Conditions: HIV Infections Tuberculosis
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 40
Healthy volunteers: no

Brief summary:
People who are infected with HIV and tuberculosis (TB) need to receive medications that treat both diseases safely and effectively. This study enrolled infants and children infected with HIV and TB and evaluated the safety and tolerance of an antiretroviral (ARV) treatment regimen for HIV that contains raltegravir when administered with a TB treatment regimen that includes rifampicin. Study researchers aimed to determine the most effective dose of raltegravir for infants and children when taken with rifampicin.

Detailed description:
People who are infected with HIV are also at risk for becoming infected with TB, particularly in many resource-limited settings, including Sub-Saharan Africa. Rifampicin is a medication commonly used to treat TB. There is a need for HIV treatment regimens that contain newer ARV medications that are well-tolerated and have minimal interactions with rifampicin-containing TB medication regimens. This study enrolled HIV-infected infants and children: who had never taken any ARV medications or who had not received ARVs for at least 30 days prior to study entry; and who were infected with TB and were taking or were starting a TB medication regimen that included rifampicin. The purpose of this study was to evaluate the safety and tolerance of raltegravir-containing ARV regimens to treat HIV when administered with a rifampicin-containing regimen used to treat TB in infants and children. Study researchers also evaluated the pharmacokinetics of the medications (i.e., how medication is absorbed and processed in the body) and determined the most effective dose of raltegravir when administered with a TB regimen that contains rifampicin.

During the study, researchers continuously monitored participant data for safety and other factors. Researchers could adjust the dose of raltegravir given to a group of participants prior to enrolling additional participants.

At study entry, participants underwent a medical and medication history review, physical examination, medication adherence assessment, blood collection, and urine collection. Participants received chewable raltegravir tablets twice daily, and they also took their TB medications, including rifampicin, and two nucleoside reverse transcriptase inhibitor (NRTI) ARV medications chosen by participants' doctors. This study provided raltegravir to participants; all other medications were prescribed by participants' own doctors.

At a study visit at Days 5 to 8, participants remained in the clinic for about 12 hours. They took part in the same study procedures that occurred at the entry visit, but they also had small amounts of blood collected several times throughout the 12 hours to measure the amount of medication in the blood. After the Day 5 to 8 visit, participants began receiving a fourth ARV medication chosen by their doctor, in addition to the other medications. Participants continued receiving raltegravir until they stopped taking their TB medications. They continued to take the third ARV medication and the other two ARV medications for three months after they stopped receiving raltegravir and the TB medications.

Additional study visits occurred at Day 14, Weeks 4 and 8, every 4 weeks until the participant stopped receiving raltegravir and their TB medications, and 4 and 12 weeks after stopping raltegravir and the TB medications. These study visits included the same study procedures that occurred at study entry. Participants were expected to participate in the study for a total of about 4 to 9 months.

Note that out of the forty (40) participants enrolled only (39) participants received the study treatment (raltegravir). The total enrollment for Cohort 1 was thirteen (13) participants, with only twelve (12) who received raltegravir. Therefore, the results of this submission is based on the 39 participants who received raltegravir.

Arms:
arm 1: Participants in this cohort received chewable raltegravir tablets, starting dose of 12 mg/kg (up to a maximum of 800 mg) orally twice daily, in addition to two NRTIs to treat HIV as part of standard of care, and a rifampicin-containing regimen to treat TB. After a study visit at Day 5 to 8, a fourth ARV medication was added to the regimen. arm 2: Participants in this cohort received chewable raltegravir tablets, starting dose of 12 mg/kg (up to a maximum of 800 mg) orally twice daily, in addition to two NRTIs to treat HIV as part of standard of care, and a rifampicin-containing regimen to treat TB. After a study visit at Day 5 to 8, a fourth ARV medication was added to the regimen. arm 3: Participants in this cohort received chewable raltegravir tablets (as a dispersible tablet), starting dose of 12 mg/kg (up to a maximum of 800 mg) orally twice daily, in addition to two NRTIs to treat HIV as part of standard of care, and a rifampicin-containing regimen to treat TB. After a study visit at Day 5 to 8, a fourth ARV medication was added to the regimen.

Interventions: intervention 1: Raltegravir
Intervention descriptions: intervention 1: Chewable raltegravir tablets, initially dosed at 12 mg/kg (up to a maximum of 800 mg) orally twice daily.

Protocol document:
ICF_000.pdf: 
 
 
IMPAACT P1101 Sample Informed Consent Form 
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APPENDIX VI 
SAMPLE INFORMED CONSENT FORM FOR STUDY PARTICIPATION 
 
P1101: PHASE I/II DOSE-FINDING, SAFETY, TOLERANCE AND PHARMACOKINETICS STUDY 
OF A RALTEGRAVIR-CONTAINING ANTIRETROVIRAL THERAPY (ART) REGIMEN IN HIV-
INFECTED AND TB CO-INFECTED INFANTS AND CHILDREN  
 
SHORT TITLE FOR THE STUDY: P1101 
 
Version 3.0, dated 24 April 2017 
 
INTRODUCTION 
Your child is being asked to take part in this research study because your child has the Human 
Immunodeficiency Virus (HIV), which is the virus that causes AIDS, and has not taken any medications 
for the treatment of HIV in the past 30 days.  Your child also has Tuberculosis (TB) and is taking or will 
be starting anti-TB medications that include Rifampicin, a medication commonly used to treat TB.  This 
study is sponsored by the National Institutes of Health (NIH).  The doctor in charge of this study at this 
site is: (insert name of Principal Investigator).  Before you decide if you want your child to be a part of 
this study, we want you to know about the study.  
 
This is a consent form.  It gives you information about this study.  The study staff will talk with you about 
this information.  You are free to ask questions about this study at any time.  If you agree to allow your 
child to take part in this study, you will be asked to sign this consent form.  You will get a copy to keep. 
 
WHY IS THIS STUDY BEING DONE? 
This study is being done to measure the amount of raltegravir (RAL, Isentress™) in the blood when it is 
taken with the anti-TB medication Rifampicin.  Raltegravir is the study medication used in this study and 
it is a type of anti-HIV medicine called an integrase inhibitor.  Integrase inhibitors work by blocking 
integrase, a protein that HIV needs to enter human cells and make more copies of itself.  Raltegravir has 
been approved for the use in adults, adolescents and children ages 4 weeks to 18 years old by the United 
States Food and Drug Administration (FDA).  The chewable tablet is approved for children ages 2 to less 
than 12 years old.  For children under 2 years of age, this study will look at a new way to give this 
medicine to young children more easily. Infants and children 4 weeks to less than 2 years old will take the 
raltegravir chewable tablet mixed with water, juice, breast milk or formula. This study will provide the 
study medication raltegravir to your child.   
 
The other medications used in this study are Rifampicin, other anti-TB medications, two anti-HIV 
medications that are called Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and a fourth anti-HIV 
medication that will be chosen by your child’s doctor.  It is possible that the fourth ARV drug chosen by 
your doctor could be a combination drug of Lopinavir and ritonavir (LPV/r).  This medication may need 
to be dose adjusted with additional ritonavir to obtain the correct dosing for your child.  This would result 
in a fifth anti- HIV medication.  Many people find the liquid form of this drug tastes bad. These 
medications will not be provided by the study.  These medications will be provided at the clinic where 
your child is receiving care.  You will need to obtain them through a prescription from your child’s 
doctor. 
 
This study will look at the levels of raltegravir in the blood and the best dose of raltegravir in HIV-
infected infants and children who are taking rifampicin for the treatment of TB compared to HIV-infected 
infants and children who are only taking raltegravir and do not require treatment for TB with rifampicin. 


 
 
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This study will also look at how the anti-HIV treatment including raltegravir when it is given with 
rifampicin is tolerated, and the levels of raltegravir and antiretroviral drugs (ARVs) when taken together 
in the blood to help find out if taking raltegravir and ARVs with rifampicin is safe. 
 
WHAT DOES MY CHILD HAVE TO DO IF HE/SHE IS IN THIS STUDY? 
Your child must be taking or starting to take anti-TB medications that include Rifampicin to be in this 
study.  Your child will be given raltegravir and will be asked to take it two times or three times a day in 
addition to your child’s other two new anti-HIV medicines.  Raltegravir will be in a chewable tablet 
formulation to be chewed or taken dissolved in a liquid.  The study staff will explain to you how to give 
the medicine to your child. Levels of raltegravir in the blood will be measured about one week after 
starting this medicine.  Then your child will begin a fourth anti-HIV medicine along with his/her anti-TB 
medications including rifampicin, raltegravir and the other two anti-HIV medicines.  Your child will take 
raltegravir until he/she stops taking the anti-TB medications prescribed by his/her doctor.  Your child will 
continue to take the third anti-HIV medicine and the other two anti-HIV medicines for 3 months after the 
anti-TB medicines and raltegravir are stopped.  
 
Deciding to allow your child to join this study is voluntary.  You may choose to allow your child to join 
or not join.  If you choose to allow your child to join, you can change your mind and take your child out 
of the study at any time.  Your choices will have no effect on the medical care that your child receives at 
this clinic.  Your child’s access to services and the benefits and rights he or she normally has will not be 
affected. 
 
Take your time and consider your decision carefully.  If you wish, you can talk to other people about 
allowing your child to join the study.  You can bring other people here to learn about the study with you. 
 
If you decide to let your child join this study, we will first do some tests to see if your child qualifies. 
 
Screening visit: 
To find out if your child qualifies for this study, we will: 
• 
Ask about your child’s medical history including questions about your child’s health and what 
symptoms, medications, and illnesses your child has had. 
• 
Give your child a physical examination: We will measure your child’s height, weight and vital signs 
(temperature, blood pressure, pulse and respiratory rate). 
• 
Draw your child’s blood for the following tests: We will take a little more than 1 teaspoon (4-6 mL) 
of blood for routine safety tests (a CBC, or complete blood count, which shows how many red and 
white blood cells there are; blood chemistries, which checks the blood sugar and how well the 
kidneys are working; a liver function test, which shows how well the liver is working) and to measure 
the amount of HIV in the blood (HIV viral load). We may draw up to an additional 3 mL to confirm 
your child’s HIV infection if there is no medical record available.  
• 
A pregnancy test: If your child is of child bearing age and pregnancy is suspected, your child may be 
asked to give an additional 1 mL of blood or a urine sample to test for pregnancy.    
• 
You will be given the results of these tests. 
 
If you agree to allow your child to enroll in this study, and your child does not qualify to be in this study, 
the reasons your child cannot enroll in this study will be shared with the protocol team, including the 
pharmaceutical company supporting the study. 
 
 


 
 
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Table 1 
 
Entry 
Day  
5 to 8 
Day 
14 
Week 
4 
Week 
8 
Every 4 
weeks 
TB and/or RAL 
treatment 
discontinuation 
4 weeks off RAL 
treatment/on 
study 
Final 
visit 
Medical history and 
review of medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pill Count 
X 
X 
X 
X 
X 
X 
X 
 
X 
CBC 
X 
X 
 
X 
X 
X 
X 
X 
X 
Liver enzymes 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV viral load 
X 
 
 
X 
X 
X 
X 
X 
X 
CD4/CD8 cell count 
X 
 
 
 
X 
X 
X 
 
X 
 
Entry visit: 
[Sites: add local information regarding how long the entry visit will take]. 
 
If your child qualifies for this study and you allow your child to enter the study, your child will come to 
the clinic for the first study visit (or the Entry visit) within 30 days after the screening visit.  The 
following will take place at the Entry visit: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Entry”. 
• 
Pill count at Entry: If your child is already taking anti-TB medications, we will check how well your 
child is taking the medications (including missed doses). 
• 
Blood tests: We will take a little more than 1.5 - 2 teaspoons (8.5 - 10.5 mL) of blood. 
− 
About 1 ½ teaspoons (5.5 - 7.5 mL) will be for the tests in Table 1.  The CD4/CD8 cell count is to 
check how well your child’s immune system is working.  The results of these tests will be 
provided to you/your child. 
− 
A little more than ½ teaspoon (3 mL) will be used for a test to check if your child’s HIV is 
resistant to some anti-HIV medications (HIV resistance test).  This test will be done after the 
study is over, and you will not be given the results. 
• 
We will also ask your child to provide a urine sample for a routine test.  The results of the test will be 
provided to you/your child. 
• 
Your child will start taking raltegravir and 2 other anti-HIV medicines called NRTIs. 
• 
If your child is a female and started to have sex since the last visit (screening), or can become 
pregnant, your child will be asked to provide a urine sample or an additional 1 mL of blood at each 
visit for a pregnancy test.  Your child will be asked to take birth control precautions (ways to prevent 
pregnancy) throughout the study period to remain in the study. If your child is pregnant, your child 
will not be allowed to continue on the study medicine, but will continue to come in for study visits. 
 
Your child will be asked to return to the clinic about 4 to 10 times in about 16 to 36 weeks (or 4 to 9 
months) until your child stops taking the anti-TB medications.  One visit will last a little over 12 hours 
where the amount of raltegravir and ARVs in the blood will be measured over 12 hours (intensive 
pharmacokinetics or intensive PK visit).  [Sites: add local information regarding how long the visits will 
take]. 
 
Intensive PK visit (Day 5 to 8): 
Approximately one week after starting raltegravir, your child will have an intensive PK visit.  The 
following will take place at this visit: 
• 
You will be contacted by the study staff one day before the visit to confirm that your child took all of 
his/her medications during the 2 days before the visit. 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Day 5 to 8”. 


 
 
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• 
In addition to the pill count that will be done by the study staff, you will need to write down the times 
your child took his/her medications during the 2 days before the visit and bring it with you to the 
clinic. 
• 
We will ask that you not give your child raltegravir, other anti-HIV, and anti-TB medicines at home 
the day of this visit. Your child will need to bring these medicines to the clinic.  Your child will be 
given these medications in the clinic after the first blood sample for the intensive PK test is taken.   
• 
Blood tests: We will take a little more than 1 ½ teaspoons (7.5 mL) of blood.  
− 
A little more than ½ teaspoon (3 mL) will be for the tests in Table 1.  The results of these tests 
will be provided to you/your child. 
− 
A little less than 1 teaspoon (4.5 mL) of blood will be taken over 12 hours to measure the amount 
of raltegravir in your child’s blood.   
 
Your child must have taken all doses as prescribed and not missed any doses of raltegravir and his/her 
other anti-HIV and TB medicines the 2 days before the PK test.  If your child misses a dose within 2 days 
before the PK test, the visit will be rescheduled.  Your child should not have breast milk, formula or any 
other high fat liquid for 2 hours before the PK test and 1 hour after taking the study medicines at the 
clinic.  Your child can have water or apple/orange juice at any time.  We will take the first blood sample 
before your child takes raltegravir at the clinic.  Your child can have a small meal 2 hours after taking 
raltegravir.  We will take blood samples 8 more times at ½ hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 
hours, 8 hours and 12 hours after your child takes raltegravir.  Your child should not be given a second 
dose of raltegravir until after the PK test. 
 
Your child may be stuck by a needle 9 times or a special needle may be inserted into your child’s arm so 
that he/she may not have to be stuck by a needle multiple times.  If possible an intravenous line will be 
placed in your child’s vein for the whole day from which blood may be drawn to avoid as much 
discomfort as possible.  
[Sites: modify or add language as appropriate regarding your site-specific arrangements for the PK visit]  
 
If your child vomits within 15 minutes after taking raltegravir, your child will be given another dose of 
raltegravir.  If your child vomits more than 15 minutes after taking raltegravir, the intensive PK test will 
be cancelled.  The test may be re-scheduled. 
 
Your child will start taking a fourth anti-HIV drug chosen by your doctor after the PK test is completed.  
Your child should take the fourth anti-HIV drug at night, with the smallest amount of food or liquid (such 
as formula, breast milk, mashed banana, yogurt, or maize-based porridge etc.), and should not be mixed 
with water or juice. 
   
Day 14 visit 
Your child will have a visit approximately two weeks after starting raltegravir. The following will take 
place at this visit: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Day 14”. 
• 
Blood tests: We will take a little less than ½ teaspoon (2 mL) of blood at this visit for the tests in 
Table 1.  The results of the tests will be provided to you/your child. 
 
Week 4 visit: 
The following will take place approximately four weeks after your child starts taking raltegravir: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Week 4”. 
• 
Blood tests:  We will take a little more than ½ to 1 teaspoon (4-6 mL) for the tests in Table 1.  The 
results of these tests will be provided to you/your child. 
• 
If your child will be stopping the anti-TB medications at the week 4 visit because your child has 


 
 
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completed anti-TB treatment prescribed by your child’s doctor, the following will also take place: 
− 
We will take less than ½ teaspoon (1.5 mL) of additional blood for a CD4/CD8 cell count test.  
The results of the CD4/CD8 cell count test will be provided to you/your child.   
− 
Your child will stop taking raltegravir at the same time the anti-TB medications are stopped.  
Your child will continue to take the anti-HIV medicines as instructed by your child’s doctor. 
 
Week 8 visit: 
The following will take place approximately eight weeks after your child starts taking raltegravir: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Week 8”. 
• 
Blood tests: We will take about 1 – 1 ½ teaspoons (5.5 – 7.5 mL) of blood for the tests in Table 1.  
The results of these tests will be provided to you/your child. 
• 
If your child will be stopping the anti-TB medications at this visit because your child has completed 
anti-TB treatment prescribed by your child’s doctor, your child will stop taking raltegravir at the same 
time the anti-TB medications are stopped.  Your child will continue to take the anti-HIV medicines as 
instructed by your child’s doctor. 
 
Visits every 4 weeks: 
If your child will continue to take the anti-TB medications and raltegravir after the Week 8 visit, your 
child will have visits every 4 weeks until the anti-TB medications and raltegravir are stopped.  The 
following will take place at these visits: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Every 4 weeks”. 
• 
Blood tests: We will take about 1 – 1 ½ teaspoons (5.5 – 7.5 mL) of blood for the tests in Table 1.  
The results of the tests will be provided to you/your child. 
• 
Depending on the amount of HIV in your child’s blood, we may also take a little more than ½ 
teaspoon (3 mL) of additional blood for an HIV resistance test.  This test may be done after the study 
is over, and you/your child will not be given the results. 
• 
If your child is stopping the anti-TB medications at any of these visits because your child has 
completed anti-TB treatment prescribed by your child’s doctor, your child will stop taking raltegravir 
at the same time the anti-TB medications are stopped. 
 
Early TB and/or RAL treatment discontinuation visit: 
If your child needs to stop taking the anti-TB medications and/or raltegravir early, your child will have a 
treatment discontinuation visit. The following will take place at this visit: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “TB and/or RAL 
treatment discontinuation.” 
• 
Blood tests: We will take about 1 – 1 ½ (5.5 – 7.5 mL) of blood for the tests in Table 1. The results of 
these tests will be provided to you/your child. 
• 
Depending on the amount of HIV in your child’s blood, we may also take a little more than ½ 
teaspoon (3 mL) of additional blood for an HIV resistance test.  This test may be done after the study 
is over, and you/your child will not be given the results. 
 
Even if your child stops taking the study medicines, your child will stay in the study and return for the 
visits at 4 weeks and 12 weeks after stopping raltegravir described below. 
 
Four weeks after stopping RAL visit: 
Four weeks after your child stops taking raltegravir, the following will take place: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “4 weeks off 
RAL treatment/on study”. 
• 
Blood test: We will take a little more than ½ - 1 teaspoon (4 – 6 mL) of blood for the tests shown in 
Table 1.  The results of the tests will be provided to you/your child. 


 
 
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Final visit: 
Twelve weeks after your child stops taking raltegravir your child will have the last study visit.  Or, if your 
child stops participating in the study before completing the study, your child will have a study 
discontinuation visit.  At the last study visit or study discontinuation visit, the following will take place: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Final visit”.  A 
pill count will only be done if your child is discontinuing raltegravir early at this visit. 
• 
Blood tests: We will take a little over ½ - 1 teaspoon (3.5 – 5.5 mL) of blood for the tests shown in 
Table 1.  The results of the tests will be provided to you/your child. 
 
The study will first enroll a small group of 6 participants into three age groups and participants in each 
group will take the same dose of raltegravir.  If the results of the intensive PK test in a specific age group 
show that the level of raltegravir is too low or too high or is found not to be safe, a new group of 6 
participants will be enrolled into that age group and will take a new dose of raltegravir.  The enrollment of 
a new group of 6 participants in each age group will be done until the best dose of raltegravir is found.   
 
When the best dose of raltegravir is found for that age group, an additional 6 participants will be enrolled 
in each age group and will take the best dose so that there will be a total of 12 participants that will be 
studied on the best dose.  If the results of the intensive PK test for a specific group show that the level of 
raltegravir is too low or too high or is found not to be safe, a new group of 6 participants will be enrolled 
into that age group and will take a new dose of raltegravir.  This process will repeat until the best and safe 
level of raltegravir is found in a group of 12 participants for a specific age group.  If the best dose is not 
found when raltegravir is taken two times a day, it may have to be taken three times a day.   
 
If there is a question about the results of the intensive PK test of your child, or the results are lower than 
what is expected or too high and may be a risk to your child, the study doctor may ask your child to have 
another intensive PK test.  Your child’s study doctor will let you know when the intensive PK test will be 
repeated. 
 
If the group that your child belongs to (whether a group of 6 or 12 participants) has raltegravir PK test 
levels that are either too low, too high or is found not to be safe, the entire group (including your child) 
will take the new dose of raltegravir that will be tested in the new group of participants, if it is considered 
safe to do so and your child’s group is still taking TB treatment and raltegravir.  Changes in the dose of 
raltegravir will be done for the entire group that a participant belongs to and not on an individual basis.  If 
the PK tests suggest that the new dose should be given three times a day, this will not apply to your child 
who will continue to take raltegravir twice a day.  The dose of raltegravir will only be changed once for 
your child and the intensive PK will not be repeated after the dose is changed.  Your child will continue in 
the study and have the rest of the visits.  This will be discussed with you by the study doctor and will 
depend on what is safest for your child. 
 
If your child is still taking raltegravir and the anti-TB medications when the best dose of raltegravir is 
found, and your child is still in the study, the study doctor will change your child’s dose of raltegravir to 
the best dose.  Your child will continue taking the new dose of raltegravir until your child stops taking the 
anti-TB medications. 
 


 
 
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OTHER INFORMATION 
Your child’s blood samples for the intensive PK tests will be shipped to a laboratory in the United States 
where the tests will be performed. 
 
Any leftover blood samples after testing is completed for this study will be destroyed. 
 
The information collected in this study may be used for other IMPAACT-approved HIV-related research. 
 
HOW MANY INFANTS AND CHILDREN WILL TAKE PART IN THIS STUDY? 
About 36 to 108 infants and children will take part in this study. 
 
HOW LONG WILL MY CHILD BE IN THIS STUDY? 
Your child will be in this study for about 4 to 9 months.   
 
WHY WOULD THE DOCTOR HAVE MY CHILD STOP TAKING RALTEGRAVIR EARLY? 
The study doctor may need to take your child off raltegravir early without your permission if: 
• 
Your child develops a side effect and continuing the study drug(s) may be harmful to your child. 
• 
Your child needs a treatment that your child may not take while on the study. 
• 
Your child is found to have multi-drug resistant (MDR) or extensively drug-resistant (XDR) TB.  
MDR-TB and XDR-TB happens when the bacteria that cause TB infection changes and cannot be 
treated by the medicines that are usually effective in treating TB.  If your child is found to have MDR 
or XDR TB, your child will be referred to the proper doctor or clinic for care. 
• 
Your child is not able to take the study drug(s) as required by the study. 
• 
New information that becomes available shows that your child should stop taking the study drug(s). 
• 
The result of the intensive PK test shows that your child has not been taking the study drugs or the 
level of raltegravir that your child’s body is taking is abnormally high or low. 
• 
The amount of HIV in your child’s blood does not go down to the levels low enough to continue the 
study drug(s). 
• 
Your child becomes pregnant or is a female that is sexually active and does not agree to take birth 
control precautions. 
 
If your child must permanently stop taking the study drug(s) before your child’s study participation is 
completed or before the study is over, the study staff will discuss other options that may be of benefit to 
your child.  In addition, your child will have the early treatment discontinuation visit and the visits four 
weeks and twelve weeks after stopping the study drug(s) as described above. 
 
After the study: 
After your child has completed study participation, the study will not be able to continue to provide your 
child with the raltegravir that he/she received on the study.  If continuing to take these or similar drugs 
would be of benefit to your child, the study staff will discuss how you may be able to obtain them. 
 
WHY WOULD THE DOCTOR TAKE MY CHILD OFF THE STUDY EARLY?  
The study doctor may need to take your child off the study early without your permission if: 
• 
You do not want your child to continue or your child does not want to continue taking raltegravir or 
completing the required visits. 


 
 
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• 
The study doctor determines that continuing participation could be harmful to your child’s health or 
well-being. 
• 
Your child is not able to attend the study visits or meet the requirements of the study, which may 
cause harm to him/her and affect the results of the study. 
• 
The study is cancelled by the IMPAACT Network, Office for Human Research Protections (OHRP), 
National Institutes of Health (NIH), the site’s Institutional Review Board (IRB) or Ethics Committee 
(EC), the U.S. Food and Drug Administration (FDA), other government agencies, or Merck & Co., 
Inc. (the drug company supporting this study).  An IRB or EC is a committee that watches over the 
safety and rights of research participants. 
• 
An IMPAACT Study Monitoring Committee (SMC) recommends that the study be stopped early.  
The SMC is a group of experts who monitor the study. 
• 
The study has to be stopped for other administrative reasons. 
 
WHAT ARE THE RISKS OF THE STUDY? 
The drugs used in this study may have side effects, some of which are listed below. Please note that these 
lists do not include all the side effects seen with these drugs. These lists include the more serious or 
common side effects with a known or possible relationship.  If you have questions concerning additional 
study drug side effects, please ask the medical staff at your site. 
 
For your child’s safety, it is important that you tell the study doctor or nurse about all medications that 
your child is taking before your child starts the study, and also before your child starts taking any new 
medications while on the study, including medicines bought from the store or pharmacy and herbal or 
natural medicines.  In addition, it is important that you tell the study doctor or nurse before your child 
enrolls in any other clinical trials while on this study. 
 
Your child’s HIV may develop resistance to raltegravir and anti-HIV drugs that are being used in this 
study.  Drug resistance develops when the HIV changes so the anti-HIV drugs become less effective.  It is 
possible that your child may not receive the correct dose of raltegravir, which can also lead to drug 
resistance.  If drug resistance develops in your child, the HIV virus may not be controlled.  However, the 
reason for adding a fourth ARV drug early in the study is to try to avoid the development of resistance to 
raltegravir. 
 
Use of Combination Antiretroviral Drugs 
Immune Reconstitution Syndrome: When your child is treated with a combination of at least 3 anti-HIV 
drugs (which is called highly active antiretroviral therapy or HAART), the way your child’s body is able 
to fight infection may change.  The immune system is the body’s defense against infection. Your child’s 
immune system may respond in a stronger way to some types of infections that your child may already 
have.  This immune response may cause your child to become sick and the condition is then called 
“immune reconstitution inflammatory syndrome” or IRIS.  
 
We do not understand who will get IRIS and who will not.  IRIS can be serious or mild.  It can begin soon 
after a person starts HIV medication for the first time.  It can also begin in people who restart their HIV 
medications after being off (or not taking) them for some time.  IRIS happens when your child’s immune 
system recovers too quickly.  It can start to “overact” and respond to other infections that may or may not 
have been known before starting therapy, even ones that may have already been under control. 
 
When your child’s immune system over acts this way it can cause inflammation (redness and tenderness), 
which is sometimes very serious.  For some people, these symptoms can be life-threatening.  Even though 
most cases of IRIS get better after a few weeks, the symptoms may be mistaken by you, and your child’s 


 
 
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15 March 2018 
Protocol Version 3.0 with Letter of Amendment #1 
doctor as the HIV disease getting worse or another condition.  IRIS can be very confusing because, as 
your child’s immune system fights an infection, the inflammation that takes place actually makes your 
child’s symptoms worse. 
 
When IRIS does happen, it happens more often after the BCG injection.  BCG stands for Bacille 
Calmette-Guerin vaccine, a vaccine that is used to prevent tuberculosis (TB) in infants.  The injection site 
can get bigger and the glands in the right armpit may become painful.  IRIS also happens more often with 
TB in 1 out of 10 infants.  Many other bacteria and viruses can lead to IRIS.  Usually, IRIS causes a 
return or worsening of at least some of the symptoms from an infection your child may have had before 
starting HAART.  While some of these reactions can be serious, they usually last for a short time and can 
be treated without stopping the anti-HIV drugs or HAART.    
 
The use of potent antiretroviral drug combinations may be associated with an abnormal placement of 
body fat and wasting.  Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 
Integrase Inhibitor  
Raltegravir, (RAL, Isentress™) 
Merck & Co., Inc. 
 
The following side effects have been associated with the use of raltegravir:  
 
• 
Rash, which can become severe or life-threatening.  Contact your child’s doctor right away if your 
child develops a rash. 
• 
Nausea 
• 
Headache 
• 
Tiredness 
• 
Weakness 
• 
Trouble sleeping 
• 
Stomach pain 
• 
Dizziness 
• 
Depression 
• 
Suicidal thoughts and actions  
• 
Feeling anxious, Paranoia 
• 
Easy bleeding (decreased blood clotting, low platelet count) 
• 
Diarrhea 
• 
Liver failure  
• 
Clumsiness and lack of coordination 
• 
Changes in behavior, like low or high activity in children 
• 
Muscle tenderness, weakness or injury which can be serious and lead to kidney damage 
 
Serious skin and allergic reactions including a rash which can become severe or life-threatening and can 
be fatal.  If your child develops a rash with any of the following symptoms stop using raltegravir and 
contact your child’s doctor right away:  


 
 
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15 March 2018 
Protocol Version 3.0 with Letter of Amendment #1 
• 
Fever  
• 
Generally ill feeling  
• 
Extreme tiredness  
• 
Muscle or joint aches  
• 
Blisters or sores in mouth  
• 
Blisters or peeling of the skin  
• 
Redness or swelling of the eyes  
• 
Swelling of the mouth or face  
• 
Problems breathing  
 
Sometimes allergic reactions can affect the body, like the liver and cause liver problems which can lead to 
liver failure. Contact your child’s doctor right away if your child has any of the following signs or 
symptoms of a liver problem: 
• 
Yellowing of the skin or whites of the eyes  
• 
Dark or tea colored urine  
• 
Pale colored stools/bowel movements  
• 
Nausea/vomiting  
• 
Loss of appetite  
• 
Pain, aching or tenderness on the right side below the ribs 
 
In some patients receiving raltegravir blood tests showed abnormally high levels of a muscle enzyme—
creatine kinase which may cause muscle pain, tenderness or weakness this type of muscle break down can 
be serious and lead to kidney damage including kidney failure. Contact your child’s doctor right away if 
your child has any unexplained muscle pain, tenderness, or weakness. 
 
Note: Raltegravir chewable tablets contain phenylalanine, a component of the sugar substitute aspartame. 
Phenylalanine can be harmful to children and adults with phenylketonuria, a birth defect that can lead to a 
variety of health problems.  
 
Risks of Blood Draws 
There is risk of some discomfort, bruising, or bleeding at the site where the blood is drawn.  Occasionally, 
there is swelling in the area where the needle enters the body and a small risk of fainting and/or infection. 
 
Other Risks 
Your child may feel uncomfortable or embarrassed by some parts of your child’s physical exam and with 
some of the questions related to sexual development and activity. 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
It is not known if the study drug raltegravir harms fetuses.  Tests in pregnant animals do show some risk.   
 
Your child will have a medical history and physical exam and we will ask you or your child questions to 
check if your child is having sex that could lead to pregnancy.  If your child is pregnant or breastfeeding, 
she cannot be in the study. If your child is a female and is sexually active, she must agree to use two 
methods of birth control to take the study medicine. Approved methods of birth control for this study 
include hormonal birth control, such as slow release inserts placed under or on the skin, and a medically 
accepted barrier method including condoms, an intrauterine device (IUD), a diaphragm or cervical cap 
with a cream or gel that kills sperm.  If your child is a female and is sexually active while in the study and 
does not agree to use two of these methods of birth control, she can remain in the study, but cannot take 


 
 
IMPAACT P1101 Sample Informed Consent Form 
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15 March 2018 
Protocol Version 3.0 with Letter of Amendment #1 
the study medicine.  If your child is having sex while in the study, your child will be referred to their 
primary provider for prevention of pregnancy.  Your child may also be asked to provide urine or 1 mL of 
blood for a pregnancy test at each visit to check if she is pregnant.  If the pregnancy test is positive, the 
study staff will refer your child to her primary provider for counseling about pregnancy and pregnancy 
care and she should stop taking raltegravir.  Your child will continue to come in for study visits and will 
be followed until the outcome of your child’s pregnancy. If you think your child has started having sex or 
you/your child thinks she may be pregnant at any time during the study, tell the study staff right away.  
The study staff will talk to you/your child about your/your child’s choices.  If your child becomes 
pregnant, she will be entered in the Antiretroviral Pregnancy Registry. 
 
Pregnancy test results will be shared confidentially with participants, even if a parent or other adult is 
consenting for the child’s participation in the study.  [Sites should modify preceding language about 
confidentiality of pregnancy test results to conform to their local practice, regulations and IRB 
requirements.] 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
If your child takes part in this study, there may be a direct benefit to your child, however we do not know 
if being in the study will benefit your child in any way.  It is also possible that your child may receive no 
benefit from being in this study.  Your child will have regular visits and frequent checks on his or her 
health, including tests for the amount of HIV in your child’s blood, called viral load, and for the amount 
of cells that fight HIV, called CD4.  Information learned from this study may help others who have HIV 
and TB. 
  
WHAT OTHER CHOICES DOES MY CHILD HAVE BESIDES THIS STUDY? 
Instead of being in this study you have the choice of: 
• treatment with prescription drugs available to your child 
• treatment with experimental drugs, if your child qualifies 
• no treatment 
 
Please talk to your doctor about these and other choices available to your child. Your doctor will explain 
the risks and benefits of these choices. 
 
WHAT ABOUT CONFIDENTIALITY? 
Efforts will be made to keep your child’s personal information confidential.  Study records and specimens 
will be kept in secure locations.  We cannot guarantee absolute confidentiality.  Despite our best efforts to 
keep your child’s information private, it is possible that the information could be obtained by someone 
who should not have it.  If this were to happen, your child could be treated unfairly.  You could feel stress 
or embarrassment.  Your child’s personal information may be disclosed if required by law.  Any 
publication of this study will not use your child’s name or identify your child personally. 
 
