ask 
you questions to see if we have explained the study clearly. 
 
After you understand the study, if you decide that you and your baby will participate, you will be asked to 
sign or make your mark on this form.  You will be offered a copy to keep. 
 
About the Study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [sites: 
insert site name] are doing this study to test an anti-HIV medicine (ARV) given to babies.  The medicine 
is called maraviroc. HIV is the virus that causes AIDS.   
 
You and your baby are being asked to participate in this study because you are infected with HIV and 
there is a risk that the infection may be passed onto your baby.  The transfer of HIV to newborn babies 
from HIV-infected mothers can occur at the time of birth.  
 
The study will include about 70 mothers who have HIV and their babies..  Your baby will receive the 
anti-HIV medicine being tested.  Mothers will be in the study for up to 3 days and babies will be in the 
study for 4 months. 
 
The person in charge of the study at this clinic is [sites: insert name of Investigator of Record].  The 
United States National Institutes of Health is paying for this study.  
 
1. The study is being done to test the safety and blood levels of maraviroc in newborn babies 
 
Babies born to mothers who have HIV usually take ARVs to prevent infection of HIV after birth.  There 
are not many ARVs available for babies because many ARVs have not yet been tested in babies.  
 
Maraviroc is an ARV that is used in adults in the United States and other countries. This study will look 
at whether maraviroc causes any bad side effects when given to newborn babies.  It will also look at 
different doses of maraviroc to find what amount of maraviroc should be given to protect newborns.  
 
2. It is your decision whether or not to join the study. 
 
Deciding to join the study with your baby is voluntary.  You are free to join or not join.  If you join, you 
can change your mind and leave the study at any time.  Your decision will have no effect on the medical 
care that you and your baby receive at this clinic.  Your access to services and the benefits and rights you 
normally have will not be affected.  


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13 April 2016  
 
Take your time and consider your decision carefully.  If you wish, you can talk to other people about 
allowing your baby to join the study.  You can bring other people here to learn about the study with you. 
 
No matter what you decide about the study, you must continue to take your anti-HIV medicines.  Your baby 
should also take anti-HIV medicine for 4-6 weeks after birth.  Taking these medicines is the best known way 
to maintain your health and avoid passing HIV to your baby while breastfeeding. 
 
3. Only mothers and their babies who qualify can participate in the study. 
 
If you decide to join the study with your baby, we will first do some tests to see if you and your baby 
qualify.  Some tests can be done while you are pregnant.  Other tests will be done after your baby is born. 
More information about the tests is given in #4 and #5. 
 
Finding out if you and your baby qualify 
 
4. We will ask questions and discuss the study requirements with you. 
 
To find out if you qualify for the study, we will:  
 
• 
Review your medical records. 
• 
Ask about your plans for feeding your baby and taking anti-HIV medicines after your baby is born. 
• 
Talk with you about the study requirements and if you are able to meet these requirements.   
• 
If needed, draw your blood (up to 10 mL or 2 teaspoons) for HIV testing. There are certain HIV tests 
that are required for mothers in this study. If the required tests are not in your medical records, we 
will do the tests that are needed.  
 
These procedures may be done while you are pregnant or within 3 days after your baby is born.  They will 
take 30-60 minutes. [sites: modify how much time this visit will take as needed].   
 
If these procedures show that you may qualify for the study, you will be given contact information for the 
study staff.  We will stay in contact as you get closer to your delivery date and ask you to contact us when 
your labor begins.  We will not be involved in the delivery of your baby but will arrange to see you soon 
after your baby is born.  You are welcome to contact us or return to the clinic at any time to talk about the 
study. 
 
5. After delivery, we will collect more information and examine your baby. 
 
To find out if your baby qualifies for the study, as soon as possible after your baby is born, we will: 
 
• 
Review your and your baby’s medical records. 
• 
Ask about your and your baby’s anti-HIV medicines. 
• 
Ask about your baby’s health and other medicines.  
• 
Ask about how you are feeding your baby. 
• 
Give your baby a physical examination 
• 
Draw your baby’s blood (about 4.5 mL or 1 teaspoon) for tests.  These tests include:  
o A test to look at your baby’s blood cells 
o A test to check how well your baby’s liver is working 
o An HIV test 
o A portion of the blood will be stored for future HIV-related tests. The samples that will be tested 
will be chosen after the study is completed.  You or the site investigator will not be told of the 


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results because the test is for investigation only and will be done after the study is completed. We 
will ask you about saving these samples in a separate form.  
 
These procedures will take about an hour [sites: modify how much time this visit will take as needed].  
The results of some of your baby’s blood tests will be available within a couple of days.  We will 
review the results and all other information to determine if you and your baby qualify for the study.   
 
• 
If you and your baby do not qualify, we will tell you this and give you information on where you and 
your baby can receive medical care and other services you may need. We will destroy any of your 
blood remaining after testing. 
 
• 
If you and your baby do qualify, we will ask you to confirm your decision for you and your baby to 
join the study.  With your confirmation, you and your baby will be entered into the study.   
 
Entering the study 
 
6. If you and your baby qualify, you and your baby will enter the study within 3 days after the baby’s birth.  
 
On the day when you and your baby enter the study, we will: 
 
• 
Draw your blood (14 mL or about 3 teaspoons) to test the amount of HIV in your blood and for future 
testing. 
• 
Ask about your health, anti-HIV medicines, and other medicines. 
 
These procedures may take up to 3 days [sites: modify how much time this visit will take as needed].   
 
Your baby will also receive his or her first dose of maraviroc during this visit.  We will show you how to 
give maraviroc to your baby.  It is very important that you give your baby maraviroc as instructed.  We 
will take as much time as needed for you to understand the instructions and identify strategies that will 
help you to give the study medicine to your baby as instructed. 
 
Being in the study 
 
7. After entering the study, your baby will have 5 scheduled visits over 4 months.    
 
Visits will be more frequent in the first 12 weeks.  During this time, your baby will have 4 visits, at 1, 4, 
6, and 12 weeks.  After that your baby will have 1 more visit at 4 months of age.    
 
Each visit will take about 1 to 2 hours [sites: modify how much time this visit will take as needed].  At 
these visits, we will:  
 
• 
Review your baby’s medical records and ask you about how your baby is doing and any side effects 
• 
Give your baby a physical examination 
• 
Draw your baby’s blood (1.5 mL - 4.5 mL or less than 1 teaspoon) for tests. These tests will check:  
o Your baby’s blood cells  
o How well your baby’s liver is working. 
o If your baby has HIV 
o If you took efavirenz within 2 weeks before delivery, we will draw your baby’s blood (about 
0.5 mL or a few drops) to test the amount of efavirenz in your baby’s blood.  
 
These procedures will take about 1 to 2 hours [sites: modify how much time this visit will take as needed].  
Babies may have more visits if they are sick or if we need to do more tests to check on their health. 


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13 April 2016  
 
8. Your baby will also participate in another study procedure.  This procedure will very closely measure the 
amount of maraviroc in their blood.   
 
Your baby will also have blood drawn to very closely measure the amount of maraviroc in his or her 
blood.  This is called a pharmacokinetic (PK) test.  There will be two of these tests.   
 
This collection will happen at the Week 1 and 4 visits. You must give your baby the medicine exactly as 
instructed and not miss but on the day of these visits, we will ask that you not give your baby maraviroc 
at home before coming to the clinic.  Your baby will be given maraviroc at the clinic, so that we know 
what time and the exact amount of maraviroc he or she took. This is called directly observed therapy. 
 
For the PK test, your baby will stay at the clinic for up to 13 hours after your baby takes maraviroc. If 
your baby is taking maraviroc two times a day, your baby will need to return to the clinic 20 - 24 hours 
after they took the medicine.  If your baby is taking maraviroc only once a day, your baby will not need to 
return to the clinic.  The study doctor will tell you how often your baby will take the medicine before the 
visit. 
 
