Clinical trial NCT01302847
Conditions: HIV Infections
Keywords: Integrase Inhibitors Infant Child Adolescent
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2011-04-20; Completion date: 2023-10-18
Enrollment: 181 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Dolutegravir (DTG) is an HIV drug in the integrase inhibitor drug class. This study evaluated the pharmacokinetics (PK), safety, tolerability of and immune response to DTG when used concurrently with optimized background therapy (OBT) in HIV-1 infected infants, children, and adolescents.

Detailed description:
DTG is an HIV medicine in the integrase inhibitor drug class. The purpose of this study was to evaluate the pharmacokinetics, safety, tolerability, and antiviral activity of DTG when used concurrently with OBT in HIV-1 infected infants, children, and adolescents.

Participants in this study were evaluated for PK, safety and tolerability through 48 weeks, followed by additional long-term study follow-up that lasted for approximately 144 weeks (3 years), for a total of 192 weeks on study. This study had two stages. Stage I provided pharmacokinetics, short-term tolerability and safety data on DTG on a limited number of participants to permit dose selection for further study in Stage II. Once a Stage I dose was accepted, enrollment to Stage II began to complete enrollment to the cohort. Stage II provided longer-term safety and antiviral activity data among a larger number of participants.

Infants, children and adolescents with HIV-1, aged ≥ 4 weeks to \< 18 years enrolled in the age and formulation cohorts specified below:

* Cohort I: Adolescents ≥ 12 to \<18 years of age (film-coated tablets)
* Cohort IIA: Children ≥ 6 to \<12 years of age (film-coated tablets)
* Cohort IIB: Children ≥ 6 to \<12 years of age (granules for suspension)
* Cohort III: Children ≥ 2 to \< 6 years of age (granules for suspension)
* Cohort IV: Children ≥ 6 months to \< 2 years of age (granules for suspension)
* Cohort III-DT: Children ≥ 2 to \< 6 years of age (dispersible tablets)
* Cohort IV-DT: Children ≥ 6 months to \< 2 years of age (dispersible tablets)
* Cohort V-DT: Infants ≥ 4 weeks to \< 6 months (dispersible tablets)

Cohorts were opened sequentially according by age group (starting with the older age group), DTG formulation, and study stage, i.e. Initial study enrollment was for Cohort I and progressed to Cohort IIA once Cohort I Stage I met the PK and safety criteria, followed by opening of Cohort IIB. Each cohort enrolled in two sequential stages: Stage I and II (the only exception is Cohort IIB, which only enrolled through Stage I). Sequential enrollment for Cohort III and IV proceeded in the same manner. Cohort V never enrolled because of the recommended changes in dosing and inclusion of enrollment weight band in the criteria for dose finding.

Stage I participants had physical examinations and had blood draws for safety assessments at study visits: Day 0; Day 5 (+5 days); and Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Stage I participants also had intensive PK sampling with blood samples collected at time 0 (pre-dose), and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing. Once a Stage I treatment dose was accepted, enrollment to Stage II began to complete enrollment to the cohort. Stage II participants had physical examinations and blood draws for safety assessment at study visits: Day 0; Day 10; and Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Blood, plasma, and urine were collected and tested to measure immune response. Females of childbearing potential underwent pregnancy testing at screening and at every study visit.

After 48 weeks, all Stage I and Stage II participants entered the long-term study follow-up and continued to receive DTG. During this time, participants had safety and/or antiviral activity assessments every 12 weeks for up to 3 years.

The study was able to determine a proposed dose (i.e. optimal dose) for Cohorts I, IIA, III-DT, IV-DT, and V-DT but not for Cohorts IIB, III, and IV. Participants on the proposed dose had intensive PK sampling between days 5 and10 of DTG initiation with blood samples collected at time 0 (pre-dose), and at 1, 2, 3, 4, 6, 8 and 24 hours post dosing.

The study is closed to accrual and study follow-up was completed on Oct 18, 2023.

Arms: arm 1: Adolescents 12 to younger than 18 years of age who received DTG film-coated tablets arm 2: Children 6 to younger than 12 years of age who received DTG film-coated tablets arm 3: Children 6 to younger than 12 years of age who received DTG granules for suspension arm 4: Children 2 to younger than 6 years of age who received DTG granules for suspension arm 5: Children 6 months to younger than 2 years of age who received DTG granules for suspension arm 6: Children 2 to younger than 6 years of age who received DTG dispersible tablets arm 7: Children 6 months to younger than 2 years of age who received DTG dispersible tablets arm 8: Infants 4 weeks to younger than 6 months of age who received DTG dispersible tablets
Interventions: intervention 1: DTG film-coated tablets intervention 2: DTG granules for suspension intervention 3: DTG dispersible tablets intervention 4: DTG dispersible tablets intervention 5: DTG dispersible tablets
Intervention descriptions: intervention 1: DTG film-coated tablets initial starting dose at \~1 mg/kg with a maximum dose of 50 mg; orally once daily. Participants weighing ≥ 35kg received the proposed dose of 50 mg of DTG film-coated tablets. intervention 2: DTG granules for suspension initial starting dose at \~0.64 mg/kg with a maximum dose of 32 mg; orally once daily. intervention 3: DTG dispersible tablets initial starting dose of \~0.8 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was:

Weight band 3 to \<6 kg: 5 mg DTG dispersible tablets; Weight band 6 to \<10 kg: 15 mg DTG dispersible tablets; Weight band 10 to \<14 kg: 20 mg DTG dispersible tablets; Weight band 14 to \<20 kg: 25 mg DTG dispersible tablets; Weight band ≥20 kg: 30 mg DTG dispersible tablets. intervention 4: DTG dispersible tablets initial starting dose of \~1.25 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was:

Weight band 3 to \<6 kg: 5 mg DTG dispersible tablets; Weight band 6 to \<10 kg: 15 mg DTG dispersible tablets; Weight band 10 to \<14 kg: 20 mg DTG dispersible tablets; Weight band 14 to \<20 kg: 25 mg DTG dispersible tablets; Weight band ≥20 kg: 30 mg DTG dispersible tablets. intervention 5: DTG dispersible tablets initial starting dose of \~1.25 mg/kg with a maximum dose of 30 mg; orally once daily. The proposed weight-band dosing was:

Weight band 3 to \<6 kg: 5 mg DTG dispersible tablets; Weight band 6 to \<10 kg: 15 mg DTG dispersible tablets.

Protocol documents:
ICF_000.pdf: 
 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
Appendix II 
Sample Consent Form for Participants Enrolling in Stage I 
 
DIVISION OF AIDS 
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS GROUP 
(IMPAACT) 
 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and  
Antiviral Activity of dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 
Infected Infants, Children and Adolescents 
 
Participants Enrolling in STAGE ONE 
P1093 Version 5.0, dated 12 July 2018   
 
SHORT TITLE FOR THE STUDY: Safety and PK of dolutegravir in HIV-1 Infected Children  
 
INTRODUCTION 
You are/your child is being asked to take part in this research study because you have /your child has the 
Human Immunodeficiency Virus (HIV), which is the virus that causes AIDS, and because the drugs 
currently available may not keep the amount of HIV in your / your child’s blood low enough or may 
cause side effects too difficult to deal with. 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 to be/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/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 study a new antiretroviral HIV medication called dolutegravir. This drug is a 
type of 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. The study will help find the best 
amount or dose of dolutegravir for infants, children and teenagers, when it is taken on its own as well as 
with other antiretroviral medications. This study will also find out the safety of using this medication in 
infants, children and adolescents and if there are any side effects from the medication. Dolutegravir has 
been tested in adults and children. The study drug (dolutegravir) is approved for use in children 12 years 
and older by the FDA [and/or local regulatory authorities].  
 
WHAT DO I / DOES MY CHILD HAVE TO DO IF I AM / HE / SHE IS IN THIS STUDY? 
If you decide to (allow your child to) enroll in this study, you / your child will be asked to come to the 
clinic at least 10 times over 48 weeks and then every 12 weeks for three more years. You / your child will 
be given dolutegravir and you / your child will be asked to take it once or twice a day for the entire study, 
in addition to your / your child’s regular HIV medicines. Dolutegravir is available in 3 different 
formulations: 1) a film-coated tablet which cannot be crushed or dissolved, 2.) a liquid suspension and, 3) 
a tablet that can be dissolved in water. If you are/your child is 12 up to 18 years old, you/your child will 
take the film-coated tablet formulation of dolutegravir. You will be given instructions on how to give 
dolutegravir to your child and how to store the dolutegravir. If your child is between 6 to less than 12 
years of age and was prescribed the liquid or dissolvable tablets of dolutegravir he/she may be allowed to 
switch to the film-coated tablet formulation at a later time. The study staff will let you know when your 
child can switch and if you request to do so. 


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
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Although the study will provide you/your child with dolutegravir, other antiretrovirals will not be 
provided by the study. 
 
This study will be done in two parts – Stage one and Stage two. Stage one will enable the doctors to find 
the right dose of study drug for you/your child and then will keep you on that dose to look for any side 
effects that you/your child might experience. In Stage two the doctors will know the right dose to put 
you/your child on and will look at any side effects that you / your child might experience as well as how 
well the drug is controlling your HIV infection. You/your child will be enrolled into either Stage one or 
Stage two, depending on when you/your child enroll and your age / the age of your child. This consent 
form is for Stage one. 
 
In this study there are 8 cohorts in Stage I – enrolling infants, children, and adolescents from 4 weeks to 
less than 18 years of age. Participants who have had their 18th birthday by the entry visit will not be 
enrolled into the study.  
 
Screening: 
If you are interested in taking part / allowing your child to enroll in this study, we will see if you are / 
your child is eligible for the study: 
 
• 
We will ask your / your child’s medical history including questions about your /your child’s 
health and what symptoms, medications, and illnesses you have/your child has had. 
• 
We will do a physical exam including height, weight and vital signs (temperature, blood pressure, 
pulse and respiratory rate). Doses may be modified based on the results of the weight. 
• 
We will take a little more than 2 teaspoons (11mL) of blood, to check for the following: 
o The amount of HIV in the blood,  
o The amount of cholesterol and triglycerides (types of fat) in the blood,  
o How well your immune system, liver and kidneys are working,  
o Other routine tests.  
You will be given the results of these tests. We will also ask you/your child to provide a urine sample for 
routine tests. Girls and women who can have a baby will also be asked to provide a urine or blood sample 
to test for pregnancy.  If you are / your child is engaged in sexual activity that could lead to pregnancy, 
you / your child will be asked to take birth control precautions throughout the study period. 
 
On Study: 
If you are/your child is eligible for this study, you/your child will come to the clinic at least 10 times in 
about 1 year. Most of the visits will last about 1-2 hours. More visits will be needed if the amount of 
study drug in your blood is too low or too high and your dose needs to be adjusted. You/your child will 
come to the clinic for the first study visit within 30 days of the screening visit.  
• 
At each visit, a medical history will be taken and you/your child will have a physical exam. At the 
enrollment visit and at the week 48 visit, you/your child’s stage of sexual development will be 
determined. For girls/women, this will be done by looking at how developed the breasts are. For 
boys/men, this will be done by measuring the size of the testes.  
• 
We will draw blood at each visit. Depending upon your/your child’s age, between 1- 4 teaspoons 
(5-17mLs) of blood will be drawn at these visits; you will be informed of results of routine blood 
tests. Some of the blood drawn will be stored and tested to find out how your/your child’s 
immune system is affected by the study drug. This testing will be done after the study is over, and 
you will not be given the results of these tests.  


 
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• 
A palatability assessment will be done at Day 10, Week 4 and Week 24 to find out what you/your 
child thinks about the taste of the study drug. 
• 
You/your child will be asked to come to the clinic to have blood drawn 8 times over 24 hours 
during one visit, approximately 5-10 days after you / your child started taking the study 
medication. This visit is known as an ‘intensive PK visit’. Depending on your/your child’s age, 
up to 9mLs (about 2 teaspoons) of blood will be drawn at this visit and you will be asked to 
withhold certain liquids and food. The study staff will give you instructions about this.  These 
blood tests are done to measure the amount of study drug in your/your child’s blood. A small 
plastic catheter (a needle that is placed in a vein for an extended period of time, so that blood can 
be drawn multiple times, without having to stick you with a needle several times) will be placed 
in your/your child’s arm to draw these blood samples. The needle will stay in place until all of the 
blood samples are drawn.  
• 
If the amount of study drug in your/your child’s blood is not enough or is too high, you/your child 
may be asked to take a different dose and may be asked to return to the clinic for another 
‘intensive PK visit’. You/your child may have blood to be drawn again 8 times over 24 hours. 
This is to make certain that the new dose is safe.  The same procedures above will be followed. 
• 
The current instructions on what you/your child can eat and drink around the intensive PK draws 
are below, but these may change.  If these instructions change, the study staff will let you know 
and provide you with different instructions.     
If you are/your child is older than 2 years old and having intensive PKs done you/your child may 
be asked to follow the guidelines below regarding eating and drinking around the intensive PK 
visit. 
• 
≥6 hours PRIOR to taking your medication – you/your child may eat and drink without 
restriction 
• 
≥4 to <6 hours PRIOR to taking your medication – milk, apple/orange juice and water may be 
consumed; No food 
• 
<4 hours PRIOR to taking your medication – water ONLY 
• 
From dosing to <2 hours AFTER taking your medication – apple/orange juice and water may 
be consumed; No food 
• 
From ≥2 to <4 hours AFTER taking your medication – you may drink apple/orange juice and 
eat a snack/light meal (around 100-150 calories)  
• 
From ≥4 hours AFTER taking your medication onwards – you may eat and drink without 
restriction 
If your child is 4 weeks to less than 2 years old and having intensive PKs done, you/your child 
may be asked to follow the guidelines below regarding eating and drinking around the intensive 
PK visit. 
• 
No breastmilk, 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.   
• 
You will have extra blood draws at three visits (week 4, week 12 and week 24). At weeks 4 and 
24, you will have two blood draws.  At week 12 you will only have one blood draw. The amount 
of blood drawn at the different study visits will be less than 1 teaspoon (0.5-1mL) depending on 
your /your child’s age. 
• 
If the amount of HIV virus in your/your child’s blood increases too much while on this study 
drug, you/your child may be asked to come back to clinic to have your blood drawn to confirm 
the level of HIV in your blood. If the level of HIV virus in your blood is still too high, your study 


 
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doctor may ask you to stop taking the study medicine and to come back to the clinic for another 
visit. As part of this visit, you/your child will have an interim medical history, physical exam and 
approximately 3 teaspoons of blood (14-16.5mL) will be drawn for testing and storage.  
• 
If you/your child experiences a severe liver reaction or inflammation while on the study, you/your 
child may be asked to come back to clinic to have less than one teaspoon of blood (2mL) drawn 
to check the level of dolutegravir in the blood. Additional testing as part of routine assessments 
for liver inflammation (e.g. checking for viruses that cause liver inflammation) may be performed 
as well.  
Long Term Follow-Up 
After you have been on study drug for approximately 48 weeks, you will enter the long term follow-up 
phase of the study. You will be asked to come back into clinic every 12 weeks (every 3 months) for 3 
more years. Most visits will last about 30 mins.  
• 
At each visit, a medical history will be taken and you/your child will have a physical exam. You 
will also be asked if you have missed taking any of your medications. 
• 
We will draw less than 1 teaspoon of blood (3-4mL) at each visit. You will be informed of results 
of routine blood tests.  
• 
As before, if the amount of HIV virus in your/your child’s blood increases too much while on this 
study drug, you/your child may be asked to come back to clinic to have your blood drawn to 
confirm the level of HIV in your blood (see above).  
You/your child must continue to take your/his/her anti-HIV medications during the study as prescribed by 
your/your child’s HIV care provider. If your/your child’s HIV care provider changes your/your child’s 
anti-HIV medications during the study, you/your child can still take the study drug. You/your child will 
be asked questions about taking your/his/her anti-HIV medications and the times you take/he/she takes 
them and if you have/he/she has missed any medications. 
 
If you/your child can become pregnant, we will collect urine or blood to test for pregnancy at each visit. 
We will also ask you/your child about contraception use.  If you think you/if your child thinks she may be 
pregnant at any time during the study, tell the study staff right away.  
 
Blood and Urine Samples 
Some of your / your child’s blood and urine samples will be shipped out of the country to the USA for 
specialized tests. These tests will tell the doctors how much study drug is in your / your child’s blood and 
if the study drug is causing any changes in your kidneys.  
 
For Participants Receiving Granules for suspension only 
 
If your child is receiving the liquid he/she will need to switch to the dissolvable tablet. The study staff 
will inform you when your child will need to switch. This is because the company will not be making the 
(granule) liquid form of dolutegravir any longer. The study staff will provide instructions on how to 
dispense the dissolvable tablet and on the day you are scheduled to come to the clinic to begin taking the 
dissolvable tablets you will be asked to not give the (granule) liquid dose to your child. The first dose of 
the dissolvable tablet will be given in the clinic. You will be asked to come back to the clinic about 2 
weeks later and will have a palatability assessment and blood drawn to confirm the level of HIV in your 
child’s blood. If you have been on the study for more than 24 weeks at each of these visits, blood samples 
will be drawn at two separate times. The amount of blood drawn will be less than 1 teaspoon (0.5 -1mL)].   
 
WHAT DO I / DOES MY CHILD HAVE TO DO IF I AM / HE / SHE BECOMES INFECTED WITH 
TUBERCULOSIS WHILE ON THIS STUDY? 
If you become/your child becomes exposed to Tuberculosis (TB) while on study and requires anti-TB 
treatment that includes Rifampin you/your child will have to increase the dose of dolutegravir from once a 


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
day to twice a day while taking Rifampin. After you/your child complete(s) treatment with Rifampin, 
you/your child will go back to taking the dolutegravir once a day depending on what other medications 
you/your child is taking.  
 
You/your child will also be required to return for at least five additional follow-up visits after starting 
Rifampin.  
• 
At each of these visits, a medical history will be taken and you/your child will have a physical 
exam and a pregnancy test.  We will draw approximately 1-3 teaspoons of blood to look at the 
following: 
o The amount of HIV, cholesterol and triglycerides (types of fat) in your blood 
o How well your immune system, liver and kidneys are working, as well as other routine 
tests 
• 
At each visit you will be asked whether you are taking your medication as instructed. 
• 
You/your child will be asked to come to the clinic to have blood drawn 8 times over 12 hours 
during one visit, approximately 5-10 days after you/ your child started taking anti-TB medication. 
For this visit, you/your child will be asked to fast for 6 hours before your daily dose of study 
medication. 
• 
The study staff will give you more instructions about this. Depending on your/your child’s age, 
up to 13mL (about 3 teaspoons) of blood will be drawn at this visit. 
• 
You will have extra blood draws at two visits. At weeks 4 and 12, you will have two blood draws 
-  blood will be drawn once before you take dolutegravir and about 12 hours later.  The amount of 
blood drawn at the different study visits will be less than 1 teaspoon (1mL) depending on your 
/your child’s age. 
OTHER INFORMATION 
The information collected in this study may be used for other IMPAACT-approved HIV-related research. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
About 300 children and adolescents will take part in this study 
 
HOW LONG WILL I/MY CHILD BE IN THIS STUDY? 
You/your child is enrolling in Stage I of the study, and so will be in the study for at least 48 weeks After 
that time you/your child will enter the long-term safety follow-up phase of the study. During this time, 
you / your child will continue to take study-provided dolutegravir and will be asked to come to clinic 
every 12 weeks for three more years. 
 
 
WHY WOULD THE DOCTOR TAKE ME / MY CHILD OFF THE STUDY DRUG / THIS STUDY 
EARLY? 
The study doctor may need to take you/your child off the study drug early, without your permission, if: 
• 
Continuing the study drug may be harmful to you / your child 
• 
You become / your child becomes pregnant while on study 
• 
If you elect not to attend repeat PK evaluations as part of the study 
 
The study doctor may need to take you/your child off the study early, without your permission, if: 
• 
You are/ your child is not able to attend the study visits as required by the study 
• 
You need / your child needs a treatment that you / your child may not take while on the study 
• 
You are / your child is not able to take the study drug as required by the study 
• 
The study is cancelled by the U.S. Food and Drug Administration (FDA), National Institutes of 
Health (NIH), the Office of Human Research Protections (OHRP), other country specific 
governmental agencies, IMPAACT, the drug company supporting this study (GSK), or the site’s 


 
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Institutional Review Board (IRB) or Ethics Committee (EC). An IRB or EC is a committee that 
watches over the safety and rights of research participants 
If your doctor wants you / your child to stop taking the study drug, you/your child will be asked to return 
to the clinic once more, four weeks after your last dose of dolutegravir, to make sure you are/your child is 
continuing to do well. This visit will include a history and physical exam, a blood draw and a review of 
your medical records.  
 
IF MY CHILD HAS TO PERMANENTLY STOP TAKING STUDY-PROVIDED MEDICINE, OR 
ONCE I LEAVE THE STUDY, HOW WOULD THE STUDY MEDICINE BE PROVIDED? 
During the study: 
If you / your child must permanently stop taking study-provided dolutegravir before your/your child’s 
study participation is over, the study staff will discuss other options that may be of benefit to you/your 
child. 
 
After the study: 
Once you / your child leaves the study, if you/they are gaining benefit from the study-provided drug, this 
drug may continue to be provided until it is available to you in your country, but there is no guarantee. 
Study clinicians will work to ensure that you/your child continue to receive appropriate care and 
treatment outside of the study. 
 
WHAT ARE THE RISKS OF THE STUDY? 
The drug 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 this drug. These lists include the more serious 
or common side effects with a known or possible relationship. It is very important that you tell your 
study doctor of any changes in your/your child’s medical condition while taking part in the study. At 
any time during the study, if you believe you are/your child is experiencing any of these side effects, 
you have the right to ask questions on possible and /or known risks. 
Possible Risks Associated with Dolutegravir 
The drug used in this study, dolutegravir, has been administered to a total of 6004 participants (4814 
HIV-infected and 1190 healthy) cumulative to 16 July 2017 in ongoing and completed ViiV sponsored 
and clinical trials ranging from Phase I to IIIb and the dolutegravir compassionate use program.  The 
following side effects have been seen with dolutegravir: 
 
 
Very Common (expected in about 100 of every 1000 people taking DTG (10%))  
Nausea or feeling sick  
Headache  
Diarrhea or loose stools 
 
Common (expected in about 10 of every 1000 people taking DTG (1%))  
Cold symptoms like runny nose and sore throat; cough; flu 
Dizziness or feeling light headed 
Trouble sleeping; abnormal dreams 
Rash  
Feeling tired  
High temperature 
Pain in the stomach; vomiting 
Changes in kidney, liver and muscle blood tests 
Ocular icterus (yellowing of the whites of the eyes) 


 
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12 July 2018 
 
Uncommon (expected in about 1 of every 1000 people taking DTG (0.1%)  
Allergic reaction (see below) 
Liver toxicity (see below) 
An inflammatory condition which may develop as the immune system becomes stronger (immune 
reconstitution syndrome or ‘IRIS’ (see below) 
Suicidal thoughts and behaviors (mainly in patients who have had depression or mental health 
problems before) (see below) 
 
Most of the side effects listed above have been mild or moderate, and have not generally stopped HIV-
infected patients treated with dolutegravir from getting on with their lives as normal. 
In one animal study, gastric erosion (irritation of the stomach lining) was seen. This finding has not been 
seen in adults in studies to date. However, if you or your child feels heartburn or stomach pain or has 
vomiting, please contact your/your child’s study doctor. 
 
Other side effects that may show up in blood tests:  
• 
An increase in bilirubin (a pigment produced from the breakdown of red blood cells) in the blood,   
• 
An increase in the level of creatinine, a waste product in the blood that gets filtered by the 
kidneys.  
 
Dolutegravir Hypersensitivity Reaction 
Hypersensitivity reactions have also been reported with integrase inhibitors, including dolutegravir, with 
signs and symptoms including general feeling of being sick, skin rash, a high temperature (fever), lack of 
energy (fatigue), swelling sometimes of the face or mouth (angioedema) causing difficulty in breathing, 
blisters or peeling skin, mouth ulcers, conjunctivitis (sore eyes), and muscle or joint aches.  If you/your 
child develop(s) any of these signs and symptoms during the study, contact you/your child’s study doctor 
immediately, who may decide to carry out tests on you/your child liver, kidneys or blood. 
Mental illness 
Some people with HIV infection occasionally have feelings of depression or may have thoughts of 
hurting or killing themselves (committing suicide). A small number of people being treated with integrase 
inhibitors for HIV infection, including dolutegravir, have had suicidal thoughts and behaviors, 
particularly patients with a prior history of depression or mental health illness. People with HIV taking 
integrase inhibitors including dolutegravir have also reported depression. 
 
Tell the study doctor if you/your child have a history of mental illness. If you/your child have thoughts of 
hurting or killing yourself or have any other unusual or distressing thoughts or feelings at any time during 
the study, you/your child should tell the study staff or go to the nearest hospital immediately.  
 
Use of Combination Antiretroviral Drugs 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, symptoms from other 
infections or certain diseases may occur soon after starting combination anti-HIV treatment but can also 
Itching (pruritus) 
Feelings of deep sadness and unworthiness (depression) 
Flatulence (gas or wind) 
Increase in the level of liver enzymes 
Increase in the level of enzymes produced in the muscles (creatinine phosphokinase) 
Anxiety (fear, worry) 


 
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occur later.  Some of these symptoms may be life threatening.  If you start having new symptoms, or 
notice that existing symptoms are getting worse after starting your antiretroviral therapy, tell your 
healthcare provider right away. 
 
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 
 
Some patients taking combination anti-HIV therapy may develop a bone disease called osteonecrosis 
(death of bone tissue caused by loss of blood supply to the bone).  The length of combination anti-HIV 
therapy, corticosteroid use, drinking alcohol, severe reduction in ability to fight off infection, higher body 
weight, among others, may be risk factors for developing this disease.  Signs of osteonecrosis are joint 
stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement.  If 
you/your child notice any of these symptoms, please inform your doctor 
 
Liver Toxicity 
Liver toxicity in the form of abnormal liver enzymes, inflammation of the liver (hepatitis) and liver 
failure have occurred in HIV-infected patients receiving regimens containing dolutegravir. The liver 
toxicity usually occurs in the first few weeks or months of taking anti-HIV medications.  These patients 
were also generally either taking other medications (both HIV treatment and non-HIV treatment) that are 
also known to cause significant liver inflammation and/or allergic reaction, or already had liver problems 
(such as hepatitis B or hepatitis C), or drank too much alcohol or had a combination of these.  Cases of 
liver toxicity have also occurred in patients who do not have these risk factors. 
 
If you/your child have (has) an unanticipated need for hepatitis C virus (HCV) therapy during the conduct 
of the study, the study doctor will discuss specific HCV treatment options with you. In case you/your 
child experience liver toxicity, the study doctor can decide to stop the administration of the study drug in 
order to assure your/your child’s safety.   
 
Other Risks 
There is the risk of serious and/or life threatening side effects when non-study medications are taken with 
the study drug. For your/your child’s safety, you must tell your/your child’s HIV care provider and the 
study doctor or nurse about all medications you take/your child takes before the start of this study and 
also before starting any new medications while you are/your child is on the study. In addition, you must 
tell the study doctor or nurse before you enroll/enrolling your child in any other clinical trials while on 
this study. The use of highly active HIV medications may also be associated with altered fat metabolism 
including increased triglycerides (fatty acid in the blood) and/or increased cholesterol. 
 
Other side effects besides those listed and side effects from taking these drugs together may occur. If any 
unusual symptoms or changes happen, you should call your/your child’s doctor immediately. It is also 
important that while participating in the study, you do not/your child does not take any other prescription 
drugs or over-the-counter medications without first talking to your/your child’s doctor or study nurse. 
 
With any drug for HIV, there is a risk that the virus in your body will become resistant, which means that 
the drug will be less effective or not effective against your HIV.  The risk that taking part in this study 
will cause your HIV to develop resistance to the study drug is unknown and will depend on how well the 
study drug works against your virus and whether instructions are followed for taking the study drug. 


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
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Blood Drawing and Heparin Lock Risks: 
Blood drawing may cause some discomfort, bleeding or bruising where the needle enters the body. A 
small blood clot may form where the needle enters the body or there may be swelling in the area. There is 
a small risk of a minor infection at the blood draw site. Lightheadedness and fainting can also occur when 
a needle enters the body.  
 
ARE THERE RISKS RELATED TO PREGNANCY? 
It is not known if the drug or drug combinations in this study harm fetuses. Tests in pregnant animals do 
not show risk to the mother.  Early results from a large study in Botswana of pregnant women showed a 
possible increased risk of certain types of serious birth defects involving the brain, and spinal cord in 
babies born to women who received dolutegravir at the time of becoming pregnant. No cases of babies 
born with these types of birth defects have been reported among women who started dolutegravir later in 
pregnancy.  
 
If you are/your child is having sex that could lead to pregnancy, you/your child must agree not to become 
pregnant. 
 
Because of the risk involved, you and your partner, or your child and their partner must use two methods 
of birth control that you discuss with the study staff. You must continue to use both methods until two 
weeks after stopping study drug. Options for birth control methods include these listed below:  
• 
Birth control drugs that prevent pregnancy given by pills, shots, placed on the skin (e.g. patch) or 
placed under the skin  
• 
Male or female condoms with or without a cream or gel that kills sperm 
• 
Diaphragm or cervical cap with a cream or gel that kills sperm 
• 
Intrauterine device (IUD) 
 
Some of these are better than others in preventing pregnancy.  You/your child will work with study staff  
to pick the options best for you.  All birth control methods listed above except condoms do not reduce the 
risk of giving HIV to someone else. HIV-infected individuals should use a birth control method that 
includes condoms to keep from giving HIV to someone else. 
If you think you/your child may be pregnant at any time during the study, tell the study staff right away. 
The study staff will talk to you about your/your child’s choices. You/your child will be tested at each 
study visit if it is possible that you/she may be pregnant.  
If you are /your child becomes pregnant while on study, you/she will not be allowed to continue on the 
study drug but will be asked to remain on study and come in for study visits as planned in case of safety 
concerns and so that the doctors can follow your/her pregnancy until your / your child’s baby is born. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
If you / your child take(s) part in this study, the amount of HIV in your / your child’s body may go down 
and your/your child’s immune system may become stronger, but no guarantee can be made. You/your 
child may receive no benefit from being in this study. Information learned from this study may help 
others who have HIV. 
  
WHAT OTHER CHOICES DO I / DOES MY CHILD HAVE BESIDES THIS STUDY? 
Instead of being in this study you have the choice of: 
• 
Treatment with prescription drugs available to you/your child 
• 
Treatment with other experimental drugs, if you/your child qualify(ies)  
• 
No treatment (NOT recommended) 


 
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12 July 2018 
Please talk to your doctor about these and other choices available to you/your child. Your doctor will 
explain the risks and benefits of these choices. 
 
WHAT ABOUT CONFIDENTIALITY? 
(For US Sites Only) 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. With this Certificate, the researchers cannot be forced to disclose information that 
may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. The researchers will use the Certificate to resist any demands for 
information that would identify you, except as explained below. The Certificate cannot be used to resist a 
demand for information from personnel of the United States Government that is used for auditing or 
evaluation of federally funded projects or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA).  
 
People who may review your/your child’s records include the U.S. Food and Drug Administration and 
other U.S., local and international regulatory entities, the Office of Human Research Protections (OHRP), 
the site IRB /EC (insert name of site IRB/EC), the National Institutes of Health, study staff, study 
monitors, drug companies supporting the study, and their designees. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about you or your participation in this research. If an 
insurer, employer, or other person obtains your written consent to receive research information, then the 
researchers may not use the Certificate of Confidentiality to withhold that information. 
 
(For sites outside the U.S.) 
Efforts will be made to keep your personal information confidential. We cannot guarantee absolute 
confidentiality. Your personal information may be disclosed if required by law. Any publication of this 
study will not use your name of identify you personally. 
Your records may be reviewed by the Ministry of Public Health in your country, the FDA and other U.S., 
local and international regulatory entities, the Office of Human Research Protections (OHRP), the NIH, 
(insert name of site) IRB/EC, study staff, study monitors and the drug companies supporting this study. 
 
WHAT ARE THE COSTS TO ME / MY CHILD? 
There are no costs to you/your child for the study drug, study visits or study procedures. However, taking 
part in this study may lead to added costs to you and your insurance company if medical complications 
arise or if your doctor decides extra tests are needed. In some cases, it is possible that your insurance 
company will not pay for these costs because [you are/ your child is] taking part in a research study.  
 
WILL I RECEIVE ANY PAYMENT? 
You will receive $XX for each study visit you attend. If you attend all study visits, you may receive up to 
$XX. 
 
WHAT HAPPENS IF I AM / MY CHILD IS INJURED? 
If you are / your child is injured as a result of being in this study, you / your child will be given immediate 
treatment for your/his/her injuries. The cost for this treatment will 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/your child’s legal rights by signing this consent 
form. 
 
WHAT ARE MY / MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT? 


 
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12 July 2018 
Taking part in this study is completely voluntary. You may choose not to take part/not to allow your child 
to take part in this study or leave this study/take your child out of the study at any time. Your decision 
will not have any impact on your participation in other studies conducted by the NIH and will not result in 
any penalty or loss of benefits to which you are otherwise entitled. We will tell you about new 
information from this or other studies that may affect your health, welfare or willingness to stay in this 
study. If you want the results of the study, let the study staff know. 
 
(For legal guardians, as applicable) 
If your child reaches the legal age of consent during the study [he/she] will be asked to provide 
independent consent at their next visit.   
 
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), Ethics Committee (EC) or other 
organization appropriate for the site 
• 
Telephone number of above   


 
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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 Legal Guardian (print) 
 
       Legal Guardian’s Signature and Date 
 
 
(As appropriate) 
 
 
________________________                        ____________________________________ 
Study Staff Conducting  
                    Study Staff Signature and Date 
 
 
Consent Discussion (print)  
 
 
________________________                        ____________________________________ 
Witness’ Name (print)  
 
        Witness’s Signature and Date 
 
 
 
(As appropriate) 
 
 
__________________________ 
       __________________________________ 
Second Guardian (print) 
   
       Second Guardian’s Signature and Date 
(If required) 
 
 
 
   
 
 


 
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Appendix III 
Sample Consent Form for Participants Enrolling in Stage II  
 
DIVISION OF AIDS 
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS GROUP 
(IMPAACT) 
 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and  
Antiviral Activity of dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 
Infected Infants, Children and Adolescents 
 
Participants Enrolling in STAGE TWO 
P1093 Version 5.0, dated 12 July 2018  
 
SHORT TITLE FOR THE STUDY: Safety and PK of dolutegravir in HIV-1 Infected Children  
 
 
INTRODUCTION 
You are/your child is being asked to take part in this research study because you have /your child has the 
Human Immunodeficiency Virus (HIV), which is the virus that causes AIDS, and because the drugs 
currently available may not keep the amount of HIV in your / your child’s blood low enough or may 
cause side effects too difficult to deal with. 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 to be/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/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 study a new antiretroviral HIV medication called dolutegravir. This drug is a 
type of 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. The study will help find the best 
amount or dose of dolutegravir for infants, children and teenagers, when it is taken on its own as well as 
with other antiretroviral medications. This study will also find out the safety of using this medication in 
infants, children and adolescents and if there are any side effects from the medication. Dolutegravir has 
been tested before in adults and children. The study drug (dolutegravir) is approved for use in children 12 
years and older by the FDA [and/or local regulatory authorities].  
 
WHAT DO I / DOES MY CHILD HAVE TO DO IF I AM / HE / SHE IS IN THIS STUDY? 
If you decide to (allow your child to) enroll in this study, you / your child will be asked to come to the 
clinic at least 10 times over 48 weeks and then every 12 weeks until the end of the study. You / your child 
will be given dolutegravir and you / your child will be asked to take it once or twice a day for the entire 
study, in addition to your / your child’s regular HIV medicines. Dolutegravir is available in three different 
formulations: 1) a film-coated tablet that cannot be crushed or dissolved, 2) a liquid suspension and 3) a 
tablet that can be dissolved in water. You will be given instructions on how to give dolutegravir to your 
child. If your child is between 6 to less than 12 years of age and was prescribed the liquid or dissolvable 
tablet tablets of dolutegravir he/she may be allowed to switch to the film-coated tablet formulation, at a 
later time. The study staff will let you know when your child can switch, if you request to do so. 
 


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
Although the study will provide you/your child with dolutegravir, other antiretrovirals will not be 
provided by the study. 
 
This study will be done in two parts – Stage One and Stage Two. Stage One will enable the doctors to 
find the right dose of study drug for you/your child and then will keep you on that dose to look for any 
side effects that you/your child might experience. In Stage Two the doctors will know the right dose to 
put you/your child on and will look at any side effects that you / your child might experience as well as 
how well the drug is controlling your HIV infection. You/your child will be enrolled into Stage One or 
Stage Two, depending on when you enroll /your child enrolls and your age / the age of your child. This 
consent form is for Stage Two. 
 
In this study there are 7 cohorts in Stage II – enrolling infants, children, and adolescents from 4 weeks to 
less than 18 years of age. Participants who have had their 18th birthday by the entry visit will not be 
enrolled into the study.  
 
Screening: 
If you are interested in taking part / allowing your child to enroll in this study, we will see if you are / 
your child is eligible for the study: 
 
• 
We will ask your / your child’s medical history including questions about your /your child’s 
health and what symptoms, medications, and illnesses you have/your child has had. 
 
• 
We will do a physical exam including height, weight and vital signs (temperature, blood pressure, 
pulse and respiratory rate). Doses may be modified based on the results of the weight.  
 
• 
We will take about 3  teaspoons (11mLs) of blood, to check for the following: 
o The amount of HIV in the blood,  
o The amount of cholesterol and triglycerides (types of fat) in the blood,  
o How well your immune system, liver and kidneys are working,  
o Other routine tests.  
 
You will be given the results of these tests. We will also ask you to provide a urine sample for routine 
tests. Girls and women of childbearing age will also be asked to provide a urine or blood sample to test 
for pregnancy. If you are / your child is engaged in sexual activity that could lead to pregnancy, you / 
your child will be asked to take birth control precautions throughout the study period. 
 
On Study: 
If you are/your child is eligible for this study, you/your child will come to the clinic at least 8 times in 48 
weeks.  Most of the visits will last about 1-2 hours. You/your child will come to the clinic for the first 
study visit within 30 days of the screening visit.  
• 
At each visit, a medical history will be taken and you/your child will have a physical exam. If you 
are/your child is older than 2 years of age, at the enrollment visit and at the week 48 visit, 
you/your child’s stage of sexual development will be determined. For girls/women, this will be 
done by looking at how developed the breasts are. For boys/men, this will be done by measuring 
the size of the testes. Girls and women of childbearing age will also be asked to provide a urine or 
blood sample to test for pregnancy at each visit. 
• 
We will draw blood at each visit. Depending upon your/your child’s age, between 1-5 teaspoons 
(5-17mLs) of blood will be drawn at these visits. You will be informed of results of routine blood 
tests. Some of the blood drawn will be stored and tested to find out how your/your child’s 


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
immune system is affected by the study drug. This testing will be done after the study is over, and 
you will not be given the results of these tests.  
• 
A palatability assessment will be done at Day 10, Week 4 and Week 24 to assess what you/your 
child thinks about the taste of the study drug. 
• 
At two visits (week 4 and week 24), blood samples will be drawn two separate times. At week 12, 
you will only have one blood draw. The amount of blood drawn at the different study visits will 
be less than 1 teaspoon (0.5-1mL) depending on your /your child’s age.  
• 
If the amount of HIV virus in your/your child’s blood increases too much while on this study 
drug, you/your child may be asked to come back to clinic to have your blood drawn to confirm 
the level of HIV in your blood. If the level of HIV virus in your blood is still too high, your study 
doctor may ask you to stop taking the study medicine and to come back to the clinic for another 
visit. As part of this visit, you/your child will have an interim medical history, physical exam and 
approximately 4 teaspoons of blood (14-17mL) will be drawn for testing and storage.  
• 
If you/your child experiences a severe liver reaction or inflammation while on the study, you/your 
child may be asked to come back to clinic to have less than one teaspoon of blood (2mL) drawn 
to check the level of dolutegravir in the blood. Additional testing as part of routine assessments 
for liver inflammation (e.g. checking for viruses that cause liver inflammation) may be performed 
as well.  
 
Long Term Follow-Up 
After you have been on study drug for approximately 48 weeks, you will enter the long term follow-up 
phase of the study. You will be asked to come back into clinic every 12 weeks (every 3 months) for 3 
more years. Most visits will last about 30 minutes.  
• 
At some visits, a medical history will be taken and you/your child will have a physical exam. You 
will also be asked if you have missed taking any of your medications. 
• 
We will draw less than 1 teaspoon of blood (3-4mL) at some visits. You will be informed of 
results of routine blood tests.  
• 
As before, if the amount of HIV virus in your/your child’s blood increases too much while on this 
study drug, you/your child may be asked to come back to clinic to have your blood drawn to 
confirm the level of HIV in your blood (see above).  
 
You/your child must continue to take your/his/her anti-HIV medications during the study as prescribed by 
your/your child’s HIV care provider. If your/your child’s HIV care provider changes your/your child’s 
anti-HIV medications during the study, you/your child can still take the study drug. You/your child will 
be asked questions about taking your/his/her anti-HIV medications and the schedule you take/he/she takes 
them on and if you have/he/she has missed any medications. 
 
If you/your child can become pregnant, we will collect urine or blood to test for pregnancy at each visit. 
We will also ask your child about contraception use. If you think you/if your child thinks she may be 
pregnant at any time during the study, tell the study staff right away.  
 
Blood and Urine Samples 
Some of your / your child’s blood and urine samples will be shipped out of the country to the US for 
specialized tests. These tests will tell the doctors how much study drug is in your / your child’s blood and 
if the study drug is causing any changes in your kidneys.  
 
[For Participants Receiving Granules for suspension only] 
 
 


 
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[If your child is receiving the (granule) liquid he/she will need to switch to the dissolvable tablet. The 
study staff will inform you when your child will need to switch. This is because the company will not be 
making the liquid form of dolutegravir any longer. The study staff will provide instructions on how to 
dispense the dissolvable tablet and on the day you are scheduled to come to the clinic to begin taking the 
dissolvable tablets you will be asked to not give the (granule)liquid dose to your child. The first dose of 
the dissolvable tablet will be given in the clinic. You will be asked to come back to the clinic about 2 
weeks later and will have a palatability assessment and blood drawn to confirm the level of HIV in your 
child’s blood. If you have been on the study for more than 24 weeks at each of these visits, blood samples 
will be drawn at two separate times. The amount of blood drawn will be less than 1 teaspoon (0.5-1mL) 
depending on your /your child’s age.]  
 
 
WHAT DO I / DOES MY CHILD HAVE TO DO IF I AM / HE / SHE BECOMES INFECTED WITH 
TUBERCULOSIS WHILE ON THIS STUDY? 
If you become/your child becomes exposed to Tuberculosis (TB) while on study and requires anti-TB 
treatment that includes Rifampin you/your child will have to increase the dose of dolutegravir from once a 
day to twice a day while taking Rifampin. After you/your child complete(s) treatment with Rifampin, 
you/your child may go back to taking the dolutegravir once a day, depending on what other medications 
you/your child is taking. 
 
You/your child will also be required to return for at least five additional follow-up visits after starting 
Rifampin.  
• 
At each of these visits, a medical history will be taken and you/your child will have a physical 
exam and we will draw approximately 1-3 teaspoons of blood to look at the following: 
o The amount of HIV, cholesterol and triglycerides (types of fat) in your blood 
o How well your immune system, liver and kidneys are working, as well as other routine 
tests 
• 
At each visit you will be asked whether you are taking your medication as instructed. 
• 
You/your child will be asked to come to the clinic to have blood drawn 8 times over 12 hours 
during one visit, approximately 5-10 days after you/ your child started taking anti-TB medication. 
For this visit, you/your child will be asked to fast for 6 hours before your daily dose of study 
medication. 
• 
The study staff will give you more instructions about this. Depending on your/your child’s age, 
up to 13mL (a little more than 4 teaspoons) of blood will be drawn at this visit. 
• 
You will have extra blood draws at two visits. At weeks 4 and 12, you will have two blood draws 
– blood will be drawn once before you take dolutegravir and about 12 hours later.  The amount of 
blood drawn at the different study visits will be less than 1 teaspoon (1mL).  
 
OTHER INFORMATION 
The information collected in this study may be used for other IMPAACT-approved HIV-related research. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
About 300 children and adolescents will take part in this study 
 
HOW LONG WILL I/MY CHILD BE IN THIS STUDY? 
By signing this consent form, you are agreeing to / allow your child to participate in Stage II of the study. 
You/your child will stay in the study for at least 48 weeks. After that time After that time you/your child 
will enter the long-term safety follow-up phase of the study. During this time, you / your child will 
continue to take study-provided dolutegravir and will be asked to come to clinic every 12 weeks for three 
more years. 


 
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12 July 2018 
  
WHY WOULD THE DOCTOR TAKE ME / MY CHILD OFF THE STUDY DRUG / THIS STUDY 
EARLY? 
 
The study doctor may need to take you/your child off the study drug early, without your permission, if: 
 
• 
Continuing the study drug may be harmful to you / your child 
• 
You become / your child becomes pregnant while on study 
The study doctor may need to take you/your child off the study early, without your permission, if: 
• 
You are/ your child is not able to attend the study visits as required by the study 
• 
You need / your child needs a treatment that you / your child may not take while on the study 
• 
You are / your child is not able to take the study drug as required by the study 
• 
If you elect not to attend repeat PK evaluations as part of the study 
 
The study doctor may need to take you/your child off the study early, without your permission, if: 
• 
The study is cancelled by the U.S. Food and Drug Administration (FDA), National Institutes of 
Health (NIH), the Office of Human Research Protections (OHRP), other country specific 
governmental agencies, IMPAACT, the drug company supporting this study (GSK), or the site’s 
Institutional Review Board (IRB) or Ethics Committee (EC). An IRB or EC is a committee that 
watches over the safety and rights of research participants 
 
If your doctor wants you / your child to stop taking the study drug, you/your child will be asked to return 
to the clinic once more, four weeks after your last dose of dolutegravir, to make sure you are/your child is 
continuing to do well. This visit will include a history and physical exam, a blood draw and a review of 
your medical records.  
 
IF MY CHILD HAS TO PERMANENTLY STOP TAKING STUDY-PROVIDED MEDICINE, OR 
ONCE I LEAVE THE STUDY, HOW WOULD THE STUDY MEDICINE BE PROVIDED? 
During the study: 
If you / your child must permanently stop taking study-provided dolutegravir before your/your child’s 
study participation is over, the study staff will discuss other options that may be of benefit to you/your 
child. 
 
After the study: 
Once you / your child leaves the study, if you/they are gaining benefit from the study-provided drug, this 
drug may continue to be provided until it is available to you in your country, but there is no guarantee. 
Study clinicians will work to ensure that you/your child continue to receive appropriate care and 
treatment outside of the study. 
 
WHAT ARE THE RISKS OF THE STUDY? 
The drug 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 this drug. These lists include the more serious 
or common side effects with a known or possible relationship. It is very important that you tell your 
study doctor of any changes in your/your child’s medical condition while taking part in the study. At 
any time during the study, if you believe you are/your child is experiencing any of these side effects, 
you have the right to ask questions on possible and /or known risks. 
Possible Risks Associated with Dolutegravir 
 


 
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12 July 2018 
DTG has been administered to a total of 6004 participants (4814 HIV-infected and 1190 healthy) 
cumulative to 16 July 2017 in ongoing and completed ViiV sponsored and clinical trials ranging from 
Phase I to IIIb and the DTG compassionate use program.   
 
The following side effects have been seen with dolutegravir: 
 
Very Common (expected in about 100 of every 1000 people taking DTG (10%))  
Nausea or feeling sick (mild to moderate) 
Headache (mild to moderate) 
Diarrhea or loose stools 
 
Common (expected in about 10 of every 1000 people taking DTG (1%))  
Cold symptoms like runny nose and sore throat; cough; flu 
Dizziness or feeling light headed 
Trouble sleeping; abnormal dreams 
Rash  
Feeling tired  
High temperature 
Pain in the stomach; vomiting 
Changes in kidney, liver and muscle blood tests 
Ocular icterus (yellowing of the whites of the eyes) 
Itching (pruritus) 
Feelings of deep sadness and unworthiness (depression) 
Flatulence (gas or wind) 
 
Increase in the level of liver enzymes 
Increase in the level of enzymes produced in the muscles (creatinine phosphokinase) 
Anxiety (fear, worry) 
 
Uncommon (expected in about 1 of every 1000 people taking DTG (0.1%))  
Allergic reaction (see below) 
Liver toxicity (see below) 
An inflammatory condition which may develop as the immune system becomes stronger (immune 
reconstitution syndrome or ‘IRIS’ (see below) 
Suicidal thoughts and behaviors (mainly in patients who have had depression or mental health 
problems before) (see below) 
 
Most of the side effects listed above have been mild or moderate, and have not generally stopped HIV-
infected patients treated with dolutegravir from getting on with their lives as normal. 
In one animal study, gastric erosion (irritation of the stomach lining) was seen. This finding has not been 
seen in adults in studies to date. However, if you or your child feels heartburn or stomach pain or has 
vomiting, please contact your/your child’s study doctor. 
 
Other side effects that may show up in blood or urine tests:  
• 
An increase in bilirubin (a pigment from the breakdown of red blood cells) in the blood.  
• 
An increase in the level of creatinine, a waste product in the blood that gets filtered by the kidney 
  
Dolutegravir Hypersensitivity Reaction 


 
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12 July 2018 
Hypersensitivity reactions have also been reported with integrase inhibitors, including dolutegravir, with 
signs and symptoms including general feeling of being sick, skin rash, a high temperature (fever), lack of 
energy (fatigue), swelling sometimes of the face or mouth (angioedema) causing difficulty in breathing, 
blisters or peeling skin, mouth ulcers, conjunctivitis (sore eyes), and muscle or joint aches.  If you/your 
child develop(s) any of these signs and symptoms during the study, contact you/your child’s study doctor 
immediately, who may decide to carry out tests on your/your child’s liver, kidneys or blood. 
 
Mental illness 
Some people with HIV infection occasionally have feelings of depression or may have thoughts of 
hurting or killing themselves (committing suicide). A small number of people being treated with integrase 
inhibitors for HIV infection, including dolutegravir, have had suicidal thoughts and behaviors, 
particularly patients with a prior history of depression or mental health illness. People with HIV and 
taking integrase inhibitors including dolutegravir have also reported depression. 
 
Tell the study doctor if you/your child have a history of mental illness. If you/your child have thoughts of 
hurting or killing yourself or have any other unusual or distressing thoughts or feelings at any time during 
the study, you/your child should tell the study staff or go to the nearest hospital immediately.  
 
Use of Combination Antiretroviral Drugs 
 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, symptoms from other 
infections or certain diseases may occur soon after starting combination anti-HIV treatment but can also 
occur later.  Some of these symptoms may be life threatening.  If you start having new symptoms, or 
notice that existing symptoms are getting worse after starting your antiretroviral therapy, tell your 
healthcare provider right away. 
 
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 
 
Some patients taking combination anti-HIV therapy may develop a bone disease called osteonecrosis 
(death of bone tissue caused by loss of blood supply to the bone).  The length of combination anti-HIV 
therapy, corticosteroid use, drinking alcohol, severe reduction in ability to fight off infection, higher body 
weight, among others, may be risk factors for developing this disease.  Signs of osteonecrosis are joint 
stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement.  If 
you/your child notice any of these symptoms, please inform your doctor. 
 
Liver Toxicity 
Liver toxicity in the form of abnormal liver enzymes, inflammation of the liver (hepatitis) and liver 
failure have occurred in HIV-infected patients receiving regimens containing dolutegravir. The liver 
toxicity usually occurs in the first few weeks or months of taking anti-HIV medications.  These patients 
were also generally either taking other medications (both HIV treatment and non-HIV treatment) that are 
also known to cause significant liver inflammation and/or allergic reaction, or already had liver problems 
(such as hepatitis B or hepatitis C), or drank too much alcohol or had a combination of these.  Cases of 
liver toxicity have also occurred in patients who do not have these risk factors. 
 


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
If you/your child has an unanticipated need for hepatitis C virus (HCV) therapy during the conduct of the 
study, the study doctor will discuss specific HCV treatment options with you. In case you/your child 
experience liver toxicity, the study doctor can decide to stop the administration of the study drug in order 
to assure your/your child’s safety.   
 
Other Risks 
There is the risk of serious and/or life threatening side effects when non-study medications are taken with 
the study drug. For your/your child’s safety, you must tell your/your child’s HIV care provider and the 
study doctor or nurse about all medications you take/your child takes before the start of this study and 
also before starting any new medications while you are/your child is on the study. In addition, you must 
tell the study doctor or nurse before you enroll/enrolling your child in any other clinical trials while on 
this study. 
 
The use of potent antiretroviral drug combinations may also be associated with altered fat metabolism 
including elevated triglycerides (fatty acid in the blood) and/or elevated cholesterol. 
 
Other side effects besides those listed and side effects from taking these drugs together may occur. If any 
unusual symptoms or changes happen, you should call your/your child’s doctor immediately. It is also 
important that while participating in the study, you do not/your child does not take any other prescription 
drugs or over-the-counter medications without first talking to your/your child’s doctor or study nurse. 
With any drug for HIV, there is a risk that the virus in your body will become resistant, which means that 
the drug will be less effective or not effective against your HIV.  The risk that taking part in this study 
will cause your HIV to develop resistance to the study drug is unknown and will depend on how well the 
study drug works against your virus and whether instructions are followed for taking the study drug. 
 
Blood Drawing and Heparin Lock Risks: 
Blood drawing may cause some discomfort, bleeding or bruising where the needle enters the body. A 
small blood clot may form at the site where the needle enters the body or there may be swelling in the 
area. There is a small risk of a minor infection at the blood draw site. Lightheadedness and fainting can 
also occur.  
 
ARE THERE RISKS RELATED TO PREGNANCY? 
It is not known if the drug or drug combinations in this study harm fetuses. Tests in pregnant animals 
do not show risk. Early results from a large study in Botswana of pregnant women showed a possible 
increased risk of certain types of serious birth defects involving the brain, and spinal cord in babies 
born to women who received dolutegravir for HIV treatment at the time of becoming pregnant. No 
cases of babies born with these types of birth defects have been reported among women who started 
dolutegravir later in pregnancy.  
 
If you are/your child is having sex that could lead to pregnancy, you/your child must agree not to become 
pregnant or make a female pregnant. 
 
Because of the risk involved, you and your partner, or your child and their partner, must use two methods 
of birth control that you discuss with the study staff. You must continue to use both methods until two 
weeks after stopping the study drug. Options for birth control methods include these listed below:  
• 
Birth control drugs that prevent pregnancy given by pills, shots, placed on the skin (e.g. patch) or 
placed under the skin  
• 
Male or female condoms with or without a cream or gel that kills sperm 
• 
Diaphragm or cervical cap with a cream or gel that kills sperm 


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
• 
Intrauterine device (IUD) 
Some of these are better than others in preventing pregnancy.  You/your child will work with study staff 
to pick the options best for you.    All birth control methods listed above except condoms do not reduce 
the risk of giving HIV to someone else. HIV-infected individuals should use a birth control method that 
includes condoms to keep from giving HIV to someone else. 
If you think you/your child may be pregnant at any time during the study, tell the study staff right away. 
The study staff will talk to you about your/your child’s choices. You/your child will be tested at each visit 
during the study if it is possible that you/she may be pregnant. If you are /your child becomes pregnant 
while on study, you/she will not be allowed to continue on the study drug but will be asked to remain on 
study and come in for study visits as planned in case of safety concerns and so that the doctors can follow 
your/her pregnancy. 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
If you / your child take(s) part in this study, the amount of HIV in your / your child’s body may go down 
and your/your child’s immune system may become stronger, but no guarantee can be made. You/your 
child may receive no benefit from being in this study. Information learned from this study may help 
others who have HIV. 
  
WHAT OTHER CHOICES DO I/DOES MY CHILD HAVE BESIDES THIS STUDY? 
Instead of being in this study you have the choice of: 
• 
Treatment with prescription drugs available to you/your child 
• 
Treatment with other experimental drugs, if you/your child qualify(ies)  
• 
No treatment (NOT Recommended)   
 
Please talk to your doctor about these and other choices available to you/your child. Your doctor will 
explain the risks and benefits of these choices. 
 
WHAT ABOUT CONFIDENTIALITY? 
(For U.S. sites only) 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. With this Certificate, the researchers cannot be forced to disclose information that 
may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. The researchers will use the Certificate to resist any demands for 
information that would identify you, except as explained below. The Certificate cannot be used to resist a 
demand for information from personnel of the United States Government that is used for auditing or 
evaluation of federally funded projects or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA).  
 
People who may review your/your child’s records include the U.S. Food and Drug Administration and 
other U.S., local, and international regulatory entities, the Office of Human Research Protections 
(OHRP), the site IRB /EC (insert name of site IRB/EC), the National Institutes of Health, study staff, 
study monitors, drug companies supporting the study, and their designees. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about you or your participation in this research. If an 
insurer, employer, or other person obtains your written consent to receive research information, then the 
researchers may not use the Certificate of Confidentiality to withhold that information. 
 
(For sites outside the U.S.) 


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
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Efforts will be made to keep your personal information confidential. We cannot guarantee absolute 
confidentiality. Your personal information may be disclosed if required by law. Any publication of this 
study will not use your name of identify you personally. 
 
Your records may be reviewed by the Ministry of Public Health in your country, the FDA and other US, 
local, and international regulatory entities, the Office of Human Research Protections (OHRP), the NIH, 
(insert name of site) IRB/EC, study staff, study monitors and the drug companies supporting this study. 
 
WHAT ARE THE COSTS TO ME / MY CHILD? 
There are no costs to you/your child for the study drug, study visits or study procedures. However, taking 
part in this study may lead to added costs to you and your insurance company if medical complications 
arise or if your doctor decides extra tests are needed. In some cases it is possible that your insurance 
company will not pay for these costs because you/ your child are taking part in a research study.  
 
WILL I RECEIVE ANY PAYMENT? 
You will receive $XX for each study visit you attend. If you attend all study visits, you may receive up to 
$XX. 
 
WHAT HAPPENS IF I AM / MY CHILD IS INJURED? 
If you are / your child is injured as a result of being in this study, you / your child will be given immediate 
treatment for your/his/her injuries. The cost for this treatment will 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/your child’s legal rights by signing this consent 
form. 
 
WHAT ARE MY / MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary. You may choose not to take part/not to allow your child 
to take part in this study or leave this study/take your child out of the study at any time. Your decision 
will not have any impact on your participation in other studies conducted by the NIH and will not result in 
any penalty or loss of benefits to which you are otherwise entitled. We will tell you about new 
information from this or other studies that may affect your health, welfare or willingness to stay in this 
study. If you want the results of the study, let the study staff know. 
 
(For legal guardians, as applicable) 
If your child reaches the legal age of consent during the study [he/she] will be asked to provide 
independent consent at their next visit.   
 
