Clinical trial NCT03332095
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2018-07-02; Completion date: 2022-05-25
Enrollment: 55 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the pharmacokinetics, safety, and tolerability of doravirine (also called MK-1439 or DOR) and doravirine/lamivudine/tenofovir disoproxil fumarate (also called MK-1439A or DOR/3TC/TDF) in HIV-1-infected children and adolescents.

Detailed description:
This study evaluated the pharmacokinetics (PK), safety, and tolerability of DOR and DOR/3TC/TDF in HIV-1-infected children and adolescents.

This study was conducted in two cohorts: Cohort 1 and Cohort 2. At study entry (Day 0), participants in Cohort 1 received a single dose of DOR added to their current HIV regimens. (The antiretroviral drugs in their current HIV regimens were not be provided by the study.) Participants in Cohort 1 underwent intensive PK evaluations, and had an additional study visit at Week 2.

The study team in consultation with a Study Monitoring Committee evaluated data from Cohort 1 before enrolling participants in Cohort 2. Participants in Cohort 2 received DOR/3TC/TDF once daily from Day 0 through Week 96. They had study visits at Weeks 1, 2, 4, 8, 12, 16, 24, 36, 48, 64, 80, and 96. Study visits included physical examinations, PK evaluations, and blood and urine collection.

Arms: arm 1: Participants received a single dose of DOR at study entry (Day 0). arm 2: Participants received DOR/3TC/TDF from Day 0 through Week 96.
Interventions: intervention 1: Doravirine (DOR) intervention 2: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) intervention 3: Antiretroviral (ARV) medications
Intervention descriptions: intervention 1: 100 mg of DOR administered orally intervention 2: DOR/3TC/TDF administered orally as a fixed-dose combination (as a tablet, 100 mg/300 mg/300 mg) once daily intervention 3: Participants in Cohort 1 received a combination of dolutegravir (DTG) or raltegravir (RAL) plus two nucleoside reverse transcriptase inhibitors (NRTIs). The ARV drugs were prescribed by participants' own health care providers and were not provided by the study.

Protocol documents:
ICF_000.pdf: 
 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 1 of 14 
26 April 2019 
Appendix III: Sample Informed Consent Form for Participation in Cohort 2 
 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-1439A)  
in HIV-1-infected Children and Adolescents 
 
Version 1.0, 7 September 2017 
 
Introduction 
 
[You are/Your child is] being asked to take part in the research study named above. 
 
This form gives information about the study.  Please read it, or have it read to you, and ask any questions 
you may have.  We will take as much time as needed for you to fully understand the study.  We will ask 
you questions to see if we have explained the study clearly. 
 
After you understand the study, if you decide that [you/your child] will participate, you will be asked to 
sign or make your mark on this form.  You will be offered a copy to keep. 
 
About the study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [insert 
site name] are doing this study to test an anti-HIV medicine (ARV) called doravirine (DOR) for children 
who have HIV.  HIV is the virus that causes AIDS. 
 
The study will include up to 65 children and adolescents 12 years to less than 18 years of age who have 
HIV.  The study will include children and adolescents from the United States, Thailand, and South Africa.  
There will be two groups of children in this study.  Your child will be in a group of up to 45 children.  
Children and adolescents in this group will be in the study for about 2 years.  
 
The person in charge of this study at this site is [insert name of Principal Investigator].  A company 
called Merck is providing the ARVs, including DOR.  The United States National Institutes of Health are 
sponsoring this study.   
 
1. The study is being done to test DOR as part of a combination medicine in children and adolescents. 
 
Children and adolescents with HIV usually take a combination of three or more ARVs to stay healthy.  
There are not as many ARVs available for children and adolescents as for adults because many ARVs 
have not yet been tested in children.   
 
DOR is a new ARV that is being tested in adults in the United States and other countries.  The 
combination of ARVs also includes two other ARVs called lamivudine (3TC) and tenofovir disoproxil 
fumarate (TDF).  [Sites: insert any locally appropriate names of combination drugs or individual drugs 
used at your site here and throughout the form.] 
 
TDF and 3TC are approved in the United States and Europe.  Both of these ARVs are commonly used in 
adults and children.  DOR is a newer ARV that is being studied in adults.  DOR is not currently approved 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 2 of 14 
26 April 2019 
in the United States or Europe.  [Sites to modify as needed:  TDF and 3TC are approved in [site 
country]].  
 
This combination of DOR, TDF, and 3TC has been studied closely in 86 healthy adults.  DOR, either 
alone or in combination with other ARVs, has been studied closely in more than 700 adults.  DOR has 
been shown to be safe and effective when compared to the approved ARVs, like efavirenz and darunavir. 
This is the first study of DOR in combination with TDF and 3TC in children. 
 
The two groups of the study are called Cohort 1 and Cohort 2.  Cohort 1 began first.  This part will 
include up to 20 children and adolescents.  Cohort 2 will be done after part of Cohort 1 is 
completed.  Cohort 2 will include up to 45 children and adolescents.  We will tell you about Cohort 1 
first.  This is a consent form for Cohort 2.  
 
In Cohort 1, DOR was given one time at one visit to children and adolescents.  This group looked at 
whether DOR causes any bad side effects when given to children and adolescents.  This group also looked 
at the amount of DOR in blood.  This is called an intensive pharmacokinetic (PK) evaluation. 
 
Because results from Cohort 1 show that DOR is safe and that the amount of DOR in the blood is correct, 
Cohort 2 will start.  The children and adolescents in this group will either have never received ARVs for 
treatment or are currently receiving ARVs for treatment and doing well.  This group will look at whether 
this new combination of ARVs is safe or causes any bad side effects when given to children and 
adolescents.  The group will also look at how the combination of ARVs control the virus for children and 
adolescents.  For ARVs to be considered effective, they must be able to control the amount of HIV so that 
HIV cannot be found in the blood.   
 
Some children and adolescents may join the study who have never taken ARVs before.  Some children 
and adolescents may join the study who are taking ARVs and are doing well on their ARVs.  If [you 
are/your child is] taking ARVs for treatment before the study, we will ask your child to start taking the 
study ARVs on the same day that your child stops taking the ARVs from before the study (see #8 below). 
 
2. We may have two different ways to take DOR/3TC/TDF. 
  
There are different ways to take ARVs, for example, as tablets that are swallowed or chewed or as liquids.  
This study may have two different ways for children to take DOR/3TC/TDF.  We will tell you if 
[you/your child] have different options. 
 
One way to take DOR/3TC/TDF is as a tablet.  The tablet needs to be swallowed whole – it cannot be 
broken or crushed. 
 
Another way to take DOR/3TC/TDF is as oral granules.  Granules are kept in larger capsules or 
containers [sites may use any locally understandable term to describe the granules].  The capsules should 
not be swallowed whole. The capsules should be opened to sprinkle the granules directly into the mouth 
or to mix the granules with soft food. 
 
[Sites may adapt the following paragraphs, depending on availability of the granule formulation: 
You [and your child] may choose how to take the DOR/3TC/TDF.  We will talk to you about the options 
and ask for your [your child’s] decision.  We will help [take/give] the DOR/3TF/TDF. 
 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 3 of 14 
26 April 2019 
During the study, we would prefer that [you/your child] take the study ARV in the same way.  However, 
[you/your child] may decide to take the study ARV the other way.  For example, [you/your child] may 
start taking the DOR as oral granules and then decide to take the DOR as a tablet.  If [you/your child] 
switch, we will also ask how it felt to take the tablet or granules (for example, how DOR tasted, how easy 
or difficult it was to swallow the tablet, how easy or difficult it was to mix the granules).] 
 
3. It is your decision whether or not [you join/your child joins] the study. 
 
Deciding to join the study is voluntary.  You may choose [to allow your child] to join or not join.  If you 
choose [to allow your child] to join, you can change your mind and [stop the study/take your child out of 
the study] at any time.  Your choices will have no effect on your [child’s] medical care at this clinic.  
Access to services and the benefits and rights [you/he or she] normally has will not be affected.  
 
We will tell you about new information from this or other studies that may affect your [child’s] health, 
welfare, or willingness to stay in this study.  If you want the results from this study, tell the study staff. 
 
Take your time and consider your decision carefully.  If you wish, you can talk to other people about 
[joining/allowing your child to join] the study.  You can bring other people here to learn about the study 
with you. 
 
No matter what you decide about the study, it is important to receive care and treatment for HIV infection.  
We will tell you about your options for obtaining care and treatment for your [child’s] HIV. 
 
4. Only children who qualify can participate in the study. 
 
If you decide to join the study, we will first do some tests to see if [you qualify/your child qualifies]. 
 
Finding out if [you qualify/your child qualifies] 
 
5. We will ask questions and discuss the study requirements with you. 
 
If you decide to [join/let your child join] the study, we will first do some tests to see if [you qualify/your 
child qualifies].  To find out, we will: 
• 
Review medical records.  We may also ask you questions about your [child’s] health 
• 
Ask about ARV use 
• 
Talk with you about the study requirements and if [you are/your child is] able to meet these 
requirements 
• 
Give a physical exam 
• 
Draw blood for tests.  We will take up to about 22 mL (less than 5 teaspoons) of blood.  These tests 
will look at your [child’s] blood cells and how well the liver and kidneys are working.  The tests will 
also: 
o Confirm that you [your child] has HIV.  There are certain HIV tests that are required for this 
study.  If the required tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in the blood.  This is called viral load. 
o If [you have/your child has] never taken any ARVs for treatment, we will check whether [you 
are/your child is] resistant to certain ARV medications.  Resistance means that an ARV may no 
longer work again HIV. 
o Check if [you have/your child has] Hepatitis B or Hepatitis C.  Hepatitis B and Hepatitis C are 
diseases of the liver. 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 4 of 14 
26 April 2019 
• 
Collect urine to check on how your [child’s] kidneys are working 
• 
For females, we may also collect urine or blood to check for pregnancy. More information is given in 
#6 below.  
 
6. For females, we may do a pregnancy test to see if [you/your daughter] qualifies for the study.  We may 
also test for pregnancy during the study.  Females who become pregnant will stop the study ARVs. 
 
If [you have/your daughter has] had her period or [you are/your daughter is] sexually active, we will 
collect urine or blood to test for pregnancy to see if [you/she] qualifies for the study.  The pregnancy test 
must show that [you/she] is not pregnant to qualify for the study.  If [you/she] enter the study, [you/she] 
will be required to use two forms of birth control while in the study.  We will talk to [you/your child] 
about how to prevent pregnancy.   
 
During the study, we will collect blood or urine to test for pregnancy.  If [you/your child] becomes 
pregnant during the study, please let us know right away.  If [you/your child] becomes pregnant, 
[you/your child] will stop taking the study ARVs and leave the study early.   
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure 
of pregnancy results to parents or legal guardians: We will talk over the test result as soon as it is 
available with [you/your child] in private without parents/guardians present.  [You/Your child] must give 
us permission before we can share these results with parents/guardians.  If [you are/your child is] 
pregnant, we will take [you/your child] off the study early.  This means that even if we did not tell your 
parent or guardian, they might find out you were pregnant.  If the test shows that [you are/she is] 
pregnant, we will give [you/your child] information on where medical care and other services can be 
received.]  
 
We will contact [you/your child] after [your/your child’s] last study visit to find out the outcome of the 
pregnancy.  We will also ask about any ARVs [you/your child] took during the pregnancy. 
 
7. We will tell you if [you/your child] qualifies. 
 
We will give you the results of all procedures and explain the results to you. 
 
If these procedures show that [you do/your child does] not qualify for the study, we will tell you this and 
[you/your child] will not be entered into the study.  We will give you information on where medical care 
and other needed services can be received. 
 
If these procedures show that [you do/your child does] qualify for the study, [you/your child] will be 
entered into the study. 
 
Being in the study 
 
8. If [you qualify/your child qualifies], [you/he or she] will enter the study.  Participants will have about 12 
scheduled visits over 2 years. 
 
Visits will be more frequent in the first year.  During this time, visits will be at entry, 2, 4, 8, 12, 16, 24, 
36, and 48 weeks.  After the first year, there will be at least three more visits, each four months apart.  
 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 5 of 14 
26 April 2019 
Some children and adolescents may need to stop the study early.  More information about this is given in 
#14 below. 
 
Each visit will take about 2 to 3 hours.  At these visits, we will: 
• 
Review medical records 
• 
Ask about ARVs 
• 
Do a physical exam.  At the first visit, this exam will include examination of your [child’s] genitals to 
see the stage of development. 
• 
Draw blood for tests.  We will take between 10 mL and 19 mL of blood at each visit (about 2 and less 
than 4 teaspoons).  At some visits, we will only do some of the tests.  At other visits, we will do all of 
the tests.  These tests may check:  
o Blood cells and the amount of fat in the blood 
o How well the liver and kidneys are working 
o How much HIV is in the blood 
o How many CD4 cells are in the blood.  CD4 cells are cells that fight infections  
o How much of the study ARVs are in the blood (see #9 below) 
o If [you have/your child has] never taken any ARVs for treatment, we will save some blood for 
later resistance testing 
o We will also save any extra blood for future testing after the study is over.  We will not tell you 
the results of any future tests.  We will ask you about saving these extra samples in a separate 
form. 
• 
Collect urine to check on how the kidneys are working.   
• 
We may also do a test to check if [you are/your child is] pregnant (see #6 above). 
 
[You/Your child] will also receive study ARVs at the entry, or first, visit.  We will show you [and your 
child] how to take the ARVs.  It is very important that [you/your child] takes the ARVs as instructed.  We 
will take as much time as needed for you [and your child] to understand the instructions and identify 
strategies that will help to take the ARVs are instructed.  After [you/your] child has been taking the study 
ARVs for two weeks, we will also ask how it felt to take the tablet or oral granules (for example, how 
DOR tasted, how easy or difficult it was to swallow the tablet, how easy or difficult it was to mix the 
granules). 
 
If [you were/your child was] taking ARVs for treatment before the study, we will ask [you/your child] to 
stop taking the ARVs from before the study and start taking the study ARVs on the same day. 
 
9. At some visits, we will look to see how much of the study ARVs are in your [child’s] blood. 
 
[You/Your child] will also have blood drawn to measure the amount of study ARVs in the blood.  This is 
called a pharmacokinetic evaluation, or PK evaluation.   
 
At 6 visits, we will take about 3.5 – 7 mL of blood drawn (less than 2 teaspoons).  This blood will be 
drawn in the same way that other blood for the study is drawn.   
 
At 4, 24, and 48 weeks after [you start/your child starts] the study, we may ask [you/your child] to take 
the study ARVs while at the study clinic so we can note the time [you/your child] took the study ARVs.  
On the day of this visit, we may ask [you/your child] to not take the study ARVs at home. We will help 
you remember this before each visit. 
 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 6 of 14 
26 April 2019 
At 24 weeks and 48 weeks after [you start/your child starts] the study, we will draw blood two times at 
least 30 minutes apart.  
 
10. For the first 10 participants in this part of the study: there will be an extra visit about one week after [you 
start/your child starts] the study where we will look very closely at the amount of study ARVs in the 
blood.  
 
About one week after [you start/your child starts] the study, [you/your child] will have blood drawn to 
very closely measure the amount of study ARVs in the blood and how long it stays.  This is called an 
intensive pharmacokinetic (PK) evaluation.   
 
At this visit, we will ask you [and your child] when she or he took the study ARVs in the past three days.  
For three days before this visit, you must be sure that the child takes the study ARVs on time.  This is 
very important.  We will help you remember this before the visit. 
 
On the day of this visit, do not [take/give] the medicine [to your child] at home.  [You/Your child] will 
take the study ARVs while at the study clinic so that we know the time [you/your child] took the study 
ARVs.     
  
[You/Your child] will then stay at the clinic or hospital for up to 24 hours.  [sites: modify language as 
appropriate to indicate procedures for overnight stays – If the study clinic is able, you and your child 
may be allowed to stay at the clinic the night before and during your first PK visit.] 
 
[Sites: modify language as appropriate to indicate procedures for the intensive PK collection.  A small 
plastic tube (like a “drip”) will be placed in your [child’s] arm to draw blood samples.  This tube is 
attached to a plastic needle so that we can draw blood several times.  We will not need to stick your child 
with a needle each time.  The plastic tube may stay in place until all the blood samples are drawn.]  
 
We will draw about 2.0 mL (less than 1 teaspoon) of blood at six different time points during the first day 
for the PK test and at one time point during the second day of the PK test (a total of about 21.5 mL or less 
than 5 teaspoons).  We will look at the amount of ARVs in your [child’s] blood at each of these times.   
 
11. Children and adolescents will have an extra visit if their HIV is not controlled. 
 
Participants will have viral load tests at all visits.  If the study ARVs are your [child’s] first anti-HIV 
medicine, your [child’s] viral load should be very low after about six months.  If tests show that the viral 
load is higher than expected after six months, [you/your child] will have an extra visit.  If [you were/your 
child was] on other ARVs before starting the study, your [child’s] viral load should stay very low during 
the study.  If tests show that the viral load is higher than expected at any time during the study, [you/your 
child] will have an extra visit.  If your [child’s] viral load is high at the last study visit, we will ask you to 
come back to the clinic after that to have an extra visit. 
 
These extra visits will take about one hour.  At these visits we will: 
• 
Review medical records 
• 
Ask about your [child’s] health, ARVs, and other medicines 
• 
Do a physical exam 
• 
Draw blood (up to 13 mL or less than 3 teaspoons) for tests.  The tests will check the HIV viral load.  
We will save some blood for later resistance testing. 
• 
Give you additional supplies of ARVs as needed 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 7 of 14 
26 April 2019 
 
If the repeat test also shows the high numbers of HIV in your [child’s] blood, we will talk with you about 
whether [you/your child] should stay on the study ARVs.   
 
12. The tests for the amount of ARVs in your [child’s] blood will be done at different laboratories. 
 
We will do most of the blood tests here at our laboratory.  Some of the blood tests will be done in the U.S. 
or other countries.  We will give you the results of most of these tests at the next scheduled visit, or 
sooner, if necessary.  We will explain the results and give you counseling and referrals as needed.   
 
We will also draw blood to check the amount of ARVs in your [child’s] blood here in the clinic.  The test 
will be done at laboratories in the U.S. or other countries.   
 
Some tests may be done while the study is ongoing; others after the study is done.  We will not give you 
the results of the pharmacokinetic tests during the study.   
 
13. We may stop your [child’s] study ARVs or take [you/your child] off the study early.  
 
We may take your child off the study ARVs if: 
• 
[You are/Your child is] not able to come to the study visits or we determine that [you/your child] 
cannot meet the study requirements. 
• 
[You are/Your child is] not able to take the study ARVs. 
• 
The study ARVs are not controlling the HIV in your [child’s] blood. 
• 
[You/Your child] becomes pregnant (see #6 above). 
• 
Continuing the study ARVs may be harmful to [you/your child]. 
• 
You request to stop the study ARVs [for your child]. 
 
If [you stop/your child stops] the study ARVs, [you/your child] will stop the study early.  We will ask you 
to come back to the clinic [with your child] about four weeks after [you stop/your child stops] the study 
ARVs.  [You/Your child] will not have any other visits after this. 
 
We may also take [you/your child] off the study early if the study is stopped for any reason.  
 
The study cannot provide other types of ARVs, but we will give information, counseling, and referrals to 
where children can get care and treatment they need.  We will help make sure [you/your child] can get 
ARVs from outside of the study. If the study stops early, every effort would be made to make certain that 
there is no interruption in your [child’s] therapy.   
 
14. Please tell us if you want [your child] to leave the study. 
 
[You are/Your child is] free to leave the study at any time for any reason.  The care that [you receive/your 
child receives] at this clinic will not be affected, but it is important for us to know about your decision.  
We will ask you to [come/bring your child] to the clinic for one last visit.  At this visit, we will do the 
same types of procedures listed in #8 (see above).  We will answer any questions you may have and give 
you information on how to contact us in the future, if you wish. 
 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 8 of 14 
26 April 2019 
After the study 
 
15. Receiving the study ARVs after the study is over.  
 
As [you come/your child comes] to the end of the study, we will work with you to plan for your [child’s] 
care and treatment outside the study.  It is important that we plan for this in advance, so that there is no 
gap in your [child’s] taking ARVs as [you finish/he or she finishes] the study.  Taking ARVs without 
interruption is the best-known way for [you/your child] to stay healthy.  
 
We will tell you where [you/your child] can go to receive needed care and treatment after [you finish/he 
or she finishes] the study.  If [you are/your child is] gaining benefit from the ARVs given in the study, the 
company that is providing these ARVs (Merck) will try to provide these ARVs to your child.  They will 
be provided until they are otherwise available locally, until [you are/your child is] no longer gaining 
benefit, or if the company decides to stop studying the ARVs.  However, there is no guarantee this will be 
possible.  If this is not possible, [you/your child] will need to switch to other ARVs that are available 
locally.  We will explain the options to you and help ensure your [child’s] access to ARVs outside the 
study.  We will also contact you again within the first four weeks after [you finish/your child finishes] the 
study to confirm that [you are/he or she is] receiving ARVs. 
 
Risks of the study 
 
16. There is little risk from the study procedures. 
 
Most procedures done in this study are routine medical procedures, with little risk to [you/your child].  
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted.  Rarely, 
drawing blood can cause fainting or infection. 
 
17. There are some risks from the study ARVs. 
 
All ARVs can cause side effects, whether taken along or when taken in combination.  This includes any 
ARVs that you would receive outside the study.  The study ARVs, doravirine, lamivudine, and tenofovir 
disoproxil fumarate, may have side effects.  Some of the most common or most serious effects are listed 
below.  There may also be unknown side effects because this is the first time DOR will be studied in 
children.  The lists do not include all the possible side effects.  If you have questions about side effects not 
included in these lists, you can ask us. 
 
Each of the study ARVs can cause side effects, when taken alone or when taken in combination.  Some 
side effects are minor; others can be severe.  Some are common and some are rare.  Some people who 
take the study ARVs have some of these effects.  Some people have different side effects.  We do not 
expect to see different side effects if the ARVs are combined or if they are given separately.   
 
If [you join/your child joins] the study, we will tell you about the side effects of the study ARVs that 
[you/your child] will take.  We will also check for any side effects during the visits and tell you what to 
do if [you have/your child has] any side effects. 
 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 9 of 14 
26 April 2019 
18. We will tell you about the most severe side effects first. 
 
First, you should know about the possible severe side effects.  These effects are rare, but they can cause 
serious health problems and can result in death: 
 
• 
Liver problems.  The liver is an organ near the stomach.  If there are liver problems, [you/your child] 
might have yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale colored stools; 
upset stomach or vomiting; loss of appetite; pain, aching or tenderness of the right side below the 
ribs; or itchy skin.  This can be caused by DOR, 3TC, and TDF. 
 
• 
Build-up of acid in blood, called lactic acidosis, very enlarged liver, fatty liver, or death have been 
reported.  If [you have/your child has] these problems, [you/your child] might have unexplained 
weight loss, stomach discomfort, nausea, vomiting, fatigue, cramps, muscle pain, weakness, 
dizziness, and shortness of breath.  This can be caused by 3TC and TDF. 
 
• 
Pancreas problems.  The pancreas is an organ near the stomach.  If your [child’s] pancreas becomes 
inflamed, [you/your child] may have stomach pain, upset stomach or vomiting, or more fats in the 
blood.  This can be caused by 3TC. 
 
• 
Kidney problems.  The kidneys are organs near the middle of the back (one on each side).  Doctors 
usually find out about kidney problems from tests of the blood.  These effects can be caused by TDF.   
 
19. There are also more common and not severe side effects from the study ARVs. 
 
You should also know about the more common side effects.  These side effects are not severe.  There are 
many possible mild and moderate side effects.  The most common ones are listed below: 
 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 10 of 14 
26 April 2019 
Overall Body Effects 
• Changes in the placement of body fat 
(increasing around the stomach, neck, or breast 
or decreasing in the arms, legs, or cheeks) 
• Overall weakness 
• Headache 
• Back pain 
• Allergic reaction 
• Numbing, tingling, or pain in the hands and feet 
• Fever 
Effects on Blood 
• Decrease in the blood cells that fight infection 
• Other changes in the blood tests that may show 
problems with the liver or pancreas.  The blood 
tests may show how well these organs are 
working, or they may look for substances made 
by the organs, or they may look for fats in the 
blood. 
Effects on Skin 
• Rash 
Effects on the Chest 
• Shortness of breath 
Effects on Muscle and Bones 
• Aches and pains 
• Loss of muscle 
• Bone thinning or softening (which could 
increase the chance of breaking a bone) 
Effects on Activity 
• Drowsiness and tiredness 
• Trouble sleeping 
• Dizziness 
• Abnormal dreams, hallucinations and 
nightmares 
• Clumsiness or lack of coordination 
• Feeling of deep sadness or unworthiness 
(depression) 
Effects on Stomach 
• Pain or upset stomach 
• Loose or watery stools 
• Vomiting 
• Gas 
• Dry mouth 
• Change in your sense of taste 
 
20. There may be other possible risks from the study ARVs. 
 
Possible effects on pregnancy or unborn babies 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby 
at birth.  We do not know if some ARVs are more likely to cause these effects than others.  We do not yet 
know if this combination of ARVs with DOR is safe in pregnancy.  There were no pregnancy 
complications seen when DOR was given in animals.    
 
If [you/your child] becomes pregnant during the study, please let us know right away. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain 
diseases may occur soon after starting combination ARVs but can also occur later.  Some of these 
symptoms may be life threatening.  If [you start/your child starts] having new symptoms, or if you notice 
that any existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 
 
Hepatitis B 
 
Some ARVs are active against hepatitis B.  For children who have hepatitis B, and take ARVs that are 
active against hepatitis B, stopping the ARVs could cause the hepatitis B to worsen.  If this happens, most 
children get better quickly without treatment, but in rare cases this has resulted in death. 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 11 of 14 
26 April 2019 
 
Risk of resistance 
 
All ARVs can cause some resistance.  Resistance means that the ARVs may not work against HIV if it is 
taken again in the future.  To stop resistance, it is important that [you take/give your child] the ARVs as 
instructed, and do not miss any doses.   
 
Risk related to stopping study ARVs 
 
If the study is unexpectedly stopped early or if you reach the end of the study and it is not possible to 
continue the study ARVs and you therefore need to change to different anti-HIV medicines, there is a risk 
that the new ARVs would not work as well as the study ARVs.  
 
[Sites should include for participants who are ART-experienced: Risk of switching ARVs 
 
If [you are/your child is] switching to study ARVs from different anti-HIV medicines, there is a 
possibility that the study ARVs will not work as well as your [child’s] current anti-HIV medicines.  We 
will test the viral load during the study to check (see #8 above).] 
 
21. There could be risks of disclosure of your [child’s] information. 
 
We will make every effort to keep your [child’s] information private and confidential.  Study records and 
specimens will be kept in secure locations.  All specimens and most records will be labeled only with a 
code number.  However, your [and your child’s] names will be written on some records.   
 
Despite our best efforts to keep your [child’s] information private, it is possible that the information could 
be obtained by someone who should not have it.  If this were to happen, [you/your child] could be treated 
badly or unfairly.  You could feel stress or embarrassment.   
 
[To be included at US sites:] To help us protect your [child’s] privacy, we have obtained a Certificate of 
Confidentiality that protects us from being forced to release information that may identify [you/your 
child], such as by the courts or police.  The certificate cannot be used in all situations, but it can be used 
to resist demands for information that would identify [you/your child].  The certificate does not protect 
against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your [child’s] 
participation in the study to others, if you wish. 
 
Benefits of the study 
 
22. There may be no benefit to [you/your child from being in the study. 
 
By joining the study, [you/your child] will be part of the search for ARVs that may be better for children.  
We do not know if being in the study will benefit [you/your child] in any way.  There may be a direct 
benefit to [you/your child] by taking part in this study, but no guarantee can be made.  For example, the 
study drugs may lower the amount of HIV in the blood.  There may also be benefit if the results from this 
study lead to a safe and effective dose of the study drugs for children.  It is also possible that [you/your 
child] may receive no direct benefit from this study.  Information learned from this study may help other 
children who have HIV. 
 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 12 of 14 
26 April 2019 
[You/Your child] will have regular visits here and frequent checks on your [child’s] health, including tests 
for amount of HIV in your [child’s] blood, called viral load, and for the amount of cells that fight HIV, 
called CD4.  It is possible that the study ARVs will slow your [child’s] HIV infection.  Information 
learned from this study may help other children with HIV. 
 
Other information about the study 
 
23. There are no costs to you from [you/your child] being in the study. 
 
There are no costs to you for study visits, study ARVs, or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits.  For each visit, you will be given (specify amount).] 
 
24. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
The IMPAACT Network that is coordinating the study 
• 
Merck Ltd. (the company that makes the study ARVs) 
• 
Other United States, local, and international regulatory entities 
 
The study staff and these groups are required to keep study records private and confidential.   
 
The results of the study may be presented publicly or published.  However, no presentation or publication 
will not use your [child’s] name or identify [you/your child] personally.   
 
A description of this study will be available on ClinicalTrials.gov.  This website will not include 
information that can identify you or your child.  At most, the website will include a summary of the 
results.  You can search this website at any time. 
 
Your [child’s] study information may be disclosed to other authorities if required by law. 
 
25. If [you take/your child takes] any new medication or uses alcohol or recreational drugs, please inform 
your study doctor. 
 
Some medications, including herbal medications, may make the ARVs not work as well or be less 
safe.  Please let the study doctor know if [you start/your child starts] any new medicines.  Use of alcohol 
or intravenous drugs may increase the risk of side effects from the ARVs. [Please discuss with the study 
doctor if [you are/your child is] using intravenous drugs or drinking alcohol]. 
 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 13 of 14 
26 April 2019 
26. If [you get/your child gets] sick or injured, contact us immediately. 
 
Your [child’s] health is important to us.  We will make every effort to protect your [child’s] well-being 
and minimize risks to [you/your child].  It is possible, however, that [you/your child] could have an 
illness or injury that is study-related.  This means that the illness or injury occurred as a direct result of 
the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.]  If a study-
related illness or injury occurs, we will treat [you/your child] or tell you were you can get the treatment 
your child needs.  The cost for this treatment may be charged to you or your insurance company.  There is 
no program for compensation either through [site name or] the National Institutes of Health.  
 
Whom to contact 
 
27. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your [child’s] rights as research participants or concerns about how [you 
are/your child is] being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization] 
 
• 
If [you have/your child has] any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want [your child] to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
Signatures 
 
If you agree to [let your child] participate in this study, please sign or make your mark below. 
 
Before deciding whether to [let your child] participate in this study, make sure you have read this form, or 
had it read to you, and that all your questions have been answered.  You should feel that you understand 
the study, its risks and benefits, and what is expected of you [and your child] if you decide [allow your 
child] to join.  
 
If you decide to [allow your child to] join, we will tell you any new information from this study or other 
studies that may affect your willingness [for your child] to stay in the study.  You are welcome to ask 
questions or request more information at any time.   
 
You do not give up any rights by signing this form. 
 
 
 


 
IMPAACT 2014 Cohort 2 Sample Informed Consent Form  
Protocol Version 1.0 with Letters of Amendment #1 and #2 and Clarification Memorandum #1 
 
 
Page 14 of 14 
26 April 2019 
[Insert signature blocks as required by site IRB/EC policies.] 
 
Signature blocks for participants below legal age to provide independent informed consent 
 
 
Participant Assent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
Parent/Guardian Consent 
 
 
_______________________________  
___________________________________ 
Parent/Guardian Name (print) 
 
 
Parent/Guardian Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 
Signature page for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 

SAP_002.pdf: 
 
IMPAACT 2014 
 
PHASE I/II STUDY OF THE PHARMACOKINETICS, SAFETY AND TOLERABILITY OF 
DORAVIRINE (MK-1439) AND DORAVIRINE/LAMIVUDINE/TENOFOVIR 
DISOPROXIL FUMARATE (MK-1439A) IN HIV-1-INFECTED CHILDREN AND 
ADOLESCENTS 
(Protocol Version 1.0) 
 
 
Pharmaceutical Support Provided by: Merck & Company Inc. 
 
 
NCT03332095 
DAIDS Study ID #34150 
IND #137,041 Held by NIAID/DAIDS 
 
 
 
 
Primary Statistical Analysis Plan 
Version 1.0 
 
 
This is IMPAACT 2014 SAP Version 1.0 with names of authors and  
names of publication writing team members redacted. 
 
 
 
June 4, 2020 
 
 
 


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 1 of 10 
 
 
Table of Contents: 
 
1. 
Introduction ......................................................................................................................................... 3 
2. 
Key SAP Updates .................................................................................................................................. 3 
3. 
Study Overview .................................................................................................................................... 3 
3.1  
Study Design .................................................................................................................................. 3 
3.2  
Study Monitoring .......................................................................................................................... 4 
3.3  
Hypothesis ..................................................................................................................................... 4 
3.4  
Study Objectives and Outcome Measures .................................................................................... 4 
3.4.1  
Primary Objectives and Outcome Measures ........................................................................ 4 
3.4.2  
Secondary Objectives and Outcome Measures .................................................................... 5 
4. 
Statistical Principles .............................................................................................................................. 6 
4.1  
General Considerations ................................................................................................................. 6 
4.2  
Visit Schedule and Analysis Windows ........................................................................................... 6 
4.3      Analyses of Outcome Measures ..................................................................................................... 9 
4.3.1  
Primary Outcome Measures ................................................................................................. 9 
4.3.2  
Secondary Outcome Measures (Cohort 2) ............................................................................ 9 
5. 
Report Contents ................................................................................................................................. 10 
6. 
Core Manuscript Writing Team ............................................................. Error! Bookmark not defined. 
 
 
  


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 2 of 10 
 
 
Version History 
 
Version 
Changes Made 
Date Finalized 
1.0 
Original Version per Protocol Version 1.0 
06/04/2020 
 
 
 
 
 


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 3 of 10 
 
 
1. 
Introduction 
 
This Primary Statistical Analysis Plan (SAP) describes the proposed content for the primary statistical 
analysis of IMPAACT 2014, focusing on analyses that address the primary and secondary objectives for 
key pharmacokinetics (PK), safety, tolerability and efficacy outcome measures.  These key analyses are 
intended to form the core of any presentation or publication used to disseminate the primary 
conclusions of the study. 
 
This document has been developed to facilitate the discussion between the statisticians, study team, 
and industry sponsors regarding the statistical analyses to be performed and presented in the Primary 
Analysis Report.  It also describes the timeline for reporting the results of the primary and secondary 
outcome measures that will be posted on ClinicalTrials.gov.  More detailed specifications of the planned 
analyses, such as data sources, table/figure specifications, definitions of data-driven coding, and 
validation requirements, are presented in a separate document called, Analysis Implementation Plan 
(AIP).  All PK analyses will be performed by the study pharmacologist who will draft a separate PK 
analysis plan.  Also, a separate SAP for other objectives and outcome measures will be developed once 
results for the primary and secondary objectives are known, and the corresponding analyses will be 
presented in a separate report.   
 
It is recognized that the primary 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.   
 
All tables, figures and listings created based on the analyses described in this document will be shared 
with the industry sponsors. 
2. 
Key SAP Updates 
 
N/A 
3. 
Study Overview 
3.1  
Study Design 
 
IMPAACT 2014 is a Phase I/II study whose primary objectives are to evaluate the PK, safety, and 
tolerability of a single dose of 100 mg doravirine (DOR, MK-1439) and once daily regimen of doravirine 
(100 mg)/lamivudine (300 mg)/tenofovir disoproxil fumarate (300 mg) (DOR/3TC/TDF, MK-1439A) in 
HIV-1-infected children and adolescents 12 years to less than 18 years of age who weigh at least 35 kg.  
Participants will be enrolled into two sequential cohorts, Cohort 1 and Cohort 2.  Participants will first be 
enrolled into Cohort 1 to evaluate the PK and safety of the 100 mg single dose of DOR, with intensive PK 
evaluations completed at entry and followed through two weeks on study to assess safety.  Upon 
enrollment of a minimum of 12 evaluable participants (with a minimum of four participants between 35 
and ≤45 kg), enrollment will be paused while the Cohort 1 PK and safety data are reviewed by the 
protocol team and the SMC.  If results from Cohort 1 are supportive, Cohort 2 will open to enrollment to 
evaluate the safety and tolerability of the once daily fixed-dose combination regimen (DOR/3TC/TDF).  
The group of participants in Cohort 1 who meet the PK targets with no safety concerns will establish the 
weight threshold for enrollment into Cohort 2. 


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 4 of 10 
 
 
 
Note:  Since identification of participants in the 35-≤45 kg weight group for enrollment into Cohort 1 
turned out to be challenging, the protocol team and SMC reviewed the Cohort 1 safety and PK data for 
the >45 kg participants and determined that Cohort 2 can be opened to accrual for this weight group, 
while Cohort 1 remained open.  The protocol was modified via Letter of Amendment (LoA) #2 to allow 
enrollment of participants >45 kg into Cohort 2, while attempting, but not requiring, to enroll at least 
four participants between 35 and ≤45 kg in Cohort 1. 
 
A minimum of 40 evaluable participants will be accrued to Cohort 2.  The first 10 participants will have 
intensive PK evaluations at Week 1 to evaluate the pharmacokinetics of 3TC and tenofovir (PK samples 
for DOR will also be collected at a subset of intensive time points).  Sparse PK samples for DOR, 3TC, and 
tenofovir will be collected through Week 48 for all participants and they will be followed on 
treatment/study for 96 weeks.  Safety, virologic, and immunologic outcomes will be collected 
longitudinally and analyzed at Weeks 24, 48 and 96.   
 
3.2  
Study Monitoring 
 
PARTICIPANT SAFETY:  On behalf of the Protocol Team, the Clinical Management Committee (CMC) will 
closely monitor participant safety.  An independent IMPAACT Study Monitoring Committee (SMC) will 
also review this study regularly.  SMC reviews will occur at least annually and may also occur on a more 
frequent or ad hoc basis if any issues or concerns arise, or if requested by the SMC or CMC.  Please refer 
to section 9.6.2 of the protocol for details regarding safety-related events that would trigger an ad hoc 
SMC review. 
 
DOSE EVALUATION:  During the dose evaluation stage of this study (Cohort 1), the CMC will review the 
pharmacokinetic data, with the aim of confirming the dose for Cohort 2 while protecting participant 
safety.  Prior to opening Cohort 2 to accrual, the CMC and SMC will review all PK and safety data from 
Cohort 1.  If Cohort 1 fails the PK targets or there are safety concerns, an SMC review will be convened 
to determine under what conditions Cohort 2 may open to accrual. 
 
As this is a small Phase I/II study there will be no use of formal interim statistical stopping rules. 
 
3.3  
Hypothesis 
 
This is an estimation study; thus, there is no hypothesis testing. 
 
3.4  
Study Objectives and Outcome Measures 
 
This Primary SAP addresses the following primary and secondary objectives listed in the study protocol. 
Other study objectives in the protocol will be addressed in subsequent analysis plans. 
3.4.1  Primary Objectives and Outcome Measures 
 
Primary Objectives for Cohort 1 
 


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 5 of 10 
 
 
• 
Evaluate the pharmacokinetics of a single dose of DOR in HIV-1-infected children and 
adolescents, when added to a stable ART regimen comprised of an InSTI plus two NRTIs, using 
intensive PK sampling at Entry for identification of minimum weight threshold for doravirine 100 
mg dose. 
• 
Evaluate the 2-week safety and tolerability of a single dose of DOR in HIV-1-infected children 
and adolescents, when added to a stable ART regimen comprised of an InSTI plus two NRTIs.  
 
Primary Outcome Measures for Cohort 1 
Pharmacokinetics 
• 
Single-dose AUC0-∞, Cmax, and C24hr of DOR 
 
Safety and Tolerability through Week 2 
• 
Safety Outcome: All adverse events, regardless of severity grade 
• 
Toxicity Endpoints Related to Study Drug: ≥ Grade 3, serious, discontinuation of study drug  
• 
Death regardless of relationship to study drug 
 
Primary Objective for Cohort 2 
 
• 
Evaluate the 24-week safety and tolerability of DOR/3TC/TDF in HIV-1-infected children and 
adolescents. 
 
Primary Outcome Measures for Cohort 2 
Safety and Tolerability through Week 24 
• 
Safety Outcome: All adverse events, regardless of severity grade 
• 
Toxicity Endpoints Related to Study Drug: ≥ Grade 3, serious, discontinuation of study drug  
• 
Death regardless of relationship to study drug 
3.4.2  Secondary Objectives and Outcome Measures 
 
Secondary Objectives for Cohort 2 
 
• 
Evaluate the pharmacokinetics of DOR, 3TC, and tenofovir in HIV-1-infected children and 
adolescents receiving DOR/3TC/TDF, using intensive (tenofovir and 3TC) and semi-intensive 
(DOR) PK sampling at Week 1. 
• 
Evaluate the 24-, 48-, and 96-week virologic efficacy of DOR/3TC/TDF in HIV-1-infected children 
and adolescents. 
• 
Evaluate the 24-, 48-, and 96-week immunologic response (CD4 cell count and percentage 
change from baseline) of HIV-1-infected children and adolescents.  
• 
Evaluate the 48- and 96-week safety and tolerability of DOR/3TC/TDF administered in HIV-1-
infected children and adolescents.  
 
Secondary Outcome Measures for Cohort 2 
Pharmacokinetics through Week 1 
• 
AUC0-24hr, Cmax, and C24hr of DOR, 3TC, and tenofovir 
 
Virologic Efficacy at Weeks 24, 48, and 96 


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 6 of 10 
 
 
• 
Plasma HIV-1 RNA<200 copies/mL 
• 
Plasma HIV-1 RNA<50 copies/mL 
• 
Plasma HIV-1 RNA<40 copies/mL 
• 
Log10 drop from baseline in plasma HIV-1 RNA (ART-naïve participants) 
 
Immunologic Response at Weeks 24, 48, and 96 
• 
Change in CD4 count and percent from baseline 
 
Safety and Tolerability through Weeks 48 and 96 
• 
Safety Outcome: All adverse events, regardless of severity grade 
• 
Toxicity Endpoints Related to Study Drug: ≥ Grade 3, serious, discontinuation of study drug  
• 
Death regardless of relationship to study drug 
 
Note: Results for the primary outcome measures are required to be submitted to ClinicalTrials.gov within 
one year of the Primary Completion Date (PCD) which, for this study, is the date when the Week 24 data 
has been collected for the last participant enrolled in Cohort 2.  Data for evaluating virologic efficacy and 
immunologic response through Week 24 will be evaluated concurrently with the data for the primary 
objective for Cohort 2 (i.e., 24-week safety and tolerability of DOR/3TC/TDF).  Longer-term secondary 
objectives such as safety, virologic efficacy, and immunologic response of DOR/3TC/TDF through Weeks 
48 and 96 will be evaluated as outcome measures become available.  The results for these longer-term 
secondary objectives will be posted to ClinicalTrials.Gov no later than one year after the last participant 
enrolled in Cohort 2 has reached Week 96. 
4. 
Statistical Principles  
4.1  
General Considerations 
 
• 
Information regarding analysis populations are provided below: 
 
- 
All Treated Population: Participants who have taken at least one dose of study drug. 
 
4.2  
Visit Schedule and Analysis Windows 
 
For Cohort 1 and Cohort 2, study entry occurs within 30 days of screening.  For analysis purposes, the 
day the participant takes the first dose of the study drug (First Dose Date), and not the study entry date,  
will be used as the reference for calculating the Study Day of Assessment.   
 
Pre study entry, Study Day of Assessment will be calculated as: 
 
 
 
 
Study Day of Assessment = (Assessment Date – First Dose Date)  
  
Post study entry, Study Day of Assessment will be calculated as: 
 
 
 
 
Study Day of Assessment = (Assessment Date – First Dose Date) + 1 
  


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 7 of 10 
 
 
This value will be used to determine the study visit associated with the assessment.  In order to include 
assessments collected outside the visit windows defined in the protocol, wider Analysis Windows will be 
formed around each study visit using the midpoints between adjacent weeks as cutoffs.  If there are 
multiple assessments within the Analysis Window for a given study week, the assessment closest to the 
Target Study Day will be used. 
 
BASELINE:  For all endpoints and outcome measures, the value used for baseline (Week 0) will be the 
latest measurement taken anytime from thirty days before First Dose Date through First Dose Date.  
Unless otherwise stated, if baseline values are missing, no derivation will be performed and baseline will 
be set to missing.  
 
TREATMENT DISCONTINUATION:  For Cohort 2 participants who discontinue the study treatment, safety 
data will be restricted through four weeks after last-dose-date.  For efficacy and immunologic response 
analyses, data will be restricted to specimens collected through one day after last-dose-date. 
 
Cohort 1 (All Participants): 
Intensive PK samples will be collected around the single dose of DOR, ideally on the day of study entry, 
and will continue up to approximately 72 hours post-dose.  Participants will have one scheduled visit at 
Week 2.  The Analysis Window and Target Study Day for these scheduled study visits will be defined as 
follows: 
 
Analysis Window  
(Based on Study Day of Assessment) 
Study Week 
Target Study Day 
-30 to 1 
Week 0 
1 
2 to 28 
Week 2 
15 
 
Cohort 2 (Participants Selected for Intensive PK Evaluations): 
Once enrolled into Cohort 2, the first 10 participants will have an extra study visit at Week 1, for 
intensive PK evaluation.  Blood samples for measuring HIV-1 RNA and CD4 cell count will not be 
collected on this extra visit.  Thereafter, participants will have scheduled visits at Weeks 2, 4, 8, 12, 16, 
24, 36, 48, and every 16 weeks through Week 96.  The Analysis Window and Target Study Day for these 
scheduled study visits will be defined as follows: 
 
Analysis Window  
(Based on Study Day of Assessment) 
Study Week 
Target Study Day 
-30 to 1 
Week 0 
1 
2 to 11 
Week 1 
8 
12 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 140 
Week 16 
113 
141 to 210 
Week 24 
169 
211 to 294 
Week 36 
253 
295 to 392 
Week 48 
337 
393 to 504 
Week 64 
449 
505 to 616 
Week 80 
561 
≥ 617 
Week 96 
673 


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 8 of 10 
 
 
> (Last Dose Date – First Dose Date) +1 
Follow-up (due to early 
treatment discontinuation)  
(Last Dose Date – First Dose Date) + 29 
 
Cohort 2 (Participants not Selected for Intensive PK Evaluations): 
Since these participants are not selected to have intensive PK evaluations, they will not have a Week 1 
visit and will only have scheduled visits at Weeks 2, 4, 8, 12, 16, 24, 36, 48, and every 16 weeks through 
Week 96.  Also, since blood samples for measuring HIV-1 RNA will not be collected on the Week 1 visit 
for participants who are selected to have intensive PK evaluations, the following table will apply to the 
scheduled visits for measuring HIV-1 RNA for all Cohort 2 participants.  The Analysis Window and Target 
Study Day for these scheduled study visits will be defined as follows: 
 
Analysis Window  
(Based on Study Day of Assessment) 
Study Week 
Target Study Day 
-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 140 
Week 16 
113 
141 to 210 
Week 24 
169 
211 to 294 
Week 36 
253 
295 to 392 
Week 48 
337 
393 to 504 
Week 64 
449 
505 to 616 
Week 80 
561 
≥ 617 
Week 96 
673 
> (Last Dose Date – First Dose Date) +1 
Follow-up (due to early 
treatment discontinuation)  
(Last Dose Date – First Dose Date) + 29 
 
Cohort 2-CD4 Cell Count and Percent Schedule (All Participants):  
Since blood collection for measuring CD4 cell count occurs on a less frequent schedule than other 
outcome measures, a different set of Analysis Windows will need to be defined for each scheduled study 
visit.  For measuring CD4 count, participants will have scheduled visits at Weeks 4, 12, 24, 48, and every 
16 weeks through Week 96. The Analysis Window and Target Study Day for these scheduled study visits 
will be defined as follows: 
 
Analysis Window  
(based on Study Day of Assessment) 
Study Week 
Target Study Day 
-30 to 1 
Week 0 
1 
2 to 56 
Week 4 
29 
57 to 126 
Week 12 
85 
127 to 252 
Week 24 
169 
253 to 392 
Week 48 
337 
393 to 504 
Week 64 
449 
505 to 616 
Week 80 
561 
≥ 617 
Week 96 
673 
> (Last Dose Date – First Dose Date) +1 
Follow-up (due to early 
treatment discontinuation)  
(Last Dose Date – First Dose Date) + 29 
 


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 9 of 10 
 
 
4.3      Analyses of Outcome Measures 
 
All analyses described below will be performed after the last participant enrolled in Cohort 2 has 
reached Week 24.   
4.3.1  Primary Outcome Measures 
 
Safety 
 
The primary safety analyses will include all participants who were exposed to the study drug and will be 
restricted to data through Week 2 for Cohort 1 and Week 24 for Cohort 2.  For Cohort 2 participants 
who discontinued the study drug prior to reaching Week 24, safety data will be restricted through four 
weeks after last dose date.   
 
An overall summary of all AEs will be presented by cohort and, for Cohort 2, the summary will be broken 
down by ART status at entry (i.e., ART-naïve versus ART-experienced).  In addition, each participant’s 
safety data will be summarized as: the worst grade of adverse event experienced and the worst grade of 
adverse event assessed as related to study drug.   
 
Frequency distributions of the four toxicity endpoints listed in Section 3.4.1 will be presented by cohort 
and by ART status at entry (Cohort 2).  Proportion of participants (bounded by exact 95% confidence 
intervals) and the listing of the participants experiencing any of these four toxicity endpoints will also be 
presented by cohort and by ART status at entry (Cohort 2). 
 
Proportion of participants experiencing Grade 3 or higher AEs and those experiencing Grade 3 or higher 
AEs assessed as related to study drug, bounded by exact 95% confidence intervals, will be presented by 
cohort and by ART status at entry (Cohort 2). 
 
4.3.2  Secondary Outcome Measures (Cohort 2) 
 
Safety 
 
Safety assessments will be performed on long-term data collected through Week 96.  These analyses will 
be similar to Week 24 (Cohort 2) analyses described above and will be performed after the last 
participant enrolled in Cohort 2 has reached Week 96, or earlier if the study team decides to do so based 
on accrual or retention issues. 
 