[Sites: modify language as appropriate to indicate procedures for the intensive PK collection.  A small 
plastic tube (like a “drip”) will be placed in your baby’s arm to draw blood samples.  This tube is attached 
to a plastic needle so that we can draw blood several times.  We will not need to stick your baby with a 
needle each time.  The plastic tube will stay in place until all of the blood samples are drawn.]  
 
We will draw a few drops, about 0.5 mL of blood at 5 different time points at each PK test (a total of 2.5 
mL or ½ teaspoon).  We will look at the amount of study medicine in your baby’s blood at each of these 
times.   
 
At 6 weeks after birth your baby will also have one sample of blood drawn to measure the amount of 
maraviroc in his or her blood.  At this visit, it is important that you can tell study staff the exact time you 
gave the study medicine to your child. We will draw about 0.5 mL (a few drops of blood) for this test.  
 
9. Tests for how much of the study medicine is in your baby’s blood will be done at different laboratories. 
 
We will do most of the HIV tests and tests to check your baby’s blood here at our laboratory, but some of 
the blood tests will be done elsewhere.  We will give you the results of these tests at the next scheduled 
visit, or sooner, if necessary.  We will explain the results and give you counseling and referrals as needed.  
 
We will also draw blood for resistance and to check the amount of maraviroc in your baby’s blood here in 
the clinic.  These tests will be done at different laboratories in the United States.  Some tests may be done 
while the study is ongoing; others after the study is done.  We will try to give you the results of these tests 
when they have been tested during the study or after the study is over.   
 
10. We may stop your baby’s maraviroc.  
 
We may stop your baby’s study medicine if: 
 
• 
Your baby is not able to come to the study visits. 
• 
Your baby is not able to take the study medicine. 
• 
Your baby becomes infected with HIV. 
• 
Continuing maraviroc may be harmful to your baby. 
• 
You request to stop the maraviroc for your baby. 
 


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13 April 2016  
Even if your baby stops the study medicine, your baby will stay in the study, with the same schedule of 
visits.   
If an HIV test that we do for the study shows that your baby has HIV infection, we will ask you to bring 
your baby to the clinic for another test.  Your baby will not receive maraviroc and your baby will have 
additional blood drawn (6 mL or a little more than 1 teaspoon) for another HIV test to see if your baby 
truly is infected and to test for resistance to maraviroc.  If the second test confirms HIV infection, your 
baby will stay in the study, with the same schedule of visits, but will be taken off the study medicine. At 
these visits your baby will have all procedures done except HIV testing and testing for how much 
maraviroc is in his or her blood.   The study cannot provide care and treatment for babies with HIV 
infection, but we will give information, counseling, and referrals to where your baby can get the care and 
treatment they need.   
 
11.  We may take you and your baby off the study if: 
 
• 
The study is stopped for any reason. 
• 
We determine that you and your baby cannot meet the study requirements (for example, if you move 
away and cannot come to the clinic). 
• 
We determine that staying in the study might harm you and your baby. 
 
12.  Please tell us if you wish you and your baby to leave the study. 
 
You and your baby are free to leave the study at any time for any reason.  The care that you and your 
baby receive at this clinic will not be affected, but it is important for us to know about your decision.  We 
will ask you to bring your baby to the clinic for one last visit.  At this visit we will ask questions about 
your baby’s health and medicines, give your baby a physical examination, and draw your baby’s blood 
(less than 1 teaspoon) for tests.  We will answer any questions you may have and give you information on 
how to contact us in the future, if you wish. 
 
Risks of the study 
 
13. There is little risk from the study procedures. 
 
Most procedures done in this study are routine medical procedures, with little risk to you and your baby.  
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted.  Rarely, 
drawing blood can cause fainting or infection. 
 
14. There are some risks from maraviroc.   
 
Maraviroc (MVC, Selzentry®) is like any other medication or drug and may have side effects.  Some of 
the most common or most serious effects are listed below.  The list does not include all of the possible 
side effects.  These lists include the more serious or common side effects with a known or possible 
relationship.  If you have questions about side effects not included in these lists, you can ask us.   
 
If your baby joins the study, we will tell you about the side effects of maraviroc that your baby will take.  
We will also check for any side effects during the visits and tell you what to do if your baby has any side 
effects. 
 
15. We will tell you about the most severe side effects first.  
 
First, you should know about the possible severe side effects.  These effects are rare, but they can cause 
serious health problems and can result in death: 
 


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13 April 2016  
• 
Liver problems.  The liver is an organ near the stomach.  If your baby gets liver problems, he or she 
might have a rash on your baby’s body; yellowing of the skin or whites of the eyes; dark or tea 
colored urine; upset stomach or vomiting; or loss of appetite.  If your baby develops any of these 
symptoms, stop maraviroc and contact your baby’s doctor immediately.    
 
• 
Heart problems, including a heart attack.  
 
• 
Low blood pressure problems.  Low blood pressure may cause your baby to be dizzy or faint.  If your 
baby has kidney problems, he or she may be at an increased risk for low blood pressure.  The kidneys 
are organs near the middle of the back and there is one kidney on each site of the body.  Doctors 
usually find out about kidney problems from blood tests.   
 
• 
Stroke 
 
16. There are also more common and not severe side effects from maraviroc.  
 
You should also know about the more common side effects.  These side effects are not severe.  There are 
many possible mild and moderate side effects.  The most common ones are listed below: 
 
Overall Body Effects 
• 
Swelling of parts of the body 
• 
Some infections, including herpes, colds, sore 
throat, flu and flu-like symptoms 
• 
Muscle aches, spasms and pain  
• 
Fever 
• 
Rash 
• 
Colds 
• 
Cough 
• 
Runny, congested nose 
Effects on Your Child’s Activity 
• 
Sleeping problems 
• 
Dizziness 
Effects on Your Child’s Belly 
• 
Stomach pain or bloating 
• 
Diarrhea 
Effects on Your Child’s Bladder 
• 
Problems with urination 
Effects on Your Child’s Blood 
• 
Low amounts of white blood cell counts 
(neutropenia), which could lead to risk of 
infection 
 
The list above is not a complete list of all side effects for maraviroc. As a reminder, if your baby joins the 
study, we will tell you about the side effects of maraviroc your baby will take. 
 
Note: Because of how maraviroc works in your baby’s body, there is a possible increased risk your baby 
may get other infections or cancer.  However, there is no evidence from clinical studies of an increase in 
serious infections or cancer. 
 
Maraviroc contains soy lecithin.  If your baby has or develops an allergy to soy (soya or soybeans) or 
peanuts, your baby may develop an allergic reaction to maraviroc. If your baby is allergic to soy or 
peanuts, please tell your baby’s doctor immediately.  
 
17. There may be other possible risks of maraviroc. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain 
diseases may occur soon after starting combination ARVs but can also occur later.  Some of these 


IMPAACT 2007, Version 1.0 
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13 April 2016  
symptoms may be life threatening.  If your baby starts having new symptoms, or if you notice that your 
baby’s existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 
 
The use of some strong ARV combinations may be related to unusual position of body fat and weight 
loss.  Some of the body changes may include body fat increasing around the abdomen, stomach area, 
chest or neck or body fat decreasing in the face, legs, or arms.  
 
Risk of resistance 
 
All ARVs can cause some resistance.  Resistance means that the ARVs may not work against HIV if it is 
taken again in the future.  To stop resistance, it is important that you give your baby the study medicine 
and ARVs as instructed, and do not miss any doses.   
 
18. There could be risks of disclosure of you and your baby’s information. 
 
We will make every effort to keep your baby’s information private and confidential.  Study records and 
specimens will be kept in secure locations.  All specimens and most records will be labeled only with a 
code number.  However, you and your baby’s names will be written on some records.  Despite our best 
efforts to keep you and your baby’s information private, it is possible that the information could be 
obtained by someone who should not have it.  If this were to happen, you and your baby could be treated 
badly or unfairly.  You could feel stress or embarrassment.   
 