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 P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
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 Legal Guardian (print) 
 
       Legal Guardian’s Signature and Date 
 
 
(As appropriate) 
 
 
________________________                        ____________________________________ 
Study Staff Conducting  
                    Study Staff Signature and Date 
 
 
Consent Discussion (print)  
 
 
________________________                        ____________________________________ 
Witness’ Name (print)  
 
        Witness’s Signature and Date 
 
 
 
(As appropriate) 
 
 
__________________________ 
       __________________________________ 
Second Guardian (print) 
   
       Second Guardian’s Signature and Date 
(If required) 
 
 
 
   
 
 
 
 


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
Appendix IV 
Sample Informed Consent Form for Specimen Storage and Future Use 
 
DIVISION OF AIDS  
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS 
GROUP (IMPAACT) 
 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and  
Antiviral Activity of dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 
Infected Infants, Children and Adolescents 
 
P1093 Version 5.0, dated 12 July 2018   
 
You have decided to allow your child to join the study named above/You are participating in the study 
named above. As part of the study, you/your child will have blood drawn and urine collected. After these 
samples are tested for the study, there may be some samples that are left over. We call these extra 
samples. The IMPAACT Network would like to keep these extra samples and use them for other research 
in the future. 
 
This form gives information about use of extra samples. Please read it, or have it read to you, and ask any 
questions you may have. After we discuss the information with you, you will record your decisions on use 
of extra samples at the end of the form.  
 
(For legal guardians, as applicable)  
If your child reaches the legal age of consent during the study [he/she] will be asked to provide 
independent consent at their next visit.   
 
1. It is your decision whether or not to allow the extra samples to be used.  
 
You are free to say yes or no, or to change your mind at any time. Your decision will not affect your/your 
child’s participation in the study. If you say no, all extra samples will be destroyed.  
 
2. If you agree, your child’s extra samples will be kept in a repository.  
 
A repository is a secure facility that is used to store samples. The IMPAACT Network repository is in the 
United States. There is no limit on how long the samples will be kept [sites may insert time limits or 
additional site-specific requirements here if required by local authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, the immune system, and other diseases. The research 
may be done in the United States or in other locations.  
 
If you agree, the extra samples could also be used for research that looks at your/your child’s genes.  
 
Any research done with the extra samples must be reviewed and approved by the IMPAACT Network. 
The research must also be approved by an ethics committee. The role of an ethics committee is to review 
the research plan and protect the rights and well-being of the persons whose samples will be used.  
 
4. There is little risk to you/your child.  


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
 
When extra samples are used for research, they are labeled with a code number only. To protect your 
child’s privacy, no names are used. However, information such as age, gender, HIV status, and other 
health information may be linked to the samples. Information on which study ARVs you/your child 
received and you/your child’s immune system responses to the ARVs may also be linked to the samples.  
 
There may be some risks from tests of you/your child’s genes. If others found out the results of these 
tests, they could treat you badly or unfairly. However, this is almost impossible because the results of 
these tests will not be in you/your child’s study records and they will not be given to you. 
 
5. There may be no benefit to you/your child.  
 
The research done with extra samples is not expected to give any information relevant to your child’s 
health. The results will not be given to you and will not be part of your study records.  
 
6. You will not be paid for use of your/your child’s samples. 
 
There is no cost to you for use of your child’s extra samples. The samples will not be sold and you will 
not be paid for use of the samples. It is possible that research done with the samples could lead to a new 
discovery or a new product. If this happens, there is no plan to share any money with you or your child.  
 
7. Information from research using extra samples may be reviewed by groups that oversee the 
research. 
 
These groups include:  
 
• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
• 
Other local, US, and international regulatory entities 
 
The people who do research with the extra samples and the groups listed above are required to make 
efforts to information private and confidential. 
 
The results of research done with extra samples may be presented publicly or published. However, no 
presentation or publication will use your/your child’s name or identify your child personally.  
 
8. If you have any questions, concerns, or problems related to your/your child’s extra samples, use 
these contacts. 
 
• 
If you have questions about use of your/your child’s extra samples, contact:  
[sites insert name and telephone number of investigator or other study staff].  
 
• 
If you later change your mind about use of your/your child’s extra samples, contact:  
[sites insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your/your child’s rights as a research participant, or problems or concerns 
about how your child is being treated in the study, contact:  


 
IMPAACT P1093, Version 5.0 Sample Informed Consent Forms 
12 July 2018 
[sites insert name and telephone number of IRB contact person or other appropriate 
person/organization].  
 
9. Signatures 
 
If you agree to let your/your child’s extra samples be used, please sign or make your mark below. 
 
__________ 
I allow my/my child’s extra samples to be used for research on HIV, the immune system, 
and other diseases. I also allow my child’s samples to be used for tests of his or her 
genes.  
 
__________ 
I allow my/my child’s extra samples to be used for research on HIV, the immune system, 
and other diseases. I do not allow my child’s samples to be used for tests of his or her 
genes.  
 
__________ 
I do not allow my/my child’s extra samples to be used for any research.  
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent’s Name (print) 
 
 
Parent’s Signature 
  
 
Date 
(Or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent’s Name (print) 
 
 
Parent’s Signature 
  
 
Date 
(Or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 
(As appropriate) 
 
 
 

SAP_004.pdf: 
 
 
 
 
Division of AIDS (DAIDS) Pharmacokinetic Statistical Analysis Plan (PK SAP) 
 
 
Protocol Name: IMPAACT P1093 - Phase I/II, Multi-Center, Open-Label Pharmacokinetic, 
Safety, Tolerability and Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination 
Regimens in HIV-1 Infected Infants, Children and Adolescents 
 
PK SAP Version and Date:  Reporting and Analysis Plan for Phase I/II, Multi-Centre, Open-Label 
Pharmacokinetic Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-
1 Infected Infants, Children and Adolescents, dated 08 April 2019 
 
 
 
 
 


 
 
 INTRODUCTION 
The purpose of this RAP is to describe the PK analyses as outlined in the protocol only and will be used for 
submission of results for the Tivicay Pediatric global regulatory submissions. The tables, figures and listings 
of the Primary Statistical Analysis Report as well as those in this RAP will be shared with the industry 
sponsors and contribute to the CSR. This PK SAP covers only the intensive pharmacokinetic assessments and 
analyses conducted in P1093. 
 
STUDY OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
To determine DTG exposure, its 
variability and clinical covariates 
that impact DTG disposition (e.g. 
age, weight) using intensive and 
sparse sampling and population 
PK analysis. 
C24h, AUC0-24 
To evaluate the steady-state 
pharmacokinetics of DTG in 
combination with OBT in 
treatment-experienced and 
treatment-naïve HIV-1 infected 
infants, children and adolescents 
and to determine the dose of DTG 
that achieves the targeted C24h 
and AUC024 PK parameters in this 
population. 
C0, Cmin, Cmax, CL/F, Vz/F and t1/2 
To evaluate the pharmacokinetic 
profile of DTG when dosed by 
weight bands. 
Subgroup analysis for primary and secondary PK endpoints 
by weight band 
 
PHARMACOKINETIC STUDY DESIGN  
The overall safety and PK data of the first 4 participants on a given cohort will be evaluated with 
respect to the safety and guidelines per protocol. If the first 4 evaluable participants of this cohort 
meet both sets of guidelines, then accrual will continue, and no dose adjustments will be made. If the 
first 4 evaluable participants of the older cohort fail either the safety or the PK guidelines in this initial 
test, then the starting dose will be adjusted in the appropriate direction, (upwards for inadequate PK 
values; downwards for safety failure), if this is feasible. Four new participants will be treated at the 
new dose, and an initial evaluation of safety and PK will be made on the basis of data from these 
participants. The evaluation will proceed as described above. In the final assessment of Stage I results, 
the starting dose of a fully accrued cohort (minimum of N = 10) will be evaluated on the basis of safety 


 
 
and PK guidelines. Failure with respect to the safety and/or PK guidelines will result in a dose 
adjustment within this cohort, with the starting dose adjusted in the appropriate direction, if this is 
feasible. New participants will be started on the new dose and evaluations will proceed as described 
above. If the Protocol Team deems a given participant’s PK data to be unevaluable (e.g. because of 
reported non-adherence or PK results that would be physiologically implausible with good adherence), 
that participant will be replaced for dose finding purposes (but will continue in the study and 
contribute to the safety analyses). 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. Once the dose finding procedures of Stage I have been completed for each cohort, the 
Protocol Team will review all safety and PK data and will make final recommendations concerning the 
doses.  These recommendations will be reviewed by the Protocol Team. The purpose of this review 
process will be to take account of all available information in determining whether the dose finding 
algorithm has converged on the best dose for further study in Stage II or whether adjustments are 
needed. As part of this review process, safety and PK data will be broken down on the basis of the 
dosing adjustments that have been made because of the inducing or inhibiting effects of the 
background regimens. If there is evidence that some adjustments may have been associated with 
undesirable PK levels or with safety concerns, these adjustments may be modified for Stage II or 
further data may be gathered prior to opening Stage II. Under Version 5, the Stage I data from Cohorts 
III-DT, IV-DT and V-DT will also be examined by weight band.  If this examination suggests that the dose 
under evaluation is not adequate for a given weight band and should not be used for that weight band 
in Stage II, then a new “weight band group” will be opened to determine an adequate dose for that 
weight band, and this weight band group will be evaluated like an age cohort, as described above. 
Participants accrued to Stage II of the study will be administered the doses determined for their age 
cohorts, with no individual dose adjustments on the basis of PK allowed. For purposes of analysis, data 
from these participants will be combined with the data from the Stage I participants who have been 
treated at the optimal doses determined for their cohorts and who have not required individual PK 
determined dose adjustments, such that their total exposure to the study drug has been at the optimal 
dose.  
 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses 
Evaluated 
Intensive  
Pharmacokinetic  
Concentration  
All enrolled subjects who undergo intensive PK sampling, 
received at least 1 dose of DTG, where samples are 
collected according to the intensive sampling schedule and 
have been analyzed. 
PK  
Intensive  
Pharmacokinetic 
Parameter  
All subjects in the Intensive Pharmacokinetic Concentration 
Population who provide at least one evaluable PK 
parameter and whose samples are not excluded for any 
reason. 
PK 


 
 
Sparse  
Pharmacokinetic  
Concentration 
All enrolled subjects who undergo Sparse PK sampling, 
received at least 1 dose of DTG, where samples are 
collected according to the sparse sampling schedule and 
have been analyzed. 
PK 
Sparse  
Pharmacokinetic  
Parameter 
All subjects in the Sparse Pharmacokinetic Concentration 
Population who provide at least one evaluable PK 
parameter and whose samples are not excluded for any 
reason. 
PK 
Sparse PK analyses will be conducted separately by the sponsor and not covered in this PK SAP 
 
Weight Band and Cohorts 
The following labels for Weight Band will be used on all tabulations where the results are displayed 
by Weight Band, in the following order: 
• 3-<6kg 
• 6-<10kg 
• 10-<14kg 
• 14-<20kg  
• 20-<25kg  
• 25-<35kg  
• ≥35kg 
• Overall 
Note, the initial cohorts were not dosed by these weight bands. In the event that subjects are not 
dosed according to their weight band category they will be grouped according to the weight band 
for the dose they received. 
 
The following labels for Cohort will be used on all tabulations where the results are displayed by 
Weight Band or Age, in the following order: 
Cohort I 
Adolescents ≥ 12 to <18 years of age (tablets) 
Cohort IIA 
Children ≥ 6 to <12 years of age (tablets) 
Cohort IIB 
Children ≥ 6 to <12 years of age (granules for suspension) 
Cohorts III 
Children ≥ 2 to < 6 years of age (granules for suspension)  
Cohort III-DT 
Children ≥ 2 to < 6 years of age (dispersible tablets)  
Cohort IV 
Children ≥ 6 months to < 2 years (granules for suspension 
Cohort IV-DT 
Children ≥ 6 months to < 2years of age (dispersible tablets) 
Cohort V-DT 
Infants ≥ 4 weeks to < 6 months (dispersible tablets) 
 
Formulation 
The following labels for Formulation will be used on all tabulations where the results are displayed 
by Weight Band or Age, in the following order: 
• 
Film Coated Tablets (FCT) and Dispersible Tablets (DT) 
 
 PHARMACOKINETIC ANALYSES 


 
 
All concentration-time samples will be registered in the Lab Data Management System (LDMS) 
database. All PK samples (including intensive and population PK) will be sent to the University of 
Alabama (UAB) Laboratory (see the Laboratory Processing Chart). The study database will be kept 
up to date by close tracking of samples. As part of Stage I, the intensive PK sample assays and 
pharmacokinetic calculations will be performed in real-time and the results will be reported and 
discussed with the Protocol Team.  
 
Steady-state pharmacokinetic parameters will be determined from plasma concentration-time 
profiles using non-compartmental methods (Phoenix WinNonlin 8.0, Certara, Princeton, NJ). 
Calculated pharmacokinetic parameters will be: area-under-the-curve (AUC0-24), maximum plasma 
concentration (Cmax), time to Cmax (Tmax), plasma concentration observed at end of 24 hour dosing 
interval (C24h), plasma concentration observed immediately to dosing of 24 hour dosing interval 
(C0), minimum plasma concentration (Cmin), apparent clearance (CL/F), apparent volume of 
distribution (Vz/F), and terminal half-life (t1/2). AUC0-24 will be determined using the linear-log 
trapezoidal rule. Cmax, Tmax, C0, C24h, and Cmin will be taken directly from the observed concentration-
time data. Intensive PK sampling is conducted between days 5 and 10 after study drug initiation 
and over the course of approximately 24 hours. Sparse population pharmacokinetic evaluation is 
scheduled at Weeks 4, 12 and 24. This will be a separate analysis conducted by the sponsor and not 
covered in this PK SAP.  
 
Derived Pharmacokinetic Parameters for subjects participating in the intensive studies 
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis according 
to current working practices and using the currently supported version of WinNonlin 6.3 or higher. 
All calculations of non-compartmental parameters will be based on actual sampling times. 
Pharmacokinetic parameters listed will be determined from the plasma concentration-time data, as 
data permits. 
 
Parameter 
Parameter Description 
AUC(0-t) 
Area under the concentration-time curve (AUC) from time 0 (predose) to time of 
the last quantifiable concentration, to be calculated using the linear trapezoidal 
rule for each incremental trapezoid and the log trapezoidal rule for each 
decremental trapezoid. 
AUC(0-24) 
Area under the concentration-time curve (AUC) over time 0 (predose) to 24 hours 
after dose administration, to be calculated using the linear trapezoidal rule for 
each incremental trapezoid and the log trapezoidal rule for each decremental 
trapezoid. 
Cmax, Cmin 
C0, and Tmax, 
The maximum observed concentration (Cmax) at steady-state and the time of its 
occurrence during a dosing interval (Tmax) will be obtained directly from the 
observed concentration-time data. The minimum observed concentration at 
steady-state (Cmin) is obtained directly from the observed concentration-time data. 


 
 
The predose concentration at steady state (C0) is obtained directly from the 
observed concentration-time data. 
C24 
The observed concentration at 24 hours after dose administration. 
t½ 
Elimination half-life associated with the terminal slope of a semi logarithmic 
concentration-time curve (ln2), where λz stands for the apparent terminal phase 
elimination rate-constant. The λz will be estimated by linear regression of 
logarithmically transformed concentration versus time data in WinNonLin. A 
minimum number of three data points will be used in calculating λz. Cmax should not 
be included among these data points. As a measure of evaluating the regression 
analysis, R-square values (square of the correlation coefficient) over 0.85 will be 
ideal, although lower R-square values may be acceptable, based on individual 
judgement:  
t½ = ln2 / λz 
λz 
Terminal-phase rate constant. 
Vd/F and 
CL/F 
Vd is the distribution volume that is used as a conversion factor between the total 
amount of the drug in the body and the plasma concentration. The F stands for 
bioavailability, which is not known for each individual because it is variable between 
the children. The apparent clearance (CL/F) will be calculated by dividing the dose 
by the AUC0-12h/24h. Vd/F will be calculated by dividing CL/F by λz. 
Additional parameters may be included as required. 
 
Terminal Slope Estimation 
Data permitting, the terminal slope, λz, of DTG will be determined from the log-linear portion of the 
curve and the terminal half-life (t1/2) calculated as 0.693/λz. The default settings for the analysis 
software will be used to estimate λz when appropriate. Appropriateness of the estimated values will 
be assessed by reviewing the length of sampling time relative to half-life and the goodness of fit line 
through the observed data (adjusted R2). If the adjusted R2 was found to be less than 85% or the 
estimated t1/2 was found to be relatively long compared to the sampling time, a statement 
highlighting that caution should be used in interpreting the t1/2 results will be included in the report. 
In general, at least three consecutive time points in the terminal phase excluding Tmax will be used 
for terminal half-life determination. Oftentimes, depending on the shape of the profile and limited 
pediatric sampling strategy, only two consecutive time points (excluding Tmax) may be used for 
terminal half-life determination, which will be noted in the report. If less than two time points are 
available, then λz, t1/2 and Vz/F will not be calculated or reported. 
 
AUC Values 
DTG AUC0-24h will be determined using the linear up-log down trapezoidal method. 
Pharmacokinetic analyses will be carried out using actual sampling times. AUC0-tau with tau (dosing 
interval) set to 24 hours will be reported as AUC0-24h since these participants are at steady-state. 


 
 
 
Below the Level of Quantification 
Concentrations for PK analyses will be used as supplied by the analytical laboratory. The lower level of 
quantification in the CPQA approved and validated PK assays for DTG and RPV are 5.0 ng/ml and 1.0 
ng/ml, respectively. Concentration values that are below the level of quantification (BLQ) will be 
handled as follows for performing NCA: 
• If a pre-dose concentration is below the limit of assay detection, this value will be set to zero.  
• If a concentration is BLQ after dosing at time zero and before the first measurable concentration, 
this value will be set to zero.  
• Any embedded BLQ value (BLQ value occurring between two quantifiable concentrations) will be 
set to missing.  
• If a concentration at 24h (C24h) is BLQ and λz is estimable, C24h will be estimated. If λz is not 
estimable, then the BLQ C24h will be set to zero. 
• Two or more BLQ values in succession after Cmax (for both DTG and RPV) or BLQ values at the end of 
collection interval (8h and 10h for RPV), the PK profile will be considered non-evaluable and the 
participant either repeats the PK or a new one is enrolled. 
 
The above approach, rather than using half the limit of quantification or some other extrapolated value 
is the most conservative approach when assessing if overall exposure is lower than 
expected/acceptable in the patient population. In data listings, BLQ values will be shown as less than 
the quantification limit, “< [limit]” or BLQ. For summary tables, plots and figures, BLQ values will be set 
at 0.001 (as zero cannot be log-transformed for depiction in logarithmic plots and calculation of 
summary statistics such as geometric mean). If an entire concentration-time profile is BLQ, the profile 
will be reported separately and excluded from the PK analysis.  
 
Profiles with Missing or Unexpected Concentrations 
For profiles with a C24h value higher than the prior post-dose concentration, C24h may be set to the 
value of the pre-dose concentration (C0h) for PK parameter calculations or C24h will be extrapolated to 
24 hours where feasible. If either the C0h or C24h is missing, then one may be used in substitution for 
the other. PK parameter summaries (tables) will use the parameters calculated with the substituted 
values, and this substitution will be noted in any tables and figures. The listings of concentrations, 
descriptive summaries of concentrations, and figures/plots should include the originally observed 
concentration, along with a note on how values were substituted for PK parameter calculations. If the 
NCA PK parameters cannot be estimated from a given participant’s intensive PK samples for any 
reason, intensive PK sampling will be repeated (either in the same participant or in a different 
participant) to achieve the quota per protocol.  
 
Presentation of Data 
Graphical representations of concentration plots by sampling time will use the nominal PK sampling for 
summary results, and actual PK sampling time for individual results. Graphical results of PK parameters 
(i.e., AUC0-24h, Cmax, C24h [Cmin]) by weight band, HIV subtype and/or in comparison to historical data in 
adults may also be generated. Additional graphical representations may also be prepared per 
CMC/SMC request. 


 
 
 
Summary Statistics  
All individual concentrations for the intensive PK evaluations at week 4 and PK parameters from 
intensive PK assessments may include, but are not limited to, the following descriptive statistics: 
number of observations available, geometric mean, geometric standard deviation (geoSD), geometric 
coefficient of variation (geoCV), geometric 95% confidence intervals, arithmetic mean, standard 
deviation (SD), CV, median, interquartile range (IQR), 5th and 95th percentiles, minimum, maximum and 
number of BLQ samples imputed.   
 

Prot_002.pdf: 
Letter of Amendment #1 
Page 1 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
Letter of Amendment #1 for: 
 
IMPAACT P1093 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic Safety, Tolerability and 
Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination 
Regimens in HIV-1 Infected Infants, Children and Adolescents 
 
Version 5.0, dated 12 July 2018 
 
DAIDS Study ID #11773 
IND #110,847 
 
Letter of Amendment Date: 10 June 2020 
 
 
Table of Contents 
 
Information/Instructions to Study Sites from the Division of AIDS ............................................................ 1 
Letter of Amendment Signature Page ........................................................................................................... 2 
Summary of Modifications and Rationale .................................................................................................... 3 
Implementation ............................................................................................................................................. 3 
A. Protocol Team Roster Updates .......................................................................................................... 3 
B. Clarifications and Corrections of Protocol Text from Corrected CM #1, dated 26 September 2018, 
and CM #2, dated 6 January 2019 ..................................................................................................... 4 
C. Operational Guidance from Protocol CM #3, dated 31 March 2020 ................................................ 7 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT P1093 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 other site regulatory entities 
if applicable per the policies and procedures of the regulatory entities. All applicable IRB/EC and 
regulatory entity requirements must be followed. 
 
Upon obtaining all required IRB/EC approvals and any other applicable regulatory entity approvals, each 
site should immediately begin implementing this LoA. Sites are required to submit an LoA registration 
packet to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory Support Center. Sites 
will receive a registration notification for the LoA after the DAIDS PRO verifies that all required 
registration documents have been received and are complete. Sites should not await this notification 
before implementing this LoA.  
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential document files for IMPAACT P1093. If the IMPAACT P1093 
protocol is amended in the future, applicable contents of this LoA will be incorporated into the next 
version of the protocol. 
 
 


Letter of Amendment #1 
Page 2 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
IMPAACT P1093 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic Safety, Tolerability and 
Antiviral Activity of Dolutegravir, a Novel Integrase Inhibitor, in Combination 
Regimens in HIV-1 Infected Infants, Children and Adolescents 
 
DAIDS Study ID #11773 
 
 
Version 5.0, Letter of Amendment #1 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Council 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 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
Summary of Modifications and Rationale 
 
The purpose of this LoA is to update the protocol team roster to reflect current membership and to 
incorporate the contents of previously-issued protocol Clarification Memoranda (CM). 
 
Section A of this LoA includes the protocol team roster updates.  
 
Section B of this LoA includes the corrections and clarifications of protocol text that were included in 
corrected CM #1 (dated 26 September 2018) and CM #2 (dated 6 January 2019).  
 
Section C of this LoA incorporates the contents of CM #3, which was issued on 31 March 2020 to 
safeguard the health and well-being of study participants in the context of circulating SARS-CoV-2 and 
the associated COVID-19 pandemic. CM #3 provided operational flexibility for conducting study visits 
and procedures when needed for participant safety monitoring and to prioritize ongoing access and 
adherence to the study drug regimen. Per the study Sponsor, sites were instructed to implement the 
guidance provided in CM #3 immediately. All sites should continue to follow applicable government, 
health authority, and institutional policies with respect to conduct of study visits and procedures during 
the COVID-19 pandemic, with utmost importance placed on the health and well-being of study 
participants and study staff. Consistent with the instructions provided in CM #3, implementation of 
Section C of this LoA is expected to be time-limited in relation to the COVID-19 pandemic. In 
consultation with IMPAACT Network leadership and the study Sponsor, the IMPAACT P1093 Protocol 
Team will determine when, in the future, the guidance in Section C is no longer applicable. When such a 
determination is made, study sites will be formally notified and instructed to inform IRBs/ECs and other 
applicable regulatory entities. 
 
Implementation 
 
Modifications of protocol text are shown in Sections A and B of this LoA, using strikethrough for 
deletions and bold type for additions where appropriate. Within these sections, modifications are 
generally shown in order of appearance in the protocol. Operational guidance for conducting study visits 
and procedures during the COVID-19 pandemic is provided in Section C of this LoA; conventions for use 
of strikethrough and bolding do not apply in this section. 
 
A. Protocol Team Roster Updates 
 
To reflect current membership, the protocol team roster is updated as follows:  
 
Protocol Statisticians 
Mona Farhad, MS  
Statistical and Data Management Center 
(SDMC)  
Frontier Science Foundation 
1371 Beacon Street, Suite #203 
Brookline, MA 02446, USA  
Phone: 617-632-2000 x4032 
E-mail: mfarhad@sdac.harvard.edu 
 


Letter of Amendment #1 
Page 4 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
Protocol Data Managers 
Mattie Bartlett, MPH 
Frontier Science Foundation  
4033 Maple Road  
Amherst, NY 14226  
Phone: 716-834-0900 x7270  
E-mail: bartlett@frontierscience.org 
 
Yvonne Woolwine-Cunningham 
Frontier Science Foundation  
4033 Maple Road  
Amherst, NY 14226  
Phone: 716-834-0900 x7332 
E-mail: woolwine@frontierscience.org  
 
Laboratory Data Coordinator Manager 
Katelynn Hergott, MPH, MSW  
Kevin Knowles, MA, PhD  
Frontier Science Foundation 
Frontier Science and Technology Research 
Foundation (FSTRF), Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 ext:7238 7212 
E-mail: knowles@frontierscience.org 
hergott@fstrf.org 
 
Protocol Pharmacists 
Shawn Chiambah, PhD, RPh 
Pharmaceutical Affairs Branch, Division of 
AIDS/OCSO/NIAID/NIH 
5601 Fishers Lane 
Room 9A26 MSC 9829 
Rockville, MD 20892-9829 
Phone: 301-761-7336 
E-mail: shawn.chiambah@nih.gov
Laboratory Center Representative 
Dale W. Dayton, RN, BS, CCRA IMPAACT 
Laboratory Center Children’s Hospital Los 
Angeles  
Phone: 301-742-9077  
Email: ddayton@impaactlabcenter.org 
 
Frances Whalen, MPH, MT(ASCP) 
IMPAACT Laboratory Center 
University of California Los Angeles 
11075 Santa Monica Blvd., Suite 200  
Los Angeles, CA 90025  
Phone: 704-422-4055  
E-mail: fwhalen@milabcentral.org 
B. Clarifications and Corrections of Protocol Text from Corrected CM #1, dated 26 September 2018, and 
CM #2, dated 6 January 2019 
 
1. In Sections 2.2, 8.2, and 8.6, the following updates are incorporated to correct inconsistencies in the 
specified timing of safety and tolerability analyses:  
 
Section 2.2, Secondary Objective 5 
To determine the extended long term (≥ > 48 weeks) safety, tolerability and efficacy of DTG in HIV-
1 infected infants, children and adolescents. 
 
Section 8.2.1.1 (section heading) 
Toxicity through Weeks 24 and 48 
 
 


Letter of Amendment #1 
Page 5 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
Section 8.2.3.1 (section heading) 
Toxicity through week 48 and beyond Week 48 
 
Section 8.6.2.1 (section heading) 
Primary Analyses (performed on data through the Week 24 and 48 visits) 
 
Section 8.6.2.2, Key Secondary Analyses, Safety 
Safety assessments will be performed on data collected through Week 48 and long term data. These 
analyses will be similar to the Weeks 24 analyses described in Section 8.6.2.1 above. In addition, 
these analyses will also be performed with participants classified by weight band. 
 
2. In Section 3.1, the following updates are incorporated to clarify screening and enrollment procedures 
for weight-band groups: 
 
• 
Stage 1 Full Cohort and Weight-band Analysis 
 
The study aims to ensure that adequate numbers of participants are enrolled into each of the age-
defined cohorts as well as each of the weight-band groups. To this end, once 10 participants with 
evaluable data are enrolled into a cohort, additional enrollments into that cohort are only 
permitted if a participant will be contributing to achieve the minimum enrollment of 8 evaluable 
in a weight-band group. To ensure continuous enrollment into cohorts during Stage 1, enrollment 
does not close until it has been confirmed that 8 participants with evaluable data have been 
enrolled and completed PK and safety assessments into a weight band. Up to A maximum of an 
additional 2 participants can be enrolled while waiting for determination that the data from 
the minimum of 8 participants in a given weight-band group are evaluable. these results to 
become available. 
 
Participants are enrolled into Stage I weight-band groups based on their weight at 
enrollment. However, if a participant is eligible for a given weight-band group by weight at 
screening but then has a different weight on the day of enrollment that places him/her into a 
different weight-band group, he/she will be allowed to enroll in Stage I, even if the 
minimum accrual targets for that weight-band group have been met. In this case, the 
participant will contribute to the Stage I full cohort and weight-band analysis based on 
weight at enrollment. 
 
3. In Section 6.1.8 and Appendix IG, the following updates are incorporated to clarify the timeline for 
resuming once daily dosing of dolutegravir after discontinuation of rifampin-containing tuberculosis 
treatment: 
 
Section 6.1.8, Management of Participants Co-infected with TB, last bullet, second sentence: 
Approximately two weeks after Upon discontinuation of the rifampin containing anti-TB therapy, 
the participant’s DTG dose will revert back to once daily administration unless on EFV, FPV/r, or 
TPV/r.  
 
Appendix IG, note directly following Schedule of Evaluations, third sentence:  
Approximately two weeks after Upon discontinuation of the rifampin containing anti-TB therapy, 
the participant’s DTG dose will revert back to once daily administration.  
 


Letter of Amendment #1 
Page 6 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
4. In Section 5.2.3, second paragraph and first and second bullets, the following updates are 
incorporated to correct an inconsistency in dispensing procedures for dolutegravir dispersible tablets: 
 
In Stage I and Prior to intensive PK sampling in Stage I, each tablet is to be dispersed using 2 to 5 
mL of water. There are two options for dispensing described below.  
 
• 
Option 1: for older children, pour drinking water into the dosing cup. For 1-2 tablets use 5mL of 
water. For 3-4 tablets use 10mL of water and for 5-6 tablets use 15 of water. For 1-3 tablets use 
5mL of water, for 4-6 tablets use 10mL of water. Add the prescribed number of tablets to the 
water. Swirl the cup gently for 1-2 minutes to fully disperse the tablets. The medicine will be 
cloudy. If any lumps of tablet remain, swirl the cup gently until they are gone. Give Administer 
the prepared dose to the child. Rinse the dosing cup before next use. Pour an additional 5 mL of 
water in the dosing cup, swirl the cup gently for approximately 15 seconds and administer 
the entire volume to the participant. Wash the dosing cup immediately after administration, 
allow to dry and store for the next use. 
 
• 
Option 2: for infants and younger children, prepare medicine in dosing cup as directed in Option 
1. Draw up all the medicine into the syringe. Place the tip of the syringe against the inside of the 
infant’s cheek and administer to give the dose slowly. Swirl Pour an additional a further 2mL 
of water into the dosing cup, draw it into the syringe, and administer the remaining volume 
give it all to the infant. Wash cup and syringe thoroughly. Wash the dosing cup immediately 
after administration, allow to dry and store for the next use 
 
After intensive PK sampling in Stage I and in Stage II each tablet can continue to be dispersed as 
described above or each tablet can be placed directly on the tongue and directly swallowed. 
Dispersible tablets may be given as multiples (up to a maximum of 6 tablets), depending on the 
weight of the child. Once dispersed, the medication should be consumed from administered 
using the supplied dosing cup or syringe, as soon as possible, preferably within 5 five minutes 
but no longer than 30 minutes after preparation.  
 
5. In Appendices IA, IB, IC, ID, and IG, footnote for chemistries, the following updates are incorporated 
to clarifies guidelines for establishing a laboratory normal value for indirect bilirubin: 
 
Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs. 
LFTs should include total bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, AST, 
ALT, and albumin. If indirect bilirubin is not reported by the site laboratory, it should be calculated at 
the site and documented. The following formula can be utilized: indirect bilirubin = total 
bilirubin – direct (or “conjugated”) bilirubin. 
 
The following (listed in order of preference) should be used to determine the upper limit of normal 
(ULN) values for indirect bilirubin.  
a. "ULN" values reported by the laboratory report for the test, or  
b. “ULN" values routinely used/established by the site or 
c. ‘ULN” values as per the most current Harriet Lane Handbook (e.g. the current "ULN" for 
indirect bilirubin as per Harriet Lane Handbook is 0.4) (In the 2018 version of the Harriet Lane 
Handbook, for a full term infant, the ULN for total bilirubin is 1.2 mg/dL (21µmol/L) and 
for direct bilirubin is 0.2 mg/dL (3.4 µmol/L); thus the ULN for indirect bilirubin would be 
1.0 mg/dL (17.6 µmol/L)). 
 


Letter of Amendment #1 
Page 7 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
C. Operational Guidance from Protocol CM #3, dated 31 March 2020 
 
This CM provides operational guidance to study sites from the IMPAACT P1093 Protocol Team. The 
Protocol Team acknowledges that the extent to which site operations may be disrupted by the COVID-
19 pandemic may vary across sites and over time. All sites should follow applicable government, 
health authority, and institutional policies with respect to conduct of study visits and procedures, 
with utmost importance placed on the health and well-being of study participants and study staff. 
Site investigators should continue to follow current protocol specifications for communication with the 
Protocol Team and should contact the team (impaact.teamp1093@fstrf.org) with any questions or 
concerns regarding this CM or management of study participants. 
 
Visit Scheduling 
• 
Sites that anticipate operational disruptions or closures in the near future are advised to conduct study 
visits early in the allowable visit window. Visits conducted prior to opening of the allowable window 
would also be preferred to completely missing a visit. 
• 
Sites that are currently experiencing operational disruptions or closures are advised to conduct 
study visits late in the allowable visit window. Visits conducted after closing of the allowable 
window would also be preferred to completely missing a visit. 
• 
Effective with the issuance of this CM, allowable windows are broadened as follows: 
 
Appendices IA, IB, IC and ID (All Cohorts, Stage I and Stage II) 
- 
Weeks 4, 8, 12 and 16 Visits: ±2 weeks 
- 
Week 24 Visit -6 to +4 weeks 
- 
Weeks 32 and 40 Visits: ±4 weeks 
- 
Week 48 Visit -4 to +6 weeks 
 
Appendix IE (Long-Term Follow-up) 
- 
Week 60 through Week 180 ±6 weeks 
- 
Week 192 Visit -6 to +12 weeks 
 
Appendix IF (Premature Discontinuation of Dolutegravir) 
- 
Week 4 Follow-Up Visit: -2 to +4 weeks 
- 
Every three months until resolved (if applicable): ±6 weeks 
 
Appendix IG (Participants who Start Rifampin) 
- Week 2 Visit ±2 weeks 
- Week 4 Visit -2 to +4 weeks 
- Week 12 and Every 8 weeks until end of rifampin therapy Visits: ±4 weeks 
 
Prioritization of Study Visit Procedures 
• 
Sites with full capacity to conduct study visits in-person at the study clinic should continue to do so 
in full compliance with the protocol. 
• 
Sites may also conduct study visits — in full or in part — off-site if permitted by applicable 
government, health authority, and institutional policies. Where this option is permitted, site 
staff should communicate with the parent/legal guardians to determine in advance where and 
when such visits will take place, with adequate protections for safety, privacy, and 
confidentiality. Off-site visit procedures should be conducted by site staff who are 
adequately qualified and trained to conduct the procedures, as determined by the site 
Investigator of Record (IoR), with attention paid to occupational health, biohazard 
containment, and specimen and data chain of custody. These staff should also be adequately 
qualified and trained to immediately assess and/or manage any adverse events or social 


Letter of Amendment #1 
Page 8 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
impacts that may occur during the visits. If adverse events requiring further evaluation or 
management are identified during an off-site visit, staff conducting the visit should arrange 
for appropriate clinical management, in consultation with the IoR or designee as needed. 
• 
Sites with limited capacity to conduct in-person scheduled study visits should prioritize 
monitoring for adverse events and provision of study drug. With respect to specimen testing and 
storage, sites should follow the priority listing in the relevant Schedules of Evaluations. At sites 
where specimen collection and processing can be performed per the Laboratory Processing Chart, 
but HIV-1 RNA testing cannot be performed in real time, sites may collect, process, and store 
specimens for later testing (alternate laboratories must adhere to local regulations for clinical 
laboratory testing). 
• 
Sites with no capacity to conduct in-person visits, either on-site or off-site, should consider whether 
any study procedures (e.g., history taking, adherence assessment) can be performed remotely (e.g., 
by telephone). If adverse events requiring further evaluation or management are identified during a 
remote contact, staff conducting the contact should arrange for appropriate clinical management, in 
consultation with the IoR or designee as needed. 
 
Study Drug Supply 
• 
To avoid gaps in drug supply between visits, sites may dispense up to three months’ supply of study 
drug, ensuring safety monitoring and addressing potential needs for dose modification due to weight 
gain. Further considerations are as follows: 
- 
Participants who have been dispensed an extra supply of study drug should still come for 
their scheduled visits, if possible. 
- 
If a participant is expected to grow into a higher weight band requiring a dose increase soon, 
sites should ensure accurate contact information with the family; if an in-person visit is not 
possible, study drug dose modifications may be implemented with dosing instructions provided 
to the participant’s caregiver by telephone based on weight reported by the caregiver. Any such 
instruction should be source documented in the participant’s study chart. 
- 
Sites should also make every effort to ensure adequate supplies of the other antiretroviral 
agents that comprise participants’ optimized background treatment regimens. 
• 
Where feasible, sites are encouraged to implement study drug delivery options involving outdoor 
pick- up or drop-off. Where outdoor pick-up or drop-off is not feasible, the Pharmacy Guidelines 
and Instructions for DAIDS Clinical Trials Networks permit shipment or courier of study drug from 
the site directly to participants. This method should only be used in the short-term and if permissible 
per local institutional and IRB/EC policies. Refer to the Guidelines for additional details on this 
method. 
• 
Sites are encouraged to provide adherence assessment, counseling, and support remotely (e.g., 
by telephone). 
 
Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in 
essential document files for IMPAACT P1093. 
• 
Documentation should be entered in participant study charts in real-time should any of the 
following occur: 
- Missed visits 
- Out-of-window visits 
- Off-site visits (document the location of the visit) 
- Incomplete or partial visits (document which procedures were performed and which were not) 
- Remote contacts performed in lieu of in-person visits (document method used to complete 
the contact and which procedures were performed) 
- Any other participant contacts 


Letter of Amendment #1 
Page 9 of 9 
10 June 2020 
IMPAACT P1093 Protocol Version 5.0 
- Use of alternate laboratories or alternate laboratory assays 
- Alternate provision of study drug 
- Dose modifications implemented remotely 
• 
In consultation with the Division of AIDS, the IMPAACT Network is developing comprehensive 
guidance for documenting and/or reporting protocol deviations that may occur due to limited site 
capacity to conduct study visits or procedures during the COVID-19 pandemic. Similar guidance 
will be provided for documentation of use of alternate laboratories or alternate laboratory assays. 
Once this Network-level guidance is available, it will be provided in a separate communication to 
all sites. 
 

SAP_003.pdf: 
 
 
  
IMPAACT P1093 
 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, 
Tolerability and Antiviral Activity of Dolutegravir, a Novel 
Integrase Inhibitor, in Combination Regimens in 
HIV-1 Infected Infants, Children and Adolescents 
 
 
 
Pharmaceutical Support Provided by: GlaxoSmithKline 
 
NCT01302847 
IND#110,847 Held by NIAID 
DAIDS ES# 11773 
EudraCT# 2010-020988-20 
 
 
Statistical Analysis Plan 
(For Protocol Version 5, Letter of Amendment #1) 
 
Version 4.0 
 
April 22, 2021 
 
 
 
This is IMPAACT P1093 SAP Version 4.0 with the names of authors and names of publication writing 
team members redacted 
 
 
 
 
 
 


P1093 SAP Version 4.0   
 
 
 
 
 
 
 
April 22, 2021 
 
 
 
 
 
 
Page 1 of 20 
 
 
 
Table of Contents 
1. 
Introduction ......................................................................................................................................... 2 
1.1 
Purpose ......................................................................................................................................... 2 
1.2 
Key Updates .................................................................................................................................. 2 
2. 
Protocol Overview ................................................................................................................................ 3 
2.1 
Study Design ................................................................................................................................. 3 
2.2 
Hypothesis .................................................................................................................................... 5 
2.3 
Study Objectives and Outcome Measures .................................................................................... 5 
2.3.1 
Primary Objectives and Outcome Measures ........................................................................ 5 
2.3.2 
Secondary Objectives and Outcome Measures .................................................................... 5 
3. 
Definitions ............................................................................................................................................ 6 
3.1 Baseline .............................................................................................................................................. 6 
3.2 Analysis Populations........................................................................................................................... 7 
4. 
Statistical Methods .............................................................................................................................. 8 
4.1 General Considerations .......................................................................................................................... 8 
4.2 Visits and Evaluation Schedule ........................................................................................................... 8 
4.3 Analyses of outcome measures ......................................................................................................... 9 
4.3.1 Primary safety outcome.............................................................................................................. 9 
Safety Analyses .................................................................................................................................. 10 
4.3.2 Secondary Outcome Measures ................................................................................................. 11 
5. 
Core Manuscript Writing Team .......................................................................................................... 13 
6. 
Protocol History .................................................................................................................................. 13 
7. 
Appendix ............................................................................................................................................ 17 
7.1 Snapshot Approach – Detailed Algorithm Steps .............................................................................. 17 
7.2 SAP Version History .......................................................................................................................... 21 
 
 


P1093 SAP Version 4.0   
 
 
 
 
 
 
 
April 22, 2021 
 
 
 
 
 
 
Page 2 of 20 
 
 
1. Introduction 
1.1 Purpose 
This Primary Statistical Analysis Plan (SAP) describes the primary and secondary outcomes measures 
of P1093 that will be included in the primary manuscript, and which address the primary and 
secondary objectives of the study, focusing on analyses that address objectives for key safety, 
tolerability and efficacy outcome measures. The Primary SAP outlines the general statistical 
approaches that will be used in the analysis. It has been developed to facilitate discussion of the 
statistical analysis components among the study team, and to provide agreement between the 
study team and statisticians regarding the statistical analyses to be performed and presented in the 
primary statistical analysis report. It also describes the results for the primary and secondary 
outcome measures that will be posted on ClinicalTrials.gov. Detailed outlines of tables, figures, and 
coding descriptions that will be included in the Primary Statistical Analysis Report are included in 
the Analysis Implementation Plan (AIP). It is recognized that this statistical analysis plan (SAP) may 
be modified by the Study Team as new 
information becomes available or to reflect 
recommendations made by the SMC, if there are any. 
 
It is noted here that all PK analyses will be done by the study pharmacologist who will draft a separate 
PK analysis plan. 
 
Data for the Primary Statistical Analysis Report will be downloaded once the last participant of the 
last cohort has completed the Week 48 study visit, all queries have been resolved, and the database 
frozen for analysis. 
The Primary Statistical Analysis Report will be used for submission of results to ClinicalTrials.gov. 
Results for primary outcomes are required to be submitted within one year of the primary 
completion date (PCD), which is the date the last participant is examined for the purposes of data 
collection for the primary outcome measure. For this study, the PCD is based on 48 weeks of 
treatment. A second submission to ClinicalTrials.gov will be done within one year after the last 
participant reaches Week 192 (the last week for long-term follow-up), at which time point the 
adverse event tables will be updated. 
The tables, figures and listings of this Primary Statistical Analysis Report will be shared with the 
industry sponsors. 
The SAP also includes analysis components that mainly support regulatory submission works as well 
as secondary manuscripts 
 
Key Updates 
 
Additional analyses will be done to present results by enrollment weight band 
Name conventions for the Analysis populations were updated. 
 
Added secondary virologic failure (VF) population and the corresponding data 


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summaries for the population. 
 
 
Additional ad-hoc analyses (listing) assessing the impact of COVID-19 will be performed and the 
details will be included in the AIP. 
Regulatory submission request: added the secondary analysis component of table summaries 
of emergent toxicities as well as figures summarizing laboratory test results and changes of 
these results over time (GSK/ViiV responsibilities) 
 
 
  
2. Protocol Overview 
2.1 Study Design 
 
P1093 is a Phase I/II multi-center, open-label, non-comparative study of pharmacokinetic (PK) 
parameters, safety, tolerability, and efficacy of DTG in pediatric populations. Formulations will be 
evaluated with up to 300 HIV-infected infants, children and adolescents aged ≥ 4 weeks to < 18 years 
of age to be enrolled in the age-specific cohorts specified below: 
 
Cohort I: 
Adolescents ≥ 12 to <18 years of age (film-coated tablets) 
Cohort IIA: 
Children ≥ 6 to <12 years of age (film-coated tablets) 
Cohort IIB: 
Children ≥ 6 to <12 years of age (granules for suspension or dispersible tablets) 
Cohorts III: 
Children ≥ 2 to < 6 years of age (granules for suspension) 
Cohort III-DT:  Children ≥ 2 to < 6 years of age (dispersible tablets) 
Cohort IV: 
Children ≥ 6 months to < 2 years (granules for suspension) 
Cohort IV-DT: 
Children ≥ 6 months to < 2 years of age (dispersible tablets) 
Cohort V-DT: 
Infants ≥ 4 weeks to < 6 months (dispersible tablets) 
 
Participants receiving the film-coated tablet formulation were initially enrolled sequentially into 
Cohorts I and IIA. Granules for suspension were introduced in Protocol Version 3.0. When it 
subsequently became clear that dispersible tablets (DT) would be the commercially available pediatric 
formulation, new cohorts for DT were opened in Protocol Version 4.0. Under protocol Version 5.0, two 
formulations of DTG (film-coated tablets and dispersible tablets) will be evaluated; the target 
enrollment in Stage I was increased to allow for additional examination of PK, safety, and tolerability 
by enrollment weight bands, including participants from all of Cohorts III-DT, IV-DT, and V-DT. The 
approach for currently open cohorts III, IV and V is described below. However, additional cohorts and 
weight-band groups might be opened or reopened to investigate data gaps or new modifications to 
dosing, for example, regarding fasting requirements or background regimens. 
 
The fundamental procedure for evaluation of DTG doses has remained unchanged through all protocol 
versions. Each cohort is enrolled in two sequential stages: Stage I and II. (The only exception is Cohort 
IIB which only enrolled through Stage I). In Stage I, participants undergo intensive PK sampling and are 
monitored for the safety and tolerability of DTG; to accept or reject a dose, the Protocol Team 
evaluates PK parameters exposures and 4-week safety and tolerability data. Once a treatment dose 
has been accepted, enrollment to Stage II begins to complete the cohort. Participants in Stage II will be 
followed for 48-weeks and evaluated for PK parameters (using population PK methods), safety and 


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tolerability. After study week 48 all Stage I and Stage II participants will transition to long-term follow-
up and remain on study for approximately three additional years (144 additional weeks of follow- up, 
for a total of 192 on study). Study drug is provided for the duration of the study. Thereafter, 
participants are transitioned into care outside of the study. 
 
Under Version 5, only Cohorts III-DT, IV-DT, and V-DT are open for accrual, and enrollment continues 
until a minimum of 10 participants in each cohort AND a minimum of 8 participants in each of the 
weight band groups below, are enrolled: 
a) 3 to < 6 kg 
b) 6 to < 10 kg 
c) 10 to < 14 kg 
d) 14 to < 20 kg 
When the PK parameters and safety are determined acceptable among participants enrolled in Stage I, 
additional participants will be enrolled to Stage II (if necessary) to achieve a minimum of 22 
participants per cohort receiving the acceptable dose for long-term safety evaluation. 
 
Under previous versions of the protocol, enrollment begun for Cohort I and progressed to Cohort IIA 
once a preliminary dose of GSK1349572 for Cohort I had been determined based upon successfully 
meeting the PK and 4 week safety criteria in Stage I. Then, Cohort IIB started to enroll when Cohort IIA 
Stage I participants’ PK and Week 4 safety data passed the criteria. Sequential enrollment for Cohorts 
III and IV proceeded in the same manner. Cohort V never enrolled because of the recommended 
changes in dosing and inclusion of enrollment weight band in the criteria for dose-finding. 
 
For the dose-finding stage of this study, the data from Stage I of this study is analyzed in three steps, a 
mini-cohort analysis, an interim cohort analysis, and the full cohort/enrollment weight band group 
analysis (Section 3.1 of the protocol). 
 
For the mini-cohort analysis, the overall safety and PK data of the first 4 participants with evaluable 
data in a given cohort will be evaluated with respect to the safety guidelines, per Section 8.5 and the 
PK guidelines, per Section 9.3 of the protocol. 
 
The interim cohort analysis occurs when there are 10 participants with evaluable data in an age 
cohort. Data will be evaluated, and safety guidelines, per Section 8.5 and the PK guidelines, per 
Section 9.3 of the protocol. 
 
For the full Stage I cohort and enrollment weight band group analysis, the starting dose of fully 
accrued cohorts are evaluated by both cohort and enrollment weight band group on the basis of 4-
week safety (as per Section 8.5) and intensive PK data (as per Section 9.3). As of Version 5.0, the full 
analysis of Stage I data for Cohorts III-DT, IV-DT and V-DT occurs when all cohorts and enrollment 
weight band groups have met minimum enrollment targets and achieved 4-weeks of follow up (See 
Section 3.1 for more details). 
 
Participants accrued to Stage II of the study will be administered the doses determined for their age 
cohorts, with no individual dose adjustments based on PK allowed. For purposes of analysis, data from 
these participants will be combined with the data from the Stage I participants who have been treated 
at the doses accepted for their cohorts and enrollment weight bands and who have not required 


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individual PK-determined dose adjustments, such that their total exposure to the study drug has been 
at the accepted dose. Sensitivity analyses will be performed to determine whether the exclusion of 
participants whose doses have been adjusted creates a selection bias which impacts upon any results. 
 
Please note that the results of these dose-finding analyses will also be presented in the planned 
Primary Statistical Analysis Report mentioned above. 
 
2.2 Hypothesis 
 
DTG will be generally well tolerated and demonstrate an acceptable safety profile, adequate PK and 
antiviral activity when used concurrently with an optimized background therapy (OBT) in HIV-1 
infected infants, children and adolescents. 
 
 
2.3 Study Objectives and Outcome Measures 
2.3.1 
Primary Objectives and Outcome Measures 
 
Primary Objectives 
• 
To select a dose for each formulation of DTG for chronic dosing in infants, children and 
adolescents that achieves similar exposure to the DTG 50 mg once daily adult dose. 
 
• 
To determine the safety and tolerability of DTG in HIV-1 infected infants, children and adolescents 
at 24 and 48 weeks. 
 
• 
To evaluate the steady-state pharmacokinetics of DTG in combination with OBT in treatment-
experienced and treatment-naïve HIV-1 infected infants, children and adolescents and to 
determine the dose of DTG that achieves the targeted C24h and AUC0-24 PK parameters in this 
population. 
 
Primary Outcomes 
• 
Toxicity through Weeks 24 and 48 
o All adverse events or lab toxicities of Grade 3 or higher severity 
o Adverse events or lab toxicities of Grade 3 or higher severity judged to be at least 
possibly attributable to the study medication 
o Termination from treatment due to a drug-related adverse event 
o Death 
• Primary Response Variables (to be handled by the pharmacologist’s analyses) 
o Pharmacokinetics: C24h, AUC0-24 
 
 
2.3.2 
 Secondary Objectives and Outcome Measures 
 
 
Secondary Objectives 
• 
To evaluate the antiviral activity of DTG in combination with an OBT by measuring virologic 


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response in infants, children and adolescents at 24 and 48 weeks. 
 
• 
To evaluate the effect on immunologic response from baseline to 24 and 48 weeks. 
 
• 
To assess changes in HIV-1 genotype and phenotype to DTG and other components of the OBT in 
participants experiencing virologic failure. 
 
 
• 
To determine DTG exposure, its variability and clinical covariates that impact DTG disposition (e.g. 
age, weight) using intensive and sparse sampling and population PK analysis. 
 
• 
To determine the extended long term (>48 weeks) safety, tolerability and efficacy of DTG in HIV-1 
infected infants, children and adolescents. 
 
• 
To explore the relationship between DTG exposure and the antiviral activity. 
 
• 
To evaluate pharmacokinetic, safety and tolerability profile of DTG when dosed by weight bands. 
 
 
Secondary Outcome Measures 
 
• 
Toxicity beyond Week 48 - aggregated, by cohort, by enrollment weight band: 
o All adverse events or lab toxicities of grade 3 or higher severity. 
o Adverse events or lab toxicities of grade 3 or higher severity judged to be at least 
possibly attributable to the study medication. 
o Termination from treatment due to a drug-related adverse event. 
o Death 
 
• 
Plasma HIV-1 RNA (copies/mL) <400 copies/mL and <50 copies/mL- aggregated, by 
cohort, by enrollment weight band 
 
• 
Pharmacokinetics (to be handled by the pharmacologist’s analyses) 
o AUC0-24, C24h, C0, Cmin, Cmax, CL/F, Vz/F and t1/2 
 
• 
Secondary response variables - aggregated, by cohort, by weight band 
o CD4/8 counts and percent 
o Genotypic and phenotypic measures of resistance at baseline and at virologic 
failure 
o Disease progression as measured by change in CDC category
 
 
3. Definitions 
3.1 Baseline 
For all endpoints (unless otherwise stated) the baseline value will be the latest pre-dose assessment 
with a non-missing value, including those from unscheduled visits. If time is not collected, Day 1 


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assessments are assumed to be taken prior to first dose and used as baseline.  
 
Unless otherwise stated, if baseline data are missing, no derivation will be performed and baseline will 
be set to missing. 
 
3.2 Analysis Populations 
 
 The analysis populations are updated as follows (for name conventions as well as relevance): 
 
Safety Evaluable Population (definition per protocol for scientific analysis/report) 
 
Participants who have taken at least 1 dose of DTG and were deemed safety evaluable by the Protocol 
 
Team. In the primary scientific analysis, the safety population will exclude Stage I participants whose 
doses have been adjusted for inadequate PK. Stage I participants who have been removed from 
treatment due to toxicities while on the optimal dose will be included and treated as safety failures in 
the primary safety analysis. However, there are participants who might have been removed from PK 
analyses for reasons other than inadequate PK and who will still be included in the safety population 
in all analyses. 
 
Safety Population (for the week 48 regulatory submission) 
Participants who have taken at least 1 dose of DTG and were deemed safety evaluable by the Protocol 
Team. 
 
Intent-To-Treat Exposed (ITT-E) Population (to replace All Treated Population or Efficacy Population) 
All participants who were enrolled and have taken at least 1 dose of DTG. 
 
Proposed Dose (PD) ITT-E Population: Participants whose exposure to DTG (ITT-E) has been based on 
the dose identified for the 2019 submission dossier, plus all additional participants enrolled into 
P1093 through Feb 2020. 
 
Proposed Dose Safety Population (= Proposed Dose ITT-E Population) 
 
Virological Failure (VF) Population (per protocol v5.0, section 6.5) 
• 
A confirmed decrease in HIV RNA of < 1.0 log10 at or after week 12 unless the HIV RNA 
is < 400 copies/mL; 
• 
A confirmed HIV RNA > 400 copies/mL starting at Week 24 or beyond on 2 consecutive 
measurements at least 1 week and within 4 weeks apart 
Virologic REBOUND is also considered as virological failure and is defined as: 
• Confirmed HIV-1 RNA > 400 copies/mL (on 2 consecutive measurements at least 1 week 
apart) after an initial confirmed response (on 2 consecutive measurements at least 1 week 
apart) of HIV-1 RNA < 400 copies/mL; 
• Confirmed > 1.0 log10 increase in HIV-1 RNA above nadir level (on 2 consecutive 
measurements at least 1 week apart). For the purposes of this study, nadir is defined as the 
lowest HIV-1 RNA while on study drug that is > 400 copies/mL. 
 
 


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4. Statistical Methods 
4.1 General Considerations 
For the week 48 analyses, the primary analyses will be based on the main analysis populations defined 
in Section 3.2. In particular, the safety, ITT-E and Proposed Dose (ITT-E or safety) populations. 
Sensitive and secondary analyses will be performed based on the subsets of main analysis populations 
and virological failure populations. 
 
 
4.2 Visits and Evaluation Schedule 
 
Entry of participants occurs within 30 days of screening. Intensive PKs occur at Day 5-10 or Week 2 
 
(+/- 3 days). Thereafter, participants will have scheduled visits at Weeks 4, 8, 12, 16, 24, 32, 40 and 48. 
Participants who successfully complete 48 weeks of DTG treatment will continue on the study in long-
term follow-up and will be seen in clinic every 12 weeks for approximately 3 additional years (192 
weeks total). Further follow-up data to 240 weeks or beyond may be collected for those stay on study 
past 3 additional years 
 
First dose date is considered as Day 1. STUDY DAY of assessment will be calculated as (Visit Date of 
Interest – First Dose Date +1). The nominal TARGET STUDY DAY of WINDOW for week is (7*week) + 1. 
 
The week windows for all analyses, other than the analyses involving CD4/CD8 counts and 
percentages, will be as follows: 
 
Study Day of Assessment 
Assessment 
Window 
Target Study Day of Window 
-30 to 1 
Week 0 
1 
2 to 21 
Week 2 
15 
22 to 42 
Week 4 
29 
43 to 70 
Week 8 
57 
71 to 98 
Week 12 
85 
99 to 126 
Week 16 
113 
127 to 210 
Week 24 
169 
211 to 252 
Week 32 
225 
253 to 294 
Week 40 
281 
295 to 378 
Week 48 
337 
379 to 462 
Week 60 
421 
463 to 546 
Week 72 
505 
547 to 630 
Week 84 
589 
631 to 714 
Week 96 
673 
715 to 798 
Week 108 
757 
799 to 882 
Week 120 
841 
883 to 966 
Week 132 
925 


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Study Day of Assessment 
Assessment 
Window 
Target Study Day of Window 
967 to 1050 
Week 144 
1009 
1051 to 1134  
Week 156 
1093 
1135 to 1218 
Week 168 
1177 
1219 to 1302 
Week 180 
1261 
1303 to 1386 
Week 192 
1345 
1387 to 1470 
Week 204 
1428 
1471 to 1554 
Week 216 
1512 
1555 to 1638 
       Week 228 
1596 
1639 to 1722 
Week 240  
1680 
> (Study Day of last dose + 1) 
Follow-up 
Study Day of last dose + 28 
 
 
 
For CD4/CD8 count and percent analyses, the following week windows will be used: 
 
Study Day of Assessment 
Assessment 
Window 
Target Study Day of Window 
-3 to 1 
Week 0 
1 
2 to 126 
Week 12 
85 
127 to 210 
Week 24 
169 
211 to 252 
Week 32 
225 
253 to 294 
Week 40 
281 
295 to 378 
Week 48 
337 
> (Study Day of last dose + 1) 
Follow-up 
Study Day of last dose + 28 
 
For the purposes of analysis, visit windows will be formed around each study visit using the midpoints 
between adjacent weeks as cutoffs. A window around a target Study Day will typically include all days 
from the midpoints between it and the target Study Days of the previous and the proceeding visits. If 
there are multiple evaluations within the analysis window for a given visit, the evaluation closest to 
the TARGET STUDY DAY of window, and the earlier measurement will be used if there are two 
measurements which are equally distant from the said target. 
 