Virologic Efficacy 
 
Virologic responses for Cohort 2 participants, based on plasma HIV-1 RNA (copies/mL), will be assessed 
at Week 24.  Virologic outcomes at additional time points might also be evaluated.  Virologic failure will 
be defined as HIV-1 RNA >200 copies/mL, >50 copies/mL, and >40 copies/mL, in three separate analyses.  
In addition, the log drop from baseline in plasma HIV-1 RNA will be calculated and summarized for ART-
naïve participants.  The proportion of participants with plasma HIV-1 RNA <200 copies/mL, <50 
copies/mL, and <40 copies/mL, bounded by 95% confidence intervals, will be presented separately for 
all Cohort 2 participants, both in the aggregate and broken down by ART status at entry (i.e., ART-naïve 
versus ART-experienced). 


IMPAACT 2014  
Primary Statistical Analysis Plan 
Page 10 of 10 
 
 
 
MISSING HIV-1 RNA DATA:  The Observed Failure Approach, which is a conservative approach to handle 
missing data, will be used.  Based on this approach, missing values are considered as failures for 
participants missing data due to discontinuation of study drug as a result of virologic failure or for non-
treatment related reasons with last available RNA >200/50/40 copies/mL; otherwise participants with 
missing values are excluded. 
 
For regulatory submission purposes, the primary definition of virologic outcome will be calculated 
according to a Missing, Switch or Discontinuation = Failure (MSDF) algorithm – as codified by the FDA’s 
snapshot algorithm.  Participants will be classified as non-responders if they have missing HIV-1 RNA 
data throughout the analysis window surrounding the time point of interest; which has been defined in 
section 4.2.  If participants discontinue the study drug prior to the time point of interest, virological 
failure will be determined by the HIV-1 RNA measurement at the time of discontinuation, if 
discontinuation occurred for reasons other than AE or death. For participants who have data collected 
within the analysis window of interest, virologic success or failure will be determined by the last 
available HIV-1 RNA measurement within that analysis window. 
 
Immunologic Response 
 
Mean changes in CD4 count and percent from baseline to Week 24 will be presented, both in the 
aggregate and broken down by ART status at entry (i.e., ART-naïve versus ART-experienced), bounded by 
95% confidence intervals.  Based on the Observed Failure Approach, missing CD4 values for participants 
who discontinued the study drug due to virologic failure or for non-treatment related reasons with last 
available RNA >200/50/40 copies/mL will be replaced with their baseline value; otherwise participants 
with missing values are excluded.   
 
Note: Since the missing HIV-1 RNA and CD4 values for Cohort 2 participants will be imputed using a 
conservative approach, sensitivity analyses will be performed to assess the effects of these data 
imputations on the final results.  
 
5. 
Report Contents  
 
The following are the main planned sections of the Primary Analysis Report.  Detailed descriptions of the 
content of each of these sections are provided in the AIP.  Data for the Primary Analysis Report will be 
downloaded once the last participant in Cohort 2 has completed the Week 24 study visit, all queries 
have been resolved, and the database has been locked for analysis.  
  
1. Accrual 
2. Protocol Deviations 
3. Study Status and Study Treatment Status 
4. Selected Characteristics at Baseline 
5. Medical History 
6. Summary of Clinical Events 
7. Summary of Laboratory Events 
8. Analysis of Primary Outcome Measures 
9. Analysis of Secondary Outcome Measures  

Prot_001.pdf: 
 
 
IMPAACT 2014 
 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir 
Disoproxil Fumarate (MK-1439A) in HIV-1-infected  
Children and Adolescents 
 
 
IND#: 137,041  
DAIDS Study ID 34150 
 
 
This file contains the current IMPAACT 2014 protocol 
comprised of the following documents, presented in 
reverse chronological order: 
 
• Clarification Memorandum #3, dated 28 April 2021 
• Letter of Amendment #3, dated 10 June 2020 
• Clarification Memorandum #2, dated 31 March 2020 
• Letter of Amendment #2, dated 26 April 2019 
• Corrected Clarification Memorandum #1, dated 13 February 2019 
• Letter of Amendment #1, dated 7 May 2018 
• Protocol Version 1.0, dated 7 September 2017 
 


Clarification Memorandum #3 to  
Page 1 of 4 
28 April 2021  
IMPAACT 2014 Protocol Version 1.0 
Clarification Memorandum #3 for:  
 
IMPAACT 2014 
 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-
1439A) in HIV-1-infected Children and Adolescents 
 
Version 1.0, dated 7 September 2017 
 
IND# 137,041  
DAIDS Study ID 34150 
 
Clarification Memorandum Date: 28 April 2021 
 
 
 
Summary of Clarifications and Rationale 
 
This Clarification Memorandum (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 wording related to the IMPAACT Network Certificate of 
Confidentiality and updates the protocol team and site representative rosters. These updates do not impact 
the study design or study-specific procedures.  
 
 
Implementation 
 
Institutional Review Board/Ethics Committee (IRB/EC) approval of this CM is not required by the study 
sponsor prior to implementation; however, sites may submit it to IRBs/ECs for their information or, if 
required by the IRBs/ECs, for their approval prior to implementation.  
 
IRBs/ECs may have acknowledged and/or approved remote site monitoring strategies prior to the 
issuance of this CM. If so, documentation of the acknowledgement and/or approval should be filed in 
your essential document files for IMPAACT 2014. This CM and any applicable IRB/EC correspondence 
should also be filed in your essential document files for IMPAACT 2014. 
 
The information included in this memorandum will be incorporated into the next protocol amendment. 
 
A. DAIDS Policy Updates  
 
1. Protocol Section 12 is updated to reflect current DAIDS policies for clinical site monitoring, which 
allow for on-site and remote monitoring. The prior contents of this section are replaced with the 
following:  
 
Under contract to DAIDS or NICHD, site monitors will inspect study site facilities and review 
participant study records — including informed consent and assent forms, paper-based CRFs 
(if used), eCRFs, medical records, laboratory records, and pharmacy records — to ensure 
protection of study participants, compliance with the IRB/EC approved protocol, and accuracy 
and completeness of records. Monitors also will review essential document files to ensure 


Clarification Memorandum #3 to  
Page 2 of 4 
28 April 2021  
IMPAACT 2014 Protocol Version 1.0 
compliance with all applicable regulatory requirements. Site investigators will make study 
facilities and documents available for inspection by monitors. 
 
Monitoring visits may be conducted on-site or remotely. Remote visits may include remote 
source document verification using methods specified for this purpose by DAIDS or NICHD. 
Remote monitoring visits may be performed in place of, or in addition to, onsite visits to ensure 
the safety of study participants and data integrity (1). Site investigators will make study 
documents available for site monitors to review utilizing a secure platform that is 21 CFR Part 
11 and HIPAA compliant. Potential platform options include: Veeva SiteVault, Medidata Rave 
Imaging Solution, Medidata Remote Source Review, site-controlled SharePoint or cloud-based 
portal, and direct access to electronic medical records. Other secure platforms that are 21 CFR 
Part 11 and HIPAA compliant may be utilized, as allowed by DAIDS Office of Clinical Site 
Oversight (OCSO) or NICHD. 
 
Reference:  
1. FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 
Public Health Emergency: Guidance for Industry, Investigators, and Institutional Review 
Boards, March 2020, Updated on January 27, 2021. Accessed at: 
https://www.fda.gov/media/136238/download 
 
2. Protocol Section 14.5 refers to the DAIDS policy on identification and classification of critical 
events. This policy has been retired. Section 14.5 is removed from the protocol and Section 13.1 has 
been updated to refer to the reporting requirements that still apply for sites conducting this study. The 
prior contents of the first paragraph in Section 13.1 are replaced with the following:  
 
Prior to study initiation, site investigators must obtain IRB/EC review and approval of this 
protocol and site-specific informed consent and assent forms in accordance with 45 CFR 46; 
subsequent to initial review and approval, IRBs/ECs must review the study at least annually. 
Site investigators must promptly report to the IRBs/ECs any changes in the study and must 
comply with the requirements of 45 CFR 46.108(a)(4) and 21 CFR 56.108(b) for promptly 
reporting the following: unanticipated problems involving risks to participants or others; 
serious or continuing noncompliance with applicable regulations or the requirements or 
determinations of their IRBs/ECs; and any suspension or termination of IRB approval. 
 
3. Protocol Section 14.6 (now re-numbered as Section 14.5) refers to requirements for entry of study 
results into ClinicalTrials.gov. To reflect current NIH and regulatory requirements, the prior contents 
of this section are replaced with the following:  
 
The NIH Policy on Dissemination of NIH-funded Clinical Trial Information establishes the 
expectation that clinical trials funded in whole or in part by the NIH will be registered and have 
summary results information submitted to ClinicalTrials.gov for public posting. The protocol 
team will comply with this policy as well as the requirements of 42 CFR 11. 
 
4. Protocol Sections 11.1, 11.2, 11.3, 13.2, 13.3, 13.7, 14.3, and 14.4 refer to the following DAIDS 
policies: 
 
• 
Requirements for Essential Documents at Clinical Research Sites Conducting DAIDS Funded 
and/or Sponsored Clinical Trials  
• 
Requirements for Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials  
• 
Requirements for Clinical Quality Management Plans 


Clarification Memorandum #3 to  
Page 3 of 4 
28 April 2021  
IMPAACT 2014 Protocol Version 1.0 
• 
Requirements for Manual of Operational Procedures 
• 
Enrolling Children (including Adolescents) in Clinical Research: Clinical Site Requirements  
 
These policies have been retired and replaced with instructions for sites that are now contained in the 
DAIDS Site Clinical Operations and Research Essentials (SCORE) Manual. Throughout the protocol, 
references to the above-listed policies are replaced with requirements specified in the DAIDS SCORE 
Manual (edits not shown here). The SCORE Manual is available at: 
https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations 
 
B. Certificate of Confidentiality 
 
The Certificate of Confidentiality described in protocol Section 13.7 has been deemed issued to the 
IMPAACT Network effective with the start date of the current Network funding cycle (1 December 
2020). The first sentence in the last paragraph of this section is replaced with the following:  
 
In addition to the above, a Certificate of Confidentiality has been deemed issued for the IMPAACT 
Network by the US Department of Health and Human Services.  
 
C. Protocol Team Roster Updates 
 
To reflect current protocol team membership, Mona Farhad, Sarah Pasyar, Hedy Teppler, Rebecca 
LeBlanc, Scott Watson, and Yvonne Woolwine-Cunningham are removed from the protocol team roster 
(deletions not shown) and the team members shown below are added. Adeola Adeyeye is also added as a 
NIAID Medical Officer on the protocol cover page. 
 
NIAID Medical Officers 
Adeola Adeyeye, MD, MPA 
DAIDS, NIAID, NIH 
Room 8B36 MSC 9831, 5601 Fishers Lane 
Rockville, MD 20852-9831 
Phone: (240) 669-5005 
Email: adeyeyeao@niaid.nih.gov 
 
Protocol Statisticians 
Mounika Yedla, PharmD, MPH 
Frontier Science Foundation 
1371 Beacon Street, Suite #203 
Brookline, MA 02446, USA 
Phone: (617) 632-2000 x4047 
Email: myedla@sdac.harvard.edu 
 
Pharmaceutical Representatives 
Randi Leavitt, MD, PhD 
Merck Research Laboratories 
Upper Gwynedd (UG) 3D-021 
309 N Sumneytown Pike 
North Wales, PA 19454 
Phone: (267) 305-7518  
Email: randi_leavitt@merck.com 
 
Protocol Data Managers 
Rebecca Dirschberger, MPH 
Frontier Science Foundation 
4033 Maple Road  
Amherst, NY 14226, USA 
Phone: (716) 834-0900 x7268 
Email: dirsch@frontierscience.org 
 
Protocol Laboratory Data Managers 
Kathleen Trabert 
Frontier Science Foundation 
4033 Maple Road 
Amherst, NY 14226-1056, USA 
Phone: (716) 834-0900 x7373 
Email: trabert@frontierscience.org 
 
Westat Clinical Research Associate 
Chanell Wilkins 
1600 Research Blvd. – WB215 
Rockville, MD 20850, USA 
Phone: (301) 610-5548 
Email: chanellwilkins@westat.com 


Clarification Memorandum #3 to  
Page 4 of 4 
28 April 2021  
IMPAACT 2014 Protocol Version 1.0 
D. Site Representative Roster Updates 
 
The following sites, which did not enroll any participants, are removed from the site representative roster: 
CRS 5051 (Mobeen Rathore, Saniyyah Mahmoudi); CRS 5092 (Allison Agwu, Aleisha Collinson-Streng, 
Thuy Anderson); CRS 6601 (Irma Febo, Ruth Santos); and CRS 8051 (Lee Fairlie, Hermien Gous). To 
reflect current site representatives, Amanda Robson (CRS 5017) and Nasreen Abrahams (CRS 8052) are 
removed (deletions not shown) and the representatives shown below are added: 
 
University of Washington Children’s Hospital 
Seattle NICHD, CRS 5017 
Chessie Snider 
6901 Sand Point Way NE  
MA.7.110, PO Box 5371 
Seattle, WA 98145-5005, USA 
Phone: (206) 987-3253 
Email: chessie.snider@seattlechildrens.org 
Soweto IMPAACT, CRS 8052 
Nastassja Ramsagar 
Perinatal HIV Research Unit 
Chris Hani Baragwanath Academic Hospital 
PO Box 114, Diepkloof, Soweto, 
Johannesburg, South Africa 
Phone: +27-11-989-9858 
Email: choonilaln@phru.co.za 
 


Letter of Amendment #3 
Page 1 of 6 
10 June 2020 
IMPAACT 2014 Protocol Version 1.0 
Letter of Amendment #3 for: 
 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
Version 1.0, dated 7 September 2017 
 
DAIDS Study ID #34150 
IND #137,041 
 
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. 
Procedural Clarifications and Corrections ........................................................................................ 4 
C. 
Operational Guidance from Protocol CM #2, dated 31 March 2020 ................................................ 4 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) affects the IMPAACT 2014 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 2014. If the IMPAACT 2014 
protocol is amended in the future, applicable contents of this LoA will be incorporated into the next 
version of the protocol. 
 


Letter of Amendment #3 
Page 2 of 6 
10 June 2020 
IMPAACT 2014 Protocol Version 1.0 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
DAIDS Study ID #34150 
 
 
Version 1.0, Letter of Amendment #3 
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 #3 
Page 3 of 6 
10 June 2020 
IMPAACT 2014 Protocol Version 1.0 
Summary of Modifications and Rationale 
 
The purpose of this LoA is to update the protocol team roster to reflect current membership, clarify and 
correct certain procedural specifications in the protocol, and incorporate the contents of protocol 
Clarification Memorandum (CM) #2. 
 
Section A of this LoA includes the protocol team roster updates. 
 
Section B of this LoA includes the procedural clarifications and corrections, which serve to: 
 
• 
Clarify the requirement for sites to notify the IMPAACT 2014 Clinical Management Committee 
(CMC) of adverse events that are life-threatening or result in death  
• 
Correct an inconsistency in clinical management requirements for participants experiencing decreased 
estimated glomerular filtration rate (eGFR)  
 
Section C of this LoA incorporates the contents of CM #2, 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 #2 provided operational flexibility for conducting study visits 
and procedures when needed to ensure ongoing access to study drug and to prioritize the conduct of 
clinically and scientifically important laboratory evaluations when possible. Per the study Sponsor, sites 
were instructed to implement the guidance provided in CM #2 immediately. All sites should continue to 
follow applicable government, health authority, and institutional policies with respect to conduct of study 
visits and procedures during the COVID-19 pandemic, with utmost importance placed on the health and 
well-being of study participants and study staff. Consistent with the instructions provided in CM #2, 
implementation of Section 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 
2014 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 protocol team membership, Andee Fox and Hye Cho are removed from the protocol 
team roster (deletion not shown). Sarah Pasyar and Lina de Montigny are added. 
 
Protocol Statisticians 
Sarah Pasyar, MSc 
1371 Beacon Street, Suite 203 
Brookline, MA 02446, USA 
Phone: 1 (617) 632-2000 x4004 
Email: spasyar@sdac.harvard.edu 
Pharmaceutical Representatives 
Lina de Montigny, MSc, DVM, MPH, PMP 
16750 Route Trans-Canada Highway 
Kirkland, QC H9H 4M7, Canada 
Phone: (438) 334-9405 
Email: lina.de.montigny@merck.com 


Letter of Amendment #3 
Page 4 of 6 
10 June 2020 
IMPAACT 2014 Protocol Version 1.0 
 
B. Procedural Clarifications and Corrections 
 
1. Protocol Section 8.1, Management of Adverse Events, fifth paragraph: 
 
Refer to Sections 8.2-8.6 for further guidance on management of adverse events, including general 
adverse events, liver toxicities, decline in renal function, non-study drug ARV-related toxicities, and 
monitoring and management of virologic failure. When management of an adverse event requires 
consultation with the CMC, the CMC should be contacted as soon as possible and within three 
business days of site awareness of the event. In the event of any adverse event that is life-
threatening or results in death, the CMC should be contacted as soon as possible and within 
three business days of site awareness, consistent with the potential triggers for SMC review 
described in Section 9.6.2. 
 
2. Protocol Section 8.4, Management of Decline in Renal Function (Cohort 2), third paragraph: 
 
Participants who experience progression to a grade 3 or higher an estimated GFR (calculated by the 
Schwartz formula; see Section 4.1.8) of <60 mL/min (1.73 m2) must return for a confirmatory 
creatinine assessment within two to four weeks. If an estimated GFR of <60 mL/min (1.73 m2) is 
confirmed, then DOR/3TC/TDF should be held and the investigator should contact the CMC to 
discuss the rationale for restarting study drugs (if appropriate). 
 
C. Operational Guidance from Protocol CM #2, dated 31 March 2020 
 
This CM provides operational guidance to study sites from the IMPAACT 2014 Protocol Team. The 
Protocol Team acknowledges that the extent to which site operations may be disrupted by the COVID-19 
pandemic may vary across sites and over time. All sites should follow applicable government, health 
authority, and institutional policies with respect to conduct of study visits and procedures, with 
utmost importance placed on the health and well-being of study participants and study staff. Site 
investigators should continue to follow current protocol specifications for communication with the 
Protocol Team and/or Clinical Management Committee and should contact the Clinical Management 
Committee (impaact.2014cmc@fstrf.org) with any questions or concerns regarding this CM or 
management of study participants. 
 
Visit Scheduling 
• 
Sites should implement safety checks by telephone (as available) prior to in-person visits to assess 
participant/parent/guardian willingness and ability to attend in-person visits, as well as assess the 
onset of any adverse events, including but not limited to signs and symptoms potentially consistent 
with COVID-19. 
• 
Sites should prioritize completion of the Week 24 visit.  
• 
Sites that anticipate operational disruptions or closures in the near future are advised to conduct study 
visits early in the allowable visit window. Visits conducted prior to opening of the allowable window 
would also be preferred to completely missing a visit at a later date. 
• 
Sites that are currently experiencing operational disruptions or closures are advised to conduct study 
visits late in the allowable visit window. Visits conducted after closing of the allowable window 
would also be preferred to completely missed visits. 
• 
Effective with the issuance of this CM, the allowable window for the Weeks 24, 36, and 48 visits is 
broadened to ±6 weeks. 
 


Letter of Amendment #3 
Page 5 of 6 
10 June 2020 
IMPAACT 2014 Protocol Version 1.0 
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 parents, guardians, and participants to determine in advance where and 
when such visits will take place, with adequate protections for safety, privacy, and confidentiality. 
Off-site visit procedures should be conducted by site staff who are adequately qualified and trained to 
conduct the procedures, as determined by the site Investigator of Record (IoR), with attention paid to 
occupational health, biohazard containment, and specimen and data chain of custody. These staff 
should also be adequately qualified and trained to immediately assess and/or manage any adverse 
events or social impacts that may occur during the visits. If adverse events requiring further 
evaluation or management are identified during an off-site visit, staff conducting the visit should 
arrange for appropriate clinical management, in consultation with the IoR or designee as needed. 
• 
Sites with limited capacity to conduct in-person study visits should prioritize provision of study drug 
(see below) and conduct of safety-related laboratory evaluations, specifically, chemistries, CBC, and, 
if applicable, pregnancy testing. In addition, at Week 24, HIV-1 RNA viral load and CD4 cell count 
should also be prioritized. If it is not possible to perform these tests consistent with the site’s Protocol 
Analyte List (PAL), tests may be performed in alternate settings using alternate laboratory methods 
(alternate laboratories must adhere to local regulations for clinical laboratory testing). Sites should 
carefully consider how to maintain privacy and confidentiality when discussing sexual activity and 
pregnancy testing. Prioritization of other laboratory evaluations may depend on whether local 
processing is available, though the recommended prioritization is as follows: (1) HIV-1 RNA viral 
load; (2) CD4 cell counts; (3) PK; (4) Lipid profiles; (5) Stored samples for resistance testing. 
• 
Sites with no ability to conduct in-person study visits, either at the study clinic or off-site, should 
consider whether any study procedures can be conducted remotely (e.g., by telephone). Evaluations 
should be prioritized as follows (as applicable for the individual participant and scheduled study visit 
in question): 
- Medical history taking and symptom-directed physical exam, noting assessment of vitals, height, 
and weight may be skipped 
- Adherence assessments and counseling, while maintaining privacy/confidentiality 
 
Study Drug Supply 
• 
Sites may dispense up to six months of study drug supplies to avoid gaps in ARV coverage. This 
should be done even if study visits or procedures cannot be performed for any reason. 
• 
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). 
• 
Sites are permitted to utilize rapid urine pregnancy test kits (either performed by study staff or given 
to and performed by participants themselves) in the context of these study drug pick-up or drop-off 
options. Sites should carefully consider how to maintain privacy and confidentiality of discussions 
related to sexual activity and the need for and results of pregnancy testing. 
 


Letter of Amendment #3 
Page 6 of 6 
10 June 2020 
IMPAACT 2014 Protocol Version 1.0 
Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for IMPAACT 2014. 
• 
Documentation should be entered in participant study charts in real-time should any of the following 
occur: 
- Missed visits 
- Out-of-window visits 
- Off-site visits (document the location of the visit) 
- Incomplete or partial visits (document which procedures were performed and which were not) 
- Remote contacts performed in lieu of in-person visits (document method used to complete the 
contact and which procedures were performed) 
- Any other participant contacts 
- Use of alternate laboratories or alternate laboratory assays 
- Alternate provision of study drug  
• 
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. 
 


Clarification Memorandum #2 
Page 1 of 3 
31 March 2020 
IMPAACT 2014 Protocol Version 1.0 
Clarification Memorandum #2 for:  
 
IMPAACT 2014 
 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
Version 1.0, dated 7 September 2017 
 
IND# 137,041  
DAIDS Study ID 34150 
 
Clarification Memorandum Date: 31 March 2020 
 
 
Summary of Clarifications 
 
This Clarification Memorandum (CM) is being issued to safeguard the health and well-being of 
IMPAACT 2014 study participants in the context of circulating severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) and the associated coronavirus disease (COVID-19) pandemic.  
 
As the study Sponsor, the Division of AIDS (DAIDS) has determined that this CM should be 
implemented immediately upon issuance. Consistent with United States Food and Drug Administration 
guidance, institutional review board/ethics committee (IRB/EC) approval of this CM is not required by 
the Division of AIDS prior to implementation. However, given the context of the COVID-19 pandemic 
and the importance of the guidance provided in this CM, sites should submit this CM to IRBs/ECs for 
their information or, if required by the IRBs/ECs, for their review and approval.  
 
The purpose of this CM is to provide operational flexibility for conducting study visits and procedures 
when needed to ensure ongoing access to study drug and to prioritize the conduct of clinically and 
scientifically important laboratory evaluations when possible. 
 
Implementation of this CM is expected to be time-limited in relation to the COVID-19 pandemic. In 
consultation with IMPAACT Network leadership and the study Sponsor, the IMPAACT 2014 Protocol 
Team will determine when, in the future, the guidance provided in this CM is no longer applicable. When 
such a determination is made, study sites will be formally notified and instructed to inform their 
IRBs/ECs. 
 
Please file this CM and any applicable IRB/EC correspondence in your essential document files for 
IMPAACT 2014. 
 
 
 
 


Clarification Memorandum #2 
Page 2 of 3 
31 March 2020 
IMPAACT 2014 Protocol Version 1.0 
Implementation 
 
This CM provides operational guidance to study sites from the IMPAACT 2014 Protocol Team. The 
Protocol Team acknowledges that the extent to which site operations may be disrupted by the COVID-19 
pandemic may vary across sites and over time. All sites should follow applicable government, health 
authority, and institutional policies with respect to conduct of study visits and procedures, with 
utmost importance placed on the health and well-being of study participants and study staff. Site 
investigators should continue to follow current protocol specifications for communication with the 
Protocol Team and/or Clinical Management Committee and should contact the Clinical Management 
Committee (impaact.2014cmc@fstrf.org) with any questions or concerns regarding this CM or 
management of study participants.  
 
Visit Scheduling 
• 
Sites should implement safety checks by telephone (as available) prior to in-person visits to assess 
participant/parent/guardian willingness and ability to attend in-person visits, as well as assess the 
onset of any adverse events, including but not limited to signs and symptoms potentially consistent 
with COVID-19. 
• 
Sites should prioritize completion of the Week 24 visit. 
• 
Sites that anticipate operational disruptions or closures in the near future are advised to conduct study 
visits early in the allowable visit window. Visits conducted prior to opening of the allowable window 
would also be preferred to completely missing a visit at a later date. 
• 
Sites that are currently experiencing operational disruptions or closures are advised to conduct study 
visits late in the allowable visit window. Visits conducted after closing of the allowable window 
would also be preferred to completely missed visits.  
• 
Effective with the issuance of this CM, the allowable window for the Weeks 24, 36, and 48 visits is 
broadened to ±6 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 parents, guardians, and participants to determine in advance where and 
when such visits will take place, with adequate protections for safety, privacy, and confidentiality. 
Off-site visit procedures should be conducted by site staff who are adequately qualified and trained to 
conduct the procedures, as determined by the site Investigator of Record (IoR), with attention paid to 
occupational health, biohazard containment, and specimen and data chain of custody. These staff 
should also be adequately qualified and trained to immediately assess and/or manage any adverse 
events or social impacts that may occur during the visits. If adverse events requiring further 
evaluation or management are identified during an off-site visit, staff conducting the visit should 
arrange for appropriate clinical management, in consultation with the IoR or designee as needed.  
• 
Sites with limited capacity to conduct in-person study visits should prioritize provision of study drug 
(see below) and conduct of safety-related laboratory evaluations, specifically, chemistries, CBC, and, 
if applicable, pregnancy testing. In addition, at Week 24, HIV-1 RNA viral load and CD4 cell count 
should also be prioritized. If it is not possible to perform these tests consistent with the site’s Protocol 
Analyte List (PAL), tests may be performed in alternate settings using alternate laboratory methods 
(alternate laboratories must adhere to local regulations for clinical laboratory testing). Sites should 
carefully consider how to maintain privacy and confidentiality when discussing sexual activity and 
pregnancy testing. Prioritization of other laboratory evaluations may depend on whether local 


Clarification Memorandum #2 
Page 3 of 3 
31 March 2020 
IMPAACT 2014 Protocol Version 1.0 
processing is available, though the recommended prioritization is as follows: (1) HIV-1 RNA viral 
load; (2) CD4 cell counts; (3) PK; (4) Lipid profiles; (5) Stored samples for resistance testing. 
• 
Sites with no ability to conduct in-person study visits, either at the study clinic or off-site, should 
consider whether any study procedures can be conducted remotely (e.g., by telephone). Evaluations 
should be prioritized as follows (as applicable for the individual participant and scheduled study visit 
in question): 
- Medical history taking and symptom-directed physical exam, noting assessment of vitals, height, 
and weight may be skipped 
- Adherence assessments and counseling, while maintaining privacy/confidentiality 
 
Study Drug Supply 
• 
Sites may dispense up to six months of study drug supplies to avoid gaps in ARV coverage. This 
should be done even if study visits or procedures cannot be performed for any reason. 
• 
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). 
• 
Sites are permitted to utilize rapid urine pregnancy test kits (either performed by study staff or given 
to and performed by participants themselves) in the context of these study drug pick-up or drop-off 
options. Sites should carefully consider how to maintain privacy and confidentiality of discussions 
related to sexual activity and the need for and results of pregnancy testing. 
 
Documentation 
• 
Site-specific contingency plans, and the implementation thereof, should be documented in essential 
document files for IMPAACT 2014.  
• 
Documentation should be entered in participant study charts in real-time should any of the following 
occur: 
- Missed visits  
- Out-of-window visits 
- Off-site visits (document the location of the visit) 
- Incomplete or partial visits (document which procedures were performed and which were not) 
- Remote contacts performed in lieu of in-person visits (document method used to complete the 
contact and which procedures were performed) 
- Any other participant contacts  
- Use of alternate laboratories or alternate laboratory assays 
- Alternate provision of study drug  
• 
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.  


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 1 of 12 
26 April 2019  
Letter of Amendment #2 for:  
 
IMPAACT 2014 
 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil 
Fumarate (MK-1439A) in HIV-1-infected Children and Adolescents 
 
Version 1.0, dated 7 September 2017 
 
IND#: 137,041  
DAIDS Study ID 34150 
 
Letter of Amendment Date: 26 April 2019 
 
 
 
TABLE OF CONTENTS 
 
INFORMATION/INSTRUCTIONS TO STUDY SITES FROM THE DIVISION OF AIDS .............. 1 
LETTER OF AMENDMENT SIGNATURE PAGE ....................................................................... 3 
SUMMARY OF MODIFICATIONS AND RATIONALE ................................................................ 4 
IMPLEMENTATION .................................................................................................................... 4 
1. Updates to allow Cohort 2 to open for children >45kg while Cohort 1 continues enrolling participants 35kg-
≤45kg............................................................................................................................................................... 4 
2. Update description of the presentation of oral granules of study drug and instructions on how to administer. 9 
3. Update to allow the enrollment of ART-experienced, virologically suppressed participants in Cohort 2, as 
specified in Clarification Memo #1 ................................................................................................................... 9 
4. Updates to protocol team and site representatives rosters ............................................................................ 10 
5. Updates to Appendices II and III, Sample Informed Consent Forms for Study Participation ......................... 11 
 
 
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) impacts the IMPAACT 2014 study, 
including the study informed consent forms (ICFs), 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.  
 
Before this LoA can be implemented at any site, an “Implementation Notice” for the LoA must be issued 
by the IMPAACT Operations Center confirming that all operational requirements for implementing the 
LoA at the network level have been completed. Sites should also follow the instructions below regarding 
site-specific timing of implementation of the LoA. 
 


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 2 of 12 
26 April 2019  
For sites that were activated to initiate the study prior to issuance of this LoA, upon obtaining all required 
IRB/EC and 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 (RSC). Sites will receive a registration notification for 
the LoA after the DAIDS PRO verifies that all required registration documents have been received and 
are complete. Sites should not await this notification before implementing this LoA. For participants 
enrolled prior to implementation of this LoA and still on-study, re-consent for study participation should 
be obtained at the next scheduled study visit, using the revised site-specific ICFs corresponding to this 
LoA.  
 
For sites that were not activated to initiate the study prior to issuance of this LoA, upon obtaining all 
required IRB/EC and regulatory entity approvals, sites are required to submit an LoA registration packet 
to the DAIDS PRO at the RSC. Sites will receive a registration notification for the LoA after the DAIDS 
PRO verifies that all required registration documents have been received and are complete. Activation 
will occur following receipt of all required IRB/EC and regulatory entity approvals for protocol Version 
1.0 and this LoA; receipt of a protocol registration notification for protocol Version 1.0; receipt of the 
protocol registration notification for this LoA; completion of all other study activation requirements; and 
receipt of a site-specific study activation notice from the IMPAACT Operations Center. 
 
Please file this LoA, corresponding site-specific informed consent forms, all associated IRB/EC and 
regulatory entity correspondence, and all correspondence with the DAIDS PRO in your essential 
documents files for IMPAACT 2014. If the IMPAACT 2014 protocol is amended in the future, the 
contents of this LoA will be incorporated into the next version of the protocol. 
 
 
 
 


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 3 of 12 
26 April 2019  
IMPAACT 2014 
 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
Version 1.0, dated 7 September 2017 
 
DAIDS Study ID #34150 
 
 
Version 1.0, Letter of Amendment #2 
 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 4 of 12 
26 April 2019  
 
Summary of Modifications and Rationale 
 
1. As identification of participants in the 35-≤45 kg weight group in Cohort 1 has been challenging, the 
protocol is modified to allow enrollment into Cohort 2 for children in the >45kg weight group, while 
attempting, but not requiring, to enroll at least four participants with weight between 35 kg and ≤45 
kg into Cohort 1.  Of note, in February 2019, the IMPAACT Study Monitoring Committee (SMC) 
conducted a safety and pharmacokinetic (PK) review of data for nine evaluable Cohort 1 participants.  
Based on review of all available data, the SMC agreed that the 100 mg once daily dose of doravirine 
met protocol-specified safety and PK guidelines.  The SMC also agreed that currently available data 
are sufficient to support opening Cohort 2 to accrual of participants weighing more than 45 kg.  The 
requirement to enroll a minimum of five participants in the 35-≤45 kg weight group into Cohort 2 was 
also revised to attempt to enroll this number but not require a minimum number of participants. 
2. Update description of the presentation of oral granules of study drug and instructions on how to 
administer. 
3. As documented in Clarification Memorandum #1, the protocol criteria to allow enrollment of ART-
experienced, virologically suppressed was met, based on review of data from adult studies switching 
participants from a stable antiretroviral regimen to a once-daily single tablet regimen of doravirine 
100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg (DOR/3TC/TDF). 
4. The protocol team and site investigator rosters have been updated to reflect current membership. 
5. The sample informed consent forms for participation in Cohort 1 and in Cohort 2 (Appendices II and 
III) have been modified in accordance with updated risk language provided by Merck for DOR (MK-
1439, Cohort 1) and DOR/3TC/TDF (MK-1439A, Cohort 2); other minor updates were incorporated 
based on additional changes included in this LoA. 
 
 
Implementation 
 
The modifications included in this LoA are listed by modification and will be incorporated into the next 
protocol amendment as specified below. Changes to the study sample informed consent forms are 
grouped at the end of the document. Additions to the text are indicated in bold; deletions are indicated by 
strikethrough.  
 
1. Updates to allow Cohort 2 to open for children >45kg while Cohort 1 continues enrolling participants 
35kg-≤45kg 
 
a. Schema, Study Population: 
 
HIV-1-infected children and adolescents, from 12 years to less than 18 years of age who weigh at 
least 35 kg.  Cohort 1 and 2 will enroll concurrently sequentially: 
 
b. Schema, Study Duration: 
 
Approximately four years total from the date the first participant is enrolled.  Accrual into Cohort 1 
is expected to require approximately three to six months and participants in this cohort will be 
followed for two weeks.  It is expected that Cohort 2 will open three months after Cohort 1 is 
completed (following review of data from the >45 kg weight group participants in Cohort 1).   
Accrual into Cohort 2 is expected to require approximately six to twelve months and participants in 
this cohort will be followed for 96 weeks.   


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 5 of 12 
26 April 2019  
c. Figure 1, IMPAACT 2014 Overview of Study Design: 
 
 
Cohort 1
Enroll: Up to 20 participants, ages 12 to <18 years old, to achieve 8 12 evaluable >45
kg (with an attempt to enroll approximately minimum of 4 evaluable participants
between 35 to ≤45 kg)
Population: Participants ≥35 kg who are virologically suppressed on 
one InSTI (DTG or RAL) + two NRTIs
Treatment Regimen: Single dose of DOR (100 mg)
Primary Evaluation: PK and safety 
Follow-up: 2 weeks
Guidelines for evaluating the dose:
Safety: Dose is safe and well tolerated
PK: AUC and C24hr are met
Safety and PK 
guidelines not met for 
any weight
There is more 
variability than 
expected to 
confidently determine 
achievement 
of PK targets
Enroll additional 
participants to further 
evaluate PK 
and safety
Safety and PK 
guidelines 
met for all weights 
Participants ≥35 kg 
are approved to 
open for Cohort 2
Convene an SMC review
Cohort 2
Enroll: Opens for up to 45 participants, ages 12 to <18 years old, to achieve 40 evaluable 
with approved weight in Cohort 1 (with an attempt to enroll approximately minimum of 
5 participants 35 to ≤45 kg weight group, if this weight group enrolls and is approved in
Cohort 1)
Population: Participants ≥35 kg (or the weight determined in Cohort 1 as meeting PK and
safety targets) who are ARV-naïve and drug susceptible OR virologically suppressed
Treatment Regimen: Once daily DOR/3TC/TDF
Primary Safety Evaluation: 24 weeks
Follow-up: 96 weeks
PK guidelines not met
for all participants 
≥35 kg
CMC may evaluate all 
PK and safety data 
and/or consider 
enrolling additional 
participants to 
determine the weight 
threshold for which PK 
targets are met. If 
safety targets are also 
met, participants ≥ 
weight threshold are 
approved to enroll for 
Cohort 2.
Safety and PK 
guidelines met for a 
minimum of 
8 12 participants 
including a minimum 
of 4 in the 35 to ≤45 
kg weight group
Participants in the 
corresponding 
weight group ≥35 
kg are approved to 
open for Cohort 2


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 6 of 12 
26 April 2019  
d. Section 1.4.1, Rationale for Dose Selection, fourth paragraph: 
 
To move forward the development of DOR and DOR/3TC/TDF for use in children and adolescents, 
children and adolescents for whom the full adult dose FDC is appropriate will be enrolled for the 
long-term portion of study (Cohort 2); enrollment into Cohort 1 will concurrently remain open 
until a minimum of 4 evaluable participants between 35 to ≤45 kg are enrolled or until Cohort 
2 is fully enrolled.  Even if Cohort 1 is not fully enrolled by the time Cohort 2 is enrolled, both 
cohorts will close for enrollment at that time.  The expectation is that the adult dose will be 
appropriate for this will be all children and adolescents with weight ≥35 kg.  If this expectation is 
not borne out based on the results of Cohort 1, only children and adolescents in the weight range for 
which the 100 mg doravirine dose is appropriate will be enrolled into Cohort 2 and followed long-
term.  If, after the dose evaluation stage, it appears that lower-weight children and adolescents (for 
example, 35 – 40 kg) may require a dose less than 100 mg DOR, an age appropriate formulation 
that is currently in development and is intended to deliver a dose below 100 mg, will be employed 
to study safety and PK in such participants in a separate study. 
 
e. Section 1.4.2, Rationale for Study Design and Cohort Selection, third paragraph: 
 
Once the PK and safety targets for Cohort 1 are confirmed for the 100 mg DOR dose, 
DOR/3TC/TDF will be studied in Cohort 2 in HIV-1-infected children and adolescents of the 
weight group(s) supported by results from Cohort 1.  While it is anticipated that the 100 mg 
DOR dose will meet PK targets for all participants with weights down to 35 kg, in the unlikely 
event that the dose is determined to be too high for lower weight participants, Cohort 2 will only 
open for those participants whose weight meet the PK and safety targets based on data from Cohort 
1.  If the 35 to ≤45 kg weight group in Cohort 1 fully enrolls and shows acceptable PK and safety, 
Cohort 2 will open for the 35 to ≤45 kg weight group and the study will attempt to enroll 
approximately a minimum of five participants in this weight group will be enrolled to Cohort 2. 
 
f. Section 3, Study Design, second and third paragraphs: 
 
The protocol will enroll two sequential cohorts, Cohorts 1 and Cohort 2, as described in Sections 
3.1 and 3.2, respectively.  In summary, participants will first be enrolled into Cohort 1 to evaluate 
the PK and safety of the 100 mg DOR dose, with intensive PK evaluation completed at entry and 
followed through two weeks on study to assess safety.  Specimens will be shipped in real time with 
ongoing testing, with team review of PK and safety data as available.  Upon enrollment of a 
minimum of eight 12 evaluable participants with weight greater than 45 kg, enrollment will be 
paused while the Cohort 1 PK and safety data are reviewed by the protocol team and the SMC.  
Data will be evaluated based on the algorithm in Section 9.2, with options of resuming enrollment 
into Cohort 1, proceeding with Cohort 2 enrollment, or assessing next steps for the study.   
 
If results from Cohort 1 are supportive, participants in the supported weight group(s) will be 
enrolled into Cohort 2 to evaluate the safety and tolerability of a fixed-dose combination regimen, 
including DOR, 3TC, and TDF.  A subset of participants will have intensive PK evaluations at 
Week 1 and all participants will have population PK evaluations through Week 48; the PK 
specimens will be shipped in batches with testing when sample collection is complete for all 
relevant participants (see Section 6.11.2).  Participants will be followed through 96 weeks on study 
to assess long-term safety, virologic efficacy, and immunologic response, among other objectives as 
in Sections 2.3 and 2.4. 
 


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 7 of 12 
26 April 2019  
g. Section 9.1, General Design Issues, first paragraph, last sentence, and second paragraph, first 
sentence: 
 
Participants will be enrolled into two sequential cohorts, as described in Section 3. 
 
A minimum of eight 12 PK evaluable in Cohort 1 and 40 evaluable participants in Cohort 2 will be 
accrued to the study. 
 
h. Section 9.2, Dose Evaluation Algorithm, Cohort 1, first paragraph and first bullet:  
 
The study will implement a dose-evaluation algorithm of the 100 mg DOR based on PK data 
around the single-dose and safety data through Week 2.  Cohort 1 will enroll an initial group of 12 
evaluable participants (at least eight in the >45 kg weight group) and their PK and safety data will 
be evaluated as follows: 
• 
If these 12 participants meet the PK guidelines (see Section 10.3.1) and there are no safety 
concerns (see Section 9.6.2, Participant Safety), then the DOR dose for Cohort 2 will be 
established and Cohort 2 will begin to accrue participants of the supported weight group, 
following an SMC review (see Section 9.6.2, Dose Evaluation).  Enrollment into Cohort 1 
will concurrently remain open until a minimum of 4 evaluable participants between 35 to 
≤45 kg are enrolled or until Cohort 2 is fully enrolled; even if Cohort 1 is not fully 
enrolled by the time Cohort 2 is enrolled, both cohorts will close for enrollment at that 
time.  
 
i. Section 9.2, Dose Evaluation Algorithm, Cohort 2, first paragraph, first sentence:  
 
This cohort will begin to enroll once the PK and safety of the 100 mg DOR dose have been 
established from Cohort 1, as described above, and once the SMC has reviewed applicable all 
Cohort 1 data and approved enrollment into Cohort 2 (see Section 9.6.2, Dose Evaluation).   
 
j. Section 9.5, Sample Size and Accrual, Cohort 1, first paragraph: 
 
At least eight 12 evaluable participants >45 kg will be enrolled in Cohort 1 with an attempt to 
enroll approximately a minimum of four evaluable participants between 35 kg and 45 kg.  
Depending on the PK results, additional participants may be enrolled.  Even if Cohort 1 is not 
fully enrolled by the time Cohort 2 is enrolled, both cohorts will close for enrollment at that 
time.  
 
k. Section 9.7.1, Primary Safety Analyses (on data through Week 2 for Cohort 1 and Week 24 for 
Cohort 2), third paragraph and Table 19: 
 
The proportions of participants experiencing Grade 3 or higher adverse events, bounded by exact 
95% confidence intervals, will be presented by cohort and population classification at entry (Cohort 
2).  Similar analyses will present the proportions of participants with Grade 3 or higher events 
assessed as related to study drug, again bounded by exact 95% confidence intervals.  Table 19 
presents the upper and lower limits of confidence intervals around potential results observed in the 
groups of n=8, n=12, n=15, and n=40, and the combined groups of n=48 and n=52 and n=55. 
 


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 8 of 12 
26 April 2019  
Table 19.  Percent of Participants Experiencing ≥Grade 3 Adverse Events (or ≥Grade 3  
Adverse Events Attributed to the Study Medication) with Exact 95% Confidence Intervals 
N 
n (%) With ≥Grade 3 Adverse Events 
95% CI 
8 
0 (0%) 
0% - 37% 
12 
0 (0%) 
0% - 26% 
15 
0 (0%) 
0% - 22% 
40 
0 (0%) 
0% - 9% 
48 
0 (0%) 
0% - 7% 
52 
0 (0%) 
0% - 7% 
55 
0 (0%) 
0% - 6% 
 
 
 
8 
1 (12%) 
0% - 53% 
12 
1 (8%) 
0% - 38% 
15 
2 (13%) 
2% - 40% 
40 
4 (10%) 
3% - 24% 
48 
5 (10%) 
3% - 23% 
52 
5 (10%) 
3% - 21% 
55 
6 (11%) 
4% - 22% 
 
 
 
8 
2 (25%) 
3% - 65% 
12 
4 (33%) 
10% - 65% 
15 
5 (33%) 
12% - 62% 
40 
12 (30%) 
17% - 47% 
48 
14 (29%) 
17% - 44% 
52 
15 (29%) 
17% - 43% 
55 
16 (29%) 
18% - 43% 
 
l. Section 10.1, Pharmacology Overview and Objectives, Cohort 1, first paragraph: 
 
Cohort 1 will assess the single dose pharmacokinetics of a 100 mg dose of doravirine in at least 
eight 12 evaluable children and adolescents ≥35kg (with an attempt to enroll approximately a 
minimum of four additional evaluable participants between 35 to ≤45 kg). 
 
m. Section 10.1, Pharmacology Overview and Objectives, Cohort 1, second paragraph: 
 
If Cohort 1 pharmacokinetic results confirm this initial model in participants >45 kg, then Cohort 
2 will open to participants weighing >45 kg ≥35 kg.  If Cohort 1 PK and safety results also 
confirm this initial model in participants 35 to ≤45 kg, then Cohort 2 will open to participants 
weighing ≥35 kg.  If exposure is deemed too high (i.e., exceeds that observed in adults at a 200 mg 
daily dose) in children or adolescents weighing closer to 35 kg, then Cohort 2 will open with a 100 
mg daily dose only in children and adolescents above the weight determined to yield appropriate 
exposure from the Cohort 1 results. 
 
n. Section 10.3.2, Timing of Interim Analyses, first paragraph: 
 
Cohort 1 DOR pharmacokinetics will be summarized once at least eight 12 participants of >45 kg 
have completed the pharmacokinetic visit to confirm the dose for this weight group in Cohort 2.  
Cohort 1 DOR pharmacokinetics will again be summarized if at least four participants 35 to 


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 9 of 12 
26 April 2019  
≤45 kg have completed the pharmacokinetic visit; if Cohort 2 has not yet fully enrolled, these 
data will be used to confirm the dose for this weight group in Cohort 2. Samples from Cohort 1 
participants should be shipped as soon as the 72-hour post-dose draw is completed and tested on an 
ongoing basis. 
 
2. Update description of the presentation of oral granules of study drug and instructions on how to 
administer 
 
a. Section 1.4.4, Rationale for Use of Tablets and Granules, second paragraph, first paragraph: 
 
The age appropriate formulation may be administered on in liquid or soft food, as described further 
in Section 5.3 5.2.2. 
 
b. Section 5.2.2, Cohort 2, second paragraph: 
 
Doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF): fixed-dose combination 
oral granules, provided in capsules to be opened for administration.  Each capsule contains 
33.6 mg of DOR, 100 mg of 3TC, and 100 mg of TDF.  The contents of three capsules is 
equivalent to the adult dose.  The formulation is comprised of 100.6 mg of DOR, 300 mg 3TC, 
and 300 mg TDF, divided between three capsules of oral granules. The capsules individual 
components may be stored refrigerated at the site pharmacy separately between 2°C and 8 30°C 
(36°-46 86°F), protected from moisture and light with a desiccant. Do not freeze. Study drug 
does not need to be refrigerated after being dispensed to the participant. The stability of the 
combination product is to be determined. 
 
c. Section 5.3, Study Drug Administration, Cohort 2: 
 
Cohort 2 
Doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) will be 
administered orally as a fixed-dose combination once daily. 
 
The fixed-dose combination DOR/3TC/TDF capsules are not to be swallowed 
whole. They must may be opened and the oral granules sprinkled on the tongue 
then swallowed (followed with water) or; sprinkled onto 1-2 teaspoons of soft food 
then swallowed; or dispersed in 5-10 mL liquid then swallowed. In any case, 
administration must occur within 15 minutes of mixing.  
 
3. Update to allow the enrollment of ART-experienced, virologically suppressed participants in Cohort 2, 
as specified in Clarification Memo #1. 
 
Review of Adult Switch Data Prior to Allowing ART-experienced, virologically suppressed 
participants into Cohort 2 of IMPAACT 2014 
 
When the IMPAACT 2014 protocol was finalized in September 2017, data were not available on 
switching participants from their current regimen to a once-daily regimen including 
DOR/3TC/TDF but were anticipated to become available during the course of the IMPAACT 
2014 study. The IMPAACT 2014 protocol therefore specified that inclusion of participants who 
are ART-experienced, virologically suppressed will be dependent on supportive results from at 
least one of the ongoing adult switch studies (PN024, PN028). 
 
Specifically, Section 1.4.2 of the IMPAACT 2014 protocol specified that data from one of the 
adult switch studies would need to be available from the 24-week time point and reviewed by the 


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 10 of 12 
26 April 2019  
IMPAACT 2014 Clinical Management Committee (CMC) and the IMPAACT Study Monitoring 
Committee (SMC) to confirm that the data were supportive of enrolling ART-experience, 
virologically suppressed participants; as noted in the protocol, data would be considered 
supportive if 90% or more of the participants maintain virologic suppression for at least 24 
weeks after switching. 
 
The 24-week data are now available from the DRIVE-SHIFT study and were reviewed by the 
CMC in October and November 2018 and by the SMC in January 2019; following review of the 
data, the CMC and SMC agreed that the protocol-specified criteria were met, as follows. At 
week 24, the data showed that 93.7% (419/447) of the immediate switch group and 94.6% 
(211/223) of the delayed switch group had HIV-1 RNA <50 copies/mL (1). As 90% or more of the 
participants maintained virologic suppression for at least 24 weeks after switching, the protocol-
specified criteria for allowing enrollment of ART-experienced, virologically suppressed 
participants into Cohort 2 of IMPAACT 2014 have been met. Once Cohort 2 is open to accrual, 
participants who meet the eligibility criteria as ART-naïve or ART-experienced will be allowed 
to enroll. 
 