[US sites, insert: To help us protect your privacy, we have obtained a Certificate of Confidentiality that 
protects us from being forced to release information that may identify you, such as by the courts or police. 
The certificate cannot be used in all situations, but it can be used to resist demands for information that 
would identify you. The certificate does not protect against requests for information from the US federal 
government or from the US Food and Drug Administration. Regardless of the certificate, you can release 
information about your participation in the study to others, if you wish.] 
 
 
Benefits of the study 
 
19. There may or may not be a benefit to your baby from being in the study. 
 
By joining the study, you and your baby will be part of the search for anti-HIV medicines that may be 
better for your baby.  There may or may not be a direct benefit to you or your baby by participating in this 
study. Your baby will have regular visits here and frequent checks on his or her health, including tests for 
HIV in your baby’s blood.  Information learned from this study may help other babies born to HIV-
infected mothers at risk of HIV infection. 
 
Other information about the study 
 
20. There are no costs to you or your baby for being in the study. 
 
There are no costs to you or your baby for study visits, maraviroc, or procedures.  [Sites: insert 
information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits.  For each visit, you will be given (specify amount).] 
 


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21. You and your baby’s study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include: 
• 
[insert name of site IRB/EC] 
• 
[insert name of other site drug entities that may review records] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Office for Human Research Protections 
• 
The US Food and Drug Administration 
• 
The IMPAACT Network that is coordinating the study 
• 
The companies that make the study medicine (PHIVCO) 
 
Like the study staff, these groups are required to make efforts to keep study records private and 
confidential. 
 
The results of the study may be presented publicly or published.  However, no presentation or publication 
will use your baby’s name or identify your baby personally.  A description of this study will be available 
on ClinicalTrials.gov.  This website will not include information that can identify you.  At most, the 
website will include a summary of the results.  You can search this website at any time. 
 
You and your baby’s study information may be disclosed to other authorities if required by law.  
 
22. If you or your baby gets sick or injured, contact us immediately. 
 
You and your baby’s health is important to us.  We will make every effort to protect you and your baby’s 
well-being and minimize risks to you and your baby.  It is possible, however, that your baby could have 
an illness or injury that is study-related.  This means that the illness or injury occurred as a direct result of 
the study procedures.   
 
If a study-related illness or injury occurs, we will treat your baby or tell you where you can get the 
treatment your baby needs.  The cost for this treatment may be charged to you or your insurance 
company.  There is no program for compensation either through this institution or the National Institutes 
of Health. 
 
Who to contact 
 
23. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study, contact:  
[sites: insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about you and your baby’s rights as a research participant, or problems or 
concerns about how you and your baby are being treated in the study, contact:  
[sites: insert name and telephone number of IRB contact person or other appropriate 
person/organization] 
 
• 
If you or your baby has any health or other problems that may be related to his or her study 
participation, contact:  
[sites: insert name and telephone number of investigator or other study staff] 
 
• 
If you or your baby want to leave the study, contact:  
[sites: insert name and telephone number of investigator or other study staff] 


IMPAACT 2007, Version 1.0 
 Page 90 of 93 
 
 
13 April 2016  
 
Signatures 
 
24. If you agree to participate in this study, and your baby, please sign or make your mark below. 
 
Before deciding whether to join this study with your baby, make sure you have read this form, or had it 
read to you, and that all of your questions have been answered.  You should feel that you understand the 
study, its risks and benefits, and what is expected of you and your baby if you decide to join.  
 
If you decide to allow your baby to join, we will tell you any new information from this study or other 
studies that may affect your willingness for your baby to stay in the study.  You are welcome to ask 
questions or request more information at any time.   
 
You do not give up any rights by signing this form. 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent’s Name (print) 
 
 
Parent’s Signature 
  
 
Date 
(Or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 
(As appropriate) 
 
 
 
 
 


IMPAACT 2007, Version 1.0 
 Page 91 of 93 
 
 
13 April 2016  
Appendix IV: Sample Informed Consent Form for Specimen Storage and Future 
Use 
 
IMPAACT 2007 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
VERSION 1.0, 13 April 2016  
 
 
You have decided to allow you and your baby to join the study named above.  As part of the study, you 
and your baby will have blood drawn.  After these samples are tested for the study, there may be some 
samples that are left over.  We call these extra samples.  The IMPAACT Network would like to keep 
these extra samples and use them for other research in the future. 
 
This form gives information about the use of extra samples.  Please read it, or have it read to you, and ask 
any questions you may have.  After we discuss the information with you, you will record your decisions 
on use of extra samples at the end of the form.  
 
1. It is your decision whether or not to allow the extra samples to be used.  
 
You are free to say yes or no, or to change your mind at any time.  Your decision will not affect your or 
your baby’s participation in the study.  If you say no, all extra samples will be destroyed.  
 
2. If you agree, you and your baby’s extra samples will be kept in a repository.  
 
A repository is a secure facility that is used to store samples.  The IMPAACT Network repository is in the 
United States.  There is no limit on how long the samples will be kept [sites may insert time limits or 
additional site-specific requirements here if required by local authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, the immune system, and other diseases.  The research 
may be done in the United States or in other locations.  
 
If you agree, the extra samples could also be used for research that looks at you or your baby’s genes.   
 
Any research done with the extra samples must be reviewed and approved by the IMPAACT Network.  
The research must also be approved by an ethics committee.  The role of an ethics committee is to review 
the research plan and protect the rights and well-being of the persons whose samples will be used.   
 
4. There is little risk to you and your baby.  
 
When extra samples are used for research, they are labeled with a code number only.  To protect you and 
your baby’s privacy, no names are used.  However, information such as age, gender, HIV status, and 
other health information may be linked to the samples.  Information on which study medicines your baby 
received and your baby’s immune system responses to the study medicines may also be linked to the 
samples.  
 
There may be some risks from tests of you and your baby’s genes.  If others found out the results of these 
tests, they could treat you or your baby badly or unfairly.  However, this is almost impossible because the 


IMPAACT 2007, Version 1.0 
 Page 92 of 93 
 
 
13 April 2016  
results of these tests will not be in you and your baby’s study records and they will not be given to you or 
your baby. 
 
5. There will be no benefit to you and your baby.  
 
The research done with extra samples is not expected to give any information relevant to you and your 
baby’s health.  The results will not be given to you and your baby and will not be part of your or your 
baby’s study records.  
 
6. You and your baby will not be paid for use of you and your baby’s samples. 
 
There is no cost to you and your baby for use of you and your baby’s extra samples.  The samples will not 
be sold and you and your baby will not be paid for use of the samples.  It is possible that research done 
with the samples could lead to a new discovery or a new product.  If this happens, there is no plan to share 
any money with you or your baby.  
 
7. Information from research using extra samples may be reviewed by groups that oversee the research. 
 
These groups include:   
 
• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
 
The people who do research with the extra samples and the groups listed above are required to make 
efforts to information private and confidential. 
 
The results of research done with extra samples may be presented publicly or published.  However, no 
presentation or publication will use you and your baby’s name or identify you and your baby personally.   
 
8. If you have any questions, concerns, or problems related to you and your baby’s extra samples, use these 
contacts. 
 
• 
If you have questions about use of you and your baby’s extra samples, contact:  
[sites insert name and telephone number of investigator or other study staff].  
 
• 
If you later change your mind about use of you and your baby’s extra samples, contact:  
[sites insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your and your baby’s rights as a research participant, or problems or 
concerns about how your baby is being treated in the study, contact:  
[sites insert name and telephone number of IRB contact person or other appropriate 
person/organization].  
 
 
 
 
 


IMPAACT 2007, Version 1.0 
 Page 93 of 93 
 
 
13 April 2016  
Signatures 
 
9. If you agree to let you and your baby’s extra samples be used, please sign or make your mark below. 
 
__________ 
I agree to the storage and use of my extra samples and my baby’s extra samples to be 
used for research on HIV, the immune system, and other diseases.  I also allow my 
samples and my baby’s samples to be used for tests of my genes and his or her genes.   
 