Your child’s records may be reviewed by the U.S. Food and Drug Administration (FDA), the Office of 
Human Research Protections (OHRP), (insert name of site) IRB/EC, National Institutes of Health (NIH), 
study staff, study monitors, Merck & Co., Inc. (the drug company supporting this study), and other US, 
local, and international regulatory entities. 
 


 
 
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15 March 2018 
Protocol Version 3.0 with Letter of Amendment #1 
WHAT ARE THE COSTS TO ME? 
Taking part in this study may lead to added costs to you and your insurance company.  In some cases it is 
possible that your insurance company will not pay for these costs because your child is taking part in a 
research study.  [Sites: Delete or modify as appropriate with any site-specific information regarding 
insurance and local costs.] 
 
WILL I RECEIVE ANY PAYMENT? 
You and your child may receive reimbursement for some expenses for this study.  You and your child 
may receive payment for transportation and meals.   
[Sites: Delete or modify as appropriate with any site-specific information about payment.] 
 
WHAT HAPPENS IF MY CHILD IS INJURED? 
Your child’s health is important to us. We will make every effort to protect your child’s well-being and 
minimized risk to him or her. If your child is injured as a result of being in this study, the study doctor 
will give or refer your child for immediate treatment for your child’s injuries.  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 (NIH).  You will not be giving up any of your legal 
rights by signing this consent form. 
[Sites: Delete or modify as appropriate with any site-specific information regarding insurance and local 
costs.] 
 
WHAT ARE MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary.  You may choose not to allow your child to take part in 
this study or take your child out of the study at any time.  Your child will be treated the same no matter 
what you decide. 
 
We will tell you about new information from this or other studies that may affect your child’s health, 
welfare or willingness to stay in this study.  If you want the results of the study, let the study staff know. 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about this study or a research-related injury, contact: 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your/your child’s/baby’s rights as a research participant, contact: 
• 
name or title of person on the Institutional Review Board (IRB) or other organization appropriate for 
the site 
• 
telephone number of above   


 
 
IMPAACT P1101 Sample Informed Consent Form 
Page 13 of 13   
 
 
 
15 March 2018 
Protocol Version 3.0 with Letter of Amendment #1 
SIGNATURE PAGE   
 
If you have read this consent form (or had it explained to you), all your questions have been answered and 
you agree to take part in this study, please sign your name below. 
 
 
____________________________________        
____________________________________ 
Participant’s Name (print) 
 
 
 
Participant’s Signature and Date  
 
 
 
____________________________________        
____________________________________ 
Participant’s Parent or Legal Guardian (print) 
 
Parent or Legal Guardian’s Signature and Date 
 
 
 
____________________________________        
____________________________________ 
Study Staff Conducting  
              
 
Study Staff Signature and Date  
 
Consent Discussion (print)  
 
 
____________________________________        
____________________________________ 
Witness’ Name (print)  
 
               
Witness’s Signature and Date 
 
 
 
(As appropriate) 
 
 
____________________________________        
____________________________________ 
Father’s Name  
 
 
 
 
Father’s Signature and Date 
(If father’s consent is required)  
 
 
(If father’s consent is required)   

SAP_002.pdf: 
 
 
 This is IMPAACT P1101 SAP Version 1.0 with names of authors, names of publication, writing team 
members, and analysis timeline redacted. 
 
 
Pharmacokinetic Statistical Analysis Plan 
Version 1.0 
 
IMPAACT P1101 
Phase I/II dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-
Containing Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected Infants and 
Children 
 
 
 
 
ClinicalTrials.gov Identifier: NCT01751568 
 
 
 
October 5, 2020 
 
 


 
TABLE OF CONTENTS  
 
1. Introduction 
3 
2. PK-Related Study Background 
3 
3. Dose-Finding Approach 
3 
4. Primary Pharmacokinetic Study Objectives 
4 
5. Non-Compartmental Pharmacokinetic Analyses 
4 
5.1. Below the Level of Quantitation 
5 
5.2. Terminal Slope Estimation 
5 
5.3. AUC Values 
5 
6. Summary Statistics 
5 
7. Presentation of Data 
6  
 
 
 
 
 


1. Introduction 
This Pharmacokinetic Statistical Analysis Plan (PK SAP) is complementary to the IMPAACT P1101 
Primary SAP (version 2.0) and the IMPAACT P1101 PK Data Management Plan (version 2.0). This 
document describes the non-compartmental pharmacokinetic (PK) analysis to be performed by 
the IMPAACT P1101 protocol pharmacologist at the end of study on the completed study 
dataset and included in study abstracts and manuscripts.  
 
2. PK-Related Study Background 
IMPAACT P1101 is a Phase I/II dose-finding, safety, tolerance and pharmacokinetics study of a 
raltegravir (RAL)-containing antiretroviral therapy (ART) regimen in HIV-infected and TB co-
infected infants and children. There is an urgent need for better tolerated, potent, simple 
agents (i.e. simple dosing, administration and storage) to be included in first line ART regimens 
to widen the treatment options for children and infants co-infected with TB and HIV. Based on 
data from prior studies of drug interactions of RIF and RAL in adults, doubling the dose of RAL 
to 12 mg/kg/dose (maximum 800 mg/dose) is an appropriate starting point for this study. The 
UGT1A1 metabolic pathway is fully mature after the first 3 months of life; therefore, co-
administration of RAL and RIF is expected to lead to significant reductions in RAL concentrations 
in children. As pediatric RAL dosing regimens have been shown to achieve PK parameters 
comparable to those in adults, doubling the RAL dose for children when given with RIF will likely 
yield similar improvements in PK parameters. Participants will be enrolled into the study into 
the following cohorts: 
• 
Cohort I: ≥ 2 to < 6 years of age on TB treatment (n = 12 minimum) 
• 
Cohort II: ≥ 6 to < 12 years of age on TB treatment (n = 12 minimum) 
• 
Cohort III: ≥ 4 weeks to < 2 years of age on TB treatment (n = 12 minimum) 
Cohorts I, II, III will enroll simultaneously.  Each age cohort will start with a mini-cohort of six 
participants, followed by six additional participants to make up a full cohort.  
 
3. Dose-Finding Approach 
HIV-infected and TB co-infected children ≥ 4 weeks to < 12 years of age taking RIF-based TB 
therapy and who are eligible for antiretroviral (ARV) treatment as defined by local or WHO 
guidelines. An initial dose of RAL will be given at 12 mg/kg (up to a maximum of 800 mg) twice 
daily for chewable formulation, with two NRTIs.  Following the intensive PK study for RAL (5 to 8 
days after the start of RAL therapy), a fourth ARV drug will be added to the regimen. The four-
drug ARV regimen will be continued until TB treatment is completed. Each child will be followed 
up to assess safety, clinical, immunological and virological parameters, from the time that RAL 
is started on a TB containing regimen until 3 months after stopping RAL while standard of care 
treatment continues.  


Each age cohort will start with a mini-cohort of six participants to assure that preliminary PK 
and safety criteria are met at that dose. Data from each age cohort will be reviewed 
independently and, if the mini-cohort data meets established metrics an additional 6 
participants per age cohort will be enrolled (full cohort), and evaluated for safety and PK. If the 
mini-cohort (n = 6) at a RAL dose of 12 mg/kg achieves 1) a geometric mean RAL AUC0-12hr of 
approximately 14 to 45 μMxhr and 2) an approximate GM C12h ≥ 75nM, and meets safety 
criteria, then 6 additional participants will be enrolled at this dose. The data from these 
participants will be combined with the previous 6 for evaluation of this dose using the same 
criteria.  
 
If the initial mini-cohort of n = 6 fails either the safety or the PK guidelines in this initial test, 
then the dose will be adjusted in the appropriate direction, unless dose reduction is likely to 
result in inadequate PK values. An initial evaluation of the new dose level will be made on the 
basis of data from the first six new participants treated at this dose. If the first six participants 
of a cohort meet both sets of guidelines, then six additional participants will be accrued to this 
cohort. The additional six participants will be evaluated on both safety and PK; if the full cohort 
of n = 12 passes both safety and PK criteria, then the dose on which they have been treated will 
become the selected dose. 
 
Note: Please see Section 8.5.1 of the protocol V3.0 for details regarding Safety Guidelines. 
 
4. Primary Pharmacokinetic Study Objectives 
To determine the pharmacokinetics and appropriate dose of RAL when administered with a RIF-
containing anti-TB therapy in HIV/TB co-infected infants and children that generates PK 
parameters generally comparable to those seen in HIV-infected infants and children in the 
absence of RIF. 
 
5. Non-Compartmental Pharmacokinetic Analyses 
PK sampling was collected at pre-dose (0), 0.5, 1, 2, 3, 4, 6, 8, and 12 hours post dosing. A single 
0.5 mL sample of whole blood was collected at each time point. Standard non-compartmental 
methods for PK parameter derivation will be performed using Phoenix WinNonlin 8.1 (or 
current, Certara USA, Inc.). Where possible, the following PK parameters will be determined 
from RAL plasma concentration-time data: 
Parameter  
Definition  
Cmax 
Observed maximum plasma concentration  
Tmax 
Time of maximum plasma concentration  
AUC(0-12) 
Area under the concentration-time curve from time zero to the 
end of the dosing interval at 12 hours at steady-state 


CLss/F 
Apparent oral clearance at steady-state 
Vz/F 
Apparent distribution volume at steady-state 
λz 
Terminal elimination rate constant  
t1/2 
Terminal half-life calculated as ln(2)/λz  
C12h 
Concentration at the end of the dose interval at 12 hours 
 
Additional PK parameters may be determined where appropriate. Pharmacokinetic analysis will 
be carried out using actual sampling times provided by the UAB PSL.  
 
5.1. 
Below the Level of Quantitation  
RAL concentration values that are below the level of quantification (LLOQ), < 10 ng/mL, will be 
set to ½ the LLOQ. If an entire concentration-time profile is LLOQ, 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 ½ the LLOQ. Any embedded BLQ value (BLQ value occurring between two quantifiable 
concentrations) in a profile will be set to missing for the purposes of PK analysis.  
 
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. In the case of only two terminal concentrations can be chosen 
for t1/2 determination, these points will be chosen by pharmacokineticist.  
 
5.3. AUC Values  
AUC is calculated by the linear trapezoidal rule. Since this study is evaluating RAL PK at steady-
state, the only important AUC parameter is the 12 hour result, AUC0-12h.  
 
6. Summary Statistics 
All individual concentrations and all pharmacokinetic parameters will be summarized using 
descriptive statistics. These will include the n, mean, standard deviation, CV%, median, range 
and geometric mean. For dissemination, selected descriptive statistics on evaluable participants 
will be used as appropriate for the data distribution. PK parameters will be summarized by 
cohort.  
 
 


 
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. RAL concentrations and PK parameters will be listed out separately for any participant 
not included in the dose-finding population. Additional tables, listings or figures may be 
prepared upon request. 

Prot_003.pdf: 
 
IMPAACT P1101 
 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-
Containing Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected 
Infants and Children  
 
A Multicenter, International Trial of the 
International Maternal Pediatric Adolescent AIDS 
Clinical Trials Network (IMPAACT) 
 
 
Protocol: VERSION 3.0 
FINAL 
24 April 20 
 
 
NCT 01751568 
 


 
 
IMPAACT P1101 
 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-Containing 
Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected Infants and Children  
 
(DAIDS Document ID 11831) 
 
A Multicenter, International Trial of the 
International Maternal Pediatric Adolescent AIDS 
Clinical Trials Network (IMPAACT) 
 
Sponsored by: 
The National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National 
Institute of Child Health and Human Development (NICHD),  
and the National Institute of Mental Health (NIMH) 
 
Pharmaceutical Support Provided by: 
Merck & Co., Inc. 
 
IND# 77,787 held by NIAID 
 
 
IMPAACT Treatment  
Scientific Committee Chair:   
Elaine Abrams, MD 
 
 
Protocol Co-Chairs:   
 
Tammy Meyers, MD 
 
 
Paul Krogstad, MD 
 
 
NIAID Medical Officer:  
 
Ellen Townley, MSN, FNP 
 
NICHD Medical Officer:  
 
Jack Moye, MD 
 
Clinical Trials Specialist:  
 
Sarah Bradford, MPH 
Kathleen George, MPH  
 
 
 
VERSION 3.0 
FINAL 
24 April 2017
 
 
 


 
 
 
IMPAACT P1101 
ii 
 
24 April 2017 
FINAL Version 3.0 
PROTOCOL SIGNATURE PAGE 
IMPAACT P1101 
 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-Containing 
Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected Infants and Children  
 
DAIDS Document ID 11831 
 
Version 3.0, dated 24 April 2017 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
__ 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 


 
 
IMPAACT P1101 PROTOCOL TEAM ROSTER 
 
 
IMPAACT P1101 
iii 
 
24 April 2017 
FINAL Version 3.0 
Protocol Co-Chairs 
Tammy Meyers, MD 
1702 Block 82 
Bamboo Grove 
74-86 Kennedy Road 
Wan Chai 
Hong Kong 
People’s Republic of China 
Phone: +852 2812 6121 
Email: tammy@meyers.net 
 
Paul Krogstad, MD 
David Geffen School of Medicine at UCLA 
Pediatrics Room 22-442 MDCC M.C. 175217 
10833 Le Conte Avenue 
Los Angeles CA 90095-1752 
Phone: (310) 825-5235 
Email: pkrogstad@mednet.ucla.edu 
 
NIAID Medical Officer  
Ellen Townley, MSN, FNP 
DAIDS/NIAID/NIH  
5601 Fishers Lane, 8B17 
Rockville, MD 20852 
Phone: (240) 292-4784 
Email: townleyem@niaid.nih.gov   
 
NICHD Medical Officer 
Jack Moye, MD 
Maternal and Pediatric Infectious Disease Branch 
Eunice Kennedy Shriver National Institute for 
Child Health and Human Development  
National Institutes of Health  
Bldg. 6710B Rm. 2146  
6710B Rockledge Drive 
Bethesda, MD  20817 
Phone: (301) 594-8624 
Email: john.moye@nih.gov 
 
Clinical Trials Specialists 
Sarah Bradford, MPH 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: (919) 544-7040 x11685 
Email: sbradford@fhi360.org 
 
Kathleen George, MPH 
FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: (919) 544-7040 x11150 
Email: kgeorge@fhi360.org 
 
Protocol Senior Statistician 
Pearl Samson, MS 
Center for Biostatistics in AIDS Research 
(CBAR), Harvard T.H. Chan School of Public 
Health/Frontier Science & Technology Research 
Foundation (FSTRF) 
1371 Beacon Street, Suite 203 
Brookline MA 02446 
Phone: (617) 632-2000 x4030 
Email: psamson@sdac.harvard.edu 
 
Protocol Data Managers 
Linda Marillo, BA 
Frontier Science & Technology Research 
Foundation  
4033 Maple Road  
Amherst, NY  14226-1056 
Phone: (716) 834-0900 x7257 
Email: marillo@fstrf.org 
 
Protocol Pharmacist 
Thucuma Sise, PharmD, BCPS 
NIH, NIAID, DAIDS, PAB  
5601 Fishers Lane, 9A27 
Rockville, MD  20852 
Phone: (240) 292-4848 
Email: thucuma.sise@nih.gov 
 
Protocol Virologists 
Grace Aldrovandi, MD 
IMPAACT Virology Laboratory 130 
4546 Sunset Blvd, MS 51 
Smith Research Tower, Room 902 
Los Angeles CA 90027 
Phone: (323) 361-8501 
Email: gracea@mac.com 
 


 
 
IMPAACT P1101 PROTOCOL TEAM ROSTER 
 
 
IMPAACT P1101 
iv 
 
24 April 2017 
FINAL Version 3.0 
Julie Nelson, PhD 
University of North Carolina at Chapel Hill 
CB 7291; GSB 2163 
Chapel Hill NC 27599 
Phone: (919) 966-6872 
Email: jnelson@med.unc.edu 
 
Protocol Immunologist 
Savita Pahwa, MD 
University of Miami School of Medicine  
Batchelor Research Institute, Room 712  
1580 Northwest 10th Avenue  
Miami, FL  33136 
Phone: (305) 243-7732 
Email: spahwa@med.miami.edu 
 
Protocol Pharmacologists 
Edward Acosta, PharmD 
Division of Clinical Pharmacology 
Department of Pharmacology and Toxicology 
1530 3rd Avenue South, VH 116 
Birmingham AL 35294-0019 
Phone: (205) 934-2655 
Email: eacosta@uab.edu 
 
Laboratory Technologist 
Paul Harding, MS 
Pediatric Infectious Diseases 
Mail Stop 8604, Building 15 
12700 E. 19th Avenue, Room 11460-A 
Aurora, CO 80045 
Phone: (303) 724-3404 
Email: Paul.Harding@ucdenver.edu 
 
Central Laboratory Specialist 
Carolyn Yanavich, MS, RAC 
IMPAACT Laboratory Center 
Children's Hospital of Los Angeles 
Smith Research Tower 
4546 Sunset Blvd, Room 902 
Los Angeles, CA 90027 
Phone: (443) 249-3851 
Fax: (323) 361-8599 
Email: cyanavich@impaactlabcenter.org 
 
Laboratory Data Coordinator 
Laura Hovind, BS, MS  
Frontier Science & Technology  
Research Foundation  
4033 Maple Road  
Amherst, NY 14226 
Phone: (716) 834-0900 x7468  
Email: hovind@fstrf.org 
 
Investigators 
Andrew Wiznia, MD 
Jacobi Medical Center 
1400 Pelham Parkway South 
Bldg 1-1W5-8 
Bronx NY 10461 
Phone: (718) 918-4664 
Email: andrew.wiznia@einstein.yu.edu 
 
Mandar Paradkar, MBBS, DCH 
BJ Medical College  
Pathology Museum, First Floor Jayprakash 
Narayan Road 
Pune, India 
Phone: +91-9823457325 
Email: drman23@gmail.com 
 
Pharmaceutical Company Representative 
Hedy Teppler, MD 
351 N. Sumneytown Pike 
P.O. Box 1000 
North Wales, PA 19454-2505 
Phone: (267) 305-7403 
Email: hedy_teppler@merck.com 


 
 
 
IMPAACT P1101 SITE INVESTIGATORS  
 
 
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Site 8051, Shandukani Research Centre 
Lee Fairlie, MD 
SMACHC 2nd Floor 
Hillbrow Health Precinct 
Corner Esselen St. and Klein St. 
Hillbrow 
Johannesburg, Gauteng 2001 
South Africa 
Phone: +27-11-3585317 
Email: lfairlie@wrhi.ac.za 
 
Hermien Gous, PharmD 
SMACHC 2nd Floor 
Hillbrow Health Precinct 
Corner Esselen St. and Klein St. 
Hillbrow 
Johannesburg, Gauteng 2001 
South Africa 
Phone: +27-11-3585502  
Email: hgous@wrhi.ac.za 
 
Site 8052, Soweto CRS 
Avy Violari, MD 
Perinatal HIV Research Unit 
Chris Hani Baragwanath Hospital 
P.O Box 114, Diepkloof, Soweto 
Johannesburg 
Soweto 2013 
South Africa 
Phone: +27-11-9899707 
Email: violari@mweb.co.za 
 
Nasreen Abrahams, MBA, BTech 
Perinatal HIV Research Unit 
Chris Hani Baragwanath Hospital 
P.O Box 114, Diepkloof, Soweto 
Johannesburg 
Soweto 2013 
South Africa 
Phone: +27-11-9899742 
Email: abrahamsn@phru.co.za 
 
Site 8950, FAM-CRU CRS 
Mark Cotton MMed, PhD, MBChB, NP 
Stellenbosch University 
Ward J8, Tygerberg Academic Hospital 
Francie Van Zijl Dr., Parow Valley, 7505 
Cape Town, South Africa 
Phone: +27-21-9384219 
Email: mcot@sun.ac.za 
 
Joan Coetzee CPN, PN 
Stellenbosch University 
Ward J8, Tygerberg Academic Hospital 
Francie Van Zijl Dr., Parow Valley, 7505 
Cape Town, South Africa 
Phone: +27-21-9384157 
Email: joan@sun.ac.za 
 
Site 31790: Desmond Tutu TB Centre CRS 
Anneke Hesseling, MD, PhD 
Director, Paediatric Research 
Desmond Tutu TB Centre 
Department of Pediatrics and Child Health 
Stellenbosch University, South Africa 
Phone: +27 219389173 
Fax: +27 21 9389702 
Email: annekeh@sun.ac.za 
 
Frieda Verheye-Dua, MD 
Desmond Tutu TB Centre 
Department of Pediatrics and Child Health 
Stellenbosch University, South Africa 
Phone: +27 21 9389772 
Fax: +27 86 689 9929 
Email: frieda@sun.ac.za 
 
 


 
 
STUDY MANAGEMENT 
 
 
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• 
All questions concerning this protocol, including questions regarding clinical management of 
study participants, should be sent via email to the IMPAACT P1101 Protocol Team 
(impaact.teamp1101@fstrf.org). Remember to include the participant’s PID when applicable. The 
appropriate team member will respond to questions via e-mail.  A response should generally be 
received within 24 hours (Monday - Friday).  
 
• 
For protocol registration questions email protocol@tech-res.com or call (301) 897-1707.  
Protocol registration material can be sent electronically to epr@tech-res.com or via fax at 1-800-
418-3544 or (301) 897-1701.  
 
• 
For data management computer and screen problems email user.support@fstrf.org or call the 
DMC at (716) 834-0900 x7302. 
 
• 
For questions or problems regarding study drug supplies, records, and returns, contact the DAIDS 
Protocol Pharmacist at thucuma.sise@nih.gov or call (301) 451-2775. 
 
• 
For Expedited Adverse Event (EAE) reporting questions contact the DAIDS RSC Safety Office 
via email (DAIDSRSCSafetyOffice@tech-res.com) or phone (1-800-537-9979 or +1-301-897-
7448) or fax (1-800-275-7619 or +1-301-897-1710).  For questions about the DAIDS Adverse 
Experience Reporting System (DAERS), please contact NIAID CRMS Support at 
CRMSSupport@niaid.nih.gov.  Questions may also be sent within the DAERS application. 
 
• 
Email the Computer Support Group at the Data Management Center (DMC) 
(user.support@fstrf.org) to have relevant site personnel added to the protocol email group 
(impaact.protp1101@fstrf.org).  Inclusion in the protocol email group will ensure that sites 
receive important information about the study during its implementation and conduct. 
 
 


 
 
 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .......................................................................................................... II 
GLOSSARY............................................................................................................................................... IX 
SCHEMA ..................................................................................................................................................... 1 
1.0 
INTRODUCTION.......................................................................................................................... 4 
1.1 
Background ......................................................................................................................... 4 
1.2 
Recommended ARV Regimen in the Presence of Rifampicin-Containing TB Treatment . 4 
1.3 
Rationale for Using Raltegravir with TB Treatment .......................................................... 6 
1.4 
Rationale for Studying Raltegravir Chewable Formulation as a Dispersible Tablet ........ 10 
1.5 
Rationale for Adding a Fourth ARV Drug with RAL during TB Treatment .................... 11 
2.0 
STUDY OBJECTIVES ................................................................................................................ 11 
2.1 
Primary Objectives ........................................................................................................... 11 
2.2 
Secondary Objectives ....................................................................................................... 11 
3.0 
STUDY DESIGN .......................................................................................................................... 11 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................... 12 
4.1 
Inclusion Criteria .............................................................................................................. 12 
4.2 
Exclusion Criteria ............................................................................................................. 15 
4.3 
Concomitant Medication Guidelines ................................................................................ 16 
4.4 
Protocol Registration and Enrollment Procedures ............................................................ 17 
4.5 
Co-enrollment Procedures ................................................................................................ 18 
5.0 
STUDY TREATMENT ............................................................................................................... 18 
5.1 
Drug Regimen, Administration and Duration ................................................................... 18 
5.2 
Drug Formulation ............................................................................................................. 20 
5.3 
Drug Supply, Distribution and Pharmacy ......................................................................... 21 
6.0 
PARTICIPANT MANAGEMENT ............................................................................................. 21 
6.1 
Toxicity Management ....................................................................................................... 21 
6.2 
Participant Management Plan ........................................................................................... 26 
6.3 
Toxicity Endpoints ............................................................................................................ 29 
6.4 
Virologic Endpoints .......................................................................................................... 29 
6.5 
Pharmacokinetic Endpoint ................................................................................................ 29 
6.6 
Permitted Changes to ARV Background Regimen ........................................................... 30 
6.7 
Criteria for Early Treatment Discontinuation ................................................................... 30 
6.8 
Criteria for Early Study Discontinuation .......................................................................... 30 
6.9 
Contraception Counselling, Pregnancy Testing and Pregnancy ....................................... 30 
7.0 
EXPEDITED ADVERSE EVENT (EAE) REPORTING ........................................................ 32 
7.1 
Adverse Event Reporting to DAIDS ................................................................................. 32 
7.2 
Reporting Requirements for this Study ............................................................................. 32 
7.3 
Grading Severity of Events ............................................................................................... 32 
7.4 
Expedited AE Reporting Period........................................................................................ 33 


 
 
 
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STATISTICAL CONSIDERATIONS ....................................................................................... 33 
8.1 
General Design Issues ....................................................................................................... 33 
8.2 
Outcome Measures ........................................................................................................... 34 
8.3 
Randomization and Stratification ..................................................................................... 35 
8.4 
Sample Size and Accrual .................................................................................................. 35 
8.5 
Monitoring ........................................................................................................................ 36 
8.6 
Analyses ............................................................................................................................ 41 
9.0 
CLINICAL PHARMACOLOGY PLAN ................................................................................... 43 
9.1 
Pharmacology Objectives ................................................................................................. 43 
9.2 
Study Design, Modeling and Data Analysis ..................................................................... 43 
9.3 
Anticipated Outcomes ....................................................................................................... 45 
10.0 
HUMAN PARTICIPANTS ......................................................................................................... 45 
10.1 
Institutional Review Board and Informed Consent........................................................... 45 
10.2 
Participant Confidentiality ................................................................................................ 46 
10.3 
Study Discontinuation ....................................................................................................... 46 
11.0 
PUBLICATION OF RESEARCH FINDINGS ......................................................................... 46 
12.0 
BIOHAZARD CONTAINMENT ............................................................................................... 46 
13.0 
REFERENCES ............................................................................................................................. 47 
APPENDICES 
I: SCHEDULE OF EVALUATIONS ...................................................................................................... 50 
II: RALTEGRAVIR WEIGHT BAND DOSING TABLES FOR CHEWABLE TABLET .............. 53 
III: SUPPLEMENTAL TOXICITY TABLE FOR GRADING SEVERITY OF 
CUTANEOUS/SKIN RASH/DERMATITIS ADVERSE EVENTS ........................................ 55 
IV: MANAGEMENT GUIDE FOR SUSPECTED ABACAVIR (ABC) HYPERSENSITIVITY 
REACTIONS ................................................................................................................................ 56 
V: TERMINOLOGY, DEFINITIONS AND MANAGEMENT GUIDE FOR IMMUNE 
RECONSTITUTION INFLMMATORY SYNDROME (IRIS) .............................................. 59 
VI: SAMPLE INFORMED CONSENT FORM FOR STUDY PARTICIPATION ........................... 61 
  
  
 
 


 
 
 
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GLOSSARY 
ABC 
Abacavir 
ACTG 
AIDS Clinical Trials Group 
AE/EAE 
Adverse Event  
AFB 
Acid Fast Bacilli 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Amino Alaninetransferase 
ART/ARV 
Antiretroviral Therapy / Antiretroviral 
AST 
Aspartate Aminotransferase 
AUC/AUC12/AUC24 
Area Under the Curve 
BCG 
Bacille Calmette-Guerin 
C12h 
Plasma concentration at the end of the 12 hour dosing interval 
Cmax 
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration 
Ctrough 
Trough Plasma Concentration 
CRF 
Case Report Form 
CRPMC 
Clinical Research Products Management Center 
CXR 
Chest X-ray 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS, NIAID 
DILI 
Drug-Induced Liver Injury 
DMC 
Data Management Center 
DSMB 
Data and Safety Monitoring Board 
EAE 
Expedited Adverse Event 
EC 
Ethics Committee 
EFV 
Efavirenz 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
GM 
Geometric Mean 
HAART 
Highly Active Antiretroviral Therapy 
HIV 
Human Immunodeficiency Virus 
HSR 
Hypersensitivity Reaction 
ICF 
Informed Consent Form 
IC50/IC90 
Inhibitory Concentration – 50% / Inhibitory Concentration 90% 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network  
INH 
Isoniazid 
IRB 
Institutional Review Board 
IRIS 
Immune Reconstitution Inflammatory Syndrome 
IUATLD 
International Union against Tuberculosis and Lung Disease 
IUD 
Intrauterine Device 
LDMS 
Laboratory Data Management System 
LFT 
Liver Function Test 
LPC 
Laboratory Processing Chart 
LPV/r 
Lopinavir/Ritonavir 
M.tb./MTB 
Mycobacterium tuberculosis 
MDR TB 
Multi-Drug-Resistant Tuberculosis 
NEC 
Network Executive Committee 
NEVEREST 
Nevirapine Resistance Study 
NIAID 
National Institute of Allergy and Infectious Diseases 
NICHD 
The Eunice Kennedy Shriver National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 


 
 
 
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NNRTI 
Non-Nucleoside Reverse Transcriptase Inhibitor 
NRTI 
Nucleoside Reverse Transcriptase Inhibitor 
NVP 
Nevirapine 
OHRP 
Office for Human Research Protections 
PCP 
Pneumocystis jirovecii (previously Pneumocystis carinii) Pneumonia  
PCR 
Polymerase Chain Reaction 
PDMC 
Protocol Development and Monitoring Committee 
PI 
Protease Inhibitor 
PK 
Pharmacokinetics 
PMTCT 
Prevention of Mother To Child Transmission 
PRO 
Protocol Registration Office 
PSWP 
Protocol-Specific Web Page 
PZA 
Pyrazinamide 
RAL 
Raltegravir 
RE 
Regulatory Entity 
RIF 
Rifampicin 
RLS 
Resource-Limited Settings 
RSC 
Regulatory Support Center 
RTV 
Ritonavir 
SAE 
Serious Adverse Event 
SJS 
Stevens-Johnson Syndrome 
SES 
Subject Enrollment System 
SMC 
Study Monitoring Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TB / PTB  
Tuberculosis / Pulmonary TB 
TEN 
Toxic Epidermal Necrolysis 
Tmax 
Time to Cmax  
TST 
Tuberculin Skin Test 
UGT 
Uridine Diphosphate Glucuronosyltransferase 
ULN 
Upper Limit of Normal 
US 
United States 
WHO 
World Health Organization 
XDR TB 
Extensively Drug-Resistant Tuberculosis 
ZDV 
Zidovudine 
 


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IMPAACT P1101 
 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-Containing 
Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected Infants and Children  
 
 
DESIGN:  
Phase I/II, dose-finding, safety, tolerability and pharmacokinetics study 
of raltegravir (RAL) in infants and children who have received ≥ 1 week 
and ≤ 20 weeks of Rifampicin (RIF)-based TB therapy prior to initiation 
of antiretroviral therapy. 
 
SAMPLE SIZE: 
Approximately 36 to 108 to achieve a target of 12 evaluable infants and 
children for each cohort at the final recommended dose. 
 
POPULATION: 
HIV-infected and TB co-infected infants and children ≥ 4 weeks to < 12 
years of age taking RIF-based TB therapy and who are eligible for 
antiretroviral (ARV) treatment as defined by local or WHO guidelines. 
 
STRATIFICATION: 
Participants will be enrolled into the study into the following cohorts: 
 
Cohort I: ≥ 2 to < 6 years of age on TB treatment (n = 12 minimum) 
 
Cohort II: ≥ 6 to < 12 years of age on TB treatment (n = 12 minimum) 
 
Cohort III: ≥ 4 weeks to < 2 years of age on TB treatment (n = 12 
minimum) 
 
Cohorts I, II, III will enroll simultaneously.  Each age cohort will start 
with a mini-cohort of six participants, followed by six additional 
participants to make up a full cohort. 
 
REGIMEN: 
Chewable RAL tablet, starting dose of 12 mg/kg (up to a maximum dose 
of 800 mg) orally twice daily in addition to, as part of standard of care, 
two NRTIs plus RIF-containing regimen for treatment of TB.    
  
Following an intensive PK visit, a fourth ARV drug will be added to the 
RIF-containing regimen. 
 
TREATMENT DURATION: The four drug ARV regimen (including 
RAL, 2 NRTIs plus an additional ARV drug per local standard of care) 
will be continued until TB treatment is completed and then RAL will be 
discontinued.  The three drug ARV regimen will be continued per local 
standard of care after RAL is discontinued.  
 
STUDY DURATION: 
Participants will be followed for up to three months post discontinuation 
of RAL. 
 
 


 
 
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PRIMARY OBJECTIVES: 
 
1. To determine the pharmacokinetics and appropriate dose of RAL when administered with a RIF-
containing anti-TB therapy in HIV/TB co-infected infants and children that generates PK parameters 
generally comparable to those seen in HIV-infected infants and children in the absence of RIF. 
 
2. To determine safety and tolerance of RAL-containing ART when administered with a RIF-containing 
anti-TB therapy in HIV/TB co-infected infants and children.    
 
SECONDARY OBJECTIVES: 
 
1. To describe the short-term treatment outcomes of infants and children using a RAL-containing ART 
regimen co-treated with a RIF-containing TB treatment (see Sections 8.2.3 and 8.2.4). 
 
2. To explore whether infants and children receiving a RAL-containing ART regimen, co-treated with a 
RIF-containing TB treatment, develop ARV drug associated resistance mutations (see Section 6.2.3). 
 