 
4.3 Analyses of outcome measures 
4.3.1 Primary safety outcome 
 
Purpose: to address whether DTG is safe among HIV-infected infants, children and adolescents aged 
≥ 4 weeks to < 18 years of age. 
 
 


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Primary Safety Outcome Measures (presented in aggregate and by age cohort and enrollment weight 
band) 
• 
All toxicity through Weeks 24 and 48 
o All adverse events or lab toxicities of Grade 3 or higher severity 
o Adverse events or lab toxicities of Grade 3 or higher severity judged to be at least possibly 
attributable to the study medication 
o Termination from treatment due to a drug-related adverse event 
o Death 
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading 
Table), Version 1.0, December 2004, Clarification August 2009, will be used to grade all adverse 
events except for psychiatric events listed in Table 13 under Section 7.3 of the protocol, Version 5. 
The DAIDS AE Grading Table is available on the RSC website at http://rsc.tech-res.com/clinical-
research-sites/safety-reporting. 
 
 
Safety Analyses 
  
Safety analysis for the regulatory submission will include all participants from the safety population as 
defined in Section 3.2. 
 
In addition, the safety analysis for the scientific report will include participants from the safety 
evaluable population. Sensitivity analyses will be performed to determine whether the exclusion of 
participants whose doses have been adjusted creates a selection bias which impacts upon any results. 
 
A subgroup analysis will be performed on participants in the Proposed Dose safety Population 
 
Each participant’s safety data will be summarized as: the worst grade of adverse event experienced 
during the first 24 weeks or 48 weeks of exposure to the study drug and the worst grade of adverse 
event judged to be at least possibly due to study drug during this time period. 
 
Frequency distributions of the safety outcomes mentioned above will be presented in the aggregate 
and broken down by age cohort and by enrollment weight band. 
 
Listings of all Grade 3+ events, will be provided, broken down by type of toxicity (hepatic, 
hematologic, etc.). 
 
The proportions of participants experiencing Grade 3+ adverse events will be presented in aggregate 
and broken down by age cohort and enrollment weight band, with these proportions bounded by 
exact 95% confidence intervals. 
 
Similar analyses will present the proportions of participants exhibiting Grade 3+ events which have 
been judged to be at least possibly related to study medication, again bounded by exact 95% 
confidence intervals. 
 
 


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4.3.2 Secondary Outcome Measures 
 
Secondary Outcome Measures (presented in aggregate, by cohort, and by enrollment weight band) 
• 
All toxicity beyond Week 48 
o All adverse events or lab toxicities of grade 3 or higher severity. 
o Adverse events or lab toxicities of grade 3 or higher severity judged to be at least possibly 
attributable to the study medication. 
o Termination from treatment due to a drug-related adverse event. 
o Death 
• 
Plasma HIV-1 RNA (copies/mL) <400 copies/mL and <50 copies/mL 
• 
CD4/8 counts and percent 
•  Genotypic and phenotypic measures of resistance at baseline and at virologic failure 
• 
Disease progression as measured by change in CDC category 
 
 
Safety Analyses 
Safety assessments will be performed on data collected beyond Week 48. The safety analyses for data 
beyond Week 48 will be similar to the primary analyses described above (section 4.3.1) and will include 
the Safety POPULATION participants. Another presentation of safety analysis results will include all 
participants in the PROPOSED DOSE SAFETY POPULATION. 
 
Viral suppression Analyses 
Virologic outcomes, based on HIV-1 RNA (copies/mL), will be assessed at weeks 24 and48. Virologic 
outcomes at additional time points might also be evaluated. These analyses will be presented by age 
cohort and by enrollment weight band for the ITT-E POPULATION and PROPOSED DOSE ITT-E 
POPULATON. 
 
For regulatory submission purposes, at both of week 24 or 48 time points the primary definition of 
virologic outcome will be calculated according to FDA’s snapshot algorithm. Participants will be 
classified as virologic failures if they have missing HIV-1 RNA data throughout the window surrounding 
the time point of interest. In addition, participants will be classified as virologic failures at either of 
these time points if they meet any of the following conditions prior to that time point: 
a)  Discontinuation of drug; 
b)  Change in background therapy not allowed in the protocol; 
c)  Change in background ART substitutions permitted per protocol, unless the decision to switch is 
documented as being before or at the first on-treatment visit after switching to OBT where HIV-
1 RNA is assessed (Week 4) or participant’s HIV-RNA is <400 copies/ml (or <50 copies/mL) 
before the switch. 
 
The Snapshot algorithm treats all participants without HIV-1 RNA data at the visit of interest (due to 
missing data or discontinuation of study drug prior to the visit window) as non-responders, as well as 
participants who switch their concomitant ART prior to the visit of interest in certain scenarios. ART 
substitutions permitted by the protocol (e.g., for toxicity reasons) are not penalized if the change 
happens while the subject is suppressed. 
 
Otherwise, virologic success or virologic failure will be determined by the last available HIV-1 RNA 


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assessment while the subject is on-treatment within the visit of interest analysis window. 
 
Virologic success includes participants who have HIV-1 RNA <400 copies/mL (or <50 copies/mL) at the 
visit of interest. 
 
Virologic failure includes participants who changed any ART; participants who discontinued study 
drug or study before Week 48 for lack or loss of efficacy, discontinued while not < 50 c/mL/< 400 
c/mL, and participants who have HIV-1 RNA ≥ 400 copies/mL (or ≥ 50 copies/mL )at the visit of 
interest. 
 
Full details of the Snapshot algorithm are in Appendix. 
 
The proportions of participants meeting the criteria for virological success at each of time points of 
analysis will be bounded by exact 95% confidence intervals, and will be presented in the aggregate 
and broken down by age cohort and by weight band. 
 
HIV Drug Resistance Analyses 
The incidence of HIV drug resistance will be presented descriptively at baseline and at the point of 
failure for participants who meet the criteria for virological failure per snapshot algorithm, Participants 
will be evaluated for HIV genotypic and phenotypic drug resistance to the OBT and to DTG.  
 
 
 
Exploratory Analysis of Virological Failure (VF) Population: summaries of virologic failure participant 
characteristics, adverse events as well as drug resistance profiles will be presented 
• Listing of selected baseline characteristics with ARV history 
• Listing of grade 3+ laboratory adverse events 
• Listing of SAE meeting ICH seriousness criteria 
• Listing of serious laboratory adverse events meeting ICH seriousness criteria 
• Listing of available phenotypic data (for participants with test results) 
• Listing of resistance data for the virological failure participants 
 
CD4/8 Analyses 
Change in CD4/8 count and percent from baseline to weeks 24 and 48 will be bounded by 95% 
confidence intervals and presented in the aggregate and broken down by age cohort, by accrual to 
Stage I vs. Stage II, and by enrollment weight band for the ITT-E POPULATION and PROPOSED DOSE ITT-
E POPULATION. Analysis results will be presented in aggregate, by age cohort and by enrollment 
weight band for the ITT-E POPULATION and PROPOSED DOSE ITT-E POPULATION. 
 
Disease Progression as Measured by Change in CDC Category Analyses 
Listing of participants who had changes in CDC category (to a worse category) while on study will be 
presented in aggregate, by age cohort, and by enrollment weight band for the ITT-E POPULATION and 
PROPOSED DOSE ITT-E POPULATION. 
The stages will include the following: CDC Category Stage 1 at enrolment to Stage 3 event; CDC 
Category Stage 2 at enrolment to Stage 3 event; CDC Category Stage 3 at enrolment to New Stage 3 
Event; CDC Category Stage 1, 2 or 3 at enrolment to Death. 


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Analysis of intensive pharmacokinetics of dolutegravir in cohorts III-V of participants who received 
the proposed dose of dispersible tablet (DT) (collaboration between study statisticians and 
pharmacologist) 
A subset analysis is performed to assess the pharmacokinetics of dolutegravir: PK parameters of C24 and 
AUC0-24, which were estimated via Phoenix WinNonlin version 6.3 and based on the whole blood 
samples collected at time 0 (before the dose) and at 1, 2, 3, 4, 6, 8 and 24 hours after ingestion; as well 
as the additional pharmacokinetic variables and tolerability, and clinical efficacy. The week 24 and 48 
safety summary include outcomes of the grade 3 or great adverse events, termination of treatment due 
to drug related adverse event, or death. Efficacy summaries include virologic success defined as 
achieving a plasma HIV-1 RNA <400 copies/m; or the proportion achieving HIV-1 RNA <50 copies/mL 
and the change from baseline in CD4 cell count and percentage. 
 
 
5. Core Manuscript Writing Team 
 
Protocol Co-Chairs: 
 
 
 
NIAID MO: 
 
NICHD MO: 
 
Study Statisticians: 
 
 
 
 
 
Clinical Trial Specialists:  
 
 
Data Managers: 
 
 
Protocol Virologist: 
 
Protocol Pharmacologist:  
 
 
6. Protocol History 
 
Protocol Version 1 
Version 1.0 was implemented on December 14, 2010. One Clarification Memo (CM) and one Letter of 
Amendment (LOA) to Version 1 were issued: CM#1 (dated 3/1/2011) and LOA#1 (dated 3/1/2011). 
 
CM#1, March 1, 2011 
This CM provides clarifications to Section 5.0 – Study Treatment and to Appendix II – Planned 
Laboratory Testing on Collected Specimens in the P1093 Version 1.0 protocol. 
 
LOA#1, March 1, 2011 
This LOA is to provide to the “Parent Fact Sheet and Template Consent Form” for the NICHD sites 
participating in IMPAACT P1093 related to specimens collected for storage purposes. 
 
 
Protocol Version 2 


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Version 2.0 was implemented on September 26, 2011. 
 
 
Protocol Version 3 
Version 3 was implemented on January 16, 2013. Three Clarification Memoranda (CM) and two Letters 
of Amendment (LOA) to Version 3 were issued: CM#1 (dated 5/6/2013), CM#2 (dated 12/3/2014) and 
CM#3 (dated 9/8/2015); LOA#1 (dated 3/8/2013) and LOA#2 9dated(11/15/2013) 
 
CM#1, May 6, 2013 
This CM provides clarification to specimens being shipped for genotyping at virologic failure, Appendix 
IA, IB, IC and ID for international laboratories. 
 
CM#2, December 3, 2014 
This CM addresses the following issues: 
• As intended and consistent with the primary and secondary endpoints, the protocol has been 
clarified to indicate that AUC24 (primary PK endpoint) will be the primary pharmacokinetic 
variable and C24h (secondary PK endpoint) will be secondary in evaluating DTG steady-state 
pharmacokinetics and any subsequent dosing changes. 
• An internal consistency in the protocol between Section 6.3, Appendix IE and the Sample 
Informed Consent Documents (amended via Letter of Amendment #1) regarding the 
frequency of visits during long term for subjects has been corrected to indicate that subjects 
receiving tablets will be seen every 12 weeks and those receiving granules will be seen every 8 
weeks. 
• The title of Appendix IG, the Schedule of Evaluations for Subjects who discontinue DTG has 
been corrected. 
 
CM#3, September 8, 2015 
This CM addresses two issues in protocol Version 3.0 as described below: 
• Protocol Section 3.0 indicates that for participants enrolled in Stage I and not receiving 
antiretrovirals (ARVs) at entry, dolutegravir (DTG) should be started as monotherapy, and the 
ARV regimen would then be optimized immediately after completion of the 24 hour PK 
sampling. For operational clarity and internal consistency throughout the protocol this 
information has been reiterated in Section 6.23 and the Schedule of Evaluations. 
• Dosing Tables D, E, and F have been updated to include a < 8 kg weight band dose 
 
LOA#1, March 8, 2013 
This LOA is to replace text that was inadvertently deleted under Section 4.0 (Inclusion Criteria), to 
update the laboratory performing the microalbumin/creatinine assay in South America, and to clarify 
the frequency of visits in the long term safety follow up per formulation in the sample informed 
consent. 
 
LOA#2, November 15, 2013 
This LOA is to change the dosing of GSK1349572 (dolutegravir, DTG) when used in combination with 
efavirenz (EFV), nevirapine (NVP), fosamprenavir (FPV)/ritonavir (r) or tipranavir/ritonavir (TPV)/r from 
once a day to twice a day. 
 


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Protocol Version 4 
Version 4 was implemented on April 13, 2016. Four Clarification Memoranda (CM) to Version 4.0 were 
issued: CM #1 (dated 8 December 2016); CM#2 (dated 7 April 2017); CM#3 (dated 11 July 2017); and 
CM#4 (dated 30 January 2018). Protocol Version 5 was implemented on 7/12/2018. 
 
CM #1, December 8, 2016: 
This CM addresses inconsistencies in the protocol regarding the study drug regimen in Cohort II; the 
maximum in-use period of the granule formulation after reconstitution; and selection of the 
optimized background therapy (OBT) for participants entering Stage II. In addition, clarification 
regarding the intended interpretation of inclusion criterion 4.1.3.1, and the requirement for collection 
of samples for genotyping during long-term follow-up are added. 
 
CM #2, April 7, 2017: 
This CM clarifies the administration of optimized background therapy (OBT) for participants in Stage I 
receiving a failing ARV regimen that will continue as OBT. In addition, the Schwartz formula for 
evaluating renal function for 1-year-old participants is corrected. 
 
CM #3, July 10, 2017: 
This CM clarifies the guidelines for general toxicity management. 
 
CM #4, January 30, 2018: 
This CM serves to document the discontinuation of use of the granule for suspension formulation of 
dolutegravir (DTG) and the transition of participants currently receiving the granule formulation to the 
dispersible tablet formulation in IMPAACT P1093. 
 
 
 
Protocol Version 5 
Version 5 was implemented on July 12, 2018. Four Clarification Memoranda (CM) and one Letter of 
Amendment (LOA) to Version 5 were issued: CM#1 (dated 26 September 2018), CM#2 (dated 16 
January 2019), CM#3 (dated 31 March 2020), and CM#4 (dated 8 April 2021); LOA#1 (dated 10 June 
2020). 
 
Changes from Version 4 to Version 5 are summarized below: 
 
• Expansion of and updates to the relevant protocol sections and informed consent forms to 
include current data from P1093 and other adult studies on the safety and PK of DTG. 
• 
Inclusion of updates to the relevant protocol sections and informed consent forms 
summarizing the interim analysis of an observational study from Botswana (Tsepamo) of 
women receiving DTG at the time of contraception. 
• 
Inclusion of updates and clarifications to the relevant protocol sections and Schedules of 
Evaluations to ensure adequate and documented contraception use for female participants of 
child bearing potential. 
• 
Inclusion of updates to the relevant protocol sections on the modeling and simulation of 
pharmacokinetic (PK) parameters to inform DTG dosing. 
• 
Modification of the study design to include evaluation of dosing by weight band in addition to 


P1093 SAP Version 4.0   
 
 
 
 
 
 
 
April 22, 2021 
 
 
 
 
 
 
Page 16 of 20 
 
age cohort, as weight-band based dosing is increasingly being recommended by WHO and 
other entities. 
• 
Modification of the intensive PK sampling procedures to include analysis of intensive PK in a 
non-fasting state – if determined necessary – in addition to a fasting state as previously 
specified. 
• 
Promotion of C24h to the primary PK parameter endpoint. 
• 
Revision of the C24h and AUC0-24 targets for evaluation of PK as follows: For C24h, geometric 
mean (GM) target value of 995 ng/mL (changed from 750 ng/mL) with a range of 697 to 2260 
ng/mL (changed from 500 – 2600 ng/mL). For AUC0-24, the GM target of 46 ug.h/mL remains 
unchanged and the range is modified to 37 to 134 ug.h/mL (changed from 37 – 86 ug.h/mL). 
• 
Increase in the overall sample size to “up to 300” participants (from “up to 160”) to ensure 
adequate numbers of participants for assessment of weight-band based dosing in addition to 
assessment within age cohorts. 
• 
Broaden eligibility criteria to include treatment-naïve participants of any age (rather than only 
treatment-naïve participants under two years of age). The inclusion of treatment-naïve children 
at any age is based on cumulative safety data, and the rationale that it is likely to be used and 
recommended as first-line therapy in children. 
• 
Inclusion of updated toxicity management guidelines and supplemental parameters for 
psychiatric events consistent with the current Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events. 
• 
Inclusion of updates to the protocol to reflect closure of Cohorts III and IV to further enrollment 
and removal of Cohort V which never opened to accrual; these three cohorts included the 
pediatric granule for suspension formulation which will not move forward for licensure. 
Evaluation of the film-coated tablets and dispersible tablets will continue under protocol 
Version 5.0. 
• 
Inclusion of updates in the protocol and sample informed consent forms regarding entities who 
may access participant records. 
• 
Modification of the sample informed consent forms to reflect all other protocol modifications, 
as needed. 
• 
Incorporation of modifications included in prior clarification memoranda and letters of 
amendment associated with protocol Version 4.0. 
• 
Other administrative corrections, clarifications and updates. 
• 
Inclusion of a Protocol Signature Page.


P1093 SAP Version 4.0  
 
April 22, 20221 
 
 
 
Page 17 of 20 
 
CM#1, 26 September 2018: 
This CM corrects an inconsistency in the dispensing procedures for dolutegravir dispersible 
tablets and clarifies the guidelines for establishing a laboratory normal value for indirect 
bilirubin. 
 
CM#2, 16 January 2019: 
This CM corrects inconsistencies related to the timing of primary safety and tolerability analyses; 
clarifies screening and enrollment procedures for weight-band groups; clarifies the timeline for 
resuming once daily dosing of dolutegravir after discontinuation of rifampin-containing 
tuberculosis (TB) treatment; and updates the Protocol Team Roster. 
 
CM#3, 31 March 2020: 
This CM is being issued to safeguard the health and well-being of IMPAACT P1093 study 
participants in the context of circulating severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) and the associated coronavirus disease (COVID-19) pandemic. The purpose of this CM is 
to provide operational flexibility for conducting study visits and procedures when needed for 
participant safety monitoring and to prioritize ongoing access and adherence to the study drug 
regimen. 
 
CM#4, 8 April 2021: 
This CM updates protocol specifications to reflect current policies of the Division of AIDS 
(DAIDS), National Institute of Allergy and Infectious Diseases (NIAID), and National Institutes of 
Health (NIH). It also updates the protocol team roster including the statisticians who work on 
the study. These updates do not impact the study design or study-specific procedures. 
 
LOA#1, 10 June 2020: 
This LOA includes the protocol team roster updates, the corrections and clarifications of protocol 
text that were included in corrected CM #1 (dated 26 September 2018), CM #2 (dated 6 January 
2019), and CM #3, which was issued on 31 March 2020 to provide operational guidance for 
conducting study visits and procedures during the COVID-19 pandemic. 
 
 
7.  Appendix 
7.1 Snapshot Approach – Detailed Algorithm Steps 
Please note that no changes, re-optimization or intensification in background ARV therapy 
after initial optimization, which is defined per protocol section 6.3.1, will be permitted prior 
to protocol-defined virologic failure, with the exception of: 
• a single substitution of a component of OBT with another approved compound for the 
management of drug toxicity 
• formula substitutions (substituting single agents for fixed dose combinations and 
IMPAACT P1093, vice versa of the same ARV) – these are not classified as a change 
and are permitted during the study 
• any changes discussed with and approved by the Protocol Team. Unless the change is 
specifically 
permitted, participants who have one or more new agents added to the optimized 
background regimen will be considered virologic failures. 


P1093 SAP Version 4.0  
 
April 22, 20221 
 
 
 
Page 18 of 20 
 
 
Condition 
(‘Week 48’ indicates Week 48 window) 
Response  
Reasons 
1. If non-permitted change in background therapy prior to Week 
48  
HIV1-RNA ≥ 50  
Change in ART 
2. If permitted change in background therapy prior to Week 48 AND 
the latest on-treatment VL prior to/on the date of change is ≥ 50 
c/m [a] 
HIV1-RNA ≥ 50  
Change in ART 
3: If non-permitted change in background therapy during Week 48  
 
 
• Last on-treatment VL during Week 48 prior to/on the date 
of change ≥ 50 c/mL 
HIV1-RNA ≥ 50  
Data in window and HIV-1 
RNA >= 50 copies/mL 
• Last on-treatment VL during Week 48 prior to/on the date 
of change <50 c/mL 
HIV1-RNA < 50  
 
• No VL during Week 48 prior to/on the date of change  
HIV1-RNA ≥ 50  
Change in ART 
4: If permitted change in background therapy during Week 48 AND 
the last on-treatment VL prior to/on the date of change is ≥ 50 c/mL 
[a] 
 
 
4.1 this last on-treatment VL occurs prior to Week 48  
HIV1-RNA ≥ 50 
Change in ART 
4. 2 this last on-treatment VL occurs during Week 48 but prior 
to/on the date of change 
HIV1-RNA ≥ 50  
Data in window and HIV-1 
RNA >= 50 copies/mL 
5: If none of the above conditions met 
 
 
5.1 VL available during Week 48  
 
 
• 
Last on-treatment VL during Week 48 ≥ 50 c/mL 
HIV1-RNA ≥ 50  
Data in window and HIV-1 
RNA >= 50 copies/mL 
• 
Last on-treatment VL during Week 48 <50 c/mL 
HIV1-RNA < 50  
 
a. No VL during Week 48  
 
 
i. 
if subjects still on study (i.e. IP has not been permanently 
stopped up to Week 48) 
No virologic data 
at Week 48 
Window  
On study but missing data in 
window 
ii. 
If subjects withdraw before/during Week 48 due to 
 
 
1. Safety reasons (e.g. AE/death, liver chemistry stopping 
criteria, renal toxicity withdrawal criteria, QTc withdrawal 
criteria et al, as recorded in eCRF Conclusion form) 
No virologic data 
at Week 48 
Window 
Disc due to AE/death 
2.  Non-safety related reasons (e.g. Lack of efficacy, 
protocol deviation, withdrew consent, loss to follow-up, 
study closed/terminated, investigator discretion et al, as 
recorded in eCRF Conclusion Form) 
 
 
• Last on-treatment VL <50 c/mL OR no on-treatment VL 
available during study  
No virologic Data 
at Week 48 
Window 
Disc for other reasons 
• Last on-treatment VL ≥ 50 c/mL AND withdrawal due to 
Lack of efficacy 
HIV1-RNA ≥ 50  
Disc. for lack of efficacy 
• Last on-treatment VL ≥ 50 c/mL AND withdrawal due to 
all other non-safety related reasons 
HIV1-RNA ≥ 50  
Dis. for other reason and HIV-
1 RNA >= 50 copies/mL 
Note the same process will be mapped out for Week 24. Also, note the same process will be mapped out 
for <400 c/mL. 
 
 
 


P1093 SAP Version 4.0  
 
April 22, 20221 
 
 
 
Page 19 of 20 
 
Examples from FDA guidance 
Data in Window 
Virologic outcome should be determined by the last available measurement while the patient is 
on treatment and continued on trial within the time window: 
• HIV-RNA = 580 copies/mL at Day 336, HIV-RNA below 50 copies/mL on Day 350. This 
should be categorized as HIV-RNA below 50 copies/mL. 
No Data in Window 
Discontinued study due to Adverse Event or Death: 
• Any patient who discontinues because of an AE or death before the window should be 
classified as Discontinued due to AE or Death (as appropriate), regardless of the HIV-RNA 
result, even if the HIV-RNA is below 50 copies/mL at the time of discontinuation. 
• However, if a patient has an HIV-RNA value in the time window and also discontinues in 
the time window, the viral load data should be used to classify the patient’s response. 
This is the Virology First hierarchy: 
a. HIV-RNA below 50 copies/mL at Day 336 and discontinues because of AE or 
even dies on Day 360 — this person is categorized as having HIV-RNA below 50 
copies/mL. 
b. HIV-RNA is 552 copies/mL on Day 336 and the patient discontinues on Day 360, 
the patient is categorized as having HIV-RNA greater than or equal to 50 
copies/mL. 
Discontinued for Other Reasons: 
• 
Only patients who have achieved virologic suppression can be counted as Discontinued 
for Other Reasons. 
• 
If a patient discontinues the study before the window because of lack of efficacy then 
the patient should be included in the HIV-RNA greater than or equal to 50 row and not 
in the Discontinued for Other Reasons row. 
• 
If a patient discontinues because of subject withdrew consent and his or her HIV-1 RNA 
result at the time of discontinuation was equal to or above 50 copies/mL, then he or she 
should be categorized as HIV-RNA greater than or equal to 50 and NOT as Discontinued 
for Other Reasons. 
• 
If a patient discontinued because of Lost to Follow-Up and the last HIV-RNA result was 
49 copies/mL, then the patient can be categorized as Discontinued for Other Reasons 
while below threshold. 
• 
If patients changed background treatment — not permitted by protocol— they should 
be considered an efficacy failure and captured in the HIV-RNA greater than or equal to 
50 copies/mL row. 
 


P1093 SAP Version 4.0  
 
April 22, 20221 
 
 
 
Page 20 of 20 
 
On study but missing data in window: 
• If there are no data during Days 294 to 377, but there is an HIV-RNA below 50 copies/mL 
on Day 380, this patient should be considered On Study but Missing Data in Window. 
• If there are no data during Days 294 to 377, but there is an HIV-RNA equal to or above 
50 copies/mL on Day 280, this patient also should be classified as On Study but Missing 
Data in Window. 
Optimized Background Therapy Substitutions After Randomization 
• 
OBT substitutions (in-class or cross-class) permitted per protocol for documented 
toxicity reasons can be permitted on or before the first trial visit without penalty. 
If OBT substitutions for toxicity reasons occur after the first trial visit, then patients should be 
categorized as having HIV-RNA greater than or equal to 50 copies/mL if they have HIV-RNA 
above 50 copies/mL at the time of switch. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


P1093 SAP Version 4.0  
 
April 22, 20221 
 
 
 
Page 21 of 20 
 
7.2 SAP Version History 
Version Changes Made 
Effective Date 
1 
Original Version 
06/1/2012 
2 
Reflected changes in Protocol Version 5 
01/17/2019 
3 
Added Mona Farhad as another Protocol Statistician; changed week 
window of baseline visit; clarified weight bands to mean enrollment 
weight band; included definition of PROPOSED DOSE POPULATION; 
and included PROPOSED DOSE POPULATION in all analyses 
09/13/2019 
4 
Updated protocol statisticians: Peihua (Jessica) Liu and Kathryn P Gray 
(04/2021) via Protocol CM #4 
The analysis populations (name conventions) were updated and 
secondary analysis (VF) population for the week 48 analyses and 
regulatory submissions were added. Specifically, 
• 
Safety Population 
• 
Safety Evaluable Population (needed for scientific 
analysis/report) 
• 
Intent-To-Treat Exposed (ITT-E) Population 
• 
Proposed Dose ITTE Population 
• 
Proposed Dose Safety Population 
• 
Virological Failure Population 
Other clarifications were added throughout the docs. 
Additional analyses were also included: 
Analyses assessing the impact of COVID-19; 
Analysis summary of virologic failure population; 
 Analysis of intensive pharmacokinetics of dolutegravir in the 
proposed dose of dispersible tablet (DT) cohorts III-V. 
12/23/2020 
 
 

Prot_001.pdf: 
IMPAACT P1093 
 
 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity 
of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in  
HIV-1 Infected Infants, Children and Adolescents 
 
 
A Multicenter, Domestic & International Trial of the  
International Maternal Pediatric Adolescent AIDS  
Clinical Trials Group (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: GlaxoSmithKline 
 
 
IND#110,847   Held by NIAID 
DAIDS ES# 11773 
EudraCT# 2010-020988-20 
 
 
The IMPAACT HIV Treatment 
Scientific Committee Chair:  
Elaine Abrams, MD 
 
Protocol Co-Chairs: 
Andrew Wiznia, MD 
Theodore Ruel, MD 
 
NIAID Medical Officer: 
Ellen Townley, MSN, FNP 
 
NICHD Medical Officer: 
Rohan Hazra, MD 
 
Clinical Trials Specialists: 
Kathleen George, MPH 
Nicole Montañez, MSW  
 
 
Final Version 5.0 
12 July 2018  
 
 


 
 
 
IMPAACT P1093, Version 5.0  
Page 2 of 135 
12 July 2018 
TABLE OF CONTENTS 
 
PROTOCOL SIGNATURE PAGE ........................................................................................................... 5 
PROTOCOL TEAM ROSTER ................................................................................................................. 6 
STUDY MANAGEMENT .......................................................................................................................... 8 
LIST OF COMMONLY USED ABBREVIATIONS AND DEFINITIONS .......................................... 9 
SCHEMA ................................................................................................................................................... 11 
1.0 
INTRODUCTION........................................................................................................................ 13 
1.1 
Background .................................................................................................................................... 13 
1.2 
Clinical Efficacy ............................................................................................................................ 14 
1.3 
Clinical Pharmacokinetics in Adults .............................................................................................. 15 
1.4 
Clinical Pharmacokinetics in P1093 .............................................................................................. 22 
1.5 
Summary of Safety in Clinical Trials ............................................................................................ 22 
1.6 
Rationale ........................................................................................................................................ 26 
1.7 
Hypothesis ..................................................................................................................................... 31 
 
2.0 
STUDY OBJECTIVES ................................................................................................................ 31 
2.1 
Primary Objectives......................................................................................................................... 31 
2.2 
Secondary Objectives..................................................................................................................... 32 
 
3.0 
STUDY DESIGN .......................................................................................................................... 32 
3.1 
Stage I Study Design ...................................................................................................................... 33 
3.2 
Stage II Study Design .................................................................................................................... 36 
3.3 
Protocol Version 4.0 – Addition of Dispersible Tablets ................................................................ 36 
3.4 
Protocol Version 5.0 – Addition of Evaluation by Weight Band or other Factors ........................ 37 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................... 37 
4.1 
Inclusion Criteria ........................................................................................................................... 37 
4.2 
Exclusion Criteria .......................................................................................................................... 40 
4.3 
Concomitant Medication Guidelines ............................................................................................. 41 
4.4 
Protocol Registration and Enrollment Procedures ......................................................................... 43 
4.5 
Co-enrollment Procedures ............................................................................................................. 44 
 
5.0 
STUDY TREATMENT ............................................................................................................... 44 
5.1 
Drug Regimens .............................................................................................................................. 44 
5.2 
Study Product Formulations and Administration ........................................................................... 48 
5.3 
Study Product Supply, Acquisition and Accountability ................................................................ 49 
 
6.0 
PARTICIPANT MANAGEMENT ............................................................................................. 50 
6.1 
Toxicity Management .................................................................................................................... 50 
6.2 
Screening ....................................................................................................................................... 55 
6.3 
Initiation of Dolutegravir and Management of Background ART ................................................. 55 
6.4 
Dose Adjustments .......................................................................................................................... 58 
6.5 
Virologic Failure for Participant Management .............................................................................. 58 
6.6 
Long Term Safety Follow-up ......................................................................................................... 60 
6.7 
Pregnancy ....................................................................................................................................... 60 
6.8 
Criteria for Study Discontinuation ................................................................................................. 61 
6.9 
Criteria for Treatment Discontinuation .......................................................................................... 61 
 
7.0 
EXPEDITED ADVERSE EVENT REPORTING .................................................................... 62 
7.1 
Adverse Event Reporting to DAIDS .............................................................................................. 62 


 
 
 
IMPAACT P1093, Version 5.0  
Page 3 of 135 
12 July 2018 
7.2 
Reporting Requirements for this Study .......................................................................................... 62 
7.3 
Grading Severity of Events ............................................................................................................ 63 
7.4 
Expedited AE Reporting Period ..................................................................................................... 63 
 
8.0 
STATISTICAL CONSIDERATIONS ....................................................................................... 64 
8.1 
General Design Issues .................................................................................................................... 64 
8.2 
Endpoints and Outcome Measures ................................................................................................. 66 
8.3 
Randomization and Stratification .................................................................................................. 67 
8.4 
Sample Size and Accrual ............................................................................................................... 67 
8.5 
Safety Guidelines for the Evaluation of Stage I Starting Doses .................................................... 68 
8.6 
Analyses ......................................................................................................................................... 72 
8.7 
Monitoring ..................................................................................................................................... 77 
 
9.0 
CLINICAL PHARMACOLOGY PLAN ................................................................................... 78 
9.1 
Pharmacology Objectives .............................................................................................................. 78 
9.2 
Primary and Secondary Data ......................................................................................................... 78 
9.3 
Evaluation of PK Exposures for Cohorts and Weight Bands ........................................................ 81 
9.4 
Evaluation of PK Exposures for Individual Dose Modification .................................................... 81 
 
10.0 
HUMAN SUBJECTS PROTECTIONS ..................................................................................... 81 
10.1 
Institutional Review Board/Ethics Committee Review and Approval .......................................... 82 
10.2 
Vulnerable Participants .................................................................................................................. 82 
10.3 
Informed Consent .......................................................................................................................... 82 
10.4 
Essential and Source Documents and Access to Source Data ....................................................... 83 
10.5 
Participant Confidentiality ............................................................................................................. 84 
10.6 
Study Discontinuation .................................................................................................................... 84 
10.7 
Access to Dolutegravir at the Close of the Study .......................................................................... 84 
10.8 
Reimbursement/Compensation ...................................................................................................... 85 
10.9 
Management of New Information Pertinent to Study Participation ............................................... 85 
 
11.0 
PUBLICATION OF RESEARCH FINDINGS ......................................................................... 85 
12.0 
BIOHAZARD CONTAINMENT ............................................................................................... 85 
13.0 
REFERENCES ............................................................................................................................. 85 
 
Appendix IA Schedule of Evaluations   Cohorts I, IIA, IIB, III and III-DT – Stage I .............................. 89 
Appendix IB Schedule of Evaluations   Cohorts I, IIA, III and III-DT – Stage II ..................................... 93 
Appendix IC Schedule of Evaluations   Cohorts IV, IV-DT, and V-DT– Stage I ..................................... 96 
Appendix ID Schedule of Evaluations   Cohorts IV, IV-DT, and V-DT – Stage II ................................ 100 
Appendix IE Schedule of Evaluations   Long-term Safety Follow-up for Participants who Continue to 
Receive Dolutegravir ................................................................................................................... 103 
Appendix IF Schedule of Evaluations  Participants who Prematurely Discontinue Dolutegravir .......... 105 
Appendix IG  Schedule of Evaluations Participants who Start Rifampin as Part of Treatment for Active 
Tuberculosis ................................................................................................................................. 106 
Appendix II Sample Consent Form for Participants Enrolling in Stage I ............................................... 109 
Appendix III Sample Consent Form for Participants Enrolling in Stage II ............................................ 121 
Appendix IV Sample Informed Consent Form for Specimen Storage and Future Use ........................... 133 
  
 
 


 
 
 
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Page 4 of 135 
12 July 2018 
LIST OF FIGURES 
 
Figure 1: DTG Day 11 Log10VL Change .................................................................................................. 14 
Figure 2: Algorithm for STAGE I Enrollment and Analysis ...................................................................... 35 
 
LIST OF TABLES 
 
Table 1: Summary of DTG PK Parameters and Mean HIV-1 RNA Reduction from Baseline by Dose .... 15 
Table 2: Summary of Week 2 DTG PK Parameters from ING112276 ...................................................... 16 
Table 3: Treatment Comparison of DTG PK Parameters (Study ING114556) .......................................... 17 
Table 4: Treatment comparison of plasma DTG PK parameters ................................................................ 18 
Table 5: Effect of concomitant medications on DTG pharmacokinetics .................................................... 19 
Table 6: Effect of DTG on the Pharmacokinetics of Concomitant Medications ........................................ 21 
Table 7: Pharmacokinetic Data Available from P1093............................................................................... 22 
Table 8: Statistic Summary of DTG PK Exposure from Combined Data in ING111521 and ING112276 28 
Table 9: IMPAACT P1093 C24 and AUC0-24 Parameters ............................................................................ 29 
Table 10: Target Accrual at the Accepted Dose in Stages I and II ............................................................. 36 
Table 11: Summary of Disallowed ARV Medications ............................................................................... 43 
Table 12. Stage I Timing and Management of DTG and Background ART .............................................. 57 
Table 13: Supplemental Table for Grading of Psychiatric Events .............................................................. 63 
Table 14: Power Estimation based on Proposed Sample Size of 10 Per Cohort for Stage I ....................... 68 
Table 15: Probability of Failing Dose Escalation Guidelines under Potential Rates of True Toxicity ...... 70 
Table 16: Probability of Failing Dose Escalation Guidelines Under Potential Rates of True Toxicity with 
n=10 participants ......................................................................................................................................... 71 
Table 17: Percent of Participants Experiencing Grade 3+ Adverse Events (or Grade 3+ Adverse Events 
Attributed to the Study Medication) With Exact 95% Confidence Intervals .............................................. 74 
Table 18: Percent of Participants Meeting Criterion for Virologic Success with Exact 95% Confidence 
Intervals ...................................................................................................................................................... 76 
 
 
 


 
 
IMPAACT P1093 
 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity 
of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in  
HIV-1 Infected Infants, Children and Adolescents 
 
IND#110,847 Held by NIAID 
DAIDS Study ID #11773  
 
Version 5.0 
 
PROTOCOL SIGNATURE PAGE 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (U.S.) Health and 
Human Service regulations (45 CFR 46); applicable U.S. Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., U.S. National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 


 
 
 
IMPAACT P1093, Version 5.0  
Page 6 of 135 
12 July 2018 
PROTOCOL TEAM ROSTER 
 
Protocol Co-Chairs 
Andrew Wiznia, MD 
Jacobi Medical Center  
1400 Pelham Parkway South  
Bldg 1, Room 1W5 
Bronx, NY  10461 
Phone: 718-918-4664 
Email: awiznia@aecom.yu.edu  
 
Theodore Ruel MD 
University of California, San Francisco 
550 16th Street, Box 0434 
San Francisco, CA 94158-0434 
Phone: 415 476-9197  
E-mail: theodore.ruel@ucsf.edu 
 
NIAID Medical Officer  
Ellen Townley MSN, FNP 
Maternal Adolescent Pediatric Branch 
Division of AIDS NIAID/NIH 
5601 Fishers Lane, RM8B39 
Rockville, Maryland 20892 
Mailstop 9831 
Phone: 240- 292-4784 
E-mail: townleyem@niaid.nih.gov 
  
NICHD Medical Officer 
Rohan Hazra, MD 
Pediatric, Adolescent and Maternal AIDS 
Branch  
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
(NICHD) 
National Institutes of Health 
6710B Rockledge Drive, Rm 2113 
Bethesda, MD 20817 
Phone: 301-435-6868 
Email: hazrar@mail.nih.gov 
 
Clinical Trials Specialists 
Kathleen George, MPH 
IMPAACT Operations - FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: 919-544-7040 x11150 
Email: kgeorge@fhi360.org 
 
Nicole Montañez, MSW  
IMPAACT Operations - FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701 
Phone: 919-544-7040 x11844 
Email: nmontanez@fhi360.org 
 
Protocol Statisticians 
Terence Fenton, Ed.D. 
Statistical & Data Analysis Center  
Harvard School of Public Health  
651 Huntington Avenue  
Boston, MA  02115 
Phone: 617-632-2009 
Email: fenton@sdac.harvard.edu 
 
Carmelita Alvero, MS 
Statistical & Data Analysis Center  
Harvard School of Public Health  
FXB Building  
900 Commonwealth Avenue  
Boston, MA  02215 
Phone: 617-582-7265  
Email: calvero@sdac.harvard.edu 
 
Protocol Data Managers 
Stephanie Popson, PhD  
Frontier Science and Technology Research 
Foundation (FSTRF), Inc. 
4033 Maple Road 
Amherst, NY 14226 
Phone: 716-834-0900 x 7356 
Email: popson@fstrf.org  
 
Protocol Pharmacist 
Thucuma Sise, Pharm D 
Pharmaceutical Affairs Branch (PAB),  
DAIDS, NIAID 
5601 Fishers Lane  
Room 9A27 MSC# 9829 
Rockville, MD 20852 
Phone: 240- 292-4848 
Email: sisetk@niaid.nih.gov  
 
 
 
 


 
 
 
IMPAACT P1093, Version 5.0  
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12 July 2018 
Protocol Virologist 
Paul Palumbo, MD 
Dartmouth-Hitchcock Medical Center 
Division of Infectious Diseases and International 
Health One Medical Center Drive 
Lebanon, NH 03756 
Phone: 603-650-8840 
Email: paul.palumbo@dartmouth.edu 
 
Protocol Pharmacologist 
Edward P. Acosta, Pharm D 
University of Alabama at Birmingham 
School of Medicine 
Shelby Interdisciplinary Biomedical Research 
Building 
1670 Univ. Boulevard, Volker Hall, Room 258  
Birmingham, AL 35294-0019 
Phone: 205-934-2655 
Email: eacosta@uab.edu  
 
Laboratory Technologist 
Patricia Anthony, CLS, MT(ASCP) 
University of Southern California 
Maternal, Child, and Adolescent Virology 
Research Laboratory 
1801 E. Marengo Street 
Los Angeles, CA 90033 
Phone: 323-226-4162 
E-mail: patricia.anthony@usc.edu 
 
Laboratory Data Coordinator 
Katelynn Hergott, MPH, MSW 
Frontier Science and Technology Research 
Foundation (FSTRF), Inc. 
4033 Maple Rd 
Amherst, NY  14226 
Phone: 716-834-0900 ext: 7212 
Fax: 716-834-8432 
E-mail: hergott@fstrf.org 
 
Laboratory Center Representative 
Dale W. Dayton, RN, BS, CCRA 
IMPAACT Laboratory Center  
Children’s Hospital Los Angeles 
Phone: 301-742-9077 
Email: ddayton@impaactlabcenter.org 
 
Westat Clinical Research Associate 
Kathryn Myers, BA 
Westat 1441 West Montgomery Avenue 
Rockville, MD 20850 
Phone: 301-610-8803 
Email: KathrynMyers@westat.com   
  
Pharmaceutical Company Representatives 
Annie Buchanan, MD, MPH 
Physician Project Lead, Dolutegravir Pediatric 
Program 
Infectious Disease R&D 
ViiV Healthcare 
Five Moore Drive 
PO Box 13398, RTP, NC 27709-3398, USA 
Mailstop 5.3200 
Phone: 919-906-4969  
Email: ann.m.buchanan@viivhealthcare.com  
 
Cindy Brothers 
Clinical Matrix Team Lead, DTG Pediatric 
Program 
ViiV Healthcare 
5 Moore Drive; 5.3200 
Research Triangle Park, NC 27709 
Phone: 919-414-1184 
Email: cindy.h.brothers@viivhealthcare.com 
 
Cindy Vavro 
Clinical Virology 
Infectious Disease, R&D 
ViiV Healthcare  
5 Moore Drive 
Research Triangle Park, NC 27709-3398 
Phone: 919 - 483-9184 
Email: cindy.l.vavro@viivhealthcare.com 
 
Rajendra Singh 
RD Projects Clinical Platforms & Sciences 
GlaxoSmithKline  
709 Swedeland Road,  
King of Prussia, PA, 19406  
Phone: 610-270-6863 
Email: rajendra.8.singh@gsk.com 
 
 


 
 
 
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STUDY MANAGEMENT 
 
 
• 
All questions concerning this protocol including questions regarding screening, clinical 
management of study participants should be sent via e-mail to impaact.teamp1093@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 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 sisetk@niaid.nih.gov or call (240) 292-4848. 
 
• 
For Expedited Adverse Event (EAE) questions contact the DAIDS RSC Safety Office via email 
(RSCSafetyOffice@tech-res.com) or phone (1-800-537-9979 or +1-301-537-1709) or fax (1-800-
275-7619 or +1-301-897-1710). For questions about the DAIDS Adverse Experience Reporting 
System (DAERS), email DAIDS-ESSupport@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.protp1093@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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LIST OF COMMONLY USED ABBREVIATIONS AND DEFINITIONS 
 
3TC 
Lamivudine 
ABC 
Abacavir 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine transaminase 
ART 
Antiretroviral therapy 
ARV 
Antiretroviral 
AST 
Aspartate aminotransferase 
ATV 
Atazanavir 
AUC0-24 
Area under the drug plasma concentration profile over time of dosing interval  
BSA  
Body Surface Area 
C0 
Drug plasma concentration immediately prior to dosing 
Cmax 
Maximal observed drug concentration during a dosing interval 
Cmin 
Minimal observed drug concentration during a dosing interval 
C24h 
Drug plasma concentration at the end of the 24 hour dosing interval 
CAP 
College of American Pathologists 
CDC 
Center for Disease Control and Prevention 
cDNA 
complementary DNA 
CL/F 
Apparent clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CPK 
Creatinine phosphokinase 
CRPMC 
Clinical Research Products Management Center 
DAERS 
DAIDS Adverse Experience Reporting System 
DAIDS 
Division of AIDS (United States) 
DMC 
Data Management Center 
DNA 
Deoxyribonucleic acid 
DRV 
Darunavir 
DSMB 
Data Safety and Monitoring Board 
DTG 
Dolutegravir 
EAE 
Expedited Adverse Event 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
EFV 
Efavirenz 
EIA 
Enzyme Immunoassay 
EMEA 
European Medicines Agency 
ETR 
Etravirine 
EU 
European Union 
EVG 
Elvitegravir 
FDA 
US Food and Drug Administration 
FPV 
Fosamprenavir 
FTC 
Emtricitabine 
GI 
Gastrointestinal 
GM 
Geometric mean 
GMR 
Geometric mean ratio 
GSK 
GlaxoSmithKline 
HAART 
Highly Active Antiretroviral Therapy 
HIV 
Human Immunodeficiency Virus 
HHS 
Department of Health & Human Services 
IB 
Investigator’s Brochure 


 
 
 
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IC50 
Half Maximal Inhibitory Concentration 
IMPAACT 
International Maternal Pediatric Adolescent AIDS Clinical Trials Network 
IgM 
Immunoglobulin M 
ICF 
Informed Consent Form 
IQ 
Inhibitory Quotient 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
LAR 
Legally Authorized Representative 
LDH 
Lactate dehydrogenase 
LMC 
low mineral content 
LPV 
Lopinavir 
MSDF  
Missing, Switch or Discontinuation = Failure 
NIAID 
National Institute of Allergy and Infectious Diseases  
NICHD 
National Institute of Child Health and Human Development 
NIH 
National Institutes of Health 
NRTI 
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors 
NVP 
Nevirapine 
OBT 
Optimized Background Therapy 
OHRP 
Office for Human Research Protections 
PCR 
Polymerase Chain Reaction 
PI 
Protease Inhibitor 
PID 
Patient Identifier 
PK 
Pharmacokinetic 
PRO 
Protocol Registration Office 
QD 
Once daily 
RAL 
Raltegravir 
RNA 
Ribonucleic acid 
RSC 
Regulatory Support Center 
RTV 
Ritonavir 
SAE 
Serious Adverse Event 
SDMC 
Statistical and Data Management Center 
SMC 
Study Monitoring Committee 
SUSAR 
Suspected, Unexpected Serious Adverse Reaction 
tmax 
time Cmax occurs 
tmin 
time Cmin occurs 
t1/2 
half-life 
TB 
Tuberculosis 
TDF 
Tenofovir 
TPV 
Tipranavir 
UAB 
University of Alabama in Birmingham 
UGT 
UDP-glucuronosyltransferases 
ULN 
Upper Limit of Normal 
US 
United States 
WB 
Western Blot 
 


 
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SCHEMA 
 
Phase I/II Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and Antiviral Activity 
of Dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in  
HIV-1 Infected Infants, Children and Adolescents 
 
DESIGN: 
Phase I/II, multi-center, open-label, non-comparative intensive PK and 
safety study 
 
Two formulations of dolutegravir (DTG), film-coated tablets and 
dispersible tablets (DT) will be evaluated under protocol Version 5.0.  
Evaluation of the film-coated tablet began under protocol Version 1.0; 
and evaluation of the DT formulation began under protocol Version 4.0. 
Evaluation of the granules for suspension formulation began under 
protocol Version 3.0; however, this formulation is no longer being 
developed for licensure.   
 
DTG is evaluated in each age-based cohort, with the exception of IIB, in 
two sequential stages: Stage I and Stage II. Stage I examines the 
pharmacokinetic (PK) parameters from intensive PK sampling, the short-
term tolerability and safety of DTG to determine a dose that is then 
studied with additional participants as Stage II.  In version 5.0, doses will 
also be examined by weight band group.   
 
POPULATION AND  
SAMPLE SIZE: 
Up to 300 HIV-infected infants, children and adolescents aged ≥ 4 weeks 
to < 18 years of age enrolled in the age-specific cohorts specified below.   
 
Cohort I:  
Adolescents ≥ 12 to <18 years of age 
 
(film-coated tablets) 
 
Cohort IIA:  
Children ≥ 6 to <12 years of age  
(film-coated tablets)  
 
Cohort IIB:  
Children ≥ 6 to <12 years of age  
 
(granules for suspension or dispersible tablets) 
 
Cohorts III:   Children ≥ 2 to < 6 years of age  
 
(granules for suspension)- Closed to Enrollment 
 
Cohort IV:  
Children ≥ 6 months to < 2 years of age  
(granules for suspension)- Closed to Enrollment  
 
Cohort III-DT: Children ≥ 2 to < 6 years of age  
 
(dispersible tablets)  
 
Cohort IV-DT: Children ≥ 6 months to < 2 years of age  
(dispersible tablets)  
 
Cohort V-DT:  Infants > 4 weeks to < 6 months   
(dispersible tablets) 


 
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12 July 2018 
Stage I enrollment into Cohorts III-DT, IV-DT, and V-DT continues 
until a minimum of 10 participants in each cohort AND a minimum of 8 
participants in each of the weight band groups below, are enrolled: 
 
a) 3 to < 6 kg 
b) 6 to < 10 kg  
c) 10 to < 14 kg  
d) 14 to < 20 kg 
 
When the PK parameters and safety are determined acceptable among 
participants enrolled in Stage I, additional participants will be enrolled to 
Stage II (if necessary) to achieve a minimum of 22 participants per 
cohort receiving the acceptable dose for long-term safety evaluation.  
 
REGIMEN:  
 
Oral once daily dose of DTG film-coated tablets or dispersible tablets, or 
twice daily dosing, if indicated.  
 
TREATMENT DURATION:  Stages I and II: 48 Weeks 
 
Long Term Safety Follow-up: All participants who successfully 
complete 48 weeks of DTG treatment will continue to receive DTG for 
up to, an additional, three years as part of long-term safety follow-up.  
 
HYPOTHESIS:  
DTG will be generally well tolerated and demonstrate an acceptable 
safety profile, adequate PK and antiviral activity when used concurrently 
with an optimized background therapy (OBT) in HIV-1 infected infants, 
children and adolescents. 
 
PRIMARY OBJECTIVES: 
 
1. To select a dose for each formulation of DTG for chronic dosing in infants, children and adolescents 
that achieves similar exposure to the DTG 50 mg once daily dose in adults.  
2. To determine the safety and tolerability of DTG in HIV-1 infected infants, children and adolescents at 
24 and 48 weeks. 
3. To evaluate the steady-state pharmacokinetics of DTG in combination with OBT in treatment-
experienced and treatment-naïve HIV-1 infected infants, children and adolescents and to determine 
the dose of DTG that achieves the targeted C24h and AUC0-24 PK parameters in this population.   
 
SECONDARY OBJECTIVES: 
 
1. To evaluate the antiviral activity of DTG in combination with an OBT by measuring virologic 
response in infants, children and adolescents at 24 and 48 weeks. 
2. To evaluate the effect on immunologic response from baseline to 24 and 48 weeks. 
3. To assess changes in HIV-1 genotype and phenotype to DTG and other components of the OBT in 
participants experiencing virologic failure. 
4. To determine DTG exposure, its variability and clinical covariates that impact DTG disposition (e.g. 
age, weight) using intensive and sparse sampling and population pharmacokinetic analysis. 
5. To determine the extended long term (> 48 weeks) safety, tolerability and efficacy of DTG in HIV-1 
infected infants, children and adolescents. 
6. To explore the relationship between DTG exposure and the antiviral activity. 
7. To evaluate pharmacokinetic, safety and tolerability profile of DTG when dosed by weight bands.  


 
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1.0 
INTRODUCTION 
 
1.1 
Background 
 
Triple combination antiretroviral therapy including a protease inhibitor (PI) or a non-nucleoside reverse 
transcriptase inhibitor (NNRTI) has become the standard treatment of HIV-infected adults and children. 
In resource-advantaged countries, triple therapy with an integrase strand transfer inhibitor (INSTI) is now 
considered a preferred regimen in adults, adolescents and children (1). The World Health Organization 
(WHO) Treatment Guidelines still recommend triple therapy with a PI or NNRTI as preferred regimens; 
raltegravir is recommended as an alternative option in some children (2). Effective antiretroviral therapy 
results in a reduction in viral load with a concomitant increase in the CD4 cell count that has been 
associated with declining morbidity and mortality in HIV-1 infected adults and children (3, 4). However, 
very few third agents have approved dosing for children of all ages from birth to adulthood.  Additionally, 
adherence, short and long-term toxicities and dosing intervals further complicate HIV management and 
may contribute to the development of drug resistance mutations further limiting treatment options in 
children.  The establishment of dosing recommendations for new antiretrovirals in children is critically 
important, especially for children and adolescents who have failed or are unable to tolerate currently 
available antiretrovirals. In addition, newer agents with novel resistance patterns not overlapping with 
established classes of therapies are also needed.  
 
Integrase, a viral enzyme essential for HIV-1 replication, mediates the integration of the viral DNA into 
the host genome. The primary role of the integrase enzyme is to catalyze the insertion of the viral cDNA 
into the chromosome of infected cells. This process requires two metal dependent consecutive steps in the 
viral replication cycle, 3’-processing and strand transfer. After the integration of the viral cDNA into the 
cell’s chromosome, viral genome is transcribed and viral proteins are produced (6). Two metal integrase 
inhibitors preferentially block the strand transfer step.  
 
Currently, four INSTI are approved and available for use.  Raltegravir (MK-0518, Isentress, Merck) was 
the first approved HIV integrase strand transfer inhibitor and has demonstrated safety and efficacy in both 
treatment-naïve and highly antiretroviral (ARV) experienced adult participants. Elvitegravir (GS-9137, 
Gilead) also showed potent antiviral activity in adults (7) and adolescents (7). However, raltegravir needs 
to be administered twice a day in children and elvitegravir (EVG), though administered only once a day, 
requires a pharmacokinetic (PK) booster. Bictegravir (currently co-formulated with emtricitabine and 
tenofovir alafenamide [Biktarvy®], Gilead) was approved in 2018 for use in adults. 
 
Clinical resistance to both raltegravir and elvitegravir has been reported in both treatment naïve and 
treatment experienced participants. Two mutation pathways emerged among participants experiencing 
virologic failure while on raltegravir. One pathway characterized by the N155H mutation lowered the 
susceptibility to raltegravir by 10-fold. The Q148H/R/K mutation pathway lowered the susceptibility to 
raltegravir by 25-fold. Additional mutations have decreased raltegravir susceptibility; the most common 
being the Q148H and G140S conferring >100 fold decrease susceptibility to raltegravir (8). Participants 
experiencing virologic failure while on elvitegravir have shown similar mutation pathways as seen with 
raltegravir (10). As the barrier to the above described resistance is low, there is a need for the 
development of new integrase inhibitors with different resistance profiles. Preliminary data suggests that 
elvitegravir exhibits similar resistance characteristics to raltegravir. 
 
Dolutegravir (DTG) was the third approved INSTI and is a potent inhibitor of the HIV-1 integrase. When 
tested against a panel of 18 integrase resistant viruses from participants failing raltegravir or elvitegravir, 
DTG showed antiviral activity comparable to that seen against wild type viruses in 17 of 18 mutant 
viruses (7);(10). Regulatory approvals of DTG are based on studies showing clinical efficacy in 
treatment-naïve, treatment-experienced, and INSTI-resistant participants. 


 
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1.2 
Clinical Efficacy 
 
DTG is approved for the treatment of HIV-1 infection in adults and children weighing at least 15 kg in 
many countries but with a minimum weight of 30 kg in the US.  The clinical development program for 
DTG was designed to support a broad patient population, from naïve to highly treatment experienced 
patients.  The program involves 40 Phase I, 4 Phase II, and 15 Phase III/IIIb clinical trials as well as a 
Named Patient Program and an Expanded Access Program.  The clinical pharmacology studies describe 
the PK and PD relationship of DTG in both healthy volunteers and special populations. 
 
The supportive Phase II package for DTG (Studies 111521, ING112276, and ING112961) include initial 
safety data in ART-naïve, -experienced, and INI-resistant participants. In these supportive studies, 
participants were treated with doses of DTG from 2 mg daily up to 100 mg daily. These data informed the 
design and conduct of this study. 
 
ING111521 was a proof of concept Phase IIA, dose-ranging, randomized, placebo-controlled study 
among 35 HIV infected adults. For ten days, participants received either DTG monotherapy at the doses 
of 2 mg, 10 mg, 50 mg or placebo. In the group receiving 50 mg of DTG monotherapy, the mean decline 
in HIV-1 was 2.5 log10 copies/mL and seven out of ten participants had a VL < 50 copies/mL during the 
study. DTG was well tolerated with only mild adverse events described including diarrhea, fatigue, and 
headache. No integrase signature resistance mutations were observed during the 10-day monotherapy 
study (11). 
 
In this study, DTG demonstrated low PK variability and a steady-state half/life (t½) of 14 hours. At 50 
mg once daily, the steady-state PK parameters (%CV) were; AUC0-24 43.4 (20%) µg h/mL, Cmax of 3.34 
(16%) µg/mL and C24h of 0.83 (26%) µg/mL. The ratio of the 10 and 50 mg C24h to the protein binding 
corrected IC90 (0.064 g/mL), also defined as inhibitory quotient (IQ), were 3 and 13, respectively. Since 
the doses in this study covered a wide range of 25-fold (2 to 50 mg), a concentration-response relationship 
was observed between C24h and change in HIV-1 RNA from baseline to day 11 using a maximum effect 
(Emax) model. The concentration required to produce 50% of the maximum effect (EC50) was estimated 
to be 0.036 g/mL (or 36 ng/mL) (12). These data provide a basis for an AUC0-24-and C24h-targeted 
trial in pediatric participants (Figure 1). 
 
Figure 1: DTG Day 11 Log10VL Change 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Table 1: Summary of DTG PK Parameters and Mean HIV-1 RNA Reduction from Baseline by Dose 
Dose 
AUC24 
µg.h/mL 
Cmax 
µg/mL 
C24 
µg/mL 
IQ 
Δ Log10 
HIV-1 RNA 
2 mg QD 
N=9 
2.56 
(29%) 
0.22 
(25%) 
0.04 
(50%) 
0.6 
-1.51 
10 mg QD 
N=7 
10.1 
(20%) 
0.80 
(23%) 
0.19 
(25%) 
3 
-2.03 
50 mg QD 
N=10 
43.4 
(20%) 
3.34 
(16%) 
0.83 
(26%) 
13 
-2.46 
Geometric mean (CV%); IQ=C24/PA-IC90 = 0.064 µg/mL 
 
Potent antiviral efficacy was demonstrated in treatment-naive and integrase-inhibitor resistant participants 
in Studies ING112276 (SPRING-1) and ING112961 (VIKING Pilot). In ING112276, a Phase IIb dose-
ranging study in 205 treatment-naive, HIV-infected participants, rapid and sustained antiviral responses 
across all DTG doses (10 mg, 25 mg, and 50 mg) were observed; 93% of participants who received DTG 
achieved HIV-1 RNA <50c/mL by Week 16 and 91%, 88%, and 90% of participants, respectively, 
sustained this viral response to Week 48 (14). At Week 96, the proportion of participants with plasma 
HIV-1 RNA <50 c/mL was 79%, 78%, and 88% in the DTG groups compared with 72% for the EFV 
group (15). Neither dose trends nor differences were noted across DTG arms (10 mg, 25 mg, and 50 mg) 
for efficacy or safety. No clinically significant dose-related trends in Adverse Events (AEs) were 
observed, and fewer participants who received DTG withdrew because of AEs (3%) compared with EFV 
(10%) (16). All three doses of DTG were generally well tolerated through 48 weeks, and the 50 mg dose 
was selected for phase III evaluation. 
 