__________ 
I agree to the storage and use of my extra samples and my baby’s extra samples to be 
used for research on HIV, the immune system, and other diseases.  I do not allow my 
samples and my baby’s samples to be used for tests of my genes or his or her genes.   
 
__________ 
I do not allow my extra samples or my baby’s extra samples to be used for any research.   
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent’s Name (print) 
 
 
Parent’s Signature 
  
 
Date 
(Or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 
(As appropriate) 
 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
 
 
This is IMPAACT 2007 SAP Version 2.0 with names of authors, names of publication, writing 
team members, and analysis timeline redacted 
 
 
Statistical Analysis Plan 
Version 2.0  
 
 
 
 
IMPAACT 2007 
 
Phase I Safety and Pharmacokinetic Study of Maraviroc in HIV-1-Exposed Infants 
at Risk of Acquiring HIV-1 Infection 
 
 
NCT: 02778204 
 
 
 
 
 
 
 
June 11, 2018 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            2  
 
 
 
 
DOCUMENT ADMINISTRATION 
 
General Information  
Protocol Document Definition  
 
IMPAACT 2007 Statistical Analysis Plan 
Version 2.0, June 11, 2018 
Related Documents 
IMPAACT 2007 (DAIDS Document ID 20734, IND 
130,613) Phase I Safety and Pharmacokinetic Study 
of Maraviroc in HIV-1-Exposed Infants at Risk of 
Acquiring HIV-1 Infection, International Trial of the 
International Maternal Pediatric Adolescent AIDS 
Clinical Trials (IMPAACT) Network,  
Final Version 1.0, Date: 13 April 2016 
 
Letter of Amendment #1 dated 12 August 
2016 for: IMPAACT 2007 Version 1.0. 
 
Clarification Memo #1, dated 17 May 2017 
for: IMPAACT 2007 Version 1.0. 
 
Letter of Amendment #2 dated 21 May 2018 
for: IMPAACT 2007 Version 1.0 
 
Document owner  
SDAC/HSPH 
Version History 
Version 1.0, October 31, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            3  
 
 
Table of Contents 
1 
Purpose of the Analysis Plan .......................................................................................... 5 
2 
Protocol Overview .......................................................................................................... 6 
2.1 
Study Population ...........................................................................................................6 
2.2 
Sample Size ....................................................................................................................6 
2.3 
Stratification ...................................................................................................................6 
2.4 
Study Drug ......................................................................................................................7 
2.5 
Study Duration ...............................................................................................................7 
2.6 
Study Objectives ............................................................................................................7 
3 
Outline of Planned Analysis ........................................................................................... 8 
4 
Data Summaries ....................................................................................................... 10 
4.1 
Screening and Entry .................................................................................................... 10 
4.1.1 
Accrual ................................................................................................................................................ 10 
4.1.2 
Eligibility Violations and Analysis Status ....................................................................................... 10 
4.2 
Participant and Study Status ...................................................................................... 11 
4.3 
Baseline Characteristics ............................................................................................. 12 
4.4 
Data Completeness for Safety Data ........................................................................... 14 
5 
Primary and Secondary Analyses ......................................................................... 15 
5.1 
Safety Analysis for SDAC Final Report ..................................................................... 16 
5.1.1 
Primary Safety Analysis of Data Representing Exposure to the Final Doses Selected For 
Each Stratum Within a Cohort (Data from the initial maraviroc dose through week 6 of life) .............. 17 
5.1.2 
Secondary Safety Data Analyses on Final-Dose and All-Treated Participants for Final 
Analysis Reports (Data from the initial maraviroc dose through week 16 of life) .................................. 19 
5.2 
Safety Analysis for Dose Finding .............................................................................. 19 
5.3 
Infant Infection Testing ............................................................................................... 20 
5.4 
Tropism Testing (By Strata within a Cohort and Aggregated) ............................... 21 
5.5 
Study Monitoring Committee (SMC) Review Reports ............................................. 21 
 
 
 
 
 
 
 
 
 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            4  
 
 
Table of Tables 
 
Table 1: Eligibility Violation and Analysis Exclusion Example ................................... 10 
Table 2: Number of Cohort 1 Infants Accrued and were Evaluable for PK/Safety 
Analysis (mock-up table) ....................................................................................................... 11 
Table 3: Cohort 1 Infant Baseline Characteristics (mock-up table) ........................... 13 
Table 4: Infant Safety Data Collection Schedule for Cohort 1 ..................................... 14 
Table 5: Infant Safety Data Collection Schedule for Cohort 2 ..................................... 15 
Table 6:  Proportion of Cohort 1 Infants Meeting the Primary Safety Endpoint 
(mock table) ............................................................................................................................... 18 
Table 7: Proportion of Cohort 1 Infants Meet the Additional Safety Outcomes ..... 19 
Table 8: Summary of Infants Meeting the Safety Endpoints for Dose Finding For 
Each Stratum within a Cohort............................................................................................... 20 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            5  
 
1 
Purpose of the Analysis Plan 
This Analysis Plan outlines the components of the primary and secondary data analysis for 
IMPAACT 2007.  The focus is on analyses of administrative, baseline, and safety data needed to 
address the study’s primary and secondary objectives, and the analyses to assess whether safety 
guidelines have been met at interim and final accrual to Cohorts 1 and 2.  This document focuses 
on analyses necessary for scientific purposes; any additional analyses needed for the regulatory 
purposes of the pharmaceutical sponsor will be specified in a separate document.  The 
procedures and reports involved with protocol team monitoring of safety data during regular 
team calls are not fully described in this document (see the Study Monitoring Plan for details 
concerning monitoring). The pharmacology data will be analyzed separately by the protocol 
pharmacologist. The purpose of this analysis plan is: 
 
 to ensure that the protocol team is aware of all the major issues that will be in the 
proposed analyses, and agrees on the contents of these analyses; and 
 to specify how we intend to investigate the study questions listed in the protocol 
objectives and the way that data are to be analyzed and presented. 
 
This analysis plan, therefore, includes the key analyses which might lead to modification or 
termination of the study and which also form the core of any presentation or publication used to 
disseminate the primary conclusions of the study. It is, however, recognized that this analysis 
plan may be modified by the core study team as new information becomes available outside of 
the study, or to reflect recommendations made by the Study Monitoring Committee (SMC).   
 
 
 
 
 
 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            6  
 
 
2 
Protocol Overview 
This is a Phase I safety, tolerability, pharmacokinetics (PK), and dose-finding study of maraviroc 
solution during the first six weeks of life for infants born to HIV-1 infected mothers. The 
objectives of the study are accomplished through two sequential dosing cohorts stratified by 
maternal use of efavirenz (EFV). 
 
2.1 
Study Population 
 
Infants born to HIV-1 infected mothers and are receiving a single or combination antiretroviral 
(ARV) regimen for prevention of perinatal HIV-1 transmission that does not include a potent 
cytochrome P450 CYP3A4 inhibitor or inducer (mother will also be enrolled in the study but 
will not receive study drug). 
 
2.2 
Sample Size 
 
Up to 72 mother-infant pairs to achieve a target of 36 evaluable infants receiving the final 
recommended dose of maraviroc. 
2.3 
Stratification 
 
Cohort 1:  Stratified by infant in utero exposure to maternal EFV, with concurrent enrollment of 
both strata.  
Up to 36 mother-infant pairs to achieve a target of 12 evaluable infants (6 in each stratum) 
receiving the dose of maraviroc that passes safety and PK guidelines for the relevant stratum and 
is recommended for Cohort 2.   
Stratum 1A: 
n = 6-18 infants without in utero exposure to maternal EFV (no EFV 
exposure during the eight weeks immediately prior to delivery).   
Stratum 1B: 
n = 6-18 infants with in utero exposure to maternal EFV (EFV exposure 
for a minimum of two weeks immediately prior to delivery).  
 
Cohort 2:  Stratified by infant exposure to maternal EFV after birth, with enrollment of each 
stratum opening upon dose selection from the corresponding stratum in Cohort 1.   
 