Reference: 
1. Kumar P, Johnson M, Molina J, Rizzardini G, Cahn P, Bickel M, Mallolas J, Zhou Y, 
Morais C, Kumar S, Sklar P. LB2.. Switch to Doravirine/ Lamivudine/ Tenofovir Disoproxil 
Fumarate (DOR/3TC/TDF) Maintains Virologic Suppression Through 48 Weeks: Results of 
the DRIVE-SHIFT Trial. InOpen Forum Infectious Diseases 2018 Nov (Vol. 5, No. Suppl 1, 
ppS759-60 
 
4. Updates to protocol team and site representatives rosters 
 
To reflect current protocol team membership, Patricia Morgan, Carmelita Alvero, Linda Marillo, 
William Murtaugh, Andrea Kehler, Xia Xu, Sushma Kumar, and Jontraye Davis are removed from the 
protocol team roster; Rachel Scheckter, Yvonne Woolwine-Cunningham, Frances Whalen, Havilland 
Campbell, Hye Cho, Anthony Rodgers, and Marcus Bolton are added: 
 
Clinical Trials Specialists 
Rachel Scheckter, MPH 
IMPAACT Operations Center, FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040 x11392 
Email: rscheckter@fhi360.org 
 
Protocol Data Managers 
Yvonne Woolwine-Cunningham, BA 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY, 14226-1056, USA 
Phone: (716) 834-0900 x7332 
Email: woolwine@frontierscience.org 
 
 
Laboratory Center Representative 
Frances Whalen MPH, MT(ASCP) 
IMPAACT Laboratory Center 
University of California, Los Angeles 
11075 Santa Monica Blvd., Suite 200 
Los Angeles, CA 90095, USA 
Phone: (704) 422-4055 
Email: fwhalen@milabcentral.org 
 
Pharmaceutical Representatives 
Havilland Campbell  
126 East Lincoln Avenue 
Building 34-4087E 
Rahway, NJ, 07065, USA 
Phone: (732) 594-7654 
Email: havilland_campbell@merck.com 
 


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 11 of 12 
26 April 2019  
Anthony Rodgers, MS 
351 N. Sumneytown Pike 
North Wales, PA 19454, USA 
Phone: (267) 305-5357 
Email: anthony_rodgers@merck.com 
 
Hye Cho, BS 
351 N. Sumneytown Pike 
North Wales, PA 19454, USA 
Phone: (215) 605-0854 
Email: hye.cho@merck.com 
Community Program Manager  
Marcus Bolton, MEd 
IMPAACT Operations Center, FHI 360  
359 Blackwell Street, Suite 200  
Durham, NC 27701, USA  
Phone: (919) 544-7040 x11678 
Email: mbolton@fhi360.org 
 
To reflect current site representative membership, Sandra Jones and Sylvia Dittmer are removed from 
the site representative roster; Jill Utech and Avy Violari are added: 
 
St. Jude Children’s Research Hospital, CRS 6501 
Jill Utech, RN, MSN, CCRC 
262 Danny Thomas Place, MS 600 
Memphis, TN 38105, USA 
Phone: (901) 595-3490 
Email: jill.utech@stjude.org 
Soweto IMPAACT, CRS 8052 
Avy Violari, MD 
Perinatal HIV Research Unit 
Chris Hani Baragwanath Academic Hospital 
PO Box 114, Diepkloof, Soweto, 
Johannesburg, South Africa 
Phone: +27 11 989 9707  
Email: violari@mweb.co.za 
 
5. Updates to Appendices II and III, Sample Informed Consent Forms for Study Participation  
 
a. Appendix II: Sample Informed Consent Form for Participation in Cohort 1, item 15, table following 
first paragraph: 
 
Overall Body Effects 
• Overall weakness 
• Headache 
• Back pain 
• Stuff, runny or uncomfortable nose 
• Fever 
Effects on the Stomach 
• Pain or upset stomach 
• Loose or watery stools 
• Vomiting 
Effects on Muscle and Bones 
• Aches and pains 
 
Effects on Activity  
• Trouble sleeping 
• Drowsiness and tiredness 
• Dizziness 
 
b. Appendix II: Sample Informed Consent Form for Participation in Cohort 1, item 1, third 
paragraph:  
 
The two groups of the study are called Cohort 1 and Cohort 2.  Cohort 1 will be done began first. 
This part will include up to 20 children and adolescents.  Cohort 2 will be done after part of Cohort 
1 is completed.  Cohort 2 will include up to 45 children and adolescents.  We will tell you about 
Cohort 1 first.  This is a consent form for Cohort 1. 
 


Letter of Amendment #2 to  
IMPAACT 2014 Version 1.0  
Page 12 of 12 
26 April 2019  
c. Appendix III: Sample Informed Consent Form for Participation in Cohort 2, item 1, fifth 
paragraph: 
 
The two groups of the study are called Cohort 1 and Cohort 2.  Cohort 1 was done began first.  This 
part will include included up to 20 children and adolescents.  Cohort 2 will be done after part of 
Cohort 1 is completed.  Cohort 2 will include up to 45 children and adolescents.  We will tell you 
about Cohort 1 first.  This is a consent form for Cohort 2. 
 
d. Appendix III: Sample Informed Consent Form for Participation in Cohort 2, item 2, third 
paragraph: 
 
Another way to take DOR/3TC/TDF is as oral granules.  Granules are kept in larger capsules or 
containers [sites may use any locally understandable term to describe the granules].  The capsules 
should not be swallowed whole. The capsules should be opened to sprinkle the granules 
directly into the mouth or to mix the granules can be sprinkled or mixed with soft food or liquid. 
 
e. Appendix III: Sample Informed Consent Form for Participation in Cohort 2, item 19, table 
following first paragraph, boxes for Overall Body Effects and Effects on Stomach: 
 
Overall Body Effects 
• Changes in the placement of body fat (increasing 
around the stomach, neck, or breast or decreasing 
in the arms, legs, or cheeks) 
• Overall weakness 
• Headache 
• Back pain 
• Stuff, runny, or uncomfortable nose 
• Allergic reaction 
• Numbing, tingling, or pain in the hands and feet 
• Fever 
 
Effects on Stomach 
• Pain or upset stomach 
• Loose or watery stools 
• Vomiting 
• Gas 
• Dry mouth 
• Change in your sense of taste 
 


Corrrected Clarification Memorandum #1 to  
Page 1 of 2 
13 February 2019  
IMPAACT 2014 Protocol Version 1.0 
Corrected Clarification Memorandum #1 for:  
 
IMPAACT 2014 
 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
Version 1.0, dated 7 September 2017 
 
IND# 137,041  
DAIDS Study ID 34150 
 
Corrected Clarification Memorandum Date: 13 February 2019 
 
 
 
Summary of Clarifications and Rationale 
 
This Clarification Memorandum (CM) documents the protocol-specified review of data from adult 
studies switching participants from a stable antiretroviral regimen to a once-daily single tablet regimen 
of doravirine 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg (DOR/3TC/TDF). 
Based on this review, protocol criteria to allow enrollment of ART-experienced, virologically suppressed 
participants into Cohort 2 of IMPAACT 2014 have been met; once Cohort 2 is open to accrual, 
participants who meet the eligibility criteria as ART-naïve or ART-experienced will be allowed to enroll. 
 
 
Implementation 
 
Institutional Review Board/Ethics Committee (IRB/EC) approval of this CM is not required by the study 
sponsor prior to implementation; however, sites may submit it to IRBs/ECs for their information or, if 
required by the IRBs/ECs, for their approval prior to implementation. The information included in this 
memorandum will be incorporated into the next full protocol amendment. 
 
Review of Adult Switch Data Prior to Allowing ART-experienced, virologically suppressed participants into 
Cohort 2 of IMPAACT 2014 
 
When the IMPAACT 2014 protocol was finalized in September 2017, data were not available on 
switching participants from their current regimen to a once-daily regimen including DOR/3TC/TDF but 
were anticipated to become available during the course of the IMPAACT 2014 study. The IMPAACT 
2014 protocol therefore specified that inclusion of participants who are ART-experienced, virologically 
suppressed will be dependent on supportive results from at least one of the ongoing adult switch studies 
(PN024, PN028). 
 
Specifically, Section 1.4.2 of the IMPAACT 2014 protocol specified that data from one of the adult 
switch studies would need to be available from the 24-week time point and reviewed by the IMPAACT 
2014 Clinical Management Committee (CMC) and the IMPAACT Study Monitoring Committee (SMC) 
to confirm that the data were supportive of enrolling ART-experience, virologically suppressed 


Corrrected Clarification Memorandum #1 to  
Page 2 of 2 
13 February 2019  
IMPAACT 2014 Protocol Version 1.0 
participants; as noted in the protocol, data would be considered supportive if 90% or more of the 
participants maintain virologic suppression for at least 24 weeks after switching. 
 
The 24-week data are now available from the DRIVE-SHIFT study and were reviewed by the CMC in 
October and November 2018 and by the SMC in January 2019; following review of the data, the CMC 
and SMC agreed that the protocol-specified criteria were met, as follows. At week 24, the data showed 
that 93.7% (419/447) of the immediate switch group and 94.6% (211/223) of the delayed switch group 
had HIV-1 RNA <50 copies/mL (1). As 90% or more of the participants maintained virologic suppression 
for at least 24 weeks after switching, the protocol-specified criteria for allowing enrollment of ART-
experienced, virologically suppressed participants into Cohort 2 of IMPAACT 2014 have been met. Once 
Cohort 2 is open to accrual, participants who meet the eligibility criteria as ART-naïve or ART-
experienced will be allowed to enroll. 
 
Reference:  
1. Kumar P, Johnson M, Molina J, Rizzardini G, Cahn P, Bickel M, Mallolas J, Zhou Y, Morais C, 
Kumar S, Sklar P. LB2.. Switch to Doravirine/ Lamivudine/ Tenofovir Disoproxil Fumarate 
(DOR/3TC/TDF) Maintains Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT 
Trial. InOpen Forum Infectious Diseases 2018 Nov (Vol. 5, No. Suppl 1, ppS759-60 


Letter of Amendment #1 to  
IMPAACT 2014 Version 1.0  
Page 1 of 7 
7 May 2018  
Letter of Amendment #1 for:  
 
IMPAACT 2014 
 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil 
Fumarate (MK-1439A) in HIV-1-infected Children and Adolescents 
 
Version 1.0, dated 7 September 2017 
 
IND#: 137,041  
DAIDS Study ID 34150 
 
 
Letter of Amendment Date: 7 May 2018 
 
 
 
TABLE OF CONTENTS 
 
INFORMATION/INSTRUCTIONS TO STUDY SITES FROM THE DIVISION OF AIDS ............. 2 
LETTER OF AMENDMENT SIGNATURE PAGE ...................................................................... 3 
SUMMARY OF MODIFICATIONS AND RATIONALE ............................................................... 4 
IMPLEMENTATION ................................................................................................................... 4 
1. Update to regulatory entities that may review study records ............................................................................... 4 
2. Align the target steady-state C24hr to be consistent with that obtained in adults .................................................. 5 
3. Update blood volume requirements for Cohort 2 Week 1 PK evaluations ........................................................... 5 
4. Add blood collection and testing for CD4 cell count for participants in Cohort 2 at Weeks 64, 80 and 96 .......... 6 
5. Corrections to Section 4.1.5.3, Cohort 2 ART-experienced................................................................................. 6 
6. Correction to Appendix III: Sample Informed Consent Form for Participation in Cohort 2, item 11, first 
paragraph, second and third sentences .............................................................................................................. 7 
7. Correction of procedural sequencing in Section 6.2.1, Cohort 1 Entry Visit, second paragraph, second bullet .. 7 
8. Other minor updates and clarifications ................................................................................................................ 7 
 
 
 
 


Letter of Amendment #1 to  
IMPAACT 2014 Version 1.0  
Page 2 of 7 
7 May 2018  
Information/Instructions to Study Sites from the Division of AIDS 
 
The information contained in this Letter of Amendment (LoA) impacts the IMPAACT 2014 study, 
including the study informed consent forms (ICFs), and must be submitted to site Institutional Review 
Boards (IRBs) and/or Ethics Committees (ECs) as soon as possible for their review and approval. 
Approval must also be obtained from site regulatory entities if applicable per the policies and procedures 
of the regulatory entities. All IRB/EC and regulatory entity requirements must be followed.  
 
Upon obtaining IRB/EC approval and any other applicable regulatory entity approvals, each site should 
immediately begin implementing this LoA and using the updated ICFs. After all required approvals are 
obtained, the updated ICFs should be used for all new participants. In addition, all previously enrolled 
participants must reconsent to ongoing study participation using the updated site-specific ICF. Re-
consenting should take place at each enrolled participant’s next study visit after all required approvals are 
obtained. 
 
Sites are required to submit an LoA registration packet to the DAIDS Protocol Registration Office 
(DAIDS PRO) at the Regulatory Support Center (RSC). Sites will receive a registration notification for 
the LoA after the DAIDS PRO verifies that all required registration documents have been received and 
are complete.  
 
Please file this LoA, all associated IRB/EC and regulatory entity correspondence, and all correspondence 
with the DAIDS PRO in your essential documents files for IMPAACT 2014. If the IMPAACT 2014 
protocol is amended in the future, the contents of this LoA will be incorporated into the next version of 
the protocol. 
 
 


Letter of Amendment #1 to  
IMPAACT 2014 Version 1.0  
Page 3 of 7 
7 May 2018  
IMPAACT 2014 
 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
Version 1.0, dated 7 September 2017 
 
DAIDS Study ID #34150 
 
 
Version 1.0, Letter of Amendment #1 
 
Letter of Amendment Signature Page 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS) and institutional policies. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 


Letter of Amendment #1 to  
IMPAACT 2014 Version 1.0  
Page 4 of 7 
7 May 2018  
 
Summary of Modifications and Rationale 
 
1. Per ICH GCP E6 4.8.10(n) and DAIDS requirements, it is mandatory that all DAIDS-sponsored 
and/or supported trials include language that informs participants that other US, local, and 
international regulatory entities may also review study records. Section 11.2 and the sample ICFs in 
Appendices II and III have been updated accordingly.  
2. As recommended by the United States Food and Drug Administration, the target steady-state C24hr for 
Cohort 1 has been updated to be consistent with the steady-state C24hr obtained in adults at the 
proposed dose. The protocol had originally targeted the value equivalent to over six times the IC50 for 
DOR against wild type virus in the presence of 100% normal human serum. This has been updated in 
Sections 10.1 and 10.3.1. 
3. The protocol team had originally anticipated that up to 2.5 mL blood would be required to assay 
lamivudine and tenofovir for the Cohort 2 intensive PK; however, EDTA blood collection tubes are 
only available in 2.0 mL and 3.5 mL sizes. In consultation with the testing laboratories, the blood 
volume has been changed to required collection of 2.0 mL.  
4. A secondary study objective related to immunologic response includes assessment at Weeks 24, 48 
and 96 for participants in Cohort 2; inclusion of testing of CD4 cell count at Week 96 was 
inadvertently left out of the protocol requirements and has been added. In addition, more frequent 
testing of CD4 cell count was recommended by the United States Food and Drug Administration; this 
testing has been added to Weeks 64 and 80. 
5. Consistent with Section 4.1.5.1, corrections have been incorporated into Section 4.1.5.3 related to 
requirements for virologic suppression. 
6. Consistent with Sections 6.4 and 8.6, corrections have been incorporated into Appendix III to indicate 
that ART-naïve participants should be recalled for confirmatory HIV-1 RNA testing if they have an 
HIV-1 RNA level ≥200 copies/mL after about six months on study. 
7. The additional guidance for sequencing of procedures at the Cohort 1 Entry Visit inadvertently 
included the selection and confirmation of formulation; as only one formulation will be available for 
participants in Cohort 1, this procedural sequence has been removed.  
8. Other minor updates and clarifications, including inclusion of the IND number and updates to the 
protocol team roster, have been incorporated for accuracy and clarity. 
 
 
Implementation 
 
The modifications included in this LoA are listed by modification and will be incorporated into the next 
protocol amendment as specified below. Additions to the text are indicated in bold; deletions are 
indicated by strikethrough.  
 
1. Update to regulatory entities that may review study records 
 
a. Section 11.2, Essential and Source Documents and Access to Source Data, fourth paragraph, first 
sentence: 
 
All study records must be accessible for inspection, monitoring, and/or auditing during and after 
the conduct of the study by authorized representatives of the study sponsors and their contracted 
monitors, IMPAACT, Merck & Company, the FDA, site drug regulatory authorities, site 
IRBs/ECs, OHRP, and other US, local, and international applicable regulatory entities. 
 


Letter of Amendment #1 to  
IMPAACT 2014 Version 1.0  
Page 5 of 7 
7 May 2018  
b. Appendix II: Sample Informed Consent Form for Participation in Cohort 1, item 20, and 
Appendix III: Sample Informed Consent Form for Participation in Cohort 2, item 24, bullet 
added to listing of groups that oversee the study: 
 
Groups that oversee the study include:  
• 
Other United States, local, and international regulatory entities 
 
2. Align the target steady-state C24hr to be consistent with that obtained in adults  
 
a. Section 10.1, Pharmacology Overview and Objectives, first paragraph, last sentence  
 
Based on simulations of ten participants (four from the 35 to 45kg group and six from the >45 
kg group) with these geometric mean exposures and C24hr and variability, the AUC criterion (i.e., 
geometric mean steady state AUC0-24hr does not exceed 64.5 μM*hr) and the C24hr criterion (i.e., 
the geometric mean C24hr in participants is greater than 560 nM at least 90% of participants 
achieving at least 78 nM) are achieved with high probability (~90% >99%).  
 
b. Section 10.3.1, PK Guidelines for Cohort 1 to Confirm the Dose for Cohort 2, second bullet defining 
acceptable PK for Cohort 1 participants 
 
• 
Steady state C24hr values for participants in Cohort 1 will be projected from the single dose 
PK profiles. The geometric mean C24hr At least 90% of Cohort 1 participants should exceed 
the proposed lower bound associated with efficacy: 60% of the steady state C24hr 
achieved at the 100 mg QD dose in adults, corresponding to 560 nM have C24hr values that 
exceed the PK target for suppression of wild type virus, currently estimated as 78 nM 
(equivalent to over six times the IC50 for DOR against wild type virus in the presence of 
100% normal human serum). 
 
3. Update blood volume requirements for Cohort 2 Week 1 PK evaluations 
 
a. Section 6.3.2, Table 15. Cohort 2 Week 1 PK Evaluation Sampling Time Points, volume required at 1 hr 
post-dose and 8 hrs post-dose 
 
Time  
Points 
1 hr  
post-dose 
8 hrs post-
dose 
Volume 
 
2.0 mL 
2.5 mL 
2.0 mL 
2.5 mL 
hr(s)=hour(s); mins=minutes 
 
b. Appendix I-B, Schedule of Evaluation for Cohort 2, volume required at Week 1 for intensive PK 
sampling and total maximum blood volume  
 
 
Study Visit 
Weeks on Study 
11 
Pharmacology 
 
Intensive PK sampling1 
21.5 mL 22.5 mL 
Total maximum blood 
volume 
21.5 mL 22.5 mL 
 


Letter of Amendment #1 to  
IMPAACT 2014 Version 1.0  
Page 6 of 7 
7 May 2018  
c. Appendix I-B, Schedule of Evaluation for Cohort 2, update to second bullet of footnote 1 
 
• 
2.0 mL 2.5 mL should be collected at 1 hour post-dose and 8 hours post-dose 
 
d. Appendix III, Sample Informed Consent Form for Participation in Cohort 2, item 10, sixth paragraph 
 
We will draw about 2.0 2.5 – 3.5 mL (less than 1 teaspoon) of blood at six different time points 
during the first day for the PK test and at one time point during the second day of the PK test (a 
total of about 21.5 mL 22.5 mL or less than 5 teaspoons).  We will look at the amount of ARVs 
in your [child’s] blood at each of these times.   
  
4. Add blood collection and testing for CD4 cell count for participants in Cohort 2 at Weeks 64, 80 and 
96  
 
a. Section 6.3.7, Table for Cohort 2 Q16 Week Visits (Weeks 64, 80, and 96) 
 
Laboratory 
Blood 
 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline 
phosphatase, AST, ALT, and albumin) 
• HIV-1 RNA 
• CD4 cell count 
• At Week 96, lipid profile 
 
b. Appendix I-B, Schedule of Evaluation for Cohort 2, volume required at Q16 week visits and total 
maximum blood volume  
 
Study Visit 
Weeks on Study 
Q163 
Laboratory Evaluations 
 
CD4 cell counts 
2 mL  
Total maximum blood 
volume 
15 mL 13 mL 
 
5. Corrections to Section 4.1.5.3, Cohort 2 ART-experienced 
 
a. Section 4.1.5.3, Cohort 2 ART-experienced, Virologic suppression, first sub-bullet: 
 
o One or more HIV RNA PCR result below level of quantification (BLLQ) within 15 months 
6 months prior to enrollment, AND 
 


Letter of Amendment #1 to  
IMPAACT 2014 Version 1.0  
Page 7 of 7 
7 May 2018  
b. Section 4.1.5.3, Cohort 2 ART-experienced, second note added following criterion: 
 
Note:  A single, unconfirmed HIV-1 RNA result greater than or equal to the level of 
quantification but less than 500 copies/mL, between 3 and 15 months, prior to enrollment is 
not exclusionary as long as the other criteria for documentation of virologic suppression are 
met. 
 
6. Correction to Appendix III: Sample Informed Consent Form for Participation in Cohort 2, item 11, 
first paragraph, second and third sentences   
 
If the study ARVs are your [child’s] first anti-HIV medicine, your [child’s] viral load should be very 
low after about six months four months.  If tests show that the viral load is higher than expected after 
six months four months, [you/your child] will have an extra visit. 
 
7. Correction of procedural sequencing in Section 6.2.1, Cohort 1 Entry Visit, second paragraph, 
second bullet  
 
• 
Selection and confirmation of formulation must precede enrollment 
 
8. Other minor updates and clarifications 
 
a. Following finalization of protocol Version 1.0, the United States Food and Drug Administration issued 
the Investigational New Drug (IND) application number under which this study will be conducted. The 
IND number is added to the protocol title page:  
 
IND #137,041 XX,XXXX Held by NIAID/DAIDS 
 
b. Updates to protocol team roster: Justine Beck is added and Jenna Kearly is removed: 
 
Protocol Pharmacists 
Justine Beck, PharmD, BCPS, RPh  
Pharmaceutical Affairs Branch 
 
OCSO/DAIDS/NIAID/NIH/DHHS 
5601 Fishers Lane, 9D39, MSC 9829 
Rockville, MD 20852 
Phone: 301-761-5288 
Email: Justine.beck@nih.gov 
 
Protocol Data Managers 
Jenna Kearly, MPH 
Frontier Science & Technology Research Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226-1056, USA 
Phone: (716) 834-0900 x7249 
Email: kearly.jenna@fstrf.org 
 


IMPAACT 2014 
 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
 
 
A Multisite Study of the  
International Maternal Pediatric Adolescent  
AIDS Clinical Trials Network 
 
 
Sponsored by: 
National Institute of Allergy and Infectious Diseases 
Eunice Kennedy Shriver 
National Institute of Child Health and Human Development 
National Institute of Mental Health 
 
 
Pharmaceutical Support Provided by: 
Merck & Company Inc. 
 
 
DAIDS Study ID #34150 
IND #XX,XXXX Held by NIAID/DAIDS 
 
 
 
Protocol Chair: 
Ann Melvin, MD, MPH  
 
Protocol Vice-Chair: 
Brookie Best, PharmD, MAS 
 
NIAID Medical Officer:  
Ellen Townley, MSN, FNP 
 
NICHD Medical Officer: 
Bill Kapogiannis, MD 
 
Clinical Trials Specialist: 
Patricia Morgan, PA, MSc 
Katie McCarthy, MPH 
 
 
 
Final Version 1.0 
7 September 2017


IMPAACT 2014, FINAL Version 1.0 
Page 2 of 129 
 
7 September 2017 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .............................................................................................. 5 
ABBREVIATIONS AND ACRONYMS ....................................................................................... 6 
PROTOCOL TEAM ROSTER .................................................................................................... 8 
SITE REPRESENTATIVE ROSTER .........................................................................................11 
SCHEMA ..................................................................................................................................14 
1 
INTRODUCTION ...........................................................................................................17 
1.1 
Background ..................................................................................................................................... 17 
1.2 
Clinical Efficacy ............................................................................................................................... 19 
1.3 
Doravirine Clinical Pharmacokinetics in Adults ................................................................................ 27 
1.4 
Rationale for the Study .................................................................................................................... 31 
1.5 
Hypotheses ..................................................................................................................................... 34 
2 
OBJECTIVES ................................................................................................................34 
2.1 
Primary Objectives for Cohort 1 ...................................................................................................... 34 
2.2 
Primary Objective for Cohort 2 ........................................................................................................ 35 
2.3 
Secondary Objectives for Cohort 2 .................................................................................................. 35 
2.4 
Other Objectives for Cohort 2 .......................................................................................................... 35 
3 
STUDY DESIGN ...........................................................................................................35 
3.1 
Cohort 1 ........................................................................................................................................... 36 
3.2 
Cohort 2 ........................................................................................................................................... 36 
4 
STUDY POPULATION ..................................................................................................37 
4.1 
Inclusion Criteria .............................................................................................................................. 37 
4.2 
Exclusion Criteria............................................................................................................................. 40 
4.3 
Co-Enrollment Considerations ......................................................................................................... 41 
4.4 
Recruitment, Screening, and Enrollment Process ........................................................................... 41 
4.5 
Participant Retention ....................................................................................................................... 43 
4.6 
Participant Withdrawal or Termination from the Study .................................................................... 43 
4.7 
Genotyping ...................................................................................................................................... 44 
5 
STUDY DRUG CONSIDERATIONS ..............................................................................44 
5.1 
Study Drug Regimens ..................................................................................................................... 44 
5.2 
Study Drug Formulations ................................................................................................................. 44 
5.3 
Study Drug Administration ............................................................................................................... 45 
5.4 
Study Drug Supply........................................................................................................................... 45 
5.5 
Study Drug Accountability ............................................................................................................... 45 
5.6 
Final Disposition of Study Drug ....................................................................................................... 45 
5.7 
Concomitant Medications ................................................................................................................ 45 
5.8 
Prohibited Medications .................................................................................................................... 46 
5.9 
Precautionary Medications .............................................................................................................. 46 
6 
STUDY VISITS AND PROCEDURES ...........................................................................47 
6.1 
Cohort 1 and Cohort 2 Screening Visit ............................................................................................ 47 
6.2 
Cohort 1 Visits and Procedures ....................................................................................................... 49 
6.3 
Cohort 2 Visits and Procedures ....................................................................................................... 51 
6.4 
Cohort 2 Confirmation of Virologic Failure Visit ............................................................................... 59 
6.5 
Cohort 2 Early Discontinuation Visit ................................................................................................ 61 
6.6 
Cohort 2 Post-Study Contacts ......................................................................................................... 62 


IMPAACT 2014, FINAL Version 1.0 
Page 3 of 129 
 
7 September 2017 
6.7 
Medical and Medications History ..................................................................................................... 62 
6.8 
Physical Examinations ..................................................................................................................... 64 
6.9 
Cohort 1 and Cohort 2 Study Drug Palatability and Acceptability .................................................... 65 
6.10 
Cohort 2 Study Drug Adherence Assessment and Counseling ....................................................... 65 
6.11 
Additional Considerations for Laboratory Procedures ..................................................................... 65 
7 
SAFETY MONITORING, ASSESSMENT AND REPORTING .......................................67 
7.1 
Safety-Related Roles and Responsibilities ...................................................................................... 67 
7.2 
Safety-Related Data Collection ....................................................................................................... 68 
7.3 
Expedited Adverse Event (EAE) Reporting ..................................................................................... 69 
8 
PARTICIPANT MANAGEMENT ....................................................................................70 
8.1 
Management of Adverse Events ..................................................................................................... 70 
8.2 
General Management (Cohort 2) ..................................................................................................... 71 
8.3 
Management of Liver Toxicities (Cohort 2) ...................................................................................... 73 
8.4 
Management of Decline in Renal Function (Cohort 2) ..................................................................... 73 
8.5 
Non-Study Drug Antiretroviral Drug-Related Toxicity ...................................................................... 73 
8.6 
Monitoring and Management of Virologic Failure (Cohort 2) ........................................................... 74 
8.7 
Criteria for Premature Discontinuation of Study Drug ...................................................................... 75 
8.8 
Contraception, Pregnancy Testing, and Management of Participants Who Become Pregnant on 
Study ............................................................................................................................................... 75 
9 
STATISTICAL CONSIDERATIONS ..............................................................................76 
9.1 
General Design Issues .................................................................................................................... 76 
9.2 
Dose Evaluation Algorithm .............................................................................................................. 77 
9.3 
Endpoints and Outcome Measures ................................................................................................. 78 
9.4 
Randomization and Stratification ..................................................................................................... 80 
9.5 
Sample Size and Accrual ................................................................................................................ 80 
9.6 
Monitoring ........................................................................................................................................ 80 
9.7 
Analyses .......................................................................................................................................... 83 
10 
PHARMACOLOGY PLAN .............................................................................................86 
10.1 
Pharmacology Overview and Objectives ......................................................................................... 86 
10.2 
Methods and Timing for Collections, Processing, Handling, and Storage ....................................... 87 
10.3 
PK Guidelines for Dose Confirmation and Timing of Interim Analyses ............................................ 87 
10.4 
Laboratory Performing the Assays .................................................................................................. 88 
10.5 
Primary and Secondary Data Analysis Plan .................................................................................... 88 
10.6 
Anticipated Outcomes ..................................................................................................................... 88 
11 
DATA HANDLING AND RECORD KEEPING ...............................................................89 
11.1 
Data Management Responsibilities ................................................................................................. 89 
11.2 
Essential and Source Documents and Access to Source Data ....................................................... 89 
11.3 
Quality Control and Quality Assurance ............................................................................................ 90 
12 
CLINICAL SITE MONITORING .....................................................................................90 
13 
HUMAN SUBJECTS PROTECTIONS...........................................................................90 
13.1 
Institutional Review Board/Ethics Committee Review and Approval ............................................... 90 
13.2 
Vulnerable Participants .................................................................................................................... 90 
13.3 
Informed Consent ............................................................................................................................ 91 
13.4 
Potential Benefits............................................................................................................................. 93 
13.5 
Potential Risks ................................................................................................................................. 93 
13.6 
Reimbursement/Compensation ....................................................................................................... 94 
13.7 
Privacy and Confidentiality .............................................................................................................. 94 
13.8 
Communicable Disease Reporting .................................................................................................. 94 
13.9 
Management of Incidental Findings ................................................................................................. 95 
13.10 
Management of New Information Pertinent to Study Participation .................................................. 95 
13.11 
Post-Study Access to Study Drug ................................................................................................... 95 


IMPAACT 2014, FINAL Version 1.0 
Page 4 of 129 
 
7 September 2017 
14 
ADMINISTRATIVE PROCEDURES ..............................................................................95 
14.1 
Regulatory Oversight ....................................................................................................................... 95 
14.2 
Protocol Registration ....................................................................................................................... 96 
14.3 
Study Implementation ...................................................................................................................... 96 
14.4 
Protocol Deviation Reporting ........................................................................................................... 97 
14.5 
Critical Event Reporting ................................................................................................................... 97 
14.6 
ClinicalTrials.gov ............................................................................................................................. 97 
15 
PUBLICATIONS ...........................................................................................................97 
16 
REFERENCES ..............................................................................................................98 
Appendix I-A: Schedule of Evaluations for Cohort 1 .......................................................... 100 
Appendix I-B: Schedule of Evaluations for Cohort 2 .......................................................... 101 
Appendix II: Sample Informed Consent Form for Participation in Cohort 1 ..................... 103 
Appendix III: Sample Informed Consent Form for Participation in Cohort 2 .................... 112 
Appendix IV: Sample Informed Consent Form for Specimen Storage and Future Use ... 126 
 
LIST OF FIGURES 
 
Figure 1.  IMPAACT 2014 Overview of Study Design .................................................................................................. 16 
Figure 2.  Mean Change from Baseline in Plasma HIV RNA (log10 copies/mL)  after Once-daily Administration of 
Doravirine (25 or 200 mg) or Placebo for 7 days ....................................................................................... 20 
Figure 3.  Mean Plasma Concentration Profiles of DOR Following  Administration of Multiple Oral Doses Once Daily 
to Health Fasted Male Participants (N=6-8) ............................................................................................... 28 
 
LIST OF TABLES 
 
Table 1.  Selected Adult Studies Using DOR or DOR/3TC/TDF .................................................................................. 19 
Table 2.  PN007 Parts 1 and 2 [15] .............................................................................................................................. 21 
Table 3.  Clinical Adverse Events (%) DOR + TDF/FTC  versus EFV + TDF/FTC at 96 Weeks [17]........................... 23 
Table 4.  Laboratory Abnormalities ≥Grade 2 (%)  DOR + TDF/FTC versus EFV + TDF/FTC at 48 Weeks [15] ........ 24 
Table 5.  Proportion of Patients with Central Nervous System Adverse Events (CNS Events)  by Week 8 and by 
Week 24 Part I/II Combined All Patients as Treated .................................................................................... 24 
Table 6.  PN018 Week 48 Summary of Clinical Adverse Events [16] .......................................................................... 25 
Table 7.  PN021: Analysis of Participants with Neuropsychiatric Adverse Events by Week 48 [17] ............................ 26 
Table 8.  PN021: Week 48 Summary of Clinical Adverse Events [18] ......................................................................... 26 
Table 9.  Single Dose DOR PK Parameters with Dose Range from 6 mg to 450 mg .................................................. 27 
Table 10.  Pharmacokinetics of Doravirine, Lamivudine, Tenofovir Disoproxil Fumarate  Administered as 
DOR/3TC/TDF or as Individual Components ........................................................................................... 29 
Table 11.  Pharmacokinetics of DOR Following Administration of  Coated Oral Granules Compared to Administration 
of the Adult DOR Tablet ............................................................................................................................. 30 
Table 12.  Pharmacokinetics of 3TC Following Administration of  Coated Oral Granules Compared to Administration 
of the Adult 3TC Tablet ............................................................................................................................ 30 
Table 13.  Pharmacokinetics of Tenofovir Following Administration of  TDF Coated Oral Granules Compared to 
Administration of the Adult TDF Tablet ..................................................................................................... 31 
Table 14.  Cohort 1 Intensive PK Evaluation Sampling Time Points ............................................................................ 50 
Table 15.  Cohort 2 Week 1 PK Evaluation Sampling Time Points .............................................................................. 54 
Table 16.  Cohort 2 Sparse PK Evaluation Sampling Time Points ............................................................................... 59 
Table 17.  Documentation Requirements for Medical and Medication Histories .......................................................... 63 
Table 18.  General Guidelines for Management of Participants in Cohort 2 ................................................................ 72 
Table 19.  Percent of Participants Experiencing ≥Grade 3 Adverse Events (or ≥Grade 3 Adverse Events Attributed to 
the Study Medication) with Exact 95% Confidence Intervals ..................................................................... 84 


IMPAACT 2014, FINAL Version 1.0 
Page 5 of 129 
 
7 September 2017 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
DAIDS Study ID #34150 
 
 
Version 1.0 
PROTOCOL SIGNATURE PAGE 
 
 
I will conduct this study in accordance with the provisions of this protocol and all applicable protocol-
related documents. I agree to conduct this study in compliance with United States (US) Health and 
Human Service regulations (45 CFR 46); applicable US Food and Drug Administration regulations; 
standards of the International Conference on Harmonization Guideline for Good Clinical Practice (E6); 
Institutional Review Board/Ethics Committee determinations; all applicable in-country, state, and local 
laws and regulations; and other applicable requirements (e.g., US National Institutes of Health, Division 
of AIDS, and institutional policies). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator of Record 
  
 
Date 
 
 
 
 
 
 
 
 
 
 
 
Name of Investigator of Record  
 
(printed) 
 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 6 of 129 
 
7 September 2017 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
ABBREVIATIONS AND ACRONYMS 
 
3TC 
lamivudine 
ABC 
abacavir 
AE 
adverse event  
AIDS 
acquired immunodeficiency 
syndrome 
ALT 
alanine transaminase 
ARV 
antiretroviral 
ART 
antiretroviral therapy 
ARV 
antiretroviral 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BLLQ 
below the level of quantification  
C24hr 
plasma drug concentration, 24 
hours post dose 
Cmax 
maximum serum concentration 
cART 
combination antiretroviral therapy 
CBC 
complete blood count 
CFR 
(US) Code of Federal Regulations 
CI 
confidence interval 
CLIA 
Clinical Laboratory Improvement 
Amendments 
CMC 
Clinical Management Committee 
CNS 
central nervous system 
CRF  
case report form 
CRPMC 
Clinical Research Products 
Management Center 
CV 
coefficient of variation 
DAIDS 
Division of AIDS  
DAIDS PRO 
DAIDS Protocol Registration 
Office 
DAERS 
DAIDS Adverse Experience 
Reporting System 
DMC 
Data Management Center 
DNA 
deoxyribonucleic acid 
DOR 
doravirine (MK-1439) 
DRV 
darunavir 
DTG 
dolutegravir 
EAE 
expedited adverse event 
EC 
Ethics Committee 
eCRF 
electronic case report form 
EFV 
efavirenz 
EIA 
enzyme immunoassay 
FDA 
(US) Food and Drug 
Administration 
FDAAA 
Food and Drug Administration 
Amendments Act of 2007 
FDC 
fixed-dose combination 
FTC 
Emtricitabine  
FSTRF 
Frontier Science and Technology 
Research Foundation 
GCLP 
Good Clinical Laboratory Practice 
GFR 
glomerular filtration rate 
GM 
geometric least-square mean 
GMR 
geometric mean ratio 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HPMC 
hydroxypropylmethyl cellulose 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
IMPAACT 
International Maternal Pediatric 
Adolescent AIDS Clinical Trials 
Network 
IND 
Investigational New Drug 
INR 
international normalized ratio 
InSTI 
integrase strand transfer inhibitor 
IoR 
Investigator of Record  
IRB  
Institutional Review Board 
IRIS 
immune reconstitution 
inflammatory syndrome 
LDL 
low-density lipoprotein 
LDMS 
Laboratory Data Management 
System 
LPC 
Laboratory Processing Chart 
MK-1439 
doravirine 
MK-1439A 
doravirine/lamivudine/tenofovir 
disoproxil fumarate  
MOP 
Manual of Procedures 
MSDF 
“Missing, Switch or 
Discontinuation = Failure” 
analysis 
NIAID 
(US) National Institute of Allergy 
and Infectious Diseases 
NICHD 
(US) National Institute of Child 
Health and Human Development 
NIH 
(US) National Institutes of Health 


IMPAACT 2014, FINAL Version 1.0 
Page 7 of 129 
 
7 September 2017 
NIMH 
(US) National Institute of Mental 
Health 
NRTI 
nucleoside reverse transcriptase 
inhibitor 
NNRTI 
non-nucleoside reverse 
transcriptase inhibitor 
NVP 
nevirapine 
OHRP 
(US) Office for Human Research 
Protections 
PCR 
polymerase chain reaction 
PI 
protease inhibitor 
PID 
participant identification number 
PK 
pharmacokinetics 
PoR 
Pharmacist of Record 
PRO 
(DAIDS) Protocol Registration 
Office 
QD 
per day 
RAL  
raltegravir 
RNA 
ribonucleic acid 
RPV 
rilpivirine 
RSC 
(DAIDS) Regulatory Support 
Center 
SAE 
Serious Adverse Event 
SDMC 
Statistical and Data Management 
Center 
SES 
Subject Enrollment System 
SID 
study identification number 
SMC 
Study Monitoring Committee 
SMR 
sexual maturity rating  
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious 
Adverse Reaction 
TDF 
tenofovir disoproxil fumarate 
TFV 
tenofovir 
Tmax 
time to reach maximum concentration 
ULN 
upper limit of normal 
UN 
United Nations 
US 
United States 
VQA 
Virology Quality Assurance 
WHO 
World Health Organization
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 8 of 129 
 
7 September 2017 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
PROTOCOL TEAM ROSTER 
 
Protocol Chair 
Ann Melvin, MD, MPH 
University of Washington 
Seattle Children’s Research Institute 
4800 Sandpoint Way NE 
Seattle, WA 98105, USA 
Phone: (206) 987-2535 
Email: ann.melvin@seattlechildrens.org  
 
Protocol Vice-Chair and Protocol 
Pharmacologist 
Brookie Best, PharmD, MAS 
University of California San Diego 
9500 Gilman Drive, MC 0657 
La Jolla, CA 92093-0657, USA 
Phone: (858) 822-5550 
Email: brookie@ucsd.edu 
 
Clinical Trials Specialists 
Patricia Morgan, PA, MSc  
IMPAACT Operations Center, FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040 x11705 
Email: pmorgan@fhi360.org 
 
Katie McCarthy, MPH  
IMPAACT Operations Center, FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040 x11439 
Email: kmccarthy@fhi360.org  
 
NIAID Medical Officer 
Ellen Townley, MSN, FNP 
Maternal Adolescent Pediatric Branch,  
DAIDS/NIAID/NIH 
5601 Fishers Lane, Rm 8B39 
Rockville, MD 20892 
Phone: 240-292-4784 
Email: townleyem@niaid.nih.gov  
NICHD Medical Officer 
Bill Kapogiannis, MD 
Maternal and Pediatric Infectious Diseases 
Branch 
Eunice Kennedy Shriver National Institute of 
Child Health and Human Development 
National Institutes of Health  
Department of Health and Human Services  
6710B Rockledge Drive, BG 6710B, Rm 2150  
Bethesda, MD 20892-7510, USA 
Phone: (301) 402-0698  
Email: kapogiannisb@mail.nih.gov  
 
Protocol Pharmacist 
Thucuma Sise, PharmD, BCPS 
NIH, NIAID, DAIDS, PAB 
5601 Fishers Lane, 9A27 
Rockville, MD 20852, USA 
Phone: (240) 292-4848 
Email: sisetk@niaid.nih.gov  
 
Protocol Statisticians 
Carmelita Alvero, MS 
Center for Biostatistics in AIDS Research, 
Harvard T.H. Chan School of Public Health 
1371 Beacon Street, Suite #203 
Brookline, MA 02446, USA 
Phone: (617) 632-2000 x4017 
Email: calvero@sdac.harvard.edu 
 
Mona Farhad, MS 
Center for Biostatistics in AIDS Research, 
Harvard T.H. Chan School of Public Health 
1371 Beacon Street, Suite #203  
Brookline, MA 02446, USA 
Phone: (617) 632-2000 x4032 
Email: mfarhad@sdac.harvard.edu  
 


IMPAACT 2014, FINAL Version 1.0 
Page 9 of 129 
 
7 September 2017 
Protocol Virologist 
Nicole Tobin, MD  
David Geffen School of Medicine 
University of California, Los Angeles 
10833 Le Conte Ave. 
22-442 MDCC 
Los Angeles, CA 90095, USA 
Phone: (310) 825-5235 
Email:  NTobin@mednet.ucla.edu 
 
Pharmaceutical Representatives 
Hedy Teppler, MD 
351 N. Sumneytown Pike 
North Wales, PA 19454, USA 
Phone: (267) 305-7403 
Email: hedy_teppler@merck.com  
 
Andrea Kehler, BA 
351 N. Sumneytown Pike 
North Wales, PA 19454, USA 
Phone: (267) 305-6794 
Email: andrea_kehler@merck.com 
 
Larissa Wenning, PhD 
351 N. Sumneytown Pike 
North Wales, PA 19454, USA 
Phone: (267) 305-4345 
Email: larissa_wenning@merck.com  
 
Kelly Yee, PhD 
770 Sumneytown Pike 
West Point, PA 19486, USA 
Phone: (215) 652-3234 
Email: ka_yee@merck.com  
 
Xia Xu, PhD 
351 N. Sumneytown Pike 
Mail Stop: UG 1C-36 
North Wales, PA 19454, USA 
Phone: (267) 305-5361 
Email: xia_xu@merck.com 
 
Sushma Kumar, PhD, PMP 
126 E. Lincoln Ave. 
Rahway, NJ 07065, USA 
Phone: (732) 594-7899 
Email: sushma.kumar@merck.com 
 
Protocol Data Managers 
Jenna Kearly, MPH 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226-1056, USA 
Phone: (716) 834-0900 x7249 
Email: kearly.jenna@fstrf.org 
 
Linda Marillo, BA 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226-1056, USA 
Phone: (716) 834-0900 x7257 
Email: marillo@fstrf.org  
 
Chelsea Krotje, MPH 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226-1056, USA 
Phone: (716) 834-0900 x7368 
Email: krotje@fstrf.org  
 
Protocol Laboratory Data Managers 
Rebecca LeBlanc, BS 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226, USA 
Phone: (716) 834-0900 x7254 
Email: leblanc@fstrf.org  
 
Andee Fox, MPH 
Frontier Science & Technology Research 
Foundation (FSTRF) 
4033 Maple Road 
Amherst, NY 14226-1056, USA 
Phone: (716) 834-0900 x7276 
Email: fox@fsrtf.org  
 


IMPAACT 2014, FINAL Version 1.0 
Page 10 of 129 
 
7 September 2017 
Laboratory Center Representative 
William Murtaugh, MPH 
IMPAACT Laboratory Center 
University of California, Los Angeles 
675 Charles E. Young Drive South 
MRL 4-629 
Los Angeles, CA 90095, USA 
Phone: (310) 825-6591 
Email: wmurtaugh@impaactlabcenter.org 
 
Protocol Laboratory Technologist 
Vandana Kulkarni, MSc 
BJ Medical College and Sassoon General Hosp. 
First Floor, Pathology Museum 
Jai Prakash Narayan Road 
Pune 411001, India 
Phone: 91 20 26052419 
Email: vandana@jhumitpune.com  
 
Westat Clinical Research Associate  
Scott Watson, RN 
Westat, Inc. 
1441 W. Montgomery Ave. 
Rockville, MD 20850, USA 
Phone: (415) 494-5575 
Email: scottwatson@westat.com  
 
Community Program Manager 
Jontraye Davis, MHA 
IMPAACT Operations Center, FHI 360 
359 Blackwell Street, Suite 200 
Durham, NC 27701, USA 
Phone: (919) 544-7040 x11715 
Email: jdavis@fhi360.org 


IMPAACT 2014, FINAL Version 1.0 
Page 11 of 129 
7 September 2017 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
SITE REPRESENTATIVE ROSTER 
 
Boston Medical Center Pediatric HIV Program 
NICHD, CRS 5011 
Ellen Cooper, MD 
Boston Medical Center, BioSquare III 
670 Albany Street, Room 623 
Boston, MA 02118, USA 
Phone: (617) 414-5588 
Email: ercooper@bu.edu  
 
Debra A. McLaud, RN 
Boston Medical Center, BioSquare III 
670 Albany Street, Room 614 
Boston, MA 02118, USA 
Phone: (617) 414-5813 
Email: demclaud@bmc.org  
 
Lisa Tucker, BA 
BMC, BioSquare III 
670 Albany Street, Room 616 
Boston, MA 02118, USA 
Phone: (617) 414-5885 
Email: lisaf.tucker@bmc.org  
 
University of Washington Children’s Hospital 
Seattle NICHD, CRS 5017 
Ann Melvin, MD, MPH 
4800 Sandpoint Way NE 
Seattle, WA 98105, USA 
Phone: (206) 987-2535 
Email: ann.melvin@seattlechildrens.org  
 
Amanda Robson 
1900 Ninth Avenue 
Seattle, WA 98101, USA 
Phone: (206) 884-1535 
Email: amanda.robson@seattlechildrens.org  
 
University of Florida Jacksonville NICHD, 
CRS 5051 
Mobeen Rathore, MD, CPE 
653-1 West 8th Street, LRC 3rd Floor 
Jacksonville, Florida 32209, USA 
Phone: (904) 798-4179 
Email: mobeen.rathore@jax.ufl.edu 
 
Saniyyah Mahmoudi, MSN, ARNP, AGPCNP 
653-1 West 8th Street, LRC 3rd Floor 
Jacksonville, Florida 32209, USA 
Phone: (904) 244-5331 
Email: saniyyah.mahmoudi@jax.ufl.edu 
 
University of Colorado Denver NICHD, 
CRS 5052 
Elizabeth (Betsy) McFarland, MD 
University of Colorado School of Medicine 
Pediatric Infectious Diseases 
Children's Hospital Colorado 
13123 East 16th Avenue, B055 
Aurora, CO 80045, USA 
Phone: (303) 724-3447 
Email: betsy.mcfarland@ucdenver.edu  
 
Emily Barr, CPNP, CNM, MSN  
Department of Pediatric Infectious Diseases 
Children's Hospital Colorado 
13123 East 16th Avenue, Box 055 
Aurora, CO 80045, USA 
Phone: (720) 777-8233 
Email: emily.barr@childrenscolorado.org  
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 12 of 129 
7 September 2017 
Johns Hopkins University Baltimore NICHD, 
CRS 5092 
Allison Agwu, MD, ScM, FAAP, FIDSA 
Division of Infectious Diseases 
Johns Hopkins University School of Medicine 
200 North Wolfe Street, Rm 3145 
Baltimore, MD 21287, USA 
Phone: (410) 614-3917 
Email: ageorg10@jhmi.edu  
 
Aleisha Collinson-Streng, RN, ACRN 
200 North Wolfe Street, Suite 3096 
Baltimore, MD 21287, USA 
Phone: (443) 801-7301 
Email: acolli14@jhmi.edu  
 
Thuy Anderson, RN, BSN 
200 North Wolfe Street, Rm 3146 
Baltimore, MD 21287, USA 
Phone: (443) 287-8942 
Email: tander34@jhmi.edu 
 
Siriraj Hospital, Mahidol University NICHD, 
CRS 5115 
Kulkanya Chokephaibulkit, MD 
2 Wanglang Road 
Bangkok-noi, Bangkok 10700, Thailand 
Phone: +66-2-418-0545 
Email: kulkanya.cho@mahidol.ac.th 
 
Nirun Vanprapar, MD 
2 Wanglang Road 
Bangkok-noi, Bangkok 10700, Thailand 
Phone: +662-418-0545 
Email: nirun.van@mahidol.ac.th  
 
Chiangrai Prachanukroh Hospital NICHD, 
CRS 5116 
Pradthana Ounchanum, MD 
1039 Sathanpayaban Road 
Chiang Rai, 57000, Thailand  
Phone: +66 (0) 53 520 359 
Email: doctorbaiplu@windowslive.com  
 
Timothy Cressey, PhD 
187/10 Changklan Road 
Changklan, Chiang Mai, 50100, Thailand 
Phone: +66 (0) 5381 9125-9  
Email: tim.cressey@phpt.org  
 
Pra-ornsuda Sukrakanchana, BSN  
187/10 Changklan Road 
Changklan, Chiang Mai, 50100, Thailand 
Phone: +66 (0) 5381 9125-9  
Email: pra-ornsuda.sukrakanchana@phpt.org   
 
St. Jude Children’s Research Hospital, 
CRS 6501 
Patricia Flynn, MD 
262 Danny Thomas Place, MS 282 
Memphis, TN 38105, USA 
Phone: (901) 595-4662 
Email: pat.flynn@stjude.org  
 
Sandra Jones, MSN, CPNP 
262 Danny Thomas Place, MS 600 
Memphis, TN 38105, USA 
Phone: (901) 595-5059 
Email: sandra.jones2@stjude.org  
 
University of Puerto Rico Pediatric HIV/AIDS 
Research Program, CRS 6601 
Irma L. Febo, MD 
PO Box 365067 
San Juan, Puerto Rico 00936-5067, USA 
Phone: (787) 759-9595 
Email: irma.febo2@upr.edu  
 
Ruth Santos RN, MPH 
PO Box 365067 
San Juan, Puerto Rico 00936-5067, USA 
Phone: (787) 759-9595 
Email: ruth.santos@upr.edu 
 


IMPAACT 2014, FINAL Version 1.0 
Page 13 of 129 
7 September 2017 
Shandukani Research, CRS 8051 
Lee Fairlie, MD 
SMACHC 2nd Floor 
Hillbrow Health Precinct 
Corner Esselen St. and Klein St. 
Hillbrow, Johannesburg, Gauteng 2001, 
South Africa 
Phone: +27-11-3585317 
Email: lfairlie@wrhi.ac.za 
 
Hermien Gous, Bpharm, PharmD 
Wits RHI Shandukani Research Centre 
Shandukani Building, 2nd Floor 
Hillbrow Health Precinct 
22 Esselen Street, Hillbrow 
Johannesburg, 2001, South Africa 
Phone: +27 11 358-5502 
Email: hgous@wrhi.ac.za  
 
Soweto IMPAACT, CRS 8052 
Sylvia Dittmer, MBBCH 
Perinatal HIV Research Unit 
Chris Hani Baragwanath Academic Hospital 
PO Box 114, Diepkloof, Soweto, Johannesburg, 
South Africa 
Phone: +27 11 989 9769 / 9869 
Email: dittmers@phru.co.za  
 
Nasreen Abrahams, MBA, BTech 
Biotechnology 
Perinatal HIV Research Unit 
Chris Hani Baragwanath Academic Hospital 
PO Box 114, Diepkloof, Soweto, Johannesburg, 
South Africa 
Phone: +27 11 989 9742 
Email: abrahamsn@phru.co.za  
 
Chiang Mai University HIV Treatment, 
CRS 31784 
Linda Aurpibul, MD, MPH 
Research Institute for Health Sciences (RIHES), 
Chiang Mai University 
110 Intavaroros Road, Muang, 
Chiang Mai, 50200, Thailand 
Phone: +66 5393 6148 x445 
Email: lindaa@rihes.org 
 
Chintana Khamrong, MSc 
Research Institute for Health Sciences (RIHES), 
Chiang Mai University 
110 Intavaroros Road, Muang, 
Chiang Mai, 50200, Thailand 
Phone: +66 5393 6148 x446 
Email: chintanak@rihes.org  
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 14 of 129 
7 September 2017 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate 
(MK-1439A) in HIV-1-infected Children and Adolescents 
 
SCHEMA 
 
Purpose: 
To evaluate the pharmacokinetics, safety, and tolerability of doravirine (DOR) 
and of doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) in 
HIV-1-infected children and adolescents 
 
Design: 
Phase I/II, multi-site, open-label, non-comparative pharmacokinetic (PK) and 
safety study 
 
Study Population: 
HIV-1-infected children and adolescents, from 12 years to less than 18 years of 
age who weigh at least 35 kg.  Cohort 1 and 2 will enroll sequentially: 
 
Cohort 1: 
Virologically suppressed on a combination of dolutegravir (DTG) or 
raltegravir (RAL) plus two nucleoside reverse transcriptase inhibitors 
(NRTIs) 
 
Cohort 2: 
Antiretroviral treatment naïve or virologically suppressed  
 
Sample Size: 
Cohort 1: 
Up to 20 participants to achieve at least 12 evaluable participants  
 
Cohort 2: 
Up to 45 participants to achieve at least 40 evaluable participants 
 
Study Drugs:   
Doravirine (DOR also referred to as MK-1439) – 100 mg oral tablet; and 
doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF also 
referred to as MK-1439A) – 100 mg/300 mg/300 mg oral tablet or, as available, 
oral granules 
 
Cohort 1: 
A single dose of DOR (100 mg) added to current regimen of DTG or 
RAL plus two NRTIs 
 
Cohort 2: 
Once daily DOR/3TC/TDF (100 mg/300 mg/300 mg) 
 
Study Duration: 
Approximately four years total from the date the first participant is enrolled.  
Accrual into Cohort 1 is expected to require approximately three to six months 
and participants in this cohort will be followed for two weeks.  It is expected that 
Cohort 2 will open three months after Cohort 1 is completed (following review of 
data from Cohort 1).  Accrual into Cohort 2 is expected to require approximately 
six to twelve months and participants in this cohort will be followed for 96 
weeks.   
 