Study ING112961 was a Phase IIb, open-label, single-arm, pilot study of HIV-infected participants with 
viral resistance to raltegravir (RAL) at Baseline.  The primary endpoint was to assess the short-term 
antiviral activity of DTG plus a failing background regimen. Participants received DTG 50 mg once daily 
(Cohort I) or 50 mg BID (Cohort II) while continuing a failing regimen (without RAL) through Day 10. 
After Day 10, the background regimen was optimized, when feasible, for Cohort I, and at least one fully 
active drug was mandated for Cohort II. Cohort I enrolled 27 participants and Cohort II enrolled 24 
participants. A rapid antiviral response was observed. More participants achieved the primary endpoint in 
Cohort II (96%), compared with Cohort I (78%) at Day 11. At Week 24, 41% and 75% of participants had 
an HIV-1 RNA load of <50 c/mL in Cohorts I and II, respectively (17). At Week 96, 26% of participants 
in Cohort I had an HIV-1 RNA load of <50 c/mL. At Week 48, 71% of participants in Cohort II had an 
HIV-1 RNA of <50 c/mL. Results from Study ING112961 concluded DTG 50 mg BID with an optimized 
background provided greater and more durable benefit than the once-daily regimen in patients with prior 
RAL treatment failure. 
 
The Phase III/IIIb clinical development program for DTG comprised studies in antiretroviral therapy 
naïve and experienced adult participants in which DTG was compared to numerous therapies. DTG 
generally demonstrated non-inferior or superior efficacy in these studies (17).  
 
1.3 
Clinical Pharmacokinetics in Adults 
 
Absorption and Effect of Formulation 
 
Following oral administration, absorption is rapid with average tmax at one to two hours and subsequently 
the plasma drug concentration declines almost mono-exponentially with average terminal half-life 
estimated at ~14 hours, supporting once daily dosing. The oral bioavailability of the tablet was less than 
that of a suspension with a mean AUC (0-) decreased by 30% following administration of the tablet 
compared to the suspension under fasted conditions. The rate of absorption of DTG from the tablet was 


 
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12 July 2018 
slower than from the suspension; the median tmax for the suspension was 0.75 hours. DTG exhibited linear 
pharmacokinetics with dose proportional increases in plasma exposure at doses from 2 to 100 mg using 
the suspension formulation, with less than dose proportional PK between 100 mg and 250 mg. For the 
tablet formulation, PK was close to linear over the dosage range of 2 to 50 mg but less than dose 
proportional between 50 mg and 100 mg. 
 
PK data (Week 2) are available across DTG doses from the Phase IIb SPRING-1 Study (ING112276)  
Table 2. At Week 2, serial samples were obtained in 46 participants and sparse samples were obtained in 
90 participants for determination of PK parameters. DTG was less than dose-proportional between 10 mg 
and 25 mg but linear between 25 mg and 50 mg. PK parameters were similar to those reported in 
ING111521, although higher PK variability was observed around AUC and Cmax. The increased 
variability is expected given that these are outpatient HIV-infected participants and the majority had 
sparse PK sampling. 
 
Table 2: Summary of Week 2 DTG PK Parameters from ING112276 
Dose 
Tablet 
Parameter 
Cmax 
(µg/mL) 
AUC 
(µg.h/mL) 
C 
(µg/mL) 
Cmin 
(µg/mL) 
10 mg 
10 mg 
N 
GeoMean 
CV% 
15 
1.10 
37 
15 
16.0 
40 
47 
0.30 
71 
15 
0.33 
64 
25 mg 
25 mg 
N 
GeoMean 
CV% 
15 
1.71 
43 
15 
23.1 
48 
44 
0.54 
67 
15 
0.44 
68 
50 mg 
2 x 25 mg 
N 
GeoMean 
CV% 
15 
3.40 
27 
15 
48.1 
40 
44 
1.20 
62 
15 
0.94 
74 
 
Pharmacokinetics of DTG Granule Formulation 
 
A granule formulation of DTG was developed as an alternative to tablets for use in pediatric populations. 
In a single-center, randomized, open-label, 5-way crossover study (ING114556) in healthy adults, 20 
participants received a single dose of DTG 50 mg as the Phase III tablet and in 10 grams of granule (0.5% 
drug load) administered 1) direct to mouth; 2) with purified water; 3) with mineral water containing high 
cation concentrations; or 4) with a milk-based infant formula. Study treatments were separated by 7 days. 
Study data demonstrated that the plasma DTG exposures in all granule treatment arms exceeded those of 
the tablet formulation (Table 3). DTG PK exposure was similar when DTG was mixed with purified or 
cation-containing mineral water or given direct to mouth. Inter-participant variability was modest with 
CV% for AUC of 31-43%. DTG was well tolerated with no withdrawals due to AEs.  
 
The exposure of DTG following administration of the granule formulation alone, with different types of 
water and with formula exceeded that of the tablet, and DTG exposure from granule formulation was 
similar when given direct to mouth, or with different types of water, indicating DTG granule can be given 
without restriction on the type of liquid, or can be administered directly to mouth (e.g., when water that is 
safe to drink is not available) (Table 3).  
 
 


 
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Table 3: Treatment Comparison of DTG PK Parameters (Study ING114556) 
Comparison to Tablet 
Geometric mean ratio (90%CI) 
AUC0-∞ 
Cmax 
Granule direct to mouth 
1.58 (1.46-1.71) 
1.62 (1.49-1.77) 
Granule with purified water 
1.57 (1.45-1.70) 
1.66 (1.52-1.81) 
Granule with mineral water 
1.55 (1.43-1.67) 
1.65 (1.51-1.79) 
Granule with formula 
1.83 (1.69-1.98) 
2.02 (1.86-2.20) 
 
This adult relative bioavailability study utilized an early formulation in which the granules contained 
0.5% DTG and were constituted as a suspension containing 2.5 mg/mL. The pediatric granule formulation 
used in the pediatric study had slightly different drug content with 0.4% of drug load (dosed as a 
1.6mg/mL suspension). 
 
However, based on input from the WHO, specifically that a dispersible tablet formulation is preferred to 
other pediatric appropriate formulations for ease of widespread distribution, stability and patient 
acceptability (e.g., liquids, granules for suspension), the manufacturer took the decision to develop a DTG 
dispersible tablet as the preferred formulation to make available globally. 
 
Pharmacokinetics of DTG Dispersible Tablet Formulation (18) 
 
A dispersible tablet formulation has been developed as an alternative to the pediatric granule formulation 
for administration in younger pediatric populations. In a single center, randomized, open-label, 5-period, 
single dose, crossover, relative bioavailability study (ING200401) in healthy adults, the PK of DTG given 
as dispersible tablet formulation was compared to a DTG pediatric granule formulation and effect of 
different types of water on the dispersible tablet in healthy adult participants was evaluated. Fifteen 
healthy participants were enrolled to provide data from at least 10 evaluable participants. Eligible 
participants were randomized to one of 5 treatment sequences. Participants received 1) DTG 20 mg of the 
pediatric granule formulation reconstituted with purified water (Treatment A); 2) DTG 20 mg of the 
dispersible tablet formulation dispersed in low mineral content (LMC) water and taken by participant 
immediately (Treatment B); 3) DTG 20 mg of the dispersible tablet formulation dispersed in Contrex 
mineral water (5% Contrex / 95% purified water) and taken by participant immediately (Treatment C); 4) 
DTG 20 mg of the dispersible tablet formulation dispersed in LMC water, held for 30 minutes, re-
dispersed, and then taken by participant (Treatment D); 5) DTG 20 mg of the dispersible tablet 
formulation dispersed in Contrex mineral water, held for 30 minutes, re-dispersed, and then taken by 
participant (Treatment E). There were washout periods of at least 7 days between treatments. DTG PK 
parameters were determined from serial PK samples collected over a 48-hour dosing interval and 
compared between treatments. Study results are shown in Table 4:  
 
• 
DTG PK exposure following a single dose oral administration of 20 mg dispersible tablets dispersed 
in low mineral content water is equivalent to that following a single dose oral administration of 20 mg 
granule formation reconstituted with purified water. 
• 
DTG PK exposure following a single dose oral administration of 20 mg dispersible tablets dispersed 
in Contrex mineral water is equivalent to that following a single dose oral administration of 20 mg 
dispersible tablets dispersed in low mineral content water. 
• 
DTG PK exposure following a single dose oral administration of 20 mg dispersible tablets dispersed 
in both low and high mineral content water held for 30 minutes before, re-dispersed, and then 
consumed is equivalent to that following a single dose oral administration of 20 mg dispersible tablets 
re-dispersed in both low or high mineral content water and consumed immediately. 
 
 


 
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Table 4: Treatment comparison of plasma DTG PK parameters 
Treatment  
GMR mean ratio (90%CI) 
 
AUC0-∞ 
Cmax 
Dispersible tablet in LMCa water 
1.07 (1.01, 1.13) 
1.13 (1.06, 1.20)  
Dispersible tablet in Contrex water 
0.944 (0.893, 0.999) 
0.918 (0.863, 0.976)   
Dispersible tablet in LMC, held for 30 minutes, then re-
dispersed 
1.03 (0.971, 1.09)  
0.987 (0.928, 1.05)   
Dispersible tablet in Contrex water, held for 30 minutes, then 
re-dispersed 
1.05 (0.988, 1.11)   
1.05 (0.986, 1.12)    
a. 
LMC= low mineral content 
 
In a 2-part phase I, single-dose crossover relative bioavailability (RBA) study, the 10 mg conventional 
film coated tablets were compared to the adult 50 mg tablet (Part 1), and the DTG 5 mg dispersible tablets 
were compared to a 25 mg tablet (Part 2) (ING205893). Part 2 of the study specifically evaluated the 
RBA of the dispersible tablet with 5 tablets administered as “dispense and immediately take” and 5 tablets 
taken direct to mouth against the DTG 25 mg film coated tablet taken direct to mouth. The geometric 
mean systemic exposure of DTG from the dispersible tablet was approximately 1.5 to 1.8-fold higher than 
that observed following administration of a single 25 mg conventional tablet taken direct to mouth. 
Comparable bioavailability was observed following disperse and immediate administration and direct to 
mouth administration. These data demonstrate that the 5 mg dispersible tablet can also be taken direct to 
mouth.  
 
Effect of Food 
 
The Phase III tablet formulation at a 50 mg dose demonstrated that low, moderate, and high fat meals 
increased DTG AUC (0-t) by 33%, 41%, and 65%, respectively. Such effect is not considered clinically 
significant based on accumulated toxicity data and safety and tolerability data in humans receiving DTG 
to date. DTG is licensed to be taken without regard to food. 
 
Accumulation and Time-dependence 
 
Following once daily dose administration, steady state was achieved after approximately 5 days of dosing. 
DTG (suspension and tablet formulations) showed time-invariant pharmacokinetics. The PK variability of 
DTG is between low to moderate with between-participant CV% for AUC and Cmax of ~20 to 30% and 
for C of 30 to 50%. 
 
Metabolism and Excretion 
 
DTG is primarily metabolized via UGT1A1 with a minor CYP3A component. DTG is the predominant 
circulating compound in plasma and renal elimination of unchanged drug is low (< 1% of the dose). Fifty-
three percent of total oral dose is excreted unchanged in the feces, but unknown if all or part of this is due 
to unabsorbed drug or biliary excretion of the glucuronidate conjugate which can be further degraded to 
form the parent compound. Protein binding in human serum is 99.3%. 
 
Drug Interaction Profile of DTG 
 
The drug interaction profile of DTG has been evaluated in a number of clinical studies in healthy 
volunteers (Table 5).  
 


 
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12 July 2018 
Table 5: Effect of concomitant medications on DTG pharmacokinetics 
Concomitant Drug 
N 
DTG Dose 
GMR1 (90% CI) 
Conclusion 
C or C24h 
AUC 
Cmax 
TDF 300 mg QD 
16 
50 mg QD 
0.920 
(0.816-1.04) 
1.01 
(0.908-1.11) 
0.969 
(0.867-1.08) 
No dose 
adjustment 
DRV/r 600/100 mg 
BID 
15 
30 mg QD 
0.620 
(0.555-0.694) 
0.782 
(0.722-0.848) 
0.892 
(0.825-0.965) 
No dose 
adjustment 
LPV/r 400/100 mg 
BID 
15 
30 mg QD 
0.944 
(0.848-1.05) 
0.973 
(0.911-1.04) 
1.00 
(0.937-1.07) 
No dose 
adjustment 
ETV 200 mg BID 
16 
50 mg QD 
0.121 
(0.093-0.157) 
0.294 
(0.257-).337) 
0.484 
(0.433-0.542) 
No dose 
adjustment 
ETV 200 mg BID + 
LPV/r 400/100 mg 
BID 
8 
50 mg QD 
1.28 
(1.13-1.45) 
1.10 
(1.02-1.20) 
1.07 
(1.02-1.13) 
No dose 
adjustment 
ETV 200 mg BID + 
DRV/r 600/100 mg 
BID 
9 
50 mg QD 
0.63 
(0.52-0.76) 
0.75 
(0.69-0.81) 
0.88 
(0.78-1.00) 
No dose 
adjustment 
Multivitamin 
16 
50 mg 
single dose 
0.679 
(0.560-0.824) 
0.668 
(0.553-0.806) 
0.646 
(0.540-0.774) 
No dose 
adjustment 
Maalox 
16 
50 mg 
single dose 
0.256 
(0.211-0.311) 
0.264 
(0.218-0.318) 
0.276 
(0.231-0.331) 
DTG should be 
taken 2 hrs. before 
or 6 hours after 
antacid 
Maalox 2 hrs. after 
dolutegravir 
16 
50 mg 
single dose 
0.703 
(0.579-0.853) 
0.743 
(0.615-0.897) 
0.821 
(0.686-0.984) 
Calcium carbonate 
(fasted) 
12 
50 mg 
single dose 
0.61 
(0.47, 0.80) 
0.61 
(0.47, 0.79) 
0.63 
(0.50, 0.81) 
DTG should be 
taken 2 hrs. before 
or 6 hours after 
supplement if taken 
without food or, 
alternatively, take 
with food 
Calcium carbonate 
(fed) 
11 
50 mg 
single dose 
1.08 
(0.81, 1.42) 
1.09 
(0.84, 1.43) 
1.07 
(0.83, 1.38) 
Calcium carbonate 2 
hrs. prior (fasted) 
11 
50 mg 
single dose 
0.90 
(0.68, 1.19) 
0.94 
(0.72, 1.23) 
1.00 
(0.7, 1.29) 
Ferrous fumarate 
(fasted) 
11 
50 mg 
single dose 
0.44 
(0.36, 0.54) 
0.46 
(0.38, 0.56) 
0.43 
(0.35, 0.52) 
DTG should be 
taken 2 hrs. before 
or 6 hours after 
supplement if taken 
without food or, 
alternatively, take 
with food 
Ferrous fumarate 
(fed) 
11 
50 mg 
single dose 
0.99 
(0.80, 1.22) 
0.87 
(0.80, 1.19) 
1.03 
(0.85, 1.26) 
Ferrous fumarate 2 
hrs. prior (fasted) 
10 
50 mg 
single dose 
0.92 
(0.74, 1.13) 
0.95 
(0.78, 1.15) 
0.99 
(0.81, 1.21) 
ATV/r 300/100 mg 
QD2 
12 
30 mg QD 
2.21 
(1.97-2.47) 
1.62 
(1.50-1.74) 
1.33 
(1.25-1.42) 
No dose 
adjustment 
ATV 400 mg QD 
12 
30 mg QD 
2.80 
(2.52-3.11) 
1.91 
(1.80-2.02) 
1.49 
(1.40-1.59) 
No dose 
adjustment 
Omeprazole 40 mg 
QD 
12 
50 mg 
single dose 
0.954 
(0.752-1.21) 
1.00 
(0.808-1.25) 
0.915 
(0.754-1.11) 
No dose 
adjustment 
Tipranavir/RTV 
500/200 mg BID 
13 
50 mg QD 
0.24 
(0.21-0.27) 
0.41 
(0.38-0.44) 
0.53 
(0.50-0.57) 
DTG 50 mg BID 
Efavirenz 600 mg 
QD 
12 
50 mg QD 
0.25 
(0.18-0.34) 
0.43 
(0.35-0.54) 
0.61 
(0.51-0.73) 
DTG 50 mg BID 


 
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Table 5: Effect of concomitant medications on DTG pharmacokinetics 
Concomitant Drug 
N 
DTG Dose 
GMR1 (90% CI) 
Conclusion 
C or C24h 
AUC 
Cmax 
FPV/RTV 
700/100 mg BID 
12 
50 mg QD 
0.51 
(0.42-0.63) 
0.65 
(0.54-0.78) 
0.76 
(0.63-0.92) 
INI naïve: No dose 
adjustment 
INI-resistant: 
Alternative 
combination that 
do not include 
FPV/RTV should 
be used where 
possible 
Rifampin 
11 
50 mg BID 
1.22 
(1.01, 1.48) 
1.33 
(1.15, 1.53) 
1.18 
(1.03, 1.37) 
DTG 50 mg BID 
11 
50 mg BID 
0.28 
(0.23, 0.34) 
0.46 
(0.38, 0.55) 
0.57 
(0.49, 0.65) 
Rifabutin 
9 
50 mg QD 
0.70 
(0.57, 0.87) 
0.95 
(0.82, 1.10) 
1.16 
(0.98, 1.37) 
No dose 
adjustment 
Prednisone 
12 
50 mg QD 
1.17 
(1.06, 1.28) 
1.11 
(1.03, 1.20) 
1.06 
(0.991, 1.14) 
No dose 
adjustment 
Boceprevir 
13 
50 mg QD 
1.08 
(0.911, 1.28) 
1.07 
(0.948, 1.20) 
1.05 
(0.960, 1.15) 
No dose 
adjustment 
Telaprevir 
15 
50 mg QD 
1.37 
(1.29, 1.45) 
1.25 
(1.20, 1.31) 
1.19 
(1.11, 1.26) 
No dose 
adjustment 
Rilpivirine 
16 
50 mg QD 
1.22 
(1.15, 1.30) 
1.12 
(1.05, 1.19) 
1.13 
(1.06, 1.21) 
No dose 
adjustment 
Carbamazepine 
14 
50 mg QD 
0.27 
(0.24, 0.31) 
0.51 
(0.48, 0.55) 
0.67 
(0.61, 0.73) 
DTG 50 mg BID 
Daclatasvir 
12 
50 mg QD 
1.45 
(1.25, 1.68) 
1.33 
(1.11, 1.59) 
1.29 
(1.07, 1.57) 
No dose 
adjustment 
1GMR = geometric mean ratio 
 
DTG has a low propensity to cause drug interactions. In a metabolic probe substudy, DTG did not alter 
the pharmacokinetics of midazolam, demonstrating that DTG does not induce or inhibit CYP3A4. In vitro 
studies in liver microsomes against other CYP isozymes demonstrate that DTG would not be expected to 
affect the exposure of concomitant medications that are metabolized by CYP450 enzymes. In addition, in 
vitro data demonstrate that DTG did not inhibit UGT2B7 and had only a 20% inhibition of UGT1A1, and 
this occurred at concentrations (IC50 > 100 M) that are not clinically relevant. DTG also had no 
significant effect on tenofovir exposure (Table 6).  
 
 


 
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Table 6: Effect of DTG on the Pharmacokinetics of Concomitant Medications 
Concomitant 
Drug 
N 
DTG 
Dose 
GMR1 (90% CI) 
Conclusion 
C 
AUC 
Cmax 
 
Midazolam 25 
mg 
10 
25 mg 
once 
daily 
ND 
0.953  
(0.790-
1.15) 
ND 
No effect on MDZ 
TDF 300 mg 
QD 
16 
50 mg 
once 
daily 
1.19 
(1.04-
1.35) 
1.12 
(1.01-
1.24) 
1.09 
(0.974-
1.23) 
No TDF dose adjustment 
Methadone 
11 
50 mg 
twice 
daily 
 
 
 
No methadone adjustment 
Oral 
contraceptive2 
15 
50 mg 
twice 
daily 
1.02 
(0.93, 
1.11) 
1.03 
(0.96, 
1.11) 
0.99 
(0.91, 
1.08) 
No OC adjustment 
Rilpivirine 
16 
50 mg 
once 
daily 
1.21 
(1.07, 
1.38) 
1.06 
(0.98, 
1.16) 
1.10 
(0.99, 
1.22) 
No RPV adjustment 
Metformin 
14 
50 mg 
once 
daily 
NA 
1.79 
(1.65, 
1.93) 
1.66 
(1.53, 
1.81) 
Consider metformin dose adjustment/reduction 
when starting or stopping co-administration 
with DTG to maintain glycemic control 
Metformin 
14 
50 mg 
twice 
daily 
NA 
2.45 
(2.25, 
2.66) 
2.11 
(1.91, 
2.33) 
Daclatasvir 
12 
50 mg 
once 
daily 
1.06 
(0.88, 
1.29) 
0.98 
(0.83, 
1.15) 
1.03 
(0.84, 
1.25) 
No DCV adjustment 
1GMR = geometric mean ratio 
2ethinyl estradiol 
 
With respect to DTG exposures, no clinically significant drug interactions requiring a dosage change have 
been observed with lopinavir/ritonavir, darunavir/ritonavir, atazanavir (ATV), atazanavir/ritonavir 
(ATV/r), fosamprenavir/ritonavir (FPV/RTV), tenofovir, and omeprazole.  
 
It is recommended that the dose of DTG be increased to twice daily in participants receiving EFV, FPV/r, 
or TPV/r concomitantly. The DTG unit dose in mg will still be based on weight banding per the 
IMPAACT P1093 Dosing Table Appendix, which is available at 
http://impaactnetwork.org/studies/P1093.asp. 
 
As the key of the PK evaluation in the pediatric study is to evaluate the impact of development (organ 
maturation, age, or body size) on DTG in order to guide dose selection, it would be optimal to limit other 
confounding factors that introduce variability as much as possible, especially during the intensive PK 
evaluation/dose determination in Stage 1. Therefore, use of ATV, boosted (ritonavir or cobicistat) ATV, 
FPV, TPV/r, FPV, and EFV will be disallowed during the intensive PK assessment in Stage 1.  
 
DTG is recommended to be taken at least two hours prior or 6 hours after antacids due to reduced 
absorption resulting from chelation with metal cations in antacids (12). However, DTG can be taken with 
proton pump inhibitors and H2 blockers without restriction. Concomitant administration with a 
multivitamin containing metal cations modestly decreased DTG AUC (0-) by 33% and DTG may be 
administered concurrently with multivitamins. These dosing recommendations are supported by clinical 
data (19). Concomitant administration with an antacid, Maalox Maximum Strength, decreased the AUC 
(0-) of DTG by 74%. The reduction in exposure was decreased to 26% when DTG was administered 2 
hours before the antacid.  


 
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Effect of Rifampin on DTG  
 
Rifampin induces UGT1A1 and CYP3A4 which are involved in DTG metabolism. In an open-label, 
three-period, fixed-sequence drug interaction study, 11 healthy participants received DTG 50 mg once 
daily for seven days (period 1), then DTG 50 mg twice daily for seven days (period 2), then DTG 50 mg 
twice daily together with rifampin 600 mg once daily (period 3) for 14 days. Twice daily DTG plus 
rifampin achieved mean PK parameters that were 18-33% higher than once daily dosing alone. Therefore, 
a dose of DTG 50 mg twice daily is recommended when co-administered with rifampin.  
 
1.4 
Clinical Pharmacokinetics in P1093 
  
Available data from P1093 as of 14 April 2018 are summarized below: 
 
Table 7: Pharmacokinetic Data Available from P1093 
Age Cohort 
DTG Dose 
(once daily) 
DTG PK Parameter Estimates 
Geometric Mean (CV%) 
AUC0-24 μg.hr/mL 
Cmax ng/mL 
C24h ng/mL 
12 to 18 yrs1, (n=10) 
50 mg (n=9) 
35 mg (n=1) 
46.0 (43) 
3490 (38) 
900 (59) 
6 to < 12 yrs1 (n=11) 
50 mg (n=5) 
35 mg (n=2) 
25 mg (n=4) 
50.5 (64) 
3960.6 (50) 
920 (89) 
2 to < 6 yrs2 (n=11) 
20 mg (n=1) 
15 mg (n=9) 
10 mg (n=1) 
43.5 (43) 
4239 (41) 
504 (61) 
6 mos to < 2 yrs2 (n=13) 
15 mg (n=5) 
10 mg (n=7) 
5 mg (n=1) 
55.9 (61) 
4691 (45) 
807 (87) 
4 wks to < 6 mos2 (n=10) 
10 mg (n=4) 
5 mg (n=6) 
61.2 (44) 
4459 (38) 
1207 (55) 
1 DTG film coated tablets 
2 DTG dispersible tablets 
 
Dosing recommendations for DTG in adolescents and in children ≥15 kg have been approved in the EU  
based on these data, and ≥30 kg in the U.S. Assessment of DTG dosing in the youngest children is 
ongoing. 
 
1.5 
Summary of Safety in Clinical Trials 
  
Summaries of findings from both clinical and non-clinical studies conducted with DTG can be found in 
the IB version 11 and product labels.  The following section outlines select summaries of safety for DTG. 
Where available, the approved country product label should be referenced.   
 
DTG has been administered to a total of 6004 participants (4814 HIV-infected and 1190 healthy) 
cumulative to 16 July 2017 in ongoing and completed ViiV sponsored and clinical trials ranging from 
Phase I to IIIb and the DTG compassionate use program.  DTG exposure has occurred among a total of 
1190 healthy adults in Phase I clinical trials; 4814 HIV-infected adults in Phase IIa-IIIb studies; 514 HIV-
infected adults via either the Named Patient Program or Expanded Access Program; and 121 HIV-
infected children and adolescents via the P1093 Study.  
 


 
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Meta-Analysis of 26 Completed Phase I/IIa Clinical Pharmacology Adult Studies 
 
Based on a safety meta-analysis of 26 clinical pharmacology Phase I/IIa studies using DTG single entity, 
the most commonly reported adverse events (AEs) were headache (14%), nausea (6%), and diarrhea 
(4%). These AEs are comparable to those seen in adult HIV clinical trials. Headache and nausea were the 
only AEs reported with greater frequency among participants receiving DTG compared to placebo, 
among common AEs reported in at least 5% in any analysis group (headache 14% vs 3%, and nausea 6% 
vs 3%).  Withdrawals due to AEs were infrequent (2%), and the majority of AEs were Grade 1. A total of 
two SAEs were reported and both were unrelated to DTG.  
 
In summary, the safety profile for DTG in healthy adult participants participating in phase I/IIa clinical 
pharmacology studies was similar to that observed in HIV-infected adults in the Phase IIb/III clinical 
adult program.  
 
Phase IIb to IIIb Adult Clinical Studies and Compassionate Use Program 
 
The integrated safety output (ISO) for the ART-naïve adult population is derived from four randomized 
controlled trials (ING112276, ING113086, ING114467, and ING114915), comprising a total of 1222 
participants who received DTG once daily. The ART-experienced population was comprised of 621 
participants from four trials (ING112961, ING112754, ING111762, and ING116529). For both ART-
naïve and ART-experienced (INI-naïve) patients, the ISO was similar to both RAL and DRV/RTV, and 
the most frequently observed AEs were diarrhea, nausea and headache, which tended to be Grade 1 or 2 
in severity and typically did not require discontinuation from study.  
 
There has been a total of 13 deaths up to 16 July 2017 across the DTG pivotal and supporting clinical 
trials. One death was considered related to investigative product (IP) (a 40-year-old male with renal 
failure, ING114467). Few participants receiving DTG have developed AEs requiring permanent 
discontinuation of study drug and withdrawal from study. Please refer to the DTG Investigator Brochure 
v11 for a complete listing of SAEs and AEs leading to withdrawals.  
 
Pregnancy Outcome data from the Tsepamo Study in Botswana 
 
In May of 2018, a preliminary analysis of the Tsepamo Study, a large observational study of pregnant 
women in Botswana, showed an increased rate of neural tube defects (NTDs) among infants born to 
women who started DTG at the time of conception.   
 
The Tsepamo birth outcomes surveillance study was designed to evaluate adverse birth outcomes by 
maternal HIV status and ART regimen, and to determine whether there is an increased risk of neural tube 
defects (NTDs) among infants exposed to EFV from conception. Botswana’s HIV program moved to 
universal ART with DTG/FTC/TDF provided as the first-line regimen for patients starting ART, 
including pregnant women, in May 2016 (women already on other regimens were not switched to a DTG-
containing regimen). The previous first-line regimen was EFV/FTC/TDF. Almost all women on DTG-
based and EFV-based ART took these drugs in combination with FTC/TDF. More than 95% of women in 
Botswana deliver in-hospital, and obstetric records are available for more than 99% of women. The 
Tsepamo study is conducted at eight of the largest public maternity wards across Botswana, representing 
approximately 45% of all births in the country. Research assistants extract exposure data from maternity 
cards for all consecutive in-hospital deliveries. Trained nurse midwives perform systematic infant surface 
examinations of all newborns, whether stillborn or live born. Reports and photographs (when available) of 
major abnormalities are reviewed by an experienced medical geneticist who is blinded to exposure 
information (20) (22) (22). 
 


 
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A preliminary unscheduled analysis of the Tsepamo study data collected between 15 August 2014 and 1 
May 2018 was recently performed at the request of colleagues who were preparing for a WHO meeting. 
This analysis identified four infants with NTDs born to 426 women who became pregnant while taking 
DTG (prevalence 0.94%, 95% CI 0.37%, 2.4%). In comparison, 14 infants with NTDs were born to 
11,300 women who became pregnant while taking a non-DTG-containing three-drug ART regimen 
(prevalence 0.12%, 95% CI 0.07%, 0.21%); approximately half of these women were taking an EFV-
containing regimen). No NTDs were identified among infants born to 2,812 women who started DTG-
containing ART during pregnancy (including 280 women who started DTG-containing ART during the 
first trimester). (23) 
 
At this time, only a small amount of additional data exists regarding birth outcomes among women taking 
DTG from conception, from multiple sources of varying data quality and completeness; from these 
sources, only one NTD was reported among infants born to approximately 323 women taking DTG from 
conception (24). Additional data will continue to be collected — in Botswana and ideally in other settings 
— to try to determine whether this signal for NTDs with DTG exposure from conception persists, and 
whether it is found in different populations. 
 
The Tsepamo study had previously showed similar rates of other adverse pregnancy outcomes (stillbirth, 
neonatal death, preterm or very preterm birth, small for gestational age or very small for gestational age) 
among 845 women initiating DTG/TDF/FTC (at median 19 weeks gestation) compared with 4593 women 
initiating EFV/TDF/FTC (at median 21 weeks gestation) in pregnancy. Among 512 women initiating 
ART in the first trimester of pregnancy (116 DTG/TDF/FTC, 396 EFV/TDF/FTC), one major congenital 
abnormality was identified (skeletal dysplasia in an EFV-exposed infant) (25). 
 
Although there is limited experience with the use of DTG in pregnancy, the data analyzed prior to May of 
2018 from all sources including the Antiretroviral Pregnancy Registry (26), other clinical trials and post 
marketing use has not indicated a similar potential safety issue.  
 
Additional Pregnancy and Lactation Data  
 
Sixty-nine pregnancies were reported across ViiV Healthcare (sponsored clinical trials and compassionate 
use program) up to 16 July 2017. Few cases resulted in an adverse pregnancy outcome, such as an ectopic 
pregnancy or spontaneous abortion. One congenital anomaly was reported for a participant who was 
taking DTG + ABC + ATV + RTV during the first month of gestation. A diagnosis of double-outlet right 
ventricle with ventricular septal defect was made on routine ultrasound at 31 weeks gestation. Surgery 
was performed for the defect following delivery of the infant but the infant died at day of life 4 due to 
post-operative complications. The investigator considered the congenital anomaly to be unrelated to IP. 
With the exception of this case, no other congenital anomalies have been reported in clinical trials.  
 
Post-marketing data identified a total of 235 pregnancies relating to the use of DTG in pregnant women 
(17).  
 
It is expected that DTG will be secreted into human milk based on animal data, though this has not yet 
been confirmed in humans (27).  
 
DTG was tested in a complete package of reproductive toxicology studies including embryofetal 
development studies.  In reproductive toxicology studies in animals, DTG was shown to cross the 
placenta. However, no adverse development outcomes, including NTDs, were identified from 
reproductive toxicology studies performed in animals.  
 
 


 
IMPAACT P1093, Version 5.0  
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Recognized Risks with Dolutegravir 
 
The following risks have been recognized for DTG and are summarized cumulatively from the clinical 
development program.  
 
Hypersensitivity Reaction: in the latest integrated analyses performed for DTG single entity, there were 
17 adult participants with AE preferred terms of “drug hypersensitivity” or “hypersensitivity” or who had 
a syndrome of drug hypersensitivity in 1856 cases (0.91%) exposed to at least one dose of DTG in ViiV-
sponsored IIb-IIIb clinical trials. DTG as a contributing factor to the event could not be ruled out in all but 
5 cases (0.27%), these were all potentially confounded by other ARVs (ABC, ETV, and/or DRV for 
which HSR and rash are possible outcomes). Thus, the frequency of HSR with DTG in clinical trials 
remains low, and SAE reports are generally confounded by concurrent ART.  
 
Rash: The overall rate for rash reported in the most recent ISO was 5% (91/1843) and was similar when 
taken once daily (5%) compared to twice daily (6%). 
 
Hepatobiliary Disorders: for ART-naïve participants, the incidence of grade 3 and 4 liver chemistry 
toxicities in the most recent ISO was low (<2%) for all liver chemistries across all treatment groups in the 
Phase III and IIIb studies. For ART-experienced participants, safety data suggests no excess risk of 
hepatic toxicity for DTG. In most cases where liver abnormalities have been present, one or more of the 
following have been present: history of hepatitis virus co-infection; medical history of alcohol abuse, or 
ART included drugs with well-described bilirubin or liver enzyme elevation. Please refer to the IB v11 
for further information on hepatobiliary disorders in HBV and HCV-co-infected participants. 
 
Renal Function: small increases in mean serum creatinine have been observed in participants on DTG 
across the entire clinical development program, related to a likely benign effect on creatinine secretion via 
blockade of the OCT2 receptor. Phase I studies on iohexol and para-aminohippurate clearance have 
confirmed, however, that there is no effect on GFR.  
 
Psychiatric Disorders including Suicidality: Patients with HIV infection may occasionally experience 
symptoms of depression and/or suicidal ideation. In the most recent ISO, the psychiatric profile for DTG 
was favourable compared to EFV and similar to RAL and DRV/r. There was no excess risk of DTG 50 
mg BID compared to 50 mg QD.  The adverse drug reaction of depression, suicidal ideation, and suicidal 
behaviors were added to the Company Global Data Sheet (GDS) and Reference Safety Information (RSI) 
after a review of cumulative data on depression, suicide, and self-harm with DTG up to November 21, 
2014. It was determined that a causal association could not be ruled out, though it is not considered to 
suggest a change in the positive risk benefit assessment for DTG as psychiatric events have already been 
recognized as potential risks and alternative backbone drugs for HIV treatment already have these adverse 
reactions in their labelling [ie – RAL, EVG, EFV]. Furthermore, the risk is primarily in those participants 
with a pre-existing history of depression or psychiatric illness. Thus, it is important to monitor 
participants being treated with DTG for depression, suicidal ideation, and behaviour, before and during 
the clinical study. Insomnia is listed as a common non-serious adverse reaction associated with DTG 
based on clinical trials and post-marketing experience. Additionally, it was observed at a greater 
frequency with the combination of DTG + ABC/3TC vs Atripla in one study, SINGLE (ING114467), but 
the incidence has been lower and similar to comparators in all other Phase III studies to date, including 
ARIA (ING117172), which compared TRIUMEQ with ATV/r +TDF/FTC (28). In the latest ISO, the 
psychiatric profile for DTG, which includes insomnia, was favourable compared with EFV, and similar to 
RAL and DRV/RTV. There was no excess risk of DTG 50 mg BID compared to 50 mg once daily.  
 
Clinical Laboratory Evaluations: No clinically significant trends in treatment emergent hematology 
abnormalities, electrolytes, or vital signs have been in any integrated safety analyses or across studies. 


 
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There was no evidence of a clinically significant impairment of the lipid profile by DTG treatment in the 
Phase III/IIIb studies. Lipase elevations have been noted among ART-naïve participants in the Phase IIb 
and Phase III studies though most have been transient. There is no evidence to suggest a higher rate of 
clinical pancreatitis with DTG vs comparator ARVs. 
 
Immune Reconstitution Inflammatory Syndrome (IRIS): Based on medical adjudication by the Phase III 
clinical trial Independent Data Monitoring Committee, despite the rapid decline in HIV-1 RNA observed 
on DTG, IRIS cases were generally infrequent on DTG, and the rates of IRIS on DTG were comparable 
to those observed on RAL, EFV, and DRV/RTV.   
 
Post-Marketing Data Sources (Spontaneous Reporting) 
 
DTG was approved by the US FDA in August 2013, by Health Canada in October 2013, and by the 
European Medicines Agency (EMA) in January 2014.  As of 16 July 2017, DTG has been approved in all 
EU member states, the US, and Japan, as well as 70 other countries.  The best estimates of post-marketing 
experience with the 50 mg once daily and BID doses are 275,818 and 13,164 patient-years, respectively, 
as calculated from Intercontinental Medical Statistics (IMS) Health “Sales Data” available from licensure 
until 31 March 2017. 
 
No new safety concerns emerged from an analysis of psychiatric diagnoses in patients prescribed DTG in 
the OPERA observational database, which indicated that use of DTG was not associated with an 
increased risk of psychiatric symptoms compared to other ARVs. These findings are also discussed in a 
paper published by the Marketing Authorization Holder (MAH) (28). As a result of a subsequent MAH 
review of psychiatric events with DTG, the term “anxiety” was added to the expected adverse reactions in 
the global datasheet for DTG-containing drugs, and has been reported with a frequency of “common”. 
These reactions were generally not severe, and were often seen in participants with a history of anxiety. 
Anxiety has been added to the Investigator’s Brochure as a non-serious adverse drug reaction, and, as 
such, is not considered to impact the Clinical Trial Reference Safety Information used for expectedness 
assessment of ‘suspected serious adverse reactions’.  ViiV Healthcare does not consider the addition of 
anxiety to the list of adverse drug reactions to change the overall benefit risk for participants in ongoing 
clinical studies.  
 
Conclusion 
 
DTG based regimen have demonstrated good tolerability as shown by the analyses of clinical trial data 
presented in the DTG IB v 11. No other new significant safety concerns or new potential or identified 
risks were identified from Post-Marketing experience or the analyses of clinical safety data, for the most 
recent Development Safety Update Report to Regulatory Agencies, with a Data Lock Point of 16 July 
2017. The safety data were consistent with the known safety profile of the DTG single entity and/or the 
treatment populations. 
 
1.6 
Rationale 
  
The accelerated development of DTG dosing recommendations for the treatment of HIV-1 infection in 
children of all ages is needed. A limited number of ARV medications have approved dosing for children; 
not all agents are available globally; and there remains an unmet international medical need for novel and 
potent ARV therapy for children with drug resistance or toxicity, or who are failing their current ARV 
regimen. Potential participants are often heavily pre-treated and have limited therapeutic options. In 
addition, younger children, who are infected despite exposure to ARVs in utero and after birth for 
prevention of perinatal transmission may have virus that is resistant to currently available medications. 


 
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Drugs with new mechanisms of action, such as the HIV integrase inhibitors, demonstrate activity even in 
participants with resistance to currently available reverse transcriptase and protease inhibitors.  
 
The purpose of P1093 is to determine the appropriate dose for the pediatric DTG formulations and 
acquire short and long-term safety data, intensive and population PK data, and efficacy experience with 
DTG in HIV-1 infected children.  These data are needed to guide potential use in children ages 4 weeks 
through adolescence.  Results from this trial are intended to support a regulatory filing for DTG use 
across the pediatric age spectrum.   
P1093 participants are enrolled in two stages.  The objectives of Stage I are to examine PK parameters 
after intense sampling and to evaluate the short-term tolerability and safety of DTG in approximately 10 
participants per cohort allowing for the selection of a dose.  Longer term safety, tolerability, and efficacy 
of that dose is then studied in additional participants enrolled in Stage II.  The intensive PK evaluation of 
Stage I is performed on days 5-10 to minimize the risk of sub-optimal doses (as identified by real-time 
PK evaluation) being used for prolonged periods of time.  A number of agents are prohibited during the 
intensive PK evaluation in Stage I, refer to Concomitant Medication Guidelines in Section 4.3 to 
minimize the impact of drug-drug interactions that might increase PK variability including ritonavir or 
cobicistat boosted ATV, NVP, FPV or TPV, or ATV, EFV and FPV.  However, concomitant introduction 
of NRTI agents or lopinavir/r is not expected to alter steady state DTG levels.   
Two sets of PK exposure criteria are developed: the minimal and maximal exposure and the target 
population exposure. The minimal and maximal exposure is developed for patient management in case of 
extreme exposure which prevents the participant to be considered as evaluable. The target population 
exposure (range) is developed for dose selection for the population.  
 
1.6.1 
Rationale for Pharmacokinetic Exposure Targets 
 
The goal of P1093 is to determine the doses for children that approximate DTG exposures (AUC0-
24 and C24h) observed in adults who received 50 mg once daily in the Phase I to III trials of DTG.  
Steady state intensive PK data of weight-based dosing for children will be collected in P1093 
under fasting condition. Two sets of PK exposure criteria are used in this protocol. The geometric 
mean of participant C24h and AUC0-24 are used to assess population exposures for dose 
determination.  In addition, ranges of acceptable individual C24h and AUC0-24 values have been 
separately designated to ensure the safe management of participants.   
 
Minimal and Maximal Exposure 
 
Since pediatric pharmacokinetics tend to be more variable than adults, a lower threshold range for 
both the AUC0-24 and C24h have been identified. Using maximum effect (Emax) models, the 
estimated AUC0-24 required to produce 95% of the maximum virologic response (EC95) is 
25µg.h/mL, and the EC95 for the C24h is 0.5µg/mL.  These are to be considered the lowest 
threshold exposures acceptable in this study. This lower threshold is in place to ensure minimum 
exposure criteria are met in case, for some reason, the targeted range cannot be met in an 
individual using the selected dose for the population. Similarly, the maximal exposure (upper 
threshold) is also defined to ensure participants are not exposed to extremely high drug 
concentrations which may cause safety concerns. Based on accumulated data in adults (in Phase I 
and IIb) to date, DTG is generally well tolerated with no significant safety issues identified. A 
dose of DTG 50 mg BID was studied in ING112961 (VIKING) and ING112574 (VIKING3) in 
adult HIV-infected participants. The exposure (geometric mean, 80% CI) at steady state 
following 50 mg BID exposure was 75.6 (48.8-115) µg.h/mL. The minimum-maximum AUC0-
24 range was 28.4-214 µg.h/mL following 50mg BID dosing. Therefore, the maximal exposure 


 
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target is 213 µg.h/mL for AUC0-24. Such upper threshold may be adjusted upon availability of 
further clinical data.   
 
 
An exception to the minimum exposure target may be allowed. When a participant has a low drug 
exposure, after consideration of the clinical, pharmacologic, immunologic and virologic data, and 
upon agreement of the site investigator, study co-chairs, pharmacologist and medical officers, a 
given participant may be allowed to continue with the study drug at the initial dosing that resulted 
in the exposures below the minimum target. Individual participants with extreme PK values (less 
than the minimal and greater than the maximal exposure as defined above) using the selected 
dose for the population are eligible for individual dosage adjustment. 
 
Target Population Exposure 
 
Steady state C24h and AUC0-24 are the key PK parameters utilized to compare drug exposures in 
P1093 to those obtained after 50 mg once daily dosing in adults. The geometric mean (GM) of 
C24h and AUC0-24 will be utilized to assess population exposure in study cohorts, with C24h as the 
primary target and the AUC0-24 as secondary target. 
 
DTG demonstrated good short-term safety/tolerability and antiviral activity as monotherapy and 
combination therapy in Phase IIb and Phase III trials in adults and adolescents (30). Based on 
Phase III trial data, a dose of 50 mg once daily dose is FDA approved for INI-naïve adult patients.  
The proof of concept (POC) study (ING111521) used doses of 2, 10, and 50 mg once daily as 
monotherapy for 10 days in treatment naïve participants. Spring-1 (ING112276) was a Phase IIb 
trial where treatment naïve participants received 10, 25, or 50 mg once daily for 96 weeks. There 
was no difference among these regimens with participants on all three doses achieving high rates 
of virologic suppression at 96 weeks. Table 8 summarizes the steady state pharmacokinetic 
parameters from 25 participants at the 50 mg once daily dose (combining these two studies). 
  
Table 8: Statistic Summary of DTG PK Exposure from Combined Data in ING111521 and 
ING112276 
PK 
Parameter* 
Dose 
(mg) 
N 
Obs Mean 
Std 
Dev 
Median 
10th 
Pctl 
25th 
Pctl 
75th 
Pctl 
90th 
Pctl 
Geometric 
Mean 
CVb (%) 
AUC0-24 
50.00 
25 
48.333 14.629 
47.732 
30.670 42.324 55.957 
67.222 
46.1385 
32.8404 
C0 
50.00 
24 
1090 
597 
1017 
464 
667 
1318 
1869 
946.3 
59.6907 
Cmax 
50.00 
25 
3464 
838 
3464 
2630 
3042 
3713 
4069 
3377.9 
22.7659 
C24 
50.00 
25 
1084 
560 
957 
604 
803 
1165 
2260 
955.5 
56.9724 
*Units: ug.h/mL for AUC (=AUC 0-24), and ng/mL for C0, Cmax, and C24 
 
The P1093 target population exposure (GM) for C24h is 995 ng/mL, with an acceptable 
range of 697 – 2260 ng/mL. The C24h population exposure (GM) target is selected as 995 ng/mL 
based on PK data from phase III adult studies ING111762 (SAILING) and ING113086 
(SPRING-2) where the PK of DTG was characterized without regard to food. The primary 
difference between phase III studies and P1093 study is the collection of the PK under fed/fasted 
conditions. In phase III studies, PK was characterized without regard to food while in P1093 
study, under fasting conditions. Notably, the PK of DTG varies with the ingestion of food in adult 
participants.  DTG C24h showed ~33% - ~73% increase with low to high fat meals, respectively 
(ING113674).  The acceptable range for GM C24h target  is selected as 697-2260 ng/mL. The 
lower limit is the 70th percent of geometric mean and the upper limit is the upper 80th percentile of 
observed C24h concentrations from combined data in ING111521 and ING112276.  The lower 


 
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limit is still significantly above the in vivo EC90 (300 ng/mL) from day 11 data in monotherapy 
(PoC) study, and there have been no toxicities observed at the upper limit.  This range for GM 
C24h also approximates values seen in adults receiving 50 mg once daily and are based on Emax 
modeled data as well as data collected in P1093 thus far; the upper value is approximately the 
95th percentile of observed C24h concentration in pediatric participants in study P1093.   
 
The P1093 target population exposure (GM) for AUC0-24 target is 46 µg.h/mL, with an 
acceptable range of 37-134 µg.h/mL. The AUC0-24 target of 46 µg.h/m is from combined data in 
ING111521 and ING112276 and was similar to seen in adults following 50 mg once daily dosing.  
To accommodate variability around this target and the high mg/kg dosing required to meet the 
higher C24h target, the acceptable range for AUC0-24 is defined as follows. The lower limit for GM 
AUC0-24 is selected as 80% of the target (37 µg.h/mL). The upper limit (134 µg.h/mL) is selected 
based on the upper 95th percentile of AUC obtained at steady state following 50 mg BID dosing. 
A DTG dose of 50 mg BID was studied in ING112961 (VIKING) and ING112574 (VIKING3) in 
adult HIV-infected participants. In the VIKING study (ING112961), the 50 mg BID dose was 
tolerated as well as the 50 mg QD dose; the observed AUC24 (min, max) from the 50 mg BID 
dose was in the range of 28.4-214 µg.h/mL. The AUC0-24 (geometric mean, 90% CI) at steady 
state following 50 mg BID exposure (from VIKING and VIKING 3) was 75.1 (40-134) µg.h/mL 
 
P1093 is designed to characterize the PK of DTG in pediatric participants comparing it to the PK 
obtained in adult participants for dose selection for children.  In protocol versions 1-4, AUC0-24 
was considered the primary target parameter and C24h was the secondary target parameter.  
Recently, a regulatory agency suggested that C24h be elevated to a primary target. Therefore, in 
protocol Version 5, C24h is selected as a primary target parameter for PK comparison, with AUC0-
24 secondary.   
 
Emerging data from Cohort IIA through V-DT showed that C24h (primary PK endpoint) was not 
comparable to the predefined target in pediatric participants weighing <30kg. Higher doses were 
selected to achieve a predefined C24h target based on modeling and simulation. Simulations from 
the interim population PK model showed that the proposed doses will provide trough 
concentrations in the target range. However, targeting a higher trough concentration may result in 
the expected geometric mean AUC0-24 being approximately 1.33-2 fold higher.   
 
Acceptable Individual Minimal and Maximal Exposure 
 
To ensure the safety and optimal management of participants, the P1093 protocol has specified 
ranges of acceptable C24h and AUC0-24 values for individuals.  The acceptable ranges have 
changed with different protocol versions based on evolution and accumulation of safety and 
efficacy data both in P1093 and outside studies, refer to Table 9.  
 
Table 9: IMPAACT P1093 C24 and AUC0-24 Parameters  
P1093 Protocol 
 
Version 3 
Version 4 
Version 5 
C24 
 
 
 
Target for GM 
960 ng/mL 
750 ng/mL 
995 ng/mL 
Range for GM 
770-2260 ng/mL 
500 – 2600 ng/mL 
697 – 2260 ng/mL 
MIN-MAX for individual 
MIN 500 ng/mL 
MIN 400 ng/mL 
MIN 500 ng/mL 
AUC 0-24 
 
 
 
Target for GM 
46 µg.h/mL 
46 µg.h/mL 
46 µg.h/mL 
Range for GM 
37 – 67 µg.h/mL 
37 – 86 µg.h/mL 
37 – 134 µg.h/mL 
MIN-MAX for individual 
25 – 92 µg.h/mL 
25 – 115 µg.h/mL 
25 – 214 µg.h/mL  


 
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Owing to difference in PK collection between the phase III studies and the pediatric study and 
relatively higher variability in the trough concentrations, these targets will be used as guide for 
dose selection. The individual data from participants will also be considered in final dose 
determination for age group and weight bands. Doses for each weight band will be selected taking 
the entirety of the PK and safety data into consideration.  
 
1.6.2 
Rationale for Selection of Initial Dose(s) 
 
The initial starting dose(s) for Cohort I and Cohort IIA using the film-coated tablet formulation is 
presented in the IMPAACT P1093 Dosing Table Appendix posted on the study-specific web 
page: http://impaactnetwork.org/studies/P1093.asp and labelled Table A. Starting doses in 
subsequent cohorts are outlined in tables also on this study specific web page. 
 
While this study is enrolled based on age cohorts to meet regulatory standards, weight-based 
dosing is also being evaluated in Version 5 in accord with WHO consensus guidelines.  The 5 mg 
dispersible tab was formulated to facilitate storage and administration globally.  
 
As the granule and the dispersible tablet formulations demonstrated higher exposure than the 
tablet formulation, the proposed initial doses using the granule formulation for Cohort IIB and 
successive cohorts was calculated by adjusting the tablet dose(s) by a common factor with the 
goal to match target exposures in adults. As DTG exposure from granule and dispersible tablet 
formulations given direct to mouth or with different types of water were similar and demonstrated 
55-58% higher exposure than the tablet formulation, initial doses for these formulations were 
obtained by dividing the tablet doses by a common factor of 1.55 for each weight band. Under 
protocol Version 3.0, the PK targets for Cohort IIB Stage I and Cohort III Stage I were met, but 
required an increased dose of ~0.8 mg/kg (granule formulation); there were no safety concerns in 
either Cohort. Under protocol Version 4.0, Cohort IV Stage I (≥ 6 months to < 2 years of age) 
opened with an initial dose of ~0.8 mg/kg (granule formulation).  In order to achieve higher 
C24concentrations higher doses were evaluated in Version 4.0.  
 
1.6.3 
Rationale for the Enrollment of HIV-infected Children < 2 years of age  
 
There is a need for new ARVs like DTG to treat HIV-infected children < 2 years of age. Access 
to ARVs for pregnant women has increased and rates of vertical transmission have decreased 
globally (30). However, the expanded use of NNRTIs has also corresponded with rising rates of 
ARV resistance that limit the utility of NVP and other NNRTI for the treatment of infected 
infants (32, 33). LPV/r is recommended by the WHO as first line for treatment of children < 2 
years (33), but there are persistent concerns about the storage requirements and palatability (35). 
 
The management of young HIV-infected children is distinguished by the clinical urgency with 
which treatment must be initiated. HIV-infected children < 2 years of age suffer extreme viremia, 
rapid disease progression and high mortality rates (36). Current guidelines recommended 
treatment for all HIV-infected children, but initiation is considered “urgent” for children < 2 years 
of age by the WHO (33) and US Department of Health and Human Services Panel on 
Antiretroviral Therapy and Medical Management of HIV-Infected Children (36). Accordingly, 
national guidelines in limited resource countries often recommend initiation of ART on the basis 
of a single positive HIV nucleic acid based test, rather than waiting for confirmatory results (37, 
38). 
 


 
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Version 4.0 of P1093 expanded eligibility to include children < 2 years who were ART-naïve or 
for those who recently started ART (< 4 weeks prior) so that treatment initiation be in accord with 
current guidelines and standard of care. In P1093, children < 2 years of age can enroll and initiate 
an ART with only a single positive nucleic acid test if a confirmatory test was pending; these 
participants started background regimens that were empiric or based on national guidelines while 
the results of genotype testing drawn at screening were pending.  Background regimens are 
subsequently optimized based upon the results of the genotype. 
 
1.6.4 
Rationale for Including ARV Naïve Participants  
 
In Versions 1.0-3.0 of P1093, only treatment-experienced children were eligible for 
enrollment.  In Version 4.0, the enrollment criteria were expanded to include treatment-naïve 
children < 2 years old. In Version 5.0, treatment-naïve children can enroll in any treatment group 
open for enrollment. The inclusion of treatment-naïve children is based on cumulative safety data, 
and the rationale that it is likely to be used and recommended as first line therapy in children 
consistent with DTG  now being recommended as first line therapy for adolescents and adults in 
U.S. Public Health guidelines (39). Cumulative safety and efficacy from P1093 cohorts I and IIA 
contributed to European Medicines Agency approval of DTG for children > 6 years of age (40)as 
well as FDA approval for children 30 kg and above (41). 
 
1.6.5 
Rationale for Adding Dose Analysis by Weight Band in Version 5.0 
 
The P1093 protocol is designed to enroll participants and analyze data based on age cohorts.  
Since the study was first initiated, the WHO (42) and other guideline groups around the world 
have advocated moving away from age-based dosing to one based upon weight band dosing. 
Regulatory Agencies are increasingly expecting to receive and analyze pediatric data by weight 
band to facilitate dosing recommendations in product labelling, based on this standard. Rather 
than completely modifying the P1093 study design from age-based cohorts to weight-based 
enrollment, analysis of WHO-recommended weight bands is included as a key secondary 
consideration in Version 5.0.  Therefore, enrollment into P1093 will be monitored to ensure that 
minimum numbers of participants are accrued into both age based cohorts as well as each 
relevant WHO weight band to facilitate gathering robust weight-based data to allow flexible 
treatment recommendations. The fundamental design of the study remains unchanged.  
 
1.7 
Hypothesis 
 
DTG will be generally well tolerated and demonstrate an acceptable safety profile, adequate PK and 
antiviral activity when used concurrently with an optimized background therapy (OBT) in HIV-1 infected 
infants, children and adolescents. 
 
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objectives 
 
1. To select a dose for each formulation of DTG for chronic dosing in infants, children and 
adolescents that achieves similar exposure to the DTG 50 mg once daily adult dose.  
 
2. To determine the safety and tolerability of DTG in HIV-1 infected infants, children and 
adolescents at 24 and 48 weeks. 
 


 
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3. To evaluate the steady-state pharmacokinetics of DTG in combination with OBT in 
treatment-experienced and treatment-naïve HIV-1 infected infants, children and adolescents 
and to determine the dose of DTG that achieves the targeted C24h and AUC0-24 PK parameters 
in this population. 
 
2.2 
Secondary Objectives 
 
1. To evaluate the antiviral activity of DTG in combination with an OBT by measuring 
virologic response in infants, children and adolescents at 24 and 48 weeks. 
 
2. To evaluate the effect on immunologic response from baseline to 24 and 48 weeks. 
 
3. To assess changes in HIV-1 genotype and phenotype to DTG and other components of the 
OBT in participants experiencing virologic failure. 
 
4. To determine DTG exposure, its variability and clinical covariates that impact DTG 
disposition (e.g. age, weight) using intensive and sparse sampling and population PK 
analysis.  
 
5. To determine the extended long term (≥48 weeks) safety, tolerability and efficacy of DTG in 
HIV-1 infected infants, children and adolescents. 
 
6. To explore the relationship between DTG exposure and the antiviral activity. 
 
7. To evaluate pharmacokinetic, safety and tolerability profile of DTG when dosed by weight 
bands. 
 
3.0 
STUDY DESIGN 
 
P1093 is a Phase I/II multi-center, open-label, non-comparative study of pharmacokinetic (PK) 
parameters, safety, tolerability, and efficacy of DTG in pediatric populations. Formulations will be 
evaluated in age-specific cohorts as shown below.  
 
Cohort I:  
Adolescents ≥ 12 to <18 years of age (film-coated tablets)  
Cohort IIA:  
Children ≥ 6 to <12 years of age (film-coated tablets)  
Cohort IIB: 
Children ≥ 6 to <12 years of age (granules for suspension or dispersible tablets)  
Cohorts III: 
Children ≥ 2 to < 6 years of age (granules for suspension) – closed to enrollment 
Cohort III-DT:  Children ≥ 2 to < 6 years of age (dispersible tablets)   
Cohort IV:  
Children ≥ 6 months to < 2 years (granules for suspension) – closed to enrollment 
Cohort IV-DT: Children ≥ 6 months to < 2 years of age (dispersible tablets)  
Cohort V-DT:  
Infants > 4 weeks to < 6 months (dispersible tablets)  
 
Participants receiving the film-coated tablet formulation were initially enrolled sequentially into Cohorts I 
and IIA. Granules for suspension were introduced in Protocol Version 3.0.  When it subsequently became 
clear that dispersible tablets (DT) would be the commercially available pediatric formulation, new cohorts 
for DT were opened in Protocol Version 4.0 (Section 3.3).  Under protocol Version 5.0, two formulations 
of DTG (film-coated tablets and dispersible tablets) will be evaluated; the target enrollment in Stage I was 
increased to allow for additional examination of PK, safety, and tolerability by weight bands, including 
participants from all of Cohorts III-DT, IV-DT, and V-DT (Section 3.4).  The approach for currently open 
cohorts III, IV and V is described below (Section 3.1).  However, additional cohorts and weight-band 


 
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groups might be opened or reopened to investigate data gaps or new modifications to dosing, for example, 
regarding fasting requirements or background regimens. 
 