Up to 36 mother-infant pairs to achieve a target of 24 evaluable infants (12 in each stratum) 
receiving the final recommended dose of maraviroc that passes safety and PK guidelines for the 
relevant stratum.   
Stratum 2A:  n = 12-18 infants without any exposure to maternal EFV either in utero 
(no EFV exposure during the eight weeks immediately prior to delivery) and if 
breastfeeding while breastfeeding. 
Stratum 2B:  n = 12-18 breastfeeding infants with exposure to maternal EFV both in 
utero and after birth while breastfeeding (EFV exposure for a minimum of two weeks 
immediately prior to delivery and while breastfeeding).  


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            7  
 
 
2.4 
Study Drug 
 
Cohort 1: Single doses of maraviroc solution at two time points:  within 3 days of life and at one 
week (7-14 days) of life.  The initial starting dose for this cohort will be 8 mg/kg; dose 
adjustment may occur as needed based on experience within the cohort. 
Cohort 2:  Based on evaluation of the Cohort 1, Stratum 1A and Stratum 1B safety and PK data, 
the initial daily dose of maraviroc oral solution to be administered in Cohort 2, Stratum 2A and 
Stratum 2B, participants in IMPAACT 2007 will be 8 mg/kg dose given twice daily.  Dose 
adjustments for the cohort may occur as needed based on experience within the cohort.  
 
 
2.5 
Study Duration 
 
Approximately 28 months total. Accrual is expected to require approximately 24 months and 
enrolled infants will be followed for four months. 
2.6 
Study Objectives 
 
Primary Objectives: 
 To evaluate the safety and tolerability of maraviroc solution, during the first six weeks of 
life, when administered with ARV prophylaxis to HIV-1 exposed infants at risk of 
acquiring HIV-1 infection with and without exposure to maternal EFV.  
 To evaluate the pharmacokinetics of maraviroc solution, during the first six weeks of life, 
when administered with ARV prophylaxis to HIV-1 exposed infants at risk of acquiring 
HIV-1 infection with and without exposure to maternal EFV.  
 To determine an appropriate dose of maraviroc solution during the first six weeks of life.  
 
Secondary Objectives: 
 To assess safety through 16 weeks of life following administration of maraviroc solution 
during the first six weeks of life. 
 To determine age-related changes in maraviroc pharmacokinetic parameters during the 
first six weeks of life. 
 To explore the impact of maraviroc treatment on viral tropism in the event of perinatal 
transmission of an X4/dual-mixed tropic strain of HIV.   
 
 
 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            8  
 
3 
Outline of Planned Analysis  
 
This section contains the details of the analyses for the Interim and the Final Statistical Reports, 
which will include: 
 
 The primary analyses will be done for each stratum based on infants who were exposed 
to the final selected dose and will be restricted to data from the initial dose of maraviroc 
through week 6 of life. 
 Secondary analyses will include all infants, in subgroups for each dose received, and will 
include data from the initial dose of maraviroc through Week 16 of life 
 
Note: Please see Section 6.0 for details on these analyses. 
 
When applicable, separate summary tables will be generated for the women and their infants.  
Separate summary tables will be generated for each subgroup within a cohort. Summary statistics 
for subgroups of infants will be provided alongside the overall cohort summary statistics.  Infant 
subgroups will be defined as Stratum 1A and 1B for Cohort 1, and Stratum 2A and 2B for 
Cohort 2.  
 
The interim and final full stratum/cohort safety reports will be prepared for the core team and, 
when applicable, for the SMC. These reports will include information concerning Screening and 
Entry, Participant and Study Status, Baseline, and Safety summary tables. Unless otherwise 
noted the SDAC final report will contain all summary tables. 
 
The analysis of the PK data will be performed by the protocol pharmacologists and is, thus, not 
included in this document. 
 
IMPAACT 2007 will be using CDISC standards for data submission. Therefore data will be 
derived from SDTM into ADaM datasets to be used for analysis. Variables listed in this 
document use the SDTM naming conventions. Some variables may differ for regulatory 
submissions and will be specified as such. 
 
 
Validation requirements as per SDAC SOPs will be as follows: 
a. All dataset creation programs will be validated with double coding for the primary safety 
endpoints. 
b. All study-specific formats will be validated. 
c. Validation of analysis programs is specified in the following subsections. 
 
For all analyses, the following will be calculated: 
 
Relative day based on the first initial maraviroc dose (RFXSTDTC) 
 ADAYDOSE=(DATE-RFXSTDTC) to be used for scientific analyses 
 ADY= (DATE-RFXSTDTC+1) to be used for regulatory submissions 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            9  
 
 
Relative day based on birthdate   
 ADAYBRTH= (DATE-BIRTHDATE) to be used for scientific analyses 
 
ADAY=(DATE-BIRTHDATE) to be used for regulatory submission 
 
 
Analysis Week is based on Birth Date: 
COHORT 1 
Week based on SOEc 
Target Study Day (Protocol 
Allowed Window) 
Analysis Windowd 
 
Week 0  
(Screening and/or Entry)a 
Day 0-3b 
  
Day 0 to 3 
Week 1  
Day 7 (7-14) 
Day 4 to (18 or 1 day 
before Week 2 visit) 
Week 2 (Cohort 1: “7 Day 
Post Dose Safety”) 
7 days after receiving the 
last dose of study drug (+/-
3) 
4-10 days after receiving 
the last dose of study drug 
Week 6 (Cohort 1) 
Day 35 (35-42) 
1 day after Week 2 visit to 
Day 77 
Week 16 (Cohort 1) 
Day 112 (112-140) 
Day 78 to 140 
Early Study 
Discontinuation 
Study day of last visit 
Last study visit day 
a Screening and enrollment must occur within 3 days of birth, and can occur at the same visit. 
b Day 0 is defined as the infant’s date of birth and all follow-up visits are scheduled from this date with the 
exception of the 7 Days Post Dose Safety Visit. 
c Analysis study week will be calculated from the date of birth, or Day 0 
dIf a visit falls out of the protocol defined time, then this column will be used to allow for the specific visit. 
 
COHORT 2 
 Week based on SOE c 
Target Study Day (Protocol 
Allowed Window) 
  Analysis Windowd 
 
Week 0  
(Screening and/or Entry)a 
Day 0-3b 
Day 0 to 3 
Week 1  
Day 7 (7-14) 
Day 4 to 18 
Week 4 (Cohort 2) 
Day 28 (21-31) 
Day 19 to 34 
Week 6 (Cohort 2) 
Day 35 (35-42) 
Day 35 to 63 
Week 12 (Cohort 2) 
Day 84 (77-91) 
Day 64 to 98 
Week 16 (Cohort 2) 
Day 112 (112-140) 
Day 99 to 140 
Early Study 
Discontinuation 
Study day of last visit 
Last study visit day 
a Screening and enrollment must occur within 3 days of birth, and can occur at the same visit. 
b Day 0 is defined as the infant’s date of birth and all follow-up visits are scheduled from this date. 
c Analysis study week will be calculated from the date of birth, or Day 0 
dIf a visit falls out of the protocol defined time, then this column will be used to allow for the specific visit. 
 
Unscheduled visits, or visits outside of the visit window, will be defined in ADaM datasets using 
a decimal value of AVISITN and a corresponding AVISIT of labeled “Unscheduled Week X”. 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            10  
 
4 
Data Summaries 
4.1 
Screening and Entry 
 
Purpose:  
To give a summary of the accrual progress of the study during interim and accrual summary for 
final analyses. 
 
Analysis Program Validation: 
Not required. 
 
Data: 
Date and institution of enrollment and eligibility status will be from the SES/Mastertables*; 
Comments related to Safety and PK exclusion will be from STUDMONR tables. Reasons for 
screening failures and non-enrollment will be from the SCR0054 CRF. Off-treatment reasons are 
from Permanent Discontinuation of Study Drug (PE4005) CRF. Off-study reasons are from Off-
Study (F1601) CRF. 
 