IMPAACT 2014, FINAL Version 1.0 
Page 15 of 129 
7 September 2017 
Primary Objectives  
 
The primary objectives for Cohort 1 are to: 
• 
Evaluate the pharmacokinetics of a single-dose of DOR in HIV-1-infected children and adolescents, 
when added to a stable antiretroviral therapy (ART) regimen comprised of an integrase strand transfer 
inhibitor (InSTI) plus two NRTIs, using intensive PK sampling at Entry for identification of 
minimum weight threshold for doravirine 100 mg dose. 
• 
Evaluate the 2-week safety and tolerability of a single-dose of DOR in HIV-1-infected children and 
adolescents, when added to a stable ART regimen comprised of an InSTI plus two NRTIs.  
  
The primary objective for Cohort 2 is to: 
• 
Evaluate the 24-week safety and tolerability of DOR/3TC/TDF in HIV-1-infected children and 
adolescents. 
 
Secondary Objectives  
 
The secondary objectives of Cohort 2 are to: 
• 
Evaluate the pharmacokinetics of DOR, 3TC, and tenofovir in HIV-1-infected children and 
adolescents receiving DOR/3TC/TDF, using intensive (tenofovir and 3TC) and semi-intensive (DOR) 
PK sampling at Week 1.  
• 
Evaluate the 24-, 48-, and 96-week virologic efficacy of DOR/3TC/TDF in HIV-1-infected children 
and adolescents. 
• 
Evaluate the 24-, 48-, and 96-week immunologic response (CD4 cell count and percentage change 
from baseline) to DOR/3TC/TDF in HIV-1-infected children and adolescents.  
• 
Evaluate the 48- and 96-week safety and tolerability of DOR/3TC/TDF in HIV-1-infected children 
and adolescents.   
 
Other Objectives  
 
The other objectives of Cohort 2 are to:  
• 
Evaluate the pharmacokinetics of DOR, 3TC, and tenofovir in HIV-1-infected children and 
adolescents receiving DOR/3TC/TDF, using sparse PK sampling through Week 48. 
• 
Assess changes in HIV-1 genotype and phenotype to DOR and other components of the regimen in 
HIV-1-infected children and adolescents experiencing virologic failure. 
• 
Evaluate acceptability, palatability, and adherence to DOR/3TC/TDF in HIV-1-infected children and 
adolescents through Week 96. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 16 of 129 
7 September 2017 
Figure 1.  IMPAACT 2014 Overview of Study Design  
 
Cohort 1
Enroll: Up to 20 participants, ages 12 to <18 years old, to achieve 12 evaluable 
(with a minimum of 4 participants between 35 to ≤45 kg)
Population: Participants ≥35 kg who are virologically suppressed on 
one InSTI (DTG or RAL) + two NRTIs
Treatment Regimen: Single dose of DOR (100 mg)
Primary Evaluation: PK and safety 
Follow-up: 2 weeks
Guidelines for evaluating the dose:
Safety: Dose is safe and well tolerated
PK: AUC and C24hr are met
Safety and PK 
guidelines not met for 
any weight
There is more 
variability than 
expected to 
confidently determine 
achievement 
of PK targets
Enroll additional 
participants to further 
evaluate PK 
and safety
Safety and PK 
guidelines 
met for all weights 
Participants ≥35 kg 
are approved to 
open for Cohort 2
Convene an SMC review
Cohort 2
Enroll: Opens for up to 45 participants, ages 12 to <18 yeaers old, to achieve 40 evaluable 
with approved weight in Cohort 1 (minimum of 5 participants 35 to ≤45 kg weight group, if 
this weight group is approved)
Population: Participants ≥35 kg (or the weight determined in Cohort 1 as meeting PK and
safety targets) who are ARV-naïve and drug susceptible OR virologically suppressed
Treatment Regimen: Once daily DOR/3TC/TDF
Primary Safety Evaluation: 24 weeks
Follow-up: 96 weeks
PK guidelines not met
for all participants 
≥35 kg
CMC may evaluate all 
PK and safety data 
and/or consider 
enrolling additional 
participants to 
determine the weight 
threshold for which PK 
targets are met. If safety 
targets are also met, 
participants ≥ weight 
threshold are approved 
to enroll for Cohort 2.
Safety and PK 
guidelines met for a 
minimum of 
12 participants 
including a minimum 
of 4 in the 35 to ≤45 
kg weight group
Participants ≥35 kg 
are approved to 
open for Cohort 2


IMPAACT 2014, FINAL Version 1.0 
Page 17 of 129 
7 September 2017 
1 
INTRODUCTION 
 
1.1 
Background 
 
Human immunodeficiency virus (HIV) infection, which causes acquired immunodeficiency 
syndrome (AIDS) and for many years was associated with substantial morbidity and mortality, 
has now become a chronic disease that can be controlled through life-long combination 
antiretroviral (ARV) therapy (cART) (1-4).  Currently, there are more than 30 individual drugs 
and fixed-dose combinations available for the treatment of HIV-1 infection.  These agents belong 
to five distinct mechanistic classes known as reverse transcriptase inhibitors [nucleos(t)ide 
reverse transcriptase inhibitors (N(t)RTIs) and non-nucleoside reverse transcriptase inhibitors 
(NNRTIs)], protease inhibitors (PIs), fusion inhibitors, entry inhibitors (CCR5 co–receptor 
antagonists), and integrase strand transfer inhibitors (InSTI).  Successful combinations of 
antiretroviral medications generally utilize three agents from at least two different mechanistic 
classes.  The goal of cART is to suppress HIV to undetectable levels so that immune function is 
preserved or restored.  Yet, while cART can delay disease progression and death, as well as 
reduce the risk of HIV transmission, it does not cure the infection.  As a result, lifelong treatment 
must be maintained, which may lead to therapy fatigue and to noncompliance if the treatment 
regimen is difficult to adhere to (e.g., pill burden, frequency of treatment) and associated with 
intolerable side-effects (5-7).  This can potentially lead to treatment failures with possible 
development of resistant virus.  Additionally, there is currently still significant concern regarding 
toxicities of some widely-used antiretroviral agents, including neuropsychiatric toxicities 
associated with efavirenz (EFV, an NNRTI), gastrointestinal toxicities such as diarrhea associated 
with multiple PIs, and serum lipid abnormalities associated with multiple mechanistic classes. 
Thus, potent treatment regimens that have an excellent safety and tolerability profile and are 
convenient are still highly desirable. 
 
For initiation of combination antiretroviral therapy for HIV infection, currently available NNRTIs 
have constituted an important option for use as anchor agents, along with two NRTIs; however, 
each has limitations, and at present are on the preferred list for first line therapy in World Health 
Organization (WHO) but not U.S. treatment guidelines (8, 9).  For example, while efavirenz has 
shown excellent efficacy over many years of use, it is associated with substantial neuropsychiatric 
intolerance and skin rash, as well as lipid abnormalities.  In addition, EFV can be a perpetrator of 
drug-drug interactions as a mixed inducer or inhibitor of CYP3A and CYP2B6 enzymes.  
Rilpivirine (RPV) has shown suboptimal efficacy in patients with high viral load or low baseline 
CD4 cells, and thus is not indicated in patients with baseline viral load above 100,000 copies/mL 
or CD4 count below 200 cells/mL.  In addition, RPV requires dosing with food and can lead to a 
prolonged QT interval at supratherapeutic doses (10).  Importantly, high level resistance may 
occur in response to a single mutation for all currently available NNRTIs except etravirine, which 
must be dosed twice daily.  Therefore, new agents of the NNRTI class that offer high potency, a 
distinct resistance profile, dosing convenience and a favorable safety and tolerability profile are 
needed. 
 
Doravirine (DOR, MK-1439) is a novel NNRTI being studied for the treatment of HIV-1 
infection in antiretroviral-naïve HIV-infected participants.  Doravirine is a potent inhibitor of 
HIV-1 replication in vitro and is active against both wild type virus and the most common 
NNRTI resistant variants at concentrations achieved with once daily dosing.  Doravirine displays 
excellent potency against wild type virus with an IC50 of 12 nM in the presence of 100% normal 
human serum.  Preclinical studies also indicate a favorable in vitro resistance profile that is 
distinct from other NNRTIs, with IC50’s of 21, 31, and 55 nM against HIV-1 mutants containing 
the most frequently transmitted NNRTI mutations, K103N, Y181C and G190A, respectively, 


IMPAACT 2014, FINAL Version 1.0 
Page 18 of 129 
7 September 2017 
under the same conditions (11).  The IC50 against viruses containing the double mutant K103N + 
Y181C is 33 nM.  The preclinical toxicity profile of doravirine is favorable in rats up to 
six months in duration at 3, 30, and 450 mg/kg/day, and in dogs up to nine months in duration at 
1, 10, and 1000 mg/kg/day.  Juvenile toxicity studies have been conducted in 14 day old rats and 
indicate no DOR related toxicity; the no-observed-effect level was >300 mg/kg/day, suggesting 
the compound is safe in adolescents and children (12).  
 
DOR can be dosed once daily, without regard to food.  Metabolism of DOR is primarily by 
CYP3A, and it is subject to induction/inhibition of this enzyme by other agents.  However, DOR 
is neither a metabolic inducer nor inhibitor, and thus is unlikely to be the cause of significant 
drug-drug interactions.  The available data from Protocol 007 (PN007), a Phase 2 study in 
treatment-naive HIV-infected patients, demonstrate that DOR at a dose of 100mg daily in 
combination with tenofovir disoproxil fumarate (TDF)/emtricitabine has favorable safety and 
tolerability profile and potent efficacy, with ~78% of patients receiving DOR achieving 
undetectable viral load (<40 copies/mL) at week 48, as compared to ~78 % in participants 
receiving efavirenz with TDF/emtricitabine (13) (Section 1.2.2).  In this study, DOR was 
generally well tolerated and demonstrated significantly less CNS toxicity than efavirenz (Section 
1.2.3).  Furthermore, DOR at a dose of 100 mg daily plus two NRTIs was shown to be non-
inferior to darunavir 800mg/ritonavir 100mg plus two NRTIs in ART-naïve adults, with 83% of 
participants achieving a viral load <50 copies/mL at 48 weeks in PN018 (Section 1.2.3). 
 
Doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF, MK-1439A) is a single-
tablet fixed-dose combination (FDC) regimen that combines DOR with lamivudine (3TC) and 
TDF, two approved and commercially available NRTIs.  A single tablet of DOR/3TC/TDF 
contains a full daily HIV treatment regimen of DOR 100 mg + 3TC 300 mg + TDF 300 mg.  This 
FDC has been evaluated in Phase 1 studies, which showed comparable pharmacokinetics to the 
component agents.  DOR/3TC/TDF is being studied in several ongoing Phase 2 and 3 studies.  
 
These preclinical and clinical data provide key support for the initiation of clinical trials in 
adolescents and children, which includes the evaluation of both DOR as a single agent and 
DOR/3TC/TDF as a single-tablet fixed-dose combination regimen.    
 
Development of DOR and DOR/3TC/TDF has included multiple Phase 1 studies, investigating 
safety, pharmacokinetics, and virologic efficacy.  Phase 2 and 3 studies are on-going, 
investigating safety and efficacy of DOR and DOR/3TC/TDF.  Table 1, below, summarizes 
selected studies, which are discussed in more detail in Sections 1.2-1.3. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 19 of 129 
7 September 2017 
Table 1.  Selected Adult Studies Using DOR or DOR/3TC/TDF 
Phase Study 
N 
1 
PN001-01: Study of single and multiple doses of DOR with and without 
midazolam in healthy adults 
58* 
PN002: Study of effect of ritonavir on DOR PK in healthy adults 
8* 
PN005: Study of multiple dose of DOR in ART-naïve HIV-1 infected patients  
18* 
PN009: Study of relative bioavailability of DOR by age and gender 
36* 
PN026: Study of bioavailability of DOR/3TC/TDF in fasted conditions in healthy 
adults 
24* 
PN029: Study of bioavailability of DOR/3TC/TDF in fed and fasted conditions in 
healthy adults  
14* 
2b 
PN007: Study of DOR plus TDF/FTC versus EFV plus TDF/FTC in treatment-
naïve patients  
208* (Part 1) 
132* (Part 2) 
2 
PN028: Study of DOR/3TC/TDF in patients switching from EFV for CNS 
intolerance 
84 
PN030: Study of DOR/3TC/TDF in treatment-naïve patients with transmitted 
resistance to NNRTIs  
10** 
3 
PN018: Study of DOR versus boosted-darunavir in treatment-naïve patients 
769* 
PN021: Study of DOR/3TC/TDF versus EFV/FTC/TDF in treatment-naïve 
patients 
734* 
PN024: Study of DOR/3TC/TDF in patients switching from a PI or NNRTI-based 
regimen 
673* 
*=fully enrolled  
**= screening halted due to enrollment challenges 
 
 
1.2 
Clinical Efficacy 
 
Evidence for clinical efficacy of DOR was established in two Merck-sponsored protocols, PN005 
and PN007 (14, 15) and confirmed by the primary end point analysis at Week 48 from two Phase 
III studies in ART-naïve adults, PN018 and PN021 (16). 
 
1.2.1 
PN005 
 
In PN005 eighteen HIV-infected, ART-naïve, adults received 25 mg DOR (n=6), 200 mg DOR 
(n=6) or placebo (n=6) for seven days and with daily HIV RNA concentrations and viral 
resistance determinations (14).  The mean change from baseline in HIV RNA at 24 hours after the 
day 7 dose was –1.52 log10 copies/mL in the DOR 25-mg group and –1.41 log10 copies/mL in the 
DOR 200-mg group, versus –0.15 log10 copies/mL in the placebo group.  Viral load reductions 
over time were similar for the two DOR groups (Figure 2).  No participant showed evidence of 
viral breakthrough or development of NNRTI-resistance mutations. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 20 of 129 
7 September 2017 
Figure 2.  Mean Change from Baseline in Plasma HIV RNA (log10 copies/mL)  
after Once-daily Administration of Doravirine (25 or 200 mg) or Placebo for 7 days 
 
 
1.2.2 
PN007, PN018, and PN021 
 
PN007 was a Phase 2b double-blind, randomized, dose-ranging study to compare the safety and 
antiretroviral activity of DOR plus TDF/FTC (Truvada®) versus efavirenz combined with 
TDF/FTC which was conducted in two parts (15).  In part 1, participants were randomized to 25 
mg (n=40), 50 mg (n=43), 100 mg (n=42) and 200 mg (n=41) of DOR versus 600 mg efavirenz 
(n=42) combined with TDF/FTC.  All DOR doses showed numerically higher response rates 
compared to efavirenz (80.0%, 76.2%, 71.4%, 78.0% versus 64.3% of patients with <40 
copies/mL for DOR 25 mg, 50 mg, 100 mg, 200 mg versus efavirenz arms, respectively).  The 
treatment differences (DOR minus EFV) were not significant, and there was no dose-response for 
efficacy observed.  Overall 76.4% of patients receiving DOR (at any dose) achieved <40 
copies/mL compared with 64.3% for EFV.  In addition, approximately 30% of participants in the 
study had baseline HIV RNA above 100,000 copies/mL, and, in this subgroup, DOR at all dosing 
levels showed virologic responses comparable to efavirenz.  These efficacy data strongly support 
that the dose range studied (25-200 mg daily) was on the plateau of the dose response curve.  The 
data from Protocol 007 showed an overall favorable safety and tolerability profile for DOR 
compared with EFV, with no differentiation among DOR doses (25 mg – 200 mg daily) with 
regard to safety.  Based upon the 24-week results of Protocol 007, DOR at doses ranging from 
25-200 mg was generally well-tolerated, with no apparent dose related toxicity.  Fewer drug 
related adverse events (AEs) were observed for DOR than for EFV (34.9% for DOR overall 
versus 57.1% for EFV), and fewer CNS AEs were reported both at Week 8 and Week 24 (20.5% 
for DOR overall versus 33.3% for EFV at Week 8 and 23.4% for DOR overall versus 33.3% for 
EFV at Week 24).  After the 24-week analysis, the 100 mg dose of DOR was selected for further 
study in Part 2 (see below for rationale) and at a subsequent visit (mostly by Week 48), the 


IMPAACT 2014, FINAL Version 1.0 
Page 21 of 129 
7 September 2017 
participants randomized to other doses of DOR continued the study on 100mg of DOR plus 
TDF/FTC (13).   
 
Part 2 of PN007 then opened, in which additional patients were randomized in a 1:1 ratio to the 
selected 100 mg dose of DOR (Total N = 108) or EFV (600 mg q.h.s.) (Total N = 108), each in 
combination with TDF/FTC for 96 weeks of blinded treatment.  Evaluation of the 216 adults from 
Part 1 and 2 provided key long-term safety and efficacy data for DOR 100 mg daily (Table 2 
through Table 4) as well as an assessment of CNS events (Table 5).  
 
Results from combined Parts 1 and 2 of the above study after 48 weeks on DOR at the selected 
100 mg dose (n=108) versus EFV (n=108) both with TDF/FTC are shown in Table 2 below.   
 
Table 2.  PN007 Parts 1 and 2 (15) 
DOR 100 mg 
(N=108) 
EFV 600 mg 
(N=108) 
n 
(%) 
n 
(%) 
Success (HIV RNA <40 copies/mL) at week 48* 
84 
(77.8) 
85 
(78.7) 
Non-success at week 48 
24 
(22.2) 
23 
(21.3) 
HIV RNA ≥40 copies/mL  
18 
(16.7) 
14 
(13.0) 
≥40 and <200 copies/mL   
8 
(7.4) 
6 
(5.6) 
≥200 copies/mL  
3 
(2.8) 
2 
(1.9) 
discontinued study due to lack of efficacy, or discontinued 
for other reasons with last HIV RNA ≥40 copies/mL† 
7 
(6.5) 
6 
(5.6) 
No virologic data at week 48 window 
6 
(5.6) 
9 
(8.3) 
discontinued study due to AE or death 
3 
(2.8) 
6 
(5.6) 
discontinued study for other reasons with last HIV RNA 
<40 copies/mL 
3 
(2.8) 
2 
(1.9) 
on study but missing data in week 48 window 
0 
(0.0) 
1 
(0.9) 
* Overall success/non-success rates are identical for Non-completer = Failure (NC=F) and the US Food and Drug 
Administration (FDA) snapshot approach.  All patients also received TDF/FTC. 
† Majority of patients in this category (5 of 7 in DOR group; 4 of 6 in EFV group) had last HIV RNA ≥200 c/mL. 
No treatment-emergent resistance mutations were detected in the 4 patients (3 DOR, 1 EFV) who had HIV RNA 
>500 c/mL at the time of virologic failure.  Another patient who failed on DOR had a sample tested for resistance 1 
month later: new NNRTI mutations (E138E/G + V179D) were present, with no change in phenotypic sensitivity 
(0.75-fold change) to DOR and 7.14-fold decreased susceptibility to EFV.  
 
Similar results were noted at Week 96, with the proportion of participants achieving HIV-1 RNA 
<40 copies/mL (for Part I/II combined) being comparable between those participants who 
received DOR 100 mg (75.0%) and those who received EFV 600 mg (75.9%). (17) 
 
The CD4 cell increase from baseline to Week 96 was 259.2 cells/mm3 versus 263.6 for 100 mg 
DOR versus EFV. 
 
In addition, the Merck adult clinical development program also includes five ongoing studies 
using DOR as single-tablet FDC or single agent in combination with TDF/FTC, as shown in 
Table 1.  
 
Because the safety and efficacy data from Protocol 007 did not distinguish among the doses 
tested, the selection of DOR100 mg daily dose for study in Part 2 of Protocol 007 and in the 
Phase 3 studies has taken into consideration a number of additional factors.  Firstly, DOR is a 
substrate of CYP3A metabolism and is subject to induction and inhibition of CYP3A by other 


IMPAACT 2014, FINAL Version 1.0 
Page 22 of 129 
7 September 2017 
concomitant medications.  Consequently, the 100 mg dose is more likely than the lower doses to 
provide adequate DOR exposures even in the setting of moderate metabolic inducers, and it 
allows for a safety margin in the setting of moderate metabolic inhibitors (since acceptable safety 
and tolerability were seen at the 200 mg dose in the Phase 2 study as well as at multiple doses and 
single doses as high as 750 mg and 1200 mg, respectively, in Phase 1 studies).  Secondly, the 
100-mg dose may provide forgiveness in the setting of the occasional missed dose.  Thirdly, 
based on modeling and simulation, the 100-mg dose is predicted to provide adequate exposures 
and Ctrough concentrations in the setting of certain common NNRTI resistance mutations against 
which DOR is considered to be active in vitro, including the K103N, Y181C, and G190A 
mutations, as well as the dual K103N/Y181C mutation. 
 
PN018 is an ongoing Phase 3, multicenter, double blind, randomized, active comparator-
controlled clinical trial to evaluate the safety and efficacy of doravirine 100 mg once-daily versus 
darunavir 800 mg once-daily plus ritonavir 100 mg once-daily (DRV/r), each in combination with 
FTC/TDF or abacavir/lamivudine (ABC/3TC), in treatment naïve HIV-1 infected participants.  
Results from the primary efficacy endpoint analysis (the proportion of participants achieving 
HIV-1 RNA <50 copies/mL) after all participants completed 48 weeks of treatment demonstrated 
DOR had antiretroviral efficacy that was high and non-inferior compared to that of DRV/r.  
Specifically, 84% (321/383) of participants randomized to DOR 100 mg and 80% (306/383) of 
participants randomized to DRV/r achieved HIV-1 RNA <50 copies/mL (difference [95% CI]: 
+3.9% [-1.6, 9.4]) by the FDA Snapshot approach. 
 
PN021 is an ongoing Phase 3, multicenter, randomized, double-blind trial designed to evaluate the 
safety and efficacy of once-daily DOR/3TC/TDF compared with once-daily EFV/FTC/TDF 
(administered as Atripla®) in treatment naïve participants with HIV-1 infection.  The proportion 
of participants achieving HIV-1 RNA <50 copies/mL at Week 48 (FDA Snapshot) was 84% 
(307/364) in the DOR/3TC/TDF group and 81% (294/364) in the EFV/FTC/TDF group.  The 
treatment difference (DOR/3TC/TDF – EFV/FTC/TDF) was 3.5% with an associated 95% CI of 
(-2.0, 9.0), demonstrating non-inferiority of DOR/3TC/TDF as compared to EFV/FTC/TDF. 
 
1.2.3 
Doravirine and Doravirine/Lamivudine/Tenofovir disoproxil fumarate Safety in Clinical Trials 
 
DOR and DOR/3TC/TDF have been studied in 35 Phase 1 trials and in one completed Phase 2b 
trial (using DOR as single agent).  Three Phase 3 (one with DOR and two with DOR/3TC/TDF) 
and two Phase 2 trials with DOR/3TC/TDF are in progress.  All Phase 3 trials have completed 
enrollment; 48-week data are available for two Phase 3 studies (PN018 and PN021). 
 
Across all Phase 1 studies, approximately 650 adult participants received at least one dose of 
DOR (including participants enrolled in DOC/3TC/TDF studies), including 372 healthy male 
participants, 206 healthy female participants, 12 healthy elderly female participants, 12 healthy 
elderly male participants, 12 male HIV-1 infected participants, eight participants with hepatic 
impairment, and eight participants with severe renal impairment.  Across the Phase I program, 
approximately 522 participants have received a single-dose of DOR; of these participants, 500 
have received a dose of ≥100 mg.  Approximately 191 participants have received consecutive 
multiple doses of DOR; of these participants, 173 participants have received doses ≥100 mg 
(note: 67 participants are counted in both the single-dose group and multiple-dose group). 
 
While the planned clinical dose in adults is 100 mg administered once-daily, the safety and 
tolerability of DOR have been investigated at single doses up to 1200 mg and multiple doses up 
to 750 mg for 10 days in healthy volunteers.  These doses provide exposure multiples 
approximately 4.4-fold the steady-state exposure anticipated at the 100 mg dose.  In addition, 12 


IMPAACT 2014, FINAL Version 1.0 
Page 23 of 129 
7 September 2017 
adult male HIV-1 infected participants have received seven days of dosing with DOR 200 
mg.  Overall, DOR was found to be generally well-tolerated with no dose-dependent increases in 
specific AE.  The majority of AEs were mild and moderate in severity.  Only one AE (syncope) 
was of severe intensity; the AE was not considered related to DOR.  Two serious adverse events 
(SAEs) have been reported (elevated liver enzymes in setting of new hepatitis C (HCV) infection 
and new onset sarcoidosis) in the Phase I program; both were not considered to be related to 
DOR. 
 
A QTc study evaluating the effect of a supratherapeutic dose (1200 mg, corresponding to 3.3-fold 
the anticipated steady state Cmax at 100 mg) of DOR on QTc and other cardiac parameters has 
been completed.  Data from this study demonstrated that DOR does not prolong the QTc interval 
to a clinically relevant degree. 
 
To date, four Phase 1 studies (Protocols 014, 015, 026, and 029) have been conducted with 
DOR/3TC/TDF.  The first two assessed prototype FDC formulations in healthy adults.  Two 
additional studies evaluated the PK of the final adult FDC formulation compared to co-
administration of individual components and the effect of food on the FDC formulation in healthy 
adults.  The adverse events in these studies were all mild.  No trends were identified in adverse 
events that differed from the labels of the marketed drugs or the Phase 2 data for DOR. 
 
PN 007 Part 1 and 2 
Safety data are available from the 108 adults receiving DOR at the 100 mg dose for 48 weeks in 
the combined Parts 1 and 2 of PN007.  The clinical adverse events and laboratory abnormalities 
are summarized in Table 3 and Table 4 below.   
 
Table 3.  Clinical Adverse Events (%) DOR + TDF/FTC  
versus EFV + TDF/FTC at 96 Weeks (17) 
Clinical Adverse Events 
DOR 100 mg 
(N=108) 
EFV 600 mg 
(N=108) 
Discontinued due to AE 
4.6 
10.2 
Drug-related AE  
35.2 
58.3 
Drug-related serious AE 
0 
2.8 
Death 
0 
0 
Diarrhea 
0.9 
6.5 
Nausea 
7.4 
6.5 
Fatigue 
3.7 
4.6 
Dizziness 
7.4 
26.9 
Headache 
2.8 
5.6 
Abnormal dreams 
5.6 
14.8 
Insomnia 
6.5 
2.8 
Nightmares 
5.6 
8.3 
Sleep disorder 
4.6 
6.5 
 


IMPAACT 2014, FINAL Version 1.0 
Page 24 of 129 
7 September 2017 
Table 4.  Laboratory Abnormalities ≥Grade 2 (%)  
DOR + TDF/FTC versus EFV + TDF/FTC at 48 Weeks (15) 
Laboratory Test 
Grade (criteria) 
DOR 100 mg 
(N=108) 
EFV 600 mg 
(N=108) 
Absolute neutrophil count 
2 (0.75-0.999 x 103/µL) 
1.9 
1.9 
4 (<0.50 x 103/µL) 
0 
0.9 
Platelet count 
2 (50 – 99.9 x 103/µL) 
0.9 
0.9 
LDL-cholesterol, fasting 
2 (160 – 189 mg/dL) 
2.0 
3.9 
3 (≥190 mg/dL) 
0 
1.9 
Total cholesterol, fasting 
2 (240 – 300 mg/dL) 
0 
6.7 
3 (>300 mg/dL) 
0 
1.9 
Triglycerides, fasting 
2 (500 – 750 mg/dL) 
0 
1.9 
Glucose, fasting 
2 (126 – 250 mg/dL) 
3.2 
1.1 
Aspartate aminotransferase 2 (2.6 – 5.0 x ULN) 
0.9 
3.7 
3 (5.1 – 10.0 x ULN) 
0.9 
0 
4 (>10.0 x ULN) 
0 
0.9 
Alanine aminotransferase 
2 (2.6 – 5.0 x ULN) 
0.9 
0 
3 (5.1 – 10.0 x ULN) 
0.9 
1.9 
Lipase 
2 (1.6–3.0 x ULN) 
4.7 
7.4 
3 (3.1 – 5.0 x ULN) 
3.7 
4.6 
4 (>5.0 x ULN) 
0.9 
1.9 
 
Data on CNS adverse events from the 108 participants in Parts 1 and 2 of the Phase 2 study who 
continued on the 100 mg DOR dose are available through Weeks 8 and 24 (Table 5).  Overall, 
CNS AEs were more frequently reported in the EFV group than in the DOR group.  The 
treatment difference was statistically significant at Weeks 8 and 24 (p <0.001). 
 
Table 5.  Proportion of Patients with Central Nervous System Adverse Events (CNS Events)  
by Week 8 and by Week 24 Part I/II Combined All Patients as Treated 
Treatment  
Percent of Patients with One or 
More Selected Adverse Events  
Doravirine minus Efavirenz ‡ 
n/N 
%(95% CI) 
Difference (95% CI) 
P-Value 
CNS Events† by Week 8 
Doravirine 100 mg  
26/108 
24.1 (16.4, 33.3) 
-20.4 (-32.4, -7.8) 
0.002 
Efavirenz 600 mg 
48/108 
44.4 (34.9, 54.3) 
 
 
CNS Events† by Week 24 
Doravirine 100 mg  
29/108 
26.9 (18.8, 36.2) 
-20.4 (-32.6, -7.5) 
0.002 
Efavirenz 600 mg 
51/108 
47.2 (37.5, 57.1) 
 
 
† Selected adverse events are from MedDRA terms of depression, nightmare, confusional state, suicidal 
ideation, nervous system disorder, psychotic disorder, abnormal dreams, suicide attempt, acute psychosis, 
delirium, depressed level of consciousness, hallucination, hallucination auditory, hallucination visual, 
completed suicide, suicidal behavior, major depression, depressed mood, depressive symptom, insomnia, 
disturbance in attention, somnolence, dizziness, concentration impaired. 
‡ A negative value favors doravirine over efavirenz. The 95% CIs and p-values were calculated using Miettinen 
and Nurminen's method.  Participants are counted once for each unique adverse event and may have had 
more than one unique adverse event. 
n/N = Number of patients included in a given category / number of patients in each treatment group. 
Note: Both doravirine and efavirenz were administered with Truvada®. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 25 of 129 
7 September 2017 
PN018 
Safety data at 48 weeks are also available from PN018, the DOR versus DRV/r randomized trial 
in ART-naïve adults described above.  Adverse event rates (overall, serious, drug-related, and 
leading to treatment discontinuation) were similar across treatment groups.  The most common 
drug-related AEs (>10% in one or more treatment groups) were diarrhea (14%, 22%), nausea 
(11%, 12%), and headache (14%, 11%) for DOR and DRV/r, respectively (Table 6).  Grade 3 or 
4 laboratory changes occurred in ≤2% of participants in the DOR group and were similar between 
groups.  Fasting LDL-C and non-HDL-C were reduced by DOR and increased by DRV/r with 
statistically significant treatment differences (p<0.0001). 
 
Table 6.  PN018 Week 48 Summary of Clinical Adverse Events (16) 
Clinical AE 
DOR (N=383) 
DRV+r (N=383) 
N 
(%) 
N 
(%) 
One or more AE 
307 
(80%) 
300 
(78%) 
Drug-related AE 
117 
(31%) 
123 
(32%) 
Serious AE 
19 
(5%) 
23 
(6%) 
Discontinued due to AE 
6 
(2%) 
12 
(3%) 
Most common AEs (≥ 10% in either group) 
Diarrhea 
54 
(14%) 
86 
(22%) 
Nausea 
41 
(11%) 
46 
(12%) 
Nasopharyngitis 
30 
(8%) 
39 
(10%) 
Headache 
53 
(14%) 
41 
(11%) 
AEs of clinical interest 
Rash† 
28 
(7%) 
32 
(8%) 
Neuropsychiatric‡ 
44 
(11%) 
50 
(13%) 
† Only 2 DOR participants and 1 DRV+r participant discontinued due to rash  
‡ Includes disturbance in attention, dizziness, somnolence, abnormal dreams, confusional state, depressed mood, 
depression, insomnia, major depression, nightmare and psychotic disorder.  No participants discontinued due to 
neuropsychiatric AEs 
 
PN021 
Week 48 safety data including neuropsychiatric AE results (Table 7 and Table 8) are available 
from PN021, the DOR/3TC/TDF versus EFV/3TC/TDF randomized trial in treatment-naïve 
adults described above.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 26 of 129 
7 September 2017 
Table 7.  PN021: Analysis of Participants with Neuropsychiatric Adverse Events by Week 48 (17) 
 
DOR/3TC/TDF Per 
Day (QD) (N=364) 
EFV/FTC/TDF QD 
(N=364) 
Treatment 
Differences 
(DOR/3TC/TDF - 
EFV/FTC/TDF), 
Estimate (95% CI)† 
Two-
Sided P-
Value‡ 
N 
(%) 
N 
(%) 
Participants in 
population 
364 
 
364 
 
 
 
With one or more 
neuropsychiatric 
adverse event 
86 
(23.6) 
207 
(56.9) 
-33.2 (-39.8, -26.4) 
 
With no 
neuropsychiatric 
adverse events 
278 
(76.4) 
157 
(43.1) 
33.2 (26.4, 39.8) 
 
Dizziness 
32 
(8.8) 
135 
(37.1) 
-28.3 (-34.0, -22.5) 
<0.001 
Sleep disorders and 
disturbances 
44 
(12.1) 
93 
(25.5) 
-13.5 (-19.1, -7.9) 
<0.001 
Altered sensorium 
16 
(4.4) 
30 
(8.2) 
-3.8 (-7.6, -0.3) 
0.033 
Depression and 
suicide/self-injury 
15 
(4.1) 
24 
(6.6) 
-2.5 (-5.9, 0.8) 
nps* 
Psychosis and 
psychotic disorders 
1 
(0.3) 
4 
(1.1) 
-0.8 (-2.5, 0.5) 
nps* 
The five categories of neuropsychiatric adverse event were predefined. Specific terms included for each category 
were based on MedDRA 19.1. Every participant is counted a single time for each applicable specific adverse event. 
A participant with multiple adverse events within a category is counted a single time for that category. 
† The 95% Cis were calculated using Meittinen and Nurminen’s method. 
‡ Superiority is tested sequentially for dizziness, sleep disorders and disturbances, and altered sensorium. 
*Not pre-specified for statistical testing. 
Only includes AEs occurring or worsening after the first dose of study medication through 14 days after the last 
dose of study medication. 
 
Table 8.  PN021 Week 48 Summary of Clinical Adverse Events (18) 
Clinical AE 
DOR/3TC/TDF (N=364) 
EFV/FTC/TDF (N=364) 
N 
(%) 
N 
(%) 
One or more AE 
301 
(83%) 
330 
(91%) 
Drug-related AE 
113 
(31%) 
229 
(63%) 
Serious AE 
13 
(4%) 
21 
(6%) 
Discontinued due to AE 
11 
(3%) 
24 
(7%) 
Most common AEs (≥ 10% in either group) 
Headache 
47 
(13%) 
45 
(12%) 
Diarrhea 
39 
(11%) 
49 
(14%) 
Nasopharyngitis 
39 
(11%) 
31 
(9%) 
Dizziness 
32 
(9%) 
135 
(37%) 
Nausea 
28 
(8%) 
39 
(11%) 
Abnormal dreams 
17 
(5%) 
42 
(12%) 
Rash 
17 
(5%) 
44 
(12%) 
 


IMPAACT 2014, FINAL Version 1.0 
Page 27 of 129 
7 September 2017 
1.3 
Doravirine Clinical Pharmacokinetics in Adults 
 
1.3.1 
Absorption and Pharmacokinetics of Single and Multiple Doses 
 
PK data for single dose oral administration of the DOR tablet from up to 450 mg to healthy male 
participants demonstrated DOR was rapidly absorbed (PN001-01).  DOR plasma concentrations 
declined in a monoexponential manner, with mean terminal elimination half-life values ranging 
from 12 to 16 hours.  In single dose administration over the range 6 to 450 mg, DOR AUC and 
Cmax values were slightly less than dose proportional with corresponding AUC0-24hr exposures 
ranging from 2.02 to 82.4 μM.hr, AUC0-∞ ranging from 2.88 to 127 μM.hr, and Cmax ranging from 
156 to 6010 nM (Table 9).  C24hr values were 44 to 2070 nM over this dose range. (12) 
 
Table 9.  Single Dose DOR PK Parameters with Dose Range from 6 mg to 450 mg 
Pharmacokinetic 
Parameters 
Panel A 6 mg 
Panel B 12 mg 
Panel A 25 mg 
Panel B 50 mg 
N 
GM 
95% CI 
N 
GM 
95% CI 
N 
GM 
95% CI 
N 
GM 
95% CI 
AUC0-∞ (μM*hr)† 
6 
2.88 
(2.35, 
3.52) 
6 
4.88 
(3.98, 
5.98) 
6 
11.5 
(9.17, 
13.7) 
6 
17.6 
(14.4, 
21.6) 
AUC0-24hr (μM*hr)† 
6 
2.02 
(1.70, 
2.41) 
6 
3.66 
(3.07, 
4.35) 
6 
7.03 
(5.91, 
8.36) 
6 
12.7 
(10.6, 
15.1) 
Cmax (nM)† 
6 
156 
(126, 
193) 
6 
297 
(240, 
367) 
6 
460 
(372, 
569) 
6 
1070 
(860, 
1320) 
C24hr (nM)† 
6 
43.9 
(35.1, 
54.8) 
6 
73.0 
(58.2, 
91.4) 
6 
194 
(155, 
243) 
6 
269 
(215, 
338) 
Tmax (hr)‡ 
6 
1.00 
(1.00, 
4.00) 
6 
1.00 
(1.00, 
3.00) 
6 
5.00 
(1.00, 
6.00) 
6 
1.00 
(1.00, 
4.00) 
Apparent t1/2 (hr)§ 
6 
11.68 
9.95 
6 
11.67 
15.70 
6 
15.67 
20.42 
6 
13.29 
10.59 
Pharmacokinetic 
Parameters 
Panel A 100 mg 
Panel B 150 mg 
Panel A 300 mg 
Panel B 450 mg 
N 
GM 
95% CI 
N 
GM 
95% CI 
N 
GM 
95% CI 
N 
GM 
95% CI 
AUC0-∞ (μM*hr)† 
6 
38.3 
(31.3, 
46.8) 
6 
49.9 
(40.7, 
61.2) 
6 
92.6 
(75.7, 
113) 
6 
127 
(104, 
155) 
AUC0-24hr (μM*hr)† 
6 
22.8 
(19.2, 
27.1) 
6 
34.0 
(28.6, 
40.5) 
6 
58.9 
(49.5, 
70.1) 
6 
82.4 
(69.3, 
98.0) 
Cmax (nM)† 
6 
1720 
(1390, 
2120) 
6 
2680 
(2170, 
3320) 
6 
3810 
(3090, 
4710) 
6 
6010 
(4870, 
7430) 
C24hr (nM)† 
6 
593 
(475, 
741) 
6 
750 
(599, 
940) 
6 
1490 
(1190, 
1870) 
6 
2070 
(1660, 
2580) 
Tmax (hr)‡ 
6 
1.50 
(1.00, 
5.00) 
6 
1.50 
(1.00, 
4.00) 
6 
3.50 
(2.00, 
5.00) 
6 
2.00 
(1.00, 
5.00) 
Apparent t1/2 (hr) § 
6 
15.26 
43.98 
6 
13.84 
27.65 
6 
15.62 
27.08 
6 
14.80 
34.52 
† Back-transformed least squares mean and confidence interval from linear mixed effects model performed on 
natural log-transformed fasted values. 
‡ Median (min, max) reported for Tmax. 
§ Geometric mean and percent geometric coefficient of variation (CV) reported for apparent t1/2. 
Square root of conditional mean squared error (residual error) from the linear mixed effects model = 0.178 for AUC0-
∞, 0.195 for Cmax, and 0.207 for C24hr.  When multiplied by 100, provides estimate of the pooled within-participant 
coefficient of variation. 
GM = Geometric least-squares mean; CI = Confidence interval. 
 
Multiple dose pharmacokinetics are consistent with the single-dose data (Figure 3) with rapid 
absorption and monoexponential plasma level decline with mean terminal elimination half-life 
values ranging from 13 to 15 hrs.  Mean observed exposures (AUC0-24hr) on the last day of dosing 
ranged from 11.5 to 60.6 μM∙hr over the 30 to 240 mg per day (QD) dose range.  Mean Cmax and 
C24hr values on the last day of dosing ranged from 796 to 4470 nM and 246 to 1340 nM, 
respectively, over the 30 to 240 mg QD dose range.  After multiple days of QD dosing, steady 


IMPAACT 2014, FINAL Version 1.0 
Page 28 of 129 
7 September 2017 
state was achieved by approximately Day 2.  At steady state, the mean AUC0-24hr, Cmax, and C24hr 
accumulation ratios, expressed as either the Day 10/Day 1 geometric mean ratios (GMRs) (30, 
60, and 240 mg QD doses) or the Day 14/Day 1 GMRs (120 mg QD dose) were 1.2-1.4, 
consistent with predictions from single dose data (19).  These data support QD dosing for DOR. 
 
Doravirine pharmacokinetics is similar in healthy participants and HIV-1 infected patients.  
Based on a preliminary population pharmacokinetic analysis conducted with pooled data from the 
Phase 2 trial, where sparse PK samples were collected, and selected Phase 1 trials, the 100 mg 
dose is associated with steady state AUC0-24hr, C24hr, and Cmax values of 35.7 μM*hr, 831 nM, and 
2.79 μM, respectively.  Median doravirine steady state AUC0-24hr for 200 mg, the highest dose 
studied in Phase 2, is 64.5 μM*hr.  
 
Figure 3.  Mean Plasma Concentration Profiles of DOR Following  
Administration of Multiple Oral Doses Once Daily to Health Fasted Male Participants (N=6-8) 
 
 
1.3.2 
Effect of Food 
 
Administration of the 100 mg DOR tablet to fourteen adults fasted and with a high fat meal 
demonstrated minimal effect on DOR pharmacokinetics when given with a high fat meal 
(PN029). The fed/fasted geometric mean ratios (GMRs) and 90% CIs of DOR AUC0-∞, Cmax and 
C24hr were 1.16 (1.06, 1.26), 1.03 (0.89, 1.19), and 1.36 (1.19, 1.55), respectively, while Tmax was 
delayed.  Such an effect is not considered to be clinically meaningful based on the tolerability 
data in humans and toxicity data in animals to date.  DOR can be administered without regard to 
food.  
 
1.3.3 
Effect of Gender 
 
The effect of gender on the PK of DOR was assessed in a clinical trial among elderly men and 
women and non-elderly women (PN009).  There was no clinically meaningful effect of gender on 
the PK of DOR.  GMRs (female/male) and 90% CIs for AUC0-∞, Cmax and C24hr for DOR are 
119.95%, (102.86, 139.88), 141.84%, (122.76, 163.87) and 101.72%, (83.63, 123.72), 
respectively.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 29 of 129 
7 September 2017 
1.3.4 
Metabolism 
 
DOR is metabolized in vitro by CYP3A and clinical drug-drug interaction studies are consistent 
with this being the major pathway of elimination.  
 
1.3.5 
Drug Interaction 
 
DOR is not anticipated to perpetrate clinically meaningful drug interactions via major drug 
metabolizing enzymes or transporters. A clinical study with midazolam indicated that DOR is not 
a strong inhibitor or inducer of CYP3A metabolism (PN001-01).  
 
Consistent with metabolism primarily via CYP3A, co-administration of DOR on Day 14 of 
ritonavir multiple dosing increased DOR exposure and Cmax.  The GMR (DOR + ritonavir/DOR 
alone) and 90% CI for DOR AUC0-∞ was 3.54 (3.05, 4.12).  Doravirine Cmax and Tmax were only 
slightly increased after co-administration with ritonavir compared to DOR administered alone, 
but the mean apparent terminal t1/2 of DOR was significantly increased from 13.9 to 34.9 hours 
(PN002).  Ritonavir has a significant effect on the clearance of DOR due to inhibition of CYP3A, 
consistent with in vitro data indicating the predominant role of CYP3A in DOR metabolism.  
Additionally, co-administration of DOR on Day 14 of once daily rifampin resulted in 
significantly decreased levels of DOR due to induction of CYP3A metabolism by rifampin.  
 
1.3.6 
DOR/3TC/TDF Pharmacokinetics of the Tablet Formulation 
 
A single tablet of DOR/3TC/TDF contains a full daily HIV treatment regimen of DOR 100 mg + 
3TC 300 mg + TDF 300 mg.  Pharmacokinetic studies conducted in adults have demonstrated 
similar levels of DOR when given as DOR or DOR/3TC/TDF).  The pharmacokinetics of 3TC 
and TDF were also generally similar when administered as DOR/3TC/TDF or the individual 
components.  While tenofovir Cmax was slightly decreased after administration of DOR/3TC/TDF 
compared to administration as TDF (Viread®), this decrease is not expected to be clinically 
meaningful (Table 10). 
 