 
 


 
 
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Notes:  
• 
For each mini-cohort, a routine Study Monitoring Committee (SMC) review of the safety and PK data will be done prior 
to accrual of the full-cohort. 
• 
All participants will stop RAL after TB treatment is completed.  The ARV regimen will continue per local standard of 
care.  All participants will be followed for 3 months after RAL is discontinued. 
• 
RAL dose adjustment will only be done once in a mini/full cohort that fails safety and RAL PK. 
• 
RAL PK will not be repeated in mini/full cohort that has adjustment in RAL dose. 
RAL PK at 5 to 8 days. 
Add a 4th ARV drug per local standard 
of care to the regimen after PK study. 
Team and SMC evaluate safety and RAL PK 
for mini-cohort of 6 participants in each age 
group in real time.   
Simultaneously enroll infants and children receiving RIF-containing treatment for TB:  
 
• 
Cohort I (≥ 2 to < 6 years of age), initial mini-cohort of 6 participants 
• 
Cohort II (≥ 6 to < 12 years of age), initial mini-cohort of 6 participants 
• 
Cohort III (≥ 4 weeks to < 2 years of age), initial mini-cohort of 6 participants 
An additional 6 participants will be enrolled in each cohort for accrual of the full cohort.  
The three age cohorts will be managed identically and independently. 
Evaluate safety and RAL PK in real 
time for these additional 6 participants. 
RAL (chewable formulation) at 12 mg/kg up to a maximum dose of 800 mg twice 
daily plus 2 NRTIs started at study entry, plus a RIF-containing TB regimen 
Mini-cohort 
fails safety 
or RAL PK. 
Mini-cohort passes 
safety and RAL PK. 
Full cohort (with 
additional 6 
participants) fails 
Enroll 6 new participants (full cohort) on same RAL dose plus 2 NRTIs. 
Adjust RAL dose.  Enroll new 
mini-cohort (n = 6) on new RAL 
dose plus 2 NRTIs.  Adjust 
dose of existing mini/full cohort 
if still on RAL. 
Full cohort passes safety and PK 
Safety and PK reviews 
of the full cohort are 
inconclusive. 
Request for Study 
Monitoring Review. 
RAL PK at 5 to 8 days.  Add a 4th ARV drug per local standard of care to the 
regimen after PK study. 
Dose is recommended 


 
 
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INTRODUCTION 
1.1 
Background 
The burden of tuberculosis (TB) among HIV-infected adults and children is very high in many resource-
limited settings (RLS). This is of particular concern in Sub-Saharan Africa where up to 75% of HIV-
infected people may have infection with agents of TB (1).  In Cape Town, South Africa, 70% of adult 
patients initiated on antiretroviral therapy (ART) either had a previous episode of active TB or had been 
treated for TB within the first year of initiating ART (2).  It is estimated that children account for about 15 
to 20% of the annually reported TB cases (3).  Up to a quarter of children starting ART have been 
reported to be receiving TB treatment in South Africa (4, 5).  
 
Bacille Calmette-Guerin vaccine (BCG) disease has also been shown to be prevalent among HIV-infected 
children, particularly as immune reconstitution inflammatory syndrome (IRIS) in the first weeks of 
administration of ART. In the Nevirapine Resistance Study (NEVEREST), BCG disease was the most 
common form (71%) of IRIS, exceeding TB (6).  Although usually localized, BCG disease is often 
treated with a Rifampicin (RIF)-containing regimen because of fear of dissemination of BCG in the 
immunocompromised child. In addition, incident TB has been described to occur after the start of ART 
(5, 6).  The implications of this are that a high proportion of children on ART in TB prevalent areas will 
require TB treatment during the course of ART. Regimens that minimize interactions between the two 
therapies are being investigated. 
 
The current World Health Organization (WHO) guidelines for ART in infants and children provide 
recommendations based on the patient age, drug availability, and history of exposure to nevirapine as part 
of efforts to prevent infection.   Nevirapine (NVP)-based therapy has been the first-line regimen for 
infants and children in most resource limited settings as NVP is relatively inexpensive, can be used in 
infants and children under 2 years of age, and is frequently a component of fixed dose combination (FDC) 
therapy.  The consolidated guidelines for HIV management, which were released in 2013, recommend the 
boosted protease inhibitor lopinavir/ritonavir (LPV/r) for use in first line therapy for infants and children 
who are younger than three years of age. These changes were based on evidence from the P1060 study 
which demonstrated that LPV/r containing regimens were superior to NVP-containing treatment in terms 
of virologic outcomes.  Efavirenz (EFV)-based treatment regimens are still recommended for first-line 
therapy in children older than 3 years (7).  Second-line therapy for children who fail the initial non-
nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimen should contain protease inhibitor 
(PI)-based therapy usually LPV/r.   
 
Drug interactions between TB treatment and ART are well described.  RIF, as a component of first-line 
antibacterial regimen for TB, is usually used in combination with isoniazid (INH) and pyrazinamide 
(PZA). RIF is a strong inducer of the cytochrome P450 enzymes including the CYP 3A4 isoenzymes, 
uridine diphosphate-glucuronosyltransferases, and P-glycoprotein. 
 
1.2 
Recommended ARV Regimen in the Presence of Rifampicin-Containing TB Treatment  
There are limited data to guide treatment options for HIV/TB coinfection in infants and children.  WHO 
recommendations include; triple NRTI regimens, NVP-containing regimens with NVP dosed at 200 
mg/m2, EFV for children who are older than 3 years, and LPV/r with extra ritonavir known as “super-
boosted”  LPV/r. (8) 
 
Evidence from the ARROW study, which showed that three-NRTI long-term maintenance was 
immunologically and clinically similar to NNRTI-based ART, was used to support this strategy for use 
with TB coinfected children. However, data were limited in the context of TB co-treatment. (9) 


 
 
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Lower NVP levels during co-administration with RIF have been documented in adults (10).  In children, 
there are limited and conflicting data (See Table 1). 
 
 
Table 1: Impact of Rifampicin on Nevirapine Pharmacokinetics 
  
Thailand (11) 
Uganda (12) 
Zambia (13) 
N 
8 with TB 
7 with TB 
21 with TB 
16 controls 
- NO TB 
Median Age (years) 
(range) 
9.7 
(4.4-11.8) 
 
1.55 
(0.66 – 3.18) 
1.33 
(0.56 – 2.51) 
Daily dose (mg/m2) 
342 (median) 
(range: 300-526) 
 
353 (mean) 
(IQR: 326 – 375) 
362 (mean) 
(IQR: 318 – 
405) 
Median Cmin 
(mg/L) (range) 
6.48 
(3.03-13.66) 
0% < 3 mg/L 
2.92 
(1.67-9.98) 
2.93 
(1.06–11.4) 
52% < 3 mg/L 
5.93 
(3.28–18.1) 
0% < 3 mg/L 
 
 
NVP at a dose of 200 mg/m2 is recommended for use in conjunction with RIF-containing TB treatment 
because of the aforementioned PK problems where enhanced metabolism of NVP occurs when co-
administered with RIF.   
 
EFV is a commonly used NNRTI in combination therapy in RLS for older children who are starting ART.  
In a small study of EFV pharmacokinetics (PK) with RIF-containing TB regimens, no significant 
difference was documented in the levels of EFV between those with and without concomitant TB 
treatment (14).  Based on these limited findings, EFV-containing therapy without dose-adjustment is 
recommended for use with TB treatment.  This finding is the participant of further evaluations in younger 
children (IMPAACT P1070, Dose-Finding and Pharmacogenetic Study of Efavirenz in HIV-Infected and 
HIV/TB Co-infected Infants and Children ≥ 3 Months to < 36 Months of Age) and may require further 
investigations in older children. 
 
A study in healthy adult volunteers treated with RIF showed that the Cmin of LPV was best preserved by 
taking additional ritonavir to the fixed LPV/r preparation yielding a LPV: Ritonavir (RTV) ratio of 1:1 
which is referred to as “super boosted” LPV/r (15).  This was investigated in a study involving an HIV-
infected pediatric cohort.  The combination of additional RTV with RIF was well tolerated in a small 
cohort of children and therapeutic LPV levels were maintained (16).    
 
While LPV/r is a potent agent, the liquid formulation of the drug has an unpleasant flavor, requires 
refrigeration for storage, and has long term lipid safety concerns. Although it has been demonstrated that 
adequate drug exposure can be maintained by ‘super-boosting’, this method of treatment is complex and 
may be poorly tolerated outside of a clinical trial.  Care providers will be challenged in insuring 
adherence with high dose RTV due to poor palatability, toxicity and extra dosing volume. RTV has a very 
short shelf life causing challenges with ensuring that pharmacies have adequate stock on hand, and 
families can store drug as required.   
 
There is an urgent need for better tolerated, potent, simple agents (i.e. simple dosing, administration and 
storage) to be included in first line ART regimens to widen the treatment options for infants and children 
co-infected with TB and HIV.  
 


 
 
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1.3 
Rationale for Using Raltegravir with TB Treatment 
There is a clear requirement for newer ART agents which are well tolerated, potent and which have 
minimal interactions with rifampicin-containing TB therapy.  One potential class of drugs to consider is 
the group of HIV-1 integrase inhibitors.  The HIV-1 integrase catalyzes the stepwise process that results 
in the integration of the HIV-1 DNA into the genome of the host cell.  This ordered series of reactions 
includes the assembly of integrase in a stable complex with the viral DNA, the endonucleolytic 
processing of the viral DNA ends, and strand transfer or joining of the viral and cellular DNAs.  
Integration is required for stable maintenance of the viral genome as well as efficient viral gene 
expression. 
 
Raltegravir (Isentress™, RAL) is a potent and selective inhibitor of HIV-1 integrase catalyzed strand 
transfer (IC50=10 nM).  Raltegravir exhibits >1,000-fold selectivity over other phosphotransferases, 
including the structurally related enzyme HIV-1 RNase H and the human DNA polymerases, α, β, and γ 
(IC50 values > 50 µM).  The antiretroviral potency of raltegravir (initially estimated as having an IC95 of 
31 ± 20 nM; 50% human serum) measured in vitro is comparable to many clinically efficacious 
antiretroviral therapeutics. 
   
RAL is not a CYP3A4 inducer or inhibitor and therefore could potentially be used with drugs 
metabolized by CYP3A4.  However, as noted above, RIF induces phase II enzymes such as UDP-
glucoronosyl transferase and since RAL undergoes glucuronidation in the liver a precaution has been 
placed on the co-administration of the two drugs without drug dose modification of RAL.  In adults, 
doubling the dose of RAL when given in conjunction with RIF partially overcame this PK interaction, 
resulting in adequate RAL plasma Cmax and AUC, but did not overcome the RIF effect on Ctrough 
concentrations (C12h) (17).  RAL was granted traditional approval by the U. S. Food and Drug 
Administration (FDA) in January 2009.  This approval was updated in February 2009 to include the 
recommendation to increase RAL dose to 800 mg twice daily during co-administration with RIF.  
Additionally, caution is recommended when co-administering RAL with other strong UGT1A1 inducers 
due to reduced RAL plasma concentrations.  This experience suggests a doubling of formulation in 
children would also be warranted.   
 
However, recent data from a study showing inferior efficacy with 800 mg once daily raltegravir compared 
to 400 mg twice daily (HIV RNA < 50 copies/mL at Week 48: QD 83.2%, BID 88.9%) have indicated 
that the shape of the raltegravir concentration-time curve is also important for long-term efficacy, as both 
regimens had the same daily exposure (AUC0-24hr), but the BID treatment arm exhibited mean trough 
concentrations 5-6 fold higher than those observed for the QD treatment arm.  More specifically, trough 
(C12h) concentrations were correlated with antiviral effect, with patients in the lowest quartile for C12h 
showing the highest rate of virologic failure (18, 19).  Based on these data, a minimum target for GM C12h 
of approximately 75 nM is now considered to be more appropriate than the previous target of 33 nM.   
 
Raltegravir is currently being investigated in pediatric populations in IMPAACT P1066 [A Phase I/II, 
Multicenter, Open-Label, Noncomparative Study of the International Maternal, Pediatric, Adolescent 
AIDS Clinical Trials (IMPAACT) Group to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Antiretroviral Activity of Raltegravir (Isentress™, MK-0518) in HIV-1 Infected Children and 
Adolescents] including a novel chewable ethylcellulose preparation for children 2 to < 12 years of age 
and granules for suspension for infants and children ≥ 4 weeks to < 2 years of age.   
 
Based on the results from P1066, final dosing recommendations for evaluation in Stage II of the study 
were made for Cohorts I and IIA receiving the adult tablet and Cohorts IIB and III receiving the chewable 
tablet. 
 


 
 
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Cohort I (12 through < 19 years) and Cohort IIA (6 through < 12 years and ≥ 25 kg):  400 mg adult tablet 
twice daily (20-23). 
 
Cohort IIB (6 through < 12 years) and Cohort III (2 through < 6 years): Weight based dosing of chewable 
tablet to approximate 6 mg/kg twice daily up to a maximum of 300 mg twice daily (Doses: 50 mg, 75 mg, 
100 mg, 150 mg, 200 mg and 300 mg) (24, 25).  
 
Cohort IV (6 months through < 2 years) and Cohort V (4 weeks through < 6 months): Weight based 
dosing of oral granules for suspension (20 mg/mL) to approximate 6 mg/kg twice daily. (26) 
 
The mean raltegravir pharmacokinetic parameters associated with the final recommended doses for each 
age group are listed in Table 2. As shown, the oral bioavailability of RAL chewable tablets is 
substantially greater than the adult tablets, with a final mean dose of approximately 6 mg/kg. 
 
Table 2: Summary of Raltegravir Pharmacokinetic Parameters Following Administration of Final 
Recommended Doses in P1066 (26, 27) 
Age 
Cohort Formulation 
Final 
Recommended 
Dose 
N† 
Mean 
Weight 
(kg) 
Mean 
Dose 
mg 
(mg/kg) 
Geometric 
Mean 
(%CV) 
AUC0-12hr 
(µMxhr) 
Geometric 
Mean 
(%CV) 
C12hr (nM) 
12 through < 19 y 
(20) 
I 
Adult tablet 
400 mg BID, 
regardless of 
weight‡ 
11 
43.55 
390.91 
(9.28) 
15.71 
(98) 
332.63 
(78) 
6 through < 12 y 
(23) 
IIA 
Adult tablet 
400 mg BID, 
for patients ≥25 
kg 
11 
31.54 
400.00 
(13.45) 
15.84 
(120) 
246.09 
(221) 
6 through < 12 y 
(25) 
IIB 
Chewable 
tablet 
6 mg/kg BID, 
maximum of 
300 mg BID 
10 
36.36 
230.00 
(6.47) 
22.58 
 (34) 
129.60 
(88) 
2 through < 6 y 
(24) 
III 
Chewable 
tablet 
6 mg/kg BID, 
maximum of 
300 mg BID 
12 
14.24 
89.58 
(6.24) 
17.95 
(59) 
71.16 
(55) 
6 mo through  
< 2 y (15) 
IV 
Granules for 
suspension 
6 mg/kg BID 
8 
8.49 
47.89 
(5.93) 
19.8 
(34) 
108.2 
(52) 
4 wk through  
< 6 mo (12) 
V 
Granules for 
suspension 
6 mg/kg BID 
11 
5.50 
30.76 
(5.70) 
22.3 
(40) 
116.6 
(68) 
† Number of participants with intensive PK results at the final recommended dose. 
‡ Cohort I participants received approximately 8 mg/kg dose at time of intensive PK which met PK and safety targets.  
Based on review of the individual profiles and receipt of a mean dose of 390 mg the team selected 400 mg BID as 
the recommended dose for this age group.  Participants receiving a dose other than 400 mg BID were switched; no 
repeat PK was performed. 
 
The U.S. FDA granted approval on December 21, 2011 for use of RAL chewable tablets in combination 
with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients ≥ 2 to < 12 years 
of age and weighing at least 10 kg. The FDA approved RAL granules for oral suspension on December 
20, 2013, in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric 
patients four weeks of age and older, weighing ≥ 3 kg to < 20 kg. 


 
 
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Based on data from prior studies of drug interactions of RIF and RAL in adults, doubling the dose of 
RAL to 12 mg/kg/dose (maximum 800 mg/dose) is an appropriate starting point for this study (17). The 
UGT1A1 metabolic pathway is fully mature after the first 3 months of life (28); therefore, co-
administration of RAL and RIF is expected to lead to significant reductions in RAL concentrations in 
children.  As pediatric RAL dosing regimens have been shown to achieve PK parameters comparable to 
those in adults, doubling the RAL dose for children when given with RIF will likely yield similar 
improvements in PK parameters.   
 
Of note, doubling the RAL dose given with RIF in adults did increase AUC (GMR 1.27) and Cmax (GMR 
1.62) when compared with standard RAL dosing.  However, the increased exposures lay well within a 
well-studied range that has been safe and well-tolerated.  Data from the Merck sponsored QTc study 
(PN024) provides guidance as to the safety of higher doses of RAL.  In this study, single doses of 1600 
mg of the lactose formulation were given to adults resulting in the following pharmacokinetic parameters:  
Cmax = 19.63 μM and AUC0-12hr = 63.05 μMxhr.  To date in the development program for RAL, there have 
been no acute safety findings that were temporally associated with peak concentrations, and RAL has 
been found to be generally well tolerated with no dose-related toxicities.   
 
In addition, after approval of the initial protocol version of P1066, data became available from a Phase I 
relative bioavailability/biocomparison study in adults (Protocol 068).  Protocol 068 compared the PK of 
raltegravir poloxamer (adult tablet) and ethylcellulose chewable tablet formulations and the granules for 
oral suspension.  This was a 4-period, crossover study in healthy, adults in which 12 participants each 
received 4 treatments (Treatments A, B, C, and D) randomized in a balanced, crossover design in Periods 
1 through 4.  Treatment A consisted of a single oral dose of 400 mg raltegravir adult formulation tablet. 
Treatment B consisted of a single oral dose of 400 mg raltegravir ethylcellulose pediatric chewable tablet 
formulation (administered as 4 x 100 mg tablets).  Treatment C consisted of a single oral dose of 400 mg 
raltegravir oral granules in a liquid suspension.  Treatment D consisted of a single oral dose of 400 mg 
raltegravir ethylcellulose pediatric chewable tablet formulation (as 4 x 100 mg tablets) administered 
following a high fat meal.  Treatments A-C were administered in the fasted state.  There was a minimum 
of 4 days of washout between the single doses in each treatment period. 
 
The geometric mean pharmacokinetic parameter values for the raltegravir pediatric chewable tablet and 
oral granules for suspension formulations were estimated and compared to the corresponding values for 
the adult tablet, all following single dose administration of 400 mg in the fasted state, with results shown 
in Table 3.  The geometric mean C12hr values were similar for all formulations, while AUC0-∞ and Cmax 
values were higher for both the pediatric chewable tablet and the oral granules formulation compared to 
the adult tablet.  For the oral granules formulation, AUC0-∞ and Cmax were moderately higher (2.6- and 
4.6-fold) than those obtained with the adult tablet and slightly higher (1.5- and 1.4-fold) than those 
obtained with the pediatric chewable tablet.  Both the pediatric chewable tablet and oral granules 
formulations had earlier median Tmax values compared with the adult tablet (0.5 and 1.0 hours for the 
chewable tablet and oral granules, respectively, compared to 4.0 hours for the adult tablet).  Half-life 
values for both the initial (α) and terminal (β) phases were similar for all formulations.  The results were 
consistent with there being some difference between formulations in the absorption phase of the 
pharmacokinetic profile, but little difference in the distribution and elimination phases of the profile.   
 
 
 


 
 
I M P A A C T P 1 1 0 1 
9 of 7 3  
2 4 A pril 2 0 1 7  
FI N A L Versi o n 3. 0  
T a ble 3 : C o m p aris o n of R alte gr a vir Pl as m a P h ar m ac o ki netics F oll o wi n g Si n gle-D ose 
A d mi nistr ati o n of t he R alte gr a vir A d ult T a blet, Pe di atric C he w a ble T a blet ( F aste d or Fe d), a n d 
R alte gr a vir Or al Gr a n ules i n a Li q ui d S us pe nsi o n t o He alt h y, A d ult, M ale a n d Fe m ale P art ici p a nts 
( Pr ot oc ol 0 6 8) 
P har mac o ki netic  
Para meter ( U nits)  
N 
A † 
B † 
C † 
D † 
C o m paris o n  
G M R ( 9 0 % CI)  
 
G M  
 
G M  
 
G M  
 
G M  
 
Treat me nt X/ Treat me nt Y  
C 1 2 hr ( n M)§ 
1 2  
1 4 9  
1 3 4  
1 6 2  
3 8 7  
C / A  
1. 0 9 ( 0. 8 4,  1. 4 1)  
C / B  
1. 2 0 ( 0. 9 2,  1. 5 6)  
D/ B  
2. 8 8 ( 2. 2 1,  3. 7 5)  
B/ A  
0. 9 0 ( 0. 7 0,  1. 1 8)  
A U C 0- ∞ ( µ M x hr)§ 
1 2  
1 9. 2  
3 4. 2  
5 0. 4  
3 2. 3  
C / A  
2. 6 2 ( 2. 1 7,  3. 1 7)  
C / B  
1. 4 7 ( 1. 2 2,  1. 7 8)  
D/ B  
0. 9 4 ( 0. 7 8,  1. 1 4)  
B/ A  
1. 7 8 ( 1. 4 7,  2. 1 5)  
C ma x  ( µ M)§ 
1 2  
5. 0 0  
1 6. 1  
2 3. 2  
6. 1 4  
C / A  
4. 6 4 ( 3. 4 1,  6. 3 0)  
C / B  
1. 4 4 ( 1. 0 6,  1. 9 5)  
D/ B  
0. 3 8 ( 0. 2 8,  0. 5 2)  
B/ A  
3. 2 2 ( 2. 3 7,  4. 3 8)  
T ma x  ( hr)  
1 2  
4. 0  
0. 5  
1. 0  
1. 0  
   
   
t1/ 2I ( hr)¶ 
 
1. 5 
( 0. 3) 
1. 7 
( 0. 2) 
1. 6 
( 0. 3) 
2. 0 
( 0. 6) 
   
   
t1/ 2 T ( hr)¶ 
1 2  
9. 0 
( 5. 9) 
9. 3 
( 5. 1) 
1 0. 0 
( 3. 2) 
9. 2 
( 3. 8) 
   
   
†   Treat me nt A = 4 0 0 m g ralte gra vir, a d ult ta blet (a d mi nistere d faste d).  
    Treat me nt B = 4 0 0 m g ralte gra vir, c he wa ble ta blet (a d mi nistere d faste d).  
    Treat me nt C = 4 0 0 m g ralte gra vir, oral gra n ules i n a li q ui d s us pe nsi o n (a d mi nistere d faste d).  
    Treat me nt D = 4 0 0 m g ralte gra vir, c he wa ble ta blet (a d mi nistere d wit h a hi g h -fat meal). 
§   Bac k -tra nsf or me d least s q uares mea n a n d c o nfi de nce i nter val fr o m mi xe d effects m o del perf or me d o n t he 
nat ural l o g -tra nsf or me d val ues. 
   Me dia n val ues prese nte d f or T
ma x . 
¶   Har m o nic mea n (jac k -k nife sta n dar d de viati o n) val ues prese nte d f or t 1/ 2I a n d t 1/ 2 T.  F or t1/ 2I, t he N's f or 
Treat me nts A, B, C, a n d D are 1 1, 1 2 , 1 2, a n d 1 0, res pecti vel y. 
 
T he hi g her A U C 0- ∞ a n d Cma x  val ues f or t he oral gra n ules f or m ulati o n are n ot e x pecte d t o ha ve a n y 
mea ni n gf ul cli nical c o nse q ue nces.  T he p har mac o ki netic pr o perties of t he t w o pe diatric f or m ulati o ns 
(c he wa ble ta blet a n d oral gra n ules) are si milar t o t he ralte gra vir P hase I lact ose f or m ulati o n w hic h was 
well t olerate d i n a d ults ( P 0 0 7).  A d diti o nal data usi n g t he lact ose f or m ulati o n was ge nerate d i n t he Q Tc 
st u d y ( P 0 2 4) a n d Pr ot oc ol 0 0 1 ( P 0 0 1), a si n gle a n d m ulti ple d ose P K a n d safet y st u d y, b ot h perf or me d i n 
a d ult healt h y v ol u nteers.  I n P 0 2 4, a si n gle 1 6 0 0 m g ralte gra vir faste d d ose pr o d uce d a ge o metric mea n 
A U C 0- 1 2 hr of 6 3. 0 5 µ M x hr a n d Cma x of 1 9. 6 3 µ M.  Ralte gra vir was ge nerall y well t olerate d wit h n o seri o us 
cli nical or seri o us la b orat or y a d verse e x perie nces re p orte d a n d n o partici pa nts disc o nti n ue d beca use of a n 
a d verse e x perie nce.  All a d verse e x perie nces re p orte d were tra nsie nt a n d, wit h  t he e xce pti o n of a re p ort of 
se vere t o ot hac he, j u d ge d t o be mil d or m o derate i n i nte nsit y. 


 
 
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In P001, the 1600 mg single dose fasted arm produced a geometric mean AUC0-∞ of 95.60 µMxhr and 
Cmax of 36.06 µM and the 800 mg multiple dose fasted arm produced a geometric mean AUC0-12hr of 45.27 
µMxhr and Cmax of 19.73 µM.  In both arms of P001, raltegravir was generally well tolerated with no 
serious clinical or serious laboratory adverse experiences reported and no participants discontinued 
because of an adverse experience.  There were no consistent treatment-related changes in laboratory, vital 
signs, or ECG safety parameters. 
 
Based on the lack of a statistically significant difference in trough values, and the otherwise moderate 
dissimilarities in the other pharmacokinetic parameters, these results supported continued clinical 
development of both the chewable tablet and oral granules for suspension pediatric formulations in 
P1066.  The hypothesis is that doubling the dose of RAL given with RIF-containing TB treatment in 
HIV/TB co-infected infants and children will result in RAL PK levels similar to those achieved in HIV-
infected infants and children in the absence of RIF.  
 
1.4 
Rationale for Studying Raltegravir Chewable Formulation as a Dispersible Tablet 
Administration of RAL granules for oral suspension formulation requires a complex constitution 
procedure, including use of single–dose 100 mg packets, mixing cups and syringes, and potable water 
required for each dose.  This may not be feasible for caregivers, particularly as multiple sachets of RAL 
granules for oral suspension for doses > 100 mg will be needed if the dose needs to be increased for use 
with RAL-containing TB treatment. Merck has generated both biocomparison and modeling data 
indicating that the Isentress chewable tablet used in 25 mg dose increments should provide appropriate 
PK to achieve both efficacy and safety PK targets across the 3 to 25 kg weight range, and in particular in 
children < 10 kg, in whom the chewable tablet was not directly studied in the pediatric development 
studies. Data indicate that the 25 mg chewable tablet can be used as a dispersible tablet, meeting WHO 
dispersibility criteria after simple crushing or pre-wetting (followed by stirring and crushing as needed to 
remove any chunks) of the chewable tablet in a variety of vehicles. Thus, this alternative proposed dosing 
scheme, using chewable tablets as dispersible for infants and children at least four weeks of age and from 
3 to 10 kg can be expected to achieve appropriate PK for both good efficacy and acceptable safety.” 
[Raltegravir: Merck’s perspective on chewable as dispersible for WHO. Unpublished data.] The 
pharmacokinetics of the raltegravir chewable tablet formulation have been compared to the granules for 
suspension formulation in a single-dose study in adults (P068) (29).  A summary of the study results is 
show below in Table 4. 
 
Table 4: Raltegravir Plasma Pharmacokinetics After Single-dose Administration of the 
Ethylcellulose (EC) Chewable Tablet and Oral Granules for Suspension (GFS)  
Formulations in Healthy Adults (29) 
Pharmacokinetic Parameter 
n 
GMR (90% CI) 
(400 mg chewable/ 400 mg 
granules) 
GM 
Chewable 
GM Granules 
C12h geometric mean, nM 
12 
0.83 (0.64, 1.09) 
134 
162 
AUC0-∞ geometric mean, μM•h 
12 
0.68 (0.56, 0.82) 
34.2 
50.4 
Cmax geometric mean, μM 
12 
0.69 (0.51, 0.94) 
16.1 
6.14 
 
A uniform pediatric formulation of raltegravir which is chewable or dispersible will also assist with the 
harmonization process for antiretroviral formulations which are recommended by the WHO. 
 


 
 
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1.5 
Rationale for Adding a Fourth ARV Drug with RAL during TB Treatment 
Inadequate dosing of one or more drugs in an antiretroviral regimen can lead to virologic failure, 
progression of disease, and selection of HIV resistance mutations that may compromise future treatment 
regimens.  This is of particular concern in the setting of co-infection with tuberculosis and HIV infection, 
in which virologic failure is more common than in the absence of HIV infection alone in children.  In 
view of the uncertain nature of interactions between RAL and RIF in children, we plan to add a fourth 
antiretroviral agent after completion of the intensive pharmacokinetic study of RAL given with two 
NRTIs receiving therapy.  The fourth drug will be added in line with local treatment recommendations for 
treatment of HIV/TB coinfection and in discussion with the Protocol Team.  All ARVs, other than EFV or 
LPV/r, must be approved by the Protocol Team prior to inclusion in the study drug regimen. 
 
2.0 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
1. To determine the pharmacokinetics and appropriate dose of RAL when administered with a 
RIF-containing anti-TB therapy in HIV/TB co-infected infants and children that generates PK 
parameters generally comparable to those seen in HIV-infected infants and children in the 
absence of RIF. 
 
2. To determine safety and tolerance of RAL-containing ART when administered with a RIF-
containing anti-TB therapy in HIV/TB co-infected infants and children. 
 
2.2 
Secondary Objectives 
1. To describe the short-term treatment outcomes of infants and children using a RAL-
containing ART regimen co-treated with a RIF-containing TB treatment (see Sections 8.2.3 
and 8.2.4). 
 
2. To explore whether infants and children receiving a RAL-containing ART regimen, co-
treated with a RIF-containing TB treatment, develop ARV drug associated resistance 
mutations (see Section 6.2.3). 
 
3.0 
STUDY DESIGN 
P1101 is a Phase I/II, dose-finding, safety, tolerability and pharmacokinetics study of RAL chewable 
tablet in HIV-infected infants and children ≥ 4 weeks to < 12 years of age who are TB co-infected and on 
≥ 1 week and ≤ 20 weeks of RIF-based TB therapy who are eligible for ARV treatment by current local or 
WHO guidelines.  The study’s objective is to determine the appropriate and safe dose of RAL to be used 
with a RIF-based TB treatment regimen to provide additional ART options in co-infected infants and 
children. 
 
• 
At least 12 participants will be enrolled in each of the three age cohorts: Cohort I: ≥ 2 to < 6 years of 
age, Cohort II: ≥ 6 to < 12 years of age, and Cohort III: ≥ 4 weeks to < 2 years of age.  Enrollment 
into each age cohort will be simultaneous, with RAL treatment initiated at Entry. Each age cohort will 
start with a mini-cohort of six participants to assure that preliminary PK and safety criteria are met at 
that dose.  See Section 9.2 for details on the intensive PK procedure.   
• 
For each mini-cohort, a routine Study Monitoring Committee (SMC) review of the safety and PK data 
will occur prior to accrual of the full-cohort. 


 
 
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• 
Data from each age cohort will be reviewed independently and, if the mini-cohort data meets 
established metrics (see Section 8.1), an additional 6 participants per age cohort will be enrolled (full 
cohort), and evaluated for safety and PK.   
• 
If upon review of all PK and safety data from the mini-cohort the dose is not acceptable, the existing 
mini-cohort dose will be adjusted and a new mini-cohort group of six participants will be enrolled 
(see Section 6.2).  The new mini-cohort, treated at the adjusted dose, will undergo safety and PK 
evaluations and, if PK and safety guidelines are satisfied, the full cohort will be enrolled.   
• 
This process will be repeated until the PK and safety evaluations result in an acceptable dose for that 
cohort.  See Section 8.1 for details on the dosing algorithm.   
• 
It is anticipated that at least 36 to 108 participants will be enrolled to achieve 12 evaluable 
participants in each cohort at the recommended dose.  Participants enrolled to mini-/full cohorts with 
failing doses (if not already completed TB treatment) may continue their RAL and have a dose 
adjustment as described in Section 6.2.1, Cohort Dosing Management.  The participants will continue 
on study following the visits in the Schedule of Evaluations (see Appendix I). 
• 
If the PK data for twice daily dosing of RAL is not acceptable, the team may decide to adjust the dose 
to three times daily.  The RAL three times daily dosing will be incorporated into a future amendment 
of the protocol. 
• 
If the results of the intensive PK are in question, unexpectedly low or high and may put the 
participant at risk for toxicity, the Protocol Team may request a repeat of the intensive PK.  The site 
will be notified by the team and the time period for obtaining the repeat PK will be given. 
 
These HIV-infected participants, diagnosed with pulmonary TB or TB adenitis according to the criteria in 
Section 4.1.6, will be treated with a RIF-containing TB regimen for approximately six months, dosed 
according to the most current WHO TB dosing guidelines and Guidelines for Prevention and Treatment 
of Opportunistic Infections among HIV-Exposed and HIV-Infected Children (30, 31).  RAL will initially 
be dosed at 12 mg/kg twice daily up to a maximum of 800 mg BID and administered with two new 
NRTIs. Intensive PK for RAL will then be conducted after 5 to 8 days.  After the intensive PK study, a 
fourth ARV drug per local standard of care for treatment in HIV/TB co-infected infants and children 
requiring RIF therapy, will be added to the regimen to provide additional ARV activity.  Safety data for 
RAL and TB drugs will also be evaluated at each study visit. The four-drug ARV regimen will be 
continued until TB treatment is completed, typically after six months of therapy.  RAL will be 
discontinued when TB therapy is completed, and the ARV regimen will continue per local standard of 
care. See Section 5.0 for additional information regarding the drug regimen. 
 
If an appropriate dose has not yet been established when accrual reaches 60 to 66 participants, the team 
will evaluate if the maximum sample size should be increased.  An increase in the maximum sample size 
will require approval by the IMPAACT network. Notice of an increase in the sample size will be sent to 
sites via a Letter of Amendment which will need to be submitted to each Institutional Review Board 
(IRB) or Ethics Committee (EC) per each site’s normal procedures.  Any additional guidance issued by a 
site’s IRB or EC will need to be followed by that site. 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
4.1 
Inclusion Criteria 
 
4.1.1 
Age ≥ 4 weeks to < 12 years at entry. 
 
4.1.2 
Weight ≥ 3.5 kg at entry. 
 


 
 
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4.1.3 
Confirmation of HIV-1 infection is defined as positive results from two samples collected 
at different time points.  All samples tested must be whole blood, serum or plasma.  For 
studies conducted under an IND, all test methods should be FDA-approved if 
available.  If FDA-approved methods are not available, test methods should be verified 
according to GCLP and  approved by the IMPAACT Laboratory Center.  
 