The fundamental procedure for evaluation of DTG doses has remained unchanged through all protocol 
versions.  Each cohort is enrolled in two sequential stages: Stage I and II. (The only exception is Cohort 
IIB which only enrolled through Stage I).   In Stage I, participants undergo intensive PK sampling and are 
monitored for the safety and tolerability of DTG; to accept or reject a dose, the Protocol Team evaluates 
PK parameters exposures (Section 8.5) and 4-week safety and tolerability data (Section 9.3).  Once a 
treatment dose has been accepted, enrollment to Stage II begins to complete the cohort. Participants in 
Stage II will be followed for 48-weeks and evaluated for PK parameters (using population PK methods), 
safety and tolerability. After study week 48 all Stage I and Stage II participants transition to long-term 
follow-up and remain on study for approximately three additional years (144 additional weeks of follow-
up, for a total of 192 on study).  Study drug is provided for the duration of the study. Thereafter, 
participants are transitioned into care outside of the study (Section 10.6).   
 
3.1 
Stage I Study Design 
 
The primary objective of Stage I enrollment is to enable selection of a treatment dose.  Participants 
enrolled during Stage I undergo intensive PK sampling and are monitored to determine the safety and 
tolerability of the study dose of DTG, as summarized in Figure 2. If the Protocol Team determines the PK 
parameters, safety or tolerability data to be unacceptable at any point, Stage I enrollment is stopped. A 
new mini-cohort might be opened to evaluate new dosing that might include changes in the weight band 
dosing tables available on the study-specific website at http://impaactnetwork.org/studies/P1093.asp or 
other modifications including the potential of an alteration in recommendations for food ingestion with 
study drug.  This cyclic process continues until the PK parameters, safety and tolerability are considered 
acceptable for all doses evaluated by cohort and weight band groups.  
 
Mini-Cohort Analysis 
The first analysis of participants enrolled in Stage I includes the “mini-cohort” of the first 4 participants 
who have evaluable PK parameters and 4-week safety and tolerability data.  The purpose of this mini-
cohort analysis is to promptly identify concerning safety or PK signals.  If data from the mini-cohort are 
acceptable, per the Protocol Team (as per Sections 8.5 and 9.3), Stage I enrollment continues in that 
cohort with participants receiving the same dose.  If data from the mini-cohort analysis are deemed 
unacceptable, Stage I enrollment to that cohort is stopped, and new dosing is selected for evaluation. In 
Version 5.0 up to a maximum of seven participants can enroll while waiting for the mini-cohort analysis 
of the week 4 PK and safety analyses of the first four participants with evaluable data. Allowing 
enrollment to continue prevents delays in this early safety analysis that can occur when participants with 
unevaluable data (i.e. inadequate PK collection, incomplete adherence) must be replaced by new 
enrollees. The Protocol Team is continuously monitoring safety of all participants real tine.  
 
Interim Cohort Analysis 
The next analysis is an interim analysis that includes PK parameters and 4-week safety and tolerability of 
a dose given to the first 10 participants in each cohort with evaluable data, according to criteria outlined 
in Sections 8.5 and 9.3.  If PK parameters safety and tolerability data in this interim analysis are 
considered unacceptable by the Protocol Team, Stage I enrollment to that cohort is stopped, and new 
dosing is selected for evaluation and the process restarts. 
 
Stage 1 Full Cohort and Weight-band Analysis 
The study aims to ensure that adequate numbers of participants are enrolled into each of the age-defined 
cohorts as well as each of the weight-band groups.  To this end, once 10 participants with evaluable data 
are enrolled into a cohort, additional enrollments into that cohort are only permitted if a participant will be 


 
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contributing to achieve the minimum enrollment of 8 evaluable in a weight-band group.  To ensure 
continuous enrollment into cohorts during Stage 1, enrollment does not close until it has been confirmed 
that 8 participants with evaluable data have been enrolled and completed PK and safety assessments into a 
weight band, up to a maximum of an additional 2 participants while waiting for these results to become 
available. 
 
Stage I enrollment of all three Cohorts III-DT, IV-DT and V-DT will therefore be considered complete 
when two conditions are met simultaneously: at least 10 participants have enrolled in each of the three 
cohorts AND a minimum of 8 participants have enrolled in each of the four weight bands (Section 3.4).  
At this point, the team will perform Stage I analyses of PK, safety, and tolerability of all three age cohorts 
(III-DT, IV-DT and V-DT) and all 4 weight band groups together.  At this point, the Protocol Team could 
pass all groups together, could “fail” a dose applied to cohort or weight band and enroll additional 
participants to investigate additional dosing questions.  New cohorts or weight-band groups will be 
evaluated in the same manner (minimum 10 for age, and minimum 8 for weight, with mini-analysis after 
first 4).   
 


 
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Figure 2: Algorithm for STAGE I Enrollment and Analysis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
          
Open Stage I enrollment of a cohort to assess a selected DTG dose 
Mini-cohort Analysis: 
PK, safety and tolerability data from first 4 participants with evaluable data.  
Enrollment may continue up to 7 before this analysis performed.  
Mini-cohort PK, safety and tolerability data 
ACCEPTABLE. 
Stage I enrollment continues. 
Interim Cohort Analysis: 
Interim PK, safety and tolerability data from first 10 
participants with evaluable data.   
 
PK, safety and 
tolerability data 
NOT ACCEPTABLE.   
New dosing selected 
for evaluation in a new 
mini-cohort.   
   
Stage I Full Cohort and Weight Band Analysis: 
Minimum of 10 in each cohort AND minimum 8 in 
each weight-band group across all of cohorts III-DT, 
IV-DT, V-DT with evaluable data. 
PK, safety and tolerability studied by cohort AND by 
weight band group. 
Stage I Cohort and weight band group PK, safety and 
tolerability data  
ACCEPTABLE.  
 
Open Stage II enrollment. 
Interim PK, safety and tolerability data 
ACCEPTABLE.  
Stage I enrollment continues to complete weight band 
groups.  
Stage I PK, safety and tolerability 
data for weight band group  
 NOT acceptable; 
new weight band group enrolled 
to evaluate new dosing 


 
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3.2 
Stage II Study Design 
 
Stage II enrollment opens once a dose has been accepted based on analysis of data from Stage I 
enrollments. The additional enrollments during Stage II are intended to complete a full cohort of 
participants receiving the accepted study dose who are followed for long-term safety, tolerability and 
efficacy outcomes.  Enrollment during Stage II for each cohort will progress independently until the target 
of 22 per cohort is met; therefore, the number enrolled during Stage II varies depending on the number 
enrolled during Stage I, as described in Table 10. 
 
Table 10: Target Accrual at the Accepted Dose in Stages I and II 
Cohort 
Cohort Description 
Approximate Accrual at the Accepted Dose 
Minimum Stage I  
Participants 
Total Stage I and II 
Participants3 
I 
Adolescents ≥ 12 to <18 years of age  
(Film-coated Tablet formulation) 
10 
22 
IIA 
Children ≥ 6 to <12 years of age  
(Film-coated Tablet formulation) 
10 
22 
IIB 
Children ≥ 6 to <12 years of age  
(Granules for Suspension or Dispersible Tablets)1  
10 
10 
III 
Children ≥ 2 to < 6 years of age  
(Granules for Suspension- closed to enrollment) 
10 
22 
III-DT 
Children ≥ 2 to < 6 years of age  
(Dispersible Tablets) 
102 
22 
IV 
Children ≥ 6 months to < 2 years  
(Granules for Suspension-closed to enrollment) 
10 
22 
IV-DT 
Children ≥ 6 months to < 2 years  
(Dispersible Tablets) 
102 
22 
V-DT 
Infants > 4 weeks to < 6 months  
(Dispersible Tablets) 
102 
22 
Note: Enrollment of children into cohorts using the granules for suspension was stopped in protocol Version 
4.0; therefore, Cohorts III, and IV did not reach full enrollment targets.  
1 Dispersible tablets may also be evaluated in this cohort if requested by the regulatory authorities. 
2 Under Version 5.0, accrual into Cohorts III-DT, IV-DT, and V-DT will be continued until a minimum of 10 
participants per cohort at the accepted dose and a minimum of 8 participants per weight band is achieved as 
per Section 3.4. 
3 Additional participants might be enrolled to a cohort for additional evaluation of weight band dosing and/or 
if requested by the regulatory authorities and/or to fill a data gap (Section 3.1).  
 
3.3 
Protocol Version 4.0 – Addition of Dispersible Tablets 
  
In addition to the film-coated tablet and granules for suspension, dispersible tablets (DT) were introduced 
for study under Protocol Version 4.0. The DT formulation is being proposed as the commercially 
available pediatric formulation. In a relative bioavailability study in adults, the dispersible tablets resulted 
in PK exposure that was, on a ‘mg to mg’ basis, equivalent to granules and there were no observed 
adverse events. Based on this PK equivalency and safety data the mini-cohorts for the dispersible tablets 
could enroll simultaneously if the dose from the respective age-equivalent granules for suspension mini-
cohort was approved under Version 4.0. With varying timelines for IRB approvals and drug importation 
at U.S. and non-U.S. sites, it was anticipated that DTG dispersible tablets would not be available to all 
sites simultaneously. Therefore, enrollment into cohorts for granules for suspension was continued with 
approval from the Protocol Team until all sites obtained the DT formulation. In January 2018, all 
participants on granules were recommended to transition to DT formulations. Participants who switched 
form granules for suspension to dispersible tablets had additional evaluations as follows: 


 
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• 
On the day of switch, the initial dose of dispersible tablets should be given in the study clinic and 
observed by study staff. 
• 
Two weeks after switching to dispersible tablets, the participant should have an additional ‘Switch 
Visit’ during which a palpability assessment and RNA PCR test will be done; if this visit falls within 
the window for another scheduled visit, a combined visit can be completed to avoid duplication of 
procedures. 
• 
For participants who have completed 24 weeks of follow-up at the time of the ‘Switch Visit’ in 
addition to the procedures mentioned above, these participants will have population PK specimens 
collected at the two-week post switch visit and at the next regularly scheduled visit.   
 
3.4 
Protocol Version 5.0 – Addition of Evaluation by Weight Band or other Factors 
 
As described in Section 1.6.5 there is increased interest globally in dosing DTG by weight band 
(independent of age). To facilitate analysis of the PK, safety, efficacy, and tolerability data by weight 
band, target enrollment in Cohorts III-DT, IV-DT and V-DT is expanded in Version 5.0 to ensure that a 
minimum of 8 participants in each following weight bands will be enrolled into Stage I: 
 
a) 3 to < 6 kg 
b) 6 to < 10 kg  
c) 10 to < 14 kg  
d) 14 to < 20 kg 
 
Note that individual participants within a given weight band group are also included in an age-based 
cohort for analysis.  Additional groups of participants based on weight band alone, also generally 
including a minimum of 8 might be enrolled if dosing within a specific weight band appears concerning 
during the full cohort analysis at the end of Stage 1 or if requested by the regulatory authorities. Such 
weight band groups will be evaluated in a similar manner as the cohorts that are based on age, with 
analysis of PK parameters and 4-week safety and tolerability data from a minimum of 8 participants have 
evaluable data.   
 
Instructions for intensive PK sampling are provided in Section 9.2.1. Initially, PK sampling will be done 
in a fasting state. If, upon review of PK data, the Protocol Team determines that an additional evaluation 
of PK should be performed with and without fasting, the team will notify the sites to which cohorts or 
weight band groups this will apply and sites will follow new instructions for non-fasting around PK 
sampling. 
 
 
4.0 
SELECTION AND ENROLLMENT OF PARTICIPANTS 
 
Participants, who fail the study inclusion / exclusion criteria for viral load or toxicities at screening, may 
be rescreened after 4 weeks. NOTE: Genotypes do not need to be repeated at screening if they were 
acceptable at the previous screen. 
 
4.1 
Inclusion Criteria 
 
4.1.1 
Age: ≥ 4 weeks to <18 years at study entry. 
 


 
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4.1.2 
Confirmed HIV-1 infection 
 
• 
Documentation of HIV-1 infection defined as positive results from two samples 
collected at different time points. All samples tested must be whole blood, serum or 
plasma. 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 central laboratory.   
• 
Sample #1 may be tested by non-study public or PEPFAR programs. However, both 
the result and the assay date must be recorded in the participant’s chart. Source 
documentation (patient’s medical record/chart, in-country Ministry of Health 
registers, laboratory results, etc.) must be available if requested. 
• 
Sample #2 must be performed in a CAP/CLIA-approved laboratory (for US sites) or 
in a laboratory that operate according to GCLP guidelines and participates’ in 
appropriate external quality assurance program (for non-US sites). 
 
4.1.2.1 Acceptable tests when participants are ≤ 18 months of age: 
 
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 of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One total HIV nucleic acid  
 
Note: Participants ≤ 18 months of age can be enrolled on the basis of one positive test 
result (from Sample #1) if the results from Sample #2 are pending. The HIV RNA test 
required at screening per the Schedule of Evaluations may serve as Sample #2 and may 
be pending at the time of enrollment. However, any participant in whom infection is not 
confirmed by the results of Sample #2 should discontinue study drug, per Section 6.9 and 
be followed per Appendix IF  
 
4.1.2.2 Acceptable tests when participants are > 18 months of age:  
 
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 of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One total HIV nucleic acid  
 
Sample #2 may be tested using any of the following: 
 
• 
Rapid antibody test. If this option is used in combination with the two tests for 
Sample #1, at least one of the three rapid antibody tests for Sample #1 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 


 
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• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One total HIV nucleic acid  
 
4.1.3 
Participants must belong to one of the ARV exposure groups below:  
 
4.1.3.1 ARV-treatment experienced (not including receipt of ARVs as prophylaxis or for 
prevention of perinatal transmission)  
 
⎯ Previously took ARVs for treatment, but not currently taking ARVs: 
• 
Must have been off treatment ≥ 4 weeks prior to screening.  
 
OR 
 
⎯ Currently taking ARVs for treatment but failing: 
• 
Must be on an unchanged, failing therapeutic regimen within the 4 to 12 weeks 
prior to screening (≤1 log drop in HIV-1 RNA within the 4 to 12 weeks prior to 
screening).   
 
NOTE:  To meet this criterion, two HIV RNA levels are required: one from a date 
between 4-12 weeks prior to study screening and a second one at study screening.  
The HIV RNA level at screening must be higher than, equal to or ≤ 1 log lower than 
the prior HIV RNA level. 
 
NOTE: Dose adjustments for growth or formula substitutions (i.e. switching from 
single agent to fixed dose combination) during this 4 to 12-week period, substitutions 
of one ARV within the same class for toxicity or tolerability management, or 
discontinuation of ARVs are permitted between the HIV RNA measurements and 
screening or enrollment. 
 
OR 
 
⎯ For participants < 2 years of age, initiated ARVs for treatment < 4 weeks prior to 
screening.  
 
4.1.3.2 ARV treatment naïve (no exposure to ARVs for treatment; could have received ARVs for 
prophylaxis or prevention of perinatal transmission)  
 
4.1.4 
If an infant has received NVP as prophylaxis to prevent perinatal transmission, he or she 
must have not received NVP for at least 14 days prior to enrollment into Stage I or II.  
 
4.1.5 
HIV-1 RNA viral load greater than 1,000 copies/mL of plasma at screening  
 
NOTE: For participants enrolling into cohorts IV, IV-DT, and V-DT, the HIV RNA test 
performed at screening may be pending at the time of enrollment. If the screening HIV 
RNA is ≤ 1000 c/mL, the participant should discontinue study drug, per Section 6.9 and 
be followed per Appendix IF  
  


 
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4.1.6 
Demonstrated ability or willingness to swallow assigned study medications.  
 
NOTE: Film coated tablets MAY NOT be crushed or dissolved. Dispersible tablets MAY 
NOT be cut and must be used in five milligram intervals. 
 
4.1.7 
Parent or legal guardian able and willing to provide signed informed consent.  
 
4.1.8 
Female participants of reproductive potential, defined as having reached menarche, and 
who are engaging in sexual activity that could lead to pregnancy must agree to use two 
contraceptive methods while on study and for two weeks after stopping study drug.  
 
4.1.9 
Males engaging in sexual activity that could lead to HIV-1 transmission must use a 
condom. 
 
4.1.10 Optimized background therapy (OBT):  
 
• 
Participants who are both ≥ 2 years of age and ARV-treatment experienced (meeting 
entry criterion 4.1.3.1) must have available at least one fully active drug for the OBT 
to enroll. If screening genotype testing is inconclusive, historical genotypes obtained 
within 1 year of screening will be considered by the Protocol Team for determination 
of fully active drugs.  
• 
Participants who are ≥ 2 years of age and ARV-treatment naïve (meeting entry 
criterion 4.1.3.2) can enroll if genotype testing has been obtained with results 
pending.  
• 
Participants < 2 years of age (either ARV-treatment experienced or ARV treatment 
naïve) can enroll if genotype testing has been obtained with results pending.   
 
4.2 
Exclusion Criteria 
 
4.2.1 
Presence of any active AIDS defining opportunistic infection 
 
4.2.2 
At enrollment, participant < 3.0 kg 
 
4.2.3 
Known Grade 3 of any of the following laboratory toxicities within 30 days prior to study 
entry: neutrophil count, hemoglobin, platelets, AST, ALT, lipase, serum creatinine and 
total bilirubin. A single repeat within the 30 days is allowed for eligibility determination.  
 
NOTE: Grade 3 total bilirubin is allowable, if the participant is on ATV.  
 
4.2.4 
ANY known Grade 4 laboratory toxicities within 30 days prior to study entry.  
 
NOTE: Grade 4 total bilirubin is allowable, if the participant is on ATV.  
 
4.2.5 
The following liver toxicities within 30 days prior to study entry: ALT > 3x ULN AND 
direct bilirubin is > 2x ULN 
 
4.2.6 
Any prior history of malignancy, with the exception of localized malignancies such as 
squamous cell or basal cell carcinoma of the skin 
 
4.2.7 
Clinical or symptomatic evidence of pancreatitis, as determined by the clinician 
 


 
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4.2.8 
Use of any disallowed medications at time of screening (see Section 4.3.2 for a complete 
list of disallowed medications) 
 
4.2.9 
Known history of exposure to integrase inhibitor treatment by the participant or 
participant’s mother prior to delivery/cessation of breast feeding  
 
4.2.10 Known resistance to an integrase inhibitor 
 
4.2.11 Women who are pregnant or breastfeeding 
 
4.2.12 Participant is currently participating in or has participated in a study with a compound or 
device that is not commercially available within 30 days of signing informed consent, 
unless permission from both Protocol Teams is granted 
 
4.2.13 Participant is unlikely to adhere to the study procedures, keep appointments, or is 
planning to relocate during the study to a non-IMPAACT study site 
 
4.2.14 Any clinically significant diseases (other than HIV 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 
 
4.2.15 Participant has used, or anticipates using, chronic systemic immunosuppressive agents or 
systemic interferon (e.g., for treatment of HCV infection) within 30 days prior to 
beginning DTG study drug. Systemic corticosteroids (e.g., prednisone or equivalent up to 
2 mg/kg/day) for replacement therapy or short courses (≤30 days) are permitted. (See 
disallowed medications Section 4.3.2) 
 
4.2.16 Any condition that would, in the opinion of the site investigator, place the participant at 
an unacceptable risk of injury or render the participant unable to meet the requirements of 
the protocol. 
 
4.2.17 Active TB disease and/or requirement for treatment that includes rifampin at the time of 
the screening visit. However, participants who need rifampin treatment while on DTG 
will be allowed to continue in P1093 provided the DTG dose is adjusted according to 
Section 6.1.8. 
 
4.3 
Concomitant Medication Guidelines  
 
The concomitant use of other medications/therapies is allowed unless specifically prohibited in the 
Disallowed Medications section below.  
 
4.3.1 
Precautionary Medications 
 
DTG should be administered two hours before or six hours after taking any products containing 
divalent cations. Examples include antacids containing aluminum, calcium, magnesium and 
supplements that contain zinc or iron.  Proton pump inhibitors and H2-antagonists may be used in 
place of antacids with no scheduling restrictions. Concurrent administration with multivitamins is 
acceptable. 
 


 
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It is the responsibility of the investigator to check on potential drug-drug interactions between 
background ARV therapy and other concomitant therapies, before placing a participant on a 
specific medication. 
 
4.3.2 
Disallowed Medications 
 
For clarity, the following information on disallowed ARV medications is summarized in Table 
11.  
 
Disallowed ARV Medications for Stage I Participants BEFORE the Intensive PK Only 
The following medications are disallowed prior to the initial intensive PK evaluation for Stage I 
participants only, since they could significantly increase or decrease the levels of DTG due to 
enzyme induction or inhibition and result in increased PK variability. However, these medications 
ARE allowed in Stage I participants as part of OBT after the intensive PK evaluation has been 
completed: 
 
Atazanavir (ATV) 
Boosted (ritonavir or cobicistat) Atazanavir  
Efavirenz (EFV)  
Boosted (ritonavir or cobicistat) Fosamprenavir   
Fosamprenavir (FPV) 
Boosted (ritonavir or cobicistat) Tipranavir 
 
Disallowed ARV Medications for Participants on Stage I (BEFORE and AFTER the Intensive 
PK) and Stage II participants 
When constructing a participant’s background ART regimen, the following medications are 
prohibited for Stage I and Stage II participants because no PK data about co-administration are 
available and/or they could significantly decrease the levels of DTG due to enzyme induction: 
 
• 
Nevirapine (NVP): Nevirapine has significant drug-drug interactions with DTG resulting in 
lowered DTG exposure. The expectation that PK interaction data would become available, 
led protocol Version 3.0 to allow concurrent therapy with increased (BID) DTG dosing. Data 
has not been become available and concomitant DTG and nevirapine use is not permitted in 
protocol Version 4.0.  Prior historical NVP treatment is permitted but NVP treatment must be 
discontinued 14 days prior to initiation of DTG.  
• 
Etravirine (ETR): Etravirine UNLESS it is co-administered with lopinavir/ritonavir or 
darunavir/ritonavir; these boosted protease inhibitors have been shown to counteract 
etravirine enzyme induction. Thus, DTG may be co-administered with etravirine if the 
participant is receiving concomitant lopinavir/ritonavir or darunavir/ritonavir. 
• 
Raltegravir (RAL) 
• 
Elvitegravir (EVG) 
• 
Bictegravir (BIC)   
• 
Other INSTI drugs, including long acting preparations 
 
Additionally, due to their enzyme induction potential, the following medications, or their 
equivalents, must NOT be administered concurrently with DTG: 
 
• 
Barbiturates 
• 
Oxcarbamazepine 
• 
Pioglitazone 


 
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• 
Troglitazone 
• 
Rifampin (NOTE: see Section 6.1.8 regarding TB exclusion) 
• 
Rifabutin 
• 
Phenytoin 
• 
Phenobarbital 
• 
Carbamazepine 
• 
St. John’s wort 
 
Dolutegravir may inhibit the renal tubular secretion of dofetilide resulting in increased dofetilide 
concentrations and potential for toxicity. 
 
• 
Dofetilide 
 
The following medications are also prohibited: 
 
• 
Medications for HCV therapy 
 
Table 11: Summary of Disallowed ARV Medications 
Medication 
STAGE I 
 
STAGE II 
Allowed Prior 
to Intensive PK 
Allowed After 
Intensive PK (OBT) 
Efavirenz (EFV) 
No 
Yes* 
Yes* 
Atazanavir (ATV) 
No 
Yes 
Yes 
Atazanavir /Ritonavir (ATV/r) 
No 
Yes 
Yes 
Tipranavir / Ritonavir (TPV/r) 
No 
Yes 
Yes 
Nevirapine (NVP)** 
No 
No 
No 
Fosamprenavir / Ritonavir 
(FPV/r) 
No 
Yes 
Yes 
Fosamprenavir (FPV) 
No 
Yes 
Yes 
Etravirine (ETR) 
No 
No 
No 
Etravirine with Lopinavir / 
Ritonavir (ETR/ LPV/r) 
Yes 
Yes 
Yes 
Etravirine with Darunavir / 
Ritonavir (ETR/ DRV/r) 
Yes 
Yes 
Yes 
Raltegravir (RAL) 
No 
No 
No 
Elvitegravir (EVG) 
No 
No 
No 
Bictegravir (BIC) 
No 
No  
No 
*May NOT be given as part of OBT if it is in combination with TPV/r  
**Prior historical NVP treatment is permitted but NVP treatment must be discontinued 14 days prior 
to initiation of DTG.  
 
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 and the protocol informed consent form(s) approved, as appropriate, by their local 
institutional review board (IRB)/ethics committee (EC) and any other applicable regulatory entity.  
 
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 


 
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PRO will review the submitted protocol registration packet to ensure that all of 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. 
 
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. 
 
Participants meeting the study eligibility criteria will be enrolled through the Data Management Center 
(DMC) registration screens. Written informed consent for study participation must be obtained before any 
study related procedures are performed.  
 
Sites interested in screening potential participants into MUST request and receive permission from the 
Protocol Team in order to proceed with screening visits. Prior to emailing the team to get permission to 
screen a patient the sites must complete the PS2001 IMPAACT Screening Checklist within the 
Participant Enrollment System to obtain a screening number, which should be included in the screening 
request. 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.  
 
NOTE: If the participant has a milestone birthday that will change cohort assignment, it is the site's 
responsibility to notify the DMC data manager to request a cohort assignment change.  
 
4.5 
Co-enrollment Procedures   
 
Co-enrollment is permitted except for protocols that would violate the exclusion criteria and where 
permitted by local/country regulations. All co-enrollments in protocols require the assent of the protocol 
chairs of the main protocol and the co-enrollment protocols.  
 
5.0 
STUDY TREATMENT 
 
Study treatment is defined as DTG film-coated tablets, DTG granules for suspension (granules mixed 
with liquid) for oral administration or DTG dispersible tablets. Refer to Section 6.3 for further 
instructions regarding the timing of initiation of DTG and OBT.  
 
5.1 
Drug Regimens  
 
All dosing tables referenced below are available in the IMPAACT P1093 Dosing Table Appendix posted 
on the study-specific web page: http://impaactnetwork.org/studies/P1093.asp. 
 


 
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Weight will be measured and recorded at each visit to verify the participant is receiving the appropriate 
dose based on the current dosing table. If a participant’s weight change requires a dose adjustment, the 
dose adjustment should be made, the Protocol Team must be notified, although Protocol Team approval 
for a weight-based dose adjustment is not required. Dose adjustments for weight decreases will only be 
made if the weight decrease persists for two consecutive study visits.   
 
Participants enrolled into a given age cohort will remain in that cohort throughout their participation in 
the study. It is possible that the dose chosen for one age cohort (based upon a “mg/kg” target) may differ 
from the accepted target dose for the next older age cohort. In this case, the participant will stay on their 
current dose and will “grow” into any subsequent increase in dosing, as per the original dosing table; their 
dose should not be automatically decreased as they age. This approach is supported by acceptable safety 
and tolerance observed in adults treated with DTG 50 mg PO BID. The Protocol Team will continue to 
monitor protocol safety and, if any signals are noticed that require a modification to this approach; the 
sites will be contacted as to any necessary changes for individual participants or cohorts, see Section 6.4.  
 
Stage 1 
 
Participants enrolled to Stage I of the study will be stratified at screening into one of the age specific 
cohorts as shown below. Participants who add EFV, FPV/r, or TPV/r as part of OBT after intensive PK 
will have the frequency of the dose of DTG changed to twice daily. Beginning with protocol version 5, 
Stage I enrollment into Cohorts III-DT, IV-DT and V-DT will continue until a minimum of 10 
participants in each cohort and a minimum of 8 participants in each of the following weight band-groups 
are enrolled: 3 kg to <6 kg, 6 kg to < 10 kg, 10 kg to <14 kg and 14 kg to < 20 kg 
 
Cohort I: Adolescents ≥ 12 to <18 years of age  
• 
Dolutegravir film-coated tablets 
• 
Participants will take an initial starting dose orally of dolutegravir tablet(s) at 
approximately 1 mg/kg once daily per Table A in the IMPAACT P1093 Dosing 
Table Appendix posted on the study-specific web page: 
http://impaactnetwork.org/studies/P1093.asp.    
 
Cohort IIA: Children ≥ 6 to <12 years of age  
• 
Dolutegravir film-coated tablets 
• 
Participants will take an initial starting dose orally of dolutegravir tablet(s) at 
approximately 1 mg/kg once daily per Table A in the IMPAACT P1093 Dosing 
Table Appendix posted on the study-specific web page:   
http://impaactnetwork.org/studies/P1093.asp.  
    
Cohort IIB: Children ≥ 6 to <12 years of age  
• 
Dolutegravir granules for suspension (1.6 mg/mL). Note: Dispersible tablets may 
also be evaluated in this cohort if requested by regulatory authorities. 
• 
Participants will take an oral starting dose* of dolutegravir granules for 
suspension or dispersible tablets once daily (or twice daily as indicated below) 
per the dose determined by review of all available data, as well as any relevant 
bioavailability studies.  
• 
Participants who add EFV, FPV/r, or TPV/r as part of OBT after intensive PK 
will have the frequency of the dose of DTG changed to twice daily.   
• 
The initial dose of dispersible tablets will be administered in the clinic and 
observed by study staff. 
 


 
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Cohort III: Children ≥ 2 to < 6 years of age (Closed to Enrollment) 
• 
Dolutegravir granules for suspension (1.6 mg/mL)  
• 
Participants will take an oral starting dose* of dolutegravir granules for 
suspension or dispersible tablets once daily (or twice daily as indicated below) 
per the dose determined by review of all available data, as well as any relevant 
bioavailability studies. Refer to the selected Dosing Table.   
• 
Participants who add EFV, FPV/r, or TPV/r as part of OBT after intensive PK 
will have the frequency of the dose of DTG changed to twice daily.   
• 
The initial dose of dispersible tablets will be administered in the clinic and 
observed by study staff for tolerability.  
 
Cohort III-DT: Children ≥ 2 to < 6 years of age 
• 
Dolutegravir dispersible tablet 
• 
Participants will take an oral starting dose* of dolutegravir dispersible tablets 
once daily (or twice daily as indicated below) per the dose determined by review 
of all available data, as well as any relevant bioavailability studies. Refer to the 
selected Dosing Table.  
• 
Participants who add EFV, FPV/r, or TPV/r as part of OBT after intensive PK 
will have the frequency of the dose of DTG changed to twice daily.   
• 
The initial dose of dispersible tablets will be administered in the clinic and 
observed by study staff for tolerability. 
 
Cohort IV: Children ≥ 6 months to < 2 years (Closed to Enrollment) 
• 
Dolutegravir granules for suspension (1.6 mg/mL).  
• 
Participants will take an oral starting dose* of dolutegravir granules for 
suspension or dispersible tablets once daily (or twice daily as indicated below) 
per the dose determined by review of all available data, as well as any relevant 
bioavailability studies. Refer to the selected Dosing Table. 
• 
Participants who add EFV, FPV/r, or TPV/r as part of OBT after intensive PK 
will have the frequency of the dose of DTG changed to twice daily.   
 
Cohort IV-DT: Children ≥ 6 months to < 2 years  
• 
Dolutegravir dispersible tablet 
• 
Participants will take an oral starting dose* of dolutegravir dispersible tablets 
once daily (or twice daily as indicated below) per the dose determined by review 
of all available data, as well as any relevant bioavailability studies. Refer to the 
selected Dosing Table.  
• 
Participants who add EFV, FPV/r, or TPV/r as part of OBT after intensive PK 
will have the frequency of the dose of DTG changed to twice daily.   
• 
The initial dose of dispersible tablets will be administered in the clinic and 
observed by study staff for tolerability. 
• 
Refer to Section 5.2.3 for additional administration procedures. 
 
Cohort V-DT: Infants ≥ 4 weeks to < 6 months  
• 
Dolutegravir dispersible tablet 
• 
Participants will take an oral starting dose* of dolutegravir dispersible tablets 
once daily (or twice daily as indicated below) per the dose determined by review 
of all available data, as well as any relevant bioavailability studies. Refer to the 
selected Dosing Table.  


 
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• 
Participants who add EFV, FPV/r, or TPV/r as part of OBT after intensive PK 
will have the frequency of the dose of DTG changed to twice daily.   
• 
The initial dose of dispersible tablets will be administered in the clinic and 
observed by study staff for tolerability. 
• 
Refer to Section 5.2.3 for additional administration procedures. 
 
*Note: The initial starting Cohort dose selected and any Cohort dose adjustments will be 
communicated to study sites by the Protocol Team. For individual participant dose adjustments, 
sites will be notified by a PID specific e-mail from the Protocol Team, see Section 6.4.  
 
Stage II 
 
 
Beginning with protocol Version 5, upon the confirmation of an acceptable cohort dose in Stage 
I, additional participants will be enrolled to Stage II (if necessary) to achieve the targeted number 
of participants per cohort (refer to Section 3.2).  Participants enrolling to Stage II of each of the 
following cohorts will receive the Stage I accepted DTG dose to be administered orally once 
daily or if on EFV, FPV/r, or TPV/r as part of OBT, DTG will be dosed twice daily, as shown 
below.     
 
Cohort I:  
Adolescents ≥ 12 to <18 years of age – dolutegravir film-coated tablets. 
Cohort IIA:  
Children ≥ 6 to <12 years of age – dolutegravir film-coated tablets  
Cohort III:   
Children ≥ 2 to < 6 years of age – dolutegravir granules for suspension   
Cohort III-DT:  Children ≥ 2 to < 6 years of age – dolutegravir dispersible tablets  
Cohort IV:  
Children ≥ 6 months to < 2 years of age – dolutegravir granules for suspension 
Cohort IV-DT:  Children ≥ 6 months to < 2 years of age – dolutegravir dispersible tablets    
Cohort V-DT:  Infants ≥ 4 weeks to < 6 months of age – dolutegravir dispersible tablets 
 
Changing Dolutegravir Study Product Formulation 
 
Provisions for changing study product formulations is outlined below. 
• 
Participants entering Cohorts III-DT, IV-DT and V-DT and receiving dispersible tablets 
must continue to receive the dispersible tablets through Week 48. After Week 48, those 
participants who reach the appropriate age and weight may elect to change to film-coated 
tablets upon approval of the Protocol Team.   
• 
Participants receiving granules will switch to dispersible tablets, see Section 3.3.  
• 
The Protocol Team will retain the ability to modify participants’ dose and formulation as per 
the protocol, based on PK data, age, weight, and/or other variables. 
 
5.1.1 
Duration of Study Product Regimen 
 
Stage I and Stage II:  48 weeks  
 
Long term follow-up: Participants who successfully complete 48 weeks of DTG treatment will 
continue to receive DTG as part of long term safety follow-up. For additional information please 
refer to Section 6.6. 
 


 
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Vomiting or Missed Doses  
 
If a participant spits out a dose of DTG or vomits within 4 hours after taking DTG, the participant 
should take a full replacement dose.  If vomiting occurs more than 4 hours after taking study 
product, a replacement dose should not be taken (the next scheduled dose should be taken).   
 
If a participant misses a dose of DTG the participant should take DTG as soon as possible, 
provided the next dose is not due within 4 hours. If the next dose is due within 4 hours, the 
participant should not take the missed dose and simply resume the usual dosing schedule. 
 
5.2 
Study Product Formulations and Administration 
 
5.2.1 
Dolutegravir Film-coated Tablets  
 
Dolutegravir film-coated tablets in 10 mg, 25 mg, and 50 mg per tablet. Store at 15C to 30C 
(59F to 86F). Dispense and store only in the original manufacturer’s container. If provided,  the 
desiccant should remain in the bottle. 
 
5.2.2 
Dolutegravir Granules for Oral Suspension  
 
Dolutegravir granules for suspension 1.6 mg/1mL suspension. When the granules in the bottle are 
reconstituted with 73mL of potable (drinkable) water as directed, each container contains 160 mg 
per 100mL. Once reconstituted, the suspension is stable for 12 weeks in the manufacturer’s 
container. The reconstituted product should be stored at temperatures up to 30ºC (86ºF). Storage 
in a refrigerator is fully acceptable and preferred, if available. 
 
Preparation of oral suspension by the site pharmacist 
 
In order for the product to be dosed as 1.6 mg/mL suspension in glass bottles: The DTG pediatric 
granules 0.4% w/w are to be reconstituted into a suspension containing 1.6mg/mL through the 
addition of water by the site pharmacist as follows: 
 
Using a graduated syringe, the dispensing pharmacist, will measure 73mL of potable (drinkable) 
water (in two portions) to mix with the DTG granules; the resulting concentration of the 
suspension after it is mixed is 1.6mg/mL of DTG if reconstituted as directed. Insert a bottle 
adapter into the neck of the bottle and replace the child resistant cap. The bottle must be shaken 
for about one minute to ensure homogeneity. After shaking, visually check to ensure that there is 
no non-dispersed material adhering to the bottom or sides of the bottle. If non-dispersed material 
is observed, additional shaking is required as above. The maximum in use period of the pediatric 
formulation after it has been reconstituted with water is 12 weeks and may be refrigerated or 
stored at room temperature up to 30ºC (86ºF). The suspension should not be frozen. The DTG 
pediatric suspension reconstituted from granules should be dispensed in the same amber glass 
bottle in which the granules were mixed with water.  An oral dispenser will also be provided with 
each bottle. The suspension must be retained within the bottle in which it is dispensed and not 
transferred to any other container except the dosing syringe used for administration. The 
reconstituted suspension should be used within 12 weeks of the initial reconstitution, but 
preferably within a single month. Following reconstitution, the suspension in EVERY glass bottle 
should be shaken EVERY day, irrespective of whether doses are being taken from that particular 
bottle. Failure to follow this instruction may lead to variability in dosing.  
 


 
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5.2.3 
Dolutegravir Dispersible Tablets 
 
Dolutegravir dispersible tablet, 5 mg per tablet. Product may be stored at temperatures up to 30ºC 
(86ºF). Storage in a refrigerator is fully acceptable, if available. Once a bottle is opened the 
product has an in-use shelf life of 60 days providing the product is stored in the original package 
to protect from moisture, with the bottle tightly closed. Do not remove the desiccant. 
 
In Stage I and prior to intensive PK sampling each tablet is to be dispersed using 2 to 5mL of 
water.  There are two options for dispensing described below.    
 
• 
Option 1: for older children, pour drinking water into the dosing cup. For 1-2 tablets use 5mL 
of water. For 3-4 tablets use 10mL of water and for 5-6 tablets use 15mL of water. Add the 
prescribed number of tablets to the water. Swirl the cup gently for 1-2 minutes to fully 
disperse the tablets. The medicine will be cloudy. If any lumps of tablet remain, swirl the cup 
gently until they are gone. Give the prepared dose to the child. Rinse the dosing cup before 
next use.  
 
• 
Option 2: for infants and younger children, prepare medicine in dosing cup as directed in 
Option 1. Draw up all the medicine into the syringe.  Place the tip of the syringe against the 
inside of the infant’s cheek to give the dose slowly. Swirl a further 2mL of water into the 
dosing cup, draw it into the syringe, and give it all to the infant. Wash cup and syringe 
thoroughly.  
 
After intensive PK sampling and in Stage II each tablet can continue to be dispersed as described 
above or each tablet can be placed directly on the tongue and directly swallowed. 
 
Dispersible tablets may be given as multiples (up to a maximum of 6 tablets), depending on the 
weight of the child. Once dispersed, the medication should be consumed from the supplied dosing 
cup or syringe within five minutes.  
 
5.3 
Study Product Supply, Acquisition and Accountability 
 
5.3.1 
Study Product Supply and Acquisition 
 
Dolutegravir study products will be supplied by GSK. All DTG study products are available 
through the NIAID Clinical Research Products Management Center (CRPMC).  
 
Other components of the ARV regimen will not be supplied by the protocol.  
 
The IMPAACT pharmacist can obtain DTG by following the instructions in the manual 
"Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks" in the section Study 
Product Management.  
 
Oral syringes and dosing cups in which to measure water for dispersion and to administer the 
dispersed product will be packaged with the dispersible tablets and will be provided to the 
parent/caregiver.  Additional instructions for administration of DTG for the parent/caregiver can 
be found in the Manual of Procedures. 
 


 
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5.3.2 
Study Product Accountability  
  
The IMPAACT pharmacist is required to maintain complete records of all study products 
received from CRPMC. All unused DTG must be returned to the CRPMC after the study is 
completed or terminated at domestic sites. The procedures to be followed are given in the manual, 
"Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks" in the section Study 
Product Control.  
 
Non-US IMPAACT pharmacists should follow the instructions on the Study Product Destruction 
Form. The only study products for this protocol to be included on the Study Product Destruction 
Form are the DTG study products.  The procedures to be followed are given in the manual, 
"Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks". 
 
 
6.0 
PARTICIPANT MANAGEMENT 
  
6.1 
Toxicity Management   
 
Refer to Section 7.3 for guidance on toxicity grading. Management of adverse experiences will be 
according to the best clinical practice and the judgment of the site investigator. Alternate explanations for 
clinical and laboratory abnormalities must be sought. Laboratory normal ranges will be the institutional 
values. Abnormal clinical and laboratory findings should be followed until resolution to < Grade 2.  
 
The remainder of this section provides further guidance on reporting and management of adverse events. 
General guidance is provided in Sections 6.1.1 and 6.1.2. With respect to management, the guidance in 
6.1.2 should be followed for all adverse events except the following:  
 
• 
Liver toxicity (follow Section 6.1.3) 
• 
Decline in renal function (follow Section 6.1.4) 
• 
Proteinuria (follow Section 6.1.5) 
• 
Peptic ulcer disease (follow Section 6.1.6) 
• 
Abacavir hypersensitivity (follow Section 6.1.7) 
 
Additional considerations for management of participants co-infected with TB are provided in Section 
6.1.8.   
  
6.1.1 
Reporting 
 
All adverse events occurring from the start of DTG study drug and until the final follow-up visit 
will be source documented and recorded on case report forms (CRFs).   
 
• 
Grades 1 and 2: All AEs should be recorded on Case Report Forms (CRFs) at each visit.  
 
• 
Grades 3, 4 and 5: 
 
o All AEs should be recorded on CRFs at each visit. 
o The Protocol Team must be notified of AEs within 72 hours of awareness.  
o The investigator should attempt to confirm any laboratory test results, as soon as 
possible, but always within 72 hours.   
 


 
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6.1.2 
Management  
 
Grade 1 – Continue study drug; routine monitoring.  
 
Grade 2 – Continue study drug; monitor closely with more frequent visits as per site PI, work-up 
to exclude other causes. 
 
For Grade 3 laboratory AEs – Continue study drug while awaiting confirmatory results unless the 
clinician believes that remaining on study drug would be unsafe and that continuing them would 
pose little additional risk.  Notify the Protocol Team of the confirmatory results within 72 hours 
of awareness. 
 
For Grade 3 clinical AEs and confirmed Grade 3 laboratory AEs – hold the study drug and 
concomitant ARV therapy until the abnormalities decrease to a Grade 2 or below unless the site 
clinician believes holding ARV therapy (including study drug) would be harmful to the 
participant and that continuing them would pose little additional risk.   
 
The Protocol Team should be informed of all Grade 3 clinical AEs and confirmed Grade 3 
laboratory AEs, within 72 hours of awareness, and the site’s plan to hold or continue study drug 
and concomitant ARV therapy.    
 
Grade 4 – Hold study drug and concomitant ARVs immediately unless the site clinician believes 
that holding ARV therapy (including study drug) would be harmful to the participant and that 
continuing them would pose little additional risk. Attempt to confirm Grade 4 laboratory AEs as 
soon as possible, but always within 72 hours of the initial result.   
 
The Protocol Team should be notified of the initial and confirmatory results within 72 hours of 
awareness.  
 
For Grade 4 clinical AEs and confirmed Grade 4 laboratory AEs that are determined to be 
probably or definitely related to study drug, study drug should be permanently discontinued. For 
Grade 4 adverse events that are determined to be possibly, probably not, or not related to study 
drug, the site investigator should contact the team to determine whether and when study drug may 
be safely continued (if not previously held) or resumed (if held).  
 
All ARV therapy including study drug should be started or stopped together whenever possible, 
except when one ARV agent can be substituted for another within class when the etiology of the 
toxicity can be determined. 
 
6.1.3 
Liver Toxicities   
 
Liver chemistry threshold stopping criteria have been designed to assure participant safety and to 
evaluate liver event etiology.  If any of the following liver chemistry stopping criteria are met 
study drug (DTG) should be held unless continuation is approved by the Protocol Team:  
• 
Hy’s Law: ALT>3xULN and bilirubin>2xULN; Direct Bilirubin > 35% of Total Bilirubin. 
NOTE: Hy’s Law is a prognostic indicator that a pure drug-induced liver injury (DILI) 
leading to jaundice, without a hepatic transplant, has a case fatality rate of 10-50%. Increased 
ALT or total bilirubin are relatively common (in HIV/AIDS) but the combination of 
ALT>3xULN and total bilirubin >2xULN is rare in drug development and of clinical 
concern.  


 
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• 
ALT  10xULN; In this case, if another cause of ALT elevation is identified, the participant 
may be re-challenged after receiving the approval of the Protocol Team.   
• 
ALT > 3xULN with symptoms of hepatitis or hypersensitivity (e.g., fatigue, nausea, 
vomiting, right upper quadrant pain, fever, rash or eosinophilia). In this case, if another cause 
of ALT elevation is identified, the participant may be re-challenged after receiving the 
approval of the Protocol Team.  
• 
ALT > 5xULN for more than 2 weeks. In this case, if another cause of ALT elevation is 
identified, the participant may be re-challenged after receiving the approval of the Protocol 
Team.  Participants who develop ALT  5xULN should be followed weekly until resolution 
or stabilization (ALT < 5xULN on 2 consecutive evaluations).  
 
If any of the above liver chemistry stopping criteria are met, sites are instructed to do the 
following: 
• 
Immediately hold study drug unless continuation is approved by the Protocol Team.  
• 
Report the event to the Protocol Team by email within 24 hours of learning of its occurrence.   
• 
Report Hy’s Law liver toxicities (see above) to the RSC as an EAE 
• 
If possible, collect a 2-mL blood draw for pharmacokinetic analysis from the participant 
within 72 hours of the last dose taken, and record the date and time of the last dose taken as 
well as the date and time of the pharmacokinetic sample collected. NOTE: If the timeframe is 
greater than 72 hours since the last dose, the specimen should not be collected. 
• 
Complete and submit the liver toxicity CRFs within 1 week to the DMC 
 
6.1.4 
Decline in Renal Function   
 
Participants who experience an increase to Grade 2 from a baseline normal or Grade 1 serum 
creatinine level, or an increase to Grade 3 or higher from a baseline Grade 2 level, must return for 
a confirmatory assessment within 2 to 4 weeks. A urinalysis and urine microalbumin/creatinine 
ratio, as well as serum creatinine should be done at this confirmatory visit. If the creatinine 
elevation is confirmed (with or without proteinuria), the investigator should contact the Protocol 
Team to discuss additional follow-up and medical management. 
 
Participants who experience progression to an estimated GFR (calculated by the Schwartz 
formula) of <50mL/min (1.73m2) must return for a confirmatory assessment within 2 to 4 weeks. 
A urinalysis and urine microalbumin/creatinine ratio should be done at this confirmatory visit (in 
addition to the serum creatinine). If an estimated GFR of <50mL/min (1.73m2) is confirmed, then 
DTG should be withheld and the investigator should contact the Protocol Team to discuss 
additional follow-up and management, which may include resumption of DTG if agreed to be 
appropriate.  
 
Schwartz formula: GFR (mL/min/ 1.73 m2) = K x Ht cm/Pcreat 
 
K=constant 
 
 
Cr mg/mL 
Infants < 1 year  
 
0.45 
Children 1-12 years 
 
0.55 
Female 13-21 years 
 
0.55 
Males 13-21 years 
 
0.70 
 
Consideration for confounding factors (e.g. background ART therapy; other medications; 
dehydration and concurrent conditions) should be considered, and a nephrology consult may be 
obtained. If participants are also receiving TDF, then a switch to an alternative nucleoside should 


 
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be considered if restarting DTG. Current local prescribing information should be consulted for 
additional details on dosing background ART therapy in renal-impaired participants. If DTG is 
re-initiated, it should have been withheld for no more than 4 weeks, unless approved by the 
P1093 Team.  
 
6.1.5 
Proteinuria 
 
Participants with an abnormal urine microalbumin/creatinine ratio (>300 mcg/mg) that represents 
a change from a normal baseline and no associated increase in creatinine should have a repeat 
spot urine microalbumin/creatinine ratio and serum creatinine assay performed within 2 to 4 
weeks. If confirmed, the investigator should contact the Protocol Team to discuss additional 
follow-up and management. Additional follow-up may include nephrology referral.  
Participants with an abnormal urine microalbumin/creatinine ratio (>300 mcg/mg representing a 
change from baseline) and a serum creatinine increase to grade 2 toxicity or above, should have 
confirmation of both results within 2 to 4 weeks. If confirmed, DTG should be held, and the 
investigator should immediately contact the Protocol Team to discuss additional follow-up and 
management, which may include resumption of DTG if agreed to be appropriate.  
 
 
6.1.6 
Peptic Ulcer Disease 
 
Symptoms suggestive of peptic ulcer disease (e.g., epigastric pain, nausea, vomiting, bloating, 
etc.) are relatively common but are also non-specific. 
 
Participants with such symptoms should be treated symptomatically as appropriate (e.g., H2 
blockers or proton pump inhibitors) and be evaluated and treated as appropriate for H. pylori. 
However, patients with these symptoms should not be prescribed cation-containing antacids for 
concomitant use, because significant reduction in DTG exposure has been observed when these 
drugs were co-administered. If deemed necessary, DTG should be administered 2 hours before or 
6 hours after taking antacid products. 
 
If symptoms consistent with peptic ulcer disease persist or worsen on symptomatic therapy, the 
investigator should consult the Protocol Team to discuss additional management, which may 
include but is not limited to discontinuation of DTG. 
 
6.1.7 
Abacavir (ABC) Hypersensitivity (HSR) 
 
The most significant toxicity associated with ABC is the well-characterized drug-related 
hypersensitivity reaction (HSR).  
Where HLA-B*5701 screening is considered standard of care, it is recommended that 
investigators screen for the presence of the HLA-B*5701 allele in any participant for whom an 
Abacavir (ABC)-containing product (e.g., ZIAGEN™, TRIZIVIR™, EPZICOM™, KIVEXA™) 
may be considered as part of the optimized background regimen and HLA-B*5701 status is 
unknown (even if the participant has previously tolerated ABC). Use of ABC in participants 
known to carry HLA-B*5701 is not recommended and should be considered only under 
exceptional circumstances where potential benefit outweighs the risk and only under close 
medical supervision. 


 
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Reporting of Abacavir Hypersensitivity Reactions 
 
All cases of potential abacavir hypersensitivity MUST be reported as an EAE, refer to Section 
7.2. In addition, the ABC HSR CRF must be completed and submitted to the DMC within one 
week of the onset of the hypersensitivity reaction.  
 
6.1.8 
Management of Participants Co-infected with TB 
 
Participants presenting at the Screening visit with active Tuberculosis (TB) co-infection are not 
eligible to participate in the study due to multiple drug interactions, overlapping toxicities, and 
other complications affecting treatment outcomes. Participants who are already enrolled and are 
on therapy who become exposed to TB, and subsequently require an anti-TB treatment that 
includes the use of rifampin, may be allowed to continue in the study if their ART options are 
compatible with co-administration of rifampin. Continuation requires the approval of the Protocol 
Team. Management of these participants is as follows:  
 
• 
When administration of the rifampin-containing anti-TB treatment begins, participants will 
switch to the Schedule of Evaluations in Appendix IG  
Schedule of Evaluations 
Participants who Start Rifampin as Part of Treatment for Active Tuberculosisand will 
increase their DTG dose from once daily to twice daily (dose is based on weight). DTG study 
drug continues to be administered twice daily while participant is on the rifampin containing 
anti-TB therapy.  
 
• 
While on the rifampin-containing anti-TB therapy, to ensure the DTG dose is appropriate, 
intensive pharmacokinetic sampling will occur two weeks after the start of anti-TB treatment 
at the following times, per Appendix IG : Pre-dose, and at 1, 2, 3, 4, 6, 8, and 12 hours post-
dose will be performed. 
 
• 
Individual dose adjustments may be made to the initial DTG dose following the Week 2 
intensive pharmacokinetic study and is participant to approval of the Protocol Team. If the 
participant assessed is adherent to therapy but does not achieve the minimum AUC0-24 of 
25 µg.h/mL after dose adjustment they may continue on study drug after consideration of the 
clinical, pharmacologic, immunologic and virologic data, and upon agreement of the site 
investigator, study co-chairs, pharmacologist and medical officers, a given participant may be 
allowed to continue with the study drug at the dosing that resulted in the exposures below the 
minimum target. 
 
• 
Population PK time points at weeks 4 and 12 should remain the same as the Schedule of 
Evaluations (Appendix IG ).  
 
• 
It is estimated the participant will be on anti-TB treatment for approximately 24 weeks. Upon 
discontinuation of the rifampin containing anti-TB therapy, the participant’s DTG dose will 
revert back to once daily administration unless on EFV, FPV/r, or TPV/r. The participant 
should complete the remainder of the first 48 weeks of DTG therapy on their original 
schedule of evaluations, or if they have completed 48 weeks of DTG therapy, they should 
move to long term follow-up (Appendix IE ). For example, if the participant was at week 16 
when they were started on rifampin, and they complete 24 weeks of rifampin therapy, they 
would then go back to week 40 of their original Schedule of Evaluation (SoE). 
 


 
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6.2 
Screening 
 
The DMC will maintain a web page informing sites as to the availability of enrollment slots per cohort. 
Participants screened for enrollment in the mini-cohort of Stage I but cannot enroll because the mini-
cohort is filled will be given priority to enroll when the remaining slots are opened for that cohort. If 
Stage I enrollment is completed before a screened participant can enroll, that participant will be given 
priority for enrollment on Stage II. The Protocol Team will maintain a waiting list for each cohort to 
ensure facilitated enrollment as well as informing sites and potential participants as to the status of the 
various cohorts and stages as the study progresses.   
 
Participants will be asked to undergo the following evaluations at screening to be eligible for enrollment: 
 
• 
Medical history and physical exam  
• 
Pregnancy test (for females of child bearing age) 
• 
Confirmation of two methods of contraception for participants of reproductive potential and who are 
engaging in sexual activity that could lead to pregnancy   
• 
Hematology, chemistries, lymphocyte subsets and lipid profiles 
• 
Urinalysis 
• 
Confirmation of HIV-infection 
NOTE: for participants ≤ 18 months of age results may be pending at the time of enrolment: see 
Section 4.1.2. 
• 
HIV-1 RNA PCR 
NOTE: for participants < 2 years of age results may be pending at the time of enrolment: see Section 
4.1.5.  
• 
Real time genotyping for resistance testing 
NOTE: for all naïve participants and participants < 2 years of age (Cohorts IV, IV-DT, and V-DT) 
results may be pending at the time of enrolment; see Section 4.1.10.  
• 
Phenotyping where possible 
 
6.3 
Initiation of Dolutegravir and Management of Background ART 
 
DTG is initiated by all participants on the day of enrollment.  Additional ARV’s taken as background 
ART vary depending on timing during follow up, age, ARV-treatment history, and availability of 
genotype results.  Detailed instructions on DTG and background ART administration follow.  
 
6.3.1 
Optimized Background Therapy (OBT) 
 
The OBT regimen should ideally include one ARV with predicted antiviral activity and (at least) 
one additional ARV, for a total two ARV drugs given in addition to DTG.  The HIV-1 genotype 
obtained at screening, as well as participant history of virologic and medication tolerance should 
be used to determine an appropriate OBT regimen.  All OBT regimens must be approved by the 
Protocol Team. Sites are requested to send the proposed OBT regimen along with resistance 
profiles by email to the Protocol Team for approval, as soon as possible, once screening genotype 
results are available; the team will respond within two business days. Additional details about the 
OBT are based on cohort and ARV experience, as follows.   
 
• 
The OBT regimen for ARV-treatment-experienced participants in Cohorts I, II, III, III-DT 
must contain at least one fully active drug AND one additional drug, and be approved by the 
Protocol Team.   


 
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• 
The OBT regimen for ARV-treatment-experienced participants in Cohorts IV, IV-DT, and V-
DT AND treatment naïve participants in all cohorts will ideally contain AT LEAST one fully 
active drug AND one additional drug, and be approved by the Protocol Team.  The 
determination of OBT for these cohorts can be made before enrollment (if genotype results 
are available) or after enrollment (once screening genotype results are available); at either 
time point, the site proposes an OBT regimen that must be approved by the Protocol Team.  
Notably, the protocol permits Stage I participants to be receiving empiric regimens while 
awaiting genotype results and OBT determination.  If the screening genotype results 
ultimately do not demonstrate any available active drugs, a participant can either discontinue 
DTG (Section 6.9) or can continue on the regimen until the 4-week HIV RNA testing results 
are available.  At that point the site should propose OBT and the Protocol Team will make a 
case-specific determination of OBT acceptability taking into consideration results of the 
screening genotype, historical genotypes (up to one year prior), 4-week virologic response 
(e.g. viral load decrease of > 1 log drop or a VL <400 at the four week visit), and other 
clinical factors.  
• 
For participants in Cohorts I, II, III, III-DT, the prescriptions should have already been 
obtained from a pharmacy and the drugs must be available during the intensive PK visit to 
have the first dose observed immediately upon completion of the PK evaluations. For 
participants in Cohorts IV, IV-DT, and V-DT, the PK should be completed on day 5-10, and 
OBT initiated as soon as possible thereafter when results are back from screening genotype 
and when agents are available, as outlined below. 
• 
To minimize the impact of drug-drug interactions on PK variability, use of ATV, FPV, EFV, 
boosted (ritonavir or cobicistat) ATV, FPV, and TPV will not be allowed PRIOR to the initial 
PK evaluation in Stage I but may be added as part of the OBT regimen after completing the 
intensive PK or as part of the OBT regimen for those in Stage II.  Refer to Section 4.3.2 and 
Table 11 for a description of the medications that are disallowed during Stage I and/or Stage 
II of each cohort.  
 
6.3.2 
Empiric Background Therapy 
 
For ART naïve participants and ARV experienced participants < 2 years of age (Cohorts IV and 
V) the empiric background therapy regimen should be chosen by site investigators, per country 
guidelines and provider discretion.  In choosing the regimen consideration should be given to the 
regimen most likely to be considered effective, but it must not include disallowed medications 
(Section 4.3.2 and Table 11) and must be approved by the Protocol Team.  
 