Table 10.  Pharmacokinetics of Doravirine, Lamivudine, Tenofovir Disoproxil Fumarate  
Administered as DOR/3TC/TDF or as Individual Components 
Parameters 
GMRs (90% CIs) 
(DOR/3TC/TDF versus DOR 100 mg tablet,  
3TC 300 mg tablet and TDF 245 mg tablet) 
Doravirine 
AUC0-∞ 
1.01 (0.94, 1.08) 
AUC0-last 
1.02 (0.95, 1.09) 
Cmax 
0.99 (0.91, 1.09) 
C24hr 
1.02 (0.94, 1.12) 
Lamivudine 
AUC0-∞ 
1.04 (1.00,1.09) 
AUC0-last 
1.04 (1.00, 1.08) 
Cmax 
1.00 (0.91,1.09) 
Tenofovir 
AUC0-∞ 
0.98 (0.93,1.03) 
AUC0-last 
0.99 (0.94, 1.04) 
Cmax 
0.87 (0.78,0.97) 
 


IMPAACT 2014, FINAL Version 1.0 
Page 30 of 129 
7 September 2017 
1.3.7 
DOR Pharmacokinetics of the Oral Granule Formulation 
 
The pharmacokinetics of the DOR coated oral granules planned to be used in this trial were 
evaluated in healthy adult participants (P052).  As the oral granules are intended to be 
administered in soft food, the pharmacokinetics were evaluated following administration alone or 
with pudding or apple sauce.  Following administration of 100 mg of DOR coated granules 
without food, there was no clinically meaningful difference in DOR AUC0-∞, Cmax, or C24 
compared to the adult tablet without food.  Administration of 100 mg of DOR coated granules in 
vanilla pudding also did not meaningfully impact DOR AUC0-∞, Cmax, and C24 compared to 
administration of coated granules without food.  While administration of 100 mg of DOR coated 
granules in apple sauce increased DOR AUC0-∞, Cmax, and C24, these increases are not considered 
clinically meaningful (Table 11). 
 
Table 11.  Pharmacokinetics of DOR Following Administration of  
Coated Oral Granules Compared to Administration of the Adult DOR Tablet 
DOR PK 
parameter 
GMR (90% CIs) 
100 mg DOR 
coated granule 
(fasted) /  
100 mg DOR adult 
tablet (fasted) 
100 mg DOR coated 
granule with vanilla 
pudding / 
100 mg DOR coated 
granule (fasted) 
100 mg DOR coated 
granule with applesauce / 
100 mg DOR coated 
granule (fasted) 
AUC0-∞ 
0.89 
(0.85, 0.94) 
0.99 
(0.91, 1.07) 
1.26 
(1.18, 1.34) 
Cmax 
0.77 
(0.70, 0.84) 
0.90 
(0.79, 1.03) 
1.59 
(1.47, 1.73) 
C24hr 
0.95 
(0.89, 1.01) 
0.96 
(0.88, 1.04) 
1.21 
(1.12, 1.30) 
 
The pharmacokinetics of the 3TC and TDF coated oral granules to be used in this trial were also 
evaluated in healthy adult participants (P054).  Following fasted administration of 300 mg coated 
granules of lamivudine, lamivudine AUC0-∞ and Cmax were similar to administration of the 
300 mg Epivir® adult tablet.  Following administration of 300 mg of lamivudine coated granules 
in vanilla pudding or applesauce, lamivudine AUC0-∞ and Cmax were slightly, but not 
meaningfully, decreased relative to administration of the coated granules without food.  The 
impact of administration of pudding or applesauce is not anticipated to be clinically meaningful 
(Table 12).  
 
Table 12.  Pharmacokinetics of 3TC Following Administration of  
Coated Oral Granules Compared to Administration of the Adult 3TC Tablet 
3TC PK 
parameter 
GMR (90% CIs) 
300 mg 3TC coated 
granule (fasted) / 
300 mg 3TC adult 
tablet (fasted) 
300 mg 3TC coated 
granule with vanilla 
pudding / 
300 mg 3TC coated 
granule (fasted) 
300 mg 3TC coated 
granule with applesauce / 
300 mg 3TC coated 
granule (fasted) 
AUC0-∞ 
1.00 
(0.96, 1.03) 
0.84 
(0.78, 0.92) 
0.86 
(0.83, 0.91) 
Cmax 
0.99 
(0.91, 1.08) 
0.84 
(0.75, 0.95) 
0.84 
(0.74, 0.96) 
 


IMPAACT 2014, FINAL Version 1.0 
Page 31 of 129 
7 September 2017 
Similarly, the pharmacokinetics of tenofovir following fasted administration of 300 mg coated 
granules of TDF were generally similar to administration of the 300 mg Viread® adult tablet. 
Following administration of 300 mg of TDF coated granules in vanilla pudding or applesauce, 
tenofovir AUC0-∞ and Cmax were slightly increased relative to administration of coated granules 
without food.  The impact of administration of pudding or applesauce is not anticipated to be 
clinically meaningful (Table 13). 
 
Table 13.  Pharmacokinetics of Tenofovir Following Administration of  
TDF Coated Oral Granules Compared to Administration of the Adult TDF Tablet 
Tenofovir 
PK 
parameter 
GMR (90% CIs) 
300 mg TDF coated 
granule (fasted) / 
300 mg TDF adult 
tablet (fasted) 
300 mg TDF coated 
granule with vanilla 
pudding / 
300 mg TDF coated 
granule (fasted) 
300 mg TDF coated 
granule with applesauce / 
300 mg TDF coated 
granule (fasted) 
AUC0-∞ 
1.04 
(0.96, 1.13) 
1.18 
(1.11, 1.25) 
1.15 
(1.08, 1.23) 
Cmax 
1.03 
(0.94, 1.14) 
1.23 
(1.12, 1.35) 
1.20 
(1.08, 1.33) 
 
1.4 
Rationale for the Study 
 
Development of tolerable, potent, once-daily dose ARV for use in children and adolescents 
remains a significant priority.  First-line therapy with non-nucleoside reverse transcriptase 
inhibitors (NNRTIs) has proven to be effective for HIV-1 infected infants, children, and 
adolescents (20, 21).  As described in the background above, each of the currently available 
NNRTIs have characteristics that make them less than optimal for preferred first-line treatment in 
HIV-1-infected children and adolescents.   
 
Based on the preclinical and clinical data to date, DOR is an excellent candidate for further 
development in the pediatric population.  The lack of evidence for reproductive toxicity, 
decreased CNS adverse events compared to EFV, wide therapeutic margin, and once-daily dosing 
provide advantages to DOR as treatment for HIV-1-infected children and adolescents.  In 
addition, if the in vitro activity of DOR against several HIV-1 strains with common NNRTI 
resistance mutations (11) is confirmed in PN030, DOR will likely be a better switch option than 
nevirapine (NVP) (22, 23) or EFV for young children previously exposed to NVP and now 
suppressed on lopinavir/ritonavir.  The proposed development plan to include an appropriate FDC 
formulation for younger age groups is also an advantage for DOR as future therapy for younger 
children.  
 
This protocol is planned to be the first in a series of protocols to evaluate DOR and 
DOR/3TC/TDF in the pediatric population.  The goal of this study is to obtain PK and safety data 
in participants from 12 years to less than 18 years who weigh ≥35 kg as a first step in the 
development of DOR for the treatment of HIV-1-infected pediatric patients.   
 
It is anticipated that the safety and PK data from this study will inform the development of DOR 
and DOR/3TC/TDF in younger children. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 32 of 129 
7 September 2017 
1.4.1 
Rationale for Dose Selection 
 
The 100 mg QD dose of DOR was selected for the Phase 3 studies in adults based on 
considerations detailed in Section 1.2.2, above.  
 
It is anticipated that the 100 mg QD adult dose will be appropriate for most, if not all, children 
and adolescents who weigh ≥35 kg; therefore, the 100 mg dose will be studied in this protocol 
(Cohort 1).  Based on modeling and simulation, the 100 mg QD dose in children and adolescents 
≥35 kg is projected to achieve steady state C24hr values similar to or greater than those achieved in 
adults at the 100 mg QD dose where efficacy was observed in the Phase 2b trial.  In addition, 
steady state exposures in children and adolescents are not expected to exceed those corresponding 
to adults at the 200 mg QD dose (median steady state AUC0-24hr of ~64.5 μM*hr), the highest 
dose studied in the Phase 2b trial.  Simulations using the 100 mg QD dose were run for children 
and adolescents with weights ranging from 31-85 kg.  Projected exposures for the 100 mg QD 
dose in children at the lower end of this weight range are at the high end of the projected 
distribution of values but are not expected to exceed the range of exposures experienced by adults 
at the 200 mg QD dose.  Thus, in this study, a weight threshold of 35 kg will be used until there is 
a better understanding of DOR PK in children, in order to minimize risk of exceeding the 
exposure observed for 200 mg in adults. 
 
Based on the US Prescribing Information for lamivudine (3TC) (24), a total daily dose of 300 mg 
is appropriate for children that weigh ≥25 kg.  The US Prescribing Information for TDF (25) 
indicates that a dose of 300 mg is appropriate for children 12 years of age and older who weigh 
35 kg or more.  The doses of 3TC (300 mg) and TDF (300 mg) used in the DOR/3TC/TDF tablet 
are thus approved for use in children and adolescents in this weight range (≥35 kg).    
 
To move forward the development of DOR and DOR/3TC/TDF for use in children and 
adolescents, children and adolescents for whom the full adult dose FDC is appropriate will be 
enrolled for the long-term portion of study (Cohort 2).  The expectation is that this will be all 
children and adolescents with weight ≥35 kg.  If this expectation is not borne out based on the 
results of Cohort 1, only children and adolescents in the weight range for which the 100 mg is 
appropriate will be enrolled into Cohort 2 and followed long-term.  If, after the dose evaluation 
stage, it appears that lower-weight children and adolescents (for example, 35 – 40 kg) may 
require a dose less than 100 mg DOR, an age appropriate formulation that is currently in 
development and is intended to deliver a dose below 100 mg will be employed to study safety and 
PK in such participants in a separate study.  
 
1.4.2 
Rationale for Study Design and Cohort Selection 
 
Virologically suppressed children and adolescents on a stable integrase inhibitor-based ART 
regimen have been selected for participation in Cohort 1 for the following reasons.  While there is 
enough efficacy data in adults and confidence in the model-based projected PK for the 100 mg 
DOR tablet to justify initiating the DOR PK analysis in HIV-infected children and adolescents 
who are treatment naive, verifying the DOR pharmacokinetics prior to initiating DOR/3TC/TDF 
as first-line therapy in ART-naïve children and adolescents provides additional safety.  Being on 
a suppressive ART regimen while taking DOR will prevent the development of resistance should 
there be an unexpected deviation from the modeling such that the 100 mg dose would provide 
inadequate drug levels.  Children and adolescents need to be stable on an integrase-based regimen 
rather than a PI-based regimen to minimize drug interactions with DOR that may affect the PK 
analysis.  As there are no drug interactions between DOR and integrase inhibitors, a single dose 
of DOR will also not affect the efficacy of the participants’ ARV regimen. 


IMPAACT 2014, FINAL Version 1.0 
Page 33 of 129 
7 September 2017 
  
Doravirine multiple dose pharmacokinetics were consistent with predictions from single-dose 
data in the adult studies and there was no evidence of time-dependent changes in PK after 
multiple dosing.  Thus, AUC0-∞ following a single dose is equivalent to a projected steady state 
AUC0-24hr.  Therefore, PK data can be obtained from a single-dose of DOR to project the steady 
state PK of DOR and verify the appropriateness of the 100 mg dose in children and adolescents 
35 kg or greater (see Section 10.3.1 for additional details).  Cohort 1 will include participants 
with weights down to 35 kg, who are more likely to deviate from the projected pediatric 
exposures at the 100 mg QD dose.  As such, adequate representation of children and younger 
adolescents in Cohort 1 to enable characterization of DOR PK and its relationship with weight 
across the entire range intended for this study (≥35 kg) will be important for further development 
of DOR and DOR/3TC/TDF for younger children.  Requirements to enroll a minimum of four 
participants between 35 to ≤45 kg were thus included for Cohort 1. 
 
Once the PK and safety targets for Cohort 1 are confirmed for the 100 mg DOR dose, 
DOR/3TC/TDF will be studied in Cohort 2 in HIV-1-infected children and adolescents.  While it 
is anticipated that the 100 mg DOR dose will meet PK targets for all participants with weights 
down to 35 kg, in the unlikely event that the dose is determined to be too high for lower weight 
participants, Cohort 2 will only open for those participants whose weight meet the PK and safety 
targets based on data from Cohort 1.  If the 35 to ≤45 kg weight group shows acceptable PK and 
safety, a minimum of five participants in this weight group will be enrolled to Cohort 2.   
  
Cohort 2 will enroll participants who are ART-naïve as well as ART-experienced, virologically 
suppressed.  However, inclusion of participants who are ART-experienced, virologically 
suppressed will be dependent on results from one of the adult switch studies (PN024, PN028).  
The primary objectives of these studies are maintenance of virologic suppression for at least 24 
weeks after switching.  The adult switch studies are ongoing and include a Phase 2 study of 
switch from an EFV-based regimen for CNS toxicity (PN028) and a Phase 3 study of switch from 
a stable antiretroviral regimen of a ritonavir- or cobicistat-boosted protease inhibitor (PI) 
(specifically, atazanavir, darunavir, or lopinavir), or cobicistat-boosted elvitegravir (an InSTI), or 
a NNRTI (specifically, EFV, NVP, or RPV), each administered with two NRTIs (PN024).  In 
both of these adult switch studies, inclusion is limited to individuals who are virologically 
suppressed with no prior virologic failure and participants switch to DOR/3TC/TDF without any 
wash-out from their prior ART regimen.  Once the 24-week data are available from one of the 
adult switch studies, the data will be reviewed by the Clinical Management Committee (CMC) 
and IMPAACT Study Monitoring Committee (SMC) prior to opening Cohort 2 for the ART-
experienced, virologically suppressed participants (see Section 9.6.2).  Data from the adult switch 
studies will be considered supportive if 90% or more of the participants maintain virologic 
suppression for at least 24 weeks after switching. 
 
It is not anticipated that the ART-experienced, virologically suppressed participants entering 
Cohort 2 would be included in the subset of participants selected for intensive PK studies, as the 
results from the switch studies, if they become available during the study, are not expected until 
Cohort 2 is close to full accrual.  However, this option is included in the protocol to allow 
flexibility and to facilitate improved accrual if any challenges arise.  
 
If the data from the switch studies are not supportive, Cohort 2 will only enroll HIV-1-infected, 
ART-naïve participants.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 34 of 129 
7 September 2017 
1.4.3 
Rationale for Pharmacokinetic Studies of Doravirine, Lamivudine, and Tenofovir in Cohort 2 
 
The tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) components in DOR/3TC/TDF 
are new generic formulations.  Intensive pharmacokinetic sampling for tenofovir and 3TC is 
planned in a subset of Cohort 2 participants to obtain data on these generic agents in children and 
adolescents.  These data will be necessary to support further development of the DOR/TDF/3TC 
FDC for younger children.  New doses of TDF and 3TC have been proposed for use in the age 
appropriate FDC for children aged 2 – 11 years and a population PK approach will be used to 
support characterization of the PK to confirm the appropriateness of the proposed new doses in a 
separate study.   
 
Pharmacokinetic samples for DOR will also be collected at a subset of the times when intensive 
PK samples are drawn for tenofovir and 3TC.  The DOR samples will be used to further 
characterize PK in the population enrolled in this study and will support the development of the 
pediatric population PK model for DOR.  Sparse PK samples will also be obtained for DOR, 
3TC, and TDF in Cohort 2 to further characterize the PK of DOR, 3TC, and tenofovir over 48 
weeks.  
 
1.4.4 
Rationale for Use of Tablets and Granules 
 
The adult film-coated tablet will be available for participants in Cohort 1 and Cohort 2.  However, 
an age appropriate formulation of DOR/3TC/TDF consisting of oral granules is being developed.  
If an age appropriate formulation is available, both the adult film-coated tablet and the granule 
formulations will be an option for participants in Cohort 2.   
 
The age appropriate formulation may be administered in liquid or soft food, as described further 
in Section 5.2.2.  This will provide flexibility for participants who cannot or prefer not to swallow 
the film-coated tablet.  This will also allow obtaining preliminary data on the palatability and 
acceptability of the granule formulation to inform the development of future protocols for 
younger children.  
 
1.5 
Hypotheses 
 
This is an estimation study; thus, there is no hypothesis testing. 
 
 
2 
OBJECTIVES 
 
2.1 
Primary Objectives for Cohort 1 
 
The primary objectives of Cohort 1 are to:  
 
2.1.1 
Evaluate the pharmacokinetics of a single dose of DOR in HIV-1-infected children and 
adolescents, when added to a stable ART regimen comprised of an InSTI plus two 
NRTIs, using intensive PK sampling at Entry for identification of minimum weight 
threshold for doravirine 100 mg dose. 
2.1.2 
Evaluate the 2-week safety and tolerability of a single dose of DOR in HIV-1-infected 
children and adolescents, when added to a stable ART regimen comprised of an InSTI 
plus two NRTIs.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 35 of 129 
7 September 2017 
2.2 
Primary Objective for Cohort 2 
 
The primary objective of Cohort 2 is to:  
 
2.2.1 
Evaluate the 24-week safety and tolerability of DOR/3TC/TDF in HIV-1-infected 
children and adolescents. 
 
2.3 
Secondary Objectives for Cohort 2 
 
The secondary objectives of Cohort 2 are to:  
 
2.3.1 
Evaluate the pharmacokinetics of DOR, 3TC, and tenofovir in HIV-1-infected children 
and adolescents receiving DOR/3TC/TDF, using intensive (tenofovir and 3TC) and semi-
intensive (DOR) PK sampling at Week 1. 
2.3.2 
Evaluate the 24-, 48-, and 96-week virologic efficacy of DOR/3TC/TDF in HIV-1-
infected children and adolescents. 
2.3.3 
Evaluate the 24-, 48-, and 96-week immunologic response (CD4 cell count and 
percentage change from baseline) of HIV-1-infected children and adolescents.  
2.3.4 
Evaluate the 48- and 96-week safety and tolerability of DOR/3TC/TDF administered in 
HIV-1-infected children and adolescents.  
 
Objectives through Week 24 will be evaluated approximately concurrently with the primary 
objective for Cohort 2; additional longer-term secondary objectives for Cohort 2 will be evaluated 
as outcomes are available. 
 
2.4 
Other Objectives for Cohort 2 
 
2.4.1 
Evaluate the pharmacokinetics of DOR, 3TC, and tenofovir in HIV-1-infected children 
and adolescents receiving DOR/3TC/TDF, using sparse PK sampling through Week 48. 
2.4.2 
Assess changes in HIV-1 genotype and phenotype to DOR and other components of the 
regimen in participants experiencing virologic failure. 
2.4.3 
Evaluate acceptability, palatability, and adherence of DOR/3TC/TDF in HIV-1-infected 
children and adolescents through Week 96. 
 
 
3 
STUDY DESIGN 
 
This is a Phase I/II, multi-site, open-label, non-comparative PK, safety, and tolerability study of 
doravirine (DOR) and a fixed-dose combination of doravirine, lamivudine, and tenofovir 
disoproxil fumarate (DOR/3TC/TDF) in HIV-1-infected children and adolescents.  Refer to 
Figure 1 for an overview of the study design, to Sections 4.1-4.2 for the study eligibility criteria, 
and to Section 4.4 for a description of the study recruitment, screening, and enrollment process.  
Participants are expected to be enrolled at study sites in South Africa, Thailand, and the United 
States.  
 
The protocol will enroll two sequential cohorts, Cohorts 1 and Cohort 2, as described in Sections 
3.1 and 3.2, respectively.  In summary, participants will first be enrolled into Cohort 1 to evaluate 
the PK and safety of the 100 mg DOR dose, with intensive PK evaluation completed at entry and 
followed through two weeks on study to assess safety.  Specimens will be shipped in real time 
with ongoing testing, with team review of PK and safety data as available.  Upon enrollment of a 


IMPAACT 2014, FINAL Version 1.0 
Page 36 of 129 
7 September 2017 
minimum of 12 evaluable participants, enrollment will be paused while the Cohort 1 PK and 
safety data are reviewed by the protocol team and the SMC.  Data will be evaluated based on the 
algorithm in Section 9.2, with options of resuming enrollment into Cohort 1, proceeding with 
Cohort 2 enrollment, or assessing next steps for the study.   
 
If results from Cohort 1 are supportive, participants will be enrolled into Cohort 2 to evaluate the 
safety and tolerability of a fixed-dose combination regimen, including DOR, 3TC, and TDF.  A 
subset of participants will have intensive PK evaluations at Week 1 and all participants will have 
population PK evaluations through Week 48; the PK specimens will be shipped in batches with 
testing when sample collection is complete for all relevant participants (see Section 6.11.2).  
Participants will be followed through 96 weeks on study to assess long-term safety, virologic 
efficacy, and immunologic response, among other objectives as in Sections 2.3 and 2.4. 
 
3.1 
Cohort 1 
 
Up to 20 HIV-1-infected children and adolescents may be enrolled at study sites, to achieve at 
least 12 evaluable participants.  Participants must be 35 kg or greater and 12 years to less than 18 
years of age, receiving DTG or RAL plus two NRTIs, with virologic suppression.  A minimum of 
four participants between 35 and ≤45 kg will be enrolled in this cohort.  A single dose of DOR in 
a 100 mg tablet formulation (the adult dose) will be added, at entry, as a fourth agent (one time 
only) with intensive PK evaluations conducted around this single-dose.  No additional doses of 
DOR will be taken; participants will continue their ARV regimen.   
 
Participants will be followed for two weeks in Cohort 1 with clinical and laboratory evaluations 
as described in Section 6 and shown in the Schedule of Evaluations in Appendix I-A (Cohort 1).  
Safety outcomes will be assessed at two weeks.  
 
Participants will be considered evaluable based on the criteria in Sections 9.1 and 10.3.1. 
 
3.2 
Cohort 2 
 
Accrual into Cohort 2 will open following review of Cohort 1 PK and safety data by the CMC 
and SMC, as described in Section 9.6.  Up to 45 HIV-1-infected children and adolescents may be 
enrolled at study sites, to achieve at least 40 evaluable participants.  Participants must be 12 years 
to less than 18 years of age and will be either ART-naïve or ART-experienced and virologically 
suppressed.  Participants who are ART-naïve should also have genotypic resistance testing results 
that indicate susceptibility to study drugs at screening; if results are available from medical 
records, participants who are ART-experienced should also have results that indicate 
susceptibility to study drugs.  All participants will initiate DOR/3TC/TDF at entry.  
DOR/3TC/TDF will initially be provided in tablet formulation, as described in Section 5; if the 
age appropriate granule formulation becomes available during implementation of Cohort 2, this 
formulation will be provided as an option for participants.  Participants may be allowed to switch 
formulations during the study, as described further in Section 6.9. 
 
Enrollment to Cohort 2 is expected to open initially with only ART-naïve participants.  It is 
anticipated that data from the Phase 2b or 3 switch studies in virologically suppressed adults 
(PN028 and PN024; see Table 1 and Section 1.2.3) may become available during the conduct of 
this study.  If these adult data indicate virologic efficacy and safety, this study will allow 
enrollment of children and adolescents who are ART-experienced and virologically suppressed 
without evidence of prior virologic failure into Cohort 2 (see Section 1.4.2).  If the data from the 
switch studies are not supportive, Cohort 2 will only enroll ART-naïve children and adolescents.   


IMPAACT 2014, FINAL Version 1.0 
Page 37 of 129 
7 September 2017 
 
The minimum weight threshold for enrollment will be determined from Cohort 1 and, if Cohort 2 
opens to participants in the 35 to ≤45 kg weight group, a minimum of five participants in this 
weight group will be enrolled.  The first 10 participants enrolled into Cohort 2 will also have 
intensive PK sampling to evaluate the pharmacokinetics of DOR, 3TC, and tenofovir.   
 
Participants will be followed for 96 weeks in Cohort 2 with clinical and laboratory evaluations 
performed as described in Section 6 and shown in the Schedule of Evaluations in Appendix I-B 
(Cohort 2).  Every attempt will be made to retain participants for the duration of the study, unless 
they meet the criteria for early discontinuation, which include but are not limited to 
discontinuation of study drug, as listed in Section 4.6.  Safety outcomes will be assessed 
throughout follow-up, with standard evaluations performed at all sites; complete physical exams 
will be done annually.  Secondary virologic efficacy outcomes will be assessed throughout 
follow-up, using a single HIV-1 RNA testing platform, at all sites in real time.   
 
Participants will be considered evaluable based on the criteria in Section 9.1. 
 
 
4 
STUDY POPULATION 
 
This study will be conducted in HIV-1-infected children and adolescents 12 years to less than 18 
years of age weighing at least 35 kg.  There is no specified route of HIV transmission.  Children 
and adolescents will be selected for the study according to the criteria in Sections 4.1 and 4.2 and 
the guidelines in Section 4.3.  The study-specific approach to recruitment, screening, and 
enrollment is described in Section 4.4.  Considerations related to participant retention and 
withdrawal/termination from the study are provided in Sections 4.5 and 4.6, respectively.  Details 
regarding genotyping are provided in Section 4.7. 
 
Note:  Participants who have completed follow-up in Cohort 1 are eligible for enrollment in 
Cohort 2 as ART-experienced, virologically suppressed children and adolescents; previous 
exposure to DOR is not exclusionary.   
 
4.1 
Inclusion Criteria 
 
All the following criteria must be met in order for individuals to be enrolled in this study: 
 
4.1.1 
Age 12 years to less than 18 years at entry  
 
4.1.2 
Weight greater than or equal 35 kg at entry 
 
4.1.3 
If not of legal age to provide independent informed consent:  Parent or guardian is willing 
and able to provide written informed consent for study participation; in addition, when 
applicable per local Institutional Review Board / Ethics Committee (IRB/EC) policies 
and procedures, potential participant is willing and able to provide written informed 
assent for study participation   
 
If of legal age to provide independent informed consent as determined by site Standard 
Operating Procedures (SOPs) and consistent with site IRB/EC policies and procedures: 
Potential participant is willing and able to provide written informed consent for study 
participation 


IMPAACT 2014, FINAL Version 1.0 
Page 38 of 129 
7 September 2017 
 
4.1.4 
Confirmed HIV-1-infection based on documented testing of two samples collected at 
different time points:  
 
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 enzyme immunoassay (EIA) OR Western Blot OR immunofluorescence OR 
chemiluminescence 
• 
One HIV DNA polymerase chain reaction (PCR) 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One HIV total nucleic acid test 
 
Sample #2 may be tested using any of the following: 
• 
Rapid antibody test. If this option is used in combination with two rapid tests for 
Sample #1, at least one of the three rapid tests must be FDA-approved, and the third 
rapid test must be from a third manufacturer or based on a third principle or epitope. 
• 
One EIA OR Western Blot OR immunofluorescence OR chemiluminescence 
• 
One HIV DNA PCR 
• 
One quantitative HIV RNA PCR (above the limit of detection of the assay) 
• 
One qualitative HIV RNA PCR 
• 
One HIV total nucleic acid test 
 
All samples tested must be whole blood, serum, or plasma.  If both samples are tested 
using antibody tests, at least one of the samples must be tested in a laboratory that 
operates according to Good Clinical Laboratory Practice (GCLP) guidelines and 
participates in an appropriate external quality assurance program.  If nucleic acid testing 
is used, at least one test must be performed in a Clinical Laboratory Improvement 
Amendments (CLIA)-certified (US sites) or Virology Quality Assurance (VQA)-
approved (non-US sites) laboratory.  For tests performed in other (non-GCLP-compliant 
or non-VQA-approved) settings, adequate source documentation including the date of 
specimen collection, date of testing, test performed, and test result must be available. 
 
4.1.5 
ART exposure, virologic suppression, and resistance requirements, as follows: 
 
4.1.5.1 Cohort 1 
• 
ART exposure requirements, based on individual or parent/guardian’s report and, 
if available, confirmed by medical records: 
o At entry, receiving combination ART with RAL or DTG plus 2 NRTIs; AND 
o At entry, has not received NNRTIs, PIs, or cobicistat within the previous 30 
days; 
AND 
• 
Virologic suppression, as documented in medical records and as defined by: 
o One or more HIV RNA PCR result below the level of quantification (BLLQ) 
within 15 months prior to enrollment, AND  
o If any HIV RNA PCR tests have been done within 3 months prior to 
enrollment, all results are below the level of quantification, AND  
o HIV RNA PCR result less than 40 copies/mL at screening, performed as per 
Section 6.11.2 


IMPAACT 2014, FINAL Version 1.0 
Page 39 of 129 
7 September 2017 
 
Note:  A single, unconfirmed HIV-1 RNA result greater than or equal to the level of 
quantification but less than 500 copies/mL, between 3 and 15 months, prior to 
enrollment is not exclusionary as long as the other criteria for documentation of 
virologic suppression are met. 
 
4.1.5.2 Cohort 2 ART-naïve  
• 
ART exposure requirements, based on individual or parent/guardian’s report and, 
if available, confirmed by medical records: 
o At entry, received no ARVs for treatment of HIV infection including 
investigational agents (prior receipt of ARVs for prevention of perinatal 
transmission is permitted);  
AND 
• 
Screening genotypic resistance test results indicate susceptibility to DOR, TDF, 
and 3TC (see Section 4.7; result must be available prior to enrollment), 
performed as per Section 6.11.2;  
 
AND 
• 
If available, as documented in medical records, any prior genotypic resistance 
test result indicates susceptibility to DOR, TDF, and 3TC (see Section 4.7) 
 
Note:  For individuals that are re-screened, the genotypic resistance test does not 
need to be repeated.  
 
4.1.5.3 Cohort 2 ART-experienced 
• 
ART exposure requirements, based on individual or parent/guardian’s report and, 
if available, confirmed by medical records: 
o No previous history of change in ARVs due to clinical or virologic failure, in 
the opinion of the site investigator or designee; 
AND 
• 
Virologic suppression, as documented in medical record and as defined by: 
o One or more HIV RNA PCR result below level of quantification (BLLQ) 
within 6 months prior to enrollment, AND 
o If any HIV RNA PCR tests have been done within 3 months prior to 
enrollment, all results are below the level of quantification, AND 
o HIV RNA PCR result less than 40 copies/mL at screening, performed as per 
Section 6.11.2;  
AND 
• 
If available, as documented in medical records, any prior genotypic resistance 
test result indicates susceptibility to DOR, TDF, and 3TC (see Section 4.7) 
 
Note: This group of ARV-experienced, virologically suppressed participants will only 
enroll once there are data from the adult switch studies indicating virologic efficacy 
and safety (see Section 1.4.2).  Sites will be informed via a Clarification 
Memorandum when ART-experienced participants can be enrolled.   
 
4.1.6 
Grade 2 or lower hemoglobin, AST, ALT, alkaline phosphatase, and lipase on specimens 
obtained at screening 
 


IMPAACT 2014, FINAL Version 1.0 
Page 40 of 129 
7 September 2017 
4.1.7 
For Cohort 2 only, grade 2 or lower creatinine, proteinuria, and glycosuria on specimens 
obtained at screening 
 
4.1.8 
Estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2, on specimens obtained 
at screening, based on the Schwartz equation which is as follows:  
 
Schwartz formula: GFR (mL/min/1.73 m2) = K x Ht cm/Pcreat 
K=constant 
 
 
Cr mg/mL 
Children 2-12 years 
 
0.55 
Female 13-21 years 
 
0.55 
Males 13-21 years 
 
0.70 
 
4.1.9 
For females who have reached menarche or who are engaging in sexual activity (self-
reported), negative pregnancy test at entry 
 
4.1.10 For females engaging in sexual activity that could lead to pregnancy (self-reported), 
agrees to use two effective, medically accepted birth control methods while on study and 
for two weeks after permanently discontinuing study drug 
 
4.1.11 For males engaging in sexual activity that could lead to pregnancy (self-reported), agrees 
to use condoms while on study and for two weeks after permanently discontinuing study 
drug 
 
4.1.12 Able and willing to swallow available formulation(s) (tablet or, as available, oral 
granules) 
 
Note:  The study is expected open to accrual with only the tablet formulation available.  
Sites will be informed when the oral granule formulation is available for participant use.  
Once the granule formulation is available, participants in Cohort 2 will be asked to 
choose which formulation they would like to take at Entry.  Formulation switches during 
the study may be allowed, as described in Section 6.9. 
 
4.2 
Exclusion Criteria 
 
Participants must be excluded from the study if, at any time during the screening period, any of 
the following are identified:   
 
4.2.1 
Evidence of decompensated liver disease manifested by the presence of or a history of 
ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy, or other signs or 
symptoms of advanced liver diseases  
 
Note:  Individuals with chronic hepatitis B who have grade 2 or lower ALT and AST and 
have no significant impairment of hepatic synthetic function (significant impairment of 
hepatic synthetic function is defined as a serum albumin <2.8 mg/dL or an INR >1.7 in 
the absence of another explanation for the abnormal laboratory value) are eligible.   
 
4.2.2 
For Cohort 2 only, detectable hepatitis C virus (HCV) by RNA PCR or current or 
planned treatment with direct antiviral agent for HCV  
 
Note:  HCV antibody positivity but undetectable by HCV RNA PCR results are permitted.  


IMPAACT 2014, FINAL Version 1.0 
Page 41 of 129 
7 September 2017 
 
4.2.3 
Presence of any active AIDS-defining opportunistic infection 
 
4.2.4 
History of malignancy (ever), with the exception of localized malignancies such as 
squamous cell or basal cell carcinoma of the skin  
 
4.2.5 
Clinical evidence of pancreatitis, as determined by the clinician (at entry) 
 
4.2.6 
Use of nafcillin, dicloxacillin, or any of the prohibited medications, within 30 days prior 
to study entry (see Section 5.8 for a complete list of prohibited medications) 
 
4.2.7 
For females, currently breastfeeding an infant at entry 
 
4.2.8 
Enrolled in another clinical trial of an investigational agent, device, or vaccine  
 
4.2.9 
Unlikely to adhere to the study procedures or keep appointments, in the opinion of the 
site investigator or designee 
 
4.2.10 Used, or anticipates using, chronic systemic immunosuppressive agents or systemic 
interferon (e.g., for treatment of HCV infection) within 30 days prior to study entry 
 
Note:  Systemic corticosteroids (e.g., prednisone or equivalent up to 2 mg/kg/day) for 
replacement therapy or short courses (≤30 days) are permitted.  See Section 5.8 for a 
complete list of prohibited medications. 
 
4.2.11 Diagnosed with current active tuberculosis and/or is currently being treated with a 
rifampicin-containing regimen 
 
4.2.12 Individual has any other condition, that in the opinion of the site investigator or designee, 
would make participation in the study unsafe, complicate interpretation of study outcome 
data, or otherwise interfere with achieving study objectives 
 
4.3 
Co-Enrollment Considerations 
 
Co-enrollment in other studies (e.g., observational studies) is permitted with approval from the 
Protocol Chairs of both studies (excluding the clinical trials noted in 4.2.8, above).  Requests for 
approval of co-enrollment should be emailed to the Clinical Management Committee (CMC; refer 
to Sections 7.1.2 and 9.6.1 for more information regarding the role of the CMC for this study).  
 
4.4 
Recruitment, Screening, and Enrollment Process 
 
Recruitment methods for this study may vary across sites and will vary based on the expected 
enrollment cohort.  All participants must be 12 years to less than 18 years of age at the time of 
enrollment and must be HIV-1-infected; participants may be perinatally or behaviorally infected.   
 
Recruitment of participants for Cohort 1 is expected to rely on current patients being seen at a 
study clinic or from active identification and referral of HIV-1-infected children and adolescents 
who are ART-experienced and virologically suppressed.  Recruitment of participants for Cohort 2 
is expected to rely more on active identification and referral of newly diagnosed HIV-1-infected 
children and adolescents (i.e., Cohort 2 ART-naïve).  In addition, if data from the adult switch 
studies indicate virologic efficacy and safety, participants who are ART-experienced and 


IMPAACT 2014, FINAL Version 1.0 
Page 42 of 129 
7 September 2017 
virologically suppressed will be allowed to enroll (see Section 1.4.2); it is expected that 
recruitment methods for these participants will more closely mirror methods to recruit for 
Cohort 1. 
 
Upon identification of a potentially eligible participant, study staff will provide information about 
the study to the parent or guardian and/or the potential participant (as applicable).  Each parent or 
guardian and/or potential participant (as applicable) who expresses interest in learning more about 
the study will be provided additional information, education, and counseling as part of the study 
informed consent process.  The process will include detailed review of the study informed 
consent and assent forms (as applicable), time to address any questions or concerns the potential 
participant, parent, or guardian may have, and an assessment of understanding, before proceeding 
to informed consent and assent decisions.  Informed consent and assent processes will be fully 
documented, consistent with the Division of AIDS (DAIDS) policies referenced in Section 11.2.  
Refer to Section 13.3 for further information on informed consent procedures for this study.   
 
Each site must establish SOPs for eligibility determination that describe where and when 
screening procedures will be performed; roles and responsibilities for performing the required 
procedures; roles and responsibilities for assessing and confirming eligibility; and procedures for 
documenting the process, taking into consideration the required timing of enrollment.  Sites are 
encouraged to minimize the time from screening to enrollment; for Cohort 2, ART-naïve 
participants, in particular, the screening period should be as short as possible so that ART 
initiation is not unduly delayed.   
 
Eligibility screening will be initiated after written informed consent is provided.  Screening will 
include confirmatory HIV-1 testing (if needed) and assessment of other entry criteria.  If at any 
time, it is determined that an individual is not eligible for the study, or that study participation 
may not be feasible or in the participant’s best interest, the eligibility screening process will be 
discontinued; these individuals should be actively referred to non-study sources of care.  
Screening assessments, unless otherwise noted (see Section 6.1), should be completed within 30 
days prior to entry.  Re-screening is permitted one time within a six-month period, as further 
described in Section 6.1.  
 
Individuals who are found to meet the study eligibility criteria will be enrolled and ideally will 
receive their first dose of study drug at study entry.  Screening procedures may be performed on 
the day of enrollment; however, individual’s HIV test results and hematology and chemistry test 
results must be available for eligibility determination prior to enrollment.  
 
Participants in Cohort 1 will undergo intensive pharmacokinetic evaluations ideally beginning on 
the day of entry through approximately 72 hours post-study drug ingestion.  As described further 
in Section 6.2.1, participants may stay at the clinical research facility overnight for the PK 
evaluations, depending on site capacity. 
 
The IMPAACT Data Management Center (DMC) Subject Enrollment System (SES) will be used 
to assist with tracking the screening and enrollment process.  When informed consent is obtained, 
participant identification numbers (PIDs) will be assigned and a study-specific screening number 
will be obtained through the SES.  For individuals found to be eligible, enrollment will occur 
upon successful entry of required eligibility data into the SES.  Successful entry into the SES will 
generate a study identification number (SID) and prescribing information for the cohort in which 
the participant has been enrolled.  For individuals who are screened and found to be ineligible for 
the study, or who do not enroll in the study for any reason, an eCRF will be entered to record the 


IMPAACT 2014, FINAL Version 1.0 
Page 43 of 129 
7 September 2017 
screening outcome.  Refer to Section 9.6 for more information on monitoring participant accrual 
in this study.  
 
4.5 
Participant Retention 
 
Once a participant is enrolled in this study, study staff will make every effort to retain the 
participant for the protocol-specified duration of follow-up and thereby minimize potential biases 
associated with loss-to-follow-up.  Refer to Section 9.6 for more information on monitoring 
participant retention in this study. 
 
4.6 
Participant Withdrawal or Termination from the Study 
 
Regardless of the participant retention procedures referenced above, participants may voluntarily 
withdraw from the study at any time.  Participants may also be terminated from the study by the 
site investigator or designee under the following circumstances: 
 
• 
Participant re-locates away from the study site and cannot be transferred to another site or is 
otherwise determined to be lost-to-follow-up 
• 
Participant or parent/guardian refuses further treatment and/or follow-up evaluations 
• 
Participant is permanently discontinued from study drug for any reason (see Section 8.7; 
participants in Cohort 2 will be asked to continue on study for at least 4 weeks after they 
discontinue study drugs or until resolution [return to baseline] or stabilization of any adverse 
events with the frequency of visits determined by the site investigator) 
• 
Site investigator or designee determines that continued participation in the study would be 
unsafe or otherwise not in the best interest of the participant, after consultation with the CMC 
• 
The study is stopped or canceled by the sponsors, government or regulatory entities, or site 
IRBs/ECs 
 
Should the consenting parent (or guardian) of a participant die or no longer be available for any 
reason, sites should follow the guidelines and procedures as directed by their IRBs/ECs.  In 
general, if participants in Cohort 2 are doing well on the study drug, it is expected that they will 
stay on study drug and will have safety assessments performed per the local standard of care 
while continued study participation is being determined.  Study sites may continue to provide 
care for the participant as needed and appropriate (outside of the study), consistent with the 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.  Refer to Section 
13.3 for further guidance on parent/guardian consent for study participation. 
 
For any participant who is withdrawn or terminated from the study prior to scheduled completion 
of follow-up, study staff will document the reason for the withdrawal or termination in detail and, 
for participants in Cohort 2, will make every effort to complete final evaluations as described in 
Section 6.5.  In the event that the circumstances that led to a participant’s withdrawal or 
termination change (e.g., the family returns to the study site area after having re-located 
previously), the site investigator or designee should contact the CMC to discuss options for 
resumption of follow-up. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 44 of 129 
7 September 2017 
4.7 
Genotyping 
 
A list of genotypes will be posted on the study-specific website:  
 
http://impaactnetwork.org/studies/IMPAACT2014.asp 
 
Participants who are re-screened do not need to repeat genotype testing.  
 
 
5 
STUDY DRUG CONSIDERATIONS  
 
Site pharmacists should consult the Pharmacy Guidelines and Instructions for DAIDS Clinical 
Trials Networks for standard pharmacy operations.  Refer to Figure 1 for an overview of the study 
design and to the Investigator’s Brochures (IBs) for further information about the study drugs. 
 
5.1 
Study Drug Regimens 
 
Cohort 1 
Participants enrolled in Cohort 1 will receive doravirine (DOR, MK-1439) once 
on the day of intensive PK evaluations.  
 
Cohort 2 
Participants enrolled in Cohort 2 will receive a fixed-dose combination of 
doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF, MK-
1439A) once daily for 96 weeks on study.  
 
5.2 
Study Drug Formulations 
 
5.2.1 
Cohort 1 
 
Doravirine (DOR): 100 mg oral tablets.  The formulation is a film-coated, compressed tablet, 
comprised of 100 mg DOR.  Store between 2°C and 30°C (36°-86°F), protected from light and 
moisture, in the original container, tightly closed.  Tablets may not be crushed or split. 
 
5.2.2 
Cohort 2 
 
Doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF): fixed-dose combination 
oral tablets.  The formulation is a film-coated, bilayer compressed tablet, comprised of 100 mg 
DOR, 300 mg 3TC, and 300 mg TDF.  Store between 2°C and 25°C (36°-77°F), protected from 
moisture and freezing.  Tablets may not be crushed or split. 
 
Doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF): fixed-dose combination 
oral granules.  The formulation is comprised of 100.6 mg of DOR, 300 mg 3TC, and 300 mg 
TDF, divided between three capsules of oral granules.  The individual components may be stored 
separately between 2°C and 30°C (36°-86°F), protected from light with a desiccant.  The stability 
of the combination product is to be determined. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 45 of 129 
7 September 2017 
5.3 
Study Drug Administration  
 
Cohort 1 
A single dose of doravirine (DOR) will be administered orally and directly 
observed in the clinic on the day of intensive PK.  Administration will occur in 
the context of PK specimen collection as described in Section 6.   
 
Cohort 2  
Doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) will be 
administered orally as a fixed-dose combination once daily. 
 
The fixed-dose combination DOR/3TC/TDF capsules may be opened and the 
oral granules sprinkled on the tongue then swallowed (followed with water); 
sprinkled onto 1-2 teaspoons of soft food then swallowed; or dispersed in 5-
10 mL liquid then swallowed. In any case, administration must occur within 15 
minutes of mixing.  
 
Doravirine tablets must be swallowed whole and may not be crushed or split. Participants and 
caregivers will be counseled as needed throughout the study to help ensure adherence.  Refer to 
Section 6.10 for additional information on adherence counseling for participants in Cohort 2.  Site 
staff will confirm full adherence with dosing three days prior to scheduling the intensive PK visit 
for the first 10 participants of Cohort 2.   
 
5.4 
Study Drug Supply 
 
Doravirine and DOR/3TC/TDF will be supplied by Merck & Company and will be available 
through the Clinical Research Products Management Center (CRPMC).   
 
The other components of the ARV regimen in Cohort 1 are not considered study product and will 
not be supplied by the study. 
 
Upon successful completion of protocol registration procedures, the site pharmacist can obtain 
the study drug for this study by following the instructions in the manual Pharmacy Guidelines 
and Instructions for DAIDS Clinical Trials Networks. 
 
5.5 
Study Drug Accountability 
 
Site pharmacists must maintain complete records of all study drugs received from the CRPMC. 
 
5.6 
Final Disposition of Study Drug 
 
Any unused study drug remaining at US sites after the study is completed or terminated must be 
returned to the CRPMC (unless otherwise directed by the sponsor).  Any unused study drug 
remaining at non-US sites after the study is completed or terminated will be destroyed.  Site 
pharmacists will follow the relevant instructions for return or destruction of unused study drug 
provided in the Pharmacy Guidelines and Instructions for DAIDS Clinical Trials Networks. 
 
5.7 
Concomitant Medications  
 
All concomitant medications received by enrolled participants will be source documented from 
30 days prior to entry through study discontinuation as part of the medical and medications 
histories obtained at each study visit (see Section 6.7).  This includes prescription and non-


IMPAACT 2014, FINAL Version 1.0 
Page 46 of 129 
7 September 2017 
prescription (over-the-counter) medications; vaccines and other preventive medications; 
contraceptives; antacids; vitamins and other nutritional supplements; and alternative, 
complementary, and traditional medications and preparations.  Requirements for entering 
concomitant medications into eCRFs are specified in Section 6.7. 
 
5.8 
Prohibited Medications  
 
Any participant who requires a medication considered prohibited while on the study drug must 
have the study drug permanently discontinued.  A list of prohibited medications is provided 
below: 
 
• 
Bosentan 
• 
Carbamazepine 
• 
Modafinil 
• 
Phenobarbital 
• 
Phenytoin 
• 
Rifabutin 
• 
Rifampicin 
• 
St. John’s Wort 
 
In the event that a need for one or more of the above-listed medications is identified, the site 
investigator or designee should consult the CMC for further guidance on management. 
 
Use of nafcillin or dicloxacillin within 30 days prior to study entry is prohibited (if needed after 
entry, see below in Section 5.9). 
 
5.9 
Precautionary Medications 
 
The site investigator or designee should consult with the CMC for any participant who requires a 
medication considered precautionary while on the study drug, ideally in advance (or as soon as 
possible) of administration.  A list of precautionary medications is provided below: 
 
• 
Nafcillin and dicloxacillin (which induce CYP3A4 activity) – if treatment with more than 7 
days of nafcillin or dicloxacillin is required while on the study drug, the study drug may need 
to be permanently discontinued; site investigators should consult with the CMC to determine 
study drug management.  Alternative antibiotics, such as oxacillin, cefazolin, or clindamycin, 
should be selected when clinically appropriate. 
• 
Herbal remedies 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 47 of 129 
7 September 2017 
6 
STUDY VISITS AND PROCEDURES 
 
An overview of the schedule of study visits and evaluations is provided in Appendix I-A (Cohort 
1) and Appendix I-B (Cohort 2); blood draw volumes for each visit are also detailed in these 
appendices.  Information related to scheduled visits is presented in Sections 6.1-6.3; information 
related to an event driven visit for virologic failure is presented in Section 6.4; information related 
to an early discontinuation visit is presented in Section 6.5; information on post-study contacts is 
presented in Section 6.6; information on medical and medications history, physical examinations, 
assessment of palatability and acceptability, and assessment of adherence are presented in 
Sections 6.7-6.10.  Additional considerations for laboratory procedures are provided in Section 
6.11. 
 
All visits and procedures must be performed at the approved clinical research site or approved 
associated facilities.  All visits and procedures must be documented in accordance with the US 
National Institute of Allergy and Infectious Diseases (NIAID) Division of AIDS (DAIDS) 
policies for source documentation; refer to Section 11 for more information on documentation 
requirements and completion of eCRFs.  Refer to Section 7 for information on expedited adverse 
event (EAE) reporting, which may be required at any time during follow-up.  All visits and 
procedures specified to be performed at scheduled visits should ideally be performed on the same 
day.  However, if this is not possible (e.g., if a participant must leave the clinical research site 
before all procedures can be performed), visits may be split, with procedures performed on more 
than one day within the allowable visit window. 
 
In addition to the protocol-specified procedures listed in this section, study staff may complete 
other tasks consistent with site SOPs, including but not limited to collecting, reviewing, and 
updating demographic and locator information; reviewing elements of informed consent; 
scheduling telephone contacts and visits; providing instructions for contacting study staff between 
visits; providing visit reminders; and following up on missed visits.  All such tasks should be 
documented consistent with site SOPs.  Study staff should inform parents/guardians (or 
participants, if applicable) of clinically meaningful physical exam findings and laboratory test 
results, when available. 
 
6.1 
Cohort 1 and Cohort 2 Screening Visit  
 
Refer to Section 4.4 for a description of the study recruitment, screening, and enrollment process. 
 
Screening may be initiated after written informed consent is obtained.  All screening procedures 
are expected to be performed within 30 days prior to study entry.  Multiple visits may be 
conducted within the 30-day time frame to complete all required procedures and to repeat 
laboratory tests, if necessary.  For Cohort 1 and Cohort 2, creatinine testing is required in relation 
to the eligibility criterion in Section 4.1.8; as soon as the screening creatinine test result is 
obtained, the estimated GFR should be calculated using the Schwartz equation, and all results 
should be graded for severity as specified in Section 7.3.3.  For Cohort 2, ART-naïve participants, 
the screening period should be as short as possible so that ART initiation is not unduly delayed.   
 