For participants less than 2 years of age or have not ceased breastfeeding for at least 4 
weeks, Sample #1 and Sample #2 may be tested using any of the following:  
• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above the limit of detection) 
• 
One qualitative HIV RNA PCR 
• 
One total HIV nucleic acid test 
 
For these participants, at least one of the two samples must be tested in the study site’s 
designated VQA-certified laboratory.  For tests performed in other (non-VQA-certified) 
settings, adequate source documentation, including the date of specimen collection, date 
of testing, test performed, and test result, must be available. 
For participants 2 years of age and older who have ceased breastfeeding for at least 4 
weeks, Sample #1 may be tested using any of the following: 
• 
Two rapid antibody tests from different manufacturers or based on different 
principles and epitopes.  
• 
One EIA OR Western Blot OR immunofluorescence OR chemiluminescence  
• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above the limit of detection) 
• 
One qualitative HIV RNA PCR 
• 
One total HIV nucleic acid test 
 
Sample #1 may be tested by non-study public or PEPFAR programs.  However, both the 
result and the assay date must be recorded in participant’s charts.  Source documentation 
(patient’s medical record/chart, Ministry of Health (MOH) registers, laboratory results, 
etc.) must be available if requested. 
For participants 2 years of age and older who have ceased breastfeeding for at least 4 
weeks, Sample #2 may be tested using any of the following: 
• 
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. 
• 
One EIA OR Western Blot OR immunofluorescence OR chemiluminescence  
• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above the limit of detection) 
• 
One qualitative HIV RNA PCR 
• 
One total HIV nucleic acid test 
 
Sample #2 must be performed in a CAP/CLIA-approved laboratory (for US sites) or in a 
laboratory that operates according to GCLP guidelines and participates in an appropriate 
external quality assurance program (for international sites). 


 
 
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Note:  HIV RNA PCR is a required screening evaluation that must be performed in a 
VQA-certified laboratory (refer to Appendix I).  Assuming the result of this test is above 
the limit of detection of the assay, this test may serve as one of the two tests required for 
documentation of HIV infection.  
 
4.1.4 
ARV treatment naïve or has not received ARVs for at least 30 days prior to entry. 
 
Note: Participants with prior exposure to ARVs for PMTCT or treatment - regardless of 
duration - are eligible provided the participant has not received ARVs for at least 30 
days prior to entry.  The reasons for interruption could include drug toxicity, poor 
adherence, or treatment failure that preceded enrollment and has not been imposed by 
study staff. ARVs should not be withheld for the purposes of enrollment into the study and 
against the participant’s best interest. 
 
 
4.1.5 
ARV treatment eligible as defined by: 
• 
Country-specific guidelines 
OR 
• 
WHO pediatric treatment algorithm 
(http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?u
a=1) 
 
 
4.1.6 
Diagnosis of pulmonary TB or TB adenitis.   
 
• 
Diagnosis of pulmonary TB with either: 
− 
A positive smear or GeneXpert test 
 
OR  
− 
If smear negative, having either a positive household contact, suggestive chest x 
ray (CXR), or positive tuberculin skin test (TST).  In addition to having at least 
one of these findings, the child must also have at least one of the following 
symptoms for more than 2 weeks: weight loss, chronic cough and/or night 
sweats. 
 
• 
Diagnosis of TB adenitis is made by at least one of the following criteria: 
− 
Smear or culture of aspirated, biopsied, or draining material positive for acid fast 
organisms (smear) or MTB 
 
 
 
OR 
− 
Presence of painless, asymmetric lymph node(s) in cervical, supraclavicular or 
axillary region AND 2 or more of the following: positive TB household contact, 
weight loss, night sweats, suggestive CXR, or a positive TST reaction. 
 
Note: Participants with BCG disease treated with rifampicin-containing TB treatment 
can be included. 
 
4.1.7 
Participant has initiated at least a two drug TB regimen containing rifampicin, and has 
tolerated at least 1 week of the TB drug regimen prior to initiation of raltegravir. 
 Note: TB treatment may be started after being diagnosed by the site investigator.  
Treatment regimens may include isoniazid, pyrazinamide, ethambutol and streptomycin 
in addition to rifampicin. 


 
 
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ART should ideally be started within 2 weeks of starting TB treatment. A patient who has 
started therapy for TB elsewhere but has not yet been started on ART is eligible for 
enrollment provided they have not had >20 weeks of TB therapy. Delay between starting 
TB treatment and ART is not encouraged, and local or international guidelines should be 
followed for managing TB and HIV coinfection in infants and children. 
4.1.8     Female participant who is of child bearing potential and sexually active has agreed to use 
two reliable methods of contraception, including a medically accepted barrier method of 
contraception (e.g., female/male condoms, diaphragm or cervical cap with a cream or gel 
that kills sperm (excluding nonoxydyl-9), intrauterine device [IUD], others) together with 
another reliable form of contraception while on study and for 4 weeks after stopping 
RAL.   
 
4.1.9 
Parent, legal guardian, or designated guardian according to country-specific guidelines, 
able and willing to provide signed informed consent and to have the participant followed 
at the clinical site. 
 
4.2 
Exclusion Criteria 
4.2.1 
Grade ≥ 2 AST (aspartate aminotransferase) or ALT (alanine aminotransferase) at 
 
screening, which must be within 30 days of entry. 
 
Note: Participants can be re-screened provided that they will have at least 4 weeks of TB 
treatment remaining at the time of entry.  
 
4.2.2 
Any Grade ≥ 4 clinical toxicity or laboratory result at screening except fever, chills, 
fatigue or malaise, unintentional weight loss, and dyspnea or respiratory distress which 
could be associated with TB. 
 
4.2.3 
Acute, serious infections other than TB requiring active treatment (e.g. Pneumocystis 
jirovecii [previously Pneumocystis carinii] pneumonia [PCP], cryptococcal meningitis, 
etc.).  Infants and children diagnosed with acute bacterial pneumonia at time of diagnosis 
of TB may be included.  Prophylaxis against opportunistic infections will be allowed. 
 
4.2.4 
Diagnosis of Kwashiorkor (< 80% expected weight-for-age with the presence of edema 
and hypoalbuminemia). 
 
4.2.5 
Current chemotherapy for active malignancy or history of chemotherapy discontinued 
within one year of entry. 
 
4.2.6 
Rifampicin therapy of > 20 weeks duration immediately prior to enrollment. 
 
4.2.7 
Known or suspected MDR or XDR TB, including contact with a documented MDR or 
XDR TB source case, as these may require longer duration of therapy or non-rifampicin 
containing regimen. 
 
Note: Participants found to have MDR or XDR TB before or during the study will be 
informed of their illness and referred for appropriate care as determined by local 
guidelines. 
 
4.2.8 
Current TB regimen containing rifabutin, macrolides and any other anti-mycobacterial 
agents with known interactions with RAL. 


 
 
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4.2.9 
Any clinically significant diseases (other than HIV and TB infection) or clinically 
significant findings during the screening medical history or physical examination that, in 
the investigator’s opinion, would compromise the outcome of this study. 
 
4.2.10 Participant is pregnant or breastfeeding.  
 
4.2.11 Participant is unlikely to adhere to the study procedures or keep appointments. 
 
4.2.12 Participant is planning to relocate during the study to a non-IMPAACT study site. 
 
4.2.13 Participant is taking any disallowed medications (see Section 4.3.2). 
 
4.3 
Concomitant Medication Guidelines 
Whenever a concomitant medication or study agent is initiated or a dose changed, investigators must 
review the concomitant medications’ and study agents’ most recent package inserts, Investigator’s 
Brochures, or updated information from Division of AIDS, NIAID (DAIDS) to obtain the most current 
information on drug interactions, contraindications, and precautions. 
 
Additional drug information may be found in the AIDS Clinical Trials Group (ACTG) Drug Interactions 
Database located at: https://actgnetwork.org/ACTG-Drug-Interactions-Database. 
 
4.3.1 
Precautionary Medications 
 
The following medications should be avoided, if possible, and alternative treatments 
sought. Please contact the Protocol Team if treatment with any of these medications is 
necessary for clinical care. 
• 
Medications which cause myopathy or rhabdomyolysis in patients at risk.   
• 
Strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 other 
than RIF. 
• 
Short courses of systemic corticosteroids (≤ 7 days) are permitted.  Topical 
corticosteroids are permitted.  Longer courses need to be discussed with the Protocol 
Team. 
 
4.3.2 
Disallowed Medications 
 
The following medications/therapies are not allowed in this study: 
• 
Dolutegravir 
• 
Elvitegravir 
• 
Astemizole  
• 
Cisapride  
• 
Ergot alkaloids and derivatives  
• 
Benzodiazepines 
• 
Zolpidem  
• 
Antiepileptic drugs 
• 
St. John's wort 
• 
Cytokines 
• 
Growth hormone 
• 
Rifabutin 


 
 
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• 
Omeprazole 
• 
Praziquantel 
• 
Nifedipine 
• 
Voriconazole 
• 
Sirolimus 
• 
Quinine 
• 
Imatinib 
• 
Itraconazole 
• 
Cyclosporine 
• 
Tacrolimus 
• 
Atovaquone 
• 
Mycophenolate 
• 
Sunitinib 
• 
Quetiapine 
• 
Tolvaptan 
• 
Immunosuppressive therapy other than intralesional or localized electron beam 
therapy for cutaneous Kaposi’s sarcoma.   
• 
Other: warfarin, oral and injectable contraceptives, ketoconazole, doxycycline, 
digoxin, verapamil, simvastatin, everolimus, atorvastatin, rosiglitazone/pioglitazone, 
celecoxib, clarithromycin, caspofungin, fluconazole, and diltiazem. 
 
Investigational agents are not permitted, unless first approved for use by the Protocol 
Team.  
 
4.4 
Protocol Registration and Enrollment Procedures 
Prior to implementation of this protocol, and any subsequent full version amendments, each site must 
have the protocol document and the consent form(s) approved, as appropriate, by their local Institutional 
Review Board (IRB)/Ethics Committee (EC), and any other applicable regulatory entity (RE).  A Site 
Implementation Plan (SIP) will be required from each site participating in the study.  The SIP will be 
reviewed and approved by members of the Protocol Team and sites will be notified that authorization to 
participate has been granted. 
 
Upon receiving final approval, sites will submit all required protocol registration documents to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC).  The 
DAIDS PRO will review the submitted protocol registration packet to ensure that all the required 
documents have been received. 
 
Site-specific informed consent forms (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. 
 
DAIDS notification of approval to begin enrollment is required before participants can be enrolled in this 
study.  Participants meeting the study eligibility criteria will be enrolled through the Data Management 
Center (DMC) Subject Enrollment System (SES) eligibility checklist screens.  Written informed consent 
for study participation must be obtained before any study related procedures are performed. Eligible 
participants will be considered enrolled in the study upon successful entry into the DMC’s SES (date of 
participant enrollment = Day 0 for determining the target dates of all follow-up visits).   


 
 
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Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, sites should 
implement the amendment immediately.  Sites are required to submit an amendment registration packet to 
the DAIDS PRO at the RSC.  The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all the required documents have been received. Site-specific ICF(s) WILL NOT be reviewed 
and approved by the DAIDS PRO and sites will receive an Amendment Registration Notification when 
the DAIDS PRO receives a complete registration packet. A copy of the Amendment Registration 
Notification should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents required for initial 
and amendment registrations, refer to the current version of the DAIDS Protocol Registration Manual. 
 
Enrollment of participants onto the study will be done through the SES on the DMC website 
(https://www.frontierscience.org). For all participants from whom informed consent is obtained, but who 
are deemed ineligible or who do not enroll into the protocol for any reason, a Screening Failure Results 
form must be completed and keyed into the database.   
 
4.5 
Co-enrollment Procedures 
Co-enrollment in other research protocols will require the consent of the P1101 Protocol Team and the 
other research Protocol Team.  Please contact the P1101 Protocol Team for co-enrollment questions. 
 
5.0 
STUDY TREATMENT 
Study treatment is defined as chewable RAL tablet(s), which will be provided by the study and initiated at 
Entry. 
 
The TB drugs (including RIF) and ARV drugs (excluding RAL) will not be provided by the study and 
must be obtained locally by the site. 
 
5.1 
Drug Regimen, Administration and Duration 
5.1.1 
Drug Regimen 
 
Cohort I: Participants ≥ 2 to < 6 years of age. 
• 
Chewable RAL tablet, starting dose of 12 mg/kg (up to a maximum dose of 800 mg) 
orally twice daily (refer to Table C in Appendix II), with two NRTIs plus RIF-
containing regimen for treatment of TB.  After the intensive PK samples are taken, a 
fourth ARV drug per local standard of care for treatment in HIV/TB co-infected 
children, will be added to the regimen. ARVs, other than EFV or LPV/r, must be 
approved by the Protocol Team prior to inclusion in the study drug regimen.  
 


 
 
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Cohort II: Participants ≥ 6 to < 12 years of age.   
• 
Chewable RAL tablet, starting dose of 12 mg/kg (up to a maximum dose of 800 mg) 
orally twice daily (refer to Table C in Appendix II), with two NRTIs plus RIF-
containing regimen for treatment of TB.  After the intensive PK samples are taken, a 
fourth ARV drug per local standard of care for treatment in HIV/TB co-infected 
children, will be added to the regimen.  ARVs, other than EFV or LPV/r, must be 
approved by the Protocol Team prior to inclusion in the study drug regimen. 
 
Cohort III: Participants ≥ 4 weeks to < 2 years of age. 
• 
Chewable RAL tablet as a dispersible tablet, starting dose of 12 mg/kg (up to a 
maximum dose of 800 mg) orally twice daily (refer to Table C in Appendix II), with 
two NRTIs plus RIF-containing regimen for treatment of TB.  After the intensive PK 
samples are taken, a fourth ARV drug per local standard of care for treatment in 
HIV/TB co-infected infants and children, will be added to the regimen.  ARVs, other 
than EFV or LPV/r, must be approved by the Protocol Team prior to inclusion in the 
study drug regimen.  
 
Note: If dose adjustment is required based on review of all available data, this will be 
communicated by the Protocol Team to Sites.  Refer to Appendix II for raltegravir dosing 
tables based on 6, 9, 15 and 18 mg/kg.  A new prescription will be required for the site 
pharmacist.                       
 
Intensive PK should be scheduled so that witnessed dosing of the ARVs is as close as 
possible to 12 hours after the previous dosing.  PK dosing should be given within a range 
of 11 to 13 hours after the previous dose.  Parents/Guardians must report that the 
participants have not missed any doses of the ARVs, including RAL, in the 48 hours 
prior to the intensive PK visit.  If a missed dose is reported, the intensive PK visit must be 
re-scheduled.  Participants should not ingest breast milk, formula, or any other high fat 
food/liquid for 2 hours prior to and 1 hour after dosing on the intensive PK day. The 
participant must bring to the clinic the doses of RAL, other ARVs and TB medications so 
they can be taken after the pre-dose (0) blood is drawn.  Doses vomited within 15 
minutes may be re-dosed once, and time restarted to be the time of the repeat dosing.  If 
dose is vomited > 15 minutes after dosing, PK must be cancelled and may be re-
scheduled.  See Section 9.2 for details on the intensive PK procedure. 
 
5.1.2 
Administration and Dispensing 
 
5.1.2.1 RAL will be administered orally twice daily.  
 
Cohort I and Cohort II: 
RAL chewable tablets dosing instructions: RAL chewable tablets are to be 
chewed before swallowing.  If they prefer, participants may swallow the 
chewable tablets whole.  The method by which the participant takes the chewable 
tablet (either chewing or swallowing whole) must be documented. 
 
Cohort III:  
RAL chewable tablets to be dispersed dosing instructions: RAL chewable tablets 
should be crushed and dispersed in water, liquid-apple juice, breast milk or 
formula. Dissolve the required dose as per Table C in Appendix II.  


 
 
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Up to three of the 25 mg chewable tablets (a total of 75mg) may be dissolved in 
approximately 5 mL of water, juice, breast milk of formula; 100 mg tablets 
should be dissolved in 10 mL of water, juice, breast milk or formula.  
Once the tablet is wetted, crush the tablet while in the liquid with a spoon and stir 
until dispersed. The full amount of liquid must be administered orally within 30 
minutes post-dissolution.  
 
RAL may be taken without regard to food, except on pharmacokinetic evaluation 
days (see Section 9.0).  
 
5.1.2.2 The three-drug ARV regimen in addition to RAL will be dosed according to local 
standard of care.     
 
 
5.1.3 
Duration 
 
Participants will be followed from the time of entry until three months after 
discontinuation of RAL.  On completion of therapy for tuberculosis, RAL will be 
discontinued while treatment for HIV will continue per local standard of care. 
 
5.2 
Drug Formulation 
5.2.1 
Description of Formulation of Raltegravir 
 
Chewable ethylcellulose tablets in 25 mg and scored 100 mg dose. 
 
The ethylcellulose tablet formulation is an orange-banana flavor, and contains the 
following: raltegravir, hydroxypropylcellulose, ethylcellulose 20 cP, saccharin sodium, 
sucralose, monoammonium glycyrrhizinate, sorbitol, fructose, natural and artificial 
flavors (orange, banana, and masking), sodium citrate, crospovidone, mannitol, red ferric 
oxide, yellow ferric oxide, magnesium stearate, sodium stearyl fumarate, ammonium 
hydroxide, medium chain triglycerides, oleic acid, hypromellose 2910/6cP, and 
macrogol/PEG 400.   
 
5.2.2 
Storage Instructions 
 
Stability studies for the ethylcellulose tablet formulation of raltegravir are ongoing.  Store 
at or below 30°C (86°F) and protect from moisture.  The bottles of the ethylcellulose 
tablets contain desiccant and may contain rayon coil.  The desiccant should remain in the 
bottle.  Ethylcellulose tablets are to be dispensed and stored in the original manufacturer's 
container.  
 


 
 
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5.3 
Drug Supply, Distribution and Pharmacy 
5.3.1 
Study Product Acquisition/Distribution 
 
RAL chewable tablets will be manufactured and supplied by Merck Research 
Laboratories and available through the NIAID Clinical Research Products Management 
Center (CRPMC).  The site pharmacist can obtain the study product for this protocol by 
following the instructions in the manual Pharmacy Guidelines and Instructions for 
DAIDS Clinical Trials Networks in the section: Study Product Management 
Responsibilities. 
 
 
 
The background ARV drugs and TB drugs (including RIF) will not be provided 
through this study and must be obtained locally by the site.  They will be prescribed by 
the health care provider according to local national and/or international guides for 
treatment of HIV/TB co-infected infants and children and supplied via non-study 
prescription. 
 
5.3.2 
Study Product Accountability 
 
 
 
The site pharmacist is required to maintain complete records of all study products have 
been received from the NIAID CRPMC and subsequently dispensed.  All unused study 
products 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. 
 
5.3.3  Instructions for breaking the raltegravir scored 100 mg chewable tablet 
 
 
Note: Merck has developed the scored 100 mg tablet to be broken into two halves by 
hand using the following method: 
 
i. 
Pick up the tablet, then using two hands, hold the tablet between the thumb and 
forefinger of each hand by placing the thumb on top of the tablet and the forefinger 
on the bottom of the tablet. 
ii. Break the tablet by either bending the outer portions of the tablet either upwards or 
downwards.  
iii. When the second half of the scored tablet is not administered with this dose, ensure 
that it is returned to the manufacturer's bottle immediately after breaking the tablet.  
 
 
6.0 
PARTICIPANT MANAGEMENT 
6.1 
Toxicity Management 
Except for rash toxicity grading, which is provided in Appendix III and discussed in Section 6.1.3, 
toxicities will be graded according to the DAIDS Table for Grading the Severity of Adult and Pediatric 
Adverse Events, (DAIDS AE Grading Table), Version 2.0, November 2014, available on the RSC 
website at http://rsc.tech-res.com/safetyandpharmacovigilance/gradingtables.aspx. 


 
 
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Management of adverse experiences will be according to the best clinical practice and the judgment of the 
site investigator, except when noted below.  For any other scenarios not described below, consult the 
Protocol Team on study drug management and frequency of repeat assessments.  
Consultation on all aspects of clinical management is available from the Protocol Team at any time.  
Alternate explanations for clinical and laboratory abnormalities must be sought.  Laboratory normals will 
be the institutional values.  However, if a site does not have an age-specific normal range/value for a 
particular lab, the site should use the latest edition of the Harriet Lane Handbook for normal ranges/values 
and document this for monitoring purposes.  The site investigator should attempt to confirm any abnormal 
laboratory test results as soon as possible and within 3 days of site awareness. All Grade ≥ 3 abnormal 
clinical and laboratory findings should be followed until resolution to ≤ Grade 2.   
Toxicity and adverse events in laboratory and clinical evaluations must be entered into the database 
within 48 hours of the time at which the results become available for the evaluation of safety and 
tolerability of RAL. 
 
Gradation of relationship will use the following terminology:  
 
• 
Definitely Related: The adverse event and administration of the medication are related in time, and a 
direct association can be demonstrated. 
• 
Probably Related: The adverse event and administration of the medication are reasonably related in 
time, and the adverse event is more likely explained by the medication than other causes. 
• 
Possibly Related: The adverse event and administration of the medication are reasonably related in 
time, and the adverse event can be explained equally well by causes other than the medication. 
• 
Probably Not Related: A potential relationship between the medication and the adverse event could 
exist (i.e., the possibility cannot be excluded), but the adverse event is most likely explained by 
causes other than the medication. 
• 
Not Related: The adverse event is clearly explained by another cause not related to the medication. 
 
NOTE: The above classification applies for AE documentation (source documentation and CRF 
completion) and management but does not apply for expedited adverse event (EAE) reporting. EAEs will 
be reported, per the DAIDS EAE Manual, as related or not related.  Please see Section 7.0 below for more 
information on EAE reporting. 
 
6.1.1 
General Toxicity Management 
The toxicity management guidelines are for events for which a relationship to RAL 
(defined as the study drug) cannot be excluded.  Clinical or laboratory adverse events 
(AEs) that are definitely unrelated to RAL may not result in RAL interruption.  TB 
medication will normally be continued unless, in the judgment of site investigators, the 
toxicity is deemed related to TB medication. 
 
General guidelines (see separate stopping rules for Liver, Rash and Abacavir toxicities 
below in Sections 6.1.2 – 6.1.4):  
 
• 
Grade 1 – Continue RAL; routine monitoring.  
 
• 
Grade 2 – Continue RAL; monitor closely with more frequent visits as per site 
investigator, work-up to exclude other causes. 
 


 
 
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• 
Grade 3 – Repeat test within 3 days to confirm.  Continue RAL while awaiting 
confirmatory results as determined by the site investigator. 
 
If repeat assessment is ≤ Grade 2, manage as per grade of repeat result.  For 
confirmed Grade 3 toxicities assessed as possibly, probably, or definitely related to 
RAL, RAL and concomitant ARVs should be withheld as follows: 
 
Participants not receiving EFV 
Hold RAL and NRTIs until the abnormalities resolve to ≤ Grade 2 unless the site 
investigator, with the approval of the Protocol Team, determines that withholding 
ART (including RAL) would be harmful to the participant. 
• 
Follow abnormal laboratory values weekly until toxicity resolves to ≤ Grade 2.   
• 
If toxicity resolves to ≤ Grade 2 in ≤ 21 days, all held ARVs, including RAL, 
may be restarted with approval from the Protocol Team. 
• 
If Grade 3 toxicity persists for > 21 days or recurs to ≥ Grade 3 after 
reintroduction of ARVs, RAL should be permanently discontinued.   
 
Participants receiving EFV 
 
Hold RAL and EFV, but NRTIs can be continued for up to two weeks at the 
discretion of the site investigator in consultation with the Protocol Team.   
• 
Follow abnormal laboratory values weekly until toxicity resolves to ≤ Grade 2.   
• 
If toxicity resolves to ≤ Grade 2 in ≤ 21 days, all held ARVs, including RAL, 
may be restarted with approval from the Protocol Team.   
• 
If Grade 3 toxicity persists for > 21 days, or recurs to ≥ Grade 3 after 
reintroduction of ARVs, EFV and RAL should be permanently discontinued.   
 
• 
Grade 4 – Hold RAL and concomitant ARVs and notify the Protocol Team.  Repeat 
test within 3 days to confirm.  
 
• 
If the site investigator determines that withholding ART (including RAL) would 
be harmful to the participant and that continuing ARVs would pose little 
additional risk, the site investigator must contact the Protocol Team for approval 
before continuing RAL and the concomitant ARVs.   
• 
If repeat assessment is ≤ Grade 3, manage as per grade of repeat result.   
• 
Confirmed Grade 4 toxicities that are assessed as possibly, probably, or definitely 
related to RAL, RAL should be permanently discontinued.   
• 
Confirmed Grade 4 toxicities assessed as not related or probably not related to 
RAL that resolve to ≤ Grade 2 in ≤ 21 days, all held ARVs, including RAL, may 
be restarted following approval from the Protocol Team.   
• 
Continue to monitor weekly until the toxicity resolves to ≤ Grade 2.   
 
Confirmed Grade 4 AEs that are determined to be not related or probably not related 
to RAL and do not resolve to ≤ Grade 2 in ≤ 21 days, the site investigator should 
contact the Protocol Team to determine when RAL may be safely resumed. 
 


 
 
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For Grade 4 toxicities, all ARVs including RAL should be started or stopped together 
whenever possible, except when one nucleoside analogue can be substituted for 
another when the etiology of the toxicity can be reasonably determined, e.g. 
neutropenia associated with zidovudine (ZDV) use. 
 
6.1.2 
Liver Toxicity 
 
RAL has seldom been associated with clinically significant liver toxicity.  However, 
since liver toxicity can occur with other antiretroviral agents and TB medications, liver 
chemistry threshold holding criteria for interruption of therapy have been designed to 
assure participant safety and to evaluate liver event etiology during administration of 
RAL, TB treatment as well as the fourth antiretroviral agent and the follow-up period.  
RAL and concomitant ARVs should be stopped at the same time if any of the following 
liver chemistry stopping criteria is met.  Stopping TB medication will occur at the 
discretion of the site staff in consultation with the Protocol Team.  All AEs related to 
liver toxicity should be recorded on the CRF at each visit. 
 
The following guidance should be followed if any of the liver chemistry stopping criteria 
listed below are met: 
• 
Hold RAL and other ARVs and notify the Protocol Team within 24 hours. The site 
investigator should assign attribution of adverse event to RAL after discussion with 
Protocol Team. 
• 
TB medications can be continued at the discretion of the site clinician. Consultation 
with the Protocol Team is recommended but not required prior to stopping/continuing 
TB medications. 
• 
Report Hy’s Law liver toxicities (as described below) to the RSC as an EAE. 
• 
Complete and submit the liver toxicity CRF within one week to the DMC. 
 
Liver Stopping Criteria: 
 
• 
Hy’s Law:  ALT > 3 times the upper limit of normal (ULN) and bilirubin > 2 x ULN; 
Direct Bilirubin > 35% of Total Bilirubin. 
Note:  Hy’s Law is a set of laboratory criteria used to identify potential drug-induced 
liver injury (DILI).  Such liver injury, leading to jaundice, without a hepatic 
transplant, has a case fatality rate of 10-50%.  Increased ALT or total bilirubin are 
relatively common (particularly in HIV/AIDS) but the combination of ALT > 3 x 
ULN and total bilirubin > 2 x ULN is rare in drug development and is of clinical 
concern.  This judgment follows exclusion of viral Hepatitis (hepatitis A, B, or C 
virus) or other known liver disease. 
• 
ALT ≥ Grade 4: If another cause of ALT elevation is identified, the participant may 
be re-challenged after receiving the approval of the Protocol Team. 
• 
ALT ≥ Grade 3 for more than two weeks: If another cause of ALT elevation is 
identified, the participant may be re-challenged after receiving the approval of the 
Protocol Team.   
• 
ALT ≥ Grade 2 with symptoms of hepatitis or hypersensitivity (e.g., fatigue, nausea, 
vomiting, right upper quadrant pain, fever, rash or eosinophilia): If another cause of 
ALT elevation is identified, the participant may be re-challenged after receiving the 
approval of the Protocol Team. 
 


 
 
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NOTE: Participants who develop ALT ≥ Grade 3 should be followed weekly until 
resolution to ALT ≤ Grade 2.   
 
6.1.3 
Rash Toxicity 
 
The Supplemental Toxicity Table for Grading Severity of Cutaneous/Skin 
Rash/Dermatitis Adverse Events (Appendix III) must be used for grading rash toxicities.  
(If a participant is taking abacavir [ABC] and an ABC hypersensitivity reaction is 
suspected, see Appendix IV). 
 
• 
Grade 1 or Grade 2A – All ARVs and TB medications should be continued.  If rash 
does not resolve ≤ 14 days of onset, contact the Protocol Team. 
 
• 
Grade 2B – If the fourth ARV drug is EFV, hold EFV and RAL, obtain liver function 
tests (LFTs), continue NRTIs unless participant is on ABC in which case all 
medications, including RAL, should be stopped.   
− 
If a definitive, alternative explanation for the rash/skin reaction cannot be 
determined, EFV should be permanently discontinued. RAL should also be 
discontinued when EFV discontinued.  Continuing the NRTIs and TB 
medications is at the discretion of the site investigator.  The site investigator must 
notify the Protocol Team of the decision.  
− 
If the rash/skin reaction is definitely due to an alternative diagnosis EFV and 
RAL may be reintroduced after consultation with and permission from the 
Protocol Team AND after the rash has resolved. 
 
• 
Grade 3 – If the fourth ARV drug is EFV, EFV and RAL should be permanently 
discontinued.  Continuing the NRTIs and TB medications is at the discretion of the 
site investigator.  LFTs should be obtained. 
 
• 
Grade 4 – If the fourth ARV drug is EFV, EFV and RAL should be permanently 
discontinued.  Continuing the NRTIs and TB medications is at the discretion of the 
site investigator.  LFTs should be obtained. 
 
6.1.4 
Abacavir (ABC) Toxicity 
 
ABC may be used as a background NRTI treatment.  Since ABC will be started prior to 
introduction of the fourth ARV drug and any hypersensitivity reaction occurring in the 
absence of the fourth ARV drug if ABC toxicity is suspected should be managed per 
Appendix IV. 
 
ABC and the fourth ARV drug may subsequently be used together and therefore 
management of rash will occur as above for management of rash toxicity.  However, if a 
participant on EFV, RAL and ABC develops ≥ 2B rash, all ARV medications, including 
RAL, should be stopped immediately unless the site investigator with approval from the 
Protocol Team, deems that the rash is not drug related.  Continuing the TB medications is 
at the discretion of the site investigator. 
 


 
 
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6.2 
Participant Management Plan 
The DMC will maintain accrual reports on the DMC web portal informing sites of the number of slots 
available.   
 
The Protocol Team will respond to sites who contact the team with questions regarding toxicity 
management, dose modifications, or other issues within one business day.  
 
All dose modifications of RAL will be recommended by the Protocol Team.  See Section 6.2.1 for 
information on dose modifications for a mini-cohort or full cohort.  The Protocol Team will review data 
from the initial mini-cohort of six participants enrolled into Cohort I (≥ 2 to < 6 years of age), Cohort II (≥ 
6 to < 12 years of age) and Cohort III (≥ 4 weeks to < 2 years of age) to determine whether a cohort dose 
adjustment is required, before opening enrollment to the remainder of the cohort.  The dose 
recommendation must be approved by the Protocol Team.  In addition, for each mini-cohort, a routine 
SMC review of the safety and PK data will be done prior to accrual of the full-cohort.  If the dose fails to 
achieve PK targets or there are safety concerns, the dose (and/or frequency) is adjusted at the discretion of 
the Protocol Team.  A new mini-cohort group of six participants will be enrolled to evaluate the adjusted 
dose.  If the dose passes safety and PK considerations, an additional six participants will be enrolled to 
complete that cohort. The additional six participants in each age cohort will be evaluated for safety and 
PK.  If the dose passes, then a dose is recommended for that cohort.  If a dose cannot be selected by the 
Protocol Team, a SMC review will be convened to review the data, understanding that no dose will be 
used to complete enrollment of one of the cohorts without the approval of the Lead Merck Representative 
in the Protocol Team. 
 
The Protocol Team will notify sites of the change in dose (and/or frequency) for any participant and 
request that the site investigator provide acknowledgement of receipt and action taken (changed dose or 
did not change dose).  This management plan does not apply to dose changes due to weight gain (See 
Appendix II). 
 
6.2.1   Cohort Dosing Management 
 
Enrollment will begin simultaneously into the three age stratified cohorts with a mini-
cohort of six participants.  Enrollment to the cohort will pause upon entry of the six 
participants to allow for evaluation of PK and safety results.  These six participants will 
have RAL combined with two NRTIs as their ARV regimen (see Section 5.0).  Steady 
state RAL levels will likely be achieved within 3 days of drug initiation; an intensive PK 
evaluation will be performed between days 5 and 8.  RAL levels will be assayed in real 
time (ideally within two weeks) and the Protocol Team will evaluate the results.   
 
Immediately after completion of the intensive PK sampling, participants will continue 
taking the assigned RAL therapy and a fourth ARV drug will be added to the ARV (see 
Section 5.1.1).   
 
In addition, for each mini-cohort, a routine SMC review of the safety and PK data will be 
done prior to accrual of the full-cohort. 
 
If mini-cohort PK data for RAL are acceptable (see Section 9.3) and 4 week safety data 
are acceptable (see Section 8.5.1), enrollment will open to complete the full cohort (six 
additional participants).    
  


 
 
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If on review of all PK data the dose does not yield an acceptable AUC0-12h, the mini-
cohort dose may be adjusted, at the discretion of the team, assuming linear dose-
proportionality and taking all data available into consideration.  
 
If the dose for the initial mini-cohort yields acceptable AUC0-12h values but does not yield 
acceptable C12h values, the team will consider increasing the dose if able to project that 
the adjusted dose would still maintain acceptable AUC0-12h values while satisfactorily 
increasing the C12h.  If dose adjustment would not be predicted to achieve acceptable 
AUC0-12h and C12h values, then the Protocol Team will also consider dosing RAL three 
times daily. 
 
An additional six participant mini-cohort will be recruited at this new dose.  If the PK 
guidelines are satisfied at the new mini-cohort dose and the safety data are acceptable, 
enrollment to complete the full cohort of 12 participants on the same dose will open, 
pending an SMC review.  This dose adjustment is likely to enhance the AUC0-12h, but 
may not yield a trough (C12h) in the range desired.  If this dose does not result in 
acceptable PK parameters, the process will be repeated with a third mini-cohort and RAL 
may continue in the previous failed mini-cohort.  If dose adjustment fails to yield 
acceptable values for C12h, despite acceptable AUC0-12h values, or acceptable C12h is 
associated with unacceptably high values for Cmax or AUC0-12h, the Protocol Team will 
consider enrolling a mini-cohort with RAL given three times daily. 
 
If the mini-cohort (or full cohort) fails the safety and PK evaluations, and dose 
adjustment is warranted, then participants in the failing mini-cohort (or full cohort) will 
have their dose adjusted to the new dose being tested.  This dose change will be 
implemented for any participants still receiving RAL at the previous dose (see Section 
9.2), and without impeding treatment-related toxicities.  However, if the Protocol Team 
decides to adjust the dose to three times daily, it will not apply to the previous failed mini 
or full cohort who may remain in the initial twice daily dosing.  There will be no 
individualized PK-driven dose adjustments. 
 