* Per 2007 MSWB, this includes the following original table source: PATIENT, SCASE, STEP, CURENT, CMINST, ANSTAB.  
Note that these will be in the DM domain. 
 
 
 
Analysis: 
4.1.1 
Accrual 
 
 Tables: Mother-infant pair accrual (Overall and by Stratum within a Cohort, at the dose 
being evaluated): 
o Accrual by month and by site (dates of first and last enrollment will be indicated 
in the text or a footnote.) 
o Accrual by stratification within a cohort 
o Total accrual 
 
 Screening failures   
o Table: Summary of Reasons for Non-enrollment (also by Month, and Site). 
4.1.2 
Eligibility Violations and Analysis Status  
 Listings of mother and infant eligibility criteria violations and analysis exclusions which 
will include (i) enrolling site; (ii) reason for eligibility violation or analysis exclusions; 
and (iii) team decision on whether to include in the safety/PK analyses; (iv) cohort 
stratification indicators. 
  
Table 1: Eligibility Violation and Analysis Exclusion Example 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            11  
 
Count 
Enrolling 
site 
Participant Cohort 
EFV 
exposure Strat 
Maraviroc 
dosing 
Reason 
Eligibility 
Violation 
Safety 
Analysis 
Status 
PK 
Analysis 
Status 
1 
XXX 
MOTHER 
1 
N/A 
1A 
N/A 
XXX 
Yes 
N/A 
N/A 
 
 
CHILD 
1 
No 
1A 
XXX 
XXX 
Yes 
Include* 
Exclude 
2 
YYY 
MOTHER 
1 
N/A 
1B 
N/A 
YYY 
No 
N/A 
N/A 
 
 
CHILD 
1 
Yes 
1B 
XXX 
YYY 
No 
Include 
Include 
*If the participant has received the study drug, then for safety purposes, their data will be report and used in 
sensitivity analyses. 
4.2 
Participant and Study Status  
 
Purpose:  
To describe infant study status, including whether they are on study, and whether they are 
evaluable for analysis. 
 
Analysis Program Validation: 
Not required. 
 
Data: 
Infant study status will be from PSTAT in CASE table. Accrued and safety/PK evaluable infants 
information will be from STATUS, STUDYMONR tables and ADM0022 CRF. Off-treatment 
reasons are from Permanent Discontinuation of Study Drug (PE4005) CRF. Off-study reasons 
are from Off-Study (F1601) CRF. 
 
Analysis: 
a) Study Status of the Infants:  
Table:  For all enrolled participants, cross-tabulation (number and proportion) of infant 
study status (e.g. on/off treatment, on/off study, death) 
Table:  Summary Table and listing of off-study reasons for infants  
 
Table:  Summary Table and listing of off-treatment reasons for infants  
 
b) Number of Infants Accrued and  Evaluable for PK/Safety Analysis (by stratum by cohort 
and overall) 
 
Table 2: Number of Cohort 1 Infants Accrued and were Evaluable for PK/Safety Analysis 
(mock-up table) 
 
Cohort 1A 
Cohort 1B 
Overall 
Infants accrued  
N(%) 
N(%) 
N(%) 
Infants evaluable for 
safety analysisa  
N(%) 
N(%) 
N(%) 
Infants evaluable for 
PK analysisb  
N(%) 
N(%) 
 
N(%) 
a   Based on infants who received at least one dose of maraviroc. 
b   Based on team determination 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            12  
 
Note: Similar table will be generated for Cohort 2 with appropriate column labels 
appropriate for Cohort 2 strata. 
 
4.3 
Baseline Characteristics 
 
Purpose:  
To describe maternal and infant baseline characteristics (demographic, health status and other 
key parameters). 
 
Analysis Program Validation: 
Not required, but code review is recommended 
 
Data: 
Baseline is defined as the latest measurement before or on the day of first dose of Maraviroc. The 
following are the CRFs/tables for this section: 
 Mother baseline data: 
o Demographic: race/ethnicity, age 
 
               SES/Master Table 
 Infant baseline data: 
o Birth weight, birth length, APGAR score at 1 minute 
NBW0014 
o Gestational age at delivery 
 
 
 
 
NBW0014 
o ALT, AST, total bilirubin, creatinine  
 
 
LBW0151 
o Platelet count, hemoglobin, WBC 
 
 
 
LBW0150 
 
Analysis: 
a) For mothers: Demographics 
 Age (years): N, N missing, median, 25th and 75th percentiles, min, max, mean, 
standard deviation 
 Race (separate Ethnicity) 
 Ethnicity (used in the eligibility screening): N (%) by category  
 Entry ARV regimen: N (%) 
 
b) For infants:  
 
Demographics/Characteristics 
 Gender 
 Race 
 Ethnicity 
 Gestational age at birth: N, N missing, median, 25th and 75th percentiles, min, 
max, mean, standard deviation  
 Birth weight (gram): N, N missing, median, 25th and 75th percentiles, min, max, 
mean, standard deviation 
 Birth length (cm): N, N missing, median, 25th and 75th percentiles, min, max, 
mean, standard deviation  
 APGAR score at 1 minute: N, N missing, median, 25th and 75th percentiles, min, 
max 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                                            13  
 
Laboratory Values At Baseline 
 ALT/SGPT (ukat/L): N, N missing, median, 25th and 75th percentiles, min, max 
 AST/SGOT (ukat/L): N, N missing, median, 25th and 75th percentiles, min, max 
 Total Bilirubin (umol/L): N, N missing, median, 25th and 75th percentiles, min, 
max 
 Creatinine (umol/L): N, N missing, median, 25th and 75th percentiles, min, max 
 Platelet count (109/L): N, N missing, median, 25th and 75th percentiles, min, max 
 Hemoglobin (g/L): N, N missing, median, 25th and 75th percentiles, min, max 
 WBC (109/L): N, N missing, median, 25th and 75th percentiles, min, max 
 
c) Baseline Summaries: 
 When appropriate, three sets of baseline characteristics summary tables will be 
generated for: (i) overall enrollments, (ii) safety evaluable participants and (iii) 
PK evaluable participants. Infant summary tables will include summary statistics 
for each stratum and overall. 
 
 
Table 3: Cohort 1 Infant Baseline Characteristics (mock-up table) 
Characteristics 
Cohort 1A 
Cohort 1B 
Overall 
Birth Weight 
(g) 
N 
N (X%) 
N (X%) 
N (X%) 
N missing 
N (X%) 
N (X%) 
N (X%) 
Min-Max 
X - Y 
X - Y 
X – Y 
Median 
(Q1-Q3) 
X (Y –Z) 
X (Y – Z) 
X (Y- Z) 
 
Mean (std 
dev) 
 
 
 
 
Additional rows for the rest of the baseline characteristics 
Note: Similar table will be generated for Cohort 2 with appropriate column labels 
appropriate for Cohort 2 strata of infants. 
 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                             14  
 
 
4.4 
Data Completeness for Safety Data 
Purpose:  
To summarize data completeness according to the scheduled visits for infant safety data. 
 
Analysis Program Validation: 
Not required. 
 
Data:  
Infant observed visit data are from the following CRFs: LBW0150 (LBDTC, AEDTC) for 
hematologies, LBW0151 (LBDTC, AEDTC) for liver chemistries, and ADE0003 (AEDTC) for 
signs/symptoms and diagnoses. 
 