For Cohort 1, participants will take the study drug as a tablet; for Cohort 2, participants may be 
offered the study drug as either a tablet or as oral granules.  If both formulations are available, the 
site investigator or designee should explain the differences between formulations as part of the 
informed consent process and document the participant’s decision prior to enrollment in the 


IMPAACT 2014, FINAL Version 1.0 
Page 48 of 129 
7 September 2017 
study.  Formulation switches may be allowed during the study, as described further in Section 
6.9. 
 
For potential participants who do not meet the eligibility criteria, screening should be 
discontinued once ineligibility is determined and these individuals should be actively referred to 
non-study sources of care.   
 
Screening Visit Procedures (within 30 days prior to study entry) 
Administrative 
and Regulatory 
• Obtain written informed consent for IMPAACT 2014 
• Assign PID to child or adolescent 
• Obtain screening number from SES 
• Obtain available documentation of participant’s HIV status  
Clinical 
• Obtain available medical records and medical and medications history  
• Assess documentation of HIV infection in relation to study requirements 
• Assess ARV history in relation to study requirements 
• Perform complete physical exam, including body weight 
• For Cohort 2, WHO staging 
Laboratory 
Blood  
Collect blood for: 
• Confirmatory HIV testing, if needed per Section 4.1.4 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Creatinine 
o Lipase 
o LFTs (AST, ALT, and alkaline phosphatase)  
• HIV-1 RNA 
• For Cohort 2, Hepatitis C antibody; if Hepatitis C antibody positive, HCV RNA 
PCR  
• For Cohort 2, Hepatitis B surface antigen  
• For Cohort 2, ART-naïve, genotypic resistance testing (real-time) 
Urine 
For Cohort 2, collect urine for: 
• Dipstick urinalysis, including specific gravity, pH, blood, ketones, glucose, 
protein, and nitrite 
 
Participants can be re-screened once in a six-month period if determined to be ineligible on the 
initial screening process and, for Cohort 2, ART-naïve participants, if re-screening would not 
delay initiation of ART.  If any participant is re-screened, all the screening procedures listed 
above must be repeated, with the exception that: 
 
• 
A new PID should not be assigned 
• 
Confirmatory HIV testing and genotype testing need not be repeated 
• 
Previously documented medical and medications history information should be reviewed and 
updated through the date of re-screening (it is not necessary to re-record history information 
that was previously documented) 
• 
Informed consent need not be repeated, if re-screening occurs less than 60 days after the 
initial consent 
 


IMPAACT 2014, FINAL Version 1.0 
Page 49 of 129 
7 September 2017 
6.2 
Cohort 1 Visits and Procedures 
 
6.2.1 
Cohort 1 Entry Visit 
 
Refer to Section 4.4 for a description of the study recruitment, screening, and enrollment process.  
Procedures that may provide information relevant to eligibility for the study should be performed 
first, prior to final eligibility determination and enrollment.  For eligible and enrolled participants, 
PK sampling should ideally begin on the day of entry.  In the event that a participant is found to 
be ineligible on the day of enrollment, enrollment should not occur.  
 
Additional guidance for sequencing of procedures at the Cohort 1 Entry Visit is as follows: 
 
• 
Final eligibility determination and confirmation (medical history, complete physical exam, 
and, if needed, pregnancy testing) must precede enrollment; if pregnancy testing is required 
per Section 4.1.9, a blood or urine pregnancy test should be performed, with results available 
for eligibility determination prior to enrollment 
• 
Selection and confirmation of formulation must precede enrollment 
• 
Enrollment must precede prescribing of study drug 
• 
Prescribing must precede dispensing of study drug 
• 
Pre-dose PK blood sample must precede ingestion of the single dose of study drug  
• 
Ingestion of study drug must precede palatability and acceptability assessment 
 
Participants will be entered into the study on Day 0, with PK procedures continuing up to 
approximately 72 hours post-dose, as outlined below. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 50 of 129 
7 September 2017 
Cohort 1 Entry Visit Procedures (Day 0) 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Clinical 
• Update medical and medications history since last visit* 
• Perform complete physical exam, including body weight*  
Laboratory 
Blood 
 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline 
phosphatase, AST, ALT, and albumin) 
• CD4 cell counts 
• HIV-1 RNA 
• Intensive PK evaluation, per Table 14 below 
Blood or 
Urine 
Collect blood or urine for: 
• Pregnancy test, if needed per Section 4.1.9* (see above for further guidance) 
Study Drug 
• Prescribe, dispense, and facilitate administration of the doravirine dose 
AFTER collection of pre-dose PK sample 
• Administer palatability and acceptability assessment AFTER administration 
of the doravirine dose 
*Perform prior to enrollment 
 
Assessment of creatinine is required at this visit.  As soon as the creatinine result is obtained, the 
estimated GFR should be calculated using the Schwartz formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 
A single dose of doravirine will be observed in the clinic on the same day as the intensive PK 
evaluation and ideally on the day of entry.  PK sampling will be conducted over the course of 
approximately 72 hours, with one sample collected pre-dose and eight samples collected post-
dose, as shown in Table 14, below. 
 
Table 14.  Cohort 1 Intensive PK Evaluation Sampling Time Points 
Time  
Points 
Pre-
dose 
1 hr 
post-
dose 
2 hrs 
post-
dose 
4 hrs 
post-
dose 
8 hrs 
post-
dose 
12 hrs 
post-
dose 
24 hrs 
post-
dose 
48 hrs 
post-
dose 
72 hrs 
post-
dose 
Window 
 
No  
window 
± 15 
mins 
± 15 
mins 
± 1 hr 
± 1 hr 
± 1 hr 
± 2 hrs 
± 2 hrs 
± 2 hrs 
hr(s)=hour(s); mins=minutes 
 
Depending on site capacity and participant preferences, participants and their parents or guardians 
may stay at the clinical research facility overnight for the PK sampling.   


IMPAACT 2014, FINAL Version 1.0 
Page 51 of 129 
7 September 2017 
 
6.2.2 
Cohort 1 Week 2 Visit 
 
The Week 2 Visit is targeted to take place on Day 14, counted from the day of entry as Day 0, 
with an allowable window of ± 2 days.  This visit is the final scheduled visit for participants in 
Cohort 1.  There is no required sequencing of procedures at this visit. 
 
Cohort 1 Week 2 Visit (Day 14 ± 2 days) 
Clinical 
• Update medical and medications history since last visit 
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
Laboratory 
Blood 
 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, 
AST, ALT, and albumin) 
 
Assessment of creatinine is required at this visit.  As soon as the creatinine result is obtained, the 
estimated GFR should be calculated using the Schwartz formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
  
At this visit, arrangements should be made to provide all clinically meaningful results to the 
participant’s parent or guardian.  The participant and parent or guardian should be informed of 
how to contact study staff with any post-study questions and how to learn about the results of the 
study when available. 
 
6.3 
Cohort 2 Visits and Procedures 
 
6.3.1 
Cohort 2 Entry Visit 
 
Refer to Section 4.4 for a description of the study recruitment, screening, and enrollment process.  
The procedures that may provide information relevant to eligibility for the study should be 
performed first, prior to final eligibility determination and enrollment.  In the event that a 
participant is found to be ineligible on the day of enrollment, enrollment should not occur.  
 
Additional guidance for sequencing of procedures at the Cohort 2 Entry Visit is as follows: 
• 
Final eligibility determination and confirmation (medical history, complete physical exam, 
and, if needed, pregnancy testing) must precede enrollment; if pregnancy testing is required 
per Section 4.1.9, a blood or urine pregnancy test should be performed, with results available 
for eligibility determination prior to enrollment 
• 
Selection and confirmation of formulation must precede enrollment 
• 
Enrollment must precede prescribing of study drug 
• 
Prescribing must precede dispensing of study drug 
• 
Pre-dose PK blood collection must precede ingestion of the first dose of study drug  
 


IMPAACT 2014, FINAL Version 1.0 
Page 52 of 129 
7 September 2017 
ART-experienced, virologically suppressed participants will discontinue previous ARVs and start 
DOR/3TC/TDF on the day of enrollment. 
 
Cohort 2 Entry Visit Procedures (Day 0) 
Administrative 
and Regulatory 
• Complete final eligibility determination and confirmation* 
• Complete paper-based eligibility checklist*, enter checklist data into SES to 
enroll the participant and generate SID; print and file a copy of the 
confirmation file 
Clinical 
• Update medical and medications history since last visit* 
• Perform complete physical exam, including body weight* 
Laboratory 
 
Blood 
 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline 
phosphatase, AST, ALT, and albumin) 
• Lipid profiles 
• HIV-1 RNA  
• CD4 cell count 
• Sparse PK evaluation (see Section 6.3.8) 
• Participants who are ART-naïve only, store plasma for phenotypic resistance 
testing 
Blood or 
Urine 
Collect blood or urine for: 
• Pregnancy test, if needed per Section 4.1.9* (see above for further guidance) 
Study Drug 
• If granule formulation is available, confirm selection of formulation* 
• Prescribe, dispense, and facilitate administration of DOR/3TC/TDF AFTER 
collection of the pre-dose PK sample 
• Provide instructions for DOR/3TC/TDF administration and adherence 
counseling to the participant, parent or guardian 
*Perform prior to enrollment 
 
Assessment of creatinine is required at this visit.  As soon as the creatinine result is obtained, the 
estimated GFR should be calculated using the Schwartz formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 53 of 129 
7 September 2017 
6.3.2 
Cohort 2 Week 1 Visit: Participants Selected for Intensive PK Evaluations ONLY 
 
For the first 10 participants enrolled in Cohort 2 only, intensive PK evaluations are targeted at 
Week 1.  The Week 1 Visit is targeted to take place on Day 8, counted from the day of entry as 
Day 0, with an allowable window of + 5 days.   
 
Additional guidelines and guidance for sequencing of procedures at the Cohort 2 Week 1 Visit is 
as follows: 
• 
The intensive PK evaluation should be scheduled so that the observed dosing of study drug is 
as close as possible to 24 hours (generally 22-26 hours) after the previous dosing.   
• 
Prior to this visit, adherence to study drug should be emphasized and supported.  Sites may 
use reminder calls or scheduling cards for participants and parents or guardians to reinforce 
adherence within the three days prior to the scheduled intensive PK evaluation.  (For 
example, sites could call or visit the participant and/or parent/guardian prior to the scheduled 
PK evaluation to reinforce adherence.) 
• 
Participants should take study drug for three days (i.e., be fully adherent) prior to the 
intensive PK visit; the study drug dose and time of the previous three study drug doses should 
be source documented and entered into eCRFs.  If a missed dose is reported within this 
period, the intensive PK evaluation should be rescheduled.  As described in Section 6.9, 
participants may change their formulation after entry if the granule formulation is available; 
however, they would need to be on the new formulation at least one day prior to the intensive 
PK at Week 1. 
• 
Participants who report intercurrent illness immediately prior to or on the day of the 
scheduled PK visit that may have interfered with study drug administration or resulted in 
malabsorption of study drug (e.g., fever, vomiting, diarrhea), the intensive PK evaluation 
should be rescheduled.  
• 
Depending on site capacity and participant preferences, participants and their parents or 
guardians may stay at the clinical research facility overnight for the PK sampling. 
 
Cohort 2 Week 1 Visit (Day 8 + 5 days) 
Clinical 
• Obtain interval medical and medications history  
• Perform symptom-directed physical exam 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
 
Blood 
 
Collect blood for: 
• Intensive PK evaluation, per Table 15 below 
Study Drug 
• Prescribe and dispense study drug, as needed 
• Provide instructions for DOR/3TC/TDF administration and adherence 
counseling to the participant, parent or guardian, as needed 
 
Samples will be collected per Table 15, below. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 54 of 129 
7 September 2017 
Table 15.  Cohort 2 Week 1 PK Evaluation Sampling Time Points 
Time  
Points 
Pre-dose 
1 hr  
post-dose 
2 hrs 
post-dose 
4 hrs 
post-dose 
8 hrs 
post-dose 
12 hrs 
post-dose 
24 hrs 
post-dose 
Window 
 
No 
window 
± 15 mins 
± 15 mins 
± 1 hr 
± 1 hr 
± 1 hr 
± 2 hrs 
Volume 
 
3.5 mL 
2.5 mL 
3.5 mL 
3.5 mL 
2.5 mL 
3.5 mL 
3.5 mL 
Analyte 
 
DOR, 
3TC, 
tenofovir 
3TC, 
tenofovir 
DOR, 
3TC, 
tenofovir 
DOR, 
3TC, 
tenofovir 
3TC, 
tenofovir 
DOR, 
3TC, 
tenofovir 
DOR, 
3TC, 
tenofovir 
hr(s)=hour(s); mins=minutes 
 
6.3.3 
Cohort 2 Week 2 Visit 
 
The Week 2 Visit is targeted to take place on Day 14, counted from the day of entry as Day 0, 
with an allowable window of ± 1 week.  There is no required sequencing of procedures at this 
visit.  For the participants selected for intensive PK evaluations (i.e., the first 10 enrolled into 
Cohort 2), although the visit windows overlap, the Week 2 visit procedures may NOT be 
combined with Week 1 visit procedures and Week 2 visit procedures must be conducted after 
Week 1 visit procedures.  
 
Cohort 2 Week 2 Visit (Day 14 ± 1 week) 
Clinical 
• Obtain interval medical and medications history 
• Perform symptom-directed physical exam  
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
 
Blood 
 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline phosphatase, 
AST, ALT, and albumin) 
• HIV-1 RNA 
Urine 
Collect urine for: 
• Dipstick urinalysis, including specific gravity, pH, blood, ketones, glucose, 
protein, and nitrite 
Study Drug 
• Prescribe and dispense study drug, as needed 
• Provide instructions for DOR/3TC/TDF administration and adherence 
counseling to the participant, parent or guardian, as needed 
• Administer palatability and acceptability assessment 
 
Assessment of creatinine is required at this visit.  As soon as the creatinine result is obtained, the 
estimated GFR should be calculated using the Schwartz formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 55 of 129 
7 September 2017 
6.3.4 
Cohort 2 Week 4 Visit  
 
The Week 4 Visit is targeted to take place on Day 28, counted from the day of entry as Day 0, 
with an allowable window of - 1 week to + 2 weeks.  If possible, pre-dose sparse PK blood 
collection should precede ingestion of the study drug (see Section 6.3.8).  As described in Section 
6.9, participants may change their formulation after entry if the granule formulation is available; 
however, they would need to be on the new formulation at least one day prior to the first sparse 
PK assessment visit at Week 4. 
 
Cohort 2 Week 4 Visit (Day 28, - 1 week / + 2 weeks) 
Clinical 
• Obtain interval medical and medications history  
• Perform symptom-directed physical exam  
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
 
Blood 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline 
phosphatase, AST, ALT, and albumin) 
• HIV-1 RNA 
• CD4 cell count 
• Sparse PK evaluation (see Section 6.3.8) 
Blood or 
Urine 
Collect blood or urine for: 
• Pregnancy test, if needed per Section 8.8.1 
Study Drug 
• Administer adherence assessment 
• Prescribe and dispense study drug, as needed (see Section 6.3.8 for additional 
detail regarding timing on study drug administration during the sparse PK 
evaluation) 
• Provide instructions for DOR/3TC/TDF administration and adherence 
counseling to the participant, parent or guardian, as needed 
 
Assessment of creatinine is required at this visit.  As soon as the creatinine result is obtained, the 
estimated GFR should be calculated using the Schwartz formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 56 of 129 
7 September 2017 
6.3.5 
Cohort 2 Weeks 8, 12, and 16 Visits 
 
After the Week 4 Visit, participants will attend follow-up visits every 4 weeks through Week 16, 
i.e., Week 8, Week 12, and Week 16.  These visits will be counted from the day of entry as 
Day 0, with a targeted window of ± 2 weeks.  There is no required sequencing of procedures at 
these visits. 
 
Cohort 2 Follow-up Week 8 (Day 56 ± 2 weeks), Week 12 (Day 84 ± 2 weeks), and  
Week 16 (Day 112 ± 2 weeks) 
Clinical 
• Obtain interval medical and medications history  
• Perform symptom-directed physical exam  
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
 
Blood 
 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline 
phosphatase, AST, ALT, and albumin) 
• HIV-1 RNA 
• At Weeks 8 and 12, sparse PK evaluation (see Section 6.3.8) 
• At Week 12, lipid profile 
• At Week 12, CD4 cell count 
Blood or 
Urine 
Collect blood or urine for: 
• Pregnancy test, if needed per Section 8.8.1 
Urine 
At Weeks 12, collect urine for: 
• Dipstick urinalysis, including specific gravity, pH, blood, ketones, glucose, 
protein, and nitrite 
Study Drug 
• Administer adherence assessment  
• Prescribe and dispense study drug, as needed 
• Provide instructions for DOR/3TC/TDF administration and adherence 
counseling to the participant, parent or guardian, as needed 
 
Assessment of creatinine is required at this visit.  As soon as the creatinine result is obtained, the 
estimated GFR should be calculated using the Schwartz formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 57 of 129 
7 September 2017 
6.3.6 
Cohort 2 Weeks 24, 36, and 48 Visits 
 
After the Week 16 Visit, participants will attend follow-up visits at Weeks 24, 36, and 48.  These 
visits will be counted from the day of entry as Day 0, with a targeted window of ± 2 weeks.  In 
addition, for these visits, an allowable window of ± 4 weeks is specified.  Every effort should be 
made to conduct all visits within the targeted window; however, visits are permitted to be 
conducted within the allowable window.  If possible, at Weeks 24 and 48, pre-dose sparse PK 
blood collection should precede ingestion of the study drug (see Section 6.3.8).  At Week 36, 
there is no required sequencing of procedures. 
 
Cohort 2 Follow-up Week 24 (Day 168 ± 2 weeks), Week 36 (Day 252 ± 2 weeks), and  
Week 48 (Day 336 ± 2 weeks); Allowable visit windows: ± 4 weeks 
Clinical 
• Obtain interval medical and medications history  
• At Weeks 24 and 36, perform symptom-directed physical exam  
• At Week 48, perform complete physical exam 
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
Blood 
 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline 
phosphatase, AST, ALT, and albumin) 
• HIV-1 RNA 
At Weeks 24 and 48, collect blood for: 
• Lipid profile 
• CD4 cell count 
• Sparse PK evaluation (see Section 6.3.8)  
Blood or  
Urine 
Collect blood or urine for: 
• Pregnancy test, if needed per Section 8.8.1 
Urine  
At Weeks 24 and 48, collect urine for: 
• Dipstick urinalysis, including specific gravity, pH, blood, ketones, nitrite, 
glucose and protein 
Study Drug 
• Administer adherence assessment  
• Prescribe and dispense study drug, as needed (at Weeks 24 and 48, see 
Section 6.3.8 for additional detail regarding timing on study drug 
administration during the sparse PK evaluation) 
• Provide instructions for DOR/3TC/TDF administration and adherence 
counseling to the participant, parent or guardian, as needed 
 
Assessment of creatinine is required at this visit.  As soon as the creatinine result is obtained, the 
estimated GFR should be calculated using the Schwartz formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 58 of 129 
7 September 2017 
6.3.7 
Cohort 2 Q16 Week Visits (Weeks 64, 80, and 96) 
 
After the Week 48 Visit, participants will attend follow-up visits every 16 weeks through Week 
96, i.e., Week 64, Week 80, and Week 96.  These visits will be counted from the day of entry as 
Day 0, with a targeted window of ± 4 weeks.  In addition, for these visits, an allowable window 
of ± 8 weeks is specified.  Every effort should be made to conduct all visits within the targeted 
window; however, visits are permitted to be conducted within the allowable window.  There is no 
required sequencing of procedures at these visits. 
 
Cohort 2 Follow-up Week 64 (Day 448 ± 4 weeks), Week 80 (Day 560 ± 4 weeks), and  
Week 96 (Day 672 ± 4 weeks); Allowable visit windows: ± 8 weeks 
Clinical 
• Obtain interval medical and medications history  
• At Weeks 64 and 80, perform symptom-directed physical exam 
• At Week 96, perform complete physical exam  
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
Blood 
 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline 
phosphatase, AST, ALT, and albumin) 
• HIV-1 RNA 
• At Week 96, lipid profile 
Blood or 
Urine 
Collect blood or urine for: 
• Pregnancy test, if needed per Section 8.8.1 
Urine  
At Weeks 64 and 96, collect urine for: 
• Dipstick urinalysis, including specific gravity, pH, blood, ketones, nitrite, 
glucose and protein 
Study Drug 
• Administer adherence assessment  
• Prescribe and dispense study drug, as needed 
• Provide instructions for DOR/3TC/TDF and adherence counseling to the 
participant, parent or guardian, as needed  
• At Week 96, collect any remaining study drug supplies 
 
Assessment of creatinine is required at this visit.  As soon as the creatinine result is obtained, the 
estimated GFR should be calculated using the Schwartz formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 
At the Week 80 Visit, information and counseling should be provided to the participant (and 
parent or guardian) to begin to prepare for study exit at the Week 96 Visit.  Referrals to non-study 
care and treatment should be discussed as needed, with emphasis on the importance of retention 
in care following study completion.   
 
At the Week 96 Visit, prior discussions of transition to non-study care and treatment should be 
reviewed, with information, counseling, and/or referrals provided as needed.  Study drug cannot 
be dispensed to participants at or after this visit; therefore, operational plans must be in place to 


IMPAACT 2014, FINAL Version 1.0 
Page 59 of 129 
7 September 2017 
permit transition to non-study care and treatment at this visit.  Arrangements should be made to 
provide all clinically meaningful results to the participant’s parent or guardian.  The participant 
and parent or guardian should be provided information on how to remain in contact with study 
staff (if desired) and how to learn about the results of the study when available.  The participant’s 
parent or guardian should also be provided information, counseling, and referrals to non-study 
sources of care and treatment for the participant, as applicable.  See also Section 6.6. 
 
6.3.8 
Cohort 2 Sparse Pharmacokinetic Evaluations (Entry and Weeks 4, 8, 12, 24, and 48) 
 
Sparse PK samples will be collected among all participants in Cohort 2, as detailed in Table 16, 
below.  At all visits when a sparse PK sample is collected, source document prior study drug dose 
and time and enter into eCRFs. 
 
Table 16.  Cohort 2 Sparse PK Evaluation Sampling Time Points 
Visit Week 
Entry 
Week 4 
Week 8 
Week 12 
Week 24 
Week 48 
Time  
Points 
Pre-
dose 
Pre-
dose* 
Random 
Random 
Pre-dose* and  
0.5 – 2 hours  
post-dose 
Pre-dose* and  
0.5 – 2 hours  
post-dose 
 
Participants and parents/guardians should be reminded to record the time that the most recent 
study drug dose was given.  Sites may use reminder calls or scheduling cards for participants and 
parents or guardians to reinforce these requirements. 
 
*Special Notes for Sparse PK Evaluations at Weeks 4, 24, and 48 
 
If possible, at Weeks 4, 24, and 48, blood collection for the pre-dose PK evaluation should 
precede ingestion of the dose of study drug.  Prior to this visit, participants and their 
parents/guardians should be reminded to hold the daily administration of study drug, so that the 
dose can be observed at the site.   
 
If not possible to schedule the visits at the time of the participant’s usual study drug dose, the PK 
draws can be done without regard to the timing of the study drug dose.  At Weeks 24 and 48, the 
last two samples should be drawn 0.5 – 2 hours apart.   
 
6.4 
Cohort 2 Confirmation of Virologic Failure Visit 
 
Refer to Section 8.6 for more information on monitoring HIV-1 viral load, definitions of virologic 
failure, and managing virologic failure. 
 
Virologic failure is defined as two consecutive plasma HIV-1 RNA test results ≥200 copies/mL.   
 
• 
For participants who were ART-naïve at enrollment, the first of the two consecutive results 
should be obtained from a specimen collected for the first test at or after Week 24, counted 
from the date of enrollment.  For example, if an ART-naïve participant has a viral load 
≥200 copies/mL at Week 16, no Confirmation of Virologic Failure Visit is needed.  If the 
same participant has a viral load ≥200 copies/mL at Week 24, the result must be confirmed 
through a Confirmation of Virologic Failure Visit. 
• 
For participants who were ART-experienced at enrollment, the consecutive results may be at 
any time after the date of enrollment.  For example, if an ART-experienced participant has a 


IMPAACT 2014, FINAL Version 1.0 
Page 60 of 129 
7 September 2017 
viral load ≥200 copies/mL at Week 12, the result must be confirmed through a Confirmation 
of Virologic Failure Visit. 
 
Any participant with a plasma HIV-1 RNA level ≥200 copies/mL either 1) at or after Week 24 
(ART-naïve) or 2) at any time after the date of enrollment (ART-experienced) should be recalled 
to the clinic for confirmatory testing within four weeks, and no more than six weeks, of the date 
of specimen collection for the initial test.  Other procedures should be performed according to the 
“Confirmation of Virologic Failure” column of the Schedule of Evaluations for Cohort 2 
(Appendix I-B).  These procedures may be combined with regularly scheduled visit procedures if 
they are performed within the allowable window of a regularly scheduled visit.   
 
The specimen collected for genotypic and phenotypic resistance testing should be stored for later 
testing (see the Laboratory Processing Chart, LPC).  
 
The site staff should investigate potential causes for virologic failure such as inadequate 
adherence, interruptions due to toxicity management, or other extenuating circumstances.  In 
addition to the protocol-specific procedures listed in this section, study staff may complete other 
tasks and assessments consistent with local standards of care and site SOPs, including separate, 
real-time resistance testing (an additional sample would need to be collected beyond the samples 
collected and stored for protocol-specific future genotypic and phenotypic resistance testing). 
 
There is no required sequencing of procedures at this visit. 
 
Confirmation of Virologic Failure Visit Procedures 
Clinical 
• Obtain interval medical and medications history  
• Perform complete physical exam, including body weight  
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
Blood 
Collect blood for: 
• HIV-1 RNA 
• Store plasma for future genotypic and phenotypic resistance testing 
 
Blood or 
Urine 
Collect blood or urine for: 
• Pregnancy test, if needed per Section 8.8.1 
Study Drug 
• Administer adherence assessment 
• Prescribe and dispense study drug, as needed 
• Provide instructions for ARV administration and adherence counseling to the 
participant, parent or guardian, as needed  
 


IMPAACT 2014, FINAL Version 1.0 
Page 61 of 129 
7 September 2017 
6.5 
Cohort 2 Early Discontinuation Visit 
 
Refer to Section 4.6 for criteria for participant withdrawal or termination from the study.  For any 
participant who is withdrawn or terminated from the study prior to the scheduled study 
completion of follow-up at Week 96 (Cohort 2 participants), every effort should be made to 
perform a final series of study evaluations, if possible, according to the “Early D/C” column of 
AppendiAppendix I-B, Schedule of Evaluations for Cohort 2.  However, any evaluations 
performed within the 28 days prior to the Early Discontinuation Visit need not be repeated at the 
visit. 
 
Early Discontinuation Visit Procedures 
Clinical 
• Obtain interval medical and medications history 
• Perform complete physical exam, including body weight  
• Identify/review/update adverse events 
• Perform additional evaluations per Section 8 and/or if clinically indicated 
(consult CMC if indicated) 
Laboratory 
 
Blood 
Collect blood for: 
• Complete blood count with differentials and platelet count 
• Chemistries: 
o Electrolytes (sodium, potassium, and HCO3) 
o Glucose 
o Creatinine 
o Lipase 
o Phosphorus 
o LFTs (total bilirubin, indirect bilirubin, direct bilirubin, alkaline 
phosphatase, AST, ALT, and albumin) 
• HIV-1 RNA 
• CD4 cell count 
• Store plasma for future genotypic and phenotypic resistance testing 
Blood or 
Urine 
Collect blood or urine for:  
• Pregnancy test, if needed per Section 8.8.1 
Study Drug 
• Administer adherence assessment 
• Collect any remaining study drug supplies 
 
Assessment of creatinine is required at this visit.  As soon as the creatinine result is obtained, the 
estimated GFR should be calculated using the Schwartz formula, graded for severity, and 
assessed for clinical significance concurrent with all other laboratory test results. 
 
The specimens collected for genotypic and phenotypic resistance testing should be stored for later 
testing at the end of the study (see the LPC).  
 
At this visit, arrangements should be made to provide all clinically meaningful results to the 
participant’s parent or guardian.  The participant and parent or guardian should be provided 
information on how to remain in contact with study staff (if desired) and how to learn about the 
results of the study when available.  The participant’s parent or guardian should also be provided 
information, counseling, and referrals to non-study sources of care and treatment for the 
participant, as applicable. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 62 of 129 
7 September 2017 
6.6 
Cohort 2 Post-Study Contacts 
 
As indicated in Section 6.3.7, planning for transition to non-study care and treatment for 
participants in Cohort 2 should begin at the Week 80 visit, and the transition should be 
implemented at the Week 96 visit.  Following the Week 96 Visit, study staff will complete a final 
study contact with each participant’s parent or guardian to confirm the transition and, in 
particular, confirm access to non-study ARVs (or continued post-study access to study drug, see 
Section 13.11).  This contact should take place within four weeks after the Week 96 visit and 
should be documented in each participant’s study chart.  These contacts are not expected to be 
entered into eCRFs.  However, eCRF data collection is required after the Week 96 Visit in the 
following scenarios:  
 
• 
If a participant becomes pregnant while on study:  Refer to Section 8.8.2; in this scenario, the 
pregnancy outcome must be ascertained and the relevant eCRFs entered after the participant 
discontinues the study to record the pregnancy outcome.  Relevant eCRFs will also be entered 
to capture any ARV changes during the pregnancy. 
 
• 
If confirmation of virologic failure is pending after the Week 96 Visit:  Refer to Section 6.4; 
in this scenario, the confirmatory HIV-1 RNA PCR assay must be performed and the relevant 
eCRFs entered to record the result of the assay. 
 
• 
If the participant has any laboratory result grade 3 or higher at the Week 96 visit:  participants 
should be asked to be continued on study for up to thirty days or until resolution (return to 
baseline) or stabilization (i.e. grade 2 or lower), whichever is sooner, with the frequency of 
visits determined by the site investigator.    
 
6.7 
Medical and Medications History  
 
Collection of medical and medication history information is required at each scheduled visit.  A 
baseline history is established at Screening and Entry, and interval (since the last visit) histories 
are obtained at subsequent follow-up visits.  All history information may be obtained based on 
participant self-report or as reported by the parent or guardian but available medical records 
should be obtained when possible to supplement self-reported information.   
 
Documented medical conditions will be assessed for severity as described in Section 7.3.3, and 
new conditions occurring during follow-up will also be assessed for relationship to study drug as 
described in Section 8.1.  Relevant dates will be recorded for all conditions and medications; see 
Section 5.9 for more information on concomitant medications.  
 
Table 17 specifies the baseline and interval medical and medications history elements that must 
be source documented for participants, as well as associated eCRF entry requirements.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 63 of 129 
7 September 2017 
Table 17.  Documentation Requirements for Medical and Medication Histories 
Assess for and  
Source Document 
Enter into  
eCRFs 
Baseline Medical and Medication History Elements 
Age and other socio-demographics 
 
Yes (all) 
HIV diagnosis, Sexual Maturity Rating (SMR), 
WHO clinical staging (Cohort 2), and ARV 
treatment history (including all ARV use within 
the 30 days prior to enrollment) 
Yes (all) 
History of allergy and/or hypersensitivity 
(including to ARVs) 
Yes (all) 
Ongoing or clinically relevant medical 
conditions (including malignancies and sleep 
history) occurring during the 30 days prior to 
enrollment 
Yes (all) 
Medications (other than ARVs, see above) 
taken within the 30 days prior to enrollment 
and/or ongoing at enrollment 
Yes (all) 
Assessment of sexual activity and contraception 
— 
Any other information needed to determine 
eligibility for the study 
— 
Interval Medical and Medication History Elements 
Current status of conditions that were ongoing 
at the previous visit 
Any updates of previous entries 
(e.g., resolution dates) 
Occurrence of any new conditions since the last 
visit 
Any newly identified adverse events that 
meet criteria in Section 7.2 
Current status of medications that were ongoing 
at the previous visit 
Any updates of previous entries  
(e.g., stop dates) 
Use of any new medications since the last visit 
(see Section 5.7 for more information on 
concomitant medications) 
 
Note: For participants in Cohort 1, DOR would 
be considered study drug and all other ARVs 
would be considered concomitant medications.  
For participants in Cohort 2, DOR/3TC/TDF 
would be considered study drug and no other 
concomitant ARVs would be expected (unless 
the study drug is not tolerated or otherwise has 
to be changed). 
• Study drug and formulation taken from 
time of enrollment through completion of 
follow-up, including timing of prior study 
drug dose at the sparse PK visits (see 
Section 6.3.8) and timing of last three 
study drug doses at the intensive PK visit 
(see Section 6.3.2) 
• Any concomitant ARVs taken while on 
study drug 
• Any new use of concomitant medications 
while on study drug 
• All medications taken at onset of or in 
response to adverse events that are 
specified to be entered into eCRFs per 
Section 7.2 
Note: eCRFs will also capture whether 
traditional medications were taken during 
follow-up. 
Assessment of current sexual maturity, sexual 
activity, and contraception 
— 


IMPAACT 2014, FINAL Version 1.0 
Page 64 of 129 
7 September 2017 
 
6.8 
Physical Examinations 
 
A physical examination is required at each scheduled visit.  For Cohort 1, complete exams are 
required at the Screening and Entry Visits; a symptom-directed exam is required at Week 2.  For 
Cohort 2, complete exams are required at the Screening and Entry visits, Weeks 48 and 96, and 
Confirmation of Virologic Failure and Early Discontinuation visits; symptom-directed exams are 
required at all other scheduled visits.   
 
Complete exams should include the following: 
• 
Height and weight 
• 
Vital signs, including heart rate, temperature and blood pressure 
• 
Examination of: 
– General appearance 
– Head 
– Eyes  
– Ears  
– Nose  
– Neck 
– Mouth and throat 
– Lymph nodes 
– Lungs 
– Heart 
– Abdomen 
– Musculoskeletal system 
– Skin 
– Neuro  
– Sexual Maturity Rating (SMR) (Entry only) 
 
• 
Examination of other body systems driven by other identified signs or symptoms 
 
Symptom-directed exam should include the following:  
• 
Height and weight 
• 
Vital signs, including heart rate, temperature and blood pressure 
• 
Examination of body systems driven by identified signs or symptoms 
 
At all visits, additional assessments may be performed at the discretion of the examining site 
investigator.   
 
All exam findings should be source documented and entered into eCRFs.  Abnormal findings 
identified prior to administration of first dose of study drug will be entered into eCRFs.  
Abnormal findings identified after administration of first dose of study drug will be entered into 
eCRFs as specified in Section 7.2. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 65 of 129 
7 September 2017 
6.9 
Cohort 1 and Cohort 2 Study Drug Palatability and Acceptability 
 
A study-specific form will document palatability and acceptability of 100 mg DOR in Cohort 1 
and the fixed-dose combination DOR/3TC/TDF in Cohort 2.  Assessment of participant 
palatability and acceptability will be assessed by questionnaire as indicated in the Schedule of 
Evaluations in Appendix I-A and Appendix I-B and may include participant or parent/guardian 
opinion on the size and shape of the tablets and, in Cohort 2, oral granules, required dosing 
frequency, or overall taste and ease of swallowing. 
 
Participants in Cohort 2 may be offered the study drug as either a tablet or as oral granules; if 
both formulations are available, participants will be asked to confirm their selection prior to 
enrollment.  Participants may change their formulation after entry; however, they would need to 
be on the new formulation at least one day prior to the intensive PK (if applicable) or the first 
sparse PK assessment visit (Week 4).   Further formulation changes during the study are 
discouraged and every effort should be made to have participants remain on the same 
formulation.  The formulation will be source documented and entered into eCRFs at Entry and 
whenever there is a change in formulation.  If the formulation is changed after Entry, assessment 
of participant palatability and acceptability will be assessed by questionnaire at the time of the 
switch.  The site investigator or designee may consult with the CMC for further guidance or 
recommendations if a participant wants to switch formulations; consultation and approval from 
the CMC are not required. 
 
6.10 
Cohort 2 Study Drug Adherence Assessment and Counseling 
 
Study staff will provide adherence counseling to participants and parents/guardians throughout 
the period of study participation.  Counseling may be provided by clinic and/or pharmacy staff 
consistent with local standards of care and site SOPs.  Counseling should be provided in a client-
centered manner, tailored as needed to the information, skills building, and support needs of each 
participant.  Information on correct use of study drugs will be provided, particularly at the time of 
enrollment and in the early stages of follow-up.  Counseling will also address challenges to 
consistent use of study drug over time, with the aim of supporting participants in identifying 
strategies to address any such challenges. 
 
Adherence to the study drug regimen will be assessed by questionnaire as indicated in the 
Schedule of Evaluations in Appendix I-B.  These data will not be used as a basis for adherence 
counseling.  The results of HIV-1 viral load testing performed throughout follow-up provide a 
biologic measure of adherence and may be used to guide feedback to participants and 
parents/guardians and associated adherence counseling.  Refer to Section 8.6 for more 
information on virologic monitoring and management. 
 
6.11 
Additional Considerations for Laboratory Procedures 
 
Each study site and laboratory involved in this study will comply with the DAIDS policy on 
Requirements for DAIDS Funded and/or Sponsored Laboratories in Clinical Trials Policy, which 
is available at:  
 
https://www.niaid.nih.gov/research/daids-clinical-research-laboratory-specimens-management 
 


IMPAACT 2014, FINAL Version 1.0 
Page 66 of 129 
7 September 2017 
6.11.1 Specimen Collection 
 
Specimens will be collected for this study as indicated in the Schedule of Evaluations and per 
detailed guidance provided in the LPC, which will be posted on the study-specific webpage:  
 
http://impaactnetwork.org/studies/IMPAACT2014.asp 
 
In accordance with US National Institutes of Health (NIH) recommendations, pediatric (less than 
18 years) blood collection will not exceed 5 mL/kg in a single day or 9.5 mL/kg over any eight-
week period.  Adult (18 years and older) blood collection will not exceed 10.5 mL/kg or 550 mL, 
whichever is smaller, over any eight-week period.   
 
In the event that blood collection must be limited, available specimens will be prioritized for use 
in the following order: (1) confirmatory HIV testing (if needed at Screening Visit), (2) safety 
(chemistries, CBC, pregnancy testing), (3) genotypic resistance testing (if needed at Screening 
Visit); (4) PK, (5) HIV-1 viral load, (6) Hepatitis B surface antigen, Hepatitis C antibody, and 
Hepatitis C RNA PCR testing (as required at Screening Visit), (7) CD4 cell counts, (8) lipid 
profiles, and (9) stored samples for resistance testing.  
 
6.11.2 Specimen Preparation, Testing, Storage, and Shipping 
 
All specimens collected for this study will be labeled, transported, processed, tested, stored and/or 
shipped in accordance with the DAIDS policy referenced in Section 6.11, site and local 
laboratory SOPs, and the LPC.  The frequency of specimen collection and testing will be directed 
by the Schedules of Evaluations in Appendix I-A and Appendix I-B and specifications for clinical 
management provided in Section 8.  The Laboratory Data Management System (LDMS) will be 
used to document specimen collection, testing, storage, and shipping as specified in the LPC.  
Any specimens stored at the Screening Visit for participants who do not subsequently enroll in 
the study will be destroyed. 
 
HIV-1 RNA assays must be performed in real time in a CLIA-certified (US sites) or VQA-
approved (non-US sites) laboratory using the testing platform specified in the LPC.  In Cohort 2, 
HIV genotypic resistance assays must also be performed in a CLIA-certified laboratory (US sites) 
and in a DAIDS-approved, GCLP-compliant laboratory that is VQA-certified (non-US sites); 
samples collected should be tested or stored as follows: 
• 
Samples from the Screen visit will be run in real-time to inform eligibility. 
• 
Samples from the Confirmation of Virologic Failure visit will be run in real-time, if the 
second consecutive test confirms the HIV-1 RNA level. 
• 
Samples from the Early Discontinuation visit will be stored for later testing at the end of the 
study. 
 
Specimens collected, processed, and stored at site laboratories for PK evaluations are expected to 
be shipped to the designated testing laboratory as follows:   
• 
Cohort 1 intensive PK samples from the Entry visit must be shipped immediately after 
completion of the visit and will be run on an ongoing basis. 
• 
Cohort 2 intensive PK samples will be batch shipped and will generally be run after all 
intensive PK samples have been collected.  
• 
Cohort 2 sparse PK samples will be batch shipped and will generally be run after all sparse 
PK samples have been collected or on an ongoing basis if needed based on sample stability 
limits.  


IMPAACT 2014, FINAL Version 1.0 
Page 67 of 129 
7 September 2017 
 
After all protocol-specified laboratory testing has been performed, residual specimens may be of 
interest for future research use.  Participants’ parents or guardians (or participants if applicable) 
will be asked to provide written informed consent for future research use of these specimens, if 
permitted by site IRBs/ECs and other applicable review bodies.  Parents or guardians (or 
participants) may choose to provide or to decline informed consent for future research use of 
residual specimens with no impact on other aspects of participation in the study.  If informed 
consent for future research use of residual specimens is initially provided but participants’ parents 
or guardians (or participants) subsequently change their mind and withdraw that consent, all 
remaining residual samples will be destroyed.  
 
6.11.3 Biohazard Containment 
 
As the transmission of HIV and other blood-borne pathogens can occur through contact with 
contaminated needles, blood, and blood products, appropriate blood and secretion precautions 
will be employed by all personnel in the drawing of blood and shipping and handling of all 
specimens for this study as currently recommended by the US Centers for Disease Control and 
Prevention, NIH, and other applicable agencies.  All specimens will be shipped using packaging 
that meets requirements specified by the International Air Transport Association Dangerous 
Goods Regulations for UN 3373, Biological Substance, Category B, and Packing Instruction 650.  
Culture isolates, if obtained in this study, are to be shipped as specified for UN 2814 Category A 
Infectious Substances. 
 
 
7 
SAFETY MONITORING, ASSESSMENT AND REPORTING 
 
Participant safety will be carefully assessed, monitored, and reported at multiple levels 
throughout this study.  Sections 7.1-7.3 describe safety-related roles, responsibilities, and 
procedures.  The safety monitoring roles of the CMC and the IMPAACT Study Monitoring 
Committee (SMC) are briefly referenced in Sections 7.1.2 and 7.1.3 and described in greater 
detail in Sections 9.6.1 and 9.6.2. 
 
7.1 
Safety-Related Roles and Responsibilities 
 
7.1.1 
Site Investigators 
 
Site investigators are responsible for monitoring of all study participants and for alerting the 
CMC if unexpected concerns arise.  Site investigators and their designees will enter safety-related 
data on eCRFs as indicated in Section 7.2 and complete expedited adverse event (EAE) reporting 
as indicated in Section 7.3.  Site investigators are also responsible for prompt reporting to their 
IRBs/ECs and other applicable review bodies of any unanticipated problems involving risks to 
participants or others. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 68 of 129 
7 September 2017 
7.1.2 
Clinical Management Committee (CMC) 
 
The following Protocol Team members comprise the CMC: Protocol Chair and Vice Chairs, 
Medical Officers, Statisticians, Data Managers, Pharmacologists, Clinical Trials Specialists, 
selected Protocol Investigators, and representatives from Merck & Company.  The CMC will 
provide guidance as needed to site investigators regarding all aspects of participant management, 
including but not limited to questions of participant eligibility, study drug administration, and 
management of adverse events.  Refer to Section 8 for more information on participant 
management. 
 
On behalf of the full Protocol Team, the CMC will also monitor participant safety through routine 
review of study data reports as described in Section 9.6. 
 
7.1.3 
Study Monitoring Committee 
 
An independent IMPAACT SMC will contribute to monitoring participant safety in this study.   
Refer to Section 9.6.2 for more information on the role of the SMC in monitoring this study. 
 
7.2 
Safety-Related Data Collection 
 
Note:  This section describes eCRF data collection for pre-existing conditions and adverse 
events.  As part of this description, reference is made to criteria for EAE reporting and severity 
grading; refer to Sections 7.3.2 and 7.3.3, respectively, for detailed information on these topics.  
 
The definition of the term adverse event provided in Version 2.0 of the Manual for Expedited 
Reporting of Adverse Events to DAIDS (DAIDS EAE Manual) will be used in this study.  
Adverse events apply to all participants from the time of initial study drug administration.   
 
Pre-Existing Conditions 
 
Any pre-existing conditions identified among enrolled participants during the 30 days prior to 
initial administration of study drug that are ongoing or clinically relevant will be entered into 
eCRFs. 
 
Adverse Events 
 
All adverse events – except as specified in the IMPAACT Do Not Report List – will be entered 
into eCRFs, regardless of severity grade and relationship to study drug.  
 
Laboratory Test Results 
 
In addition to the recording specified above, all protocol-specified laboratory test results will be 
entered into the relevant eCRFs.  In addition, any abnormal results of laboratory tests ordered by 
the site investigator to evaluate adverse events considered related to study drug should be entered 
on eCRFs. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 69 of 129 
7 September 2017 
Overdose 
 
For this study, an overdose is defined as more than twice the recommended daily dose in a 
calendar day.  All study drug overdoses should be entered into the relevant eCRF and will be 
reported routinely to the pharmaceutical sponsor. 
 
7.3 
Expedited Adverse Event (EAE) Reporting 
 
7.3.1 
EAE Reporting to DAIDS 
 
Requirements, definitions, and methods for expedited reporting of adverse events (AEs) are 
outlined in Version 2.0 of the DAIDS EAE Manual, which is available on the Regulatory Support 
Center (RSC) website at:  
 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/manual 
 
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting 
system, must be used for EAE reporting to DAIDS.  In the event of system outages or technical 
difficulties, EAEs may be submitted via the DAIDS EAE Form.  This form is available on the 
DAIDS RSC website at:  
 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids/paper-eae-reporting 
 
For questions about DAERS, contact NIAID Clinical Research Management System at 
CRMSsupport@niaid.nih.gov.  Questions may also be sent from within the DAERS application 
itself.  
 
For questions about expedited reporting, contact the DAIDS RSC Safety Office at 
DAIDSRSCSafetyOffice@tech-res.com. 
 
7.3.2 
EAE Reporting Requirements for this Study 
 
The serious adverse event (SAE) Reporting Category, as defined in Version 2.0 of the DAIDS 
EAE Manual, will be used for this study.  The study agent for which expedited reporting is 
required is doravirine (DOR) for Cohort 1 and doravirine/lamivudine/tenofovir disoproxil 
fumarate (DOR/3TC/TDF) for Cohort 2.   
 
In addition to the above, the following must also be reported in an expedited manner (i.e., as 
EAE):  
• 
All Grade 4 adverse events 
• 
All pregnancy complications, including intrauterine fetal demise, spontaneous abortions, or 
therapeutic or otherwise medically indicated abortions 
• 
All malignancies 
• 
Any immune reconstitution inflammatory syndrome (IRIS) events 
 


IMPAACT 2014, FINAL Version 1.0 
Page 70 of 129 
7 September 2017 
7.3.3 
Grading Severity of Events (applies to EAEs and all other adverse events) 
 
The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events 
(DAIDS AE Grading Table), Corrected Version 2.1, dated July 2017, will be used in this study.  
This table is available on the RSC website:  
 
http://rsc.tech-res.com/clinical-research-sites/safety-reporting/daids-grading-tables 
 
7.3.4 
EAE Reporting Period 
 
For each enrolled participant, the EAE reporting period begins at the time of administering the 
first dose of study drug and continues through the protocol-specified end of follow-up for each 
cohort.   
 
After the above specified period, only suspected, unexpected, serious adverse reactions (SUSAR) 
as defined in Version 2.0 of the EAE Manual will be reported if the study staff become aware of 
the events on a passive basis (e.g., from publicly available information). 
 
 
8 
PARTICIPANT MANAGEMENT 
 
8.1 
Management of Adverse Events 
 
All adverse events identified in this study will be source documented in research records, 
consistent with the policies and procedures referenced in Section 7.  Among other details, source 
documentation will include the severity of each event (graded as described in Section 7.3) and 
relationship to study product, assessed by the site clinician according to the following categories 
and definitions: 
 
Related 
There is a reasonable possibility that the adverse event may be related to study 
drug. 
 
Not related 
There is not a reasonable possibility that the adverse event may be related to 
study drug. 
 
Further standardized guidance on determining whether there is a reasonable possibility of a 
relationship is available in the DAIDS EAE Manual, referenced in Section 7.3.1 above. 
 
As described in greater detail below, adverse events identified in participants will be managed 
based on their severity and assessed relationship to study drug.   
 
All adverse events must be followed to resolution (return to baseline) or stabilization, with the 
frequency of repeat evaluations determined by the clinical significance of each event.  Additional 
evaluations beyond those listed in Appendix I-A and Appendix I-B may be performed at the 
discretion of the site investigator to determine the etiology of a given event and/or further assess 
its severity or relationship to study product.  Clinical management of all adverse events should be 
provided consistent with the best medical judgment of the site investigator and local clinical 
practice standards. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 71 of 129 
7 September 2017 
Refer to Sections 8.2-8.6 for further guidance on management of adverse events, including 
general adverse events, liver toxicities, decline in renal function, non-study drug ARV-related 
toxicities, and monitoring and management of virologic failure.  When management of an adverse 
event requires consultation with the CMC, the CMC should be contacted as soon as possible and 
within three business days of site awareness of the event. 
 
Criteria for premature discontinuation of study drug are presented in Section 8.7 and guidance 
and requirements for contraception, pregnancy testing, and management of participants who 
become pregnant are presented in Section 8.8. 
 
8.2 
General Management (Cohort 2)   
 
The general guidelines (by grade, Table 18) apply to management of study drug in response to 
toxicities other than hepatic and renal events, for which guidelines are provided in Sections 8.3 
and 8.4, respectively.   
 
Any interruption of DOR/3TC/TDF of more than seven days should be discussed with the CMC 
prior to restarting. 
 