Adjustment of RAL dose will only be done once for a mini cohort (or full cohort) that 
fails safety and PK evaluations.  Intensive PK for RAL will not be repeated in a mini 
cohort (or full cohort) that has a RAL dose adjustment. 
 
Participants who are replaced for PK purposes because they have discontinued due to 
toxicity will not be replaced with respect to applying safety guidelines to their cohorts; 
rather, they will continue to be counted as failures.  However, the safety data from the 
participants who replace them for PK purposes will also be used when applying the safety 
guidelines (see Section 6.7).  Participants opting to discontinue in the mini or full cohort 
prior to completion of the intensive PK will be replaced for PK and safety purposes, 
provided there are no toxicities.  A patient that discontinues prior to the completion of 
his/her week 4 safety visit, provided there are no toxicities, should be replaced for the 
purposes of applying the safety guidelines. 
 
If the results of the intensive PK are in question, unexpectedly low or high and may put 
the participant at risk for toxicity, the Protocol Team may request a repeat of the intensive 
PK. 
 


 
 
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On completion of therapy for tuberculosis, RAL will be discontinued and antiretroviral 
therapy will continue with the fourth ARV drug and two NRTI drugs per local standard 
of care. Participants will continue to be followed for an additional three months after 
discontinuation of RAL. 
 
6.2.2 
Virologic Failure Management 
 
 
 
 
For the purposes of participant management, virologic failure in this study is defined as: 
• 
Non-response defined as the participant never achieved ≥ 1 log drop from baseline in 
plasma HIV RNA or HIV RNA ≤ 400 copies/mL while on RAL. 
• 
Virologic Rebounder while on RAL is defined as: 
− 
HIV RNA > 400 copies/mL after initial response with HIV RNA ≤ 400 
copies/mL;  
 
OR 
− 
> 1.0 log10 increase in HIV RNA above nadir level after initial response.  For the 
purposes of this study, nadir is defined as the lowest HIV RNA while on study 
drug. 
 
If − at Week 8 − a participant meets the definition for virologic failure AND is clearly not 
clinically responding, the participant may be taken off RAL after consultation with the 
Protocol Team and following the local standard of care for HIV, and followed off 
treatment/on study as per Appendix I for 3 months, with visits at 4 and 12 weeks off 
treatment (see Section 6.7).    
  
If − at Week 8 − a participant meets the definition for virologic failure, but the site 
clinician, in consultation with the Protocol Team believes that there has been a good 
clinical response to therapy and that the viral load is likely to continue to decrease and 
suppress, the participant may remain on RAL.  If − at Week 12 − the definition of 
virologic failure is still met, RAL will be discontinued within one week of receiving the 
Week 12 viral load result.  The treatment regimen will then be changed according to local 
treatment standards. 
 
Participants who are virologic failures at Week 12 as defined above will, after 
consultation with the Protocol Team, be taken off study drug and follow local standard of 
care for HIV treatment. These participants will be followed off treatment/on study as per 
Appendix I for 3 months with visits at 4 and 12 weeks off treatment (see Section 6.7). 
 
6.2.3 
Viral Resistance Samples/Testing 
 
For all participants after enrollment but prior to initiation of RAL, blood samples for viral 
genotyping will be collected at entry.  In addition, to evaluate development of resistance 
to RAL and to other antiretroviral agents used in the treatment regimen, blood samples 
will be collected (if there is evidence of virologic failure per Section 6.2.2) while the 
participant is on RAL and at any early treatment discontinuation visit (see Appendix I). 
 


 
 
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6.2.4 
Algorithm for Resistance Testing 
 
• 
All participants will have genotyping of entry specimens; these will be analyzed at the 
end of the study. 
• 
While on RAL, if a participant is a virologic failure (see Section 6.2.2) with HIV RNA 
> 1,000 copies/mL, the collected specimen should be sent for resistance testing, as 
outlined in the Laboratory Processing Chart (LPC), which can be found on the 
IMPAACT website at http://impaactnetwork.org/ 
• 
If a participant discontinues from the study treatment early for any reason at any time 
point, the collected specimen will be sent for resistance testing if the participant's HIV 
RNA level is > 1,000 copies/mL at the time of discontinuation. 
• 
Genotyping will not be conducted in real time. 
 
6.2.5 
Immune Reconstitution Inflammatory Syndrome (IRIS) 
 
IRIS will be diagnosed and managed according to Appendix V.  After a diagnosis of IRIS 
is made, the site investigator should consult with the Protocol Team in deciding whether 
or not continuation of study treatment is in the participant’s best interests.  However, 
clinical management of IRIS will be at the discretion of the site investigator.  Other 
clinical scenarios suggestive of IRIS should be discussed with the Protocol Team.  
 
6.3 
Toxicity Endpoints 
• 
Permanent discontinuation of RAL due to an adverse event of ≥ Grade 3 severity, deemed to be 
possibly, probably, or definitely related to RAL. 
• 
Death, Grade 4 life-threatening adverse events deemed to be possibly, probably or definitely related 
to RAL. 
• 
Grade 2B rash 
 
6.4 
Virologic Endpoints 
Virologic Success is defined as: achieving at least 1- log10 copies/mL drop from baseline OR HIV RNA  
≤ 400 copies/mL at Week 8.  
 
Failure to respond is defined as: 
• 
HIV RNA (copies/mL) > 400 copies/mL;  
AND 
• 
Less than 1-log10 copies/mL drop from baseline. 
 
6.5 
Pharmacokinetic Endpoint 
The principal goal of this study is to determine the PK and appropriate dose of RAL when administered 
with a RIF-containing anti-TB therapy in HIV/TB co-infected infants and children that generates PK 
parameters generally comparable to those seen in HIV-infected infants and children from P1066 in the 
absence of RIF.  Key PK parameters that will be assessed include Cmax, AUC0-12h, and C12h. 
 
RAL will be stopped in any individual that has an AUC0-12hr ≥ 63 µMxhr, per Section 9.0. 
 


 
 
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6.6 
Permitted Changes to ARV Background Regimen 
Any changes in background ARV therapy after initial selection must be discussed with the Protocol 
Team.  Permitted changes include: 
 
• 
Substitution within class or rarely, across class, for documented toxicity or tolerance. 
• 
Formula substitutions (substituting single agents for fixed dose combinations and vice versa of the 
same ARV). 
 
The Protocol Team should be notified before changes occur. 
 
6.7 
Criteria for Early Treatment Discontinuation 
• 
The participant experiences drug toxicity as defined in Section 6.1 and continuing RAL would be 
detrimental to the participant's health. 
• 
The participant requires treatment with medications that are disallowed while on this study.  
• 
Drug resistant TB (MDR or XDR) is discovered after the participant is already on study. 
• 
New data become available that indicate treatment should be discontinued. 
• 
Participant has an AUC0-12hr ≥ 63 µMxhr, per Section 9.0. 
• 
PK results indicative of consistent non-adherence with the ARV regimen, or anomalously low 
absorption of RAL. 
• 
The participant becomes pregnant, see Section 6.9.2.  
• 
A female participant becomes sexually active and does not agree to use contraception as specified in 
Section 6.9.1   
• 
Virologic failure and participant does not meet criterion for continuation of RAL (see Section 6.2.2). 
 
Note that in the event of early treatment discontinuation, participants will still be asked to continue on 
study/off study drug for 3 months, and complete the TB and/or RAL treatment discontinuation, 4 weeks 
off RAL treatment/on study, and end of study evaluations listed in Appendix I. 
 
6.8 
Criteria for Early Study Discontinuation 
• 
The participant or legal guardian refuses further treatment and/or follow-up evaluations. 
• 
The site investigator determines that further participation would be detrimental to the participant's 
health or well-being. 
• 
The participant fails to comply with the study requirements to cause harm to him/herself or seriously 
interfere with the validity of the study results. 
• 
The study is discontinued by the IMPAACT network, the Office for Human Research Protections 
(OHRP), the National Institutes of Health (NIH), the local IRB or EC, US FDA, other governmental 
agencies, or Merck & Co, Inc. 
• 
An IMPAACT SMC recommends that the study be stopped early. 
• 
The study is discontinued for other administrative reasons. 
 
6.9 
Contraception Counselling, Pregnancy Testing and Pregnancy   
6.9.1 
Contraception and Pregnancy Testing  
 
All female study participants of child bearing potential should be counseled about NOT 
becoming pregnant while in the study. Female study participants of reproductive potential 


 
 
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are defined as girls who have reached menarche and have not undergone a sterilization 
procedure (bilateral tubal ligation, hysterectomy or bilateral oophorectomy).  
  
If participating in sexual activity that could lead to pregnancy, female participants of 
childbearing potential must agree to use two reliable methods of contraception 
simultaneously while receiving RAL and for four weeks after stopping RAL. Hormonal 
birth control alone would not be considered adequate (e.g. slow release inserts placed 
under/on the skin). Oral and injectable contraceptives are not permitted per Section 4.3.2. 
An effective, medically accepted barrier method of contraception (e.g. female/male 
condoms, diaphragm or cervical cap with a cream or gel that kills sperm (excluding 
nonoxydyl-9), intrauterine device [IUD], others) also must be used during the study. 
Condoms are recommended because their appropriate use is the only contraception 
method effective for preventing HIV-1 transmission. Use of an IUD may increase the risk 
of pelvic inflammatory disease. 
  
All female participants who are sexually active must have a negative pregnancy test at 
screening to be eligible for enrollment. During follow-up, pregnancy testing, if indicated, 
will be conducted at all visits and at any time during the trial when pregnancy is 
suspected. Pregnancy tests may be performed on either blood or urine.  
  
At every visit for youth that are at risk of becoming pregnant, pregnancy prevention will 
be discussed with these participants, including specific counseling, provision of 
information and advice as needed.  Verbal confirmation of the use of two methods of 
contraception should also be obtained. This discussion should be documented in the 
participant’s study record. 
  
6.9.2     Pregnancy  
  
Any participant who becomes pregnant (intrauterine) while receiving RAL will have 
study drug discontinued. However, these participants should remain on study but off 
study drug.   
  
The pregnancy must also be followed to determine the outcome (including premature 
termination) and status of mother and child(ren), which will be recorded and submitted to 
the Statistical and Data Management Center (SDMC) using the Pregnancy Outcome form 
within one week of the site becoming aware of the outcome.  
  
HIV-1 infected women who are pregnant should be treated according to the most recent 
Public Health Service Task Force Recommendations for Use of Antiretroviral Drugs in 
Pregnant HIV-Infected Women for Maternal Health and Interventions to Reduce 
Perinatal HIV Transmission in the United States: Tables 
(http://www.aidsinfo.nih.gov/Guidelines/) or WHO Antiretroviral drugs for treating 
pregnant women and preventing HIV-infection in infants (2010) and locally applicable 
guidelines. 
 
NOTE:  The Protocol Team encourages the clinical sites to prospectively register the 
participant’s pregnancy in the Antiretroviral Pregnancy Registry. 
http://www.apregistry.com/.    
 
 


 
 
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7.0 
EXPEDITED ADVERSE EVENT (EAE) REPORTING  
7.1 
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/clinical-research-sites/safety-reporting. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting system, must 
be used for EAE reporting to DAIDS. In the event of system outages or technical difficulties, EAEs may 
be submitted via the DAIDS EAE Form. This form is available on the DAIDS RSC website at 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids/paper-eae-reporting.  
 
For questions about DAERS, please contact NIAID CRMS Support at CRMSSupport@niaid.nih.gov. 
Please note that site queries may also be sent from within the DAERS application itself. 
 
For questions about expedited reporting, please contact the DAIDS RSC Safety Office at 
DAIDSRSCSafetyOffice@tech-res.com. 
 
7.2 
Reporting Requirements for this Study 
• 
The SAE (Serious Adverse Event) Reporting Category, as defined in Version 2.0 of the DAIDS EAE 
Manual, will be used for this study for the period of time defined in Section 7.4.  
• 
Other medically significant events for which expedited reporting is required include all cancers and 
pregnancies, fetal losses, IRIS events that qualify as serious adverse events, Hy’s Law liver toxicities, 
and all Grade 3 and 4 toxicities. 
 
• 
Overdoses, (defined as two times the prescribed dose within a 24-hour period) of RAL, do not require 
expedited reporting, but will be reported to Merck quarterly by the SDMC.  Overdoses of RAL 
should be recorded on the CRF and keyed in the database in a timely manner. 
 
• 
The drug for which expedited reporting is required is raltegravir (RAL). 
 
7.3 
Grading Severity of Events 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE 
Grading Table), Version 2.0, November 2014, must be used and is available on the DAIDS RSC website 
at http://rsc.tech-res.com/safetyandpharmacovigilance/. 
 
The Supplemental Toxicity Table for Grading Severity of Cutaneous/Skin Rash/Dermatitis Adverse 
Events (Appendix III) will also be used.  The parameters specified in this table supersede the DAIDS 
Toxicity Table when grading these events. 
 
For reporting of all adverse experiences, the investigator will determine the causality and relationship to 
study drug.  However, in regards to patient safety and PK evaluations which will support the selection of 
a dose for a given cohort, the Protocol Team will also have input as to the causality and drug relation of 
specific adverse experiences. 
 


 
 
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7.4 
Expedited AE Reporting Period 
• 
The expedited AE reporting period for this study is up to the end of TB treatment for an individual 
participant (from study enrollment until end of TB treatment or discontinuation of the participant 
from study participation for any reason), beginning at the time of administration of the first dose of 
study drug.  
 
• 
After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs as defined in 
Version 2.0 of the EAE Manual will be reported to DAIDS if the study staff become aware of the 
events on a passive basis (from publicly available information). 
 
8.0 
STATISTICAL CONSIDERATIONS 
8.1 
General Design Issues 
P1101 is a Phase I/II, dose-finding, safety, tolerability and pharmacokinetics study of RAL chewable 
tablets in HIV-infected infants and children ≥ 4 weeks to < 12 years of age who are TB co-infected and on 
a stable RIF-based TB therapy who are eligible for ARV treatment by current local or WHO guidelines.  
The study’s objective is to determine the proper and safe dose of RAL to be used with a RIF-based TB 
treatment regimen to provide additional ART options in co-infected infants and children. 
 
An initial dose of RAL chewable tablets will be given at 12 mg/kg twice daily (up to a maximum of 800 
mg twice daily), with two NRTIs.  Following intensive PK sampling for RAL (5 to 8 days after the start 
of RAL therapy), a fourth ARV drug per local standard of care will be added to the regimen (see Section 
5.1.1).  The four drug ARV regimen will be continued until TB treatment is completed.  Each child will 
be followed up to assess safety, clinical, immunological and virological parameters, from the time that 
RAL is started until 3 months after stopping RAL while standard of care treatment continues.  See 
Section 3.0 for details.  Participants aged ≥ 4 weeks to < 12 years of age who have had at least one week 
and not more than 20 weeks of RIF-containing TB therapy will be enrolled.  The sample will be stratified, 
by age into the following groups: Cohort I:  ≥ 2 to < 6 years; Cohort II: ≥ 6 to < 12 years; Cohort III: ≥ 4 
weeks to < 2 years of age, and these three cohorts will accrue simultaneously.  At least 12 participants in 
each age cohort will be enrolled.   
 
For each age cohort, initial tests of safety and PK will examine data from the first mini-cohort of n = 6.  
These tests will proceed as follows: The starting dose administered to the first six participants will be 
evaluated on the basis of RAL PK data, based on blood samples taken 5 to 8 days after the start of therapy 
on that dose.  For all participants, safety will be evaluated on the basis of all available data collected 
through the fourth week on a given dose within each cohort. 
 
The overall safety and PK data of the first six participants on a given cohort will be evaluated with respect 
to the safety guidelines specified in Section 8.5.1 and the PK guidelines specified in Section 9.0.  In 
addition to the P1101 team’s assessment, a routine SMC review of the safety and PK data will be 
performed for each mini-cohort prior to accrual of the full-cohort. If the initial mini-cohort of n = 6 fails 
either the safety (see Section 8.5.1) or the PK (see Section 9.2) guidelines in this initial test, then the dose 
will be adjusted in the appropriate direction, unless dose reduction is likely to result in inadequate PK 
values.  An initial evaluation of the new dose level will be made on the basis of data from the first six new 
participants treated at this dose.  If the first six participants of a cohort meet both sets of guidelines, then 
six additional participants will be accrued to this cohort.  The additional six participants will be evaluated 
on both safety and PK; if the full cohort of n = 12 passes both safety and PK criteria, then this dose will 
become the selected dose.  Otherwise, a new starting dose may be tested on a new cohort of participants. 
 


 
 
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If a mini-cohort of n=6 (or a full cohort) fails the safety guidelines per Section 8.5.1, then the dose may be 
reduced and the new dose evaluated on a new cohort.  If a mini-cohort (or a full cohort) fails, due to 
inadequate PK, then the dose may be increased, provided that safety criteria have been met.  Whenever a 
new dose is to be tested, safety criteria will be evaluated on a new cohort of participants whose exposure 
has been to the dose to be tested.  PK and safety results from failed doses will not be included in the 
evaluation of new doses, since this would introduce bias. 
 
If the mini-cohort (or full cohort) fails the safety and/or PK evaluations, and dose adjustment is 
warranted, then participants in the failing mini-cohort (or even full cohort) will have their dose adjusted to 
the new dose being tested.  This dose change will be implemented for any participants still receiving RAL 
at the previous dose (see Section 9.2), and without impeding treatment-related toxicities.  However, if the 
Protocol Team decides to adjust the dose to three times daily, it will not apply to the previous failed mini 
or full cohort.  There will be no individualized PK-driven dose adjustments. 
 
For these safety algorithm guidelines, “evaluable” will be defined as “having been treated exclusively on 
the dose being evaluated for a given age cohort and having either four (4) weeks of exposure to the study 
drug or having been classified as a safety failure, due to a study drug related adverse event occurring 
during the first four weeks of treatment”.   
 
If the Protocol Team judges a given participant’s PK data to be unevaluable (e.g., because of non-
adherence), that participant will be replaced for dose finding purposes.  Note that the participant would be 
replaced for evaluating safety, as well as PK, criteria, if unevaluable PK data reflect uncertainty about 
appropriate exposure to the study medication. 
 
8.2 
Outcome Measures 
 
8.2.1 
Primary Endpoints 
 
• 
Toxicity Endpoint for Analytic Purposes: 
- 
Termination from treatment due to adverse events of ≥ Grade 3 deemed at least 
possibly related to RAL. 
- 
Death, Grade 4 life-threatening adverse events deemed at least possibly related to 
RAL. 
- 
Grade 4 non-life threatening adverse events deemed as probably or definitely 
related to RAL. 
- 
Adverse events of > Grade 3 deemed at least possibly related to RAL. 
 
• 
Pharmacokinetic Endpoints: 
(See Section 9.0: Clinical Pharmacology Plan) 
 
• 
Early termination of TB therapy if there is MDR/XDR detected subsequent to 
starting ARV treatment or if due to toxicity attributable to TB medication. 
 
 
8.2.2 
Primary Response Variables 
 
• 
Pharmacokinetic parameters (See Section 9.0)  
 


 
 
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8.2.3 
Secondary Endpoints 
 
• 
Virologic Endpoint: Failure to respond at Week 8 
- 
HIV RNA (copies/mL) > 400 copies/mL;  
AND 
- 
Less than 1-log10 drop from baseline. 
 
Therefore, virologic success is defined as achieving at least 1- log10 drop from baseline 
OR HIV RNA ≤ 400 copies/mL. 
 
A secondary, more stringent definition of virologic response is to achieve HIV RNA ≤ 50 
copies/mL. 
 
• 
Development of new OIs 
 
 
8.2.4 
Secondary Response Variables 
 
• 
Changes in log-RNA from baseline to Week 8 
• 
Changes in CD4 percent/count from baseline to Week 8 
• 
Clinical response (weight, height, BMI gains) 
• 
Genotypic resistance measures 
 
8.3 
Randomization and Stratification 
There will be no randomization.  Participants will be stratified by age:  
Cohort I:  ≥ 2 to < 6 years; Cohort II: ≥ 6 to < 12 years; Cohort III: ≥ 4 weeks to < 2 years of age. 
 
8.4 
Sample Size and Accrual 
Each successful age cohort will include at least 12 participants almost all of whom will have been treated 
continuously on the recommended dose.  To achieve 12 evaluable participants in each cohort at the 
recommended dose, 36 – 108 participants are anticipated to be enrolled. 
 
The following tables show the width of estimated 95% confidence intervals for the geometric mean for 
AUC0-12hr (µMxhr) and C12h (nM) with sample sizes of 6, 12 and 18 and standard deviations equal to that 
seen in P1066 (for AUC 0.52 and for C12h 0.85 on natural logarithm scale) and for standard deviations 
either 30% smaller or larger than in P1066.  The confidence intervals are centered around the estimated 
geometric means for P1066.   
 
• 
As the sample size increases, the width of the estimated confidence interval decreases. 
• 
As the standard deviation increases, the width of the estimated confidence interval increases. 
• 
Note that the estimated confidence intervals are not symmetric as they are calculated on the natural 
logarithm scale and then anti-logged, and the width would be different if centered at a different value. 
• 
The choice of sample size of 12 per cohort reflects the Protocol Team’s assumption that the standard 
deviation of the RAL on the current study will not exceed 130% of that observed in the absence of TB 
drugs on IMPAACT P1066.  Given this assumption, the team’s judgment is that samples of 12 
participants would estimate AUC and C12h parameters with adequate precision. 
 


 
 
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Table 4: AUC0-12hr (µMxhr) - geometric mean - centered at 19.93 
N 
SD 
95%- 
-CI 
Width 
of 95% CI 
6 
70% of P1066 SD 
14.89 
26.68 
11.79 
 
P1066 SD 
13.14 
30.23 
17.09 
 
130% of P1066 SD 
11.60 
34.25 
22.65 
12 
70% of P1066 SD 
16.22 
24.50 
8.28 
 
P1066 SD 
14.85 
26.76 
11.91 
 
130% of P1066 SD 
13.59 
29.23 
15.64 
18 
70% of P1066 SD 
16.85 
23.59 
6.74 
 
P1066 SD 
15.67 
25.35 
9.68 
 
130% of P1066 SD 
14.58 
27.25 
12.67 
 
Table 5: C12h (nM) - geometric mean - centered at 92.85 
N 
SD 
95%- 
CI 
Width 
of 95% CI 
6 
70% of P1066 SD 
57.67 
149.52 
91.85 
 
P1066 SD 
47.02 
183.38 
136.36 
 
130% of P1066 SD 
38.34 
224.91 
186.57 
12 
70% of P1066 SD 
66.30 
130.05 
63.74 
 
P1066 SD 
57.39 
150.24 
92.85 
 
130% of P1066 SD 
49.68 
173.57 
123.90 
18 
70% of P1066 SD 
70.53 
122.25 
51.72 
 
P1066 SD 
62.69 
137.55 
74.85 
 
130% of P1066 SD 
55.72 
154.75 
99.03 
 
 
8.5 
Monitoring 
The study will be monitored monthly by the Protocol Team which will review safety and pharmacokinetic 
data as required during the dose-finding stage with the aim of determining the optimal dose for each 
cohort while protecting patient safety.  In addition, the IMPAACT Network will appoint a Study 
Monitoring Committee (SMC) prior to study commencement to provide independent reviews to ensure 
participant safety.  In accordance with IMPAACT and DAIDS procedures, this committee will be 
composed of two individuals from the Primary Scientific Committee, one Protocol Development and 
Monitoring Committee (PDMC) member and a statistician, independent of the Protocol Team and drug 
manufacturer (Merck).  Members of said SMC will have: 
 
1) No financial interest in the study; 
2) No planned authorship in publication of study results; and 
3) No involvement in the conduct of the study. 
 


 
 
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8.5.1 
Safety Guidelines 
 
8.5.1.1 Evaluation of the Starting Doses During the Dose-Finding Stage 
 
The attribution of relationship of serious adverse events, including all ≥ Grade 3, 
to study drug for the purposes of employing the start, stop and pause rules 
specified below will be by consensus among the site investigator, the Protocol 
Team (which includes representatives from Merck) and the DAIDS medical 
officers.  If unanimous agreement between them cannot be established, the 
relevant data will be reviewed by the independent SMC, which will make the 
final judgment concerning the relationship between study drug and the adverse 
event. Within this committee the decision will be determined by the majority 
opinion of this study’s independent SMC clinicians.  
 
Gradation of relationship will use the following terminology:  
• 
Not related 
• 
Probably not related 
• 
Possibly related 
• 
Probably related 
• 
Definitely related 
 
8.5.1.2 Initial Safety Guidelines for the Evaluation of Starting Doses For the first n = 6 
of each age mini-cohort (See Section 9.0 for Pharmacokinetic Guidelines) 
 
For each age cohort, the frequency of adverse events to the starting dose of the 
study medication will be evaluated on the first six participants. The data will 
extend to the Week 4 visit for these six participants.  Further accrual into this 
cohort will be contingent upon meeting PK targets as well as the following safety 
guidelines. In addition to the team’s assessment, a routine SMC review of the 
safety and PK data from each mini-cohort will be performed prior to accrual of 
the full-cohort. 
 
If any of the first six participants experiences death, has a life threatening Grade 
4 adverse event deemed at least possibly related to the study medication, or any 
Grade 4 event that is at least possibly attributable to the study medication, stop 
accrual into this dose group until a safety review by an independent Study 
Monitoring Committee composed according to DAIDS/IMPAACT policies has 
occurred.  (Note: A possibly related Grade 4 non-life threatening event would 
trigger an accrual stop and SMC review, but if confirmed by SMC as possibly 
related, and if only such event, then accrual could restart). Only proceed if this 
review has led to a recommendation that it is safe to do so and the Protocol Team 
agrees.  The safety review may lead to a recommendation that the dose be de-
escalated.  Before implementing such a recommendation, the study team will 
review the PK and safety data to determine whether a lower dose is likely to 
achieve adequate drug exposure. 
 
If none of the first six participants has experienced death, a life-threatening 
Grade 4 adverse event deemed at least possibly related to the study medication, 
or any Grade 4 event that is probably or definitely attributable to the study 
medication and no more than 2 of these 6 participants have permanently 


 
 
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discontinued study drug due to a Grade 3 or Grade 4 adverse event that is at least 
possibly treatment related, then this cohort has passed the initial safety 
guidelines, pending a SMC review. If these six participants also meet the PK 
guidelines, accrue additional six participants into this cohort and re-evaluate both 
safety and PK.  Note that a routine SMC review of both safety and PK data is 
required for each mini-cohort before enrolling the full cohort of 12 participants. 
 
Given the small sample sizes within each cohort, the information available for 
preliminary safety decisions will be imperfect.  Two types of sampling errors are 
possible: 1) in a cohort where the true rate of toxicity is too high to warrant 
increased exposure to the current starting dose of the medication, the sample data 
may pass the safety guidelines; 2) in a cohort where the true rate of toxicity is 
low enough that further exposure to the current starting 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 medication were used extensively among the 
patient population at the dose level under question.  The hypothetical situations 
presented below range from conditions under which a given dose level would 
cause a high incidence of severe and life threatening adverse events deemed to be 
at least possibly related to study drug 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 participants is drawn 
from the patient population and that the safety guidelines, summarized above, are 
followed.  
 


 
 
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Table 6: Probability of Failing Safety Guidelines Under Potential Rates of True Toxicity 
True Toxicity Rates 
Probability of 
Failing Safety 
Guidelines 
Non-Life Threatening Grade 3 or 
Grade 4 deemed at least possibly 
related to study medication that 
would result in Tx 
discontinuation, excluding Grade 
4 events probably or definitely 
attributable to study medication 
Life Threatening serious adverse 
events (including death) deemed 
to be at least possibly related to 
study medication or Grade 4 
events probably or definitely 
attributable to study medication 
.50 
.00 
.66 
.50 
.05 
.78 
.50 
.25 
.98 
.25 
.00 
.17 
.25 
.05 
.41 
.25 
.25 
.88 
.10 
.00 
.02 
.10 
.05 
.28 
.10 
.25 
.83 
.05 
.00 
.00 
.05 
.05 
.27 
.05 
.25 
.82 
.00 
.05 
.26 
.00 
.25 
.82 
 
Table 6 shows (e.g.) 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 or Grade 4 events is 50%.  Assuming that it 
would be undesirable to open a new cohort 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 2% chance 
of failing, when the true rate of non-life threatening Grade 3 or Grade 4 events is 
only 10% and the true rate of life threatening toxicity is zero.  Assuming that the 
potential benefits associated with exposing a new cohort to this dose of the drug 
would outweigh the risks associated with this relatively low rate of toxicity, 
failing the safety guidelines under these conditions would be an error. 
 
8.5.1.3 Final Evaluations of Starting Doses For the Full Cohort of Each Age Group 
Based on Safety Guidelines (Section 8.5.1.2) and PK guidelines (Section 9.2). 
 
The final safety guidelines applied to a given starting dose of the study 
medication within a cohort will make use of data from all participants (n = 12) in 
that cohort who have taken the dose under evaluation. For all participants, safety 
will be evaluated on the basis of all available data collected through the fourth 
week since initiation of RAL on a given dose as described in Section 8.1 above.  
 


 
 
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If any of these participants experiences death, a life threatening Grade 4 adverse 
event deemed at least possibly related to the study medication, or any Grade 4 
event that is probably or definitely attributable to the study medication, this 
starting dose will fail the safety guidelines for the cohort under investigation. 
 
If none of these participants has experienced death, a life-threatening Grade 4 
adverse event deemed at least possibly related to the study medication, or any 
Grade 4 event that is probably or definitely attributable to the study medication, 
and no more than 33% of these participants have permanently discontinued from 
the study drug due to a Grade 3 or Grade 4 adverse event that is deemed at least 
possibly treatment related, then this starting dose will pass the safety guidelines 
for the cohort under investigation.  
 
 
8.5.2 
Study Safety Monitoring 
 
The safety and tolerability of the study agent will be monitored by means of adverse 
events reports and toxicity reports presenting laboratory and clinical events.  It is required 
that these data be entered into the database within 48 hours of the time at which the 
results of the laboratory tests or clinical examinations become available.   
 
Reports compiled by the Data Management Center (DMC) will be reviewed and 
discussed by the Protocol Team on conference calls at least monthly.  Conference calls 
will also be scheduled as needed in response to any adverse event that requires the 
immediate attention of the Protocol Team.  Notification of team members will be by e-
mail, phone or fax, depending on time differences.  Data on accrual, PK and toxicity will 
be reviewed.   
 
Since Phase I studies are not routinely reviewed by a Data and Safety Monitoring Board 
(DSMB), it is the responsibility of the Protocol Team to interpret the toxicity data, and 
make any decisions regarding adverse events that are needed to protect participants from 
undue risk.  The SMC appointed by the IMPAACT Network will review the data if a 
situation arises which requires independent review. 
 
Adverse events will be monitored by the Protocol Team throughout the follow-up period.  
If the Protocol Team identifies any potentially treatment-related toxicities, which may 
compromise participant safety, it will determine whether the study needs to be suspended 
or modified. 
 
 
8.5.2.1 Rules for Suspending Accrual to Assess Safety Following an Adverse Event 
 
Accrual will be temporarily suspended if any participant experiences death, has a 
life threatening Grade 4 adverse event deemed at least possibly related to the 
study medication or any Grade 4 event that may not be judged to be life-
threatening but is judged to be possibly, probably or definitely attributable to the 
study medication. (Note: A possibly related Grade 4 non-life threatening event 
would trigger an accrual stop and SMC review, but if confirmed by SMC as 
possibly related, and if only such event, then accrual could restart). 
 
Following temporary suspension of accrual, the SMC will be convened and will 
further review the safety data within 48 hours of notification of the event to 


 
 
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determine if continuation of accrual is appropriate.  If the SMC agrees that the 
study drug is likely to be safe for additional participants, they may allow accrual 
to resume.  Regulatory agencies will be notified of the event and the team’s 
decision after this review of the safety data has taken place. 
 
 
8.5.2.2   Accrual Rate Evaluation 
 
Accrual into this study will be monitored by the by the team and IMPAACT 
leadership.  Monthly conference calls will be held by the study team to review 
accrual reports prepared by the Data Management Center.  Rate of enrollment 
will be closely monitored with input provided from team members and 
participating sites.  If any of the dosing cohorts has not accrued half of its 
evaluable participants within six months after opening the current version of the 
protocol, the team will communicate with all sites to identify potential barriers to 
accrual and take corrective actions to improve enrollment.  In the event that 
barriers identified by the team involve current protocol specifications, 
consideration may be given to amending the protocol to address the identified 
barriers. 
 
8.6 
Analyses 
 
8.6.1 
Summary of Dose Finding Data 
 
The analysis of dose finding data will consist of descriptive statistics summarizing the 
safety and PK data from the dose finding phase of the study (See Section 9.0 for PK 
analysis).  The safety data will be broken down by cohort and will present the results of 
the safety evaluations applied to each starting dose tested within each cohort, including 
information indicating which starting doses have passed or failed the safety guidelines.  
For each starting dose within each cohort, every adverse event of ≥ Grade 3 will be listed, 
along with patient demographics, the dose prescribed to the patient at the time of the 
event and the Protocol Team’s assessment of the probability that this event was due to the 
study treatment.  
 
 
8.6.2 
Analysis of Data Representing Exposure to the Doses Selected for Each Cohort 
 
 
The following analyses will be applied to each age cohort. 
 
The primary analyses will be conducted on patients who were only exposed to the final 
selected dose.  Secondary analyses will be done to include all patients. 
 
 
 
8.6.2.1 Primary Analyses 
 
The following analyses will be performed through the final study visit. 
 


 
 
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Safety 
Each participant’s safety data will be summarized as: the worst grade of adverse 
event experienced while on the selected dose of the study treatment and the worst 
grade of adverse event judged to be at least possibly due to study treatment 
during this time period.  Frequency distributions of these safety outcomes will be 
presented.  Listings of all ≥ Grade 3 events, including deaths, will be provided, 
broken down by type of toxicity (hepatic, hematologic, etc.). 
 
The proportions of participants experiencing grade 3+ adverse events, bounded 
by exact 95% confidence intervals.  Similar analyses will present the proportions 
of participants exhibiting ≥ Grade 3 events (including deaths) which have been 
judged to be at least possibly related to study medication, again bounded by exact 
95% confidence intervals.  
 
 
 
8.6.2.2 Key Secondary Analyses 
 
Viral Load  
A descriptive assessment of virologic response will be assessed on the basis of 
HIV viral load HIV-1 RNA (copies/mL), after 8 weeks of RAL-containing ARV 
therapy when most participants will still be on RAL, thus having relatively 
complete data.  This will be an as-treated analysis.  Note that participants who 
discontinue RAL due to TB-drug cessation will be excluded from the analysis.  
Virologic response will also be summarized at other time points (see Appendix 
I). 
 