Analysis: 
a) Infant Safety Data Collection Schedule and Visit Windows for Cohort 1 and 2  
Table 4: Infant Safety Data Collection Schedule for Cohort 1 
 
Study Visit 
 
Screen  
 
 
Entry 
 
 
Week 1 
 
 
7 Days 
Post 
Dose 
Safety  
Week 6  
 
Week 16 or 
Early Study 
Discontinuation 
Visit Window 
0 – 3 
days  
0 – 3 days 
7 – 14 
days  
+/- 3days 
35 – 42 
days 
112 – 140 days 
Analysis Window  
0 to 3 
0 to 3 
4 to 18 
(or 1 day 
before 
Week 2 
visit) 
4-10 days 
after 
receiving 
the last 
dose of 
study 
drug 
1 day after 
Week 2 
visit to 77   
78 to 140 
 
 
 
 
 
 
 
Hematologies 
(LBW01050) 
X  
 
X 
X 
X 
X 
Liver Chemistries 
(LBW0151)  
X 
 
X 
X 
X 
X 
Signs/Symptoms 
and Diagnoses 
(ADE0003) 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                             15  
 
 
 
 
 
 
Table 5: Infant Safety Data Collection Schedule for Cohort 2 
Study Visit  
 
Screen/Entry 
 
 
Week 
1 
 
 
Week 
4  
 
 
 
Week 
6 
 
 
 
Week 
12   
 
 
Week 16 or Early 
Study 
Discontinuation  
 
Visit Window  
0 –  3 days  
7 – 14 
days 
21 – 31 
days 
35 – 
42 
days 
77 –  
91 
days 
112 – 140 days  
Analysis Window 
0-3 
4 to 18 
19 to 
34 
35 to 
63 
64 to 
98 
99 to 140 
Hematologies 
(LBW0150) 
X 
X 
X 
X 
X 
X 
Liver Chemistries 
(LBW0151)  
X 
X 
X 
X 
X 
X 
Signs/Symptoms and 
Diagnoses (ADE0003) 
X 
X 
X 
X 
X 
X 
 
b) Data Completeness Summaries of Infant Safety Data 
Table: Frequency of infant expected and observed clinic visits with completed forms of 
IMPAACT 2007 Hematologies (LBW0150), Liver Chemistries (LBW0151), 
Signs/Symptoms and Diagnoses (ADE0003). 
Note: Separate tables will be created for infant subgroups and overall. 
 
 
5 
Primary and Secondary Analyses 
 
Procedures 
 
Safety data will include death, signs/symptoms, diagnoses and laboratory test results, which will 
include results of evaluations specified in the protocol and results from the infant’s clinical care.   
 
Note: If an infant has unevaluable PK data, which reflects uncertainty about appropriate 
exposure to the study drug, then the infant will be replaced and will be excluded from both the 
PK and safety analyses during the dose-evaluation. However, the infant may be allowed to 
continue on study drug and will be followed through week 16. It may be necessary to prefer 
sensitivity analyses on the final data to test whether the results of the final safety analysis are 
consistent with and without this infant’s data. 
 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                             16  
 
 
 
5.1 
Safety Analysis for SDAC Final Report 
 
Purpose: 
To list the endpoints and tables of primary and secondary safety analyses for the SDAC final 
report.   
 
Primary Safety Endpoints (from the initial maraviroc dose through week 6 of life) 
 For dose finding purposes: Any life threatening adverse event, including death, assessed 
as at least possibly related to the study drug, adverse events of grade 3 or higher judged 
by the Core Protocol team to be probably or definitely related to the study drug, or that 
result in permanent discontinuation of study drug due to an adverse event, judged by 
Core Protocol Team to be at least possibly related to study drug. (Cohort 1: through 7 
Day Post Dose Visit; Cohort 2: through Week 6 visit) 
 
 For analysis purposes: Any life threatening adverse event, including death, assessed as at least 
possibly related to the study drug, adverse events of Grade 3 or higher judged by the Core 
Protocol team to be probably or definitely related to the study drug, or that result in permanent 
discontinuation of study drug due to an adverse event, judged by the Core Protocol Team, to be at 
least possibly related to study drug. (Cohort 1 and Cohort 2: through Week 6 Visit). 
Secondary Safety Endpoints (from the initial maraviroc dose through week 16 of life) 
Safety: 
 For analysis purposes: Any life threatening adverse event, including death, assessed as at least 
possibly related to the study drug, adverse events of Grade 3 or higher judged by the Core 
Protocol team to be probably or definitely related to the study drug, or that result in permanent 
discontinuation of study drug due to an adverse event, judged by the Core Protocol Team to be at 
least possibly related to the study drug. 
 
Primary Outcome Measures (from the initial maraviroc dose through week 6 of life) 
 Safety: All adverse events (all severity grades). 
Secondary Outcome Measures (from the initial dose of maraviroc through week 16 of life) 
 Safety: All adverse events (all severity grades). 
 Tropism: (1) Infant’s viral tropism after expose to maraviroc (infants who are HIV-1 
infected only); (2) Viral tropism at entry (mothers of infants who are HIV-1 infected 
only). 
 
Analysis Program Validation: 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                             17  
 
Code review required.  Primary/Secondary analyses for both primary/secondary safety endpoints 
will require double coding. 
 
Data: 
Infant safety data are adverse clinical and laboratory events reported on the following CRFs: 
Hematology (LBW0150), Liver Chemistries (LBW0151), Signs/Symptoms and Diagnosis 
(ADE0003) and Death (PE1414). The following variables in the SDAC SAS datasets will be 
used: AETERM, LBTOXGR, AESEV, and AETRTREL;(team’s drug attribution assessment 
variable) in ADE0003; and Code =40 (Subject reached protocol-defined toxicity endpoint) of 
Reason for Treatment Discontinuation of PE4005 CRF.  
 
Analysis:   
 
5.1.1 Primary Safety Analysis of Data Representing Exposure to the Final Doses Selected 
For Each Stratum Within a Cohort (Data from the initial maraviroc dose through 
week 6 of life) 
 
The primary analyses will be conducted for each stratum within a cohort based on infants who 
were exposed to the final selected dose and will be restricted to data from the initial maraviroc 
dose through week 6 of life.   
 
Each participant’s safety data will be summarized as: the worst grade of adverse event 
experienced, and the worst grade of adverse event assessed as at least probably related to study 
drug.   Frequency distributions of these safety outcomes will be presented. Also, listings of all Grade 3 or 
higher events will be provided, including the Core Protocol Team’s attribution to the study drug, and 
adverse events deemed to be at least possibly related that result in permanent discontinuation of study 
drug. 
 
 
 
Tables and Listings: 
 
The safety analysis will consist of listings and descriptive statistics summarizing outcomes by 
strata within cohorts, bounded by exact 95% confidence intervals. 
 
Safety endpoint tables: 
 Tables for the primary safety endpoint for the final analysis:  
o Summary table [number (%) and 95% exact CI] and listing of life-threatening 
adverse events, including death,  judged by the protocol team to be at least 
possibly related to Maraviroc 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                             18  
 
o Summary table [number (%) and 95% exact CI] and listing of adverse events 
of Grade 3 or 4 severity judged by the protocol team as non-life threatening,  
and probably related or definitely related to Maraviroc 
o Summary table [number (%) and 95% exact CI] and listing of adverse events 
which lead to permanent termination of study treatment judged to be at least 
possibly related to Maraviroc. 
 
Additional Safety Outcome Tables  
o Summary table [number (%)] and listing of the worst grade adverse event 
experienced. 
o Summary table [number (%)] and listing of the worst grade adverse event 
experienced assessed as at least probably related to Maraviroc. 
o Summary table [number (%)] and listing of adverse events of Grade 3 or 4 
severity. The listing will include the team’s attribution to Maraviroc. 
o Summary table [number (%)] and listing of participant deaths. The listing will 
include the team’s attribution to Maraviroc. 
 
 
 
 
 
Table 6:  Proportion of Cohort 1 Infants Meeting the Primary Safety Endpoint (mock table) 
Primary Safety Endpoints 
Cohort 1A 
Cohort 1B  
Total 
  Participants who had life-
threatening adverse events, 
including death,  judged by the 
protocol team to be at least 
possibly related to Maraviroc 
N (%) [95% CI] 
N (%) [95% CI] 
N (%) [95% CI] 
Participants who had adverse 
events of Grade 3 or 4 severity 
judged by the protocol team as 
non-life threatening,  and 
probably related or definitely 
related to Maraviroc 
N (%) [95% CI] 
N (%) [95% CI] 
N (%) [95% CI] 
Participants who had adverse 
events which lead to permanent 
termination of study treatment 
judged to be at least possibly 
related to Maraviroc. 
N (%) [95% CI] 
N (%) [95% CI] 
N (%) [95% CI] 
 
Note: Similar table will be generated for Cohort 2 with appropriate column labels 
appropriate for Cohort 2 strata.  