Any participant who permanently discontinues study drug will be transitioned to the local 
standard of care to receive an alternative, locally-available ARV treatment regimen.  To the 
extent possible and as medically indicated, site staff should work to ensure any ART interruptions 
are as short as possible.  Participants should be transitioned to non-study care and treatment 
should be reviewed, with information, counseling, and/or referrals provided as needed.  
Participants will be asked to continue on study for at least four weeks after they discontinue study 
drugs or until resolution (return to baseline) or stabilization of any adverse events with the 
frequency of visits determined by the site investigator.  All procedures will be done with the 
expectation that no further PK sampling will be done.    
 


IMPAACT 2014, FINAL Version 1.0 
Page 72 of 129 
7 September 2017 
Table 18.  General Guidelines for Management of Participants in Cohort 2 
Grade 1 
Continue study drug and perform routine monitoring. 
 
Grade 2 Continue study drug; monitor closely as per site investigator and work-up to exclude 
other causes. 
 
Grade 3 Upon initial identification of a Grade 3 event, the CMC should be notified (within 
three business days) and non-study drug explanations for the event should be 
considered.  The participant should be re-evaluated weekly until improvement to 
Grade 2 or lower or until stabilized and no longer in need of frequent monitoring, as 
determined by the site investigator in consultation with the CMC. 
 
If the initial Grade 3 event is a laboratory abnormality, the test should be repeated as 
soon as possible (within three business days of site’s awareness).  If the initial event 
is assessed as not related to study drug, study drug may be continued while awaiting 
the repeat test result; otherwise study drug should be held.  If the repeat test does not 
yield a Grade 3 result, the event should be managed according to the grade of the 
repeat result.  
 
For Grade 3 clinical events and confirmed a Grade 3 laboratory events:  
• 
If the event is assessed as not related to study drug, study drug should be 
continued (or resumed if previously held). 
• 
If the event is assessed as related to study drug, the CMC should be notified 
AND study drug should be held unless the site investigator feels that 
continuation of the study drug is in the participant’s best interest.  In this case, 
the decision whether to hold study drug should be made in consultation with the 
CMC. 
If study drug is held, resumption may be considered in consultation with the CMC 
once the event has improved to Grade 2 or lower.  If study drug is resumed and the 
Grade 3 event recurs (confirmed), study drug must be permanently discontinued.   
 
Grade 4 Upon initial identification of a Grade 4 event, the CMC should be notified (within 
three business days of site awareness) AND study drug should be held unless the site 
investigator feels that continuation of the study drug is in the participant’s best 
interest. In this case, the decision whether to hold study drug should be made in 
consultation with the CMC.  Non-study drug explanations for the event should be 
considered.  The participant should be re-evaluated weekly until improvement to 
Grade 2 or lower or until stabilized and no longer in need of frequent monitoring, as 
determined by the site investigator in consultation with the CMC. 
 
If the Grade 4 event is a laboratory abnormality, the test should be repeated as soon 
as possible (within 3 business days).  If the repeat test does not yield a Grade 4 
result, the event should be managed according to the grade of the repeat result.  
 
For Grade 4 clinical events and confirmed Grade 4 laboratory events:  
• 
If the event is assessed as not related to study drug, study drug may be resumed 
only with approval from the CMC.  
• 
If the event is assessed as related to study drug, study drug must be permanently 
discontinued. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 73 of 129 
7 September 2017 
 
8.3 
Management of Liver Toxicities (Cohort 2) 
 
Study drug will be held if any of the following liver chemistry criteria are confirmed:    
 
• 
Grade 2 or higher AST or ALT AND Grade 2 or higher total bilirubin AND, at the same 
time, alkaline phosphatase less than Grade 2 (Hy’s Law) 
• 
Grade 4 ALT; if another cause of ALT elevation is identified, the participant may be re-
challenged after receiving the approval of the CMC.  
• 
Grade 2 or higher ALT with symptoms of hepatitis or hypersensitivity (e.g., fatigue, nausea, 
vomiting, right upper quadrant pain, fever, rash or eosinophilia).  If another cause of ALT 
elevation is identified, the participant may be re-challenged after receiving the approval of the 
CMC.  
 
If any of the above liver chemistry hold criteria are met, sites must: 
• 
Repeat laboratory testing as soon as possible (within three business days of site awareness) 
• 
Report the event to the CMC within 24 hours of site awareness 
 
8.4 
Management of Decline in Renal Function (Cohort 2) 
 
Participants who experience an increase in serum creatinine to a grade 2 or above or from grade 2 
(baseline) to grade 3 or above must return for a confirmatory creatinine assessment within two to 
four weeks.  If the creatinine elevation is confirmed, the investigator should contact the CMC to 
discuss additional follow-up and medical management. 
 
Participants who experience an increase in proteinuria or glycosuria to a grade 2 or above or from 
grade 2 (baseline) to grade 3 or above must return for a confirmatory urinalysis within two to four 
weeks.  If the increased proteinuria or glycosuria is confirmed, the investigator should contact the 
CMC to discuss additional follow-up and medical management. 
 
Participants who experience progression to a grade 3 or higher estimated GFR (calculated by the 
Schwartz formula; see Section 4.1.8) of <60 mL/min (1.73 m2) must return for a confirmatory 
creatinine assessment within two to four weeks.  If an estimated GFR of <60 mL/min (1.73 m2) is 
confirmed, then DOR/3TC/TDF should be held and the investigator should contact the CMC to 
discuss the rationale for restarting study drugs (if appropriate).   
 
Consideration for confounding factors (e.g., other medications; dehydration and concurrent 
conditions) should be taken into account, and a nephrology consult may be obtained.  
 
8.5 
Non-Study Drug Antiretroviral Drug-Related Toxicity  
 
Toxicities resulting from components of a standard of care ART in Cohort 1 will be managed by 
the site investigator, according to best clinical practice; consultation with the CMC is available 
but not required.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 74 of 129 
7 September 2017 
8.6 
Monitoring and Management of Virologic Failure (Cohort 2) 
 
Monitoring 
 
HIV-1 RNA (viral load) will be monitored closely with frequent testing as specified in the 
Schedule of Evaluations, Appendix I-B.  All HIV-1 RNA assays must be performed in a CLIA-
certified (US) or VQA-approved (non-US) laboratory using the testing platform specified in the 
LPC.  Site investigators should review the results of each test as well as trends over time and 
consult with the CMC regarding any individual test results or trends of concern.  As noted in 
Section 6.10, viral load results should be provided to participants’ parents or guardians (and/or 
participants, if applicable) and may be used to guide adherence counseling. 
 
Definition of Virologic Failure 
 
Virologic failure is defined as two consecutive plasma HIV-1 RNA test results ≥200 copies/mL.  
For participants who were ART-naïve at enrollment, the consecutive results should be from 
specimens collected for the first test at or after Week 24, counted from the date of enrollment.  
For participants who were ART-experienced at enrollment, the consecutive results may be at any 
time after the date of enrollment. 
 
Confirmation of Virologic Failure 
 
Any participant with a plasma HIV-1 RNA level ≥200 copies/mL either 1) at or after Week 24 
(ART-naïve) or 2) at any time after the date of enrollment (ART-experienced) should be recalled 
to the clinic for confirmatory testing ideally within four weeks, and no more than six weeks, of 
the date of specimen collection for the initial test.  As indicated in Section 6.4, other evaluations – 
including specimen collection and storage for future genotypic and phenotypic resistance testing 
– will also be performed at the time of specimen collection for confirmatory HIV-1 RNA testing.   
 
The stored specimen collected for genotypic and phenotypic resistance testing should be stored 
for later testing (see the LPC).  
 
Participant should ideally be contacted prior to the confirmatory virologic failure visit to assess 
and address any issues with adherence, access, intercurrent illness or other situation which might 
have impacted the virologic response. 
 
Management of Confirmed Virologic Failure 
 
The CMC should be consulted regarding management of all participants with confirmed virologic 
failure (or if the confirmatory sample cannot be collected within six weeks of the date of 
specimen collection for the initial test). 
 
Participants with confirmed virologic failure due to remediable causes (e.g., non-adherence, 
intercurrent illness, or other factors not associated with DOR/3TC/TDF) may potentially remain 
on the study drug.   
 
If the HIV-1 RNA test result is not confirmed (i.e., is less than 200 copies/mL), the participant 
should remain on DOR/3TC/TDF.  Enhanced adherence support or other interventions to address 
the virologic increase should be provided, as applicable.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 75 of 129 
7 September 2017 
8.7 
Criteria for Premature Discontinuation of Study Drug  
 
Administration of study drug will be permanently discontinued in the following circumstances:  
• 
Pregnancy (see Section 8.8.2) 
• 
The participant experiences an adverse event that requires discontinuation as defined in 
Sections 8.2-8.4.  
• 
The site investigator determines that further administration of study drug would be 
detrimental to the participant’s health or well-being. 
• 
Virologic failure as described in Section 8.6. 
• 
New data become available that indicate study drug should be discontinued as determined by 
the CMC.  
 
NOTE:  In the event of discontinuation of study drug, participants will be asked to continue on 
study for at least four weeks after they discontinue study drugs or until resolution (return to 
baseline) or stabilization of any adverse events with the frequency of visits determined by the site 
investigator.    
 
8.8 
Contraception, Pregnancy Testing, and Management of Participants Who Become Pregnant 
on Study 
 
8.8.1 
Contraception and Pregnancy Testing 
 
At the Entry visit but prior to enrollment, all participants must meet the contraception and 
pregnancy testing requirements as described in Sections 4.1.9-4.1.11.   
 
During study participation, all participants should be provided with contraception counseling, as 
applicable, and consistent with requirements in Sections 4.1.10-4.1.11.  Sites should reinforce 
directions related to use of effective, medically accepted contraception methods and all female 
participants who are engaging in sexual activity that could lead to pregnancy should be counseled 
about NOT becoming pregnant while in the study.  For participants engaging in sexual activity 
that could lead to pregnancy, self-reported confirmation of contraception use should be obtained 
at every visit.  These discussions should be source documented in research records.  If 
participants engaging in sexual activity that could lead to pregnancy report discontinuation of 
contraception use, the site should consult the CMC on further management.  
 
Counseling should be provided per site SOPs, which should reflect WHO guidelines for HIV-
infected men and women as well as local standards of care.  Counseling should reflect the ARVs 
that participants are currently taking and the potential interactions between these ARVs and 
available contraceptive methods.  Study sites should ideally integrate provision of contraceptive 
methods with other services offered to study participants and should provide referrals to non-
study sources of methods that cannot be provided at the study site.  All participants will be 
counseled about use of condoms.  Condoms are recommended because their appropriate use is the 
only contraception method effective for preventing HIV-1 transmission. 
 
Pregnancy testing will be conducted among female participants who have reached menarche or 
who are engaging in sexual activity that could lead to pregnancy at follow-up visits consistent 
with the Schedule of Evaluations (Appendix I-A and Appendix I-B).  For both cohorts, pregnancy 
testing is required at the Entry visit, prior to enrollment to confirm eligibility.  For Cohort 2, 
additional testing is required at follow-up visits consistent with the Schedule of Evaluations 
(Appendix I-B).   


IMPAACT 2014, FINAL Version 1.0 
Page 76 of 129 
7 September 2017 
 
8.8.2 
Management of Participants Who Become Pregnant on Study 
 
Any participant who becomes pregnant (intrauterine) while on study drug should have study drug 
permanently discontinued as soon as an alternative, locally-available treatment regimen can be 
started (i.e., there should be no break or lapse in HIV treatment).  Participants should be 
transitioned to non-study care and treatment, with information, counseling, and/or referrals 
provided as needed.  
 
Participants who become pregnant will be permanently discontinued from study drug and 
permanently discontinued from the study, per Section 8.7.  Any pregnancy that occurs during 
study participation must be reported to the CMC immediately (within 24 hours of site awareness). 
Pregnancy test results will be disclosed to participants and their parent/guardians consistent with 
local standards of care; local standard procedures will be noted in site-specific informed consent 
and assent forms.  In settings where disclosure to parents/guardians will be at the choice of the 
participant, participants will be counseled that — because pregnancy will result in discontinuation 
of study drug and study participation — proactive (rather than potential inadvertent) disclosure to 
parents/guardians may be advised. 
 
Participants or parents/guardians will be contacted following study discontinuation to ascertain 
the pregnancy outcome (completion/termination of the pregnancy) and any ARV changes during 
the pregnancy.  Pregnancy complications, including intrauterine fetal demise, spontaneous 
abortions, or therapeutic or otherwise medically indicated abortions should be reported to the 
CMC immediately (within 24 hours of site awareness) and reported as an EAE (see Section 
7.3.2).  Additional post-study contacts should be completed to ascertain pregnancy outcomes (see 
Section 6.6).  Outcomes may be ascertained based on maternal report but medical records should 
be obtained whenever possible to supplement maternal reports. 
 
Study sites are encouraged to prospectively register pregnant participants in the Antiretroviral 
Pregnancy Registry (APR) prior to pregnancy outcome by calling the following number in the 
US: +1-800-258-4263.  Outside of the US, see the APR website (www.apregistry.com) for 
additional toll-free numbers. 
 
 
9 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
IMPAACT 2014 is a Phase I/II study whose primary objectives are to evaluate the PK, safety, 
and tolerability of a single dose of doravirine (DOR, MK-1439) and once daily regimen of 
doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF, MK-1439A) in HIV-1-
infected children and adolescents 12 years to less than 18 years of age who weigh at least 35 kg.  
Participants will be enrolled into two sequential cohorts, as described in Section 3. 
 
A minimum of 12 PK evaluable in Cohort 1 and 40 evaluable participants in Cohort 2 will be 
accrued to the study.  Participants in Cohort 1 will be considered evaluable if they received the 
prescribed dose and had PK samples collected and assayed per protocol (PK evaluability defined in 
Section 10.3.1); participants in Cohort 2 will be considered evaluable if they either, 1) completed 
24 weeks of study on the study drug, OR 2) were classified as a safety or virologic failure, due to 


IMPAACT 2014, FINAL Version 1.0 
Page 77 of 129 
7 September 2017 
incurring a study drug related adverse event or meeting virologic failure criteria during the first 24 
weeks of treatment.   
 
If a participant in Cohort 1 is deemed PK unevaluable, then the participant will be replaced and 
will be excluded from the PK analysis during the dose evaluation.  If there is some uncertainty 
about the participant’s exposure to the correct dose of the study drug, then that participant may 
also be excluded from the safety analysis, in addition to the PK analysis.   
 
If a participant in Cohort 2 is deemed unevaluable, then the participant will be replaced and may 
be excluded from the PK and safety analyses.  In addition, if Cohort 2 opens enrollment to ART-
experienced participants (see Section 3.2), enrollment into Cohort 2 of participants who have 
completed their two-week follow-up in Cohort 1 may introduce a selection bias.  In such cases, it 
may be necessary to perform sensitivity analyses on the final data to test whether the results of 
the final safety analysis are consistent with and without such participants’ data.  In addition, since 
participants in Cohort 2 will only be followed while on study drug and some of their missing viral 
load and CD4 values will be imputed using a conservative approach, sensitivity analyses will be 
performed to assess the effects of these data imputations on the final results. 
 
9.2 
Dose Evaluation Algorithm  
 
Cohort 1 
 
The study will implement a dose-evaluation algorithm of the 100 mg DOR based on PK data 
around the single-dose and safety data through Week 2.  Cohort 1 will enroll an initial group of 
12 evaluable participants and their PK and safety data will be evaluated as follows: 
• 
If these 12 participants meet the PK guidelines (see Section 10.3.1) and there are no safety 
concerns (see Section 9.6.2, Participant Safety), then the DOR dose for Cohort 2 will be 
established and Cohort 2 will begin to accrue, following an SMC review (see Section 9.6.2, 
Dose Evaluation). 
• 
If the DOR dose does not achieve the PK targets in the lower weight group of 35 to ≤45 kg, 
the following will be done:  
– If DOR exposure is considered too high for all participants in this weight group, no 
participants ≤45 kg will be enrolled in Cohort 2.   
– If DOR exposure is considered too low for all participants in this weight group, the CMC 
will evaluate all PK and safety data and consider enrolling additional participants in this 
weight group to reach a final decision regarding the lower weight cut-off for enrollment 
into Cohort 2.  
– If only a subset of participants in the lower weight group achieve the PK targets, the 
CMC may consider enrolling additional participants to confirm the weight determined to 
yield appropriate exposure to the DOR dose.  Accrual into Cohort 2 will then be limited 
to participants above this weight cut-off, provided there were no safety concerns for this 
group based on results from Cohort 1. 
• 
If there is more variability than expected in the PK results such that a confident determination 
regarding achievement of the PK targets cannot be made, additional participants may be 
enrolled into Cohort 1 to clarify the PK results as needed.  The group of participants in 
Cohort 1 who meet the PK targets with no safety concerns will establish the weight threshold 
for enrollment into Cohort 2. 


IMPAACT 2014, FINAL Version 1.0 
Page 78 of 129 
7 September 2017 
 
The goal is to enroll 12 participants at a 100 mg DOR dose in Cohort 1 who meet the PK 
guidelines and have no drug-related grade 3 or higher AEs, providing adequate data to establish 
the 100 mg DOR dose, with the appropriate lower weight threshold, for Cohort 2. 
 
Cohort 2 
 
This cohort will begin to enroll once the PK and safety of the 100 mg DOR dose have been 
established from Cohort 1, as described above, and once the SMC has reviewed all Cohort 1 data 
and approved enrollment into Cohort 2 (see Section 9.6.2, Dose Evaluation).  Participants will 
receive DOR/3TC/TDF.  The first 10 participants will have intensive PK sampling to evaluate the 
pharmacokinetics of 3TC and tenofovir.  PK samples for DOR will also be collected in these first 
10 participants at a subset of intensive time points.  Sparse PK samples for DOR, 3TC, and 
tenofovir will be collected through Week 48 to further describe the DOR, 3TC, and tenofovir 
exposure achieved with DOR/3TC/TDF (see Section 6.3.8).  Safety, virologic, and immunologic 
outcomes will be collected longitudinally and analyzed at Weeks 24, 48 and 96. 
 
The goal is to enroll 40 participants in Cohort 2 to evaluate the PK, safety, virologic efficacy and 
immunologic response of DOR/3TC/TDF.  
 
9.3 
Endpoints and Outcome Measures 
 
In the following sections, the words “Endpoint” and “Outcome” refer to dependent variables on 
which objectives will be evaluated.  “Endpoint” refers to whether a specific criterion has been 
met, while “Outcome” refers to a continuous or categorical variable, which is relevant to protocol 
objectives, but does not reflect a specific criterion.  Each of the four listed toxicity endpoints will 
be analyzed separately. 
 
Note: The numbering of the outcome measures in this section corresponds to the numbering of 
the objectives in Section 2. 
 
The primary outcome measures listed in Sections 9.3.1 and 9.3.2 as well as secondary outcome 
measures in Sections 9.3.3.1-9.3.3.3 through Week 24 will be addressed in the study’s primary 
statistical analysis plan, which will define the content of the primary analysis report.  This report 
will form the basis for the primary study publication and results reporting to ClinicalTrials.gov.  
A secondary analysis report will address the secondary outcomes measures listed in Sections 
9.3.3.2-9.3.3.4 at Weeks 48 and 96 and will form the basis for secondary publication(s) and 
additional results reporting to ClinicalTrials.gov.  Outcomes of interest for other objectives 
(intended for subsequent publications) are listed in Section 9.3.4. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 79 of 129 
7 September 2017 
9.3.1 
Primary Endpoints and Outcome Measures for Cohort 1 
9.3.1.1  Pharmacokinetics 
• Single-dose AUC0-∞, Cmax, and C24hr of DOR 
9.3.1.2  Safety and Tolerability through Week 2 
• Safety Outcome: All adverse events, regardless of severity grade 
• Toxicity Endpoints: 
- Grade 3 or higher adverse events assessed as related to study drug 
- Serious adverse events assessed as related to study drug  
- Permanent discontinuation of study drug due to adverse events assessed as related to 
study drug 
- Grade 5 adverse events (death) regardless of relationship to study drug 
9.3.2 
Primary Endpoints and Outcome Measures for Cohort 2 
9.3.2.1  Safety and Tolerability through Week 24 
• Safety Outcome: All adverse events, regardless of severity grade 
• Toxicity Endpoints: 
- Grade 3 or higher adverse events assessed as related to study drug 
- Serious adverse events assessed as related to study drug  
- Permanent discontinuation of study drug due to adverse events assessed as related to 
study drug 
- Grade 5 adverse events (death) regardless of relationship to study drug 
9.3.3 
Secondary Endpoints and Outcome Measures for Cohort 2 
9.3.3.1  Pharmacokinetics through Week 1 
• AUC0-24hr, Cmax, and C24hr of DOR, 3TC, and tenofovir  
9.3.3.2  Virologic Efficacy at Weeks 24, 48, and 96 
• Plasma HIV-1 RNA<200 copies/mL  
• Plasma HIV-1 RNA<50 copies/mL  
• Plasma HIV-1 RNA<40 copies/mL  
• Log10 drop from baseline in plasma HIV-1 RNA (ART-naïve participants) 
9.3.3.3  Immunologic Response at Weeks 24, 48, and 96 
• Change in CD4 count and percent from baseline  
9.3.3.4  Safety and Tolerability through Weeks 48 and 96 
• Safety Outcome: All adverse events, regardless of severity grade 
• Toxicity Endpoints: 
- Grade 3 or higher adverse events assessed as related to study drug 
- Serious adverse events assessed as related to study drug  
- Permanent discontinuation of study drug due to adverse events assessed as related to 
study drug 
- Grade 5 adverse events (death) regardless of relationship to study drug 
9.3.4 
Other Endpoints and Outcome Measures for Cohort 2 
9.3.4.1  Pharmacokinetics through Week 48 
• Plasma concentrations of DOR, 3TC, and tenofovir  
9.3.4.2  Genotypic and Phenotypic 
• Genotypic and phenotypic measures of resistance at baseline and at virologic failure 
9.3.4.3  Acceptability, Palatability, and Adherence through Week 96 
• Acceptability, palatability, and adherence measures 
 


IMPAACT 2014, FINAL Version 1.0 
Page 80 of 129 
7 September 2017 
9.4 
Randomization and Stratification 
 
There will be no randomization and no stratification.  Participants will be enrolled into Cohort 1 
and Cohort 2 as described below. 
 
9.5 
Sample Size and Accrual 
 
Sample sizes and the expected accrual timeframes for each cohort are described below.  See 
Section 9.1 for definitions of evaluability. 
 
Cohort 1 
 
At least 12 evaluable participants will be enrolled in Cohort 1 with a minimum of four 
participants between 35 kg and 45 kg.  Depending on the PK results, additional participants may 
be enrolled.   
 
Accrual into Cohort 1 is expected to be completed within 3-6 months after the first participant is 
enrolled.  However, if additional participants are required based on PK results, additional time 
may be needed to fully meet the accrual and PK targets. 
 
Cohort 2 
 
Up to 45 participants will be enrolled in Cohort 2 to achieve at least 40 evaluable participants.  
Based on the PK and safety evaluations in Cohort 1, if 35 kg is established as the lower weight 
threshold, a minimum of five participants between 35 kg and 45 kg will be enrolled.   
 
Accrual into Cohort 2 will begin following confirmation of the DOR dose in Cohort 1.  Accrual is 
expected to be completed within 6-12 months after the first participant is enrolled in Cohort 2.  
However, if additional participants are required (e.g., some participants considered unevaluable), 
additional time may be needed to fully meet the accrual targets. 
 
9.6 
Monitoring 
 
Implementation of this study will be monitored at multiple levels, consistent with standard 
procedures described in the IMPAACT Manual of Procedures.  Included in these standard 
procedures is monthly review of participant accrual and retention by the IMPAACT Management 
Oversight Group.  A study monitoring plan that details monitoring roles and responsibilities and 
data to be reviewed at each level will be prepared before the study opens to accrual.  Sections 11 
and 12 provide more information on on-site monitoring and quality management at the site level.  
Further information on monitoring of study progress, quality of study conduct, and participant 
safety across sites is provided below. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 81 of 129 
7 September 2017 
9.6.1 
Monitoring by the Protocol Team 
 
Study Progress and Quality of Study Conduct 
 
The Protocol Team is responsible for continuous monitoring of study progress, including timely 
achievement of key milestones, and the quality of study conduct.   
 
The team will closely monitor participant accrual and retention based on reports that will be 
generated at least monthly by the SDMC.  The team has developed a study accrual plan that 
includes site-specific and total enrollment projections over the course of the accrual period, and 
actual accrual will be monitored relative to these projections.  The team will monitor the timing 
of site-specific study activation, which will determine when each site will begin accruing 
participants, and accrual performance following activation.  For any site that is delayed in 
completing the study activation process, or that falls short of its accrual projections, the team will 
communicate with the site to identify the barriers the site has encountered and the operational 
strategies and action plans to address these.   
 
The Protocol Team will monitor participant retention in a manner similar to participant accrual.  
On behalf of the Protocol Team, the CMC will monitor other key indicators of the quality of 
study conduct (e.g., adherence to study drug regimen, data quality, and data and specimen 
completeness) based on reports generated by the SDMC and will take action with study sites as 
needed to ensure high quality study conduct throughout the period of study implementation.  
 
Participant Safety 
 
On behalf of the Protocol Team, the CMC will closely monitor participant safety through routine 
review of safety reports generated by the SDMC.  These reports will provide tabulations of 
adverse events specified for entry into eCRFs, as described in Section 7.2.  The CMC will review 
these reports via conference call or other meeting at least monthly.  At the time of each review, 
the DAIDS Medical Officer will also review any EAEs (defined in Section 7.3) reported to the 
DAIDS Safety Office that are not yet reflected in the data reports.  The CMC will continually 
evaluate the pattern and frequency of reported events and assess for any individual occurrences or 
trends of concern.   
 
The CMC will also monitor whether any of the safety-related triggers specified in Section 9.6.2 
are met.  If so, the CMC will rapidly review the triggering events and notify the SMC that an ad 
hoc review is required.  The CMC will likewise request SMC review of any other safety concerns 
that may be identified throughout the course of the study.  
 
Dose Evaluation 
 
During the dose evaluation stages of this study (Cohort 1), the CMC will also review the 
pharmacokinetic data, with the aim of confirming the dose for Cohort 2 while protecting 
participant safety.  The CMC will review PK and safety data reports at least monthly and take 
action as needed according to the guidelines in Section 10.3.1 (PK) and Section 9.6.1, Participant 
Safety, above.  
 
Following any pause, participant accrual may be resumed if resumption is recommended by the 
CMC or SMC.   
 


IMPAACT 2014, FINAL Version 1.0 
Page 82 of 129 
7 September 2017 
9.6.2 
Monitoring by the SMC  
 
An independent IMPAACT SMC will review this study regularly, following policies described in 
the IMPAACT Network Manual of Procedures.   
 
SMC reviews will occur at least annually and may also occur on a more frequent or ad hoc basis 
if any issues or concerns arise, or if requested by the SMC or CMC.  Reviews will focus on 
participant accrual, retention, study conduct, and safety.  An SMC review of safety and PK data 
will also take place prior to opening Cohort 2 for accrual.  Additional SMC reviews focused on 
safety may also occur as indicated below (Participant Safety and Dose Evaluation).  Based on 
any of its reviews, the SMC may recommend that the study proceed as currently designed, 
proceed with design modifications, or be discontinued.  The SMC may also provide operational 
recommendations to help address any study implementation challenges identified during their 
reviews.   
 
Study Progress and Quality of Study Conduct 
 
The SMC will monitor study progress and the quality of study conduct through review of the 
same types of data reports as the Protocol Team and CMC.   
 
Participant Safety 
 
The SMC will monitor participant safety through review of the same types of safety data reports 
as the CMC.  For ad hoc or triggered safety reviews, more limited data may be provided, focusing 
on the events that triggered the reviews. 
 
Triggered SMC reviews will occur in the following scenarios: 
 
(1) In the event of any adverse event that is life-threatening or results in death, the CMC will 
review the event as soon as possible (ideally within three business days of site awareness) and 
assess its relationship to study drug: 
• 
If either the site investigator or the CMC assesses the event as related to study drug, 
participant accrual will immediately be paused.  An ad hoc SMC review will be convened 
as soon as possible to discuss how the study should proceed. 
• 
If the site investigator and the CMC assess the event as not related to study drug, 
participant accrual will continue.  The SMC will be informed of any of these events along 
with the CMC’s assessment and decision-making. 
(2) In the event of any unresolvable disagreement within the CMC on an issue that would impact 
decision making or if the CMC encounters any other event or trend of concern, an SMC 
review of the relevant data will be convened.  The CMC may choose to pause participant 
accrual and/or administration of study drug, pending the outcome of the SMC review.  
(3) For Cohort 1, if more than 20% of participants experience grade 3 or higher AEs determined 
to be related to study drug, an ad hoc SMC review will be convened as soon as possible.  The 
SMC will review all the relevant safety and pharmacokinetic data, along with the 
recommendations of the CMC, and will determine whether and under what conditions 
(1) further dose-evaluation activities for this cohort may proceed, and (2) Cohort 2 may open 
for accrual.   
 


IMPAACT 2014, FINAL Version 1.0 
Page 83 of 129 
7 September 2017 
Dose Evaluation 
 
The team and the SMC will review all PK and safety data from Cohort 1 to determine if Cohort 2 
will open to accrual.  If Cohort 1 fails the PK targets or there are safety concerns, an SMC review 
will be convened to determine under what conditions Cohort 2 may open to accrual. 
 
Enrollment of ART-Experienced, Virologically Suppressed Participants in Cohort 2 
 
As noted in Section 1.4.2, once the 24-week data are available from one of the adult switch 
studies, the data will be reviewed by the CMC and SMC prior to opening Cohort 2 for the ART-
experienced, virologically suppressed participants.  If the CMC and SMC agree to open Cohort 2 
for ART-experienced, virologically suppressed participants, sites will be informed via a 
Clarification Memorandum when ART-experienced participants can be enrolled (see Section 
4.1.5.3). 
 
9.7 
Analyses 
 
The safety analysis will consist of descriptive statistics summarizing outcomes by cohorts.  See 
pharmacology Section 10 for description of PK analyses. 
 
9.7.1 
Primary Safety Analyses (on data through Week 2 for Cohort 1 and Week 24 for Cohort 2) 
 
The primary analyses will include all participants exposed to the 100 mg DOR dose and will be 
restricted to data through Week 2 for Cohort 1 and Week 24 for Cohort 2.  For participants who 
discontinued the study drug prematurely, safety data will be restricted through four weeks after 
last dose date (see Section 4.6).  These analyses will be performed after the last participant 
enrolled in Cohort 2 has reached Week 24.  For regulatory submission purposes, all safety 
outcomes will be presented in the aggregate as well as broken down by cohort. 
 
An overall summary of all AEs will be presented by cohort and, for Cohort 2, the summary will 
be broken down by population classification at entry (i.e., ART-naïve versus ARV-experienced).  
In addition, each participant’s safety data will be summarized as: the worst grade of adverse event 
experienced through these time points and the worst grade of adverse event assessed as related to 
study drug.  Frequency distributions of the safety outcomes, which will include (1) grade 3 or 
higher adverse events assessed as related to study drug, (2) serious adverse events assessed as 
related to study drug, (3) permanent discontinuation of study drug due to adverse events assessed 
as related to study drug, and (4) death due to adverse events regardless of relationship to study 
drug, will be presented by cohort and by population classification at entry (Cohort 2).  The 
proportions (bounded by exact 95% confidence intervals) and the listings of the participants 
experiencing these safety outcomes will also be presented by cohort and by population 
classification at entry (Cohort 2). 
 
The proportions of participants experiencing Grade 3 or higher adverse events, bounded by exact 
95% confidence intervals, will be presented by cohort and population classification at entry 
(Cohort 2).  Similar analyses will present the proportions of participants with Grade 3 or higher 
events assessed as related to study drug, again bounded by exact 95% confidence intervals.  Table 
19 presents the upper and lower limits of confidence intervals around potential results observed in 
the groups of n=12, n=15, and n=40, and the combined groups of n=52 and n=55. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 84 of 129 
7 September 2017 
Table 19.  Percent of Participants Experiencing ≥Grade 3 Adverse Events (or ≥Grade 3 Adverse 
Events Attributed to the Study Medication) with Exact 95% Confidence Intervals 
N 
n (%) With ≥Grade 3 Adverse Events 
95% CI 
12 
0 (0%) 
0% - 26% 
15 
0 (0%) 
0% - 22% 
40 
0 (0%) 
0% - 9% 
52 
0 (0%) 
0% - 7% 
55 
0 (0%) 
0% - 6% 
 
 
 
12 
1 (8%) 
0% - 38% 
15 
2 (13%) 
2% - 40% 
40 
4 (10%) 
3% - 24% 
52 
5 (10%) 
3% - 21% 
55 
6 (11%) 
4% - 22% 
 
 
 
12 
4 (33%) 
10% - 65% 
15 
5 (33%) 
12% - 62% 
40 
12 (30%) 
17% - 47% 
52 
15 (29%) 
17% - 43% 
55 
16 (29%) 
18% - 43% 
 
9.7.2 
Key Secondary Analyses for Cohort 2 
 
All secondary analyses will be performed after the last participant enrolled in Cohort 2 has 
reached Week 96, or earlier if the study team decides to do so based on accrual or retention 
issues. 
 
Safety  
 
Safety assessments will be performed on long term data collected through Week 96.  These 
analyses will be similar to Week 24 (Cohort 2) analyses described in Section 9.7.1 above.  In 
addition, any participant who discontinued the study due to a study drug related adverse event or 
virologic failure will be classified as a safety failure through Week 96.  For participants who 
discontinued the study due to other reasons, sensitivity analyses will be performed to see whether 
the final results will change by classifying these participants as safety failures versus excluding 
them from the long-term safety analyses. 
 
Viral Load 
 
Virologic responses for Cohort 2, based on plasma HIV-1 RNA (copies/mL), will be assessed at 
Weeks 24, 48, and 96.  Virologic failure will be defined for the analyses as HIV-1 RNA >200 
copies/mL, >50 copies/mL, and >40 copies/mL, in three separate analyses at Weeks 24, 48, and 
96.  For analysis purposes, the log drop from baseline in plasma HIV-1 RNA will be calculated 
and summarized for ART-naïve participants at Weeks 24, 48, and 96.  The Observed Failure 
Approach, which is a conservative approach to handle missing data, will be used: missing values 
are considered as failures for participants missing data due to discontinuation of study drug as a 
result of virologic failure or for non-treatment related reasons with last available 
RNA >200/50/40 copies/mL; otherwise participants with missing values are excluded.  The 
proportion of participants with plasma HIV-1 RNA <200 copies/mL, <50 copies/mL, and <40 


IMPAACT 2014, FINAL Version 1.0 
Page 85 of 129 
7 September 2017 
copies/mL, bounded by 95% confidence intervals, will be presented separately for all Cohort 2 
participants, both in the aggregate and broken down by participant population (i.e., ART-naïve 
versus ART-experienced). 
 
For regulatory submission purposes, at all these time points the primary definition of virologic 
outcome will be calculated according to a Missing, Switch or Discontinuation = Failure (MSDF) 
algorithm – as codified by the 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 any of these time points if they discontinue 
study drug prior to that time point.  Participants who switched or changed from the study drug to 
another regimen prior to the time points of interest, except for those who substituted single agents 
for the FDC, will be classified 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. 
 
CD4  
 
Median and the associated interquartile range for changes in CD4 count and percent from 
baseline to Weeks 24, 48, and 96 will be presented, both in the aggregate and broken down by 
population classification at entry (i.e., ART-naïve versus ART-experienced), bounded by 95% 
confidence intervals.  Based on the Observed Failure Approach, missing CD4 values for 
participants who discontinued the study drug due to virologic failure or for non-treatment related 
reasons with last available RNA >200/50/40 copies/mL will be replaced with their baseline value; 
otherwise participants with missing values are excluded.   
 
HIV Drug Resistance  
 
Participants who meet the criteria for protocol-defined virologic failure (see Section 8.6) will be 
evaluated for HIV-1 drug resistance to DOR and other components of the regimen.  For these 
participants, changes in the HIV-1 genotype and phenotype from baseline to the point of virologic 
failure will be presented descriptively. 
 
Acceptability, Palatability, and Adherence  
 
Acceptability, palatability, and adherence measures reported by the participant will be 
summarized, both in the aggregate and broken down by population classification at entry 
(i.e., ART-naïve versus ARV-experienced). 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 86 of 129 
7 September 2017 
10 
PHARMACOLOGY PLAN  
 
The design and analysis plans for objectives 2.1.1, 2.3.1, and 2.4.1 are described in this section. 
 
10.1 
Pharmacology Overview and Objectives 
 
Cohort 1 
 
Cohort 1 will assess the single dose pharmacokinetics of a 100 mg dose of doravirine in 12 
evaluable children and adolescents ≥35kg (with a minimum of four participants between 35 to 
45 kg).  The goal of Cohort 1 is to confirm the weight range for which a 100 mg once daily dose 
of DOR is appropriate.  Preliminary modeling suggests that a 100 mg daily dose of doravirine 
should be safe and effective for children or adolescents who weigh 35 kg or more.  The projected 
geometric mean steady state AUC0-24hr in children weighing 35 to 45 kg is 50 μM*hr (%CV: 
50.7%) and for children weighing >45 kg is 35.4 μM*hr (%CV: 61.1%).  Similarly, projected 
geometric mean steady state C24hr in children weighing 35 to 45 kg is 935 nM (%CV: 105%) and 
for children weighing >45 kg is 740 nM (%CV: 120%).  Based on simulations of ten participants 
(four from the 35 to 45kg group and six from the >45 kg group) with these geometric mean 
exposures and C24hr and variability, the AUC criterion (i.e., geometric mean steady state AUC0-24hr 
does not exceed 64.5 μM*hr) and the C24hr criterion (i.e., at least 90% of participants achieving at 
least 78 nM) are achieved with high probability (>99%).  
 
If Cohort 1 pharmacokinetic results confirm this initial model, then Cohort 2 will open to 
participants weighing ≥35 kg.  If exposure is deemed too high (i.e., exceeds that observed in 
adults at a 200 mg daily dose) in children or adolescents weighing closer to 35 kg, then Cohort 2 
will open with a 100 mg daily dose only in children and adolescents above the weight determined 
to yield appropriate exposure from the Cohort 1 results. 
 
The primary pharmacokinetic objective for Cohort 1 is to evaluate the single-dose 
pharmacokinetics of DOR in children and adolescents receiving DOR along with a stable ART 
regimen including an integrase inhibitor plus two NRTIs, using intensive PK sampling at Entry. 
 
Cohort 2 
 
Cohort 2 will assess the steady-state sparse pharmacokinetics of DOR, 3TC, and tenofovir once 
daily in 40 evaluable participants weighing ≥35 kg (or the weight determined in Cohort 1), using 
intensive PK sampling at Week 1 and sparse PK sampling through 48 weeks.  In addition, Cohort 
2 will evaluate the steady-state intensive pharmacokinetics of TFV and 3TC given as the FDC to 
the first 10 participants enrolled into Cohort 2 (see Section 1.4.3 for rationale).  PK samples for 
DOR will also be obtained at a subset of the intensive sampling time points.  Pharmacokinetic 
data and models generated through this study will inform further development of the 
DOR/3TC/TDF FDC for treatment of HIV in younger children in future studies and inform the 
pediatric sparse PK model for DOR. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 87 of 129 
7 September 2017 
10.2 
Methods and Timing for Collections, Processing, Handling, and Storage 
 
PK sample collection methods, processing, storage and shipping instructions are detailed in the 
LPC. 
 
Pharmacokinetic sampling will occur as detailed in Section 6 and as summarized below: 
 
Intensive PK collections 
 
• 
Cohort 1, Entry:  Intensive PK samples should be collected around the single dose of DOR 
administered in addition to the standard ARV regimen as described in Section 6.2.1.   
• 
Cohort 2, Week 1: Intensive PK samples for 3TC and tenofovir should be collected around a 
dose at steady state as per Section 6.3.2.  PK samples for DOR will also be collected in a 
subset of time points. 
 
Sparse PK collections 
 
• 
Cohort 2, Entry, Weeks 4, 8, 12, 24, and 48: Sparse PK samples for DOR, 3TC, and tenofovir 
should be collected at each required study visit, as per Section 6.3.8.  
 
10.3 
PK Guidelines for Dose Confirmation and Timing of Interim Analyses 
 
10.3.1 PK Guidelines for Cohort 1 to Confirm the Dose for Cohort 2      
 
For Cohort 1 participants, acceptable PK is defined as follows: 
• 
Exposure that does not exceed that observed at the 200 mg QD doravirine dose in adult HIV-
infected patients (currently estimated to be 64.5 µM*hr; the target value may be updated as 
additional doravirine PK data in adult patients become available).  Since AUC0-∞ following a 
single dose is equivalent to steady state AUC0-24hr, the AUC0-∞ values for Cohort 1 should be 
generally similar to the corresponding steady state AUC0-24hr values in adult HIV-infected 
patients.  A geometric mean steady state AUC0-∞ that does not exceed the steady state AUC0-
24hr associated with the 200 mg QD dose in adults will be targeted, but additional 
considerations based on the observed PK in Cohort 1 relative to the total distribution of 
exposures at 200 mg QD may also be taken into account.  
• 
Steady state C24hr values for participants in Cohort 1 will be projected from the single dose 
PK profiles.  At least 90% of Cohort 1 participants should have C24hr values that exceed the 
PK target for suppression of wild type virus, currently estimated as 78 nM (equivalent to over 
six times the IC50 for DOR against wild type virus in the presence of 100% normal human 
serum).    
 
Cohort 1 participants will be evaluable for PK guidelines if the AUC and C24hr values can be 
calculated or estimated with the data available.  If these PK parameters cannot be estimated, then 
the participant will be unevaluable for PK guidelines.  An unevaluable participant will be 
replaced.  All PK data (from unevaluable and evaluable participants and visits) will be reported at 
the end of the study.  Only evaluable participant PK data will be used in the PK guidelines 
assessment. 
 
As described in Sections 9.3.1.1 and 10.5, Cmax will be evaluated among participants in Cohort 1; 
however, Cmax will not be used in the evaluation to confirm the dose for Cohort 2. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 88 of 129 
7 September 2017 
10.3.2 Timing of Interim Analyses 
 
Cohort 1 DOR pharmacokinetics will be summarized once 12 participants have completed the 
pharmacokinetic visit to confirm the dose for Cohort 2.  Samples from Cohort 1 participants 
should be shipped as soon as the 72-hour post-dose draw is completed and tested on an ongoing 
basis. 
 
Cohort 2 DOR, 3TC and TFV pharmacokinetics will be summarized after the first 10 participants 
have completed the PK evaluation at Week 1.  These assays may be performed in batch once 
these visits have been completed.  Cohort 2 DOR, 3TC, and tenofovir sparse pharmacokinetics 
will be summarized at the end of the study. 
 
Additional interim pharmacokinetic analyses may be performed at any time the CMC deems it 
necessary to assess the exposure to the current dose. 
 
10.4 
Laboratory Performing the Assays 
 
The laboratories performing the doravirine, tenofovir, and lamivudine assays will be detailed in 
the LPC.   
 
10.5 
Primary and Secondary Data Analysis Plan 
 
The primary pharmacokinetic outcome variables for Cohort 1 participants are AUC0-∞, C24hr, and 
Cmax of DOR.  Other standard pharmacokinetic parameter estimates will also be calculated (Tmax, 
apparent terminal half-life, apparent clearance [CL/F], and apparent volume of distribution 
[Vz/F]). 
 
The pharmacokinetic outcome variables for Cohort 2 (intensive or sparse sampling only) for 
DOR, TFV, and 3TC are AUC0-24hr, Cmax, and C24hr.  Other standard pharmacokinetic parameter 
estimates may also be calculated (e.g., Tmax).   
 
For all intensive, semi-intensive, or sparse PK evaluations (Cohort 1: DOR and Cohort 2: DOR, 
3TC, and TFV), non-compartmental analyses will be conducted.  Cmax, Tmax, and C24hr will be 
observed from the concentration versus time curve for each participant.  AUC0-∞ predicted will be 
estimated by the linear up/log down trapezoidal rule up to the last measurable concentration plus 
Clast-predicted/λz.  AUC0-24hr will be estimated by the linear up/log down trapezoidal rule up to the last 
measurable concentration.  Apparent clearance will be calculated as dose divided by AUC.  The 
apparent Vz/F will be determined as CL/F divided by λz, where λz is the terminal slope of the log 
concentration versus time curve.  The half-life (t1⁄2) is calculated as 0.693/λz.  Sparse PK samples 
will be included in population PK analyses.  
 
10.6 
Anticipated Outcomes 
 
The goal of this study is to gain an understanding of DOR and FDC component pharmacokinetics 
in children and adolescents, and to define the dose(s) that achieve the desired systemic exposure 
in this population. 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 89 of 129 
7 September 2017 
11 
DATA HANDLING AND RECORD KEEPING 
 
11.1 
Data Management Responsibilities 
 
As described in Section 4.4, data on screening and enrollment in this study will be collected using 
the DMC SES.   
 
Study sites must maintain adequate and accurate research records containing all information 
pertinent to the study for all screened and enrolled individuals, including paper-based CRFs (if 
used), eCRFs, and supporting source data.  In maintaining these records, sites must comply with 
the standards of source documentation specified in the DAIDS policy on Requirements for 
Source Documentation in DAIDS Funded and/or Sponsored Clinical Trials (available on the 
website referenced in Section 11.2). 
 
eCRFs and an eCRF completion guide will be made available to study sites by the DMC.  Study 
site staff will enter required data into eCRFs, with system checks applied and data queries 
generated immediately upon saving the entered data.  Data must be entered within timeframes 
specified by the DMC; queries must also be resolved in a timely manner.  Selected laboratory 
data (including pharmacokinetic data) are transferred electronically to the DMC through the 
LDMS or through other secure mechanisms.   
 
Further information on eCRFs and IMPAACT data management procedures will be provided by 
the DMC.  A User Manual for the Subject Enrollment System is available on the DMC portal at 
www.frontierscience.org.   
 
11.2 
Essential and Source Documents and Access to Source Data 
 
All DAIDS policies referenced in this section are available at:  
 
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 drugs 
for the indication for which it is evaluated in this study; or, if no application is filed, or if the 
application is not approved for this indication, records must be retained two years after the study 
is discontinued and the FDA is notified.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 90 of 129 
7 September 2017 
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, Merck & Company, the FDA, site drug regulatory authorities, site 
IRBs/ECs, OHRP, and other applicable regulatory entities.  Records must be kept on-site 
throughout the period of study implementation; thereafter, instructions for off-site storage may be 
provided by NIAID or NICHD.  No study records may be removed to an off-site location or 
destroyed prior to receiving approval from NIAID or NICHD.  
 
11.3 
Quality Control and Quality Assurance 
 
Study sites must ensure that essential documents and participant research records are subject to 
continuous quality control and quality assurance procedures consistent with the DAIDS policy on 
Requirements for Clinical Quality Management Plans, which is available at:  
 
https://www.niaid.nih.gov/sites/default/files/qmppolicy.pdf 
 
 
12 
CLINICAL SITE MONITORING 
 
Site monitors under contract to NIAID or NICHD will visit study sites to inspect study facilities 
and review participant study records including consent forms, paper-based CRFs (if used), 
eCRFs, medical records, laboratory records, and pharmacy records, to ensure protection of study 
participants, compliance with the IRB/EC approved protocol, and accuracy and completeness of 
records.  The monitors also will review essential document files to ensure compliance with all 
applicable regulatory requirements.  Site investigators will make study facilities and documents 
available for inspection by the monitors.   
 
 
13 
HUMAN SUBJECTS PROTECTIONS 
 
13.1 
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 CFR 46; subsequent to initial review and 
approval, IRBs/ECs must review the study at least annually.  Site investigators must also 
promptly report to the IRB/EC any changes in the study and any unanticipated problems 
involving risks to participants or others. 
 
All IRB/EC policies and procedures must be followed and complete documentation of all 
correspondence to and from the IRBs/ECs must be maintained in site essential document files.  
Sites must submit documentation of both initial review and approval and continuing review to the 
DAIDS Protocol Registration Office (PRO) in accordance with the DAIDS Protocol Registration 
Manual (see also Section 14.2). 
 
13.2 
Vulnerable Participants 
 
The NIH is mandated by law to ensure that children be included in clinical research when 
appropriate (26).  This study responds to that mandate and will provide clinical research data to 
inform doravirine and DOR/3TC/TDF safety and dosing in children and adolescents.  
Nonetheless, the children and adolescents who take part in this study are considered vulnerable 


IMPAACT 2014, FINAL Version 1.0 
Page 91 of 129 
7 September 2017 
participants per the US Code of Federal Regulations, and site IRBs/ECs must consider the 
potential risks and benefits to child and adolescent 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 14.2, and the risk 
category assigned by the IRB/EC further determines the parental informed consent requirements 
for the study at each site.   
 
The specifications of 45 CFR 46.404 and 45 CRF 46.405 are generally expected to apply to 
Cohort 1 and Cohort 2, respectively; therefore, the consent of one parent is expected to be 
obtained for this study.  Nonetheless, each site’s IRBs/ECs must document their risk 
determination and the consent requirements associated with the IRB/EC determination must be 
followed; study sites should adapt the signature pages of their site-specific ICFs as needed to 
reflect the IRB/EC determination.  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 all IRB/EC requirements and the requirements of the DAIDS policy 
on Enrolling Children (including Adolescents) in Clinical Research, which is available at:  
 
https://www.niaid.nih.gov/sites/default/files/enrollingchildrenrequirements.pdf 
 
13.3 
Informed Consent 
 
As indicated in Section 4.1.3, site investigators and their designees will be required to determine 
participant age and ability to provide independent informed consent for study participation 
consistent with IRB/EC policies and procedures.  Each site must establish SOPs, roles, and 
responsibilities for completing these determinations, and study staff involved in completing these 
determinations must have documented training in the relevant policies and procedures prior to 
study initiation.  
 
Written informed consent and written assent will be obtained for study participation as follows: 
 
• 
If the potential participant is not of legal age to provide independent informed consent:  
Parent or legal guardian must provide written informed consent.  Written informed assent 
from the potential participant will be conducted per site IRB/EC policies and will generally 
be obtained if the participant is able to understand the nature, significance, and risks of the 
study.   
 