The primary definition of virologic response is defined as achieving: (1) at least a 
1 log10 reduction in HIV-1 RNA (copies/mL) from baseline OR (2) HIV-1 RNA 
≤ 400 copies/mL.  A secondary, more stringent definition of virologic response is 
to achieve HIV RNA ≤ 50 copies/mL. 
 
The proportions of participants meeting the criteria for virologic response at each 
of these time points will be bounded by exact 95% confidence intervals, and will 
be presented in aggregate and by age cohort. 
 
CD4 
 
As Treated Analysis:  
For participants who have remained on the study treatment and have data for 
both baseline and Week 8: Change in CD4 count and percent from baseline at 
Week 8 will be bounded by 95% confidence intervals and presented in aggregate 
and by age cohort.  Immunologic response will also be summarized at other time 
points (see Appendix I). 
 


 
 
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9.0 
CLINICAL PHARMACOLOGY PLAN 
9.1 
Pharmacology Objectives 
 
9.1.1 
Primary Objective 
 
To determine the pharmacokinetics and appropriate dose of RAL when administered with 
a RIF-containing anti-TB therapy in HIV/TB co-infected infants and children that 
generates PK parameters generally comparable to those seen in HIV-infected infants and 
children in the absence of RIF. 
 
 
9.1.2 
Secondary Objective 
 
To evaluate the pharmacokinetics of RAL in HIV/TB co-infected infants and children 
ages ≥ 4 weeks to < 2 years, ≥ 2 to < 6 years and ≥ 6 to < 12 years also receiving 
concomitant ARVs in the presence of rifampicin to determine the influence of the other 
ARVs on RAL pharmacokinetics. 
 
9.2 
Study Design, Modeling and Data Analysis 
P1101 is a Phase I/II, dose-finding, safety, tolerability and pharmacokinetics study of RAL chewable 
tablet in HIV-infected infants and children ≥ 4 weeks to < 12 years of age who are TB co-infected and on 
a stable RIF-based TB regimen who are eligible for ARV treatment by current local or WHO guidelines.  
The study’s objective is to determine the proper and safe dose of RAL to be used with a RIF-based TB 
treatment regimen to provide additional ART options in co-infected infants and children. 
 
An initial dose of RAL will be given at 12 mg/kg (up to a maximum of 800 mg) twice daily for chewable 
formulation, with two NRTIs.  Following the intensive PK study for RAL (5 to 8 days after the start of 
RAL therapy), a fourth ARV drug will be added to the regimen (see Section 5.1.1).  The four-drug ARV 
regimen will be continued until TB treatment is completed.  Each child will be followed up to assess 
safety, clinical, immunological and virological parameters, from the time that RAL is started on a TB 
containing regimen until 3 months after stopping RAL while standard of care treatment continues.  See 
Section 3.0 for details. 
 
Participants aged ≥ 4 weeks to < 12 years of age who have had ≥ 1 week and ≤ 20 weeks of RIF-
containing TB therapy will be enrolled.  The sample will be stratified, by age into the following groups: 
Cohort I: ≥ 2 to < 6 years; Cohort II: ≥ 6 to < 12 years; Cohort III: ≥ 4 weeks to < 2 years of age, and 
these three cohorts will accrue simultaneously.  At least 12 participants in each age cohort will be 
enrolled.  
 
For each age cohort, initial tests of safety and PK will examine data from the first mini-cohort of n = 6.  
These tests will proceed as follows: The starting dose administered to the first six participants will be 
evaluated on the basis of RAL PK data, based on blood samples taken 5 to 8 days after the start of therapy 
on that dose.  For all participants, safety will be evaluated on the basis of all available data collected 
through the fourth week on a given dose within each cohort as described in Section 8.5.1.2. 
 
The overall safety and PK data of the first six participants on a given cohort will be evaluated with respect 
to the safety guidelines specified in Section 8.5.1 and the PK guidelines specified below.  In addition to 
the team’s assessment, a routine SMC review of the safety and PK data for each mini-cohort will be 
performed prior to accrual of the full-cohort accrual. If the initial mini-cohort of n = 6 fails either the 


 
 
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safety (see Section 8.5.1) or the PK guidelines in this initial test, then the dose will be adjusted in the 
appropriate direction, unless dose reduction is likely to result in inadequate PK values.  An initial 
evaluation of the new dose level will be made on the basis of data from the first six new participants 
treated at this dose.  If the first six participants of a cohort meet both sets of guidelines, then six additional 
participants will be accrued to this cohort.  The additional six participants will be evaluated on both safety 
and PK; if the full cohort of n = 12 passes both safety and PK criteria, then the dose on which they have 
been treated will become the selected dose.  Otherwise, a new starting dose may be tested (see Section 
8.1). 
 
If the mini-cohort (or full cohort) fails the safety and/or PK evaluations, and dose adjustment is 
warranted, then participants in the failing mini-cohort (or even full cohort) will have their dose adjusted to 
the new dose being tested.  This dose change will be implemented for any participants still receiving RAL 
at the previous dose, and without impeding treatment-related toxicities.  However, if the Protocol Team 
decides to adjust the dose to three times daily, it will not apply to the previous failed mini or full cohort.  
There will be no individualized PK-driven dose adjustments. 
 
The regimen of medications for TB and their dosages will be reviewed at the screening visit to ensure that 
entry criteria are met.  The importance of adherence and of reporting deviations in adherence will be 
emphasized.  The PK evaluation of RAL will be performed between days 5 and 8 after treatment 
initiation.  Parents/Guardians must report that the participants have not missed any doses of the ARVs, 
including RAL, in the 48 hours prior to the intensive PK visit.  If a missed dose is reported, the intensive 
PK visit must be rescheduled.  Participants should not ingest breast milk, formula, or any other high fat 
food/liquid for 2 hours prior to and 1 hour after dosing on the intensive PK day. Water and other fluids 
(i.e. apple/orange juice and oral rehydration solution) may be consumed as desired.  Participants may 
consume a light meal of their choice two hours after RAL dosing on the intensive PK day. 
Parents/Guardians should be instructed not to administer the second dose of RAL to participants until the 
intensive PK sampling is completed. Once the intensive PK visit is scheduled, a reminder call to the 
parent/guardian regarding the PK visit, the required fasting and reinforcing adherence will be made 3 to 4 
days prior to the PK visit.  A follow-up call to the parent/guardian should be made 1 day prior to the PK 
visit to confirm adherence.  If a missed dose is reported the scheduled PK visit should be cancelled and 
rescheduled. 
 
The participant must bring to the clinic the doses of RAL, other ARVs and TB medications so they can be 
taken after the pre-dose (0) blood is drawn.  Doses vomited within 15 minutes may be re-dosed once, with 
t = 0 to then be time of repeat dosing.  If vomited > 15 minutes after dosing, PK must be cancelled and 
may be rescheduled.  A (0.5) mL of blood sample will be drawn at pre-dose (0), 0.5, 1, 2, 3, 4, 6, 8, and 
12 hours post dosing.   
 
All PK samples will be registered in the Lab Data Management System (LDMS) database.  The 
Laboratory Processing Chart (LPC) provides instructions regarding processing and shipping of intensive 
PK samples.  The study database will be kept up to date by close tracking of samples.  Sample assays and 
PK calculations for RAL will be performed in real time and the reported to the Protocol Team and sites. 
 
Pharmacokinetic Guidelines 
 
Pharmacokinetic parameters will be determined from plasma concentration-time profiles using 
noncompartmental methods (32).  Calculated pharmacokinetic parameters will be: area-under-the-curve 
(AUCτ), maximum plasma concentration (Cmax), time to Cmax (Tmax), and plasma concentration at the end 
of the 12 hour dosing interval (C12h).  AUCτ will be determined using the linear-log trapezoidal rule.  Cmax 
and Tmax will be taken directly from the observed concentration-time data.  
 
 
 


 
 
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This is a RAL AUC0-12hr and C12h-targeted study where participants between the ages of ≥ 4 weeks and < 
12 years of age will be enrolled simultaneously into three cohorts (≥ 4 weeks to < 2 years, ≥ 2 to < 6 years 
and ≥ 6 to < 12 years).  Each cohort will start with enrollment of a mini-cohort of n = 6 participants.   
 
If the mini-cohort (n = 6) at a RAL dose of 12 mg/kg achieves 1) a geometric mean RAL AUC0-12hr of 
approximately 14 to 45* µMxhr and 2) an approximate GM C12h ≥ 75nM, and meets safety criteria, then 6 
additional participants will be enrolled at this dose.  The data from these participants will be combined 
with the previous 6 for evaluation of this dose using the same criteria.    
 
Note: * The cohort upper bound is based on mean exposures observed in the 800 mg multiple dose arm of 
P001 in adults, the highest raltegravir multiple dose exposure data available.  
 
If the minimum targets above are not achieved, the dose will be increased in linear fashion, up to a 
maximum of 18 mg/kg not exceeding 800 mg/dose.  If the GM RAL AUC0-12hr falls above a maximal 
acceptable target of 45 µMxhr, the dose will be similarly reduced.  Use of a three times daily regimen 
may also be considered by the Protocol Team in order to provide adequate cohort GM C12h values (≥ 
75nM) without exceeding exposures observed in the 800 mg multiple dose arm of P001 (GM AUC0-12hr ≤ 
45 µMxhr).   
 
If any individual has an AUC0-12hr ≥ 63 µMxhr **, the participant will stop taking RAL.  However, their 
PK and safety data will be used in the assessment of the dose for that cohort.   
 
Note: ** Individual limit is based on mean exposure observed in the raltegravir QTc study (P024), since 
this study was closely monitored for safety. 
 
Dosing decisions will be made by the Protocol Team after careful deliberation of all available data 
pertaining to the study drug.   
 
If the results of the intensive PK are in question, unexpectedly low or high and may put the participant at 
risk for toxicity, the Protocol Team may request a repeat of the intensive PK. 
 
9.3 
Anticipated Outcomes 
We anticipate that doubling the RAL dose in the presence of RIF will produce RAL AUC0-12h and C12h 
within the acceptable range (33).  If acceptable AUC0-12h and C12h are not achieved up to 800mg per dose, 
the use of RAL with RIF-containing TB treatment in infants and children may not be advisable.  
 
10.0 
HUMAN PARTICIPANTS 
10.1 
Institutional Review Board and Informed Consent 
This protocol, the informed consent document (Appendix VI), and any subsequent modifications must be 
reviewed and approved by the IRB or EC responsible for oversight of the study. Written informed consent 
must be obtained from the participant (or parents or legal guardians of participants who cannot consent 
for themselves, such as those below the legal age).  The participant's assent must also be obtained if he or 
she is able to understand the nature, significance, and risks of the study.  The informed consent will 
describe the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation.  A copy of the consent form will be given to the participant (or parent or legal guardian). 
 
Each site which receives US HHS funding and follows the United States Code of Federal Regulations 
Title 45-Public Welfare, Part 46-Protection of Human Participants (also known as the Common Rule) 


 
 
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should have on record at the site a plan that detects and addresses any change in guardianship occurring in 
pediatric participants and determines when a study participant must have a consent process which 
involves a legally authorized representative (LAR) other than a family member with guardianship. The 
plan will include how the site determines when a LAR is initially or no longer needed and how frequently 
the LAR re-signs the consent. The plan should follow all IRB/EC, local, state, national and/or host 
country guidelines. Confirmation of such a plan at a site should be submitted with protocol registration 
materials. 
 
10.2 
Participant Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified only by a coded 
number to maintain participant confidentiality.  All records will be kept in a secured area.  All computer 
entry and networking programs will be done with coded numbers only.  Clinical information will not be 
released without written permission of the participant, except as necessary for monitoring by the study 
staff, study monitors, FDA, the OHRP, NIH, the local IRB/EC, or Merck & Co., Inc. 
 
10.3 
Study Discontinuation 
The study may be discontinued at any time by the IMPAACT Network, NIAID, the OHRP, NIH, FDA, 
local IRB/ EC, Merck & Co., Inc., or other governmental agencies as part of their duties to ensure that 
research participants are protected.  
 
11.0 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by IMPAACT policies.  Any presentation, abstract, 
or manuscript will be made available for review by the pharmaceutical sponsors prior to submission. 
 
12.0 
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 Centers for Disease Control and Prevention and any host country 
public health guidelines. 
 
All infectious specimens will be sent using the ISS-1 SAF-T-PAK mandated by the International Air 
Transport Association Dangerous Goods Regulations-Packing Instruction 602.  Refer to individual carrier 
guidelines (e.g., Federal Express or Airborne) for specific instructions. 


 
 
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13.0 
REFERENCES 
 
1. 
UNAIDS. UNAIDS calls for a virtual elimination of mother to child transmission of HIV by 
2015. 2009. 
2. 
Lawn SD, Myer L, Bekker LG, Wood R. Burden of tuberculosis in an antiretroviral treatment 
programme in sub-Saharan Africa: impact on treatment outcomes and implications for 
tuberculosis control. AIDS. 2006;20(12):1605-12. 
3. 
Nelson LJ, Wells CD. Global epidemiology of childhood tuberculosis. The international journal 
of tuberculosis and lung disease : the official journal of the International Union against 
Tuberculosis and Lung Disease. 2004;8(5):636-47. 
4. 
Moultrie HY, Kuhn L, Meyers T. Mortality and virological outcomes of HIV-infected children 
receiving antiretroviraltegravir therapy (ART) in Soweto, South Africa. Conference on 
Retroviruses and Opportunistic Infections; Montreal, Canada. 2009. 
5. 
Walters E, Cotton MF, Rabie H, Schaaf HS, Walters LO, Marais BJ. Clinical presentation and 
outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral 
therapy. BMC Pediatr. 2008;8:1. 
6. 
Smith K, Kuhn L, Coovadia A, Meyers T, Hu CC, Reitz C, et al. Immune reconstitution 
inflammatory syndrome among HIV-infected South African infants initiating antiretroviral 
therapy. AIDS. 2009;23(9):1097-107. 
7. 
World Health Organization. Antiretroviral therapy for HIV infection in infants and children: 
towards universal access: recommendations for a public health approach. Geneva: World Health 
Organization; 2010. 
8. 
World Health Organization. Consolidated Guidelines on the Use of Antiretroviral Drugs for 
Treating and Preventing HIV Infection: Recommendations for a Public Health Approach. Second 
Edition. June 2016. 
9. 
Kekitiinwa A, Cook A, Nathoo K, Mugyenyi P, Nahirya-Ntege P, Bakeera-Kitaka S, et al. 
Routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy 
strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. 
Lancet. 2013;381(9875):1391-403. 
10. 
Cohen K, van CG, Boulle A, McIlleron H, Goemaere E, Smith PJ, et al. Effect of rifampicin-
based antitubercular therapy on nevirapine plasma concentrations in South African adults with 
HIV-associated tuberculosis. J Antimicrob Chemother. 2008;61(2):389-93. 
11. 
Prasithsirikul W. Pharmacokinetics of Nevirapine when Co-administered with Rifampin in HIV-
Infected Thai Children with Tuberculosis. Conference on Retroviruses and Opportunistic 
Infections; Montreal, Canada. 2009. 
12. 
Barlow-Mosha L. Nevirapine Concentrations in HIV-infected Ugandan Children on Adult Fixed-
dose Combination Tablet ART, with and without Rifampicin-based Treatment for Active M. 
tuberculosis Infection. Conference on Retroviruses and Opportunistic Infections; Montreal, 
Canada. 2009. 


 
 
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13. 
Oudijket JA. Pharmacokinetics of nevirapine in young children during combined ART and 
rifampicin-containing antituberculosis treatment. 5th IAS Conference, Cape Town, South Africa, 
2009. 
14. 
Ren Y, Nuttall JJ, Egbers C, Eley BS, Meyers TM, Smith PJ, et al. High prevalence of 
subtherapeutic plasma concentrations of efavirenz in children. Journal of acquired immune 
deficiency syndromes (1999). 2007;45(2):133-6. 
15. 
la Porte CJ, Colbers EP, Bertz R, Voncken DS, Wikstrom K, Boeree MJ, et al. Pharmacokinetics 
of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob 
Agents Chemother. 2004;48(5):1553-60. 
16. 
Ren Y, Nuttall JJ, Egbers C, Eley BS, Meyers TM, Smith PJ, et al. Effect of rifampicin on 
lopinavir pharmacokinetics in HIV-infected children with tuberculosis. Journal of acquired 
immune deficiency syndromes (1999). 2008;47(5):566-9. 
17. 
Wenning LA, Hanley WD, Brainard DM, Petry AS, Ghosh K, Jin B, et al. Effect of rifampin, a 
potent inducer of drug-metabolizing enzymes, on the pharmacokinetics of raltegravir. 
Antimicrobial agents and chemotherapy. 2009;53(7):2852-6. 
18. 
QDMRK, A phase III study of the safety & efficacy of once daily (QD) versus twice daily (BID) 
raltegravir (RAL) in combination therapy for treatment-na‹ve HIV-infected patients (Pts). Feb 27. 
2011. 
19. 
PK/PD analyses for QDMRK, a phase III study of the safety & efficacy of once versus twice 
daily raltegravir in treatment-naIve HIV-infected patients. 11 Apr 2011. 
20. 
Nachman S, Acosta E, Wiznia A, Teppler H, Long M, Homony B, et al. Raltegravir (RAL) 
Pharmacokinetics (PK) and Safety in Adolescents: Preliminary Results from IMPAACT P1066. 
Poster presented at: 48th ICAAC, Washington DC, October 25-28, 2008. 
21. 
Wiznia A, Samson P, Acosta E, Teppler H, Sheeran E, Graham B, et al. Safety and Efficacy of 
Raltegravir (RAL) in Pediatric HIV Infection. Preliminary analysis from IMPAACT P1066. 
CROI 2009. 
22. 
Frenkel LM, Nachman S, Samson P, Acosta E, Teppler H, Fenton T, et al. 24 week safety and 
efficacy from IMPAACT P1066: A Phase I/II, multicenter, open-label, noncomparative study to 
evaluate raltegravir (RAL) in HIV-1 infected youth [abstract]. 49th Interscience Conference on 
Antimicrobial Agents and Chemotherapy, 2009 Sep 11-15, San Francisco, CA. 
23. 
Nachman S, Samson P, Acosta E, Teppler H, Welebob C, Fenton T, et al. Pharmacokinetic (PK), 
Safety and Efficacy Data on Cohort IIA; youth aged 6-11 from IMPAACT P1066: A Phase I/II 
Study to Evaluate Raltegravir (RAL) in HIV-1 Infected Youth. 17th Conference on Retroviruses 
and Opportunistic Infections, San Francisco, CA. 
24. 
Nachman S, Acosta E, Zheng N, Teppler H, Homony B, Fenton T, et al. Interim results from 
IMPAACT P1066: raltegravir (RAL) oral chewable tablet (CT) formulation in children 2-5 years. 
18th Conference on Retroviruses and Opportunistic Infections, 27 Feb 2011, Boston, MA. 


 
 
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25. 
Nachman S, Acosta E, Samson P, et al. Interim Results from IMPAACT P1066: Raltegravir 
(RAL) Oral Chewable Tablet (OCT) Formulation in Children 6-11 Years. 17th Conference on 
Retroviruses and Opportunistic Infections, San Francisco, CA, 16-19 Feb 2010. 
26. 
Nachman S, Alvero C, Acosta EP, Teppler H, Homony B, Graham B, et al. Pharmacokinetics and 
48-Week Safety and Efficacy of Raltegravir for Oral Suspension in Human Immunodeficiency 
Virus Type-1-Infected Children 4 Weeks to 2 Years of Age. J Pediatric Infect Dis Soc. 
2015;4(4):e76-83. 
27. 
Nachman S, Zheng N, Acosta EP, Teppler H, Homony B, Graham B, et al. Pharmacokinetics, 
Safety, and 48-Week Efficacy of Oral Raltegravir in HIV-1–Infected Children Aged 2 Through 
18 Years. Clinical infectious diseases. 2014;58(3):413-22. 
28. 
de Wildt SN, Kearns GL, Leeder JS, van den Anker JN. Glucuronidation in humans. 
Pharmacogenetic and developmental aspects. Clin Pharmacokinet. 1999;36(6):439-52. 
29. 
Rhee EG, Rizk ML, Brainard DM, Gendrano IN, 3rd, Jin B, Wenning LA, et al. A 
pharmacokinetic comparison of adult and paediatric formulations of raltegravir in healthy adults. 
Antivir Ther. 2014;19(6):619-24. 
30. 
World Health Organization. Guidance for national tuberculosis and HIV programmes on the 
management of tuberculosis in HIV-infected children: Recommendations for a public health 
approach. Geneva, 2010. 
31. 
Mofenson LM, Brady MT, Danner SP, Dominguez KL, Hazra R, Handelsman E, et al. Guidelines 
for the Prevention and Treatment of Opportunistic Infections among HIV-exposed and HIV-
infected children: recommendations from CDC, the National Institutes of Health, the HIV 
Medicine Association of the Infectious Diseases Society of America, the Pediatric Infectious 
Diseases Society, and the American Academy of Pediatrics. MMWR Recomm Rep. 2009;58(RR-
11):1-166. 
32. 
Pharsight C. WinNonlinr version 4.1: Industry-Standard PK/PD Modeling and Analysis. 4.1 ed. 
Mountain View, CA, 28 October 2003: Pharsight Corporation (OTCBB:PHST); 2011. 
33. 
Iwamoto M, Wenning LA, Petry AS, Laethem M, De SM, Kost JT, et al. Minimal Effects of 
Ritonavir and Efavirenz on the Pharmacokinetics of Raltegravir. Antimicrobial agents and 
chemotherapy. 2008. 


 
 
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APPENDIX I 
SCHEDULE OF EVALUATIONS 
 
 
Screening1 
On treatment study weeks 
TB and/or RAL 
Treatment 
Discontinuation17, 19 
4 Wks Off 
RAL 
treatment / 
On study 
(± 2 wks)19 
Early Study 
Discontinuation 
or End of Study  
(at 12 wks off 
RAL treatment 
± 2 wks)19 
Entry 
Day  
5 - 8 
Day 14 
(± 3 days)  
Wk 414 
(± 1 wk) 
Wk 814 
(± 2 wks) 
Every 4 
wks15 
(± 2 wks) 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
History2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical exam3 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Pill count4 
 
x 
x 
x 
x 
x 
x 
x 
 
x 
LABORATORY 
EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
Hematology5 
1 mL 
1 mL 
1 mL 
 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
LFT6 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
 
Chemistries 7 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
 
Urinalysis8 
 
x 
 
 
 
 
 
 
 
 
Pregnancy test9 
1 mL [x] 
1 mL [x] 
1 mL [x] 
1 mL [x] 
1 mL [x] 
1 mL [x] 
1 mL [x] 
1 mL [x] 
1 mL [x] 
1 mL [x] 
Confirmation/Documentation 
of HIV Infection  
[0-3 mL] 
 
 
 
 
 
 
 
 
 
Virology 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA PCR10 
1-3 mL 
1-3 mL 
 
  
 
1-3 mL 
1-3 mL 
1-3 mL 
1-3 mL 
1-3 mL 
1-3 mL 
Sequencing13 
 
3 mL 
 
 
 
 
3 mL16 
3 mL18 
 
 
Immunology 
 
 
 
 
 
 
 
 
 
 
Lymphocyte subsets11 
 
1.5 mL 
 
 
 
1.5 mL 
1.5 mL 
1.5 mL 
 
1.5 mL 
Pharmacology 
 
 
 
 
 
 
 
 
 
 
Intensive PK12 
 
 
4.5 mL 
 
 
 
 
 
 
 
Total Maximum Blood 
Volume 
4 – 10 mL 
8.5 – 11.5 
mL 
7.5 – 8.5 
mL 
2 – 3 mL 
4 – 7 mL 
5.5 – 8.5 
mL 
5.5 – 11.5 
mL 
5.5 – 11.5 mL 
4 – 7 mL 
3.5 – 6.5 mL 
 
 
 
 
 


 
 
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APPENDIX I FOOTNOTES 
 
1. 
Screening evaluations must be performed within 30 days of Entry.  Participants must be enrolled ≥ 1 week to ≤ 20 weeks after starting TB 
treatment.  If sufficient documentation of HIV status as specified in Section 4.1.3 is not available, HIV diagnostic testing is to be done 
according to the definition. If testing is required to fulfill the requirements of inclusion criterion 4.1.3, the HIV-1 RNA PCR required at 
Screening may serve as one of the two required tests, and additional blood (1-3 mL) may be collected as Sample #1 and/or Sample #2. 
2. 
A complete history is required at Screening; a targeted history is sufficient at subsequent visits.  Targeted history should include symptoms 
of toxicity (such as skin rash, liver dysfunction) and diagnosis. HIV clinical classification is required at Entry only.  ARV and concomitant 
medications will be recorded at each visit.  For participants of reproductive potential, onset of sexual activity will be assessed by history.  A 
female participant who becomes sexually active while on study will be referred for contraception as specified in Section 6.9.1; additionally, 
female participants will have a pregnancy test (see footnote 9 below). 
3. 
Physical exam should include height, weight, and vital signs (temperature, blood pressure, pulse and respiratory rate).  Evaluation for 
lymphadenopathy should be done at baseline.  Evaluations for presence of jaundice, hepatosplenomegaly, skin rash, chest signs, 
musculoskeletal abnormalities, and joint abnormalities for TB should be performed at all study visits.   
4. 
Adherence will be measured using the standardized IMPAACT pill count.  Adherence to TB medications will be assessed at the time that 
study drug is initiated at Entry.  Adherence to HIV and TB medications will be assessed at all on-treatment visits and at early 
discontinuation of study drug.  The participant should be reminded of the importance of adherence and of reporting deviations in adherence 
at all on-treatment visits.   
5. 
Hematology should include complete blood count (CBC) with cell differential and platelet count. 
6. 
ALT, AST, Alkaline phosphatase, Total Bilirubin, Indirect Bilirubin and Direct Bilirubin. 
7. 
Chemistries should include BUN, electrolytes (bicarbonate, sodium, potassium, calcium, and magnesium), glucose, creatinine, and total 
amylase. If total amylase is elevated, serum fractionated pancreatic amylase should be performed and recorded on the CRF.  If amylase 
fractionation is not available, lipase may be used instead of pancreatic amylase for clinical assessment of pancreatitis. 
8. 
Dipstick urinalysis is sufficient. The following dipstick results should be reported: specific gravity, pH, blood, ketones, glucose, protein and 
nitrite.  Abnormal findings should be followed with complete urinalysis and microscopic examination.  The following microscopic results 
should be reported: RBC, WBC, squamous epithelial cells, hyaline casts and granular casts. 
9. 
Pregnancy test will be done at screening if participant is sexually active.  During follow-up, sexually active females will have pregnancy 
testing done if clinically indicated by the study site clinician.  A urine or blood pregnancy test will be done. See Section 6.9.  
10. 
Must be performed at a DAIDS VQA-certified laboratory.  Blood volume may vary from 1 – 3 mL depending on the FDA-approved method 
that the laboratory is VQA-certified to perform.  Screening viral load must be performed within 30 days of Entry. 
11. 
Lymphocyte subsets include CD4/CD8 counts and percentages. Must be performed at DAIDS IQA-certified laboratory. 
12. 
Intensive PK should be scheduled so that witnessed dosing of the ARVs is as close as possible to 12 hours after the previous dosing.  PK 
dosing within a range of 11-13 hours after the previous dose is acceptable.  Participants should not ingest breast milk, formula, or any other 
high fat food/liquid for 2 hours prior to and 1 hour after dosing on the intensive PK day. Water and other fluids (i.e. apple/orange juice and 
oral rehydration solution) can be taken at any time.  Participants may consume a light meal of their choice 2 hours after RAL dosing on the 
intensive PK day. Parents/Guardians must report that the participants have not missed any doses of the ARVs, including RAL, in the 48 


 
 
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hours prior to the intensive PK visit.  If a missed dose is reported, the intensive PK visit must be rescheduled. Parents/Guardians should be 
instructed not to administer the second dose of RAL to participants until the intensive PK sampling is completed. 
• 
Once the intensive PK visit is scheduled, a reminder call regarding the PK visit, the required food/liquid limitations and reinforcing 
adherence should be made about 3 to 4 days prior to the PK visit.  A follow-up call to the parent/guardian should be made 1 day 
prior to the PK visit to confirm adherence.  If a missed dose is reported, the scheduled PK visit should be cancelled and rescheduled. 
• 
Sampling time points: 0.5 mL is to be collected at pre-dose (0) and 0.5, 1, 2, 3, 4, 6, 8 and 12 hours post-dose.   
• 
Doses vomited within 15 minutes may be re-dosed once, with t = 0 to then be time of repeat dosing.  If dose is vomited > 15 minutes 
after dosing, PK must be cancelled and may be rescheduled.   
• 
If the results of the RAL intensive PK are in question, unexpectedly low or high and may put the participant at risk for toxicity, the 
Protocol Team may request a repeat of the intensive PK.  The site will be notified by the team and the time period for obtaining the 
repeat PK will be given.   
• 
ARVs must be taken at night the day before the RAL PK.  The RAL PK samples will be taken in the morning and timed to the RAL 
dose.  
13. 
Refer to the LPC for shipping instructions for viral sequencing. 
14. 
If a participant will discontinue TB treatment and RAL at the Week 4 or 8 visit due to completion of their prescribed TB treatment, the 
evaluations at the TB and/or RAL Treatment Discontinuation visit should also be completed. Only the evaluations that are not already being 
done for the Week 4 or 8 visit need to be completed. 
15. 
These visits will only be done if a participant will continue TB treatment and RAL after the Week 8 visit. 
16. 
If a participant is not virally suppressed by the Week 8 visit, or has viral rebound subsequently, blood will be collected for sequencing at the 
next visit.  
17. 
Evaluations for TB and/or RAL Treatment Discontinuation will be performed at any of the on-treatment visits that coincide with the 
discontinuation of TB treatment and/or RAL or when a participant has met the criteria for virologic failure and early treatment 
discontinuation as defined in Sections 6.2.2 and 6.7, respectively.  Only the evaluations that are not already being done for the on-treatment 
visit need to be completed.  Discontinuation of TB treatment and RAL due to completion of prescribed TB treatment can occur anytime 
beginning at Week 4 depending on the duration that the participant has been on TB treatment at the time of entry. 
18. 
If a participant discontinues RAL early due to virologic failure per Section 6.2.2, blood will be collected for sequencing at the treatment 
discontinuation visit.   
19. 
Participants that discontinue treatment early for any reason will continue on study/off study drug for 3 months, and complete the TB and/or 
RAL treatment discontinuation, 4 weeks off RAL treatment/on study, and end of study evaluations. 
 
Note:  NIH recommendations for maximum pediatric blood draw volumes will be followed in this study.  The volume of blood drawn at any study 
visit should not exceed 5 mL/kg in a single day and 9.5 mL/kg over any eight-week period. Priority of draw should be as follows: (1) Safety 
(hematology, chemistries, LFT) (2) Pharmacokinetics, (3) Virology, (4) Immunology.


 
 
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APPENDIX II 
 
RALTEGRAVIR WEIGHT BAND DOSING TABLES FOR CHEWABLE TABLET 
 
Note:  The tables below should be followed for chewable RAL tablet administered as a chewable and as a 
dispersible tablet.  If the Protocol Team determines that a cohort dose adjustment is required and the 
appropriate dose is not included in the tables below, an updated dosing table will be provided via a 
Clarification Memorandum. 
 
Table A – Dose of ~6 mg/kg 
Weight Band (kg) 
6 mg/kg 
# of Tablets 
 
Dose 
Administer 
3 – 5.9 
25 
1 x 25 mg 
6 – 9.9 
50 
2 x 25 mg 
10 – 13.9 
75 
3 x 25 mg 
14 – 19.9 
100 
1 x 100 mg 
20 – 27.9 
150 
1.5 x 100 mg 
28 – 39.9 
200 
2 x 100 mg 
> 40 
300 
3 x 100 mg 
 
Table B – Dose of ~9 mg/kg 
Weight Band (kg) 
9 mg/kg 
# of Tablets 
 
Dose 
Administer 
3 – 5.9 
50 
2 x 25 mg 
6 – 9.9 
75 
3 x 25 mg 
10 – 13.9 
100 
1 x 100 mg 
14 – 19.9 
150 
1.5 x 100 mg 
20 – 27.9 
200 
2 x 100 mg 
28 – 39.9 
300 
3 x 100 mg 
> 40 
400 
4 x 100 mg 
 
Table C – Dose of ~12 mg/kg 
Weight Band (kg) 
12 mg/kg 
# of Tablets 
 
Dose 
Administer 
3 – 5.9 
50 
2 x 25 mg 
6 – 9.9 
100 
1 x 100 mg 
10 – 13.9 
150 
1.5 x 100 mg 
14 – 19.9 
200 
2 x 100 mg 
20 – 27.9 
300 
3 x 100 mg 
28 – 39.9 
400 
4 x 100 mg 
> 40 
500 
5 x 100 mg 
 
 


 
 
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Table D – Dose of ~15 mg/kg 
Weight Band (kg) 
15 mg/kg 
# of Tablets 
 
Dose 
Administer 
3 – 5.9 
75 
3 x 25 mg 
6 – 9.9 
125 
1 x 100 mg and 1 x 25 mg 
10 – 13.9 
200 
2 x 100 mg 
14 – 19.9 
250 
2.5 x 100 mg 
20 – 27.9 
350 
3.5 x 100 mg 
28 – 39.9 
500 
5 x 100 mg 
> 40 
600 
6 x 100 mg 
 
Table E – Dose of ~18 mg/kg 
Weight Band (kg) 
18 mg/kg 
# of Tablets 
 
Dose 
Administer 
3 – 5.9 
75 
3 x 25 mg 
6 – 9.9 
150 
1.5 x 100 mg 
10 – 13.9 
225 
2 x 100 mg and 1 x 25 mg 
14 – 19.9 
300 
3 x 100 mg 
20 – 27.9 
450 
4.5 x 100 mg 
28 – 39.9 
600 
6 x 100 mg 
> 40 
800* 
8 x 100 mg 
*maximum dose = 800 mg twice daily 


 
  
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APPENDIX III 
SUPPLEMENTAL TOXICITY TABLE FOR GRADING SEVERITY OF  
CUTANEOUS/SKIN RASH/DERMATITIS ADVERSE EVENTS 
 
GRADE 1 
GRADE 2 
GRADE 3 
GRADE 4 
CUTANEOUS/SKIN RASH/DERMATITIS 
Erythema, with 
or without 
pruritis 
A. Diffuse erythematous macular or 
maculopapular cutaneous eruption or dry 
desquamation with or without pruritis 
(without the presence of any additional 
constitutional findings as described in Grade 3 
of DAIDS Toxicity tables); OR typical target 
lesions without blistering, vesicles, or 
ulcerations in the lesions. 
 