 
 
IMPAACT 2007 SAP Version 2.0                                                                                             19  
 
 
 
 
Table 7: Proportion of Cohort 1 Infants Meet the Additional Safety Outcomes 
 
Additional Safety 
Outcomes 
Cohort IA 
Cohort IB 
Total 
Participants with AEs of 
grade 3 or 4 severity 
N (%) [95% CI] 
N (%) [95% CI] 
N (%) [95% CI] 
Participants with death 
N (%) [95% CI] 
N (%) [95% CI] 
N (%) [95% CI] 
 
5.1.2 Secondary Safety Data Analyses on Final-Dose and All-Treated Participants for Final 
Analysis Reports (Data from the initial maraviroc dose through week 16 of life) 
 
The secondary analyses will be conducted for each stratum within a cohort based on infants who 
were exposed to the final selected dose, and from all-treated participants, and will be restricted to 
data from the initial maraviroc dose through week 16 of life.   
 
 
Tables and Listings: 
 
The safety analysis will consist of the same analyses as detailed in Section 6.1.1. 
 
Listings of infants’ adverse events which occurred between Day 0 (birthdate) and up to when the 
first dose of maraviroc is taken will also be presented. 
 
 
5.2 
Safety Analysis for Dose Finding 
 
Purpose: 
To list the endpoints and summary tables of safety analysis for dose finding. Analyses will be 
generated for the full accrual of Strata 1A, 1B, 2A, 2B, and at the interim mini-cohorts, at 
specific doses being tested.  
 
Analysis Program Validation: 
Code review required. Primary analysis will require double coding. 
 
Data: 
Infant Safety Data are adverse clinical and laboratory events reported in Hematology 
(LBW0150), Liver Chemistries (LBW0151) Signs/Symptoms and Diagnosis (ADE0003) and 
Death (PE1414) CRFs. The following variables in the SDAC SAS datasets will be used:  
AETERM, LBTOXGR, AESEV, and AETRTREL; (team’s drug attribution assessment variable) 
in ADM0003; and Code =40 (Subject reached protocol-defined toxicity endpoint) of Reason for 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                             20  
 
Treatment Discontinuation of PE4005 CRF.   
 
Analysis: 
If an infant has unevaluable PK data, which reflects uncertainty about appropriate exposure to 
the study drug, then the infant will be excluded from the safety analyses during the dose-
evaluation, provided the infant does not have any toxicities related to Maraviroc.  
 
AEs will exclude events classified by the team as “baseline” or “ongoing baseline” events. 
 
a) Summary table for the interim and cohort full accrual safety reports (analysis for dose 
finding).  
 
Note: The analysis will be done for the following timeframe: Cohort 1 (through 7 Day 
Post Dose Visit); Cohort 2 (through Week 6 Visit). 
 
Table:  Summary table showing number (%) [95% Exact CI] of infants who meet the 
safety endpoints for dose finding and possible early study discontinuation. 
 
Table 8: Summary of Infants Meeting the Safety Endpoints for Dose Finding For Each 
Stratum within a Cohort 
Endpoint 
Number and Proportion 
95% Exact CI 
 Life threatening adverse event including death 
assessed as at least possibly related to the study 
drug, 
N (%) 
 
Non-life threatening Grade 3 or higher adverse 
event judged to be probably or definitely related to 
study drug 
N (%) 
 
Permanent discontinuation of study drug due to an 
AE, judged to be at least possibly related to study 
drug 
N (%) 
 
Meeting any of the three safety guideline 
endpoints 
N (%) 
 
 
 
b) Safety Data Listing: For each starting dose within each stratum, every grade 3 or higher 
adverse event, and permanent treatment discontinuations due to an AE will be listed, 
along with participant demographics, the dose prescribed to the participant at the time of 
the event and the protocol team’s assessment of the probability that this event was due to 
the study drug. 
5.3 
Infant Infection Testing 
 
Purpose:  
To describe the infant HIV infection status. 
 
Analysis Program Validation: 
Not required. 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                             21  
 
Data:  
SCORRES where SCTESTCD=”HIVSTAT” holds the current infection status. 
 
Analysis: 
Table: Frequency and proportion of infants who become HIV- infected will be presented 
and bounded by 95% exact confidence intervals. The results will be presented 
separately for each stratum within a cohort. 
 
 
 
Listing of HIV Nucleic Acid Test Results 
All Treated Neonates 
Cohort 
 
Participant 
Number 
Visit 
RNA 
Specimen 
Relative 
Day 
RNA 
Specimen 
Date 
RNA Assay Result 
(copies/mL) 
DNA 
Specimen 
Relative 
Day 
DNA PCR 
Specimen 
Date 
DNA Assay Result 
 
 
5.4 
Tropism Testing (By Strata within a Cohort and Aggregated) 
 
 
Purpose: 
In the event of perinatal transmission of an X4/dual-mixed tropic strain of HIV, to explore the 
impact of maraviroc treatment on viral tropism.   
 
Analysis Program Validation: 
Not required. 
 
Data: 
 From the VIROTROP table 
 
Analysis: 
 
Table: Listing of Viral Tropism for HIV infected infants compared with their respective 
mother’s Viral Tropism at entry. 
 
Exploratory analysis will be performed in infants who become HIV-1 infected: (1) to determine 
the infant’s viral tropism after exposure to maraviroc; and (2) to assess if the infant’s viral 
tropism matches the mother's. 
 
Therefore, this will be a listing of the infected infant’s tropism and the corresponding tropism of 
the mother. 
 
 
5.5 
Study Monitoring Committee (SMC) Review Reports 
 


 
 
IMPAACT 2007 SAP Version 2.0                                                                                             22  
 
Purpose and Mechanism: To provide accrual, toxicity and/or PK reports for the SMC review 
for the following occasions, as specified in the protocol: 
 Routine SMC reviews of participant accrual, retention, study conduct, and safety will 
be performed annually. 
 Ad hoc SMC Review: In the event of any unresolvable disagreement within the Core 
Team on an issue which would impact decision making or if the Core Team 
encounters any other event or trend of concern, an SMC review of the relevant data 
will be requested. The Core Protocol Team may choose to suspend accrual and/or 
administration of study drug, pending the outcome of the SMC review. 
 
Analysis Program Validation: Code review is required. Primary analysis for primary safety 
endpoint will require double coding. 
 
Data: Infant safety data are adverse clinical and laboratory events reported on the following 
CRFs: Hematology (LBW0150), Liver Chemistries (LBW0151), Signs/Symptoms and Diagnosis 
(ADE0003) and Death (PE1414). (The following variables in the SDAC SAS datasets will be 
used: AETERM, LBTOXGR, AESEV, AETERM, and AETRTREL;(team’s drug attribution 
assessment variable) in ADE0003) and reasons for treatment discontinuations using PE4005 
CRF 
 
Analyses: 
Summary tables and listings similar to reports mentioned above, which may include but not 
limited to: 
 Accrual report 
 Study Status Report 
 Screening Failure Report 
 Baseline Characteristic Report 
 ARV Regimen Report (see Study Monitoring Plan Version 1.0) 
 Safety Summary Report  
o Safety analyses will be based on all data available at the time of preparation of the 
SMC report, and adverse events will be summarized by stratum within each 
cohort and in aggregate for each cohort. 
o This will also include notes from the interim safety report (if interim checks on 
safety have been done on the strata). 
 PK Report (completed by team pharmacologist) 
 Retention (study/participant summary report) 
 Data and specimen completeness 
 Data Delinquency report (appendix)