6.3.3 
Stage I: Initiation of DTG 
 
The timing and management of DTG and background ART is outlined in Table 12 below. Note 
that age ≥ 2 years effectively applies Cohorts I, II, and III-DT and age < 2 year applies to 
participants in Cohorts IV-DT and V-DT. 
 


 
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Table 12. Stage I Timing and Management of DTG and Background ART 
ARV Exposure 
Group 
(Section 4.1) 
Age at 
Enrollment 
ARV at Entry 
ARV Management 
Immediately after  
Intensive PK Visit  
on day 5-10 
Subsequent ARV 
Modifications 
Based on 
Screening 
Genotype 
(if necessary) 
ARV-treatment 
experienced 
participants, not 
currently receiving 
ARVs  
≥ 2 years    
Start DTG alone. 
No other ARVs. 
Continue DTG. 
Start OBT. 
 
Not applicable 
< 2 years 
Start DTG. 
Start empiric 
background ART. 
Continue DTG. 
Either change background ART 
to OBT, or continue empiric 
ART (if screening genotype 
results pending). 
Change 
background ART 
to OBT when 
genotype available 
and OBT 
approved. 
ARV-treatment 
experienced 
participants currently 
receiving a failing 
regimen of ARVs (all 
ages) or who recently 
started an empiric 
regimen (<2 years old 
only). 
 
≥ 2 years    
Start DTG. 
Continue current 
ARV regimen. 
Continue DTG. 
Change background ART to 
OBT. 
 
Not applicable 
< 2 years 
Start DTG. 
Continue current 
ARV regimen. 
Continue DTG. 
Either change background ART 
to OBT, or continue empiric 
ART (if screening genotype 
results pending) 
Change 
background ART 
to OBT when 
genotype available 
and OBT 
approved. 
ARV-naïve 
participants 
  
≥ 2 years 
Start DTG alone. 
No other ARVs. 
Continue DTG. 
Start OBT or start empiric 
background ART if screening 
genotype results pending. 
 
Change 
background ART 
to OBT when 
genotype available 
and OBT 
approved. 
< 2 years 
Start DTG. 
Start OBT or 
empiric 
background ART 
if screening 
genotype results 
pending. 
Continue DTG. 
Continue OBT, start OBT or 
continue empiric background 
ART if screening genotype 
results pending. 
 
Change 
background ART 
to OBT when 
genotype available 
and OBT 
approved. 
 
6.3.4 
Stage II: Initiation of DTG 
 
During stage II, all participants initiate DTG on enrollment. ARV-treatment experienced 
participants in Cohorts I, II, III and III-DT will be based on screening results, and the regime will 
start simultaneously with DTG. ARV-naïve participants of Cohorts II and III, and all participants 
in Cohorts IV, IV-DT, and V-DT can start OBT on enrollment, or start empiric ART and change 
to OBT as soon as genotype results are available.  
 
6.3.5 
Permitted Changes to ARV Regimens (Stages I and II) 
 
No changes, re-optimization or intensification in background ARV therapy after initial 
optimization will be permitted prior to protocol-defined virologic failure, with the exception of a 
single substitution of a component of OBT with another approved compound for the management 
of drug toxicity. Formula substitutions (substituting single agents for fixed dose combinations and 


 
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vice versa of the same ARV) are not classified as a change and are permitted during the study. 
Any changes must be discussed with the Protocol Team. Unless the change is specifically 
permitted, participants who have one or more new agents added to the optimized background 
HAART regimen will be considered virologic failures. 
 
6.4 
Dose Adjustments  
 
Dose modifications will be considered after the Protocol Team reviews the intensive PK parameters and 
safety data as part at any stage of analysis (mini-cohort, interim, full cohort or weight band group) in 
Stage I. If a dose is deemed unacceptable then the Team will review the clinical, virologic and PK data 
for individual participants who are currently receiving the dose deemed unacceptable and decide whether 
a modification is in the participant’s best interest. If the dose is modified in these participants, additional 
PK sampling may be requested by the team. The type of PK sampling (intensive, specific timed samples) 
will be determined by the Protocol Team on an individual basis and communicated to the site. 
Participants who undergo a dose increase will have an additional study visit four weeks after the dose 
modification to monitor safety and then continue follow-up with no further changes in the visit schedule. 
Refer to schedule of evaluations for procedures indicated for a dose modification.  
 
In addition, at any point during study follow-up, an individual participant’s dose may be modified on a 
case-by-case basis by the Protocol Team if determined to be in the individual’s best interest. As specified 
above, the Protocol Team may request additional PK sampling and all participants who undergo a dose 
increase will have an additional visit for safety.  
 
6.5 
Virologic Failure for Participant Management 
 
 
All HIV-1 RNA PCR test results should be reviewed and entered into the Lab Data Management System 
(LDMS) within two weeks of specimen collection. If extenuating circumstances prevent results from 
being entered during this timeframe, the Protocol Team should be notified.   
 
Virologic FAILURE in this study is defined as: 
 
• 
A confirmed decrease in HIV RNA of < 1.0 log10 at or after week 12 unless the HIV RNA is < 400 
copies/mL. 
 
OR 
 
• 
A confirmed HIV RNA > 400 copies/mL starting at Week 24 or beyond on 2 consecutive 
measurements at least 1 week and within 4 weeks apart; 
 
Virologic REBOUND in this study is defined as: 
 
• 
Confirmed HIV-1 RNA > 400 copies/mL (on 2 consecutive measurements at least 1 week apart) after 
an initial confirmed response (on 2 consecutive measurements at least 1 week apart) of HIV-1 RNA < 
400 copies/mL; 
 
OR 
 
• 
Confirmed > 1.0 log10 increase in HIV-1 RNA above nadir level (on 2 consecutive measurements at 
least 1 week apart). For the purposes of this study, nadir is defined as the lowest HIV-1 RNA while 
on study drug that is > 400 copies/mL. 


 
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NOTE: A confirmatory HIV-1 RNA sample is to be collected ≥ 1 week to ≤ 4 weeks after the date of 
the HIV sample suggesting HIV virologic failure or rebound.  
 
NOTE: Participants should continue to be evaluated for virologic failure beyond Week 48 as part of 
their schedules of evaluations.  This includes participants who experience their initial or subsequent 
virologic failure (if they suppressed after a prior failure), provided that at least 24 weeks have lapsed 
from the prior virologic failure drug resistance samples.  
 
Participants, who are confirmed as virologic failures as defined above, should undergo a Virologic 
Failure Visit, as described in the Schedules of Evaluations.  At this visit, a specimen should be drawn 
for resistance testing (genotyping and phenotyping), as described in the Schedules of Evaluations. Sites 
should notify the Protocol Team of all virologic failures. Participants may then, at the discretion of the 
participant’s clinician and with the approval of the Protocol Team: 
• 
Be taken off study drug and followed as per Appendix IF . 
 
OR 
 
• 
Have background therapy re-optimized, with the participant remaining on study drug;  
 
OR 
 
• 
Continue with no changes made to the current regimen. 
 
Any re-optimization of background therapy must first be approved by the Protocol Team.   
 
6.5.1 
Viral Resistance Samples/Testing 
 
For all participants, blood samples for viral resistance assays and integrase resistance will be 
collected and stored at entry. In addition, to evaluate development of resistance to DTG and to 
other ARV therapies, used in the treatment regimen, blood samples will be collected at the 
Virologic Failure visit (as defined above) and at the Premature Discontinuation of Study Drug (if 
not already obtained at virologic failure) to assess development of genotypic or phenotypic 
resistance to DTG and/or OBT. 
 
 
6.5.2 
Algorithm for Resistance Testing 
 
• 
If a participant reaches virologic failure at or after 24 weeks and discontinues because of viral 
failure, the earliest sample with a corresponding HIV-1 RNA result above 400 copies/mL 
should be sent for all resistance testing, as outlined in the Laboratory Processing Chart which 
can be found on the P1093 protocol specific webpage: 
http://impaactnetwork.org/studies/P1093.asp 
 
• 
If a participant is a virological failure but continues in the study (on study drug), the second 
consecutive sample with a corresponding HIV RNA result above 400 copies /mL will be sent 
for all testing. In addition, resistance testing will be done for participants who continue on 
study after confirmation of virologic failure if HIV RNA is >400 copies/mL.  
 
• 
If a participant discontinues from the study early, a sample will be sent for resistance testing 
if the participant's HIV RNA level is above 400 copies /mL at the time of discontinuation.  


 
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6.6 
Long Term Safety Follow-up   
 
Participants who successfully complete 48 weeks of DTG treatment will continue on the study in long-
term follow-up and will be seen in clinic every 12 weeks for approximately 3 additional years (192 weeks 
total follow-up) per Appendix IE Appendix IE Schedule of Evaluations  
Long-term Safety Follow-up for Participants Who Continue to Receive DolutegravirStudy drug will be 
provided for the duration of the study. Thereafter, participants will be transitioned into care and treatment 
outside of the study, refer to Section 10.7. 
 
6.7 
Pregnancy and Contraception   
 
6.7.1 
Pregnancy Testing and Contraception 
 
A female participant is considered to be of reproductive potential if she has reached menarche.  
The protocol includes multiple measures to prevent and monitor for pregnancy in study 
participants, as there is concern for potential toxicity of DTG early in gestation (Section 1.5). 
 
During follow-up, all female participants over the age of 9 years are asked about menarche at 
each visit (until it occurs). 
 
 
At each visit, all female participants of reproductive potential 
• 
must have a test for pregnancy  
• 
are asked about sexual activity that could lead to pregnancy  
• 
must have their choice of TWO contraceptives (see below) documented if they are currently 
or could possibly be engaging in sexual activity that could lead to pregnancy 
• 
are reminded that if they change their minds (since enrollment) and now seek pregnancy they 
should inform the study staff 
 
One of the TWO forms of contraception must be highly effective, such as hormonal birth control 
(e.g., pills, shots, or slow release inserts placed under/on the skin) and/or an intrauterine device 
(IUD).  The second form contraception is ideally an accepted barrier method (e.g. female/male 
condoms, diaphragm or cervical cap with a cream or gel that kills sperm [excluding nonoxydyl-
9]). 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.   
 
Female participants with reproductive potential who are currently or could possibly engage in 
sexual activity that could lead to pregnancy and are unable to utilize two forms of contraception 
for some reason (such as local availability), alternative contraceptive management can be 
discussed with and approved by the Protocol Team.  Any female participant with reproductive 
potential who is sexually active in a way that could lead to pregnancy AND is unwilling or unable 
to take effective contraception must stop taking DTG.   
 
Pregnancy testing will be conducted, per the relevant Schedule of Evaluations for females with 
reproductive potential and at any time during the study when pregnancy is suspected. 
Additionally, a pregnancy test should also be performed prior to DTG re-administration, when 
dosing is disrupted for more than 7 days. Pregnancy tests may be performed on either blood or 
urine. At every visit (or some other more frequent interval), pregnancy prevention will be 


 
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discussed with the participants, including specific counseling, provision of information and 
advice as needed. This discussion should be documented in the participant’s study record. 
 
 
 
6.7.2 
Pregnancy 
 
Any participant who becomes pregnant while participating in this study should discontinue study 
drug immediately. However, these participants should remain on study but off study drug and 
followed per Appendix IF Appendix IF Schedule of Evaluations  
Participants who Prematurely Discontinue Dolutegravir, to monitor for any safety issues until the 
birth of the baby. Any pregnancy that occurs during study participation must be reported to the 
Protocol Team. All pregnancy complications, elective terminations for medical reasons and 
spontaneous abortions must be reported as an EAE.  
 
Pregnancy test results and pregnancy outcomes should be ascertained and entered into eCRFs.  
Outcomes may be ascertained based on maternal report but medical records should be obtained 
whenever possible to supplement maternal reports.   
 
Note:  Study sites will also be encouraged to prospectively register the participant’s pregnancy in 
the Antiretroviral Pregnancy Registry: http://www.apregistry.com/ (in U.S.: 1-800-258-4263; 
non-US: 1-910-679-1598).  
 
6.8 
Criteria for Study Discontinuation  
 
6.8.1 
The participant or legal guardian refuses further treatment and/or follow-up evaluations. 
 
6.8.2 
The participant fails to comply with the study requirements so as to cause harm to 
him/herself or seriously interfere with the validity of the study results. 
 
6.8.3 
The participant requires treatment with medications that are disallowed while on this 
study.  
 
6.8.4 
Virologic failure and participant does not meet the criteria for continuation of study drug.  
 
6.8.5 
Non-adherence of study medications. 
 
6.8.6 
The Protocol Team has determined that there would be no benefit to continue on study 
and receive DTG.  
 
6.9 
Criteria for Treatment Discontinuation   
 
6.9.1 
Pregnancy, refer see Section 6.7. 
 
6.9.2 
New data become available that indicate treatment should be discontinued. 
 
6.9.3 
Drug toxicity that requires permanent study drug discontinuation, see Section 6.1. 
 
6.9.4 
Liver toxicities, see Section 6.1.3. 
 
6.9.5 
The investigator determines that further participation would be detrimental to the 
participant's health or well-being. 


 
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6.9.6 
HIV infection not confirmed, see Section 4.1.2. 
 
6.9.7 
Participant was enrolled but found to have HIV RNA ≤ 1000 copies /mL at screening 
(applies only to Cohorts IV, IV-DT, and V-DT).  
 
6.9.8 
Participant was enrolled but found to have no active drugs per genotype performed at 
screening (applies only to Cohorts IV, IV-DT, and V-DT who enrolled with genotype 
results pending); and whom the Protocol Team determined the proposed OBT as non-
acceptable, see Section 6.3.1.   
 
NOTE: In the event of treatment discontinuation, participants will be asked to continue on study for 4 
weeks after they discontinue study drugs or until the adverse event resolves. 
 
 
7.0 
EXPEDITED ADVERSE EVENT REPORTING   
 
7.1 
Adverse Event Reporting to DAIDS    
 
Requirements, definitions, and methods for expedited reporting of adverse events are outlined in Version 
2.0 of the Manual for Expedited Reporting of Adverse Events to DAIDS (DAIDS EAE Manual), which is 
available on the DAIDS RSC website at http://rsc.tech-res.com/clinical-research-sites/safety-
reporting/manual. 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting system, must 
be used for EAE reporting to DAIDS. In the event of system outages or technical difficulties, EAEs may 
be submitted using 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. 
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 Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be used for this 
study.   
 
The study agents for which expedited reporting are required are DTG tablets, DTG granules for 
suspension (granules mixed with liquid) and DTG dispersible tablets for oral administration. 
 
In addition to the EAE Reporting Category identified above, other adverse events that must be reported in 
an expedited manner are:  
• 
All grade 4 toxicities,  
• 
Hy’s law liver toxicities, see Section 6.1.3,  
• 
Abacavir (ABC) hypersensitivity (HSR), see Section 6.1.7, and 
• 
All pregnancy complications, elective terminations and spontaneous abortions. 
 


 
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7.3 
Grading Severity of Events    
 
The DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading 
Table), Version 1.0, December 2004, Clarification August 2009, will be used to grade all adverse events 
except for psychiatric events listed in Table 13 below, which will be graded as shown. The DAIDS AE 
Grading Table is available on the RSC website at http://rsc.tech-res.com/clinical-research-sites/safety-
reporting. 
 
Table 13: Supplemental Table for Grading of Psychiatric Events 
 Parameter 
Grade 1 
Mild 
Grade 2 
Moderate 
Grade 3 
Severe 
Grade 4  
Potentially 
Life-Threatening 
Insomnia  
  
 
Mild difficulty 
falling asleep, 
staying asleep, or 
waking up early 
causing no or 
minimal interference 
with usual social & 
functional activities   
Moderate difficulty 
falling asleep, staying 
asleep, or waking up 
early causing more 
than minimal 
interference with 
usual social & 
functional activities 
Severe difficulty falling 
asleep, staying asleep, or 
waking up early causing 
inability to perform usual 
social & functional 
activities requiring 
intervention or 
hospitalization  
NA 
Psychiatric 
Disorders 
(includes 
anxiety, 
depression, 
mania, and 
psychosis)  
Specify 
disorder 
Symptoms with 
intervention not 
indicated OR 
Behavior causing no 
or minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
intervention indicated 
OR Behavior causing 
greater than minimal 
interference with 
usual social & 
functional activities 
Symptoms with 
hospitalization indicated 
OR Behavior causing 
inability to perform usual 
social & functional 
activities  
Threatens harm to 
self or others OR 
Acute psychosis OR 
Behavior causing 
inability to perform 
basic self-care 
functions 
Suicidal 
Ideation or 
Attempt  
Report only 
one  
Preoccupied with 
thoughts of death 
AND No wish to kill 
oneself  
 
Preoccupied with 
thoughts of death 
AND Wish to kill 
oneself with no 
specific plan or intent  
Thoughts of killing 
oneself with partial or 
complete plans but no 
attempt to do so OR 
Hospitalization indicated  
Suicide attempted 
 
7.4 
Expedited AE Reporting Period    
 
• 
The expedited AE reporting period for this study is the duration of the study.  
• 
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). 
 
NOTE: For reporting of all adverse experiences the Investigator will determine the causality and 
relationship to study drug. However, regarding participant 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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8.0 
STATISTICAL CONSIDERATIONS 
 
8.1 
General Design Issues 
 
This is a Phase I/II study whose primary objectives are to assess the safety and pharmacokinetics of DTG 
administered to HIV-1-infected infants, children and adolescents with ages ranging from 4 weeks to < 18 
years. The sample will be stratified into the following groups:  
 
Cohort I:  
Adolescents ≥ 12 to <18 years of age (tablets)   
 
Cohort IIA:  
Children ≥ 6 to <12 years of age (tablets)  
 
Cohort IIB: 
Children ≥ 6 to <12 years of age (granules for suspension) 
 
Cohorts III:  
Children ≥ 2 to < 6 years of age (granules for suspension or dispersible tablets)  
 
Cohort III-DT: Children ≥ 2 to < 6 years of age (dispersible tablets)  
 
 
 
 
 
 
 
Cohort IV:  
 Children ≥ 6 months to < 2 years (granules for suspension) 
 
Cohort IV-DT: Children ≥ 6 months to < 2years of age (dispersible tablets)  
 
Cohort V-DT:  Infants > 4 weeks to < 6 months (dispersible tablets) 
 
A minimum of ten participants will be enrolled into each age cohort in Stage I for purposes of dose 
finding. Under Version 5, for stage I enrollment intro Cohorts III-DT, IV-DT, and V-DT, there is also a 
requirement to enroll a minimum of eight participants (which may include those already enrolled into the 
age cohort) into each of the following weight band groups: 
 
1) 3 to <6 kg 
2) 6 to <10 kg 
3) 10 to <14kg 
4) 14 to <20 kg 
 
To this end, once a cohort has enrolled 10 participants, additional participants will be allowed to enroll 
during Stage I only if their weights fall within a weight band that has not yet reached its enrollment target 
of N=8 with evaluable PK and safety data; enrollment of up to 2 additional participants to a total of 10 per 
weight band will be allowed while evaluation of the minimum of 8 is ongoing (i.e. to confirm data are 
evaluable). Additional participants will be enrolled into Stage II of the study and treated at the doses 
determined optimal for their cohorts based on Stage I results. The total sample will provide a minimum of 
120 evaluable participants (Stage I + Stage II) who have been treated exclusively at the doses judged to 
be optimal for their age cohorts (see Schema for breakdown by cohort) and weight band groups.  
 
Under previous protocol versions, accrual to Stage I followed an algorithm in which younger children’s 
exposure to the study medication was contingent upon success in meeting safety and pharmacokinetic 
guidelines in the older strata. Thus, Cohort I was the first to opened with enrollment in Cohort IIA 
contingent upon whether members of Cohort I met the guidelines for safety and PK parameters. Cohort 
IIB then opened once members of Cohort IIA passed safety and PK criteria and a pediatric formulation 
was available. A similar approach was used for the rest of the younger cohorts, each of whose opening 
was contingent upon successful results from the next older age cohort. Because data have already now 


 
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been obtained from all cohorts, under protocol Version 5.0 accrual to Stage I for Cohorts III-DT, IV-DT 
and V-DT will be simultaneous, rather than sequential.   
 
The data from Stage I is analyzed in three steps, a mini-cohort analysis, an interim cohort analysis, and 
the full cohort and weight band group analysis (Section 3.1). For the mini-cohort analysis, the overall 
safety and PK data of the first 4 participants with evaluable data in a given cohort will be evaluated with 
respect to the safety guidelines, per Section 8.5 and the PK guidelines, per Section 9.3. If the first 4 
evaluable participants of this cohort meet both sets of guidelines, then accrual will continue and no dose 
adjustments will be made.  If the first 4 evaluable participants of the older cohort fail either the safety or 
the PK guidelines in this initial test, then the starting dose will be adjusted in the appropriate direction, 
(e.g. upwards for inadequate PK values; downwards for safety failure), if this is feasible. New doses will 
be tested in the same manner, enrolling new participants and reviewing PK and safety data from the first 4 
participants with evaluable data.  The evaluation will proceed as described above.   
 
The interim cohort analysis occurs when there are 10 participants with evaluable data in an age cohort. 
Data will be evaluated, and safety guidelines, per Section 8.5 and the PK guidelines, per Section 9.3. If 
there are no concerns, enrollment continues but additional participants can only into a cohort if they also 
contribute to meeting the weight band group minimums.  
 
For the full Stage I cohort and weight band group analysis, the starting dose of fully accrued cohorts are 
evaluated by BOTH cohort and weight band group on the basis 4 week safety (as per Section 8.5) and 
intensive PK data (as per Section 9.3). As of Version 5.0, the full analysis of Stage I data for Cohorts III-
DT, IV-DT and V-DT occurs when all cohorts and weight band groups have met minimum enrollment 
targets and achieved 4-weeks of follow up (See Section 3.1 for more details).  The purpose of this review 
process is to take account of all available information in determining whether the dose finding algorithm 
has converged on the best dose for further study in Stage II or whether adjustments are needed. As part of 
this review process, safety and PK data will be broken down based on the dosing adjustments that have 
been made because of the inducing or inhibiting effects of the background regimens. If there is evidence 
that some adjustments may have been associated with undesirable PK levels or with safety concerns, 
these adjustments may be modified for Stage II or further data may be gathered prior to opening Stage II.     
 
If a dose is “failed” by the Protocol Team, considering the safety and/or PK targets (refer to Section 3.1) 
at the mini-cohort, interim or full cohort analysis stages, a new test dose will be examined. New 
participants will be started on the new dose and evaluations will proceed as described above. For 
participants who meet PK targets, safety will be evaluated based on all available data collected through 4 
weeks on that dose. For participants who fail to meet PK targets and are required to have a dose 
adjustment, safety will be evaluated based on data gathered until the time of the visit at which the dose is 
adjusted.  
 
If the Protocol Team deems a given participant’s PK data to be unevaluable (e.g., because of reported 
non-adherence or PK results that would be physiologically implausible with good adherence), that 
participant will be replaced for dose finding purposes (but will continue in the study and contribute to the 
safety analyses). 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. 
 
If the dosing recommendation for a given subgroup of participants should differ between that based on 
age cohort vs. that based on weight band, the Protocol Team will review all relevant data and make a final 
dosing recommendation. In a situation where a final dosing recommendation cannot be made with 
available data, the Protocol Team can enroll additional cohorts or weight band groups until a dosing 
recommendation can be made. 
 


 
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Participants accrued to Stage II of the study will be administered the doses determined for their age 
cohorts, with no individual dose adjustments based on PK allowed. For purposes of analysis, data from 
these participants will be combined with the data from the Stage I participants who have been treated at 
the doses accepted for their cohorts and weight bands and who have not required individual PK 
determined dose adjustments, such that their total exposure to the study drug has been at the accepted 
dose. Sensitivity analyses will be performed to determine whether the exclusion of participants whose 
doses have been adjusted creates a selection bias which impacts upon any results.  
 
Participants who switched formulation will be included in sensitivity analyses whose purpose would be to 
(1) identify safety issues for all children exposed to the study drug, and (2) determine whether the results 
of those switching formulations differed descriptively from those of the primary analysis. 
 
Participants with no study drug dose adjustments, except for those due to change in age and/or weight 
where the adjusted doses conform those to be recommended for the resulting group, will be included in 
the primary analysis and classified in the original cohort and weight band in which they enrolled. For 
participants whose study drug dose is adjusted due to PK outcomes (after the week 4 visit), safety data up 
to the date of dose adjustment will be analyzed in the original cohort/weight band, and sensitivity 
analyses will be performed to assess whether conclusions drawn from primary dose confirmation 
evaluations would be affected by inclusion of these data. 
  
Study accrual is designed to yield at least 120 evaluable participants for the weeks 24 and 48 safety 
analyses: some participating in Stage I and some participating in Stage II.  In order to ensure that the 
primary safety analyses will yield results that can be generalized to the overall patient population, the 
“evaluable” participants for the primary analysis will be defined as those participants whose treatment 
will conform to the final dosing recommendation that will result from this protocol.  This sample will 
consist of participants: 1) whose starting dose was the dose determined to be the final confirmed starting 
dose of DTG for their cohort/weight band; 2) whose dose may have been changed, due to changes in age 
and/or weight, provided that the dose they received at that cohort/weight band is the dose that will be 
recommended for members of the treatment population who experience a similar progression.  
Participants whose treatment regimens conform to those described in #1 and #2, above, but who leave the 
study due to treatment failure or toxicity prior to completing 24 weeks or 48 weeks of treatment, will be 
included in the sample for the primary analyses and will be treated as failures in those analyses.” 
 
8.2 
Endpoints and Outcome Measures 
 
For safety reporting and monitoring purposes, a drug related adverse event is defined as an adverse event 
that is judged to be definitely, probably, or possibly related to the study drug. Endpoints and outcome 
measures are generally to be assessed by cohort, unless otherwise specified. 
 
8.2.1 
Primary Endpoints - presented aggregated and by cohort 
 
8.2.1.1 Toxicity through Week 24 
• 
All adverse events or lab toxicities of Grade 3 or higher severity 
• 
Adverse events or lab toxicities of Grade 3 or higher severity judged to be at least 
possibly attributable to the study medication 
• 
Termination from treatment due to a drug-related adverse event 
• 
Death 
 


 
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8.2.2 
Primary Response Variables 
 
8.2.2.1 Pharmacokinetics  
• 
C24h, AUC0-24 
 
8.2.3 
Secondary Endpoints -  presented aggregated, by cohort, and by weight band 
 
8.2.3.1 Toxicity through week 48 and beyond 
• 
All adverse events or lab toxicities of grade 3 or higher severity.  
• 
Adverse events or lab toxicities of grade 3 or higher severity judged to be at least 
possibly attributable to the study medication. 
• 
Termination from treatment due to a drug-related adverse event.  
• 
Death 
 
8.2.3.2  Plasma HIV-1 RNA (copies/mL) <400 copies/mL and <50 copies/mL 
 
8.2.3.3 Pharmacokinetics 
• 
AUC0-24, C24h, C0, Cmin, Cmax, CL/F, Vz/F and t1/2 
 
8.2.4 
Secondary response variables 
• 
CD4/8 counts and percent 
• 
Genotypic and phenotypic measures of resistance at baseline and at virologic failure 
• 
Disease progression as measured by change in CDC category 
 
8.3 
Randomization and Stratification 
 
There will be no randomization. In each stage, participants will be stratified into cohorts defined by age 
and formulation, as described in Section 8.1. In addition, under Version 5, enrollment of participants by 
weight band will be monitored. 
 
8.4 
Sample Size and Accrual 
 
Total accrual will depend upon the number of participants who must be accrued to yield at least 120 
evaluable participants for purposes of the primary safety analyses and the regulatory submissions. There 
is some uncertainty concerning the number needed to complete the dose finding procedures in Stage I and 
the number who may be lost to follow-up for reasons other than treatment failure. Each successful cohort 
on Stage I will include a minimum of 10 participants; the majority of whom will have been treated 
continuously on the dose that has been chosen for Stage II. This will likely yield additional participants 
from Stage I who will contribute to the evaluation of the optimal dose. Thus, approximately300 
participants will be accrued to ensure that the total sample includes at least 120 evaluable participants 
who have been treated only on the optimal dose and that the quotas for each cohort, specified in the 
Schema, have been filled.  
 
The selection of a sample size of ten participants in Stage I for each age cohort is based on feasibility and 
the historical pediatric recruitment experience of GSK and IMPAACT, as well as justification to target a 
95% confidence interval (CI) within 60% and 140% of the point estimate for the geometric mean 
estimates of clearance (CL/F) and volume of distribution (Vd) for DTG with an at least 78% power.  
 


 
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Variability (CV%) in CL/F and Vd for each age cohort are predicted based on the population PK model 
developed using adult data from ING111521 and ING112276. In the adult population PK model, CL/F 
and Vd are modeled as the following: 
 
CL/F (L/hr)  =  0.873 * (WT/70)^0.713*EXP(eta1), eta1 ~ N (0, 0.0857) 
Vd (L) = 17.5 * (WT/70)^1.02 * EXP(eta2) + 1.6, eta2 ~ N (0, 0.0365) where WT is body weight 
in kg. 
 
Using predicted variability in CL/F and Vd, simulations (10,000 simulations with a sample size of 10 for 
each simulation) were performed to estimate % chance for 95% CI of geometric mean estimates of 
simulated CL/F and Vd to fall within 60% to 140% of the point estimates (equivalent to power).  
 
Table 14 presents the projected weight range, predicted mean and variability (coefficient of variability, 
CV) in CL/F and Vd, and estimated power for a sample size of 10 in each age cohort. 
 
Table 14: Power Estimation based on Proposed Sample Size of 10 Per Cohort for Stage I 
Age Cohort 
Projected 
Weight Range 
(kg) 
PK Parameter 
Predicted 
Mean 
Predicted CV 
Power (%) 
12-18yr 
30-100 
CL/F 
0.85 
0.38 
94.1 
 
 
Vd 
18.1 
0.34 
98.5 
6-<12yr 
17-52 
CL/F 
0.54 
0.38 
95.1 
 
 
Vd 
10.3 
0.30 
99.7 
2-<6yr 
10.7-23 
CL/F 
0.21 
0.34 
98.4 
 
 
Vd 
5.77 
0.21 
100 
6mo-<2yr 
6.75-15.1 
CL/F 
0.13 
0.34 
98.2 
 
 
Vd 
4.28 
0.19 
100 
4wk-<6mo 
3.77-9.26 
CL/F 
0.084 
0.35 
97.5 
 
 
Vd 
3.18 
0.16 
100 
 
Power for a sample size of 10 and CV of 0.45, which is 20% higher than the highest predicted CV, was 
estimated to be >78%. Power for a sample size of 9 and CV of 0.45, was estimated to be >68%. 
 
8.5 
Safety Guidelines for the Evaluation of Stage I Starting Doses 
 
The attribution of serious adverse events to study drug for the purposes of employing the start, stop and 
pause rules will be by consensus among the site investigator and the Protocol Team. If unanimous 
agreement between them cannot be established, the relevant data will be reviewed by the P1093 Study 
Monitoring Committee, 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 the P1093 Study Monitoring Committee clinicians. Gradation of relationship will use the 
following terminology: ‘Not related’, ‘Probably not related’, ‘Possibly related’, ‘Probably related’ or 
‘Definitely related’.  
 
Table 15 and Table 16 below use a multinomial response model to assess the probability of failing the 
safety criteria under each of the hypothetical situations specified in those tables. The calculations are 
performed as follows: Each of the total number of participants represents a trial, which may have 1 of 3 
mutually exclusive outcomes: (1) a life threatening drug-related adverse event or a grade 4 event judged 
to be at least probably related to treatment; (2) a Grade 3+ event, not satisfying the criteria set forth in #1, 
immediately above, but judged to be at least possibly related to study drug and resulting in termination of 


 
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study drug; and (3) a relatively benign outcome, satisfying neither the criteria in #1 nor #2, immediately 
above.  
 
Each table has its sets of results under which the set of trials would pass the safety criteria. The 
probability of passing the safety criteria represents the sum of the probabilities of these sets of results, and 
“1 minus the probability of passing the safety criteria” represents the probability of failing them. The 
“True Toxicity Rates” presented in the tables, along with the true rate of having neither of the types of 
toxicity represented by the true toxicity rates (which is 1 - the sum of the true toxicity rates), provide the 
probabilities for the outcomes which are used in the multinomial calculations for each of the hypothetical 
situations.  
 
8.5.1 
Safety Guidelines for the First Four Participants Started at a Given Dose Level in Each Stage I 
Cohort  
 
For each Cohort, for the mini-cohort analysis (see Stage I Study Design3.1), the frequency of 
adverse reactions to the starting dose of the study medication will be evaluated on the first 4 
participants with evaluable data. The data will extend to the week 4 visit for participants not 
requiring PK determined dose adjustment or until the visit on which the dose is adjusted, as 
described above. Further accrual into this cohort will be contingent upon meeting the following 
safety guidelines. 
 
If any of the first 4 participants has a life threatening drug-related adverse event or any Grade 4 
event that is probably or definitely attributable to the study medication, or in the first four 
evaluable participants 2 or more have terminated study drug due to a grade 3+ drug-related 
adverse event stop accrual into this dose group, until a safety review by the Protocol Team has 
been conducted.  All of the relevant safety and pharmacokinetic data will be reviewed to 
determine whether it is safe to continue the attempt to find an optimal dose for this cohort. If the 
team determines that it is safe to proceed, it will make any changes in the dosing and monitoring 
procedures which have been judged to be necessary. If there are any concerns regarding safety, 
the P1093 Study Monitoring Committee will then review all relevant safety and pharmacokinetic 
data, along with the recommendations of the Protocol Team, and will determine whether and 
under what conditions further dose finding activities for this cohort may proceed.  
 
The protocol will only proceed if this review has led to a recommendation that it is safe to do so 
and the team agrees. The safety review may lead to a recommendation that the dose be de-
escalated. Before implementing such a recommendation, the Protocol Team will review the PK 
data to determine whether a lower dose is likely to achieve adequate drug exposure. 
 
If none of the first 4 participants has experienced a life-threatening drug-related adverse event or 
a Grade 4 event that is probably or definitely attributable to the study medication and fewer than 
2 of these 4 participants have terminated study drug due to a grade 3+ drug-related adverse event, 
then this group has passed the initial interim safety guidelines. If these 4 participants also meet 
the PK guidelines, the cohort will continue to enroll a minimum of 10 participants to evaluate the 
safety and PK. 
 
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 group 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 group 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.  


 
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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 participant population at the dose level under 
question. The hypothetical situations presented in Table 15 range from conditions under which a 
given dose level would cause a high incidence of severe and life threatening drug-related adverse 
events to conditions under which severe drug-related adverse events would be relatively rare and 
would not be life threatening. For each of these hypothetical situations, a sample of four 
participants is drawn from the participant population and that the safety guidelines is assumed, 
summarized above, are followed.  
 
For example, Table 15 shows that there is a 78% chance of failing the safety guidelines under 
conditions in which the true rate of life-threatening toxicity is 5% and the rate of non-life 
threatening drug-related adverse event is 50%. 
 
Table 15: Probability of Failing Dose Escalation Guidelines under Potential Rates of True 
Toxicity 
True Toxicity Rates 
Probability of 
Failing Safety 
Guidelines 
Non-Life Threatening drug-related 
adverse events that would result in Tx 
discontinuation, excluding Grade 4 events 
probably or definitely attributable to study 
medication 
Life Threatening drug-related 
adverse events (including death) 
or Grade 4 events probably or 
definitely attributable to study 
medication 
.50 
.00 
.69 
.50 
.05 
.78 
.50 
.25 
.96 
.25 
.00 
.26 
.25 
.05 
.42 
.25 
.25 
.81 
.05 
.00 
.01 
.05 
.05 
.20 
.05 
.25 
.69 
.00 
.05 
.19 
.00 
.25 
.68 
 
Assuming that it would be undesirable to accrue additional participants 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 1 % chance of failing, when the true 
rate of non-life threatening drug-related adverse events is only 5% and the true rate of life 
threatening drug-related adverse events is zero. Assuming that the potential benefits associated 
with exposing additional participants 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. 
 
8.5.2 
Safety Guidelines for the Interim and Full Cohort Analyses, with a Minimum of Ten Participants 
Started at a Given Dose Level in Each Stage I Cohort 
 
The safety guidelines applied to a given starting dose of the study medication within a cohort for 
either the interim cohort analysis or full cohort analysis (see Section 3.1), will make use of data 
from all participants started at that dose. The data will extend to the week 4 visit for participants 
not requiring PK determined dose adjustment or until the visit on which the dose is adjusted, as 


 
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described above. If any of these participants has a life threatening drug-related adverse event or 
any Grade 4 event that is probably or definitely attributable to the study medication, or more than 
25% terminated study drug due to grade 3+ drug-related adverse event, this starting dose will fail 
the safety guidelines for the cohort under investigation. If none of these participants has 
experienced a life-threatening drug-related adverse event or a Grade 4 event that is probably or 
definitely attributable to the study medication and no more than 25% terminated study drug due 
to Grade 3+ drug-related adverse events, then this starting dose will pass the safety guidelines for 
the group under investigation.  
 
If any of these participants has a life threatening drug-related adverse event or any Grade 4 event 
that is probably or definitely attributable to the study medication or more than 25% terminated 
study drug due to Grade 3+ drug-related adverse event, this starting dose will fail the safety 
guidelines for the cohort under investigation. Should this occur, the Protocol Team will review all 
the relevant safety and pharmacokinetic data to determine whether it is safe to continue the 
attempt to find an optimal dose for this cohort. If the team determines that it is safe to proceed, it 
will make any changes in dosing and monitoring procedures which are judged to be necessary. If 
there are any concerns regarding safety, the P1093 Study Monitoring Committee (SMC) will then 
review all of the relevant safety and pharmacokinetic data, along with the recommendations of 
the Protocol Team, and will determine whether and under what conditions further dose finding 
activities for this cohort may proceed.  
 
Following Table 16, the hypothetical rates of "true toxicity" which could occur if the study 
medication were used extensively among the participant population at the dose level are again 
presented in Table 16, this time assuming that a sample of ten participants is drawn from the 
participant population and the safety guidelines allows no participant with life threatening drug-
related adverse event  or any Grade 4 event that is probably or definitely attributable to the study 
medication or no more than 2 participants who  terminated study drug due to Grade 3+ drug-
related adverse event.   
 
Table 16: Probability of Failing Dose Escalation Guidelines Under Potential Rates of True 
Toxicity with n=10 participants 
True Toxicity Rates 
Probability of Failing 
Safety Guidelines 
Non-life threatening drug-related adverse 
event that would result in treatment 
discontinuation, excluding Grade 4 
events probably or definitely attributable 
to study medication 
Life threatening drug-
related adverse event or 
Grade 4 events probably 
or definitely attributable 
to study medication 
.50 
.00 
.95 
.50 
.05 
.98 
.50 
.25 
1.00 
.25 
.00 
.47 
.25 
.05 
.71 
.25 
.25 
.98 
.05 
.00 
.01 
.05 
.05 
.41 
.05 
.25 
.95 
.00 
.05 
.40 
.00 
.25 
.94 
 


 
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For example, Table 16 shows that there is a 98 % 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 drug-related adverse event is 50%.  
 
8.5.3 
Safety Guidelines for Minimum Eight Participants Started at a Given Dose Level in Each Weight 
Band  
 
Under protocol Version 5, a secondary examination of safety data by weight band will be 
performed.  An additional safety assessment of a given starting dose of the study medication 
within a weight band will make use of data from all participants within that weight band who 
started at that dose. The data will extend to the week 4 visit for participants not requiring PK 
determined dose adjustment or until the visit on which the dose is adjusted, if adjustment occurs 
prior to 4 weeks on study. If any of these participants has a life-threatening drug-related adverse 
event or any Grade 4 event that is probably or definitely attributable to the study medication, or 
more than 25% terminated study drug due to grade 3+ drug-related adverse event, this dose will 
fail the safety guidelines for the weight band under investigation. If none of these participants has 
experienced a life-threatening drug-related adverse event or a Grade 4 event that is probably or 
definitely attributable to the study medication and no more than 25% have terminated study drug 
due to Grade 3+ drug-related adverse events, then this dose will pass the safety guidelines for the 
weight band under investigation.  
 
If any of these participants has a life-threatening drug-related adverse event or any Grade 4 event 
that is probably or definitely attributable to the study medication or more than 25% terminated 
study drug due to Grade 3+ drug-related adverse event, this dose will fail the safety guidelines for 
the weight band under investigation. Should this occur, the Protocol Team will review all the 
relevant safety and pharmacokinetic data to determine whether it is safe to continue the attempt to 
find an optimal dose for this weight band. If the team determines that it is safe to proceed, it will 
make any changes in dosing and monitoring procedures which are judged to be necessary. If there 
are any concerns regarding safety, the P1093 SMC will then review all the relevant safety and 
pharmacokinetic data, along with the recommendations of the Protocol Team, and will determine 
whether and under what conditions further dose finding activities for this weight band may 
proceed.  
 
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 0 for PK analysis.  The safety data 
will be broken down by cohort and by weight band, and will present the results of the safety 
evaluations applied to each starting dose tested within each cohort/weight band, including 
information indicating which starting doses have passed or failed the safety guidelines. For each 
starting dose within each cohort/weight band, every adverse event of Grade 3 or higher will be 
listed, along with participant demographics, the dose prescribed to the participant at the time of 
the event and the Protocol Team’s assessment of the probability that this event was due to the 
study drug (not related, possibly related, probably related or definitely related).  
 
8.6.2 
Analysis of Data Representing Exposure to the Doses Judged to be Optimal for Each Cohort 
 
These analyses will be stratified by Age Cohort. The findings will be presented both in aggregate 
and broken down by this stratification factor, with estimates bounded by 95% confidence limits. 


 
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Given that the small sample sizes within strata will provide limited power for statistical tests of 
differences across age groups, interpretation of the results will depend upon whether differences 
across strata are great enough to be considered to be clinically significant. If no such differences 
are observed, then the clearest interpretation of the findings will come from the aggregated data, 
where analyses will have the greatest statistical precision. However, if results vary across strata to 
a clinically important extent, interpretation of results should take account of the issues 
represented by the stratification factor.  
 
8.6.2.1 Primary Analyses (performed on data through the Week 24 visit) 
 
Safety 
The primary safety analysis will include only participants whose starting doses have been 
those judged to be optimal for their groups. Stage I participants whose doses have been 
adjusted for inadequate PK will be excluded. Stage I participants who have been removed 
from treatment due to toxicities while on the optimal dose will be included and treated as 
safety failures in the primary safety analysis. Sensitivity analyses will be performed to 
determine whether the exclusion of participants whose doses have been adjusted creates a 
selection bias which impacts upon any results. 
 
Each participant’s safety data will be summarized as: the worst grade of adverse event 
experienced during the first 24 weeks (and 48 weeks) of exposure to the optimal dose of 
the study drug and the worst grade of adverse event judged to be at least possibly due to 
study drug during this time period. Frequency distributions of these safety outcomes will 
be presented in the aggregate and broken down by age cohort. Listings of all Grade 3+ 
events will be provided, broken down by type of toxicity (hepatic, hematologic, etc.). 
 
The proportions of participants experiencing Grade 3+ adverse events will be presented 
in aggregate and broken down by age, with these proportions bounded by exact 95% 
confidence intervals. Similar analyses will present the proportions of participants 
exhibiting Grade 3+ events which have been judged to be at least possibly related to 
study medication, again bounded by exact 95% confidence intervals.  
 


 
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Table 17: Percent of Participants Experiencing Grade 3+ Adverse Events (or Grade 3+ 
Adverse Events Attributed to the Study Medication) With Exact 95% Confidence Intervals 
N 
% With Grade 3+ 
Adverse Events 
95% C.I. 
10 
0% 
0% -- 31% 
20 
0% 
0% -- 17% 
40 
0% 
0% -- 9% 
60 
0% 
0% -- 6% 
90 
0% 
0% -- 4% 
150 
0% 
0% -- 2% 
 
 
 
10 
10% 
0.3% -- 45% 
20 
10% 
1% -- 32% 
40 
10% 
3% -- 24% 
60 
10% 
4% -- 21% 
90 
10% 
5% -- 18% 
150 
10% 
6% -- 16% 
 
 
 
10 
20% 
3% -- 56% 
20 
20% 
6% -- 44% 
40 
20% 
9% -- 36% 
60 
20% 
11% -- 32% 
90 
20% 
12% -- 30% 
150 
20% 
14% -- 27% 
 
 
 
10 
30% 
7% -- 65% 
20 
30% 
12% --54% 
40 
30% 
17% -- 47% 
60 
30% 
19% -- 43% 
90 
30% 
21% -- 41% 
150 
30% 
23% -- 38% 
 
Table 17 presents exact 95% confidence intervals around various potential rates of grade 
3+ adverse events which might be observed in a total sample of 100 evaluable 
participants, a sample of 10 participants representing the minimal sample that could be 
accrued within any of the Stage I stratification factors and potential sample sizes that 
might occur if subgroups are analyzed (N = 20, 40, 60, 90) This table indicates that 
confidence intervals will be quite wide around the minimal sample size of 10 participants 
within a given stratum, but would be reasonably precise around samples of 90-150 
participants. 
 
8.6.2.2 Key Secondary Analyses 
 
Safety  
 
Safety assessments will be performed on data collected through Week 48 and on long 
term data. These analyses will be similar to the Week 24 analyses described in Section 


 
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8.6.2 above.  In addition, these analyses will also be performed with participants 
classified by weight band. 
 
Viral Load  
 
Virologic outcomes, based on HIV-1 RNA (copies/mL), will be assessed at weeks 24 and 
48. Virologic outcomes at additional time points might also be evaluated. For regulatory 
submission purposes, at both of these time points the primary definition of virologic 
outcome will be calculated according to FDA’s snapshot algorithm. Participants will be 
classified as virologic failures if they have missing HIV-1 RNA data throughout the 
window surrounding the time point of interest. (This window will be defined in the 
analysis plan.) In addition, participants will be classified as virologic failures at either of 
these time points if they meet any of the following conditions prior to that time point:  
 
a) Discontinuation of drug;  
b) Change in background therapy not allowed in the protocol;  
c) Change in background ART substitutions permitted per protocol, unless the decision 
to switch is documented as being before or at the first on-treatment visit after 
switching to OBT where HIV-1 RNA is assessed (Week 4) or participant’s HIV-
RNA is <400/<50 copies/mL before the switch. 
 
Participants who only discontinued a background ARV or who had formula substitutions 
(substituting single agents for fixed dose combinations and vice versa of the same ARV) 
in their OBT are not considered as having OBT changes and will not be analyzed as 
virologic failures. Otherwise, virologic success or failure will be determined by the last 
available HIV-1 RNA assessment while the participant is on-treatment within the visit of 
interest window. The proportions of participants meeting the criteria for virologic success 
at each of these time points will be bounded by exact 95% confidence intervals, and will 
be presented in the aggregate and broken down by age cohort and by weight band. 
 


 
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Table 18: Percent of Participants Meeting Criterion for Virologic Success with Exact 95% 
Confidence Intervals 
N 
% Undetectable RNA 
95% C.I. 
10 
10% 
0.3% -- 45% 
20 
10% 
1% -- 32% 
40 
10% 
3% -- 24% 
60 
10% 
4% -- 21% 
80 
10% 
4% -- 19% 
100 
10% 
5% -- 18% 
10 
30% 
7% -- 65% 
20 
30% 
12% -- 54% 
40 
30% 
17% -- 47% 
60 
30% 
19% -- 43% 
80 
30% 
20% -- 41% 
100 
30% 
21% -- 40% 
10 
50% 
19% -- 81% 
20 
50% 
27% -- 73% 
40 
50% 
34% -- 66% 
60 
50% 
37% -- 63% 
80 
50% 
39% -- 61% 
100 
50% 
40% -- 60% 
10 
70% 
35% -- 93% 
20 
70% 
46% -- 88% 
40 
70% 
53% -- 83% 
60 
70% 
57% -- 81% 
80 
70% 
59% -- 80% 
100 
70% 
60% -- 79% 
10 
90% 
55% -- 99.7% 
20 
90% 
68% -- 99% 
40 
90 % 
76% -- 97% 
60 
90% 
79% -- 96% 
80 
90% 
81% -- 96% 
100 
90% 
82% -- 95% 
 
Table 18 presents exact 95% confidence intervals around various potential rates of 
virologic success which might be observed in a total sample of 100 participants or in 
subsamples of various sizes (N=10, 20, 40, 60, 80). Participants whose OBT is changed 
after initial optimization will be considered treatment failures in these analyses, unless 
the change is one specifically allowed by the protocol. 
CD4/8   
 
Change in CD4/8 count and percent from baseline to weeks 24 and 48 will be bounded by 
95% confidence intervals and presented in the aggregate and broken down by age cohort, 
by accrual to Stage I vs. Stage II and by weight band.  
 


 
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HIV Drug Resistance   
 
The incidence of HIV drug resistance will be presented descriptively at baseline and at 
the point of failure for participants who meet the criteria for virologic failure. Participants 
will be evaluated for HIV genotypic and phenotypic drug resistance to the OBT and to 
DTG. Analysis results will be presented in aggregate, by cohort and by weight band. 
 
Interim Analysis of Data from Cohort I 
 
An interim analysis based upon the 24 week data from Cohorts I and IIA was performed. 
This focus of this analysis was primarily on safety data, presented as described in Section 
8.6.2.1 and pharmacokinetic data, as described in Section 0. A secondary analysis of 
virologic success, as described in Section 8.6.2.2 was also performed.  The results of 
these analyses were used as part of a regulatory submission for pediatric use of DTG.  
 
8.7 
Monitoring 
 
The study will be monitored by the Protocol Team, which includes Protocol Co-Chairs, Medical Officers, 
Pharmacologists, Statisticians, Data Managers, and GlaxoSmithKline representatives. The Protocol Team 
will review safety and pharmacokinetic data with the aim of determining the optimal dose for each cohort 
and weight band, while protecting participant safety.  
 
Participant Safety 
 
The Protocol Team will closely monitor participant safety through routine review of safety and toxicity 
reports summarizing laboratory and clinical data from the study database (CRFs and laboratory data).  
The Protocol Team will review these reports via conference call or other meeting at least twice a month 
during the dose finding stage (Stage I) and less frequently thereafter. The data required for the toxicity 
reports must be entered into the database within 48 hours of the time at which the results of the laboratory 
tests or clinical examinations become available.   
 
In addition to regular safety and toxicity reviews by the Protocol Team, according to standard IMPAACT 
procedures an SMC will provide impartial independent reviews in situations where participant safety is in 
question.   
 
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. If this occurs, 
the SMC will review all relevant data and will determine whether, and under what conditions, the study 
will be allowed to proceed. 
 
8.7.1 
Rules for Suspending Accrual to Assess Safety Following an Adverse Event 
 
Accrual will be temporarily suspended if any participant has a life threatening drug-related 
adverse event or any Grade 4 event that may not be judged to be life-threatening but is judged to 
be probably or definitely attributable to the study medication. Following temporary suspension of 
accrual, the team will further review the safety data within 48 hours of notification of the event to 
determine if continuation of accrual is appropriate. If the team agrees that the study drug is likely 
to be safe for additional participants, they may allow accrual to resume. The SMC will be 
informed of this decision, and the study will not reopen without the approval of the SMC.  
Regulatory agencies will be notified of the event and the team’s decision after this review of the 
safety data has taken place.  


 
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8.7.2 
Accrual Rate Evaluation 
 
Accrual to this study will be monitored by the IMPAACT leadership in accordance with standard 
operating procedures. The team will monitor feasibility quarterly based on accrual.  If any open 
Cohort has not accrued half its participants within 6 months of opening, the team will identify the 
reasons for lack of accrual and determine whether/how the issues can be addressed with the SMC.  
 
 
9.0 
CLINICAL PHARMACOLOGY PLAN 
 
9.1 
Pharmacology Objectives  
 
The clinical pharmacology objectives are:  
 
1. To evaluate the steady-state pharmacokinetics of DTG and its various formulations in combination 
with other ARVs in treatment-experienced HIV-1 infected infants, children and adolescents and to 
determine the dose of DTG that achieves a targeted C24h (primary PK endpoint) and AUC0 -24 
(secondary PK endpoint) in this population.  
 
2. To evaluate the steady state plasma concentration profiles and pharmacokinetic parameters of DTG 
administered as the film-coated tablet, the oral-granules for suspension and the dispersible tablet -  
pediatric formulations. 
 
3. To determine DTG exposure, its variability and clinical covariates that impact DTG disposition (e.g. 
age, weight) using intensive and sparse sampling and population pharmacokinetic analysis. 
 
9.2 
Primary and Secondary Data  
 
All concentration-time samples will be registered in the LDMS database. All PK samples (including 
intensive and population PK) will be sent to the University of Alabama (UAB) Laboratory (see the 
Laboratory Processing Chart). The study database will be kept up to date by close tracking of samples. As 
part of Stage I, the intensive PK sample assays and pharmacokinetic calculations will be performed in 
real-time and the results will be reported and discussed with the Protocol Team.  
 
9.2.1 
Intensive PKs (Stage I only) 
 
Steady-state pharmacokinetic parameters will be determined from plasma concentration-time 
profiles using non-compartmental methods (Phoenix WinNonlin 8.0, Certara, Princeton, NJ). 
Calculated pharmacokinetic parameters will be: area-under-the-curve (AUC0-24), maximum 
plasma concentration (Cmax), time to Cmax (tmax), plasma concentration observed at end of 24 hour 
dosing interval (C24h), plasma concentration observed immediately to dosing of 24 hour dosing 
interval (C0), minimum plasma concentration (Cmin), apparent clearance (CL/F), apparent volume 
of distribution (Vz/F), and terminal half-life (t1/2). AUC0-24 will be determined using the linear-log 
trapezoidal rule. Cmax, Tmax , C0, C24h, and Cmin will be taken directly from the observed 
concentration-time data. 
 
Intensive PK sampling will be conducted between days 5 and 10, after study drug initiation, and 
over the course of approximately 24 hours. The pharmacokinetic evaluation should be scheduled 
so that a witnessed dosing of DTG is as close as possible to 24 hours (generally 22-26 hours) after 
the previous dosing. One sample will be collected pre-dose and 7 samples will be collected post-


 
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dose, at 1, 2, 3, 4, 6, 8 and 24 hours post-dosing, per footnotes in Appendix IA and Appendix IC 
The 24-hour sample must be collected prior to the next dose. To allow for some flexibility, the 8-
hour sample can be collected with a window of 7-9 hours post-dose and the 24-hour sample 
within a window of 22-26 hours. Actual sampling time will be recorded and used in the PK 
analysis.  US sites will ship intensive PK samples in real time to UAB; all non-US sites will ship 
PK samples in real time to the BRI repository for a ‘pass-through’ (see LPC for instructions). 
 
Study staff will review the regimen, dosage, dosing intervals, and timing relative to meals with 
participants or their caregivers in advance of the visit. The importance of adherence to the study 
drug and of reporting non-adherence will be emphasized. The date and time of doses taken 3 days 
prior to the PK visit should be recorded. The actual sampling time recorded on the CRF will be 
used in the PK analysis.  Participants should have no missed doses 3 days prior to the scheduled 
intensive PK visit. The PK visit should be scheduled so that the pre-dose PK samples and the 
witnessed dosing of DTG are as close as possible to 24 hours (generally 22-26 hours) after the 
previous dosing. Participants should have been adherent in taking their medications for 3 days 
prior to the intensive PK visit; otherwise the intensive PK visit should be re-scheduled. 
Participants who vomited within 4 hours after dosing, or who cannot complete the PK that day for 
any other reason, the PK should be cancelled and MUST be rescheduled AND completed within 
the following 7 days. 
 
Additionally, any participant who cannot have the intensive PK visit completed within 5-10 days 
of study drug initiation, must have the visit completed within 17 days of study drug initiation. 
The participant will remain on study and be included for safety analyses but will be replaced for 
PK analyses. 
 
Intensive PK sampling will be done in a fasting state and sites will follow the instructions as 
described below in Sections 9.2.1.1 and 9.2.1.2. If upon review of PK data, the Protocol Team 
determines that an additional evaluation of PK should be performed in a non-fasted state, the 
team will notify the sites to which cohorts or weight bands this will apply and sites will follow the 
instructions in Section 9.2.1.3. 
 
9.2.1.1 Sampling with Fasting (Cohorts I, II III, and III-DT) 
 
The guidelines for intensive PK sampling in Cohorts I, II, III and III-DT while fasting 
follow: 
 
• 
Participants must be fasted for 6 hours prior to dosing on the intensive PK day.  
• 
≥6 hours PRIOR to dosing – participants may eat and drink without restriction 
• 
≥4 to <6 hours PRIOR to dosing – milk, apple/orange juice and water may be 
consumed; No food 
• 
<4 hours PRIOR to dosing – water ONLY 
• 
From dosing to <2 hours POST dose – apple/orange juice and water may be 
consumed; No food 
• 
From ≥2 to <4 hours POST dose – participants may drink apple/orange juice and eat 
a snack/light meal (around 100-150 calories). High fat foods should be avoided.  
• 
From ≥4 hours POST dose onwards – participants may eat and drink without 
restriction 
 


 
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9.2.1.2 Sampling with Fasting (Cohorts IV, IV-DT, and V-DT) 
 
The guidelines for intensive PK sampling in Cohorts IV, IV-DT, and V-DT while fasting 
follow: 
 
• 
Participants should not ingest breastmilk, 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 (with the exception of grapefruit juice) 
and oral rehydration solution)) can be taken at any time.   
• 
Participants may consume a light meal of their choice four hours after dosing on the 
intensive PK day.  
 
9.2.1.3 Sampling Non-Fasting (All Cohorts) 
 
If upon review of PK data, the Protocol Team determines that collected PK data supports 
an additional evaluation of PK in a non-fasted state, the Protocol Team will notify the 
sites to which cohorts or weight band groups this will apply.  Sites will be informed if 
there are restrictions on the choice or quantity of food permitted prior to, and during the 
day of intensive PK sampling.  However, all food must be consumed within 30 minutes 
prior to dose administration. All PK sample collection and processing procedures will 
remain the same as for fasting. 
 
9.2.2 
Population PK (Stage I and II) 
 
Population pharmacokinetic evaluations will be scheduled at Weeks 4, 12 and 24. In addition 
population PK sampling will be scheduled for participants who have completed 24 weeks of 
follow-up and who have switched from granules for suspension to dispersible tablets. Population 
PK will be collected at the 2-week post-switch visit and at the next scheduled visit per footnotes 
in the relevant Schedules of Evaluations.  These evaluations should be scheduled so that the pre-
dose PK sample and the witnessed dosing of DTG are as close to possible to 24 hours (generally 
22-26 hours) after the previous dose. 
 
9.2.2.1 Cohorts I, II, and III 
 
In all cases, the participant will need to provide a self-reported time and date of their last 
dose. Appendix IA and Appendix IB footnotes describe the sampling time points for 
Stage I and II respectively.  
 
9.2.2.2 Cohorts IV, IV-DT and V-DT 
 
In all cases, the participant will need to provide a self-reported time and date of their last 
dose. Appendix IC andAppendix ID Schedule of Evaluations   
Cohorts IV, IV-DT, and V-DT – Stage IIAppendix ID footnotes describe the sampling 
time points for Stage I and II respectively.  
 