B. Urticaria 
A. Diffuse erythematous macular or maculopapular cutaneous eruption or moist 
desquamation with or without pruritis together with any of the following 
constitutional findings considered related to study drug: 
  1. 5 x ULN AST, ALT or 2 x baseline if baseline > ULN. 
  2. fever, >39oC 
  3. blistering and/or vesiculation of cutaneous eruptions 
  4. any site of mucosal lesions; OR  
 
B. angioedema; OR  
 
C. exfoliative dermatitis defined as severe widespread erythema and dry scaling 
of the skin, with generalized superficial lymphadenopathy, and with other 
constitutional findings such as fever, weight loss, hypoproteinemia possibly 
related to study drug; OR  
 
D. diffuse rash and serum sickness-like reactions defined as a clinical symptom 
complex manifested as fever, lymphadenopathy, edema, myalgia, and/or 
arthralgia; OR  
 
E. diffuse cutaneous eruptions, usually starting on the face, trunk or back, often 
with prodromal symptoms plus one of the following: 
  1. cutaneous bullae, sometimes confluent with widespread sheet-like 
detachment of skin (<10% body surface area), (Nikolski's sign) (Stevens    
Johnson Syndrome, SJS) 
  2. two or more anatomically distinct sites of mucosal erosion or ulceration not 
due to another cause. 
 
Diffuse cutaneous 
eruptions, usually starting 
on the face, trunk or back, 
often with prodromal 
symptoms plus cutaneous 
bullae with widespread 
sheet-like detachment of 
skin (>10% of body 
surface area), (Nikolski's 
sign), (SJS/Toxic 
Epidermal Necrolysis 
(TEN) overlap syndrome; 
TEN) 
For all Grade 3 and 4 cutaneous/skin rash/dermatitis adverse experiences, photo documentation of the rash is strongly recommended. 


 
  
 
 
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APPENDIX IV 
 
MANAGEMENT GUIDE FOR SUSPECTED ABACAVIR (ABC)  
HYPERSENSITIVITY REACTIONS 
 
I. 
Hypersensitivity Reaction to ABC 
 
a. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is 
recommended; this approach has been found to decrease the risk of hypersensitivity reaction 
(HSR).  
 
b. For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is not 
recommended and should be considered only with close medical supervision and under 
exceptional circumstances when the potential benefit outweighs the risk. 
 
c. The diagnosis of hypersensitivity to ABC remains a clinical diagnosis.  There is no 
pathognomonic clinical sign or laboratory finding that renders the diagnosis.  The key feature 
is that HSR is a multi-organ system reaction.  
 
d. Hypersensitivity Reaction 
 
The following is a brief description of the signs, symptoms and laboratory abnormalities that 
have been associated with ABC HSR. 
 
In clinical studies, approximately 3%-5% of patients receiving ABC develop a HSR that in 
rare cases has proved fatal.  HSR is characterized by the appearance of symptoms indicating 
multiorgan/body system involvement.  Symptoms usually appear within the first six weeks of 
starting treatment with ABC (median time to onset is 11 days), but may occur at any time 
while on therapy, and most often include fever, rash, gastrointestinal symptoms (nausea, 
vomiting, diarrhea, or abdominal pain), respiratory symptoms (dyspnea, sore throat, cough), 
and lethargy or malaise.  Other signs and symptoms may include musculoskeletal symptoms 
(myalgia, rarely myolysis, arthralgia), headache, paresthesia, and edema.  Respiratory tract 
symptoms (dyspnea, sore throat, and cough) have been observed in approximately 20% of 
participants who experience HSR.  Some patients with HSRs were initially thought to have 
respiratory tract disease (pneumonia, bronchitis, pharyngitis) or a flu-like illness.  The 
multisystem nature of the HSR has led to misdiagnosis of the HSR as an intercurrent medical 
illness or as being related to another medication.  HSR also has been unrecognized when it 
presents with less common symptoms or as a single symptom. 
 
This misattribution of the symptoms of HSR to another medical condition or delay in 
diagnosis of hypersensitivity has resulted in ABC being continued or reintroduced, leading to 
more severe or rapid (within hours) onset of HSR or death.  Therefore, the diagnosis of HSR 
should be carefully considered for patients presenting with symptoms of these diseases, even 
if another medical diagnosis seems likely.  Renal failure and anaphylaxis have also been 
reported in association with HSRs.  Reintroduction of ABC in participants after treatment 
interruption, with no preceding symptoms of HSR, has, rarely, resulted in HSR. 
 
Physical findings may include lymphadenopathy and, occasionally, mucous membrane 
lesions (conjunctivitis and/or mouth ulceration) and hypotension.  The rash is variable and 


 
  
 
 
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may be absent, but often appears maculopapular or urticarial.  Laboratory abnormalities that 
may accompany ABC hypersensitivity include elevated liver function tests (LFTs), creatine 
kinase, or creatinine or lymphopenia. 
 
II. 
Severity of HSR: 
 
Fatal HSRs have been associated with ABC therapy.  ABC therapy SHOULD NOT be restarted 
following a HSR, because more severe symptoms will occur within hours and may include life-
threatening hypotension and death.  Participants who develop signs or symptoms of 
hypersensitivity should discontinue treatment as soon as a HSR is first suspected and should seek 
medical evaluation immediately, preferably on the same day that symptoms are reported.  
 
III. 
Management of HSR: 
 
If a participant reports symptoms suggestive of hypersensitivity, the participant should be 
instructed not to take any additional doses and should be evaluated at the clinic.  The evaluation 
should consist of a careful history and physical examination.  Laboratory studies should be 
obtained as clinically indicated.  There is no diagnostic test available to confirm the clinical 
diagnosis.  If, upon evaluation, the participant does have a presentation consistent with 
hypersensitivity, therapy with ABC must be immediately and permanently discontinued and the 
Protocol Team should be notified. 
 
The hematology, chemistry, signs and symptoms, diagnoses, and event evaluation forms in the 
CRF should also be completed as indicated.   
 
Symptoms usually start to resolve soon (within 24 hours) after stopping therapy.  Symptomatic 
support, such as intravenous fluids for those who develop hypotension, is advised.  There are no 
clinical data demonstrating the benefit of antihistamines or corticosteroids in the management of 
hypersensitivity.  Nevertheless, symptomatic and/or supportive treatment may be reasonable.  
 
IV. 
Discontinuation and Re-initiation of ABC Therapy: 
 
Participants who discontinue ABC for any reason should be queried regarding signs and 
symptoms of HSR.  Unrecognized HSR at the time of discontinuation can lead to serious, rapid, 
and fatal HSR if the drug is reinitiated.  Rarely, ABC HSR has occurred when ABC was stopped 
and restarted for reasons other than medical illness, such as an interruption of drug supply.  In 
those rare cases, no preceding signs and symptoms of ABC HSR could be identified.  
 
If any participant has discontinued ABC due to symptoms that are judged by the site PI to be 
suspicious for HSR, the team should be notified and reintroduction of ABC is prohibited. 
 
Participants who have had a HSR must be advised that they should never take ABC or an ABC-
containing drug combination again, since a life-threatening second HSR can occur.  Patients 
should be advised to return all unused ABC at the time of discontinuation to reduce the risk of 
inadvertent rechallenge. 
 
a. Rash in Participants Receiving ABC 
 
Participants receiving ABC who develop rash of any grade should be evaluated as soon as 
possible for the possibility of hypersensitivity.  Notify the Protocol Team within 3 days.   If 


 
  
 
 
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there is no indication of any other organ system involvement and the participant has no 
systemic symptoms (fever, malaise, fatigue, headache), ABC may be continued for rash ≤ 
Grade 2 with the warning to discontinue immediately and permanently if other signs and/or 
symptoms consistent with hypersensitivity appear. 
 
b. Fever in Participants Receiving ABC 
 
The onset of fever may also herald hypersensitivity in persons treated with ABC.  Participants 
reporting fever should be evaluated as soon as possible for the possibility of hypersensitivity.  
Notify the Protocol Team within 3 days.  In the event of a clinical presentation consistent 
with hypersensitivity, ABC should be discontinued immediately and permanently. 
 
 
 
 


 
 
 
 
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APPENDIX V 
 
TERMINOLOGY, DEFINITIONS AND MANAGEMENT GUIDE FOR  
IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME (IRIS) 
 
I. 
BCG IRIS 
 
BCG IRIS usually occurs at a median of 7 to 8 months of age, and is unlikely to affect the study 
population to be enrolled in P1101.  Criteria have been developed for diagnosis of BCG IRIS by 
the BCG Safety Working Group of the International Union against Tuberculosis and Lung 
Disease (IUATLD).  Criteria for this study are as follows: 
 
a. Acute onset enlargement of ≥ 2 cm in the vertical and horizontal diameter of a single or 
multiple regional lymph-node/s draining the arm on which BCG vaccine was administered, 
occurring between 1 week to 6 months after the initiation of highly active antiretroviral 
therapy.  The horizontal and/or the vertical diameter of the affected lymph node should have 
increased by at least 2 cm if the lymph-node was documented to have been previously 
enlarged. 
 
b. The lymph-node should show one or more of the following features: 
• 
granulomatous infiltrate with or without necrosis 
• 
presence of acid fast bacilli 
• 
culture of mycobacterium tuberculosis complex, which should include attempt at 
specification between MTB and M. bovis 
 
II. 
TB IRIS 
 
Since all infants and children will be on TB treatment, the definition of TB IRIS for this study 
will be paradoxical flare up of TB symptoms in a patient who is on treatment for TB.  
Pulmonary/extra-pulmonary TB may occur. 
 
a. In participants already receiving TB treatment, initial improvement of symptoms of TB is 
required, such as: 
• 
Defervescence 
• 
Improvement of respiratory symptoms 
• 
Decrease in size of lymph nodes 
 
b. Clinical symptoms/manifestations suggestive of TB-IRIS may include one or more of the 
following:  
• 
General: persistent fever, weakness 
• 
Pulmonary: cough, new/worsening dyspnea, stridor as minor criteria 
• 
CNS: headache, fever, meningismus, neck pain, photophobia 
• 
Abdominal pain, diarrhea 
• 
Localized symptoms (e.g., lymphadenitis, subcutaneous nodules and abnormal skin 
lesions) 
 


 
 
 
 
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c. Based on the presentation, the TB IRIS events can be classified as: 
• 
Pulmonary TB 
Presence of a new pulmonary infiltrate that is associated with intra-thoracic 
lymphadenopathy, which may or may not cause compression of large airways, or an 
increase of an existing pulmonary infiltrate, occurring 1 week to 6 months after the 
initiation of ARV regimen. 
• 
TB Pleuritis 
New pleural effusions or deterioration of existing pleural effusions, occurring 1 week 
to 6 months after the initiation of ARV regimen. 
• 
TB Brain 
Demonstration of a ring-enhancing lesion on CT scan of the brain which is 
demonstrated 1 week to 6 months after the initiation of ARV regimen in an 
individual that did not have any previous documented intracerebral lesion, or no 
clinical abnormalities suggesting central nervous abnormality, or deterioration or 
enlargement of preexisting CNS lesions. 
• 
TB Meningitis 
New-onset signs and symptoms of meningitis or deteriorating symptoms of 
meningitis, all 1 week to 6 months after the initiation of ARV regimen. 
• 
TB Peritonitis 
Abdominal pain plus ultrasound evidence of peritonitis/abdominal lymphadenopathy 
with/without ascites occurring 1 week to 6 months after the initiation of ARV 
regimen. 
 
d. Other factors that can aid the diagnosis of TB-IRIS: 
• 
Alternative explanations for deterioration or appearance of new clinical presentation 
have been excluded  
• 
The diagnosis of pulmonary TB or of “tuberculoma” is substantiated by a reactive 
TST (≥ 10 mm) using the Mantoux method. 
• 
HIV viral load decline (> 1 log10 decline of HIV RNA) or substantial increase in CD4 
(> 5 percentage points) favor the diagnosis of IRIS but are not essential or sufficient. 
• 
Growth of M. tuberculosis upon culture of clinical specimens: Positive AFB smear or 
positive histopathology consistent with TB are suggestive of TB-IRIS; clinical 
criteria only can confirm suggested TB IRIS.  Where facilities are available, 
PCR/other assays will be used to perform species identification of Mycobacterium 
spp.   
 
In the case of TB IRIS, continued treatment with anti-tuberculosis therapy is warranted and this should be 
continued.  If the participant is taking a 3-drug TB regimen and addition of a fourth drug is indicated, this 
may be allowed in consultation with the Protocol Team. 
 
Since there are many different organisms which may cause IRIS, if other medication is indicated and 
provided the medication is not on the disallowed list (see Section 4.3.2), this may be added with approval 
from the Protocol Team. 


 
 
 
 
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APPENDIX VI 
SAMPLE INFORMED CONSENT FORM FOR STUDY PARTICIPATION 
 
P1101: PHASE I/II DOSE-FINDING, SAFETY, TOLERANCE AND PHARMACOKINETICS STUDY 
OF A RALTEGRAVIR-CONTAINING ANTIRETROVIRAL THERAPY (ART) REGIMEN IN HIV-
INFECTED AND TB CO-INFECTED INFANTS AND CHILDREN  
 
SHORT TITLE FOR THE STUDY: P1101 
 
Version 3.0, dated 24 April 2017 
 
INTRODUCTION 
Your child is being asked to take part in this research study because your child has the Human 
Immunodeficiency Virus (HIV), which is the virus that causes AIDS, and has not taken any medications 
for the treatment of HIV in the past 30 days.  Your child also has Tuberculosis (TB) and is taking or will 
be starting anti-TB medications that include Rifampicin, a medication commonly used to treat TB.  This 
study is sponsored by the National Institutes of Health (NIH).  The doctor in charge of this study at this 
site is: (insert name of Principal Investigator).  Before you decide if you want your child to be a part of 
this study, we want you to know about the study.  
 
This is a consent form.  It gives you information about this study.  The study staff will talk with you about 
this information.  You are free to ask questions about this study at any time.  If you agree to allow your 
child to take part in this study, you will be asked to sign this consent form.  You will get a copy to keep. 
 
WHY IS THIS STUDY BEING DONE? 
This study is being done to measure the amount of raltegravir (RAL, Isentress™) in the blood when it is 
taken with the anti-TB medication Rifampicin.  Raltegravir is the study medication used in this study and 
it is a type of anti-HIV medicine called an integrase inhibitor.  Integrase inhibitors work by blocking 
integrase, a protein that HIV needs to enter human cells and make more copies of itself.  Raltegravir has 
been approved for the use in adults, adolescents and children ages 4 weeks to 18 years old by the United 
States Food and Drug Administration (FDA).  The chewable tablet is approved for children ages 2 to less 
than 12 years old.  For children under 2 years of age, this study will look at a new way to give this 
medicine to young children more easily. Infants and children 4 weeks to less than 2 years old will take the 
raltegravir chewable tablet mixed with water, juice, breast milk or formula. This study will provide the 
study medication raltegravir to your child.   
 
The other medications used in this study are Rifampicin, other anti-TB medications, two anti-HIV 
medications that are called Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and a fourth anti-HIV 
medication that will be chosen by your child’s doctor.  It is possible that the fourth ARV drug chosen by 
your doctor could be a combination drug of Lopinavir and ritonavir (LPV/r).  This medication may need 
to be dose adjusted with additional ritonavir to obtain the correct dosing for your child.  This would result 
in a fifth anti- HIV medication.  Many people find the liquid form of this drug tastes bad. These 
medications will not be provided by the study.  These medications will be provided at the clinic where 
your child is receiving care.  You will need to obtain them through a prescription from your child’s 
doctor. 
 
This study will look at the levels of raltegravir in the blood and the best dose of raltegravir in HIV-
infected infants and children who are taking rifampicin for the treatment of TB compared to HIV-infected 
infants and children who are only taking raltegravir and do not require treatment for TB with rifampicin. 


 
 
 
 
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This study will also look at how the anti-HIV treatment including raltegravir when it is given with 
rifampicin is tolerated, and the levels of raltegravir and antiretroviral drugs (ARVs) when taken together 
in the blood to help find out if taking raltegravir and ARVs with rifampicin is safe. 
 
WHAT DOES MY CHILD HAVE TO DO IF HE/SHE IS IN THIS STUDY? 
Your child must be taking or starting to take anti-TB medications that include Rifampicin to be in this 
study.  Your child will be given raltegravir and will be asked to take it two times or three times a day in 
addition to your child’s other two new anti-HIV medicines.  Raltegravir will be in a chewable tablet 
formulation to be chewed or taken dissolved in a liquid.  The study staff will explain to you how to give 
the medicine to your child. Levels of raltegravir in the blood will be measured about one week after 
starting this medicine.  Then your child will begin a fourth anti-HIV medicine along with his/her anti-TB 
medications including rifampicin, raltegravir and the other two anti-HIV medicines.  Your child will take 
raltegravir until he/she stops taking the anti-TB medications prescribed by his/her doctor.  Your child will 
continue to take the third anti-HIV medicine and the other two anti-HIV medicines for 3 months after the 
anti-TB medicines and raltegravir are stopped.  
 
Deciding to allow your child to join this study is voluntary.  You may choose to allow your child to join 
or not join.  If you choose to allow your child to join, you can change your mind and take your child out 
of the study at any time.  Your choices will have no effect on the medical care that your child receives at 
this clinic.  Your child’s access to services and the benefits and rights he or she normally has will not be 
affected. 
 
Take your time and consider your decision carefully.  If you wish, you can talk to other people about 
allowing your child to join the study.  You can bring other people here to learn about the study with you. 
 
If you decide to let your child join this study, we will first do some tests to see if your child qualifies. 
 
Screening visit: 
To find out if your child qualifies for this study, we will: 
• 
Ask about your child’s medical history including questions about your child’s health and what 
symptoms, medications, and illnesses your child has had. 
• 
Give your child a physical examination: We will measure your child’s height, weight and vital signs 
(temperature, blood pressure, pulse and respiratory rate). 
• 
Draw your child’s blood for the following tests: We will take a little more than 1 teaspoon (4-6 mL) 
of blood for routine safety tests (a CBC, or complete blood count, which shows how many red and 
white blood cells there are; blood chemistries, which checks the blood sugar and how well the 
kidneys are working; a liver function test, which shows how well the liver is working) and to measure 
the amount of HIV in the blood (HIV viral load). We may draw up to an additional 3 mL to confirm 
your child’s HIV infection if there is no medical record available.  
• 
A pregnancy test: If your child is of child bearing age and pregnancy is suspected, your child may be 
asked to give an additional 1 mL of blood or a urine sample to test for pregnancy.    
• 
You will be given the results of these tests. 
 
If you agree to allow your child to enroll in this study, and your child does not qualify to be in this study, 
the reasons your child cannot enroll in this study will be shared with the protocol team, including the 
pharmaceutical company supporting the study. 
 
 


 
 
 
 
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Table 1 
 
Entry 
Day  
5 to 8 
Day 
14 
Week 
4 
Week 
8 
Every 4 
weeks 
TB and/or RAL 
treatment 
discontinuation 
4 weeks off RAL 
treatment/on 
study 
Final 
visit 
Medical history and 
review of medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pill Count 
X 
X 
X 
X 
X 
X 
X 
 
X 
CBC 
X 
X 
 
X 
X 
X 
X 
X 
X 
Liver enzymes 
X 
X 
X 
X 
X 
X 
X 
X 
 
Blood chemistries 
X 
X 
X 
X 
X 
X 
X 
X 
 
HIV viral load 
X 
 
 
X 
X 
X 
X 
X 
X 
CD4/CD8 cell count 
X 
 
 
 
X 
X 
X 
 
X 
 
Entry visit: 
[Sites: add local information regarding how long the entry visit will take]. 
 
If your child qualifies for this study and you allow your child to enter the study, your child will come to 
the clinic for the first study visit (or the Entry visit) within 30 days after the screening visit.  The 
following will take place at the Entry visit: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Entry”. 
• 
Pill count at Entry: If your child is already taking anti-TB medications, we will check how well your 
child is taking the medications (including missed doses). 
• 
Blood tests: We will take a little more than 1.5 - 2 teaspoons (8.5 - 10.5 mL) of blood. 
− 
About 1 ½ teaspoons (5.5 - 7.5 mL) will be for the tests in Table 1.  The CD4/CD8 cell count is to 
check how well your child’s immune system is working.  The results of these tests will be 
provided to you/your child. 
− 
A little more than ½ teaspoon (3 mL) will be used for a test to check if your child’s HIV is 
resistant to some anti-HIV medications (HIV resistance test).  This test will be done after the 
study is over, and you will not be given the results. 
• 
We will also ask your child to provide a urine sample for a routine test.  The results of the test will be 
provided to you/your child. 
• 
Your child will start taking raltegravir and 2 other anti-HIV medicines called NRTIs. 
• 
If your child is a female and started to have sex since the last visit (screening), or can become 
pregnant, your child will be asked to provide a urine sample or an additional 1 mL of blood at each 
visit for a pregnancy test.  Your child will be asked to take birth control precautions (ways to prevent 
pregnancy) throughout the study period to remain in the study. If your child is pregnant, your child 
will not be allowed to continue on the study medicine, but will continue to come in for study visits. 
 
Your child will be asked to return to the clinic about 4 to 10 times in about 16 to 36 weeks (or 4 to 9 
months) until your child stops taking the anti-TB medications.  One visit will last a little over 12 hours 
where the amount of raltegravir and ARVs in the blood will be measured over 12 hours (intensive 
pharmacokinetics or intensive PK visit).  [Sites: add local information regarding how long the visits will 
take]. 
 
Intensive PK visit (Day 5 to 8): 
Approximately one week after starting raltegravir, your child will have an intensive PK visit.  The 
following will take place at this visit: 
• 
You will be contacted by the study staff one day before the visit to confirm that your child took all of 
his/her medications during the 2 days before the visit. 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Day 5 to 8”. 


 
 
 
 
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• 
In addition to the pill count that will be done by the study staff, you will need to write down the times 
your child took his/her medications during the 2 days before the visit and bring it with you to the 
clinic. 
• 
We will ask that you not give your child raltegravir, other anti-HIV, and anti-TB medicines at home 
the day of this visit. Your child will need to bring these medicines to the clinic.  Your child will be 
given these medications in the clinic after the first blood sample for the intensive PK test is taken.   
• 
Blood tests: We will take a little more than 1 ½ teaspoons (7.5 mL) of blood.  
− 
A little more than ½ teaspoon (3 mL) will be for the tests in Table 1.  The results of these tests 
will be provided to you/your child. 
− 
A little less than 1 teaspoon (4.5 mL) of blood will be taken over 12 hours to measure the amount 
of raltegravir in your child’s blood.   
 
Your child must have taken all doses as prescribed and not missed any doses of raltegravir and his/her 
other anti-HIV and TB medicines the 2 days before the PK test.  If your child misses a dose within 2 days 
before the PK test, the visit will be rescheduled.  Your child should not have breast milk, formula or any 
other high fat liquid for 2 hours before the PK test and 1 hour after taking the study medicines at the 
clinic.  Your child can have water or apple/orange juice at any time.  We will take the first blood sample 
before your child takes raltegravir at the clinic.  Your child can have a small meal 2 hours after taking 
raltegravir.  We will take blood samples 8 more times at ½ hour, 1 hour, 2 hours, 3 hours, 4 hours, 6 
hours, 8 hours and 12 hours after your child takes raltegravir.  Your child should not be given a second 
dose of raltegravir until after the PK test. 
 
Your child may be stuck by a needle 9 times or a special needle may be inserted into your child’s arm so 
that he/she may not have to be stuck by a needle multiple times.  If possible an intravenous line will be 
placed in your child’s vein for the whole day from which blood may be drawn to avoid as much 
discomfort as possible.  
[Sites: modify or add language as appropriate regarding your site-specific arrangements for the PK visit]  
 
If your child vomits within 15 minutes after taking raltegravir, your child will be given another dose of 
raltegravir.  If your child vomits more than 15 minutes after taking raltegravir, the intensive PK test will 
be cancelled.  The test may be re-scheduled. 
 
Your child will start taking a fourth anti-HIV drug chosen by your doctor after the PK test is completed.  
Your child should take the fourth anti-HIV drug at night, with the smallest amount of food or liquid (such 
as formula, breast milk, mashed banana, yogurt, or maize-based porridge etc.), and should not be mixed 
with water or juice. 
   
Day 14 visit 
Your child will have a visit approximately two weeks after starting raltegravir. The following will take 
place at this visit: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Day 14”. 
• 
Blood tests: We will take a little less than ½ teaspoon (2 mL) of blood at this visit for the tests in 
Table 1.  The results of the tests will be provided to you/your child. 
 
Week 4 visit: 
The following will take place approximately four weeks after your child starts taking raltegravir: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Week 4”. 
• 
Blood tests:  We will take a little more than ½ to 1 teaspoon (4-6 mL) for the tests in Table 1.  The 
results of these tests will be provided to you/your child. 
• 
If your child will be stopping the anti-TB medications at the week 4 visit because your child has 


 
 
 
 
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completed anti-TB treatment prescribed by your child’s doctor, the following will also take place: 
− 
We will take less than ½ teaspoon (1.5 mL) of additional blood for a CD4/CD8 cell count test.  
The results of the CD4/CD8 cell count test will be provided to you/your child.   
− 
Your child will stop taking raltegravir at the same time the anti-TB medications are stopped.  
Your child will continue to take the anti-HIV medicines as instructed by your child’s doctor. 
 
Week 8 visit: 
The following will take place approximately eight weeks after your child starts taking raltegravir: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Week 8”. 
• 
Blood tests: We will take about 1 – 1 ½ teaspoons (5.5 – 7.5 mL) of blood for the tests in Table 1.  
The results of these tests will be provided to you/your child. 
• 
If your child will be stopping the anti-TB medications at this visit because your child has completed 
anti-TB treatment prescribed by your child’s doctor, your child will stop taking raltegravir at the same 
time the anti-TB medications are stopped.  Your child will continue to take the anti-HIV medicines as 
instructed by your child’s doctor. 
 
Visits every 4 weeks: 
If your child will continue to take the anti-TB medications and raltegravir after the Week 8 visit, your 
child will have visits every 4 weeks until the anti-TB medications and raltegravir are stopped.  The 
following will take place at these visits: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Every 4 weeks”. 
• 
Blood tests: We will take about 1 – 1 ½ teaspoons (5.5 – 7.5 mL) of blood for the tests in Table 1.  
The results of the tests will be provided to you/your child. 
• 
Depending on the amount of HIV in your child’s blood, we may also take a little more than ½ 
teaspoon (3 mL) of additional blood for an HIV resistance test.  This test may be done after the study 
is over, and you/your child will not be given the results. 
• 
If your child is stopping the anti-TB medications at any of these visits because your child has 
completed anti-TB treatment prescribed by your child’s doctor, your child will stop taking raltegravir 
at the same time the anti-TB medications are stopped. 
 
Early TB and/or RAL treatment discontinuation visit: 
If your child needs to stop taking the anti-TB medications and/or raltegravir early, your child will have a 
treatment discontinuation visit. The following will take place at this visit: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “TB and/or RAL 
treatment discontinuation.” 
• 
Blood tests: We will take about 1 – 1 ½ (5.5 – 7.5 mL) of blood for the tests in Table 1. The results of 
these tests will be provided to you/your child. 
• 
Depending on the amount of HIV in your child’s blood, we may also take a little more than ½ 
teaspoon (3 mL) of additional blood for an HIV resistance test.  This test may be done after the study 
is over, and you/your child will not be given the results. 
 
Even if your child stops taking the study medicines, your child will stay in the study and return for the 
visits at 4 weeks and 12 weeks after stopping raltegravir described below. 
 
Four weeks after stopping RAL visit: 
Four weeks after your child stops taking raltegravir, the following will take place: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “4 weeks off 
RAL treatment/on study”. 
• 
Blood test: We will take a little more than ½ - 1 teaspoon (4 – 6 mL) of blood for the tests shown in 
Table 1.  The results of the tests will be provided to you/your child. 


 
 
 
 
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Final visit: 
Twelve weeks after your child stops taking raltegravir your child will have the last study visit.  Or, if your 
child stops participating in the study before completing the study, your child will have a study 
discontinuation visit.  At the last study visit or study discontinuation visit, the following will take place: 
• 
Your child will have the examinations and tests shown in Table 1 under the column “Final visit”.  A 
pill count will only be done if your child is discontinuing raltegravir early at this visit. 
• 
Blood tests: We will take a little over ½ - 1 teaspoon (3.5 – 5.5 mL) of blood for the tests shown in 
Table 1.  The results of the tests will be provided to you/your child. 
 
The study will first enroll a small group of 6 participants into three age groups and participants in each 
group will take the same dose of raltegravir.  If the results of the intensive PK test in a specific age group 
show that the level of raltegravir is too low or too high or is found not to be safe, a new group of 6 
participants will be enrolled into that age group and will take a new dose of raltegravir.  The enrollment of 
a new group of 6 participants in each age group will be done until the best dose of raltegravir is found.   
 
When the best dose of raltegravir is found for that age group, an additional 6 participants will be enrolled 
in each age group and will take the best dose so that there will be a total of 12 participants that will be 
studied on the best dose.  If the results of the intensive PK test for a specific group show that the level of 
raltegravir is too low or too high or is found not to be safe, a new group of 6 participants will be enrolled 
into that age group and will take a new dose of raltegravir.  This process will repeat until the best and safe 
level of raltegravir is found in a group of 12 participants for a specific age group.  If the best dose is not 
found when raltegravir is taken two times a day, it may have to be taken three times a day.   
 
If there is a question about the results of the intensive PK test of your child, or the results are lower than 
what is expected or too high and may be a risk to your child, the study doctor may ask your child to have 
another intensive PK test.  Your child’s study doctor will let you know when the intensive PK test will be 
repeated. 
 
If the group that your child belongs to (whether a group of 6 or 12 participants) has raltegravir PK test 
levels that are either too low, too high or is found not to be safe, the entire group (including your child) 
will take the new dose of raltegravir that will be tested in the new group of participants, if it is considered 
safe to do so and your child’s group is still taking TB treatment and raltegravir.  Changes in the dose of 
raltegravir will be done for the entire group that a participant belongs to and not on an individual basis.  If 
the PK tests suggest that the new dose should be given three times a day, this will not apply to your child 
who will continue to take raltegravir twice a day.  The dose of raltegravir will only be changed once for 
your child and the intensive PK will not be repeated after the dose is changed.  Your child will continue in 
the study and have the rest of the visits.  This will be discussed with you by the study doctor and will 
depend on what is safest for your child. 
 
If your child is still taking raltegravir and the anti-TB medications when the best dose of raltegravir is 
found, and your child is still in the study, the study doctor will change your child’s dose of raltegravir to 
the best dose.  Your child will continue taking the new dose of raltegravir until your child stops taking the 
anti-TB medications. 
 


 
 
 
 
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OTHER INFORMATION 
Your child’s blood samples for the intensive PK tests will be shipped to a laboratory in the United States 
where the tests will be performed. 
 
Any leftover blood samples after testing is completed for this study will be destroyed. 
 
The information collected in this study may be used for other IMPAACT-approved HIV-related research. 
 
HOW MANY INFANTS AND CHILDREN WILL TAKE PART IN THIS STUDY? 
About 36 to 108 infants and children will take part in this study. 
 
HOW LONG WILL MY CHILD BE IN THIS STUDY? 
Your child will be in this study for about 4 to 9 months.   
 
WHY WOULD THE DOCTOR HAVE MY CHILD STOP TAKING RALTEGRAVIR EARLY? 
The study doctor may need to take your child off raltegravir early without your permission if: 
• 
Your child develops a side effect and continuing the study drug(s) may be harmful to your child. 
• 
Your child needs a treatment that your child may not take while on the study. 
• 
Your child is found to have multi-drug resistant (MDR) or extensively drug-resistant (XDR) TB.  
MDR-TB and XDR-TB happens when the bacteria that cause TB infection changes and cannot be 
treated by the medicines that are usually effective in treating TB.  If your child is found to have MDR 
or XDR TB, your child will be referred to the proper doctor or clinic for care. 
• 
Your child is not able to take the study drug(s) as required by the study. 
• 
New information that becomes available shows that your child should stop taking the study drug(s). 
• 
The result of the intensive PK test shows that your child has not been taking the study drugs or the 
level of raltegravir that your child’s body is taking is abnormally high or low. 
• 
The amount of HIV in your child’s blood does not go down to the levels low enough to continue the 
study drug(s). 
• 
Your child becomes pregnant or is a female that is sexually active and does not agree to take birth 
control precautions. 
 
If your child must permanently stop taking the study drug(s) before your child’s study participation is 
completed or before the study is over, the study staff will discuss other options that may be of benefit to 
your child.  In addition, your child will have the early treatment discontinuation visit and the visits four 
weeks and twelve weeks after stopping the study drug(s) as described above. 
 
After the study: 
After your child has completed study participation, the study will not be able to continue to provide your 
child with the raltegravir that he/she received on the study.  If continuing to take these or similar drugs 
would be of benefit to your child, the study staff will discuss how you may be able to obtain them. 
 
WHY WOULD THE DOCTOR TAKE MY CHILD OFF THE STUDY EARLY?  
The study doctor may need to take your child off the study early without your permission if: 
• 
You do not want your child to continue or your child does not want to continue taking raltegravir or 
completing the required visits. 


 
 
 
 
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• 
The study doctor determines that continuing participation could be harmful to your child’s health or 
well-being. 
• 
Your child is not able to attend the study visits or meet the requirements of the study, which may 
cause harm to him/her and affect the results of the study. 
• 
The study is cancelled by the IMPAACT Network, Office for Human Research Protections (OHRP), 
National Institutes of Health (NIH), the site’s Institutional Review Board (IRB) or Ethics Committee 
(EC), the U.S. Food and Drug Administration (FDA), other government agencies, or Merck & Co., 
Inc. (the drug company supporting this study).  An IRB or EC is a committee that watches over the 
safety and rights of research participants. 
• 
An IMPAACT Study Monitoring Committee (SMC) recommends that the study be stopped early.  
The SMC is a group of experts who monitor the study. 
• 
The study has to be stopped for other administrative reasons. 
 
WHAT ARE THE RISKS OF THE STUDY? 
The drugs used in this study may have side effects, some of which are listed below. Please note that these 
lists do not include all the side effects seen with these drugs. These lists include the more serious or 
common side effects with a known or possible relationship.  If you have questions concerning additional 
study drug side effects, please ask the medical staff at your site. 
 
For your child’s safety, it is important that you tell the study doctor or nurse about all medications that 
your child is taking before your child starts the study, and also before your child starts taking any new 
medications while on the study, including medicines bought from the store or pharmacy and herbal or 
natural medicines.  In addition, it is important that you tell the study doctor or nurse before your child 
enrolls in any other clinical trials while on this study. 
 