These data will be pooled to build a population pharmacokinetic model to assess pediatric 
DTG exposure and possible changes in exposure during the study. This population 
pharmacokinetic model will be created using NONMEM version VII (or similar 
software) or higher software program. The model may also be used to determine if 
covariates, such as age, weight, sex, BSA, and concomitant medications alter DTG 
pharmacokinetic parameters in pediatric participants.  


 
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9.3 
Evaluation of PK Exposures for Cohorts and Weight Bands 
 
The target population exposure (GM) for C24h is 995 ng/mL, with an acceptable range of 697– 2,260 
ng/mL. The target population exposure (GM) for AUC0-24 target is 46 µg.h/mL, with an acceptable range 
of 37-134 µg.h/mL. Rationale for these targets is provided in Section 1.6.  At the mini-cohort stage, the 
PK parameters for the four participants will be reviewed to ensure that individual PK parameter values are 
not so extreme as to be unsafe for the participant or make attainment of the target values for the 
population exposure - the GM of all participants at the end of Stage I - unlikely.  At the completion of 
Stage I, the GMs of C24h and AUC0-24 of cohorts and independent weight bands will be evaluated by the 
Protocol Team to determine if a dose is acceptable or not for that respective group.  As the primary target, 
the GM C24h will be weighted most heavily in this decision, but AUC0-24 as well as participant specific 
factors that may have altered the PK data will also be considered.  
 
If on review of all PK and safety data the dose is not acceptable, a new test dose (i.e. dosing table) will be 
determined.  
The ultimate decision about a new test dose may also be guided by other data from this study (e.g. drug 
clearance, CV in different ages) as well as information about DTG metabolism, safety, or efficacy 
generated outside the context of this protocol.  Additionally, PK modeling work will be used to assist in 
new dose decisions. If there is disagreement among the Protocol Team, the study monitoring committee 
(SMC) will be asked to review the data. Further information on the SMC can be found in Section 8.7. 
 
Of note, DTG is dosed for P1093 participants according to dosing tables in which participants within a 
given weight range are given the same quantity of a formulation (DT, film-coated tablets). While dosing 
tables may target a certain mg/kg dose overall, individual participants with weights on the edges of 
weight bands will inevitably receive a range of mg/kg dosing which may result in a wide range of drug 
exposure, especially in younger populations. The Protocol Team will monitor the range of exposures 
within age cohorts and within weight band groups that cross age cohorts. In addition, enrollment within a 
cohort or weight band might be evenly distributed or skewed towards an extreme, which could limit 
generalization for populations likely to be treated with DTG in the future. The Protocol Team will 
continue to monitor enrollment to ensure that information from a normally distributed population is 
collected so that appropriate dosing guidelines can be formulated If this goal is not being met, the 
Protocol Team reserves the right to reopen an age or weight band cohort to include a subset of 
participants who were underrepresented in that full group’s analysis. For example, this may include the 
smallest infants within the 3-6 kg weight band.   
 
9.4 
Evaluation of PK Exposures for Individual Dose Modification 
 
If the C24h and/or AUC0-24 of any individual participant falls outside of the individual target ranges (refer 
to Table 9) the Protocol Team will consider all clinical, pharmacologic, immunologic and virologic data 
to determine if it in the participants best interest to continue or if the dose should be modified.  Additional 
PK sampling may be performed, at the discretion of the Protocol Team and site investigators, if felt to be 
in the best interest of participants, refer to Section 6.4.  
 
 
10.0 
HUMAN SUBJECTS PROTECTIONS    
 
The Division of AIDS has concluded that this protocol does NOT meet Federal requirements governing 
prisoner participation in clinical trials and should NOT be considered by local IRBs / ECs for the 
recruitment of prisoners. 


 
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10.1 
Institutional Review Board/Ethics Committee Review and Approval  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this protocol and 
site-specific ICFs in accordance with 45 CRF 46; subsequent to initial review and approval, IRBs/ECs 
must review the study at least annually. Site investigators must also promptly report to the IRB/EC any 
changes in the study and any unanticipated problems involving risks to participants or others. 
 
All IRB/EC policies and procedures must be followed and complete documentation of all correspondence 
to and from the IRBs/ECs must be maintained in site essential document files. Sites must submit 
documentation of both initial review and approval and continuing review to the DAIDS Protocol 
Registration Office (PRO) in accordance with the DAIDS Protocol Registration Manual (see also Section 
4.4). 
 
10.2 
Vulnerable Participants  
 
The NIH is mandated by law to ensure that children be included in clinical research when appropriate. 
This study responds to that mandate and will provide clinical research data to inform ARV treatment 
guidelines for pediatric populations. Nonetheless, the children who take part in this study are considered 
vulnerable participants per the U.S. Code of Federal Regulations, and site IRBs/ECs must consider the 
potential risks and benefits to infant and child participants as described in 45 CFR 46 Subpart D (for 
children). 
 
With respect to 45 CFR 46 Subpart D, IRBs/ECs must determine the level of risk to children in the 
categories specified in 45 CFR 46.404-407. Documentation of this determination is required to complete 
the DAIDS protocol registration process described in Section 4.4, and the risk category assigned by the 
IRB/EC further determines the parental informed consent requirements for the study at each site. Per 45 
CFR 46.408 (b), the IRB/EC may find that the consent of one parent is sufficient for research to be 
conducted under 46.404 or 46.405. If the IRB/EC finds that the research is covered by 46.406 or 46.407, 
both parents must give their consent, unless one parent is deceased, unknown, incompetent, or not 
reasonably available or when only one parent has legal responsibility for the care and custody of the child 
(as determined locally). IRBs/ECs must document their risk determination, and study sites should adapt 
the signature pages of their site-specific ICFs as needed to accommodate the parental consent 
requirements associated with the IRB/EC determination. However, it is generally expected that the 
consent of one parent is sufficient for this study. 
 
Study sites must comply with the requirements of the DAIDS policy on Enrolling Children (including 
Adolescents) in Clinical Research, which is available at: https://www.niaid.nih.gov/research/daids-
clinical-research-policies-standard-procedures. 
 
10.3 
Informed Consent   
 
Written informed consent for study participation will be obtained before any study-specific procedures 
are performed. The informed consent process will be conducted prior to screening.  
 
The informed consent process will include information exchange, detailed discussion, and assessment of 
understanding of all required elements of informed consent, including the potential risks, benefits, and 
alternatives to study participation. 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 


 
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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).  
  
Participants providing assent or parents or legal guardians will also be asked whether they agree to 
storage and future research testing of biological specimens remaining after all protocol-specified testing 
has been completed. Future research testing of residual specimens may be declined with no impact on 
other aspects of study participation.  
 
It is generally expected that only one parent or legal guardian will provide informed consent for the 
child’s participation in this study. However, parental consenting requirements at each site will depend on 
the IRB/EC risk determination described in Section 10.2; all IRB/EC requirements will be followed.  
 
Should the consenting parent (or guardian) of a participant die sites should follow the guidelines 
described by their IRBs/ECs.  Study sites may continue to provide care for the participant as needed and 
appropriate (outside of the study), consistent with local standard of care.  If a guardian cannot be 
identified, or if the guardian does not consent to continued study participation, the participant must be 
withdrawn from the study.  In accordance with the DAIDS policy on Enrolling Children (including 
Adolescents) in Clinical Research (available at the website referenced in Section 10.2, all sites must 
establish and maintain written procedures describing the standards that will be followed to identify who 
may serve as guardian for an enrolled child or adolescent, reflective of applicable IRB/EC guidance for 
conduct of human subjects research within the context of available local law, regulation, or government 
policy.   
 
Participants may also reach the legal age of consent during follow-up.  In this case, written informed 
consent for continued participation and specimen storage and future use will be obtained from participants 
once they reach legal age at their next study visit.  If participants do not consent for continued study 
participation, they should be discontinued from the study; similarly, if they do not consent for specimen 
storage and future use, all specimens will be destroyed after all protocol-related testing is complete. 
 
10.4 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at: 
https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures 
 
Study sites must comply with DAIDS policies on Requirements for Essential Documents at Clinical 
Research Sites Conducting DAIDS Funded and/or Sponsored Clinical Trials and Requirements for 
Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials. In its policy on 
Requirements for Manual of Operational Procedures, DAIDS requires sites to establish SOPs for 
maintaining essential and source documents in compliance with these policies. Site SOPs should be 
updated and/or supplemented as needed to describe roles, responsibilities, and procedures for this study, 
and site SOPs should be followed throughout the study.  
 
Per the DAIDS policy on Storage and Retention of Clinical Research Records, study records must be 
stored in a manner that ensures privacy, confidentiality, security, and accessibility during the conduct of 
the study and after the study is completed. Records must be retained for a minimum of three years after 
the completion of the study. Per 21 CFR 312.62, records must be maintained for two years after the date 
a marketing application is approved for one or more of the study products for the indication for which it 
is evaluated in this study; or, if no application is filed, or if the application is not approved for this 
indication, records must be retained two years after the study is discontinued and the FDA is notified.  
 


 
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All study records must be accessible for inspection, monitoring, and/or auditing during and after the 
conduct of the study by authorized representatives of the study sponsors and their contracted monitors, 
IMPAACT, GSK, the FDA, site drug regulatory authorities, site IRBs/ECs, OHRP, and other US, local, 
and international regulatory entities. Records must be kept on-site throughout the period of study 
implementation; thereafter, instructions for off-site storage may be provided by NIAID or NICHD. No 
study records may be removed to an off-site location or destroyed prior to receiving approval from 
NIAID or NICHD. 
 
10.5 
Participant Confidentiality   
 
Study procedures will be conducted in private and every effort will be made to protect participant privacy 
and confidentiality to the extent possible. Participant information will not be released without written 
permission to do so except as necessary for review, monitoring, and/or auditing. If any photographs of 
observed reactions are taken, standard precautions will be followed to ensure that participant privacy and 
confidentiality are protected. 
 
All study-related information will be stored securely. Participant research records will be stored in locked 
areas with access limited to study staff. All laboratory specimens, CRFs, and other documents that may be 
transmitted off-site (e.g., EAE report forms) will be identified by PID only. Likewise, communications 
between study staff and Protocol Team members regarding individual participants will identify 
participants by PID only.  
 
Study sites are encouraged but not required by DAIDS policies to store study records that bear participant 
names or other personal identifiers separately from records identified by PID. All local databases must be 
secured with password protected access systems. Lists, logbooks, appointment books, and any other 
documents that link PID numbers to personal identifying information should be stored in a separate, 
locked location in an area with limited access.  
 
10.6 
Study Discontinuation    
 
The study may be discontinued at any time by NIAID, the IRB or EC, GSK, the FDA, OHRP, IMPAACT 
or other country-specific governmental agencies as part of their duties to ensure that research participants 
are protected. 
 
10.7 
Access to Dolutegravir at the Close of the Study  
 
Participants will be transitioned into care and treatment outside of the study at the end of the study as per 
local standards. If the DTG formulations are not locally available for a participant completing study then 
DTG will be provided by the pharmaceutical partners following the participant’s completion of the study 
through a mechanism outside of the protocol, or until one or more of the following events occur: 
 
• 
Until the age-appropriate formulations provided by the study are available from another source (e.g. 
government programs, aid programs, assistance programs etc.) to all participants in each specific 
country; OR 
• 
Until participants are no longer deriving benefit; OR 
• 
Until clinical development of DTG is terminated.  
 


 
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10.8 
Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be reimbursed for costs associated with completing study 
visits (e.g., transport costs). Reimbursement amounts will be specified in site-specific informed consent 
forms and/or other materials as applicable per IRC/EC policies and procedures.(3) 
 
10.9 
Management of New Information Pertinent to Study Participation  
 
Study staff will provide parents or guardians with any new information learned over the course of the 
study that may affect their willingness to allow their children to continue receiving study drug and/or 
remain in follow-up in the study. 
 
 
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 GlaxoSmithKline 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. 
All infectious specimens will be transported in compliance with Federal Regulations and 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 and to the ACTN Guidelines 
for Shipment and Receipt of Category B Biological Substance Shipment and ACTN Instruction for 
Overnight Shipments documents at: 
http://www.hanc.info/labs/labresources/procedures/Pages/actnShippingDemo.aspx 
 
 
13.0 
REFERENCES    
 
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Mocroft A, Ledergerber B, Katlama C, Kirk O, Reiss P, d'Arminio Monforte A, et al. 
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30. 
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31. 
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infections among children and keeping their mothers alive  2015. 
32. 
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systematic reviews. 2012;7:Cd004772. 


 
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Page 88 of 135 
12 July 2018 
36. 
Newell ML, Coovadia H, Cortina-Borja M, Rollins N, Gaillard P, Dabis F. Mortality of 
infected and uninfected infants born to HIV-infected mothers in Africa: a pooled 
analysis. Lancet. 2004;364(9441):1236-43. 
37. 
Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. 
Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed 
and HIV-Infected Children. Department of Health and Human Services. 2013. 
38. 
National Department of Health SA. National Consolidated Guidelines for the prevention 
of mother-to-child transmission of HIV (PMTCT) and the management of HIV in 
children, adolescents and adults. 2015. 
39. 
The Integrated National Guidelines on Antiretroviral Therapy, Prevention of Mother to 
Child Transmission of HIV and Infant & Young Child Feeding. The Republic of Uganda 
Ministry of Health. 2011;1st, edition. 
40. 
Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and 
Adolescents. U.S. Department of Health and Human Services; 2015. 
41. 
(EMA) EMA. Summary of Product Characteristics, Delamanid. . 2014. 
42. 
Services USDoHaH. Dolutegravir (TIVICAY) Drug Information 2018 [Available from: 
https://aidsinfo.nih.gov/drugs/509/dolutegravir/167/professional#nlm34069-5. 
43. 
World Health O. Antiretroviral therapy of HIV infection in infants and children: Towards 
universal access. 2006. 
 


 
IMPAACT P1093, Version 5.0 
 
Page 89 of 135 
 
12 July 2018 
Appendix IA Schedule of Evaluations   
Cohorts I, IIA, IIB, III and III-DT – Stage I 
 
Screen through Week 48 
 
 
Screen 1 
Entry 
12 
Day 0 
Intensive 
PK  
Day 5-10 
Week  
4 
Week  
8 
Week 
12 
Week 
16 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Visit Windows 
- 
- 
- 
±1 
wk 
±1 wk 
±1 wk 
±1 
wk 
±2 wks 
±2 
wks 
±2 
wks 
±2 wks 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
History and Physical exam 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tanner Staging 3 
 
X 
 
 
 
 
 
 
 
 
X 
Adherence Questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDC Classification 
 
X 
 
 
 
 
 
X 
 
 
 
Palatability Assessment 
 
 
X 
X 
 
 
 
X 
 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
Hematology   
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
Chemistries 4 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
Lipid profiles 5 
1mL 
 
 
 
 
 
 
1mL 
 
 
1mL 
PBMCs / plasma for storage 
(includes integrase resistance 
sample) 
 
7mL  
 
 
 
 
 
6.5mL 
 
 
6.5mL 
Urinalysis 
X 
 
 
 
X 
 
 
X 
 
 
X 
Microalbumin/creatinine ratio 
urine6 
 
X 
 
 
X 
 
 
X 
 
 
X 
Pregnancy test7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Virology 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA PCR 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
Genotyping   
2mL 
 
 
 
 
 
 
 
 
 
 
Phenotyping 8 
2mL 
 
 
 
 
 
 
 
 
 
 
Immunology 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte subsets 9 
1mL 
1mL 
 
 
 
1mL 
 
1mL 
1mL 
1mL 
1mL 
Pharmacokinetic studies 
 
 
 
 
 
 
 
 
 
 
 
STAGE I - Intensive PK 10 
 
 
4mL 
 
 
 
 
 
 
 
 
STAGE I - Population PK 11 
 
 
 
1mL 
 
0.5mL 
 
1mL 
 
 
 
Total Maximum Blood 
Volumes 20 
11mL 
13mL 
9mL 
6mL 
5mL 
6.5mL 
5mL 
14.5mL 
6mL 
6mL 
13.5mL 
 
 


 
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Appendix IA Schedule of Evaluations (cont’d) 
Cohorts I, IIA, IIB, III and III-DT – Stage I  
Virologic Failure, Dose Adjustment and Premature/DC of Study Drug Visits 
 
 
Confirm 
Suspected virologic failure 13 
Virologic Failure 
14 
[Dose Adjustment 
PK Visit ] 15 
[Dose 
Adjustment 
Safety 
Visit] 16 
Premature/DC 
of Study Drug 
On study 17 
Visit Windows 
 
- 
If requested, 5 to 14 days after initiation 
of the dose adjustment 
4 weeks 
post dose 
modification 
(-1 wk/+ 2 
wk)  
- 
CLINICAL EVALUATIONS 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
History and Physical exam 2 
 
X 
 
[X] 
X 
Tanner Staging 3 
 
 
 
 
 
Adherence Questionnaire 
 
X 
 
[X] 
X 
CDC Classification 
 
X 
 
 
X 
Palatability Assessment 
 
 
 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
Hematology   
 
1mL 
 
 
1mL 
Chemistries 4 
 
1mL 
 
 
1mL 
Lipid profiles 5 
 
 
 
 
 
PBMCs / plasma for storage 
(includes integrase resistance 
sample) 
 
6.5mL 
 
 
 
Urinalysis 
 
 
 
 
 
Microalbumin/creatinine ratio -  
urine6 
 
 
 
 
 
Pregnancy test7 
 
X 
 
 
X 
Virology 
 
 
 
 
 
HIV-1 RNA PCR 
3mL 
3mL 
 
 
3mL 
Genotyping   
 
2mL18 
 
 
2mL18,19 
Phenotyping 8 
 
2mL 
 
 
2mL19 
Immunology 
 
 
 
 
 
Lymphocyte subsets 9 
 
1mL 
 
 
1mL 
Pharmacokinetic studies 
 
 
 
 
 
STAGE I - Intensive PK 10 
 
 
[4mL] 
 
 


 
IMPAACT P1093, Version 5.0 
 
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12 July 2018 
STAGE I - Population PK 11 
 
 
[0.5 – 1mL] 
 
 
Total Maximum Blood 
Volumes 20 
3mL 
16.5mL 
[0.5 – 4mL] 
 
10mL 
Appendix IA Footnotes 
 
1. After obtaining Informed Consent, evaluations should be completed within 30 days prior to study entry.  
 
2. History and physical exam (including height, weight, vital signs [temperature, pulse, respirations and blood pressure), occurrence of adverse events since last study 
visit and HIV-1 associated conditions). Weight should be measured without shoes and with minimal clothing.  For female participants 9 years of age and older, 
menarche status and for participants who have reached menarche; sexual activity and contraceptive use. 
 
3. For information on Tanner Staging assessment, see P1093 MOP. 
 
4. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs. LFTs should include total bilirubin, indirect bilirubin, direct bilirubin, 
alkaline phosphatase, AST, ALT, and albumin. If indirect bilirubin is not reported by the site laboratory, it should be calculated at the site and documented.  
 
 
The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) values for indirect bilirubin.  
a. 
“ULN” values reported by the laboratory report for the test, or  
b. “ULN” values routinely used/established by the site, or  
c. 
“ULN” values as per the Harriet Lane Handbook (e.g. the current "ULN" for indirect bilirubin as per Harriet Lane Handbook is 0.4)  
 
Sites must be consistent with the way toxicities are evaluated for all participants in the study; sites should use the same source throughout the study. Remember to 
have documentation of calculated indirect bilirubin and source of "ULN", when not reported by your laboratory.  
 
5. Lipid Profile (triglycerides, cholesterol, HDL, LDL) will be drawn in a non-fasting state. However, if triglycerides are grade 2 (using DAIDS toxicity table for fasting 
triglycerides), a complete fasting state lipid profile (triglycerides, cholesterol, HDL, and LDL) must be drawn. Fasting intervals will be overnight or at least 8 hours. 
After a participant has had a grade 2 triglycerides in non-fasting state, all future triglycerides must be obtained in fasting state.  
 
6. M/C ratio – microalbumin / creatinine ratio (mcg/mg creatinine) 
 
7. Pregnancy test (urine or serum beta hCG) must be performed on all females of reproductive potential within 72 hours prior to enrollment. Subsequent tests should be 
performed at each visit. If a blood test is performed, collect 1.0mL in a red top serum tube. 
 
8. Phenotyping will occur where there is sufficient blood volume collected. HIV-1 phenotyping will NOT be performed in real time and will NOT be used to determine 
optimized background therapy (OBT). Specimens should be stored at the local site and shipped in batches when requested by the Protocol Team.  
9. Lymphocyte subset blood samples should be collected in EDTA tubes. These samples will be analyzed for CD4 and CD8. 
 
10. Refer to Section 9.2 for additional instructions around intensive PK sampling.  
 
The pharmacokinetic evaluation should be scheduled so that witnessed dosing of DTG is as close as possible to 24 hours (generally 22-26 hours) after the previous 
dosing. Participants should have been compliant in taking their medications for 3 days prior to the intensive PK visit; otherwise the intensive PK visit should be re-
scheduled.  
 
Intensive PK should be done in a fasted state following the guidelines below and Section 9.2.1.1, unless instructed otherwise by the Protocol Team.  


 
IMPAACT P1093, Version 5.0 
 
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12 July 2018 
• 
≥6 hours PRIOR to dosing – participants may eat and drink without restriction 
• 
≥4 to <6 hours PRIOR to dosing – milk, apple/orange juice and water may be consumed; No food 
• 
<4 hours PRIOR to dosing – water ONLY 
• 
From dosing to <2 hours POST dose – apple/orange juice and water may be consumed; No food 
• 
From ≥2 to <4 hours POST dose – participants may drink apple/orange juice and eat a snack/light meal (around 100-150 calories)  
• 
From ≥4 hours POST dose onwards – participants may eat and drink without restriction 
 
For participants who vomit within 4 hours after dosing; PK must be cancelled and may be rescheduled. Blood samples (0.5mL) will be collected at the following 
timepoints: pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dosing. The 24-hour sample must be collected prior to the next dose. To allow for some flexibility, the 8-hour 
sample can be collected with a window of 7-9 hours post-dose and the 24-hour sample with a window of 22-26 hours. US sites will ship intensive PK samples in real 
time to UAB; all non-US sites will ship PK samples in real time to BRI repository for a ‘pass-through’ (see LPC for instructions). 
 
11. Blood samples (0.5mL per sample) will be collected per time point at Weeks 4, 12 and 24.  Participants will have 2 blood sample collected at week 4: pre-dose and 2-
4 hours post dose. At week 12, 1 blood sample will be collected at any time point post dose. At week 24, 2 blood samples will be collected two hours apart between 
12 and 26 hours post-dose. Samples to be batched and shipped as described in the LPC. For sample collection timepoints for the ‘Two Weeks Post Switch Visit’ and 
‘Next Scheduled Visit after Post Switch Visit’ refer to footnotes 14 and 15 below. For participants on BID dosing refer to the study MOP for sampling time points.  
 
12. Entry must occur within 30 days of screening. 
 
13. If a participant meets a criterion for suspected virologic failure, as defined in Section 6.5, collect a confirmatory HIV-1 RNA PCR sample at least 1 week but not 
more than 4 weeks from the date of specimen collection of the initial RNA PCR test. If a sample cannot be obtained within weeks, samples should be collected as 
soon as possible beyond 4 weeks. 
 
14. If a participant is confirmed as having virologic failure, as defined in Section 6.5, conduct a Virologic Failure Visit at least one week and within four weeks later. 
 
15. Per Section 6.4, participants who underwent a dose modification and for whom additional PK sampling (intensive or population sampling) was requested by the 
Protocol Team collect intensive or population PK samples (per Protocol Team request only) 5 – 14 days after initiation of the DTG dose adjustment. (If this visit is 
scheduled to occur during another scheduled visit a combined visit can be done and procedures do not need to be duplicated.)  
 
16. Per Section 6.4, for participants who underwent a dose modification, as requested by the Protocol Team, a safety visit should be done 4 weeks (- 1 wk/+ 2 wks) after 
initiation of the DTG dose adjustment. (If this visit is scheduled to occur during another scheduled visit a combined visit can be done and procedures do not need to 
be duplicated.)  
 
17. Participants, who discontinue study drug early, should remain on study and follow Appendix IF .  
 
18. A baseline specimen should also be sent with the genotype virologic failure specimen. This specimen may be a baseline (Day 0 entry) storage sample or left over 
sample from baseline genotyping (screening). Please refer to the Laboratory Processing Chart (LPC) for additional details. 
 
19. Only if not done at virologic failure. 
 
20. The blood volumes listed are ideal, but may not always be possible due to site-specific regulations or challenges with phlebotomy in certain participants.  For 
insufficient blood draws, priorities are as follows: hematology; chemistry; pharmacokinetic studies; HIV-1 RNA; genotyping; lymphocyte subsets; plasma and 
PBMCs/plasma for storage; phenotyping; lipid profiles. 


 
IMPAACT P1093, Version 5.0 
 
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12 July 2018 
 
Appendix IB Schedule of Evaluations   
Cohorts I, IIA, III and III-DT – Stage II 
 
 
Screen1 
Entry11 
Day 0 
Day 
10 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Confirm 
Suspect 
Virologic 
Failure12 
Virologic 
failure13 
Pre-mature 
DC of Study 
Drug/ 
On study14 
Visit Windows 
- 
- 
±3 
days 
±1 
wk 
±1 
wk 
±1 wk 
±1 
wk 
±2 
wks 
±2 
wks 
±2 
wks 
±2 
wks 
- 
- 
- 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical 
exam2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Tanner Staging 3 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Adherence 
Questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
CDC Classification 
X 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Palatability Assessment 
 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology   
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
 
1mL 
1mL 
Chemistries4 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
 
1mL 
1mL 
Lipid profiles5 
1mL 
 
 
 
 
 
 
1mL 
 
 
1mL 
 
 
 
PBMCs / plasma for 
storage (includes 
integrase resistance 
sample) 
 
7mL 
 
 
 
 
 
6.5mL 
 
 
6.5mL 
 
6.5mL 
 
Urinalysis 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Microalbumin/creatinine 
ratio -  urine 6 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Pregnancy test 7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Virology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA PCR 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
Genotyping   
2mL 
 
 
 
 
 
 
 
 
 
 
 
2mL15 
2mL15,16 
Phenotyping 8 
2mL 
 
 
 
 
 
 
 
 
 
 
 
2mL 
2mL16 
Immunology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte subsets 9 
1mL 
1mL 
 
 
 
1mL 
 
1mL 
1mL 
1mL 
1mL 
 
1mL 
1mL 
Pharmacokinetic studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STAGE II - Population 
PK10 
 
 
 
1mL 
 
0.5mL 
 
1mL 
 
 
 
 
 
 


 
IMPAACT P1093, Version 5.0 
 
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12 July 2018 
Total Maximum Blood 
Volumes 17 
11mL 
13mL 
5mL 
6mL 
5mL 
6.5mL 
5mL 
14.5 
mL 
6mL 
6mL 
13.5 
mL 
3mL 
16.5mL 
10mL 
Appendix IB Footnotes 
 
1. After obtaining Informed Consent, evaluations should be completed within 30 days prior to study entry.  
 
2. History and physical exam (including height, weight, vital signs [temperature, pulse, respirations and blood pressure], occurrence of adverse events since last study 
visit and HIV-1 associated conditions). Weight should be measured without shoes and with minimal clothing. For female participants 9 years of age and older, 
menarche status and for participants who have reached menarche; sexual activity and contraceptive use. 
 
3. For information on Tanner assessment, see P1093 MOP. 
 
4. Chemistries will be performed at all visits. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs. LFTs should include total 
bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, AST, ALT, and albumin. If indirect bilirubin is not reported by the site laboratory, it should be 
calculated at the site and documented.  
 
The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) values for indirect bilirubin.  
a. 
"ULN" values reported by the laboratory report for the test, or  
b. “ULN" values routinely used/established by the site, or  
c. 
"ULN" values as per the Harriet Lane Handbook (e.g. the current "ULN" for indirect bilirubin as per Harriet Lane Handbook is 0.4)  
Sites must be consistent with the way toxicities are evaluated for all participants in the study; sites should use the same source throughout the study. Remember to 
have documentation of calculated indirect bilirubin and source of "ULN", when not reported by your laboratory.  
 
5. Lipid Profile (triglycerides, cholesterol, HDL, LDL) will be drawn in a non-fasting state. However, if triglycerides are grade 2 (using DAIDS toxicity table for fasting 
triglycerides), a complete fasting state lipid profile (triglycerides, cholesterol, HDL, and LDL) must be drawn. Fasting intervals will be overnight or at least 8 hours. 
After a participant has had a grade 2 triglycerides in non-fasting state, all future triglycerides must be obtained in fasting state.  
 
6. M/C ratio – microalbumin / creatinine ratio 
 
7. Pregnancy test (urine or serum beta hCG) must be performed on all females of reproductive potential within 72 hours prior to enrollment. Subsequent tests should be 
performed at each visit. If a blood test is performed, collect 1.0mL in a red top serum tube. 
 
8. Phenotyping will occur where there is sufficient blood volume collected. HIV-1 phenotyping will NOT be performed in real time and will NOT be used to determine 
optimized background therapy (OBT). Specimens should be stored at the local site and shipped in batches when requested by the Protocol Team.  
 
9. Lymphocyte subset blood samples should be collected in EDTA tubes. These samples will be analyzed for CD4 and CD8. 
 
10. Blood samples (0.5mL per sample) will be collected per time point at Weeks 4, 12 and 24. All participants will have 2 blood sample collected at week 4: pre-dose and 
2-4 hours post dose. At week 12, 1 blood sample will be collected at any time point post dose. At week 24, 2 blood samples will be collected two hours apart between 
12 and 26 hours post-dose.  Samples to be batched and shipped as described in the Laboratory Processing Chart (LPC). For sample collection timepoints for the ‘Two 
Weeks Post Switch Visit’ and ‘Next Scheduled Visit after Post Switch Visit’ refer to footnotes 13 and 14 below. For participants on BID dosing refer to the study 
MOP for sampling time points. 
 


 
IMPAACT P1093, Version 5.0 
 
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12 July 2018 
11. Entry must occur within 30 days of screening.  
 
12. If a participant meets a criterion for suspected virologic failure, as defined in Section 6.5, collect a confirmatory HIV-1 RNA PCR sample at least 1 week but not 
more than 4 weeks from the date of the initial RNA PCR test. If a sample cannot be obtained within weeks, samples should be collected as soon as possible beyond 4 
weeks) 
 
13. If a participant is confirmed as having virologic failure as defined, in Section 6.5, conduct a Virologic Failure Visit at least one week and within four weeks.   
 
14. Participants, who discontinue study drug early, should remain on study and follow Appendix IF Appendix IF Schedule of Evaluations  
Participants who Prematurely Discontinue Dolutegravir. 
 
15. A baseline specimen should also be sent with the genotype virologic failure specimen. This specimen may be a baseline (Day 0 entry) storage sample or left-over 
sample from baseline genotyping (screening). Please refer to the Laboratory Processing Chart (LPC) for additional details. 
 
16. Only if not done at virologic failure. 
 
17. The blood volumes listed are ideal, but may not always be possible due to site-specific regulations or challenges with phlebotomy in certain participants.  For 
insufficient blood draws, priorities are as follows: hematology; chemistry; pharmacokinetic studies; HIV-1 RNA; genotyping; lymphocyte subsets; plasma and 
PBMCs/plasma for storage; phenotyping; lipid profiles. 
 
 
 


 
IMPAACT P1093, Version 5.0 
 
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12 July 2018 
Appendix IC Schedule of Evaluations   
Cohorts IV, IV-DT, and V-DT– Stage I 
Screen through Week 48 
 
 
Screen1 
Entry10 
Day 0 
Intensive PK: 
Day 5-10 
Week 
4 
Week 
8 
Week 12 
Week 16 
Week 24 
Week 32 
Week 40 
Week 48 
Visit Windows 
- 
- 
- 
±1 wk 
±1 wk 
±1 wk 
±1 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
History and Physical exam 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence Questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CDC Classification 
 
X 
 
 
 
 
 
X 
 
 
 
Palatability Assessment 
 
 
X 
X 
 
 
 
X 
 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
Hematology   
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
Chemistries 3 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
Lipid profiles4 
1mL 
 
 
 
 
 
 
1mL 
 
 
1mL 
PBMCs / plasma for storage 
(includes integrase resistance)  
 
5mL 
 
 
 
 
 
4.5mL 
 
 
4.5mL 
Urinalysis 
X 
 
 
 
X 
 
 
X 
 
 
X 
Microalbumin/creatinine ratio -urine5 
 
X 
 
 
X 
 
 
X 
 
 
X 
Virology 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA PCR 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
Genotyping 
2mL 
 
 
 
 
 
 
 
 
 
 
Phenotyping6 
2mL 
 
 
 
 
 
 
 
 
 
 
Immunology 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte subsets7 
1mL 
1mL 
 
 
 
1mL 
 
1mL 
1mL 
1mL 
1mL 
Pharmacokinetic studies 
 
 
 
 
 
 
 
 
 
 
 
STAGE I - Intensive PK8 
 
 
4mL 
 
 
 
 
 
 
 
 
STAGE I – Population PK9 
 
 
 
1mL 
 
0.5mL 
 
1mL 
 
 
 
Total Maximum Blood Volumes18 
10.5mL 
10.5 
mL 
8.5mL 
5.5mL 
4.5mL 
6.0mL 
4.5mL 
12mL 
5.5mL 
5.5mL 
11mL 
 
 


 
IMPAACT P1093, Version 5.0 
 
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12 July 2018 
Appendix IC Schedule of Evaluations (cont’d) 
Cohorts IV, IV-DT, and V-DT– Stage I 
Virologic Failure, Dose Adjustment and Premature/DC of Study Drug Visits 
 
 
Confirm 
Suspected virologic 
failure11 
Virologic Failure12 
[Dose Adjustment 
PK Visit ]13 
[Dose Adjustment 
Safety Visit]14 
Premature/DC 
of Study Drug 
On study15 
Visit Windows 
 
- 
If requested, 5 to 14 
days after initiation of 
the dose adjustment 
4 weeks post dose 
modification 
(-1 wk/+ 2 wk)  
- 
CLINICAL EVALUATIONS 
 
 
 
 
 
Informed Consent 
 
 
 
 
 
History and Physical exam 2 
 
X 
 
[X] 
X 
Adherence Questionnaire 
 
X 
 
[X] 
X 
CDC Classification 
 
X 
 
 
X 
Palatability Assessment 
 
 
 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
Hematology   
 
0.5mL 
 
 
0.5mL 
Chemistries 3 
 
1mL 
 
 
1mL 
Lipid profiles 4 
 
 
 
 
 
PBMCs / plasma for storage 
(includes integrase resistance 
sample) 
 
4.5mL 
 
 
 
Urinalysis 
 
 
 
 
 
Microalbumin/creatinine ratio -  
urine5 
 
 
 
 
 
Virology 
 
 
 
 
 
HIV-1 RNA PCR 
3mL 
3mL 
 
 
3mL 
Genotyping   
 
2mL16 
 
 
2mL16,17 
Phenotyping 6 
 
2mL 
 
 
2mL17 
Immunology 
 
 
 
 
 
Lymphocyte subsets 7 
 
1mL 
 
 
1mL 
Pharmacokinetic studies 
 
 
 
 
 
STAGE I - Intensive PK 8 
 
 
[4mL] 
 
 
STAGE I - Population PK 9 
 
 
[0.5 – 1mL] 
 
 
Total Maximum Blood 
Volumes18 
3mL 
14mL 
[0.5 – 4mL] 
 
9.5mL 
 
 


 
IMPAACT P1093, Version 5.0 
 
Page 98 of 135 
 
12 July 2018 
 
Appendix IC – Footnotes 
 
1. After obtaining Informed Consent, evaluations should be completed within 30 days prior to study entry.  
 
2. History and physical exam (including height, weight, vital signs [temperature, pulse, respirations and blood pressure], occurrence of adverse events since last study 
visit and HIV-1 associated conditions). Weight should be measured without shoes and with minimal clothing. 
 
3. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs. LFTs should include total bilirubin, indirect bilirubin, direct bilirubin, 
alkaline phosphatase, AST, ALT, and albumin. If indirect bilirubin is not reported by the site laboratory, it should be calculated at the site and documented.  
 
The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) values for indirect bilirubin.  
a. 
“ULN” values reported by the laboratory report for the test, or  
b. “ULN” values routinely used/established by the site, or  
c. 
“ULN” values as per the Harriet Lane Handbook (e.g. the current "ULN" for indirect bilirubin as per Harriet Lane Handbook is 0.4)  
Sites must be consistent with the way toxicities are evaluated for all participants in the study, using the same source all the way through the study. Remember to have 
documentation of calculated indirect bilirubin and source of "ULN", when not reported by your laboratory.  
 
4. Lipid Profile (triglycerides, cholesterol, HDL, LDL) will be drawn in a non-fasting state. However, if triglycerides are grade 2 (using DAIDS toxicity table for fasting 
triglycerides), a complete fasting state lipid profile (triglycerides, cholesterol, HDL, and LDL) must be drawn. Fasting intervals will be overnight or at least 8 hours. 
After a participant has had a grade 2 triglycerides in non-fasting state, all future triglycerides must be obtained in fasting state.  
 
5. M/C ratio – microalbumin / creatinine ratio 
 
6. Phenotyping will occur where there is sufficient blood volume collected. HIV-1 phenotyping will NOT be performed in real time and will NOT be used to determine 
optimized background therapy (OBT). Specimens should be stored at the local site and shipped in batches when requested by the Protocol Team.  
 
7. Lymphocyte subset blood samples should be collected in EDTA tubes. These samples will be analyzed for CD4 and CD8. 
 
8. Refer to Section 9.2 for additional instructions around intensive PK sampling.  
 
The pharmacokinetic evaluation should be scheduled so that witnessed dosing of DTG is as close as possible to 24 hours (generally 22-26 hours) after the previous 
dosing. Participants should have been compliant in taking their medications for 3 days prior to the intensive PK visit; otherwise the intensive PK visit should be re-
scheduled.  
 
Intensive PK should be done in a fasted state following the guidelines below and Section 9.2.1.1, unless instructed otherwise by the Protocol Team.  
 
• 
Participants should not ingest breastmilk, 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 four hours after dosing on the intensive PK day. 
 
For participants who vomit within 4 hours after dosing; PK must be cancelled and may be rescheduled. Blood samples (0.5mL per sample) will be collected at the 
following time points: pre-dose, 1, 2, 3, 4, 6, 8 and 24 hours post dosing. The 24-hour sample must be collected prior to the next dose. To allow for some flexibility, 


 
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the 8-hour sample can be collected with a window of 7-9 hours post-dose and the 24-hour sample with a window of 22-26 hours. US sites will ship intensive PK 
samples in real time to UAB; all non-US sites will ship PK samples in real time to BRI repository for a ‘pass-through’ (see Laboratory Processing Chart (LPC).  
 
9. Blood samples (0.5mL per sample) will be collected per time point at Weeks 4, 12 and 24. All participants will have 2 blood samples collected at week 4: pre-dose 
and 2-4 hours post dose. At week 12, 1 blood sample will be collected at any time point post dose. At week 24, 2 blood samples will be collected two hours apart 
between 12 and 26 hours post-dose.  Samples to be batched and shipped as described in the LPC. For sample collection timepoints for the ‘Two Weeks Post Switch 
Visit’ and ‘Next Scheduled Visit after Post Switch Visit’ refer to footnotes 13 and 14 below. For participants on BID dosing refer to the study MOP for sampling time 
points. 
 
10. Entry must occur within 30 days of screening 
 
11. If a participant meets a criterion for suspected virologic failure, as defined in Section 6.5, collect a confirmatory HIV-1 RNA PCR sample at least 1 week but not 
more than 4 weeks from the date of specimen collection of the initial RNA PCR test. If a sample cannot be obtained within weeks, samples should be collected as 
soon as possible beyond 4 weeks).   
 
12. If a participant is confirmed as having virologic failure, as defined in Section 6.5, conduct a Virologic Failure Visit at least one week later, and within four weeks.   
 
13. Per Section 6.4, participants who underwent a dose modification and for whom additional PK sampling (intensive or population sampling) was requested by the 
Protocol Team collect intensive or population PK samples (per Protocol Team request only) 5 – 14 days after initiation of the DTG dose adjustment. (If this visit is 
scheduled to occur during another scheduled visit a combined visit can be done and procedures do not need to be duplicated.)  
 
14. Per Section 6.4, for participants who underwent a dose modification, as requested by the Protocol Team, a safety visit should be done 4 weeks (- 1 wk/+ 2 wks) after 
initiation of the DTG dose adjustment. (If this visit is scheduled to occur during another scheduled visit a combined visit can be done and procedures do not need to 
be duplicated.)  
 
15. Participants, who discontinue study drug early, should remain on study and follow Appendix IF  
 
16. A baseline specimen should also be sent with the genotype virologic failure specimen. This specimen may be a baseline (Day 0 entry) storage sample or left over 
sample from baseline genotyping (screening). Please refer to the Laboratory Processing Chart (LPC) for additional details. 
 
17. Only if not done at virologic failure. 
 
18. The blood volumes listed are ideal, but may not always be possible due to site-specific regulations or challenges with phlebotomy in certain participants.  For 
insufficient blood draws, priorities are as follows: hematology; chemistry; pharmacokinetic studies; HIV-1 RNA; genotyping; lymphocyte subsets; plasma and 
PBMCs/plasma for storage; phenotyping; lipid profiles. 
 
 


 
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Appendix ID Schedule of Evaluations   
Cohorts IV, IV-DT, and V-DT – Stage II 
 
Screen1 
Entry9 
Day 0 
Day 
10 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
24 
Week 
32 
Week 
40 
Week 
48 
Confirm 
Suspected 
Virologic 
Failure10 
Virologic 
failure11 
Premature 
DC of 
Study 
Drug/ 
On study12 
Visit Windows 
- 
- 
±3 
days 
±1wk 
±1wk 
±1wk 
±1wk 
±2wk 
±2wk 
±2wk 
±2wk 
 
- 
- 
CLINICAL EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
History and Physical 
exam2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
Adherence 
Questionnaire 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
CDC Classification 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
X 
Palatability Assessment 
 
 
X 
X 
 
 
 
X 
 
 
 
 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology   
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
0.5mL 
 
0.5mL 
0.5mL 
Chemistries3 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
1mL 
 
1mL 
1mL 
Lipid profiles4 
1mL 
 
 
 
 
 
 
1mL 
 
 
1mL 
 
 
 
PBMCs / plasma for 
storage 
Includes integrase 
resistance) 
 
5mL 
 
 
 
 
 
4.5mL 
 
 
4.5mL 
 
4.5mL 
 
Urinalysis 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Microalbumin/ 
creatinine ratio assay - 
urine5 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Virology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA PCR 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
Genotyping   
2mL 
 
 
 
 
 
 
 
 
 
 
 
2mL13 
2mL13,14 
Phenotyping6 
2mL 
 
 
 
 
 
 
 
 
 
 
 
2mL 
2mL14 
Immunology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lymphocyte subsets7 
1mL 
1mL 
 
 
 
1mL 
 
1mL 
1mL 
1mL 
1mL 
 
1mL 
1mL 
Pharmacokinetic studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
STAGE II - Population 
PK 8 
 
 
 
1mL 
 
0.5mL 
 
1mL 
 
 
 
 
 
 
Total Maximum Blood 
Volumes15 
10.5mL 
10.5mL 
4.5mL 
5.5mL 
4.5mL 
6mL 
4.5mL 
12mL 
5.5mL 
5.5mL 
11mL 
3mL 
14mL 
9.5mL 
Appendix ID – Footnotes 


 
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1. After obtaining Informed Consent, evaluations should be completed within 30 days prior to study entry.  
 
2. History and physical exam (including height, weight, vital signs [temperature, pulse, respirations and blood pressure], occurrence of adverse events since last study 
visit and HIV-1 associated conditions). Weight should be measured without shoes and with minimal clothing. 
 
3. Blood Chemistries will be performed at all visits. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs. LFTs should 
include total bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, AST, ALT, and albumin. If indirect bilirubin is not reported by the site laboratory, it 
should be calculated at the site and documented.  
 
The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) values for indirect bilirubin.  
a. 
"ULN" values reported by the laboratory report for the test, or  
b. “ULN" values routinely used/established by the site, or  
c. 
"ULN" values as per the Harriet Lane Handbook (e.g. the current "ULN" for indirect bilirubin as per Harriet Lane Handbook is 0.4)  
Sites must be consistent with the way toxicities are evaluated for all participants in the study, using the same source all the way through the study. Remember to have 
documentation of calculated indirect bilirubin and source of "ULN", when not reported by your laboratory.  
 
4. Lipid Profile (triglycerides, cholesterol, HDL, LDL) will be drawn in a non-fasting state. However, if triglycerides are grade 2 (using DAIDS toxicity table for fasting 
triglycerides), a complete fasting state lipid profile (triglycerides, cholesterol, HDL, and LDL) must be drawn. Fasting intervals will be overnight or at least 8 hours. 
After a participant has had a grade 2 triglycerides in non-fasting state, all future triglycerides must be obtained in fasting state.  
 
5. M/C ratio – microalbumin / creatinine ratio 
 
6. Phenotyping will occur where there is sufficient blood volume collected. HIV-1 phenotyping will NOT be performed in real time and will NOT be used to determine 
optimized background therapy (OBT). Specimens should be stored at the local site and shipped in batches when requested by the Protocol Team.  
 
7. Lymphocyte subset blood samples should be collected in EDTA tubes. These samples will be analyzed for CD4 and CD8. 
 
8. Blood samples (0.5mL per sample) will be collected per time point at Weeks 4, 12 and 24. All participants will have 2 blood samples collected at week 4: pre-dose 
and 2-4 hours post dose. At week 12, 1 blood samples will be collected at any time point post dose. At week 24, 2 blood samples will be collected two hours apart 
between 12 and 26 hours post-dose. Samples to be batched and shipped as described in the LPC. For sample collection timepoints for the ‘Two Weeks Post Switch 
Visit’ and ‘Next Scheduled Visit after Post Switch Visit’ refer to footnotes 11 and 12 below. For participants on BID dosing refer to the study MOP for sampling time 
points. 
 
9. Entry must occur within 30 days of screening. 
 
10. If a participant meets a criterion for suspected virologic failure, as defined in Section 6.5, collect a confirmatory HIV-1 RNA PCR sample at least 1 week but not 
more than 4 weeks from the date of specimen collection of the initial RNA PCR test. If a sample cannot be obtained within weeks, samples should be collected as 
soon as possible beyond 4 weeks). 
 
11. If a participant is confirmed as having virologic failure, as defined in Section 6.5, conduct a Virologic Failure Visit at least one week later, and within four weeks.  
 
12. Participants, who discontinue study drug early, should remain on study and follow Appendix IF  


 
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13. A baseline specimen should also be sent with the genotype virologic failure specimen. This specimen may be a baseline (Day 0 entry) storage sample or left over 
sample from baseline genotyping (screening). Please refer to the LPC for additional details. 
 
14.  Only if not done at virologic failure.  
 
15. The blood volumes listed are ideal, but may not always be possible due to site-specific regulations or challenges with phlebotomy in certain participants.  For 
insufficient blood draws, priorities are as follows: hematology; chemistry; pharmacokinetic studies; HIV-1 RNA; genotyping; lymphocyte subsets; plasma and 
PBMCs/plasma for storage; phenotyping; lipid profiles. 
 


 
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2018 
Appendix IE Schedule of Evaluations  
Long-term Safety Follow-up for Participants Who Continue to Receive Dolutegravir  
 
 
Every 12 Weeks 
[Weeks 60, 72, 
84, 96, 108, 120, 
132, 144, 156, 
168,180, and 
192(End of 
Study Visit)] 
Every 48 Weeks 
[Weeks 96, 144 
and 192 (End of 
Study Visit)] 
Confirm 
suspected 
virologic failure6 
Virologic failure7 
Premature 
Discontinuation 
of Study 
Drug/On Study9 
Visit Windows 
±4 wks 
±4 wks 
 
 
 
CLINICAL EVALUATIONS 
 
 
 
 
History and Physical1 
X 
 
 
X 
X 
Adherence Questionnaire 
X 
 
 
X 
 
Palatability Assessment 
 
 
 
 
 
LABORATORY EVALUATIONS 
 
 
 
 
HIV-1 RNA PCR 
3mL 
 
3mL 
3mL 
 
PBMCs/plasma for storage 
 
 
 
6.5mL 
 
Genotyping 
 
2mL2 
 
2mL3 
2mL3,4 
Phenotyping 
 
 
 
2mL 
2mL4 
Lipid profiles 
 
1mL 
 
 
 
Pregnancy test5 
X 
X 
 
X 
X 
Total Maximum Blood 
Volumes8 
3mL 
3mL 
 
13.5mL 
4mL 
 
 
 


 
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2018 
Appendix IE - Footnotes: 
1. History and physical exam (including height, weight, vital signs [temperature, pulse, respirations and blood pressure, occurrence of 
adverse events since last study visit and any HIV-1 associated conditions). Weight should be measured without shoes and with minimal 
clothing. For female participants 9 years of age and older, menarche status and for participants who have reached menarche, sexual 
activity and contraceptive use. 
2. Genotyping to be done for participants post virologic failure, ONLY if requested to do so by the Protocol Team.   
3. Specimens for genotyping and phenotyping should be obtained and stored at this visit, but only sent for processing if the confirmatory 
HIV RNA test at this visit is > 400 c/ml. Please refer to the Laboratory Processing Chart (LPC) for additional details. 
4. Only if not done at virologic failure visit. 
5. Pregnancy testing, after the initial 48 weeks of study drug, should be determined as per local practice. If pregnancy occurs, it is an event 
that should be captured on the CRFs.  
6. If a participant meets a criterion for suspected virologic failure, as defined in Section 6.5, collect a confirmatory HIV-1 RNA PCR sample 
at least 1 week but not more than 4 weeks from the date of specimen collection of the initial RNA PCR test. If a sample cannot be 
obtained within weeks, samples should be collected as soon as possible beyond 4 weeks) 
7. If a participant is confirmed as having virologic failure, as defined in Section 6.5, conduct a Virologic Failure Visit at least one week and 
within four weeks.   
8. The blood volumes listed are ideal, but may not always be possible due to site-specific regulations or challenges with phlebotomy in 
certain participants.  For insufficient blood draws, priorities are as follows: pharmacokinetic studies; HIV-1 RNA; genotyping; plasma and 
PBMCs/plasma for storage; phenotyping; lipid profiles. 
9. Participants, who discontinue study drug early, should remain on study and follow Appendix IF   
 
 
 


 
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Appendix IF Schedule of Evaluations  
Participants who Prematurely Discontinue Dolutegravir 
 
 
Participants who continue DTG will be followed as per Appendix IE  
 
 
4 Week Follow-Up Visit2 
Every 3 months until 
resolved (if applicable)3  
Visit Windows  
±2 wks 
±4 wks 
History and Physical1 
X 
X 
 
Appendix IF - Footnotes: 
 
1. History and physical exam (including height, weight, vital signs [temperature, pulse, respirations and blood pressure], occurrence of adverse 
events since last study visit and any HIV-1 associated conditions). Weight should be measured without shoes and with minimal clothing. 
 
2. This follow up visit should be performed 4 weeks after the participant’s last exposure to DTG. 
 
3. Participants who are pregnant or who have a drug related adverse event that has not resolved within 3 months of stopping study drug, should 
come back to clinic every 3 months for follow-up until the AE is resolved or the mother delivers the baby. Study required tests are an interim 
history and physical exam at these visits. If sites perform safety tests at these visits as a result of standard of care, sites should document all 
results in the case report forms. If the participant discontinues for any reason other than pregnancy or drug related AE, no other visit after the 4 
week visit is required. 
 
 


 
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Appendix IG  
Schedule of Evaluations 
Participants who Start Rifampin as Part of Treatment for Active Tuberculosis 
 
 
Study Visits Following Initiation of Rifampin Therapy 
 
Virologic 
failure 11 
Premature 
Discontinua
tion of 
Study 
Drug/ 
On study 12 
Day 1 of 
rifampin 
therapy 1 
Week 2 
Week 4 
Week 12 
Every 8 
weeks until 
end of 
rifampin 
therapy  
Confirm 
Suspected 
Virologic 
Failure10 
Visit Windows 
 
±1 wk 
±1 wk 
±1 wk 
±2 wks 
 
- 
- 
CLINICAL EVALUATIONS 
History and Physical exam 2 
X 
X 
X 
X 
X 
 
X 
X 
Adherence Questionnaire 
X 
X 
X 
X 
X 
 
X 
X 
LABORATORY EVALUATIONS 
Hematology   
1mL 
1mL 
1mL 
1mL 
1mL 
 
1mL 
1mL 
Chemistries3 
1mL 
1mL 
1mL 
1mL 
1mL 
 
1mL 
1mL 
Lipid profiles4 
1mL 
 
 
1mL 
 
 
 
 
Microalbumin/creatinine ratio 
assay – urine5 
 
 
X 
X 
X 
 
X 
 
PBMCs / plasma for storage 
 
 
 
 
 
 
6.5mL 
 
Pregnancy test6 
X 
X 
X 
X 
X 
 
X 
X 
Virology 
HIV-1 RNA PCR 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
3mL 
Immunology 
Lymphocyte subsets7 
 
 
 
1mL 
1mL 
 
1mL 
1mL 
Pharmacokinetics 
Intensive PK8 
 
8mL 
 
 
 
 
 
 
Population PK 9 
 
 
1mL 
1mL 
 
 
 
 
Total Maximum Blood 
Volumes 13 
6mL 
13mL 
6mL 
8mL 
6mL 
 
12.5mL 
6mL 
NOTE: Participants who are diagnosed with active tuberculosis while taking DTG as part of P1093, will have their medications changed as per Section 
6.1.8 and should be followed as per Appendix IG . It is estimated the participant will be on anti-TB treatment for approximately 24 weeks. Upon 
discontinuation of the rifampin containing anti-TB therapy, the participant’s DTG dose will revert back to once daily administration. The participant 
should complete the remainder of the first 48 weeks of DTG therapy on their original schedule of evaluations, or if they have completed 48 weeks of 
DTG therapy, they should move to long- term follow-up (Appendix IE ). For example, if the participant was at week 16 when they were started on 
rifampin, and they complete 24 weeks of rifampin therapy, they would then go back to week 40 of their original SOE. 
 


 
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Appendix IG Footnotes: 
 
1. Participants who are already enrolled in P1093 and become exposed to TB, and subsequently require an anti-TB treatment that includes the use of 
rifampin, may be allowed to continue in the study if their ART options are compatible with co-administration of rifampin. Continuation requires the 
approval of the Protocol Team.   
 
2. History and physical exam (including height, weight, vital signs [temperature, pulse, respirations and blood pressure], occurrence of adverse events 
since last study visit and HIV-1 associated conditions). Weight should be measured without shoes and with minimal clothing. 
3. Chemistries will be performed at all visits. Electrolytes (sodium, potassium, and HCO3), glucose, creatinine, lipase, phosphorus, and LFTs. LFTs should 
include total bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, AST, ALT, and albumin. If indirect bilirubin is not reported by the site 
laboratory, it should be calculated at the site and documented.  
The following (listed in order of preference) should be used to determine the upper limit of normal (ULN) values for indirect bilirubin.  
a. 
"ULN" values reported by the laboratory report for the test, or  
b. “ULN" values routinely used/established by the site, or  
c. 
"ULN" values as per the Harriet Lane Handbook (e.g. the current "ULN" for indirect bilirubin as per Harriet Lane Handbook is 0.4)  
Sites must be consistent with the way toxicities are evaluated for all participants in the study; sites should use the same source throughout the study. 
Remember to have documentation of calculated indirect bilirubin and source of "ULN", when not reported by your laboratory.  
 
4. Lipid Profile (triglycerides, cholesterol, HDL, LDL) will be drawn in a non-fasting state. However, if triglycerides are grade 2 (using DAIDS toxicity 
table for fasting triglycerides), a complete fasting state lipid profile (triglycerides, cholesterol, HDL, and LDL) must be drawn. Fasting intervals will be 
overnight or at least 8 hours. After a participant has had a grade 2 triglycerides in non-fasting state, all future triglycerides must be obtained in fasting 
state.  
 
5. M/C ratio – microalbumin / creatinine ratio 
 
6. Pregnancy test (urine preferably) must be performed on all females of reproductive potential at each visit. If a serum beta hCG test is performed, collect 
1.0mL in a red top serum tube. 
 
7. Lymphocyte subset blood samples should be collected in EDTA tubes. These samples will be analyzed for CD4 and CD8. 
 
8. The pharmacokinetic evaluation should be scheduled so that witnessed dosing of DTG is as close as possible to 24 hours (generally 22-26 hours) after 
the previous dosing. Participants should have been compliant in taking their medications for 3 days prior to the intensive PK visit; otherwise the 
intensive PK visit should be re-scheduled. For participants who vomit within 4 hours after dosing; PK must be cancelled and may be rescheduled. Blood 
samples (0.5mL per sample) will be collected at the following time points: pre-dose, and at 1, 2, 3, 4, 6, 8, and 12 hours post-dose. To allow for some 
flexibility, the 8-hour sample can be collected with a window of 7-9 hours post-dose and the 12 hour sample with a window of 11-13 hours. US sites 


 
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2018 
will ship intensive PK samples in real time to UAB; all non-US sites will ship PK samples in real time to BRI repository for a ‘pass-through’ (see LPC 
for instructions). See dosing and fasting instructions for Cohorts I-III and Cohorts IV-V-DT, below.  
Instructions for Cohorts I-III: 
• 
≥6 hours PRIOR to dosing – participants may eat and drink without restriction 
• 
≥4 to <6 hours PRIOR to dosing – milk, apple/orange juice and water may be consumed; No food 
• 
<4 hours PRIOR to dosing – water ONLY 
• 
From dosing to <2 hours POST dose – apple/orange juice and water may be consumed; No food 
• 
From ≥2 to <4 hours POST dose – participants may drink apple/orange juice and eat a snack/light meal (around 100-150 calories)  
• 
From ≥4 hours POST dose onwards – participants may eat and drink without restriction 
 
Instructions for Cohorts IV-V-DT: 
 
Participants should not ingest breastmilk, 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.   
 
9. All participants will have 2 blood samples (0.5mL per sample) collected at weeks 4 and 12: pre-dose and 8-14 hours post dose. Samples to be batched 
and shipped as described in the LPC.  
 
10. If a participant meets a criterion for suspected virologic failure, as defined in Section 6.5, collect a confirmatory HIV-1 RNA PCR sample at least 1 
week but not more than 4 weeks from the date of specimen collection of the initial RNA PCR test. If a sample cannot be obtained within weeks, samples 
should be collected as soon as possible beyond 4 weeks) 
 
11. If a participant is confirmed as having virologic failure, as defined in Section 6.5, conduct a Virologic Failure Visit at least one week and within four 
weeks.   
 
12. Participants who discontinue study drug (DTG) early are required to come back to clinic four weeks after stopping study drug or after resolution of any 
adverse event.  
 
13. The blood volumes listed are ideal, but may not always be possible due to site-specific regulations or challenges with phlebotomy in certain participants.  
For insufficient blood draws, priorities are as follows: pharmacokinetic studies; HIV-1 RNA; genotyping; plasma and PBMCs/plasma for storage; 
phenotyping; lipid profiles. 
 
1. F


 
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Appendix II 
Sample Consent Form for Participants Enrolling in Stage I 
 
DIVISION OF AIDS 
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS GROUP 
(IMPAACT) 
 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and  
Antiviral Activity of dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 
Infected Infants, Children and Adolescents 
 
Participants Enrolling in STAGE ONE 
P1093 Version 5.0, dated 12 July 2018   
 
SHORT TITLE FOR THE STUDY: Safety and PK of dolutegravir in HIV-1 Infected Children  
 
INTRODUCTION 
You are/your child is being asked to take part in this research study because you have /your child has the 
Human Immunodeficiency Virus (HIV), which is the virus that causes AIDS, and because the drugs 
currently available may not keep the amount of HIV in your / your child’s blood low enough or may 
cause side effects too difficult to deal with. 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 to be/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/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 study a new antiretroviral HIV medication called dolutegravir. This drug is a 
type of 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. The study will help find the best 
amount or dose of dolutegravir for infants, children and teenagers, when it is taken on its own as well as 
with other antiretroviral medications. This study will also find out the safety of using this medication in 
infants, children and adolescents and if there are any side effects from the medication. Dolutegravir has 
been tested in adults and children. The study drug (dolutegravir) is approved for use in children 12 years 
and older by the FDA [and/or local regulatory authorities].  
 
WHAT DO I / DOES MY CHILD HAVE TO DO IF I AM / HE / SHE IS IN THIS STUDY? 
If you decide to (allow your child to) enroll in this study, you / your child will be asked to come to the 
clinic at least 10 times over 48 weeks and then every 12 weeks for three more years. You / your child will 
be given dolutegravir and you / your child will be asked to take it once or twice a day for the entire study, 
in addition to your / your child’s regular HIV medicines. Dolutegravir is available in 3 different 
formulations: 1) a film-coated tablet which cannot be crushed or dissolved, 2.) a liquid suspension and, 3) 
a tablet that can be dissolved in water. If you are/your child is 12 up to 18 years old, you/your child will 
take the film-coated tablet formulation of dolutegravir. You will be given instructions on how to give 
dolutegravir to your child and how to store the dolutegravir. If your child is between 6 to less than 12 
years of age and was prescribed the liquid or dissolvable tablets of dolutegravir he/she may be allowed to 
switch to the film-coated tablet formulation at a later time. The study staff will let you know when your 
child can switch and if you request to do so. 


 
IMPAACT P1093, Version 5.0 
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12 July 2018 
 
Although the study will provide you/your child with dolutegravir, other antiretrovirals will not be 
provided by the study. 
 
This study will be done in two parts – Stage one and Stage two. Stage one will enable the doctors to find 
the right dose of study drug for you/your child and then will keep you on that dose to look for any side 
effects that you/your child might experience. In Stage two the doctors will know the right dose to put 
you/your child on and will look at any side effects that you / your child might experience as well as how 
well the drug is controlling your HIV infection. You/your child will be enrolled into either Stage one or 
Stage two, depending on when you/your child enroll and your age / the age of your child. This consent 
form is for Stage one. 
 
In this study there are 8 cohorts in Stage I – enrolling infants, children, and adolescents from 4 weeks to 
less than 18 years of age. Participants who have had their 18th birthday by the entry visit will not be 
enrolled into the study.  
 
Screening: 
If you are interested in taking part / allowing your child to enroll in this study, we will see if you are / 
your child is eligible for the study: 
 
• 
We will ask your / your child’s medical history including questions about your /your child’s 
health and what symptoms, medications, and illnesses you have/your child has had. 
• 
We will do a physical exam including height, weight and vital signs (temperature, blood pressure, 
pulse and respiratory rate). Doses may be modified based on the results of the weight. 
• 
We will take a little more than 2 teaspoons (11mL) of blood, to check for the following: 
o The amount of HIV in the blood,  
o The amount of cholesterol and triglycerides (types of fat) in the blood,  
o How well your immune system, liver and kidneys are working,  
o Other routine tests.  
You will be given the results of these tests. We will also ask you/your child to provide a urine sample for 
routine tests. Girls and women who can have a baby will also be asked to provide a urine or blood sample 
to test for pregnancy.  If you are / your child is engaged in sexual activity that could lead to pregnancy, 
you / your child will be asked to take birth control precautions throughout the study period. 
 
On Study: 
If you are/your child is eligible for this study, you/your child will come to the clinic at least 10 times in 
about 1 year. Most of the visits will last about 1-2 hours. More visits will be needed if the amount of 
study drug in your blood is too low or too high and your dose needs to be adjusted. You/your child will 
come to the clinic for the first study visit within 30 days of the screening visit.  
• 
At each visit, a medical history will be taken and you/your child will have a physical exam. At the 
enrollment visit and at the week 48 visit, you/your child’s stage of sexual development will be 
determined. For girls/women, this will be done by looking at how developed the breasts are. For 
boys/men, this will be done by measuring the size of the testes.  


 
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• 
We will draw blood at each visit. Depending upon your/your child’s age, between 1- 4 teaspoons 
(5-17mLs) of blood will be drawn at these visits; you will be informed of results of routine blood 
tests. Some of the blood drawn will be stored and tested to find out how your/your child’s 
immune system is affected by the study drug. This testing will be done after the study is over, and 
you will not be given the results of these tests.  
• 
A palatability assessment will be done at Day 10, Week 4 and Week 24 to find out what you/your 
child thinks about the taste of the study drug. 
• 
You/your child will be asked to come to the clinic to have blood drawn 8 times over 24 hours 
during one visit, approximately 5-10 days after you / your child started taking the study 
medication. This visit is known as an ‘intensive PK visit’. Depending on your/your child’s age, 
up to 9mLs (about 2 teaspoons) of blood will be drawn at this visit and you will be asked to 
withhold certain liquids and food. The study staff will give you instructions about this.  These 
blood tests are done to measure the amount of study drug in your/your child’s blood. A small 
plastic catheter (a needle that is placed in a vein for an extended period of time, so that blood can 
be drawn multiple times, without having to stick you with a needle several times) will be placed 
in your/your child’s arm to draw these blood samples. The needle will stay in place until all of the 
blood samples are drawn.  
• 
If the amount of study drug in your/your child’s blood is not enough or is too high, you/your child 
may be asked to take a different dose and may be asked to return to the clinic for another 
‘intensive PK visit’. You/your child may have blood to be drawn again 8 times over 24 hours. 
This is to make certain that the new dose is safe.  The same procedures above will be followed. 
• 
The current instructions on what you/your child can eat and drink around the intensive PK draws 
are below, but these may change.  If these instructions change, the study staff will let you know 
and provide you with different instructions.     
If you are/your child is older than 2 years old and having intensive PKs done you/your child may 
be asked to follow the guidelines below regarding eating and drinking around the intensive PK 
visit. 
• 
≥6 hours PRIOR to taking your medication – you/your child may eat and drink without 
restriction 
• 
≥4 to <6 hours PRIOR to taking your medication – milk, apple/orange juice and water may be 
consumed; No food 
• 
<4 hours PRIOR to taking your medication – water ONLY 
• 
From dosing to <2 hours AFTER taking your medication – apple/orange juice and water may 
be consumed; No food 
• 
From ≥2 to <4 hours AFTER taking your medication – you may drink apple/orange juice and 
eat a snack/light meal (around 100-150 calories)  
• 
From ≥4 hours AFTER taking your medication onwards – you may eat and drink without 
restriction 
If your child is 4 weeks to less than 2 years old and having intensive PKs done, you/your child 
may be asked to follow the guidelines below regarding eating and drinking around the intensive 
PK visit. 


 
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• 
No breastmilk, 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.   
• 
You will have extra blood draws at three visits (week 4, week 12 and week 24). At weeks 4 and 
24, you will have two blood draws.  At week 12 you will only have one blood draw. The amount 
of blood drawn at the different study visits will be less than 1 teaspoon (0.5-1mL) depending on 
your /your child’s age. 
• 
If the amount of HIV virus in your/your child’s blood increases too much while on this study 
drug, you/your child may be asked to come back to clinic to have your blood drawn to confirm 
the level of HIV in your blood. If the level of HIV virus in your blood is still too high, your study 
doctor may ask you to stop taking the study medicine and to come back to the clinic for another 
visit. As part of this visit, you/your child will have an interim medical history, physical exam and 
approximately 3 teaspoons of blood (14-16.5mL) will be drawn for testing and storage.  
• 
If you/your child experiences a severe liver reaction or inflammation while on the study, you/your 
child may be asked to come back to clinic to have less than one teaspoon of blood (2mL) drawn 
to check the level of dolutegravir in the blood. Additional testing as part of routine assessments 
for liver inflammation (e.g. checking for viruses that cause liver inflammation) may be performed 
as well.  
Long Term Follow-Up 
After you have been on study drug for approximately 48 weeks, you will enter the long term follow-up 
phase of the study. You will be asked to come back into clinic every 12 weeks (every 3 months) for 3 
more years. Most visits will last about 30 mins.  
• 
At each visit, a medical history will be taken and you/your child will have a physical exam. You 
will also be asked if you have missed taking any of your medications. 
• 
We will draw less than 1 teaspoon of blood (3-4mL) at each visit. You will be informed of results 
of routine blood tests.  
• 
As before, if the amount of HIV virus in your/your child’s blood increases too much while on this 
study drug, you/your child may be asked to come back to clinic to have your blood drawn to 
confirm the level of HIV in your blood (see above).  
You/your child must continue to take your/his/her anti-HIV medications during the study as prescribed by 
your/your child’s HIV care provider. If your/your child’s HIV care provider changes your/your child’s 
anti-HIV medications during the study, you/your child can still take the study drug. You/your child will 
be asked questions about taking your/his/her anti-HIV medications and the times you take/he/she takes 
them and if you have/he/she has missed any medications. 
 
If you/your child can become pregnant, we will collect urine or blood to test for pregnancy at each visit. 
We will also ask you/your child about contraception use.  If you think you/if your child thinks she may be 
pregnant at any time during the study, tell the study staff right away.  
 
Blood and Urine Samples 
Some of your / your child’s blood and urine samples will be shipped out of the country to the USA for 
specialized tests. These tests will tell the doctors how much study drug is in your / your child’s blood and 
if the study drug is causing any changes in your kidneys.  


 
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For Participants Receiving Granules for suspension only 
 
If your child is receiving the liquid he/she will need to switch to the dissolvable tablet. The study staff 
will inform you when your child will need to switch. This is because the company will not be making the 
(granule) liquid form of dolutegravir any longer. The study staff will provide instructions on how to 
dispense the dissolvable tablet and on the day you are scheduled to come to the clinic to begin taking the 
dissolvable tablets you will be asked to not give the (granule) liquid dose to your child. The first dose of 
the dissolvable tablet will be given in the clinic. You will be asked to come back to the clinic about 2 
weeks later and will have a palatability assessment and blood drawn to confirm the level of HIV in your 
child’s blood. If you have been on the study for more than 24 weeks at each of these visits, blood samples 
will be drawn at two separate times. The amount of blood drawn will be less than 1 teaspoon (0.5 -1mL)].   
 
WHAT DO I / DOES MY CHILD HAVE TO DO IF I AM / HE / SHE BECOMES INFECTED WITH 
TUBERCULOSIS WHILE ON THIS STUDY? 
If you become/your child becomes exposed to Tuberculosis (TB) while on study and requires anti-TB 
treatment that includes Rifampin you/your child will have to increase the dose of dolutegravir from once a 
day to twice a day while taking Rifampin. After you/your child complete(s) treatment with Rifampin, 
you/your child will go back to taking the dolutegravir once a day depending on what other medications 
you/your child is taking.  
 
You/your child will also be required to return for at least five additional follow-up visits after starting 
Rifampin.  
• 
At each of these visits, a medical history will be taken and you/your child will have a physical 
exam and a pregnancy test.  We will draw approximately 1-3 teaspoons of blood to look at the 
following: 
o The amount of HIV, cholesterol and triglycerides (types of fat) in your blood 
o How well your immune system, liver and kidneys are working, as well as other routine 
tests 
• 
At each visit you will be asked whether you are taking your medication as instructed. 
• 
You/your child will be asked to come to the clinic to have blood drawn 8 times over 12 hours 
during one visit, approximately 5-10 days after you/ your child started taking anti-TB medication. 
For this visit, you/your child will be asked to fast for 6 hours before your daily dose of study 
medication. 
• 
The study staff will give you more instructions about this. Depending on your/your child’s age, 
up to 13mL (about 3 teaspoons) of blood will be drawn at this visit. 
• 
You will have extra blood draws at two visits. At weeks 4 and 12, you will have two blood draws 
-  blood will be drawn once before you take dolutegravir and about 12 hours later.  The amount of 
blood drawn at the different study visits will be less than 1 teaspoon (1mL) depending on your 
/your child’s age. 
OTHER INFORMATION 
The information collected in this study may be used for other IMPAACT-approved HIV-related research. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
About 300 children and adolescents will take part in this study 


 
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HOW LONG WILL I/MY CHILD BE IN THIS STUDY? 
You/your child is enrolling in Stage I of the study, and so will be in the study for at least 48 weeks After 
that time you/your child will enter the long-term safety follow-up phase of the study. During this time, 
you / your child will continue to take study-provided dolutegravir and will be asked to come to clinic 
every 12 weeks for three more years. 
 
 
WHY WOULD THE DOCTOR TAKE ME / MY CHILD OFF THE STUDY DRUG / THIS STUDY 
EARLY? 
The study doctor may need to take you/your child off the study drug early, without your permission, if: 
• 
Continuing the study drug may be harmful to you / your child 
• 
You become / your child becomes pregnant while on study 
• 
If you elect not to attend repeat PK evaluations as part of the study 
 
The study doctor may need to take you/your child off the study early, without your permission, if: 
• 
You are/ your child is not able to attend the study visits as required by the study 
• 
You need / your child needs a treatment that you / your child may not take while on the study 
• 
You are / your child is not able to take the study drug as required by the study 
• 
The study is cancelled by the U.S. Food and Drug Administration (FDA), National Institutes of 
Health (NIH), the Office of Human Research Protections (OHRP), other country specific 
governmental agencies, IMPAACT, the drug company supporting this study (GSK), or the site’s 
Institutional Review Board (IRB) or Ethics Committee (EC). An IRB or EC is a committee that 
watches over the safety and rights of research participants 
If your doctor wants you / your child to stop taking the study drug, you/your child will be asked to return 
to the clinic once more, four weeks after your last dose of dolutegravir, to make sure you are/your child is 
continuing to do well. This visit will include a history and physical exam, a blood draw and a review of 
your medical records.  
 
IF MY CHILD HAS TO PERMANENTLY STOP TAKING STUDY-PROVIDED MEDICINE, OR 
ONCE I LEAVE THE STUDY, HOW WOULD THE STUDY MEDICINE BE PROVIDED? 
During the study: 
If you / your child must permanently stop taking study-provided dolutegravir before your/your child’s 
study participation is over, the study staff will discuss other options that may be of benefit to you/your 
child. 
 
After the study: 
Once you / your child leaves the study, if you/they are gaining benefit from the study-provided drug, this 
drug may continue to be provided until it is available to you in your country, but there is no guarantee. 
Study clinicians will work to ensure that you/your child continue to receive appropriate care and 
treatment outside of the study. 
 
WHAT ARE THE RISKS OF THE STUDY? 
The drug 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 this drug. These lists include the more serious 


 
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or common side effects with a known or possible relationship. It is very important that you tell your 
study doctor of any changes in your/your child’s medical condition while taking part in the study. At 
any time during the study, if you believe you are/your child is experiencing any of these side effects, 
you have the right to ask questions on possible and /or known risks. 
Possible Risks Associated with Dolutegravir 
The drug used in this study, dolutegravir, has been administered to a total of 6004 participants (4814 
HIV-infected and 1190 healthy) cumulative to 16 July 2017 in ongoing and completed ViiV sponsored 
and clinical trials ranging from Phase I to IIIb and the dolutegravir compassionate use program.  The 
following side effects have been seen with dolutegravir: 
 
 
 
Uncommon (expected in about 1 of every 1000 people taking DTG (0.1%)  
Allergic reaction (see below) 
Liver toxicity (see below) 
An inflammatory condition which may develop as the immune system becomes stronger (immune 
reconstitution syndrome or ‘IRIS’ (see below) 
Suicidal thoughts and behaviors (mainly in patients who have had depression or mental health 
problems before) (see below) 
 
Most of the side effects listed above have been mild or moderate, and have not generally stopped HIV-
infected patients treated with dolutegravir from getting on with their lives as normal. 
In one animal study, gastric erosion (irritation of the stomach lining) was seen. This finding has not been 
seen in adults in studies to date. However, if you or your child feels heartburn or stomach pain or has 
vomiting, please contact your/your child’s study doctor. 
 
Other side effects that may show up in blood tests:  
Very Common (expected in about 100 of every 1000 people taking DTG (10%))  
Nausea or feeling sick  
Headache  
Diarrhea or loose stools 
 
Common (expected in about 10 of every 1000 people taking DTG (1%))  
Cold symptoms like runny nose and sore throat; cough; flu 
Dizziness or feeling light headed 
Trouble sleeping; abnormal dreams 
Rash  
Feeling tired  
High temperature 
Pain in the stomach; vomiting 
Changes in kidney, liver and muscle blood tests 
Ocular icterus (yellowing of the whites of the eyes) 
Itching (pruritus) 
Feelings of deep sadness and unworthiness (depression) 
Flatulence (gas or wind) 
Increase in the level of liver enzymes 
Increase in the level of enzymes produced in the muscles (creatinine phosphokinase) 
Anxiety (fear, worry) 


 
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• 
An increase in bilirubin (a pigment produced from the breakdown of red blood cells) in the blood,   
• 
An increase in the level of creatinine, a waste product in the blood that gets filtered by the 
kidneys.  
 
Dolutegravir Hypersensitivity Reaction 
Hypersensitivity reactions have also been reported with integrase inhibitors, including dolutegravir, with 
signs and symptoms including general feeling of being sick, skin rash, a high temperature (fever), lack of 
energy (fatigue), swelling sometimes of the face or mouth (angioedema) causing difficulty in breathing, 
blisters or peeling skin, mouth ulcers, conjunctivitis (sore eyes), and muscle or joint aches.  If you/your 
child develop(s) any of these signs and symptoms during the study, contact you/your child’s study doctor 
immediately, who may decide to carry out tests on you/your child liver, kidneys or blood. 
Mental illness 
Some people with HIV infection occasionally have feelings of depression or may have thoughts of 
hurting or killing themselves (committing suicide). A small number of people being treated with integrase 
inhibitors for HIV infection, including dolutegravir, have had suicidal thoughts and behaviors, 
particularly patients with a prior history of depression or mental health illness. People with HIV taking 
integrase inhibitors including dolutegravir have also reported depression. 
 
Tell the study doctor if you/your child have a history of mental illness. If you/your child have thoughts of 
hurting or killing yourself or have any other unusual or distressing thoughts or feelings at any time during 
the study, you/your child should tell the study staff or go to the nearest hospital immediately.  
 
Use of Combination Antiretroviral Drugs 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, symptoms from other 
infections or certain diseases may occur soon after starting combination anti-HIV treatment but can also 
occur later.  Some of these symptoms may be life threatening.  If you start having new symptoms, or 
notice that existing symptoms are getting worse after starting your antiretroviral therapy, tell your 
healthcare provider right away. 
 
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 
 
Some patients taking combination anti-HIV therapy may develop a bone disease called osteonecrosis 
(death of bone tissue caused by loss of blood supply to the bone).  The length of combination anti-HIV 
therapy, corticosteroid use, drinking alcohol, severe reduction in ability to fight off infection, higher body 
weight, among others, may be risk factors for developing this disease.  Signs of osteonecrosis are joint 
stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement.  If 
you/your child notice any of these symptoms, please inform your doctor 
 
Liver Toxicity 
Liver toxicity in the form of abnormal liver enzymes, inflammation of the liver (hepatitis) and liver 
failure have occurred in HIV-infected patients receiving regimens containing dolutegravir. The liver 
toxicity usually occurs in the first few weeks or months of taking anti-HIV medications.  These patients 
were also generally either taking other medications (both HIV treatment and non-HIV treatment) that are 
also known to cause significant liver inflammation and/or allergic reaction, or already had liver problems 


 
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(such as hepatitis B or hepatitis C), or drank too much alcohol or had a combination of these.  Cases of 
liver toxicity have also occurred in patients who do not have these risk factors. 
 
If you/your child have (has) an unanticipated need for hepatitis C virus (HCV) therapy during the conduct 
of the study, the study doctor will discuss specific HCV treatment options with you. In case you/your 
child experience liver toxicity, the study doctor can decide to stop the administration of the study drug in 
order to assure your/your child’s safety.   
 
Other Risks 
There is the risk of serious and/or life threatening side effects when non-study medications are taken with 
the study drug. For your/your child’s safety, you must tell your/your child’s HIV care provider and the 
study doctor or nurse about all medications you take/your child takes before the start of this study and 
also before starting any new medications while you are/your child is on the study. In addition, you must 
tell the study doctor or nurse before you enroll/enrolling your child in any other clinical trials while on 
this study. The use of highly active HIV medications may also be associated with altered fat metabolism 
including increased triglycerides (fatty acid in the blood) and/or increased cholesterol. 
 
Other side effects besides those listed and side effects from taking these drugs together may occur. If any 
unusual symptoms or changes happen, you should call your/your child’s doctor immediately. It is also 
important that while participating in the study, you do not/your child does not take any other prescription 
drugs or over-the-counter medications without first talking to your/your child’s doctor or study nurse. 
 
With any drug for HIV, there is a risk that the virus in your body will become resistant, which means that 
the drug will be less effective or not effective against your HIV.  The risk that taking part in this study 
will cause your HIV to develop resistance to the study drug is unknown and will depend on how well the 
study drug works against your virus and whether instructions are followed for taking the study drug. 
 
Blood Drawing and Heparin Lock Risks: 
Blood drawing may cause some discomfort, bleeding or bruising where the needle enters the body. A 
small blood clot may form where the needle enters the body or there may be swelling in the area. There is 
a small risk of a minor infection at the blood draw site. Lightheadedness and fainting can also occur when 
a needle enters the body.  
 
ARE THERE RISKS RELATED TO PREGNANCY? 
It is not known if the drug or drug combinations in this study harm fetuses. Tests in pregnant animals do 
not show risk to the mother.  Early results from a large study in Botswana of pregnant women showed a 
possible increased risk of certain types of serious birth defects involving the brain, and spinal cord in 
babies born to women who received dolutegravir at the time of becoming pregnant. No cases of babies 
born with these types of birth defects have been reported among women who started dolutegravir later in 
pregnancy.  
 
If you are/your child is having sex that could lead to pregnancy, you/your child must agree not to become 
pregnant. 
 
Because of the risk involved, you and your partner, or your child and their partner must use two methods 
of birth control that you discuss with the study staff. You must continue to use both methods until two 
weeks after stopping study drug. Options for birth control methods include these listed below:  
• 
Birth control drugs that prevent pregnancy given by pills, shots, placed on the skin (e.g. patch) or 
placed under the skin  


 
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• 
Male or female condoms with or without a cream or gel that kills sperm 
• 
Diaphragm or cervical cap with a cream or gel that kills sperm 
• 
Intrauterine device (IUD) 
 
Some of these are better than others in preventing pregnancy.  You/your child will work with study staff  
to pick the options best for you.  All birth control methods listed above except condoms do not reduce the 
risk of giving HIV to someone else. HIV-infected individuals should use a birth control method that 
includes condoms to keep from giving HIV to someone else. 
If you think you/your child may be pregnant at any time during the study, tell the study staff right away. 
The study staff will talk to you about your/your child’s choices. You/your child will be tested at each 
study visit if it is possible that you/she may be pregnant.  
If you are /your child becomes pregnant while on study, you/she will not be allowed to continue on the 
study drug but will be asked to remain on study and come in for study visits as planned in case of safety 
concerns and so that the doctors can follow your/her pregnancy until your / your child’s baby is born. 
 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
If you / your child take(s) part in this study, the amount of HIV in your / your child’s body may go down 
and your/your child’s immune system may become stronger, but no guarantee can be made. You/your 
child may receive no benefit from being in this study. Information learned from this study may help 
others who have HIV. 
  
WHAT OTHER CHOICES DO I / DOES MY CHILD HAVE BESIDES THIS STUDY? 
Instead of being in this study you have the choice of: 
• 
Treatment with prescription drugs available to you/your child 
• 
Treatment with other experimental drugs, if you/your child qualify(ies)  
• 
No treatment (NOT recommended) 
Please talk to your doctor about these and other choices available to you/your child. Your doctor will 
explain the risks and benefits of these choices. 
 
WHAT ABOUT CONFIDENTIALITY? 
(For US Sites Only) 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. With this Certificate, the researchers cannot be forced to disclose information that 
may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. The researchers will use the Certificate to resist any demands for 
information that would identify you, except as explained below. The Certificate cannot be used to resist a 
demand for information from personnel of the United States Government that is used for auditing or 
evaluation of federally funded projects or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA).  
 
People who may review your/your child’s records include the U.S. Food and Drug Administration and 
other U.S., local and international regulatory entities, the Office of Human Research Protections (OHRP), 
the site IRB /EC (insert name of site IRB/EC), the National Institutes of Health, study staff, study 
monitors, drug companies supporting the study, and their designees. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about you or your participation in this research. If an 


 
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insurer, employer, or other person obtains your written consent to receive research information, then the 
researchers may not use the Certificate of Confidentiality to withhold that information. 
 
(For sites outside the U.S.) 
Efforts will be made to keep your personal information confidential. We cannot guarantee absolute 
confidentiality. Your personal information may be disclosed if required by law. Any publication of this 
study will not use your name of identify you personally. 
Your records may be reviewed by the Ministry of Public Health in your country, the FDA and other U.S., 
local and international regulatory entities, the Office of Human Research Protections (OHRP), the NIH, 
(insert name of site) IRB/EC, study staff, study monitors and the drug companies supporting this study. 
 
WHAT ARE THE COSTS TO ME / MY CHILD? 
There are no costs to you/your child for the study drug, study visits or study procedures. However, taking 
part in this study may lead to added costs to you and your insurance company if medical complications 
arise or if your doctor decides extra tests are needed. In some cases, it is possible that your insurance 
company will not pay for these costs because [you are/ your child is] taking part in a research study.  
 
WILL I RECEIVE ANY PAYMENT? 
You will receive $XX for each study visit you attend. If you attend all study visits, you may receive up to 
$XX. 
 
WHAT HAPPENS IF I AM / MY CHILD IS INJURED? 
If you are / your child is injured as a result of being in this study, you / your child will be given immediate 
treatment for your/his/her injuries. The cost for this treatment will 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/your child’s legal rights by signing this consent 
form. 
 
WHAT ARE MY / MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT? 
Taking part in this study is completely voluntary. You may choose not to take part/not to allow your child 
to take part in this study or leave this study/take your child out of the study at any time. Your decision 
will not have any impact on your participation in other studies conducted by the NIH and will not result in 
any penalty or loss of benefits to which you are otherwise entitled. We will tell you about new 
information from this or other studies that may affect your health, welfare or willingness to stay in this 
study. If you want the results of the study, let the study staff know. 
 
(For legal guardians, as applicable) 
If your child reaches the legal age of consent during the study [he/she] will be asked to provide 
independent consent at their next visit.   
 
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), Ethics Committee (EC) or other 
organization appropriate for the site 
• 
Telephone number of above   


 
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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 Legal Guardian (print) 
 
       Legal Guardian’s Signature and Date 
 
 
(As appropriate) 
 
 
________________________                        ____________________________________ 
Study Staff Conducting  
                    Study Staff Signature and Date 
 
 
Consent Discussion (print)  
 
 
________________________                        ____________________________________ 
Witness’ Name (print)  
 
        Witness’s Signature and Date 
 
 
 
(As appropriate) 
 
 
__________________________ 
       __________________________________ 
Second Guardian (print) 
   
       Second Guardian’s Signature and Date 
(If required) 
 
 
 
   
 
 


 
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Appendix III 
Sample Consent Form for Participants Enrolling in Stage II  
 
DIVISION OF AIDS 
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS GROUP 
(IMPAACT) 
 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and  
Antiviral Activity of dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 
Infected Infants, Children and Adolescents 
 
Participants Enrolling in STAGE TWO 
P1093 Version 5.0, dated 12 July 2018  
 
SHORT TITLE FOR THE STUDY: Safety and PK of dolutegravir in HIV-1 Infected Children  
 
 
INTRODUCTION 
You are/your child is being asked to take part in this research study because you have /your child has the 
Human Immunodeficiency Virus (HIV), which is the virus that causes AIDS, and because the drugs 
currently available may not keep the amount of HIV in your / your child’s blood low enough or may 
cause side effects too difficult to deal with. 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 to be/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/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 study a new antiretroviral HIV medication called dolutegravir. This drug is a 
type of 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. The study will help find the best 
amount or dose of dolutegravir for infants, children and teenagers, when it is taken on its own as well as 
with other antiretroviral medications. This study will also find out the safety of using this medication in 
infants, children and adolescents and if there are any side effects from the medication. Dolutegravir has 
been tested before in adults and children. The study drug (dolutegravir) is approved for use in children 12 
years and older by the FDA [and/or local regulatory authorities].  
 
WHAT DO I / DOES MY CHILD HAVE TO DO IF I AM / HE / SHE IS IN THIS STUDY? 
If you decide to (allow your child to) enroll in this study, you / your child will be asked to come to the 
clinic at least 10 times over 48 weeks and then every 12 weeks until the end of the study. You / your child 
will be given dolutegravir and you / your child will be asked to take it once or twice a day for the entire 
study, in addition to your / your child’s regular HIV medicines. Dolutegravir is available in three different 
formulations: 1) a film-coated tablet that cannot be crushed or dissolved, 2) a liquid suspension and 3) a 
tablet that can be dissolved in water. You will be given instructions on how to give dolutegravir to your 
child. If your child is between 6 to less than 12 years of age and was prescribed the liquid or dissolvable 
tablet tablets of dolutegravir he/she may be allowed to switch to the film-coated tablet formulation, at a 
later time. The study staff will let you know when your child can switch, if you request to do so. 
 


 
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Although the study will provide you/your child with dolutegravir, other antiretrovirals will not be 
provided by the study. 
 
This study will be done in two parts – Stage One and Stage Two. Stage One will enable the doctors to 
find the right dose of study drug for you/your child and then will keep you on that dose to look for any 
side effects that you/your child might experience. In Stage Two the doctors will know the right dose to 
put you/your child on and will look at any side effects that you / your child might experience as well as 
how well the drug is controlling your HIV infection. You/your child will be enrolled into Stage One or 
Stage Two, depending on when you enroll /your child enrolls and your age / the age of your child. This 
consent form is for Stage Two. 
 
In this study there are 7 cohorts in Stage II – enrolling infants, children, and adolescents from 4 weeks to 
less than 18 years of age. Participants who have had their 18th birthday by the entry visit will not be 
enrolled into the study.  
 
Screening: 
If you are interested in taking part / allowing your child to enroll in this study, we will see if you are / 
your child is eligible for the study: 
 
• 
We will ask your / your child’s medical history including questions about your /your child’s 
health and what symptoms, medications, and illnesses you have/your child has had. 
 
• 
We will do a physical exam including height, weight and vital signs (temperature, blood pressure, 
pulse and respiratory rate). Doses may be modified based on the results of the weight.  
 
• 
We will take about 3  teaspoons (11mLs) of blood, to check for the following: 
o The amount of HIV in the blood,  
o The amount of cholesterol and triglycerides (types of fat) in the blood,  
o How well your immune system, liver and kidneys are working,  
o Other routine tests.  
 
You will be given the results of these tests. We will also ask you to provide a urine sample for routine 
tests. Girls and women of childbearing age will also be asked to provide a urine or blood sample to test 
for pregnancy. If you are / your child is engaged in sexual activity that could lead to pregnancy, you / 
your child will be asked to take birth control precautions throughout the study period. 
 
On Study: 
If you are/your child is eligible for this study, you/your child will come to the clinic at least 8 times in 48 
weeks.  Most of the visits will last about 1-2 hours. You/your child will come to the clinic for the first 
study visit within 30 days of the screening visit.  
• 
At each visit, a medical history will be taken and you/your child will have a physical exam. If you 
are/your child is older than 2 years of age, at the enrollment visit and at the week 48 visit, 
you/your child’s stage of sexual development will be determined. For girls/women, this will be 
done by looking at how developed the breasts are. For boys/men, this will be done by measuring 


 
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the size of the testes. Girls and women of childbearing age will also be asked to provide a urine or 
blood sample to test for pregnancy at each visit. 
• 
We will draw blood at each visit. Depending upon your/your child’s age, between 1-5 teaspoons 
(5-17mLs) of blood will be drawn at these visits. You will be informed of results of routine blood 
tests. Some of the blood drawn will be stored and tested to find out how your/your child’s 
immune system is affected by the study drug. This testing will be done after the study is over, and 
you will not be given the results of these tests.  
• 
A palatability assessment will be done at Day 10, Week 4 and Week 24 to assess what you/your 
child thinks about the taste of the study drug. 
• 
At two visits (week 4 and week 24), blood samples will be drawn two separate times. At week 12, 
you will only have one blood draw. The amount of blood drawn at the different study visits will 
be less than 1 teaspoon (0.5-1mL) depending on your /your child’s age.  
• 
If the amount of HIV virus in your/your child’s blood increases too much while on this study 
drug, you/your child may be asked to come back to clinic to have your blood drawn to confirm 
the level of HIV in your blood. If the level of HIV virus in your blood is still too high, your study 
doctor may ask you to stop taking the study medicine and to come back to the clinic for another 
visit. As part of this visit, you/your child will have an interim medical history, physical exam and 
approximately 4 teaspoons of blood (14-17mL) will be drawn for testing and storage.  
• 
If you/your child experiences a severe liver reaction or inflammation while on the study, you/your 
child may be asked to come back to clinic to have less than one teaspoon of blood (2mL) drawn 
to check the level of dolutegravir in the blood. Additional testing as part of routine assessments 
for liver inflammation (e.g. checking for viruses that cause liver inflammation) may be performed 
as well.  
 
Long Term Follow-Up 
After you have been on study drug for approximately 48 weeks, you will enter the long term follow-up 
phase of the study. You will be asked to come back into clinic every 12 weeks (every 3 months) for 3 
more years. Most visits will last about 30 minutes.  
• 
At some visits, a medical history will be taken and you/your child will have a physical exam. You 
will also be asked if you have missed taking any of your medications. 
• 
We will draw less than 1 teaspoon of blood (3-4mL) at some visits. You will be informed of 
results of routine blood tests.  
• 
As before, if the amount of HIV virus in your/your child’s blood increases too much while on this 
study drug, you/your child may be asked to come back to clinic to have your blood drawn to 
confirm the level of HIV in your blood (see above).  
 
You/your child must continue to take your/his/her anti-HIV medications during the study as prescribed by 
your/your child’s HIV care provider. If your/your child’s HIV care provider changes your/your child’s 
anti-HIV medications during the study, you/your child can still take the study drug. You/your child will 
be asked questions about taking your/his/her anti-HIV medications and the schedule you take/he/she takes 
them on and if you have/he/she has missed any medications. 
 


 
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If you/your child can become pregnant, we will collect urine or blood to test for pregnancy at each visit. 
We will also ask your child about contraception use. If you think you/if your child thinks she may be 
pregnant at any time during the study, tell the study staff right away.  
 
Blood and Urine Samples 
Some of your / your child’s blood and urine samples will be shipped out of the country to the US for 
specialized tests. These tests will tell the doctors how much study drug is in your / your child’s blood and 
if the study drug is causing any changes in your kidneys.  
 
[For Participants Receiving Granules for suspension only] 
 
 
[If your child is receiving the (granule) liquid he/she will need to switch to the dissolvable tablet. The 
study staff will inform you when your child will need to switch. This is because the company will not be 
making the liquid form of dolutegravir any longer. The study staff will provide instructions on how to 
dispense the dissolvable tablet and on the day you are scheduled to come to the clinic to begin taking the 
dissolvable tablets you will be asked to not give the (granule)liquid dose to your child. The first dose of 
the dissolvable tablet will be given in the clinic. You will be asked to come back to the clinic about 2 
weeks later and will have a palatability assessment and blood drawn to confirm the level of HIV in your 
child’s blood. If you have been on the study for more than 24 weeks at each of these visits, blood samples 
will be drawn at two separate times. The amount of blood drawn will be less than 1 teaspoon (0.5-1mL) 
depending on your /your child’s age.]  
 
 
WHAT DO I / DOES MY CHILD HAVE TO DO IF I AM / HE / SHE BECOMES INFECTED WITH 
TUBERCULOSIS WHILE ON THIS STUDY? 
If you become/your child becomes exposed to Tuberculosis (TB) while on study and requires anti-TB 
treatment that includes Rifampin you/your child will have to increase the dose of dolutegravir from once a 
day to twice a day while taking Rifampin. After you/your child complete(s) treatment with Rifampin, 
you/your child may go back to taking the dolutegravir once a day, depending on what other medications 
you/your child is taking. 
 
You/your child will also be required to return for at least five additional follow-up visits after starting 
Rifampin.  
• 
At each of these visits, a medical history will be taken and you/your child will have a physical 
exam and we will draw approximately 1-3 teaspoons of blood to look at the following: 
o The amount of HIV, cholesterol and triglycerides (types of fat) in your blood 
o How well your immune system, liver and kidneys are working, as well as other routine 
tests 
• 
At each visit you will be asked whether you are taking your medication as instructed. 
• 
You/your child will be asked to come to the clinic to have blood drawn 8 times over 12 hours 
during one visit, approximately 5-10 days after you/ your child started taking anti-TB medication. 
For this visit, you/your child will be asked to fast for 6 hours before your daily dose of study 
medication. 
• 
The study staff will give you more instructions about this. Depending on your/your child’s age, 
up to 13mL (a little more than 4 teaspoons) of blood will be drawn at this visit. 


 
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• 
You will have extra blood draws at two visits. At weeks 4 and 12, you will have two blood draws 
– blood will be drawn once before you take dolutegravir and about 12 hours later.  The amount of 
blood drawn at the different study visits will be less than 1 teaspoon (1mL).  
 
OTHER INFORMATION 
The information collected in this study may be used for other IMPAACT-approved HIV-related research. 
 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
About 300 children and adolescents will take part in this study 
 
HOW LONG WILL I/MY CHILD BE IN THIS STUDY? 
By signing this consent form, you are agreeing to / allow your child to participate in Stage II of the study. 
You/your child will stay in the study for at least 48 weeks. After that time After that time you/your child 
will enter the long-term safety follow-up phase of the study. During this time, you / your child will 
continue to take study-provided dolutegravir and will be asked to come to clinic every 12 weeks for three 
more years. 
  
WHY WOULD THE DOCTOR TAKE ME / MY CHILD OFF THE STUDY DRUG / THIS STUDY 
EARLY? 
 
The study doctor may need to take you/your child off the study drug early, without your permission, if: 
 
• 
Continuing the study drug may be harmful to you / your child 
• 
You become / your child becomes pregnant while on study 
The study doctor may need to take you/your child off the study early, without your permission, if: 
• 
You are/ your child is not able to attend the study visits as required by the study 
• 
You need / your child needs a treatment that you / your child may not take while on the study 
• 
You are / your child is not able to take the study drug as required by the study 
• 
If you elect not to attend repeat PK evaluations as part of the study 
 
The study doctor may need to take you/your child off the study early, without your permission, if: 
• 
The study is cancelled by the U.S. Food and Drug Administration (FDA), National Institutes of 
Health (NIH), the Office of Human Research Protections (OHRP), other country specific 
governmental agencies, IMPAACT, the drug company supporting this study (GSK), or the site’s 
Institutional Review Board (IRB) or Ethics Committee (EC). An IRB or EC is a committee that 
watches over the safety and rights of research participants 
 
If your doctor wants you / your child to stop taking the study drug, you/your child will be asked to return 
to the clinic once more, four weeks after your last dose of dolutegravir, to make sure you are/your child is 
continuing to do well. This visit will include a history and physical exam, a blood draw and a review of 
your medical records.  
 


 
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IF MY CHILD HAS TO PERMANENTLY STOP TAKING STUDY-PROVIDED MEDICINE, OR 
ONCE I LEAVE THE STUDY, HOW WOULD THE STUDY MEDICINE BE PROVIDED? 
During the study: 
If you / your child must permanently stop taking study-provided dolutegravir before your/your child’s 
study participation is over, the study staff will discuss other options that may be of benefit to you/your 
child. 
 
After the study: 
Once you / your child leaves the study, if you/they are gaining benefit from the study-provided drug, this 
drug may continue to be provided until it is available to you in your country, but there is no guarantee. 
Study clinicians will work to ensure that you/your child continue to receive appropriate care and 
treatment outside of the study. 
 
WHAT ARE THE RISKS OF THE STUDY? 
The drug 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 this drug. These lists include the more serious 
or common side effects with a known or possible relationship. It is very important that you tell your 
study doctor of any changes in your/your child’s medical condition while taking part in the study. At 
any time during the study, if you believe you are/your child is experiencing any of these side effects, 
you have the right to ask questions on possible and /or known risks. 
Possible Risks Associated with Dolutegravir 
 
DTG has been administered to a total of 6004 participants (4814 HIV-infected and 1190 healthy) 
cumulative to 16 July 2017 in ongoing and completed ViiV sponsored and clinical trials ranging from 
Phase I to IIIb and the DTG compassionate use program.   
 
The following side effects have been seen with dolutegravir: 
 
Very Common (expected in about 100 of every 1000 people taking DTG (10%))  
Nausea or feeling sick (mild to moderate) 
Headache (mild to moderate) 
Diarrhea or loose stools 
 
Common (expected in about 10 of every 1000 people taking DTG (1%))  
Cold symptoms like runny nose and sore throat; cough; flu 
Dizziness or feeling light headed 
Trouble sleeping; abnormal dreams 
Rash  
Feeling tired  
High temperature 
Pain in the stomach; vomiting 
Changes in kidney, liver and muscle blood tests 
Ocular icterus (yellowing of the whites of the eyes) 
Itching (pruritus) 
Feelings of deep sadness and unworthiness (depression) 
Flatulence (gas or wind) 
 
Increase in the level of liver enzymes 
Increase in the level of enzymes produced in the muscles (creatinine phosphokinase) 
Anxiety (fear, worry) 


 
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Uncommon (expected in about 1 of every 1000 people taking DTG (0.1%))  
Allergic reaction (see below) 
Liver toxicity (see below) 
An inflammatory condition which may develop as the immune system becomes stronger (immune 
reconstitution syndrome or ‘IRIS’ (see below) 
Suicidal thoughts and behaviors (mainly in patients who have had depression or mental health 
problems before) (see below) 
 
Most of the side effects listed above have been mild or moderate, and have not generally stopped HIV-
infected patients treated with dolutegravir from getting on with their lives as normal. 
In one animal study, gastric erosion (irritation of the stomach lining) was seen. This finding has not been 
seen in adults in studies to date. However, if you or your child feels heartburn or stomach pain or has 
vomiting, please contact your/your child’s study doctor. 
 
Other side effects that may show up in blood or urine tests:  
• 
An increase in bilirubin (a pigment from the breakdown of red blood cells) in the blood.  
• 
An increase in the level of creatinine, a waste product in the blood that gets filtered by the kidney 
  
Dolutegravir Hypersensitivity Reaction 
Hypersensitivity reactions have also been reported with integrase inhibitors, including dolutegravir, with 
signs and symptoms including general feeling of being sick, skin rash, a high temperature (fever), lack of 
energy (fatigue), swelling sometimes of the face or mouth (angioedema) causing difficulty in breathing, 
blisters or peeling skin, mouth ulcers, conjunctivitis (sore eyes), and muscle or joint aches.  If you/your 
child develop(s) any of these signs and symptoms during the study, contact you/your child’s study doctor 
immediately, who may decide to carry out tests on your/your child’s liver, kidneys or blood. 
 
Mental illness 
Some people with HIV infection occasionally have feelings of depression or may have thoughts of 
hurting or killing themselves (committing suicide). A small number of people being treated with integrase 
inhibitors for HIV infection, including dolutegravir, have had suicidal thoughts and behaviors, 
particularly patients with a prior history of depression or mental health illness. People with HIV and 
taking integrase inhibitors including dolutegravir have also reported depression. 
 
Tell the study doctor if you/your child have a history of mental illness. If you/your child have thoughts of 
hurting or killing yourself or have any other unusual or distressing thoughts or feelings at any time during 
the study, you/your child should tell the study staff or go to the nearest hospital immediately.  
 
Use of Combination Antiretroviral Drugs 
 
Immune Reconstitution Syndrome: In some people with advanced HIV infection, symptoms from other 
infections or certain diseases may occur soon after starting combination anti-HIV treatment but can also 
occur later.  Some of these symptoms may be life threatening.  If you start having new symptoms, or 
notice that existing symptoms are getting worse after starting your antiretroviral therapy, tell your 
healthcare provider right away. 
 
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: 


 
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• 
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 
 
Some patients taking combination anti-HIV therapy may develop a bone disease called osteonecrosis 
(death of bone tissue caused by loss of blood supply to the bone).  The length of combination anti-HIV 
therapy, corticosteroid use, drinking alcohol, severe reduction in ability to fight off infection, higher body 
weight, among others, may be risk factors for developing this disease.  Signs of osteonecrosis are joint 
stiffness, aches and pains (especially of the hip, knee and shoulder) and difficulty in movement.  If 
you/your child notice any of these symptoms, please inform your doctor. 
 
Liver Toxicity 
Liver toxicity in the form of abnormal liver enzymes, inflammation of the liver (hepatitis) and liver 
failure have occurred in HIV-infected patients receiving regimens containing dolutegravir. The liver 
toxicity usually occurs in the first few weeks or months of taking anti-HIV medications.  These patients 
were also generally either taking other medications (both HIV treatment and non-HIV treatment) that are 
also known to cause significant liver inflammation and/or allergic reaction, or already had liver problems 
(such as hepatitis B or hepatitis C), or drank too much alcohol or had a combination of these.  Cases of 
liver toxicity have also occurred in patients who do not have these risk factors. 
 
If you/your child has an unanticipated need for hepatitis C virus (HCV) therapy during the conduct of the 
study, the study doctor will discuss specific HCV treatment options with you. In case you/your child 
experience liver toxicity, the study doctor can decide to stop the administration of the study drug in order 
to assure your/your child’s safety.   
 
Other Risks 
There is the risk of serious and/or life threatening side effects when non-study medications are taken with 
the study drug. For your/your child’s safety, you must tell your/your child’s HIV care provider and the 
study doctor or nurse about all medications you take/your child takes before the start of this study and 
also before starting any new medications while you are/your child is on the study. In addition, you must 
tell the study doctor or nurse before you enroll/enrolling your child in any other clinical trials while on 
this study. 
 
The use of potent antiretroviral drug combinations may also be associated with altered fat metabolism 
including elevated triglycerides (fatty acid in the blood) and/or elevated cholesterol. 
 
Other side effects besides those listed and side effects from taking these drugs together may occur. If any 
unusual symptoms or changes happen, you should call your/your child’s doctor immediately. It is also 
important that while participating in the study, you do not/your child does not take any other prescription 
drugs or over-the-counter medications without first talking to your/your child’s doctor or study nurse. 
With any drug for HIV, there is a risk that the virus in your body will become resistant, which means that 
the drug will be less effective or not effective against your HIV.  The risk that taking part in this study 
will cause your HIV to develop resistance to the study drug is unknown and will depend on how well the 
study drug works against your virus and whether instructions are followed for taking the study drug. 
 
Blood Drawing and Heparin Lock Risks: 
Blood drawing may cause some discomfort, bleeding or bruising where the needle enters the body. A 
small blood clot may form at the site where the needle enters the body or there may be swelling in the 


 
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area. There is a small risk of a minor infection at the blood draw site. Lightheadedness and fainting can 
also occur.  
 
ARE THERE RISKS RELATED TO PREGNANCY? 
It is not known if the drug or drug combinations in this study harm fetuses. Tests in pregnant animals 
do not show risk. Early results from a large study in Botswana of pregnant women showed a possible 
increased risk of certain types of serious birth defects involving the brain, and spinal cord in babies 
born to women who received dolutegravir for HIV treatment at the time of becoming pregnant. No 
cases of babies born with these types of birth defects have been reported among women who started 
dolutegravir later in pregnancy.  
 
If you are/your child is having sex that could lead to pregnancy, you/your child must agree not to become 
pregnant or make a female pregnant. 
 
Because of the risk involved, you and your partner, or your child and their partner, must use two methods 
of birth control that you discuss with the study staff. You must continue to use both methods until two 
weeks after stopping the study drug. Options for birth control methods include these listed below:  
• 
Birth control drugs that prevent pregnancy given by pills, shots, placed on the skin (e.g. patch) or 
placed under the skin  
• 
Male or female condoms with or without a cream or gel that kills sperm 
• 
Diaphragm or cervical cap with a cream or gel that kills sperm 
• 
Intrauterine device (IUD) 
Some of these are better than others in preventing pregnancy.  You/your child will work with study staff 
to pick the options best for you.    All birth control methods listed above except condoms do not reduce 
the risk of giving HIV to someone else. HIV-infected individuals should use a birth control method that 
includes condoms to keep from giving HIV to someone else. 
If you think you/your child may be pregnant at any time during the study, tell the study staff right away. 
The study staff will talk to you about your/your child’s choices. You/your child will be tested at each visit 
during the study if it is possible that you/she may be pregnant. If you are /your child becomes pregnant 
while on study, you/she will not be allowed to continue on the study drug but will be asked to remain on 
study and come in for study visits as planned in case of safety concerns and so that the doctors can follow 
your/her pregnancy. 
ARE THERE BENEFITS TO TAKING PART IN THIS STUDY? 
If you / your child take(s) part in this study, the amount of HIV in your / your child’s body may go down 
and your/your child’s immune system may become stronger, but no guarantee can be made. You/your 
child may receive no benefit from being in this study. Information learned from this study may help 
others who have HIV. 
  
WHAT OTHER CHOICES DO I/DOES MY CHILD HAVE BESIDES THIS STUDY? 
Instead of being in this study you have the choice of: 
• 
Treatment with prescription drugs available to you/your child 
• 
Treatment with other experimental drugs, if you/your child qualify(ies)  
• 
No treatment (NOT Recommended)   
 


 
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Please talk to your doctor about these and other choices available to you/your child. Your doctor will 
explain the risks and benefits of these choices. 
 
WHAT ABOUT CONFIDENTIALITY? 
(For U.S. sites only) 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from the National 
Institutes of Health. With this Certificate, the researchers cannot be forced to disclose information that 
may identify you, even by a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. The researchers will use the Certificate to resist any demands for 
information that would identify you, except as explained below. The Certificate cannot be used to resist a 
demand for information from personnel of the United States Government that is used for auditing or 
evaluation of federally funded projects or for information that must be disclosed in order to meet the 
requirements of the federal Food and Drug Administration (FDA).  
 
People who may review your/your child’s records include the U.S. Food and Drug Administration and 
other U.S., local, and international regulatory entities, the Office of Human Research Protections 
(OHRP), the site IRB /EC (insert name of site IRB/EC), the National Institutes of Health, study staff, 
study monitors, drug companies supporting the study, and their designees. 
 
You should understand that a Certificate of Confidentiality does not prevent you or a member of your 
family from voluntarily releasing information about you or your participation in this research. If an 
insurer, employer, or other person obtains your written consent to receive research information, then the 
researchers may not use the Certificate of Confidentiality to withhold that information. 
 
(For sites outside the U.S.) 
Efforts will be made to keep your personal information confidential. We cannot guarantee absolute 
confidentiality. Your personal information may be disclosed if required by law. Any publication of this 
study will not use your name of identify you personally. 
 
Your records may be reviewed by the Ministry of Public Health in your country, the FDA and other US, 
local, and international regulatory entities, the Office of Human Research Protections (OHRP), the NIH, 
(insert name of site) IRB/EC, study staff, study monitors and the drug companies supporting this study. 
 
WHAT ARE THE COSTS TO ME / MY CHILD? 
There are no costs to you/your child for the study drug, study visits or study procedures. However, taking 
part in this study may lead to added costs to you and your insurance company if medical complications 
arise or if your doctor decides extra tests are needed. In some cases it is possible that your insurance 
company will not pay for these costs because you/ your child are taking part in a research study.  
 
WILL I RECEIVE ANY PAYMENT? 
You will receive $XX for each study visit you attend. If you attend all study visits, you may receive up to 
$XX. 
 
WHAT HAPPENS IF I AM / MY CHILD IS INJURED? 
If you are / your child is injured as a result of being in this study, you / your child will be given immediate 
treatment for your/his/her injuries. The cost for this treatment will 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/your child’s legal rights by signing this consent 
form. 
 
WHAT ARE MY / MY CHILD’S RIGHTS AS A RESEARCH PARTICIPANT? 


 
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Taking part in this study is completely voluntary. You may choose not to take part/not to allow your child 
to take part in this study or leave this study/take your child out of the study at any time. Your decision 
will not have any impact on your participation in other studies conducted by the NIH and will not result in 
any penalty or loss of benefits to which you are otherwise entitled. We will tell you about new 
information from this or other studies that may affect your health, welfare or willingness to stay in this 
study. If you want the results of the study, let the study staff know. 
 
(For legal guardians, as applicable) 
If your child reaches the legal age of consent during the study [he/she] will be asked to provide 
independent consent at their next visit.   
 
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 P1093, Version 5.0 
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12 July 2018 
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 Legal Guardian (print) 
 
       Legal Guardian’s Signature and Date 
 
 
(As appropriate) 
 
 
________________________                        ____________________________________ 
Study Staff Conducting  
                    Study Staff Signature and Date 
 
 
Consent Discussion (print)  
 
 
________________________                        ____________________________________ 
Witness’ Name (print)  
 
        Witness’s Signature and Date 
 
 
 
(As appropriate) 
 
 
__________________________ 
       __________________________________ 
Second Guardian (print) 
   
       Second Guardian’s Signature and Date 
(If required) 
 
 
 
   
 
 
 
 


 
IMPAACT P1093, Version 5.0 
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12 July 2018 
Appendix IV 
Sample Informed Consent Form for Specimen Storage and Future Use 
 
DIVISION OF AIDS  
INTERNATIONAL MATERNAL PEDIATRIC ADOLESCENT AIDS CLINICAL TRIALS 
GROUP (IMPAACT) 
 
Phase I/II, Multi-Center, Open-Label Pharmacokinetic, Safety, Tolerability and  
Antiviral Activity of dolutegravir, a Novel Integrase Inhibitor, in Combination Regimens in HIV-1 
Infected Infants, Children and Adolescents 
 
P1093 Version 5.0, dated 12 July 2018   
 
You have decided to allow your child to join the study named above/You are participating in the study 
named above. As part of the study, you/your child will have blood drawn and urine collected. After these 
samples are tested for the study, there may be some samples that are left over. We call these extra 
samples. The IMPAACT Network would like to keep these extra samples and use them for other research 
in the future. 
 
This form gives information about use of extra samples. Please read it, or have it read to you, and ask any 
questions you may have. After we discuss the information with you, you will record your decisions on use 
of extra samples at the end of the form.  
 
(For legal guardians, as applicable)  
If your child reaches the legal age of consent during the study [he/she] will be asked to provide 
independent consent at their next visit.   
 
1. It is your decision whether or not to allow the extra samples to be used.  
 
You are free to say yes or no, or to change your mind at any time. Your decision will not affect your/your 
child’s participation in the study. If you say no, all extra samples will be destroyed.  
 
2. If you agree, your child’s extra samples will be kept in a repository.  
 
A repository is a secure facility that is used to store samples. The IMPAACT Network repository is in the 
United States. There is no limit on how long the samples will be kept [sites may insert time limits or 
additional site-specific requirements here if required by local authorities]. 
 
3. Extra samples could be used for different types of research.  
 
Extra samples may be used for research on HIV, the immune system, and other diseases. The research 
may be done in the United States or in other locations.  
 
If you agree, the extra samples could also be used for research that looks at your/your child’s genes.  
 
Any research done with the extra samples must be reviewed and approved by the IMPAACT Network. 
The research must also be approved by an ethics committee. The role of an ethics committee is to review 
the research plan and protect the rights and well-being of the persons whose samples will be used.  
 
4. There is little risk to you/your child.  


 
IMPAACT P1093, Version 5.0 
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12 July 2018 
 
When extra samples are used for research, they are labeled with a code number only. To protect your 
child’s privacy, no names are used. However, information such as age, gender, HIV status, and other 
health information may be linked to the samples. Information on which study ARVs you/your child 
received and you/your child’s immune system responses to the ARVs may also be linked to the samples.  
 
There may be some risks from tests of you/your child’s genes. If others found out the results of these 
tests, they could treat you badly or unfairly. However, this is almost impossible because the results of 
these tests will not be in you/your child’s study records and they will not be given to you. 
 
5. There may be no benefit to you/your child.  
 
The research done with extra samples is not expected to give any information relevant to your child’s 
health. The results will not be given to you and will not be part of your study records.  
 
6. You will not be paid for use of your/your child’s samples. 
 
There is no cost to you for use of your child’s extra samples. The samples will not be sold and you will 
not be paid for use of the samples. It is possible that research done with the samples could lead to a new 
discovery or a new product. If this happens, there is no plan to share any money with you or your child.  
 
7. Information from research using extra samples may be reviewed by groups that oversee the 
research. 
 
These groups include:  
 
• 
The IMPAACT Network  
• 
The ethics committees that review and approve the research  
• 
Government and other agencies that pay for the research  
• 
Government and other agencies that monitor the research  
• 
Other local, US, and international regulatory entities 
 
The people who do research with the extra samples and the groups listed above are required to make 
efforts to information private and confidential. 
 
The results of research done with extra samples may be presented publicly or published. However, no 
presentation or publication will use your/your child’s name or identify your child personally.  
 
8. If you have any questions, concerns, or problems related to your/your child’s extra samples, use 
these contacts. 
 
• 
If you have questions about use of your/your child’s extra samples, contact:  
[sites insert name and telephone number of investigator or other study staff].  
 
• 
If you later change your mind about use of your/your child’s extra samples, contact:  
[sites insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your/your child’s rights as a research participant, or problems or concerns 
about how your child is being treated in the study, contact:  


 
IMPAACT P1093, Version 5.0 
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12 July 2018 
[sites insert name and telephone number of IRB contact person or other appropriate 
person/organization].  
 
9. Signatures 
 
If you agree to let your/your child’s extra samples be used, please sign or make your mark below. 
 
__________ 
I allow my/my child’s extra samples to be used for research on HIV, the immune system, 
and other diseases. I also allow my child’s samples to be used for tests of his or her 
genes.  
 
__________ 
I allow my/my child’s extra samples to be used for research on HIV, the immune system, 
and other diseases. I do not allow my child’s samples to be used for tests of his or her 
genes.  
 
__________ 
I do not allow my/my child’s extra samples to be used for any research.  
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent’s Name (print) 
 
 
Parent’s Signature 
  
 
Date 
(Or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parent’s Name (print) 
 
 
Parent’s Signature 
  
 
Date 
(Or Legal Guardian) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Staff Conducting  
 
Study Staff Signature 
 
 
Date 
Consent Process Name (print) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness Name  
 
 
Witness Signature 
 
 
Date 
(As appropriate)