Your child’s HIV may develop resistance to raltegravir and anti-HIV drugs that are being used in this 
study.  Drug resistance develops when the HIV changes so the anti-HIV drugs become less effective.  It is 
possible that your child may not receive the correct dose of raltegravir, which can also lead to drug 
resistance.  If drug resistance develops in your child, the HIV virus may not be controlled.  However, the 
reason for adding a fourth ARV drug early in the study is to try to avoid the development of resistance to 
raltegravir. 
 
Use of Combination Antiretroviral Drugs 
Immune Reconstitution Syndrome: When your child is treated with a combination of at least 3 anti-HIV 
drugs (which is called highly active antiretroviral therapy or HAART), the way your child’s body is able 
to fight infection may change.  The immune system is the body’s defense against infection. Your child’s 
immune system may respond in a stronger way to some types of infections that your child may already 
have.  This immune response may cause your child to become sick and the condition is then called 
“immune reconstitution inflammatory syndrome” or IRIS.  
 
We do not understand who will get IRIS and who will not.  IRIS can be serious or mild.  It can begin soon 
after a person starts HIV medication for the first time.  It can also begin in people who restart their HIV 
medications after being off (or not taking) them for some time.  IRIS happens when your child’s immune 
system recovers too quickly.  It can start to “overact” and respond to other infections that may or may not 
have been known before starting therapy, even ones that may have already been under control. 
 
When your child’s immune system over acts this way it can cause inflammation (redness and tenderness), 
which is sometimes very serious.  For some people, these symptoms can be life-threatening.  Even though 
most cases of IRIS get better after a few weeks, the symptoms may be mistaken by you, and your child’s 


 
 
 
 
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doctor as the HIV disease getting worse or another condition.  IRIS can be very confusing because, as 
your child’s immune system fights an infection, the inflammation that takes place actually makes your 
child’s symptoms worse. 
 
When IRIS does happen, it happens more often after the BCG injection.  BCG stands for Bacille 
Calmette-Guerin vaccine, a vaccine that is used to prevent tuberculosis (TB) in infants.  The injection site 
can get bigger and the glands in the right armpit may become painful.  IRIS also happens more often with 
TB in 1 out of 10 infants.  Many other bacteria and viruses can lead to IRIS.  Usually, IRIS causes a 
return or worsening of at least some of the symptoms from an infection your child may have had before 
starting HAART.  While some of these reactions can be serious, they usually last for a short time and can 
be treated without stopping the anti-HIV drugs or HAART.    
 
The use of potent antiretroviral drug combinations may be associated with an abnormal placement of 
body fat and wasting.  Some of the body changes include: 
• 
Increase in fat around the waist and stomach area 
• 
Increase in fat on the back of the neck 
• 
Thinning of the face, legs, and arms 
• 
Breast enlargement 
 
Integrase Inhibitor  
Raltegravir, (RAL, Isentress™) 
Merck & Co., Inc. 
 
The following side effects have been associated with the use of raltegravir:  
 
• 
Rash, which can become severe or life-threatening.  Contact your child’s doctor right away if your 
child develops a rash. 
• 
Nausea 
• 
Headache 
• 
Tiredness 
• 
Weakness 
• 
Trouble sleeping 
• 
Stomach pain 
• 
Dizziness 
• 
Depression 
• 
Suicidal thoughts and actions  
• 
Feeling anxious, Paranoia 
• 
Easy bleeding (decreased blood clotting, low platelet count) 
• 
Diarrhea 
• 
Liver failure  
• 
Clumsiness and lack of coordination 
• 
Changes in behavior, like low or high activity in children 
• 
Muscle tenderness, weakness or injury which can be serious and lead to kidney damage 
 
Serious skin and allergic reactions including a rash which can become severe or life-threatening and can 
be fatal.  If your child develops a rash with any of the following symptoms stop using raltegravir and 
contact your child’s doctor right away:  


 
 
 
 
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• 
Fever  
• 
Generally ill feeling  
• 
Extreme tiredness  
• 
Muscle or joint aches  
• 
Blisters or sores in mouth  
• 
Blisters or peeling of the skin  
• 
Redness or swelling of the eyes  
• 
Swelling of the mouth or face  
• 
Problems breathing  
 
Sometimes allergic reactions can affect the body, like the liver and cause liver problems which can lead to 
liver failure. Contact your child’s doctor right away if your child has any of the following signs or 
symptoms of a liver problem: 
• 
Yellowing of the skin or whites of the eyes  
• 
Dark or tea colored urine  
• 
Pale colored stools/bowel movements  
• 
Nausea/vomiting  
• 
Loss of appetite  
• 
Pain, aching or tenderness on the right side below the ribs 
 
In some patients receiving raltegravir blood tests showed abnormally high levels of a muscle enzyme—
creatine kinase which may cause muscle pain, tenderness or weakness this type of muscle break down can 
be serious and lead to kidney damage including kidney failure. Contact your child’s doctor right away if 
your child has any unexplained muscle pain, tenderness, or weakness. 
 
Note: Raltegravir chewable tablets contain phenylalanine, a component of the sugar substitute aspartame. 
Phenylalanine can be harmful to children and adults with phenylketonuria, a birth defect that can lead to a 
variety of health problems.  
 
Risks of Blood Draws 
There is risk of some discomfort, bruising, or bleeding at the site where the blood is drawn.  Occasionally, 
there is swelling in the area where the needle enters the body and a small risk of fainting and/or infection. 
 
Other Risks 
Your child may feel uncomfortable or embarrassed by some parts of your child’s physical exam and with 
some of the questions related to sexual development and activity. 
 
ARE THERE RISKS RELATED TO PREGNANCY? 
It is not known if the study drug raltegravir harms fetuses.  Tests in pregnant animals do show some risk.   
 
Your child will have a medical history and physical exam and we will ask you or your child questions to 
check if your child is having sex that could lead to pregnancy.  If your child is pregnant or breastfeeding, 
she cannot be in the study. If your child is a female and is sexually active, she must agree to use two 
methods of birth control to take the study medicine. Approved methods of birth control for this study 
include hormonal birth control, such as slow release inserts placed under or on the skin, and a medically 
accepted barrier method including condoms, an intrauterine device (IUD), a diaphragm or cervical cap 
with a cream or gel that kills sperm.  If your child is a female and is sexually active while in the study and 
does not agree to use two of these methods of birth control, she can remain in the study, but cannot take 


 
 
 
 
IMPAACT P1101 
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the study medicine.  If your child is having sex while in the study, your child will be referred to their 
primary provider for prevention of pregnancy.  Your child may also be asked to provide urine or 1 mL of 
blood for a pregnancy test at each visit to check if she is pregnant.  If the pregnancy test is positive, the 
study staff will refer your child to her primary provider for counseling about pregnancy and pregnancy 
care and she should stop taking raltegravir.  Your child will continue to come in for study visits and will 
be followed until the outcome of your child’s pregnancy. If you think your child has started having sex or 
you/your child thinks she may be pregnant at any time during the study, tell the study staff right away.  
The study staff will talk to you/your child about your/your child’s choices.  If your child becomes 
pregnant, she will be entered in the Antiretroviral Pregnancy Registry. 
 
Pregnancy test results will be shared confidentially with participants, even if a parent or other adult is 
consenting for the child’s participation in the study.  [Sites should modify preceding language about 
confidentiality of pregnancy test results to conform to their local practice, regulations and IRB 
requirements.] 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
If your child takes part in this study, there may be a direct benefit to your child, however we do not know 
if being in the study will benefit your child in any way.  It is also possible that your child may receive no 
benefit from being in this study.  Your child will have regular visits and frequent checks on his or her 
health, including tests for the amount of HIV in your child’s blood, called viral load, and for the amount 
of cells that fight HIV, called CD4.  Information learned from this study may help others who have HIV 
and TB. 
  
WHAT OTHER CHOICES DOES MY CHILD HAVE BESIDES THIS STUDY? 
Instead of being in this study you have the choice of: 
• treatment with prescription drugs available to your child 
• treatment with experimental drugs, if your child qualifies 
• no treatment 
 
Please talk to your doctor about these and other choices available to your child. Your doctor will explain 
the risks and benefits of these choices. 
 
WHAT ABOUT CONFIDENTIALITY? 
Efforts will be made to keep your child’s personal information confidential.  Study records and specimens 
will be kept in secure locations.  We cannot guarantee absolute confidentiality.  Despite our best efforts to 
keep your child’s information private, it is possible that the information could be obtained by someone 
who should not have it.  If this were to happen, your child could be treated unfairly.  You could feel stress 
or embarrassment.  Your child’s personal information may be disclosed if required by law.  Any 
publication of this study will not use your child’s name or identify your child personally. 
 
Your child’s records may be reviewed by the U.S. Food and Drug Administration (FDA), the Office of 
Human Research Protections (OHRP), (insert name of site) IRB/EC, National Institutes of Health (NIH), 
study staff, study monitors, and Merck & Co., Inc. (the drug company supporting this study). 
 


 
 
 
 
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WHAT ARE THE COSTS TO ME? 
Taking part in this study may lead to added costs to you and your insurance company.  In some cases it is 
possible that your insurance company will not pay for these costs because your child is taking part in a 
research study.  [Sites: Delete or modify as appropriate with any site-specific information regarding 
insurance and local costs.] 
 
WILL I RECEIVE ANY PAYMENT? 
You and your child may receive reimbursement for some expenses for this study.  You and your child 
may receive payment for transportation and meals.   
[Sites: Delete or modify as appropriate with any site-specific information about payment.] 
 
WHAT HAPPENS IF MY CHILD IS INJURED? 
Your child’s health is important to us. We will make every effort to protect your child’s well-being and 
minimized risk to him or her. If your child is injured as a result of being in this study, the study doctor 
will give or refer your child for immediate treatment for your child’s injuries.  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 (NIH).  You will not be giving up any of your legal 
rights by signing this consent form. 
[Sites: Delete or modify as appropriate with any site-specific information regarding insurance and local 
costs.] 
 
WHAT ARE MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary.  You may choose not to allow your child to take part in 
this study or take your child out of the study at any time.  Your child will be treated the same no matter 
what you decide. 
 
We will tell you about new information from this or other studies that may affect your child’s health, 
welfare or willingness to stay in this study.  If you want the results of the study, let the study staff know. 
 
WHAT DO I DO IF I HAVE QUESTIONS OR PROBLEMS? 
For questions about this study or a research-related injury, contact: 
• 
name of the investigator or other study staff 
• 
telephone number of above  
 
For questions about your/your child’s/baby’s rights as a research participant, contact: 
• 
name or title of person on the Institutional Review Board (IRB) or other organization appropriate for 
the site 
• 
telephone number of above   


 
 
 
 
IMPAACT P1101 
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SIGNATURE PAGE   
 
If you have read this consent form (or had it explained to you), all your questions have been answered and 
you agree to take part in this study, please sign your name below. 
 
 
____________________________________        
____________________________________ 
Participant’s Name (print) 
 
 
 
Participant’s Signature and Date  
 
 
 
____________________________________        
____________________________________ 
Participant’s Parent or Legal Guardian (print) 
 
Parent or Legal Guardian’s Signature and Date 
 
 
 
____________________________________        
____________________________________ 
Study Staff Conducting  
              
 
Study Staff Signature and Date  
 
Consent Discussion (print)  
 
 
____________________________________        
____________________________________ 
Witness’ Name (print)  
 
               
Witness’s Signature and Date 
 
 
 
(As appropriate) 
 
 
____________________________________        
____________________________________ 
Father’s Name  
 
 
 
 
Father’s Signature and Date 
(If father’s consent is required)  
 
 
(If father’s consent is required)   

Prot_005.pdf: 
Letter of Amendment #2 for: 
 
IMPAACT P1101 
 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-
Containing Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected 
Infants and Children 
 
A Multicenter, International Trial of the 
International Maternal Pediatric Adolescent AIDS 
Clinical Trials Network (IMPAACT) 
 
Protocol: Version 3.0, dated 24 April 2017 
 
Letter of Amendment Date: 21 June 2018 
 
 
 
NCT 01751568 
 


Letter of Amendment #2       
Page 1 of 3 
21 June 2018 
IMPAACT P1101 Protocol Version 3.0 
Letter of Amendment #2 for: 
IMPAACT P1101 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-
Containing Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected 
Infants and Children 
Version 3.0, dated 24 April 2017 
 DAIDS Document ID #11831 
IND #77,787 Held By DAIDS 
Letter of Amendment Date: 21 June 2018 
Information/Instructions to Study Sites from the Division of AIDS 
The information contained in this Letter of Amendment (LoA) impacts the IMPAACT P1101 study, and 
must be submitted to site Institutional Review Boards and/or Ethics Committees (IRBs/ECs) as soon as 
possible for their review and approval. Approval must also be obtained from site regulatory entities if 
applicable per the policies and procedures of the regulatory entities. All IRB/EC and regulatory entity 
requirements must be followed. 
Upon receiving IRB/EC approval and any other applicable regulatory entity approvals, all sites should 
immediately begin implementing this LoA. Sites are required to submit a LoA registration packet to the 
DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center (RSC). Sites will 
receive a registration notification for the LoA after the DAIDS PRO verifies that all required registration 
documents have been received and are complete. Sites should not await this notification before 
implementing this LoA.  
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential documents files for P1101. If the P1101 protocol is amended in 
the future, the contents of this LoA will be incorporated into the next version of the protocol. 


Letter of Amendment #2       
Page 2 of 3 
21 June 2018 
IMPAACT P1101 Protocol Version 3.0 
IMPAACT P1101 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-Containing 
Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected Infants and Children 
 
Version 3.0, dated 24 April 2017 
DAIDS Document ID #11831 
 
Version 3.0, Letter of Amendment #2 
Dated 21 June 2018 
 
Letter of Amendment Signature Page 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
Signature of Investigator of Record 
 
Date 
 
 
 
 
 
Name of Investigator of Record 
 
 
(printed) 
 


Letter of Amendment #2       
Page 3 of 3 
21 June 2018 
IMPAACT P1101 Protocol Version 3.0 
Summary of Modifications and Rationale 
 
The following modifications are included in this LoA: 
 
1. Sections 6.5, 6.7, and 9.2 are modified to clarify the pharmacokinetic (PK) criteria for early study 
drug discontinuation for participants with AUC0-12hr ≥ 63 µMxhr.  
2. Section 7.2 is updated to clarify that confirmed Grade 3 and 4 adverse events are required to be 
reported as expedited adverse events. 
 
Implementation 
 
Detailed modifications of the protocol text included in this LoA are listed below.  Additions to the text are 
indicated in bold; deletions are indicated by strikethrough.  
 
1. Pharmacokinetic criteria for early study drug discontinuation 
 
a. Section 6.5, Pharmacokinetic Endpoint, second paragraph: 
 
RAL will be stopped in any individual that has an AUC0-12hr ≥ 63 µMxhr, per Section 9.0. Per 
Section 9.0, if any individual has an AUC0-12hr ≥ 63 µMxhr, the Protocol Team will review all 
available clinical, safety, PK, immunologic, and virologic data for the participant and 
determine if discontinuation of RAL is indicated.  For participants that permanently 
discontinue RAL, evaluable PK and safety data will be used in the assessment of the dose 
for that cohort. 
 
b. Section 6.7, Criteria for Early Treatment Discontinuation, fifth bullet: 
 
• Participant has an AUC0-12hr ≥ 63 µMxhr, and the protocol team determines that RAL 
should be permanently discontinued, per Section 9.0. 
 
c. Section 9.2, Study Design, Modeling and Data Analysis, Pharmacokinetic Guidelines, sixth 
paragraph: 
 
If any individual has an AUC0-12hr ≥ 63 µMxhr **, the Protocol Team will review all available 
clinical, safety, PK, immunologic, and virologic data for the participant and determine if 
discontinuation of RAL is indicated participant will stop taking RAL.  However, their For 
participants that permanently discontinue RAL, evaluable PK and safety data will be used in 
the assessment of the dose for that cohort. 
 
2. Expedited Adverse Event Reporting Requirements 
 
Section 7.2, Reporting Requirements for this Study, second bullet: 
 
• 
Other medically significant events for which expedited reporting is required include all cancers 
and pregnancies, fetal losses, IRIS events that qualify as serious adverse events, Hy’s Law liver 
toxicities, and all confirmed Grade 3 and 4 toxicities. 
 

Prot_004.pdf: 
Letter of Amendment #1 for: 
 
IMPAACT P1101 
 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-
Containing Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected 
Infants and Children 
 
A Multicenter, International Trial of the 
International Maternal Pediatric Adolescent AIDS 
Clinical Trials Network (IMPAACT) 
 
Protocol: Version 3.0, dated 24 April 2017 
 
Letter of Amendment Date: 15 March 2018 
 
 
 
NCT 01751568 
 


Letter of Amendment #1       
Page 1 of 3 
15 March 2018 
IMPAACT P1101 Protocol Version 3.0 
Letter of Amendment #1 for: 
 
IMPAACT P1101 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-
Containing Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected 
Infants and Children 
 
Version 3.0, dated 24 April 2017 
 
 DAIDS Document ID # 11831 
IND # 77,787 Held By NIAID 
 
Letter of Amendment Date: 15 March 2018 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) impacts the IMPAACT P1101 study, 
including the sample informed consent form (ICF), and must be submitted to site Institutional Review 
Boards and/or Ethics Committees (IRBs/ECs) as soon as possible for their review and approval. Approval 
must also be obtained from site regulatory entities if applicable per the policies and procedures of the 
regulatory entities. All IRB/EC and regulatory entity requirements must be followed. 
 
Upon receiving IRB/EC approval and any other applicable regulatory entity approvals, all sites should 
immediately begin implementing this LoA and using the updated ICFs. After all required approvals are 
obtained, the updated ICFs should be used for all new participants. In addition, all previously enrolled 
participants must reconsent to ongoing study participation using the updated site-specific ICF. Re-
consenting should take place at each enrolled participant’s next study visit after all required approvals are 
obtained.  
 
Sites are required to submit a LoA registration packet to the DAIDS Protocol Registration Office (DAIDS 
PRO) at the Regulatory Support Center (RSC). Sites will receive a registration notification for the LoA 
after the DAIDS PRO verifies that all required registration documents have been received and are 
complete. Sites should not await this notification before implementing this LoA.  
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential documents files for P1101. If the P1101 protocol is amended in 
the future, the contents of this LoA will be incorporated into the next version of the protocol. 
 
 


Letter of Amendment #1       
Page 2 of 3 
15 March 2018 
IMPAACT P1101 Protocol Version 3.0 
IMPAACT P1101 
Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a Raltegravir-Containing 
Antiretroviral Therapy (ART) Regimen in HIV-infected and TB Co-infected Infants and Children 
 
Version 3.0, dated 24 April 2017 
(DAIDS Document ID 11831) 
 
Version 3.0, Letter of Amendment #1 
Dated 15 March 2018 
 
Letter of Amendment Signature Page 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
Signature of Investigator of Record 
 
Date 
 
 
 
 
 
Name of Investigator of Record 
 
 
(printed) 
 


Letter of Amendment #1       
Page 3 of 3 
15 March 2018 
IMPAACT P1101 Protocol Version 3.0 
Summary of Modifications and Rationale 
 
This LoA updates language regarding regulatory entities that may review study records. Per ICH GCP E6 
4.8.10(n) and DAIDS requirements, it is mandatory that all DAIDS-sponsored and/or supported trials 
include language that informs participants that other US, local, and international regulatory entities may 
also review study records. Protocol Section 10.2 and the sample ICF have been updated accordingly. 
 
Implementation 
 
The modifications included in this LoA are listed below in order of appearance in the protocol. Additions to 
the text are indicated in bold; deletions are indicated by strikethrough.  
 
In Section 10.2, Participant Confidentiality: 
 
All laboratory specimens, evaluation forms, reports, and other records will be identified only by a coded 
number to maintain participant confidentiality. All records will be kept in a secured area. All computer 
entry and networking programs will be done with coded numbers only. Clinical information will not be 
released without written permission of the participant, except as necessary for monitoring by the study 
staff, study monitors, FDA, the OHRP, NIH, the local IRB/EC, or Merck & Co., Inc, and other US, 
local, and international regulatory entities. 
 
In Appendix VI, Sample Informed Consent Form for Study Participation, WHAT ABOUT 
CONFIDENTIALITY?, second paragraph: 
 
Your child’s records may be reviewed by the U.S. Food and Drug Administration (FDA), the Office of 
Human Research Protections (OHRP), (insert name of site) IRB/EC, National Institutes of Health (NIH), 
study staff, study monitors, and Merck & Co., Inc. (the drug company supporting this study), and other 
US, local, and international regulatory entities. 
 
 

SAP_001.pdf: 
 
 
This is IMPAACT P1101 SAP Version 2.0 with names of authors, names of publication, writing 
team members, and analysis timeline redacted. 
 
 
Primary Statistical Analysis Plan (for Protocol V3.0, LoA#1-2) 
Version 2.0  
 
IMPAACT P1101 
 Phase I/II Dose-finding, Safety, Tolerance and Pharmacokinetics Study of a 
Raltegravir-Containing Antiretroviral Therapy (ART) Regimen in HIV-infected 
and TB Co-infected Infants and Children  
  
 
ClinicalTrials.gov Identifier: NCT01751568 
 
  
 
 
 
March 28, 2019 
 
 
  
 
 
 
 
 
 
 


 
 
 
1 
INTRODUCTION ...................................................................................................................... 3 
1.1 
Purpose of the Statistical Analysis Plan .............................................................................. 3 
1.2 
Key SAP Updates ................................................................................................................ 3 
1.3 
Study Design ...................................................................................................................... 4 
2 
STUDY OBJECTIVES ............................................................................................................... 5 
2.1 
Primary Objectives ............................................................................................................ 5 
2.2 
Secondary Objectives ......................................................................................................... 5 
3 
OUTLINE OF PLANNED ANALYSIS ....................................................................................... 5 
4 
DATA SUMMARIES .................................................................................................................. 6 
4.1 
Administrative Data ........................................................................................................... 6 
4.1.1 
Recruitment and Accrual ......................................................................................... 7 
4.1.2 
Participants Deemed Ineligible and Analysis Status ................................................... 7 
4.1.3 
Study Status ........................................................................................................... 7 
4.2 
Baseline Characteristics ..................................................................................................... 7 
4.2.1 
Demographics ........................................................................................................ 7 
4.2.2 
Health Status .......................................................................................................... 7 
5 
PRIMARY ANALYSES .............................................................................................................. 8 
5.1 
Primary Safety Data Analyses on Final-Dose Participants for Final Analysis Reports (Data 
through the final study visit) .................................................................................. 8 
6 
SECONDARY ANALYSES ........................................................................................................ 9 
6.1 
Short Term Efficacy and Other Treatment Outcomes of Final-Dose and All-Treated 
Participants for Final Analysis Reports .................................................................. 9 
 
 
 


 
 
1 
Introduction 
1.1 
Purpose of the Statistical Analysis Plan 
This Analysis Plan outlines the components of the primary and secondary data analyses 
for IMPAACT P1101.  The focus is on analyses of administrative, baseline and safety 
data, analyses needed to address the study’s primary and secondary objectives, and the 
analyses to assess whether safety guidelines have been met at final accrual to all cohorts.  
This document focuses on analyses necessary for scientific purposes.  The procedures 
and reports involved with protocol team monitoring of safety data during regular team 
calls are not 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 the team intends to investigate the study questions listed in the 
protocol objectives, and how the data will be analyzed and presented. 
This analysis plan includes the key analyses that will 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).   
1.2 
Key SAP Updates 
Version 
Changes Made 
Date Finalized 
1 
Original SAP Version 
(Per Protocol V1.0-3.0) 
June 12, 2017 
2 
Protocol Amendment review (V3.0, LOA #1-2) 
 Pearl Samson 
March 28, 2019 
 
 
 


 
 
Changes made under V2.0 of the SAP 
 
Modified the title page (shows protocol version and LoAs), headers and footers. 
 
Removed the Team Roster, and replaced it with Key SAP Updates. 
 
Noted requirements for validation based on Risk Assessments. 
 
Bolded minor edits. 
 
Added a signature page. 
 
1.3 
Study Design 
This is a Phase I/II, dose-finding, safety, tolerability and pharmacokinetics study of 
raltegravir (RAL) in infants and children who have received ≥ 1 week and ≤ 20 weeks of 
Rifampicin (RIF)-based TB therapy prior to initiation of antiretroviral therapy. 
Sample Size:  Approximately 36 to 108 to achieve a target of 36 evaluable children at 
the final recommended dose.  
Population:   HIV-infected and TB co-infected infants and children ≥ 4 weeks to < 12 
years of age taking RIF-based TB therapy and who are eligible for antiretroviral (ARV) 
treatment as defined by local or WHO guidelines. 
Stratification: Participants will be enrolled into the study into the following cohorts:  
 Cohort I: ≥ 2 to < 6 years of age, on TB treatment (n = 12 minimum)  
 Cohort II: ≥ 6 to < 12 years of age on TB treatment (n = 12 minimum)  
 Cohort III: ≥ 4 weeks to < 2 years of age on TB treatment (n = 12 minimum) 
Cohorts will enroll simultaneously. Each age cohort will start with a mini-cohort of 6 
participants, followed by 6 additional participants to make up a full cohort.  
Regimen: Chewable RAL tablet, starting dose of 12 mg/kg (up to a maximum dose of 
800 mg) orally twice daily in addition to, as part of standard of care, two NRTIs plus 
RIF-containing regimen for treatment of TB.    
Following an intensive PK visit, a fourth ARV drug will be added to the RIF-containing 
regimen per local standard of care. 
Treatment Duration:  The four drug ARV regimen (including RAL, 2 NRTIs plus an 
additional ARV drug per local standard of care) will be continued until TB treatment is 
completed and then RAL will be discontinued.  The three drug ARV regimen will be 
continued per local standard of care after RAL is discontinued. 
Study Duration: Participants will be followed for up to three months post 
discontinuation of RAL.  
 
 


 
 
 
2 
Study Objectives 
2.1 
Primary Objectives 
• 
To determine the pharmacokinetics and appropriate dose of RAL when 
administered with a RIF-containing anti-TB therapy in HIV/TB co-infected 
infants and children that generates PK parameters generally comparable to 
those seen in HIV-infected infants and children in the absence of RIF. 
 
• 
To determine safety and tolerance of RAL-containing ART when 
administered with a RIF-containing anti-TB therapy in HIV/TB co-infected 
infants and children.   
 
2.2 
Secondary Objectives 
• 
To describe the short-term treatment outcomes of infants and children using a 
RAL-containing ART regimen co-treated with a RIF-containing TB treatment 
(see Sections 8.2.3 and 8.2.4 of the protocol). 
• 
To explore whether infants and children receiving a RAL-containing ART 
regimen, co-treated with a RIF-containing TB treatment, develop ARV drug 
associated resistance mutations (see Section 6.2.3 of the protocol). 
 
3 
Outline of Planned Analysis 
This section contains the details of the analyses for: 
 
Full cohort accrual safety/efficacy reports: at full accrual to each Cohort.  
 
SDAC final report: The final report will focus on safety, efficacy and treatment outcomes 
until the end of study follow-up. Summary tables will be generated by cohort and 
aggregated.   
The full cohort accrual safety reports will be prepared for the core team.  These reports 
will include information concerning Accrual/Screening, Participant and Study Status, 
Baseline Characteristics, Safety summary and Efficacy (HIV-RNA/CD4) tables.  Unless 
otherwise noted the SDAC final reports will contain all summary tables. 
Additional participant listings, not mentioned in this plan but which may be necessary in 
writing up the SDAC final report, will be generated and will be used internally at SDAC.  
Highlights of these listings will be included in the SDAC final report.  These participant 
listings will be provided to the manuscript writing team.  The manuscript writing team, 
which is a subset of the protocol team, will be identified by the protocol team. 
The analysis of the PK data will be performed by the protocol pharmacologist, thus, not 
included in this document. 


 
 
Validation requirements as per SDAC SOPs will be as follows: 
a. All dataset creation programs will be validated for the primary and secondary safety 
endpoints as specified below. 
b. All study-specific formats will be validated. 
c. Validation of analysis programs is specified in the subsections below. 
 
For all analyses, the relative weeks of visit date/specimen date/onset date/other dates 
(“Assessment Window”) will be calculated using the following guidelines: 
Assessment Window 
Target Study Day of Window 
Entry/Week 0 
1 
Day 5-8/Week 1 
5-8 
Day 14/Week 2 
+/- 3 days 
Week 4 
+/- 1 week 
Week 8 
+/- 2 weeks 
Every 4 weeks* 
 +/- 2 weeks 
 TB and/or RAL Treatment 
Discontinuation** 
  
 4 Wks Off RAL treatment / On study 
+/- 2 weeks 
Early Discontinuation or End of Study 
 at 12 wks off RAL treatment ± 2 wks 
* These visits will only be done if a participant will continue TB treatment and RAL after the Week 8 visit. 
**At any of the on-treatment visits that coincide with the discontinuation of TB treatment and/or RAL or when a 
participant has met the criteria for virologic failure and early treatment discontinuation as defined in Sections 6.2.2 and 
6.7, respectively. 
4 
Data Summaries 
4.1 
Administrative Data 
Purpose: To give a summary of accrual and retention progress of the study during 
interim and final analyses. 
Data: Date and institution (with country) of enrollment and eligibility status will be from 
the STATUS table; comments related to eligibility deviations will be from COMENT 
table. Comments related to PK exclusion will be from COMENT table. Reasons for 
screening failures and non-enrollment will be from the SCR0049 CRF. Off-study reasons 
are from Off-Study (F1601) CRF. Off-treatment reasons are from Permanent 
Discontinuation of Study Drug (PE4005) CRF.  
Analysis Program Validation: Not required. 
 
 
 


 
 
Analyses (tables and listings presented by cohort and aggregated): 
4.1.1 Recruitment and Accrual  
 Summary table of accrual by site (dates of first and last enrollment will be indicated in the 
text or a footnote.)  
4.1.2 Participants Deemed Ineligible and Analysis Status  
 Listing table of violations of eligibility criteria, and details of reasons for exclusions from 
analyses 
4.1.3 Study Status 
 Summary table [number (%)] disposition of participants;  
 Summary table [number (%)] and listing of participant off-study reasons 
 Summary table [number (%)] and listing of off-study treatment reasons 
 
4.2 
Baseline Characteristics 
Purpose: To describe participant baseline characteristics  
Data: Demographics are from DMC’s STATUS derived dataset; Health status will also 
include HIV-RNA and CD4 data. 
Analysis Program Validation: Not required 
Analyses (tables and listings presented by cohort and aggregated): 
4.2.1 Demographics 
 Gender: number (%)  
 Race: number (%)  
 Ethnicity: number (%)  
 Age (yrs): median (interquartile range), min/max, q1/q3 
 Weight (kg): median (interquartile range), min/max, q1/q3 
 
4.2.2 Health Status 
 Baseline HIV-1 RNA and CD4%: median (interquartile range), min/max, q1/q3 
 
 
 


 
 
 
5 
Primary Analyses 
5.1 
Primary Safety Data Analyses on Final-Dose Participants for Final Analysis 
Reports (Data through the final study visit) 
Purpose: To list the endpoints and tables of primary and secondary safety analyses on 
final dose participants for the SDAC final analysis reports. 
Data: Safety data are adverse clinical and laboratory events reported on the following 
CRFs: Clinical: Signs/Symptoms (PE6833/PE6832/PE6831), Diagnoses 
(PE6853/PE6852), Death (PE1414); Laboratory: Hematology (PE6813/PE6812), 
Chemistries (PE6818/PE6817). The following variables in the SDAC SAS datasets will 
be used:  EVENTDSC, EVNGRDE, FORMNM, FORMTYP in TRAC table; TRACKCD 
(team’s drug attribution assessment variable) in TRAC table; and Code =40 (Subject 
reached protocol-defined toxicity endpoint) of Reason for Treatment Discontinuation of 
PE4005 CRF.  
Analysis Program Validation: Code review is required.  Primary analysis for primary 
safety endpoints will require validation. 
Analyses (tables and listings presented by cohort and aggregated):  
The following section includes information on: outcome measures, statistical 
methods and contents of the corresponding analyses. 
 Safety endpoints by cohort and aggregated (worst grade per AE per participant): 
 
Primary safety endpoint for the final analysis (by cohort and aggregated):  
o 
Summary table [number (%), with 95% Exact CI] and listing of adverse 
events which lead to termination of study treatment 
 
Specifically, due to adverse events of ≥ Grade 3 deemed at least 
possibly related to RAL. 
o 
Summary table [number (%), with 95% Exact CI] and listing of adverse 
events of Grade 3 or 4 severity  
o 
Summary table [number (%), with 95% Exact CI] and listing of adverse 
events of Grade 3 or 4 severity judged by the protocol team to be at least 
possibly related to RAL 
o 
Summary table [number (%), with 95% Exact CI] and listing of participant 
deaths and those who experienced Grade 4 life-threatening events (with 
focus on possibly RAL related). 
o 
Summary table [number (%), with 95% Exact CI] and listing of participants 
who experienced Grade 4 non-life-threatening events deemed probably or 
definitely related to RAL. 
o Summary table [number (%), with 95% Exact CI] and listing of participants’ 
worst grade of adverse event experienced while on the selected dose RAL 
and the worst grade of adverse event judged to be at least possibly due to 
RAL.  
 
 


 
 
 
6 
Secondary Analyses 
 
6.1 
Short Term Efficacy and Other Treatment Outcomes of Final-Dose and All-
Treated Participants for Final Analysis Reports 
Purpose: To describe the short term efficacy and other treatment outcomes in children 
for the final analysis reports.  
Data: HIV-RNA, CD4, Clinical Response (weight, height, BMI), genotypic resistance 
(from virologic failures only). 
Analysis Program Validation: Code review is required for programs creating 
derived datasets. 
Analyses (tables and listings presented by cohort and aggregated): 
The following section includes information on: outcome measures, statistical 
methods and contents of the corresponding analyses. 
 Summary table [number (%), bounded with 95% exact confidence interval] and listing of 
participants who have exhibited virologic response at week 8 (i.e., virologic success is 
defined as achieving at least 1- log10 drop from baseline OR HIV RNA ≤ 400 copies/mL; 
A secondary, more stringent definition of virologic response is to achieve HIV RNA ≤ 50 
copies/mL). This will be in an as-treated analysis. Note that participants who discontinue 
RAL due to TB-drug cessation will be excluded from the analysis.   
 Summary tables and listings showing changes from baseline in: HIV-RNA (to week 8 and 
other time points), CD4 percent and count (to week 8, and other time points), weight, 
height, BMI. 
 Listing of participants who had both virologic failures and developed genotypic 
resistance. 
 Listing of participants who developed opportunistic infections.