Note:  Refer to Section 13.2 for considerations related to parental consenting requirements; 
IRB/EC risk determinations will guide whether the consent of one or both parents may be 
required for this study.  All IRB/EC requirements must be followed.   
 


IMPAACT 2014, FINAL Version 1.0 
Page 92 of 129 
7 September 2017 
• 
If the potential participant is of legal age and able to provide independent informed consent 
as determined by site SOPs:  The potential participant must provide written informed consent 
for study participation. 
 
Written informed consent and assent (as applicable) for participation will be obtained before any 
study-specific procedures are performed (see Appendix II and Appendix III).  The informed 
consent process will include information exchange, detailed discussion, and assessment of 
understanding of all required elements of informed consent, including the potential risks, benefits, 
and alternatives to study participation.  The process will describe what is known about the safety 
and tolerability of the study drugs and participants and parents/guardians will be extensively 
counseled on the importance of adherence to the ARV regimen.  The informed assent process will 
include a similar process, with the amount of information and level of detail provided as part of 
assent processes will be tailored to the age of the potential participant, guided by IRB/EC policies 
and procedures; the sample informed consent forms (Appendix II and Appendix III) can be 
modified to meet the requirements for assent.   
 
As part of the informed consent and assent process, consenters will be asked whether they agree 
to storage and future research testing of biological specimens remaining after all protocol-
specified testing has been performed (see Appendix IV).  This storage and future use is optional 
and may be declined with no impact on other aspects of study participation.  Likewise, genetic 
testing of residual specimens is optional and may be declined.  As with the main study sample 
informed consent forms, the sample informed consent form for storage and future research testing 
(Appendix IV) can be modified to meet the requirements for assent. 
 
If the participant, parent, or guardian (as applicable) is unable to read, the process for consenting 
illiterate participants, as defined or approved by the local IRB/EC, should be followed.  Sites 
must also establish and maintain written procedures describing standards for obtaining informed 
assent, reflective of applicable IRB/EC guidance. 
 
As indicated above, it is generally expected that only one parent or guardian will provide 
informed consent for the child’s or adolescent’s participation in the study.  However, parental 
consenting requirements at each site will depend on the IRB/EC risk determination described in 
Section 13.2; all IRB/EC requirements will be followed.  Participants will enroll in the study as 
minors and will generally require consent from a parent or guardian.   
 
Should the consenting parent (or guardian) of a participant die or no longer be available for any 
reason, sites should follow the guidelines and procedures as described by their IRBs/ECs.  In 
general, if participants are doing well on the study drug, it is expected that they will stay on study 
drug and will have safety assessments performed per the local standard of care while continued 
study participation is being determined.  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 13.2), all sites must establish and maintain written procedures 
describing the standards that will be followed to identify who may serve as guardian for an 
enrolled 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.   
 


IMPAACT 2014, FINAL Version 1.0 
Page 93 of 129 
7 September 2017 
The sample informed consent forms provided in Appendix II, Appendix III, and Appendix IV 
include signature pages to accommodate potential participants to provide both assent with 
parental/guardian consent (as would be expected for most participants) and consent (as would be 
expected for participants considered of legal age, such as emancipated minors).  In the scenario of 
assent with parental consent, the participant would be expected to complete the participant’s 
signature block on the form and the parent or guardian would be expected to complete the 
participant’s parent/guardian signature block on the form.  As such, the sample forms may be 
used for both assent and consent, with the appropriate signatures entered on the appropriate 
pages.  Study sites are also permitted to develop separate assent and consent forms for this study, 
if required by site or IRB/EC policies and procedures; for example, sites may develop one assent 
form for children 12 to 15 years of age at lower reading and comprehension levels than another 
assent form for children 16 to less than 18 years of age. 
 
Each participant is expected to take part in the informed consent process with his or her parent or 
legal guardian and, in general, both the assent of the participant and the consent of the parent or 
legal guardian will be required for all consent decisions.  For example, if the participant does not 
provide assent, or the parent or legal guardian does not provide consent, the participant will not 
be enrolled in the study.  The same approach will be taken for consent for storage and future 
research testing of biological specimens.  Participants may also reach the legal age of consent 
during follow-up.  In this case, written informed consent for continued participation (Appendix II 
and Appendix III) and specimen storage and future use (Appendix IV) 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. 
 
Refer to Section 4.4 for further information on informed consent procedures for this study.   
 
13.4 
Potential Benefits 
 
There may be no direct benefit to participants who take part in this study.  However, information 
learned in this study may be of benefit to participants and others in the future, particularly 
information that may lead to more treatment options for HIV-infected children and adolescents.  
Participants may also appreciate the opportunity for themselves to contribute to HIV-related 
research. 
 
13.5 
Potential Risks  
 
The potential risks of participation in this study include risks associated with study procedures 
and risks associated with receipt of DOR and DOR/3TC/TDF.   
 
Most study procedures are routine medical procedures that are associated with minimal to no risk 
in participants.  Blood collection may cause pain, bruising, swelling, or fainting.  There is a very 
small chance of infection where the needle is inserted. 
 
Refer to Section 1.2.3 and the Investigator’s Brochures for the study drugs for a complete 
description of the potential risks associated with the use of these drugs.   
 
For virologically suppressed, ART-experienced participants enrolling into Cohort 2, there is the 
potential risk that the study drugs may not be as effective in maintaining viral suppression as 
participants’ current regimen. 


IMPAACT 2014, FINAL Version 1.0 
Page 94 of 129 
7 September 2017 
 
Refer to Section 13.7 for further information on privacy and confidentiality.  Despite all efforts to 
maintain confidentiality, involvement in the study could become known to others, possibly 
leading to unfair treatment, discrimination, or other social impacts (e.g., because participants 
could become known as having HIV).  For example, participants could be treated unfairly or 
discriminated against or could have problems being accepted by their families and/or 
communities.  
 
13.6 
Reimbursement/Compensation 
 
Pending IRB/EC approval, participants will be reimbursed for costs associated with completing 
study visits (e.g., transport costs).  Reimbursement amounts will be specified in site-specific ICFs 
or other materials if applicable per IRC/EC policies and procedures.  
 
13.7 
Privacy and Confidentiality 
 
All study procedures will be conducted in private and every effort will be made to protect 
participant privacy and confidentiality to the extent possible.  Participant information will not be 
released without written permission to do so except as necessary for review, monitoring, and/or 
auditing as described in Section 11.2. 
 
All study-related information will be stored securely.  Participant research records will be stored 
in locked areas with access limited to study staff.  All laboratory specimens, CRFs, and other 
documents that may be transmitted off-site (e.g., EAE report forms) will be identified by PID 
only.  Likewise, communications between study staff and protocol team members regarding 
individual participants will identify participants by PID only.   
 
Study sites are encouraged but not required by DAIDS policies to store study records that bear 
participant names or other personal identifiers separately from records identified by PID.  All 
local databases must be secured with password protected access systems.  Lists, logbooks, 
appointment books, and any other documents that link PID numbers to personal identifying 
information should be stored in a separate, locked location in an area with limited access.   
 
In addition to the above, a Certificate of Confidentiality has been obtained for this study from the 
US Department of Health and Human Services.  This certificate protects study staff from being 
compelled to disclose study-related information by any US federal, state, or local civil, criminal, 
administrative, legislative, or other proceedings.  It thus serves to protect the identity and privacy 
of study participants.  Because the certificate cannot be enforced outside of the US, however, it 
applies only to US sites and participants. 
 
13.8 
Communicable Disease Reporting 
 
Study staff will comply with local requirements to report communicable diseases including, HIV 
infection identified among study participants to health authorities.  Participants will be made 
aware of all applicable reporting requirements as part of the study informed consent process. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 95 of 129 
7 September 2017 
13.9 
Management of Incidental Findings 
 
Site investigators will inform parents or guardians (or participants, if applicable) of all clinically 
meaningful physical exam findings and laboratory test results.  PK test results in this study will 
not be routinely provided.  When applicable, site investigators will provide referrals to non-study 
sources of medical care for further evaluation and/or treatment of these findings.  
 
13.10 Management of New Information Pertinent to Study Participation 
 
Study staff will provide parents or guardians (or participants, if applicable) with any new 
information learned over the course of the study that may affect willingness to continue receiving 
study drug and/or remain in follow-up in the study.   
 
13.11 Post-Study Access to Study Drug 
 
Participants will be transitioned into care and treatment outside of the study at the end of their 
study participation as per local standards.  If DOR/3TC/TDF is not locally available for a 
participant in Cohort 2 completing the study, then the pharmaceutical company or their partners 
will make every effort to provide DOR/3TC/TDF following the participant’s completion of the 
study through a mechanism outside of the protocol, until one or more of the following events 
occur:   
 
• 
DOR/3TC/TDF is 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 
• 
If development of DOR/3TC/TDF is terminated, if this occurs.  
 
However, because in-country provision is not only dependent on the pharmaceutical company’s 
willingness to provide DOR/3TC/TDF, but also on the country’s importation requirements and 
other approvals and processes, the consent form acknowledges the possibility that 
DOR/3TC/TDF may not be available post-study, despite the company’s efforts.   
 
 
14 
ADMINISTRATIVE PROCEDURES 
 
14.1 
Regulatory Oversight 
 
This study is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), 
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), 
and National Institute of Mental Health (NIMH), which are part of the United States National 
Institutes of Health (NIH).  Merck & Company will provide study drugs for this study but is not 
involved in sponsorship or regulatory oversight of the study.   
 
Within NIAID, DAIDS is responsible for regulatory oversight of this study.  DAIDS will 
distribute safety-related information pertaining to the study drugs prior to and during the conduct 
of the study, in accordance with its sponsor obligations.  
 
NIAID and NICHD provide funding to the clinical research sites at which this study will be 
conducted.  Each institute contracts with independent clinical site monitors who will perform 
monitoring visits as described in Section 12.  As part of these visits, monitors will inspect study-


IMPAACT 2014, FINAL Version 1.0 
Page 96 of 129 
7 September 2017 
related documentation to ensure compliance with all applicable US and local regulatory 
requirements. 
 
14.2 
Protocol Registration 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site 
must have the protocol and the protocol ICFs approved, as appropriate, by their local IRBs/ECs 
and any other applicable regulatory entity.  Upon receiving final approval, sites will submit all 
required protocol registration documents to the DAIDS PRO at the RSC.  The DAIDS PRO will 
review the submitted protocol registration packet to ensure that all of the required documents 
have been received.   
 
Site-specific ICFs will be reviewed and approved by the DAIDS PRO and sites will receive an 
Initial Registration Notification from the DAIDS PRO that indicates successful completion of the 
protocol registration process.  A copy of the Initial Registration Notification should be retained in 
the site's regulatory files. 
 
For any future protocol amendments, upon receiving final IRB/EC and any other applicable 
regulatory entity approvals, sites should implement the amendment immediately.  Sites are 
required to submit an amendment registration packet to the DAIDS PRO at the RSC.  The 
DAIDS PRO will review the submitted protocol registration packet to ensure that all the required 
documents have been received.  Site-specific ICFs will not be reviewed and approved by the 
DAIDS PRO and sites will receive an Amendment Registration Notification when the DAIDS 
PRO receives a complete registration packet.  A copy of the Amendment Registration 
Notification should be retained in the site's regulatory files. 
 
For additional information on the protocol registration process and specific documents required 
for initial and amendment registrations, refer to the current version of the DAIDS Protocol 
Registration Manual, which is available on the RSC website:  
 
http://rsc.tech-res.com/clinical-research-sites/protocol-registration 
 
14.3 
Study Implementation 
 
This study will be conducted in accordance with the protocol, international good clinical practice 
guidelines, and all applicable US and local regulations.  Study implementation will also be guided 
by the IMPAACT Manual of Procedures (MOP), LPC, and other study implementation materials, 
which will be available on the IMPAACT website:  www.impaactnetwork.org. 
 
Study implementation at each site will also be guided site-specific SOPs.  The DAIDS policy on 
Requirements for Manual of Operational Procedures specifies the minimum set of SOPs that must 
be established at sites conducting DAIDS funded and/or sponsored clinical trials (available on the 
website referenced in Section 11.2).  These SOPs should be updated and/or supplemented as 
needed to describe roles, responsibilities, and procedures for this study. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 97 of 129 
7 September 2017 
14.4 
Protocol Deviation Reporting 
 
Per the policy for Requirements for Source Documentation in DAIDS Funded and/or Sponsored 
Clinical Trials (available at the website referenced in Section 11.2), all protocol deviations must 
be documented in participant research records.  Reasons for the deviations and corrective and 
preventive actions taken in response to the deviations should also be documented.  
 
Deviations should be reported to site IRBs/ECs and other applicable review bodies in accordance 
with the policies and procedures of these review bodies.  Serious deviations that are associated 
with increased risk to one or more study participants and/or significant impacts on the integrity of 
study data must also be reported within IMPAACT, following procedures specified in the 
IMPAACT MOP. 
 
14.5 
Critical Event Reporting 
 
Per the DAIDS policy on Identification and Classification of Critical Events, a critical event is 
defined as an unanticipated study-related incident that is likely to cause harm or increase the risk 
of harm to participants or others or has a significant adverse impact on study outcomes or 
integrity.  All such events must be reported following procedures specified in the DAIDS Critical 
Events Manual, which is available at:  
 
https://www.niaid.nih.gov/sites/default/files/criticaleventsmanual.pdf 
 
14.6 
ClinicalTrials.gov 
 
This protocol is not subject to the Food and Drug Administration Amendments Act of 2007 
(FDAAA).  However, it will be registered in ClinicalTrials.gov to meet International Committee 
of Medical Journal Editors requirements. 
 
 
15 
PUBLICATIONS 
 
All presentations and publications of data collected in this study are governed by IMPAACT 
policies, which are available in the IMPAACT Manual of Procedures.  
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 98 of 129 
7 September 2017 
16 
REFERENCES 
 
1. 
Kapogiannis BG, Soe MM, Nesheim SR, Abrams EJ, Carter RJ, Farley J, et al. Mortality trends 
in the US Perinatal AIDS Collaborative Transmission Study (1986-2004). ClinInfect Dis. 
2011;53(10):1024-34. 
2. 
De Beaudrap P, Boulle C, Lewden C, Gabillard D, Nacro B, Diagbouga S, et al. Morbidity after 
antiretroviral therapy initiation in HIV-1-infected children in West Africa: temporal trends and 
relation to CD4 count. The Pediatric infectious disease journal. 2013;32(4):354-60. 
3. 
Gona P, Van Dyke RB, Williams PL, Dankner WM, Chernoff MC, Nachman SA, et al. Incidence 
of opportunistic and other infections in HIV-infected children in the HAART era. Jama. 
2006;296(3):292-300. 
4. 
Prasitsuebsai W, Kariminia A, Puthanakit T, Lumbiganon P, Hansudewechakul R, Siew Moy F, 
et al. Impact of antiretroviral therapy on opportunistic infections of HIV-infected children in the 
therapeutic research, education and AIDS training asia pediatric HIV observational database. The 
Pediatric infectious disease journal. 2014;33(7):747-52. 
5. 
Chadwick EG, Yogev R, Alvero CG, Hughes MD, Hazra R, Pinto JA, et al. Long-term outcomes 
for HIV-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination 
antiretroviral therapy. AIDS. 2011;25(5):643-9. 
6. 
Bratholm C, Johannessen A, Naman E, Gundersen SG, Kivuyo SL, Holberg-Petersen M, et al. 
Drug resistance is widespread among children who receive long-term antiretroviral treatment at a 
rural Tanzanian hospital. J AntimicrobChemother. 2010;65(9):1996-2000. 
7. 
Salou M, Dagnra AY, Butel C, Vidal N, Serrano L, Takassi E, et al. High rates of virological 
failure and drug resistance in perinatally HIV-1-infected children and adolescents receiving 
lifelong antiretroviral therapy in routine clinics in Togo. J Int AIDS Soc. 2016;19(1):20683. 
8. 
Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and 
Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and 
adolescents. 14 July 2016 ed2016. 
9. 
World Health Organization. Consolidated guidelines on HIV prevention, diagnosis, treatment and 
care for key populations 2016. Available from: 
http://apps.who.int/iris/bitstream/10665/246200/1/9789241511124-eng.pdf?ua=1. 
10. 
European Medicines Agency. Annex I: Summary of Product Characteristics, Edurant 2016. 
Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/002264/WC500118874.pdf. 
11. 
Lai MT, Feng M, Falgueyret JP, Tawa P, Witmer M, DiStefano D, et al. In vitro characterization 
of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Antimicrobial agents 
and chemotherapy. 2014;58(3):1652-63. 
12. 
Merck Sharp & Dohme Corp.-a Subsidiary of Merck & Co. I. Investigator's Brochure for MK-
1439/MK-1439A. 8 ed2016. 
13. 
Gatell JM, Morales-Ramirez JO, Hagins DP, Thompson M, Keikawus A, Hoffmann C, et al. 
Forty-eight-week efficacy and safety and early CNS tolerability of doravirine (MK-1439), a novel 
NNRTI, with TDF/FTC in ART-naive HIV-positive patients. J Int AIDS Soc. 2014;17(4 Suppl 
3):19532. 
14. 
Schurmann D, Sobotha C, Gilmartin J, Robberechts M, De Lepeleire I, Yee KL, et al. A 
randomized, double-blind, placebo-controlled, short-term monotherapy study of doravirine in 
treatment-naive HIV-infected individuals. Aids. 2016;30(1):57-63. 
15. 
Gatell JM, Raffi F, Plettenberg A, Smith D, Portilla J, Hoffmann C, et al. Doravirine 100mg QD 
vs Efavirenz +TDF/FTC in ART-Naive HIV+ Patients: Week 48 Results.  CROI; Boston, 
Massachusetts2016. 
16. 
Molina J-M, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, et al. Doravirine is non-inferior 
to darunavir+ritonavir in Phase 3 treatment-naive trial at Week 48.  Conference on Retroviruses 
and Opportunistic Infections; February 13-16, 2017; Seattle, Washington 2017. 


IMPAACT 2014, FINAL Version 1.0 
Page 99 of 129 
7 September 2017 
17. 
Merck Sharp & Dohme Corp.-a Subsidiary of Merck & Co. I. Investigator's Brochure for MK-
1439/MK-1439A. 9 ed2017. 
18. 
Squires K, Molina JM, Sax PE, Wong W, Orkin C, Sussmann O, et al. Fixed Dose Combination 
of Doravirine/Lamivudine/TDF is Non-Inferior to Efavirenz/Emtricitabine/TDF in Treatment-
naïve Adults with HIV-1 Infection: Week 48 Results of the Phase 3 DRIVE-AHEAD Study.  
International AIDS Society; Paris, France 2017. 
19. 
Anderson MS, Gilmartin J, Cilissen C, De Lepeleire I, Van Bortel L, Dockendorf MF, et al. 
Safety, tolerability and pharmacokinetics of doravirine, a novel HIV non-nucleoside reverse 
transcriptase inhibitor, after single and multiple doses in healthy subjects. Antivir Ther. 
2015;20(4):397-405. 
20. 
Lapphra K, Vanprapar N, Chearskul S, Phongsamart W, Chearskul P, Prasitsuebsai W, et al. 
Efficacy and tolerability of nevirapine- versus efavirenz-containing regimens in HIV-infected 
Thai children. International journal of infectious diseases : IJID : official publication of the 
International Society for Infectious Diseases. 2008;12(6):e33-8. 
21. 
Puthanakit T, Oberdorfer A, Akarathum N, Kanjanavanit S, Wannarit P, Sirisanthana T, et al. 
Efficacy of highly active antiretroviral therapy in HIV-infected children participating in 
Thailand's National Access to Antiretroviral Program. ClinInfect Dis. 2005;41(1):100-7. 
22. 
Kuhn L, Coovadia A, Strehlau R, Martens L, Hu CC, Meyers T, et al. Switching children 
previously exposed to nevirapine to nevirapine-based treatment after initial suppression with a 
protease-inhibitor-based regimen: long-term follow-up of a randomised, open-label trial. The 
Lancet Infectious diseases. 2012;12(7):521-30. 
23. 
Coovadia A, Abrams EJ, Stehlau R, Meyers T, Martens L, Sherman G, et al. Reuse of nevirapine 
in exposed HIV-infected children after protease inhibitor-based viral suppression: a randomized 
controlled trial. Jama. 2010;304(10):1082-90. 
24. 
AIDS Info. Lamivudine 2016 [cited 2016 19 October]. Available from: 
https://aidsinfo.nih.gov/drugs/126/lamivudine/0/professional#. 
25. 
Gilead Sciences. Viread(R) (tenofovir disproxil fumarate) tablets, for oral use [package insert]. 
Foster City, CAFebruary 2016. 
26. 
National Institutes of Health. NIH Policy and Guidelines on the Inclusion of Children as 
Participants in Research Involving Human Subjects. 1998 March 6. Report No. 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 100 of 129 
7 September 2017 
Appendix I-A: Schedule of Evaluations for Cohort 1 
 
Study Visit 
Screen 
Entry 
Week 2 
Visit Window 
 
Day 0 
±2 days 
CLINICAL EVALUATIONS 
 
 
 
Informed consent 
X 
 
 
Medical history 
X 
X 
X 
Complete physical exam 
X 
X 
 
Symptom-directed physical exam 
 
 
X 
Study drug administration 
 
X 
 
Palatability and acceptability assessment 
 
X 
 
LABORATORY EVALUATIONS 
 
 
 
Confirmatory HIV testing [if needed] 
[0 – 6mL] 
 
 
Pregnancy test1 
 
X 
 
CBC with differential and platelets 
1 mL 
1 mL 
1 mL 
Chemistries 
3 mL 
3 mL 
3 mL 
HIV-1 RNA 
6 mL 
6 mL 
 
CD4 cell count 
 
2 mL 
 
Intensive PK sampling2 
 
9 mL 
 
Total maximum blood volume 
16 mL 
22 mL 
4 mL 
1At entry, all females who have reached menarche or who are engaging in sexual activity that could 
lead to pregnancy must have a pregnancy test, with results available prior to enrollment.  Urine 
(5 mL) or blood (1 mL) tests are acceptable.  The total blood volume shown above accommodates 
collection of 1 mL of blood, if needed. 
2Intensive PK sampling will be done as indicated in Section 6.2.1 from entry through 72 hours post-
dose.  The blood volume per sample is 1 mL.   
 


IMPAACT 2014, FINAL Version 1.0 
Page 101 of 129 
7 September 2017 
Appendix I-B: Schedule of Evaluations for Cohort 2 
 
Study Visit 
Screen 
Entry 
Weeks on Study 
Confirmation 
of Virologic 
Failure 
Early 
D/C 
11 
2 
4 
8 
12 
16 
242 
362 
482 
Q163 
Visit Window 
 
Day 0 
8-13 d 
±1 
wk 
-1 wk-
+2 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
±2 wk 
±4 wk 
CLINICAL EVALUTIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete physical exam  
X 
X 
 
 
 
 
 
 
 
 
X 
Wk 96 
X 
X 
Symptom-directed 
physical exam  
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Wks 64  
& 80 
 
 
Adherence assessment 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
WHO staging 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Palatability and 
acceptability assessment 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
LABORATORY 
EVALUATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confirmatory HIV testing 
[if needed] 
[0-6 
mL] 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with differential and 
platelets 
1 mL 
1 mL 
 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
1 mL 
 
1 mL 
Chemistries 
3 mL 
3 mL 
 
3 mL 
3 mL 
3 mL 
3 mL 
3 mL 
3 mL 
3 mL 
3 mL 
3 mL 
 
3 mL 
Lipid profiles  
 
2 mL 
 
 
 
 
2 mL 
 
2 mL 
 
2 mL 
2 mL  
(Wk 96 only) 
 
 
Urinalysis  
X 
 
 
X 
 
 
X 
 
X 
 
X 
Wks 64  
& 96 
 
 
Hepatitis B and C 
4 mL 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test4 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV-1 RNA  
6 mL 
6 mL 
 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
6 mL 
CD4 cell counts 
 
2 mL 
 
 
2 mL 
 
2 mL 
 
2 mL 
 
2 mL 
 
 
2 mL 
Genotypic resistance test5 
2 mL5 
 
 
 
 
 
 
 
 
 
 
 
 
 
Store for resistance 
testing 
 
4 mL5 
 
 
 
 
 
 
 
 
 
 
6 mL6 
6 mL6 
Pharmacology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Intensive PK sampling1 
 
 
22.5 mL 
 
 
 
 
 
 
 
 
 
 
 
Sparse PK sampling7 
 
3.5 mL 
 
 
3.5 mL 3.5 mL 3.5 mL 
 
7 mL 
 
7 mL 
 
 
 
Total maximum blood 
volume 
22 mL 
22.5 mL 
22.5 mL 
10 mL 16.5 mL 14.5 mL 18.5 mL 11 mL 
22 mL 
11 mL 
22 mL 
13 mL 
13 mL 
19 mL 


IMPAACT 2014, FINAL Version 1.0 
Page 102 of 129 
7 September 2017 
 
Appendix I-B Footnotes: 
1 Only for the first 10 participants enrolled, intensive PK sampling will be done as indicated in Section 6.3.2.  Samples should be collected per Table 15 and 
as below: 
• 3.5 mL should be collected at pre-dose, 2 hours post-dose, 4 hours post-dose, 12 hours post-dose, and 24 hours post-dose 
• 2.5 mL should be collected at 1 hour post-dose and 8 hours post-dose 
2 The target visit window for Weeks 24, 36, and 48 is  2 weeks; however, the allowable visit window is  4 weeks. 
3 Refer to Section 6.3.7.  After Week 48, participants will complete scheduled follow-up visits every 16 weeks (Q16) through Week 96.  The target visit 
window for Q16 visits is  4 weeks; however, the allowable visit window is  8 weeks.  Refer to Section 6.6 for potential post-study contacts after 
Week 96. 
4 At entry, all females who have reached menarche or who are engaging in sexual activity that could lead to pregnancy must have a pregnancy test, with 
results available prior to enrollment.  During follow-up, all females who have reached menarche or who are engaging in sexual activity must have 
pregnancy testing performed.  Pregnancy testing may also be performed if pregnancy is suspected.  Urine (5 mL) or blood (1 mL) tests are acceptable.  The 
total blood volume shown in the relevant columns above accommodates collection of 1 mL of blood, if needed. 
5 For ART-naïve participants only: a sample for genotypic resistance testing should be collected at Screening and tested prior to Entry; a sample for 
phenotypic resistance testing should be collected and stored at Entry.   
6 Specimens should be collected and stored for future genotypic and phenotypic resistance testing at the Confirmation of Virologic Failure Visit and the 
Early D/C Visit from all participants. 
7 Sparse PK sampling will be done as indicated in Section 6.3.8.  
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 103 of 128 
7 September 2017 
 
Appendix II: Sample Informed Consent Form for Participation in Cohort 1 
 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-1439A)  
in HIV-1-infected Children and Adolescents 
 
Version 1.0, 7 September 2017 
 
Introduction 
 
[You are/Your child is] being asked to take part in the research study named above. 
 
This form gives information about the study.  Please read it, or have it read to you, and ask any questions 
you may have.  We will take as much time as needed for you to fully understand the study.  We will ask 
you questions to see if we have explained the study clearly. 
 
After you understand the study, if you decide that [you/your child] will participate, you will be asked to 
sign or make your mark on this form.  You will be offered a copy to keep. 
 
About the study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [insert 
site name] are doing this study to test an anti-HIV medicine (ARV) called doravirine (DOR) for children 
who have HIV.  HIV is the virus that causes AIDS. 
 
The study will include up to 65 children and adolescents 12 years to less than 18 years of age who have 
HIV.  The study will include children and adolescents from the United States, Thailand, and South Africa.  
There will be two groups of children in this study.  [You/Your child] will be in a group of up to 20 
children.  Children and adolescents in this group will be in the study for about 2 weeks.  
 
The person in charge of this study at this site is [insert name of Principal Investigator].  A company 
called Merck is providing the ARV, doravirine (DOR).  The United States National Institutes of Health 
are sponsoring this study.   
 
1. The study is being done to test DOR in children and adolescents. 
 
Children and adolescents with HIV usually take a combination of three or more ARVs to stay healthy.  
There are not as many ARVs available for children and adolescents as for adults because many ARVs 
have not yet been tested in children.   
 
DOR is a new ARV that is being tested in adults in the United States and other countries.  DOR is not 
currently approved in the United States or Europe.  DOR, either alone or in combination with other 
ARVs, has been studied closely in more than 700 adults.  DOR has been shown to be safe and effective 
compared with other approved ARVs, like efavirenz and darunavir.  This is the first study of DOR in 
children. 
 
The two groups of the study are called Cohort 1 and Cohort 2.  Cohort 1 will be done first.  This part will 
include up to 20 children and adolescents.  Cohort 2 will be done after Cohort 1 is completed.  Cohort 2 


IMPAACT 2014, FINAL Version 1.0 
Page 104 of 129 
7 September 2017 
 
will include up to 45 children and adolescents.  We will tell you about Cohort 1 first.  This is a consent 
form for Cohort 1.   
 
In Cohort 1, DOR will be given at one time.  [You/Your child] will continue to take [your/his or her] 
regular ARVs.  
 
The study will look at whether DOR is safe or causes any bad side effects when given to children and 
adolescents who have HIV.  The study will also look at the amount of DOR in blood.  This is called an 
intensive pharmacokinetic (PK) evaluation.  More information on this evaluation is in #8 below. 
 
If the results from Cohort 1 show that DOR is safe and that the amount of DOR in the blood is correct, 
Cohort 2 will start.  In Cohort 2, children and adolescents will take DOR once per day with other ARVs 
for about two years.  We will look at whether this combination of ARVs is safe when given to children 
and adolescents.  The study will also look at how the combination of ARVs control the virus for children 
and adolescents.  For ARVs to be considered effective, they must be able to control the amount of HIV so 
that HIV cannot be found in the blood. 
 
2. We will give [you/your child] DOR as a tablet. 
  
There are different ways to take ARVs, for example, as tablets that are swallowed or chewed or as liquids.  
We will give [you/your child] DOR as a tablet.  The tablet needs to be swallowed whole – it cannot be 
broken or crushed. 
 
3. It is your decision whether or not [you join/your child joins] the study. 
 
Deciding to join the study is voluntary.  You may choose [to allow your child] to join or not join.  If you 
choose [to allow your child] to join, you can change your mind and [stop the study/take your child out of 
the study] at any time.  Your choices will have no effect on your [child’s] medical care at this clinic.  
Access to services and the benefits and rights [you normally have/your child normally has] will not be 
affected.  
 
We will tell you about new information from this or other studies that may affect your [child’s] health, 
welfare, or willingness to stay in this study.  If you want the results from this study, tell the study staff. 
 
Take your time and consider your decision carefully.  If you wish, you can talk to other people about 
[joining/allowing your child to join] the study.  You can bring other people to the clinic with you to learn 
about the study. 
 
No matter what you decide about the study, it is important to receive care and treatment for HIV infection. 
[You/Your child] should continue taking the regular ARVs as usual. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 105 of 129 
7 September 2017 
 
Finding out if [you qualify/your child qualifies] 
 
4. We will ask questions and discuss the study requirements with you. 
 
If you decide to [join/let your child join] the study, we will first do some tests to see if [you qualify/your 
child qualifies].  To find out, we will: 
• 
Review medical records.  We may also ask you questions about your [child’s] health 
• 
Ask about ARV use 
• 
Talk with you about the study requirements and if [you are/your child is] able to meet these 
requirements 
• 
Give a physical exam 
• 
Draw blood for tests.  We will take up to about 16 mL (about 3 teaspoons) of blood.  These tests will 
look at your [child’s] blood cells and how well the liver and kidneys are working.  The tests will also: 
o Confirm that you [your] child has HIV.  There are certain HIV tests that are required for this 
study.  If the required tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in the blood.  This is called viral load. 
 
These procedures will take about two hours [here and throughout this form, sites may modify the expected 
visit duration as needed]. 
 
5. For females, we may also do a test to check for pregnancy. 
 
If [you have/your daughter has] had her period or [you are/your daughter is] sexually active, we will 
collect urine or blood to test for pregnancy to see if [you/she] qualifies for the study at the Entry visit (see 
#7 below).  The pregnancy test must show that [you/she] is not pregnant in order to qualify for the study.   
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure 
of pregnancy results to parents or guardians:  We will talk over the test result as soon as it is available 
with [you/your child] in private without parents/guardians present.  [You/Your child] must give us 
permission before we can share these results with parents/guardians.  If the test shows that [you are/she is] 
pregnant, we will give [you/your child] information on where medical care and other services can be 
received.] 
 
If [you/she] enter the study, [you/she] will be required to use two forms of birth control while in the study 
and for two weeks after stopping DOR.  We will talk to [you/your child] about how to prevent pregnancy.   
 
6. We will tell you if [you/your child] qualifies. 
 
We will give you the results of all procedures and explain the results to you. 
 
If these procedures show that [you do/your child does] not qualify for the study, we will tell you this and 
[you/your child] will not be entered into the study.  We will give you information on where medical care 
and other needed services may be received.  
 
If these procedures show that [you do/your child does] qualify for the study, [you/your child] will be 
entered into the study. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 106 of 129 
7 September 2017 
 
Being in the study 
 
7. If [you qualify/your child qualifies], [you/he or she] will have two additional study visits. 
 
[You/Your child] will have two visits about two weeks apart.  At these visits, we will: 
• 
Review medical records 
• 
Ask about ARVs 
• 
Ask how you/your child is feeling 
• 
Do a physical exam.  At the first visit, this exam will include examination of your [child’s] genitals to 
see the stage of development.  
• 
Draw blood for tests.  We will take up to 12 mL of blood (about 2 ½ teaspoons) for these tests.  These 
tests will check: 
o Blood cells  
o How well the liver and kidneys are working 
o At the first visit, how much HIV is in the blood  
o How many CD4 cells are in the blood.  CD4 cells are cells that fight infections  
• 
For females, we will also collect urine or blood to check for pregnancy at the first visit (see #5 
above). 
 
8. At the first visit, we will give DOR to [you/your child].  We will also look very closely at the amount of 
DOR in your [child’s] blood.  
 
This is called an intensive pharmacokinetic (PK) evaluation.  This is to see how much of the medication is 
in the blood and how long it stays.   
 
On the first day of this visit, we will give [you/your child] DOR while at the study clinic.  This is so that 
we can note the time [you/your child] took DOR.  We will ask [you/your child] how it felt to take the 
tablet (for example, how the tablet tasted or how easy or difficult it was to swallow the tablet).  The 
procedures for this visit will happen over about 72 hours (about 3 days). 
  
[Sites may modify this paragraph to appropriately describe how the intensive PK evaluation will be 
conducted, including procedures for overnight stays: In the first 24 hours after [you/your child] takes 
DOR, we will draw about 1 mL (about ¼ teaspoon) of blood at seven different times.  We will draw about 
1 mL after about two days and again after about three days.  We will draw about 9 mL total (about 2 
teaspoons).  We will look at the amount of DOR in the blood at each of these times.  We will help you 
remember this before and during the visit.  [You/Your child] may be able to stay at the clinic or hospital 
during this visit.] 
 
[Sites: modify language as appropriate to indicate procedures for the intensive PK collection.  A small 
plastic tube (like a “drip”) will be placed in your [child’s] arm to draw blood samples.  This tube is 
attached to a plastic needle so that we can draw blood several times.  We will not need to stick [you/your 
child] with a needle each time.  The plastic tube may stay in place for the blood draws in the first 24 
hours.]  
 
9. The tests for the amount of DOR in your [child’s] blood will be done at different laboratories. 
 
We will do most of the tests of blood or urine here at our laboratory.  We will give you the results of most 
of these tests at the next scheduled visit, or sooner, if necessary.  We will explain the results and give you 
counseling and referrals as needed.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 107 of 129 
7 September 2017 
 
We will also draw blood to check the amount of DOR in your [child’s] blood.  The test will be done at 
laboratories in the United States or other countries.  We will not give you the results of this test during the 
study.  
 
All of the tests will be done while the study is ongoing.   
 
10. We may take [you/your child] off of the study. 
 
We may take [you/your child] off the study early if: 
• 
The study is stopped for any reason.  
• 
We determine that the study requirements cannot be met (for example, if [you/your child] cannot 
come to the clinic). 
• 
We determine that staying in the study might cause harm.  
 
11. Please tell us if you want [your child] to leave the study. 
 
[You are/Your child is] free to leave the study at any time for any reason.  The care at this clinic will not 
be affected, but it is important for us to know about your decision.  We will answer any questions you 
may have and give you information on how to contact us in the future, if you wish. 
 
Risks of the study 
 
12. There is little risk from the study procedures. 
 
Most procedures done in this study are routine medical procedures, with little risk to [you/your child]. 
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted.  Rarely, 
drawing blood can cause fainting or infection. 
 
13. There are some risks of DOR. 
 
DOR may have side effects and some of the most common or most serious effects are listed below.  There 
may also be unknown side effects because this is the first time DOR will be studied in children.  The lists 
do not include all the possible side effects.  If you have questions about side effects not included in these 
lists, you can ask us. 
 
Some side effects are minor and some can be severe.  Some are common and some are rare.  Some people 
who take DOR have some of these effects.  Some people have different side effects. 
 
If [you join/your child joins] the study, we will tell you about the side effects of DOR. We will also check 
for any side effects during the visits and tell you what to do if [you have/your child has] any side effects. 
 
14. We will tell you about the most severe side effects first. 
 
First, you should know about the possible severe side effects that can be caused by DOR.  These effects 
are rare, but they can cause serious health problems and can result in death: 
 
• 
Liver problems.  The liver is an organ near the stomach.  If there are liver problems, [you/your child] 
might have yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale colored stools; 
upset stomach or vomiting; loss of appetite; pain, aching or tenderness of the right side below the 
ribs; or itchy skin.  This effect was seen in one adult who took DOR. 


IMPAACT 2014, FINAL Version 1.0 
Page 108 of 129 
7 September 2017 
 
 
15. There are also more common and not severe side effects from DOR. 
 
You should also know about the more common side effects.  They were reported in two or more of 100 
healthy adults who took DOR.  These side effects are not severe.  There are many possible mild and 
moderate side effects.  The most common ones are listed below: 
 
Overall Body Effects 
• Overall weakness 
• Headache 
• Back pain 
• Stuff, runny or uncomfortable nose 
• Fever 
Effects on the Stomach 
• Pain or upset stomach 
• Loose or watery stools 
• Vomiting 
Effects on Muscle and Bones 
• Aches and pains 
 
Effects on Activity  
• Drowsiness and tiredness 
• Dizziness 
 
16. There is a possible effect on pregnancy or unborn babies. 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby 
at birth.  We do not know if some ARVs are more likely to cause these effects than others.  We do not yet 
know if DOR is safe in pregnancy.  There were no pregnancy complications seen when DOR was given 
in animals.    
 
17. There could be risks of disclosure of your [child’s] information. 
 
We will make every effort to keep your [child’s] information private and confidential.  Study records and 
specimens will be kept in secure locations.  All specimens and most records will be labeled only with a 
code number.  However, your [and your child’s] name[s] will be written on some records.   
 
Despite our best efforts to keep your [child’s] information private, it is possible that the information could 
be obtained by someone who should not have it.  If this were to happen, [you/your child] could be treated 
badly or unfairly.  You could feel stress or embarrassment.   
 
[To be included at US sites: To help us protect your [child’s] privacy, we have obtained a Certificate of 
Confidentiality that protects us from being forced to release information that may identify [you/your 
child], such as by the courts or police.  The certificate cannot be used in all situations, but it can be used 
to resist demands for information that would identify [you/your child].  The certificate does not protect 
against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your [child’s] 
participation in the study to others, if you wish.] 
 
Benefits of the study 
 
18. There may be no benefit to [you/your child] from being in the study. 
 
By joining the study, [you/your child] will be part of the search for ARVs that may be better for children.  
We do not expect that being in the study will benefit [you/your child] in any way.   
 


IMPAACT 2014, FINAL Version 1.0 
Page 109 of 129 
7 September 2017 
 
[You/Your child] will have health checks, including tests for amount of HIV in your [child’s] blood, 
called viral load, and for the amount of cells that fight HIV, called CD4.  Information learned from this 
study may help other children with HIV. 
 
Other information about the study 
 
19. There are no costs from being in the study. 
 
There are no costs to you for study visits, DOR, or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits.  For each visit, you will be given (specify amount).] 
 
20. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
The IMPAACT Network that is coordinating the study 
• 
Merck Ltd. (the company that makes DOR) 
 
The study staff and these groups are required to keep study records private and confidential.   
 
The results of the study may be presented publicly or published.  However, no presentation or publication 
will use your [child’s] name or identify [you/your child] personally.   
 
A description of this study will be available on ClinicalTrials.gov.  This website will not include 
information that can identify you or your child.  At most, the website will include a summary of the 
results.  You can search this website at any time. 
 
Your [child’s] study information may be disclosed to other authorities if required by law. 
 
21. If [you get/your child gets] sick or injured, contact us immediately. 
 
Your [child’s] health is important to us.  We will make every effort to protect your [child’s] well-being 
and minimize risks.  It is possible, however, that [you/your child] could have an illness or injury that is 
study-related.  This means that the illness or injury occurred as a direct result of the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.]  If a study-
related illness or injury occurs, we will treat [you/your child] or tell you were you can get treatment.  The 
cost for this treatment may be charged to you or your insurance company.  There is no program for 
compensation either through [site name or] the U.S. National Institutes of Health.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 110 of 129 
7 September 2017 
 
Whom to contact 
 
22. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your [child’s] rights as research participants or concerns about how [you 
are/your child is] being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization] 
 
• 
If [you have/your child has] any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want [your child] to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 
Signatures 
 
If you agree to [let your child] participate in this study, please sign or make your mark below. 
 
Before deciding whether to [let your child] participate in this study, make sure you have read this form, or 
had it read to you, and that all of your questions have been answered.  You should feel that you 
understand the study, its risks and benefits, and what is expected of you [and your child] if you decide [to 
allow your child] to join.  
 
If you decide [to allow your child] to join, we will tell you any new information from this study or other 
studies that may affect your willingness [for your child] to stay in the study.  You are welcome to ask 
questions or request more information at any time.   
 
You do not give up any rights by signing this form. 
 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 111 of 129 
7 September 2017 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
Signature blocks for participants below legal age to provide independent informed consent 
 
Participant Assent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
Parent/Legal Guardian Consent 
 
 
_______________________________  
___________________________________ 
Parent/Guardian Name (print) 
 
 
Parent/Guardian Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 112 of 129 
7 September 2017 
 
Appendix III: Sample Informed Consent Form for Participation in Cohort 2 
 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-1439A)  
in HIV-1-infected Children and Adolescents 
 
Version 1.0, 7 September 2017 
 
Introduction 
 
[You are/Your child is] being asked to take part in the research study named above. 
 
This form gives information about the study.  Please read it, or have it read to you, and ask any questions 
you may have.  We will take as much time as needed for you to fully understand the study.  We will ask 
you questions to see if we have explained the study clearly. 
 
After you understand the study, if you decide that [you/your child] will participate, you will be asked to 
sign or make your mark on this form.  You will be offered a copy to keep. 
 
About the study 
 
The International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) and [insert 
site name] are doing this study to test an anti-HIV medicine (ARV) called doravirine (DOR) for children 
who have HIV.  HIV is the virus that causes AIDS. 
 
The study will include up to 65 children and adolescents 12 years to less than 18 years of age who have 
HIV.  The study will include children and adolescents from the United States, Thailand, and South Africa.  
There will be two groups of children in this study.  Your child will be in a group of up to 45 children.  
Children and adolescents in this group will be in the study for about 2 years.  
 
The person in charge of this study at this site is [insert name of Principal Investigator].  A company 
called Merck is providing the ARVs, including DOR.  The United States National Institutes of Health are 
sponsoring this study.   
 
1. The study is being done to test DOR as part of a combination medicine in children and adolescents. 
 
Children and adolescents with HIV usually take a combination of three or more ARVs to stay healthy.  
There are not as many ARVs available for children and adolescents as for adults because many ARVs 
have not yet been tested in children.   
 
DOR is a new ARV that is being tested in adults in the United States and other countries.  The 
combination of ARVs also includes two other ARVs called lamivudine (3TC) and tenofovir disoproxil 
fumarate (TDF).  [Sites: insert any locally appropriate names of combination drugs or individual drugs 
used at your site here and throughout the form.] 
 
TDF and 3TC are approved in the United States and Europe.  Both of these ARVs are commonly used in 
adults and children.  DOR is a newer ARV that is being studied in adults.  DOR is not currently approved 
in the United States or Europe.  [Sites to modify as needed:  TDF and 3TC are approved in [site 
country]].  


IMPAACT 2014, FINAL Version 1.0 
Page 113 of 129 
7 September 2017 
 
 
This combination of DOR, TDF, and 3TC has been studied closely in 86 healthy adults.  DOR, either 
alone or in combination with other ARVs, has been studied closely in more than 700 adults.  DOR has 
been shown to be safe and effective when compared to the approved ARVs, like efavirenz and darunavir. 
This is the first study of DOR in combination with TDF and 3TC in children. 
 
The two groups of the study are called Cohort 1 and Cohort 2.  Cohort 1 was done first.  This part 
included up to 20 children and adolescents.  Cohort 2 will be done after Cohort 1 is completed.  Cohort 2 
will include up to 45 children and adolescents.  We will tell you about Cohort 1 first.  This is a consent 
form for Cohort 2.  
 
In Cohort 1, DOR was given one time at one visit to children and adolescents.  This group looked at 
whether DOR causes any bad side effects when given to children and adolescents.  This group also looked 
at the amount of DOR in blood.  This is called an intensive pharmacokinetic (PK) evaluation. 
 
Because results from Cohort 1 show that DOR is safe and that the amount of DOR in the blood is correct, 
Cohort 2 will start.  The children and adolescents in this group will either have never received ARVs for 
treatment or are currently receiving ARVs for treatment and doing well.  This group will look at whether 
this new combination of ARVs is safe or causes any bad side effects when given to children and 
adolescents.  The group will also look at how the combination of ARVs control the virus for children and 
adolescents.  For ARVs to be considered effective, they must be able to control the amount of HIV so that 
HIV cannot be found in the blood.   
 
Some children and adolescents may join the study who have never taken ARVs before.  Some children 
and adolescents may join the study who are taking ARVs and are doing well on their ARVs.  If [you 
are/your child is] taking ARVs for treatment before the study, we will ask your child to start taking the 
study ARVs on the same day that your child stops taking the ARVs from before the study (see #8 below). 
 
2. We may have two different ways to take DOR/3TC/TDF. 
  
There are different ways to take ARVs, for example, as tablets that are swallowed or chewed or as liquids.  
This study may have two different ways for children to take DOR/3TC/TDF.  We will tell you if 
[you/your child] have different options. 
 
One way to take DOR/3TC/TDF is as a tablet.  The tablet needs to be swallowed whole – it cannot be 
broken or crushed. 
 
Another way to take DOR/3TC/TDF is as oral granules.  Granules are kept in larger capsules or 
containers [sites may use any locally understandable term to describe the granules].  The granules can be 
sprinkled or mixed with soft food or liquid. 
 
[Sites may adapt the following paragraphs, depending on availability of the granule formulation: 
You [and your child] may choose how to take the DOR/3TC/TDF.  We will talk to you about the options 
and ask for your [your child’s] decision.  We will help [take/give] the DOR/3TF/TDF. 
 
During the study, we would prefer that [you/your child] take the study ARV in the same way.  However, 
[you/your child] may decide to take the study ARV the other way.  For example, [you/your child] may 
start taking the DOR as oral granules and then decide to take the DOR as a tablet.  If [you/your child] 
switch, we will also ask how it felt to take the tablet or granules (for example, how DOR tasted, how easy 
or difficult it was to swallow the tablet, how easy or difficult it was to mix the granules).] 
 


IMPAACT 2014, FINAL Version 1.0 
Page 114 of 129 
7 September 2017 
 
3. It is your decision whether or not [you join/your child joins] the study. 
 
Deciding to join the study is voluntary.  You may choose [to allow your child] to join or not join.  If you 
choose [to allow your child] to join, you can change your mind and [stop the study/take your child out of 
the study] at any time.  Your choices will have no effect on your [child’s] medical care at this clinic.  
Access to services and the benefits and rights [you/he or she] normally has will not be affected.  
 
We will tell you about new information from this or other studies that may affect your [child’s] health, 
welfare, or willingness to stay in this study.  If you want the results from this study, tell the study staff. 
 
Take your time and consider your decision carefully.  If you wish, you can talk to other people about 
[joining/allowing your child to join] the study.  You can bring other people here to learn about the study 
with you. 
 
No matter what you decide about the study, it is important to receive care and treatment for HIV infection.  
We will tell you about your options for obtaining care and treatment for your [child’s] HIV. 
 
4. Only children who qualify can participate in the study. 
 
If you decide to join the study, we will first do some tests to see if [you qualify/your child qualifies]. 
 
Finding out if [you qualify/your child qualifies] 
 
5. We will ask questions and discuss the study requirements with you. 
 
If you decide to [join/let your child join] the study, we will first do some tests to see if [you qualify/your 
child qualifies].  To find out, we will: 
• 
Review medical records.  We may also ask you questions about your [child’s] health 
• 
Ask about ARV use 
• 
Talk with you about the study requirements and if [you are/your child is] able to meet these 
requirements 
• 
Give a physical exam 
• 
Draw blood for tests.  We will take up to about 22 mL (less than 5 teaspoons) of blood.  These tests 
will look at your [child’s] blood cells and how well the liver and kidneys are working.  The tests will 
also: 
o Confirm that you [your child] has HIV.  There are certain HIV tests that are required for this 
study.  If the required tests are not in the medical records, we will do the tests that are needed. 
o Check the amount of HIV in the blood.  This is called viral load. 
o If [you have/your child has] never taken any ARVs for treatment, we will check whether [you 
are/your child is] resistant to certain ARV medications.  Resistance means that an ARV may no 
longer work again HIV. 
o Check if [you have/your child has] Hepatitis B or Hepatitis C.  Hepatitis B and Hepatitis C are 
diseases of the liver. 
• 
Collect urine to check on how your [child’s] kidneys are working 
• 
For females, we may also collect urine or blood to check for pregnancy. More information is given in 
#6 below.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 115 of 129 
7 September 2017 
 
6. For females, we may do a pregnancy test to see if [you/your daughter] qualifies for the study.  We may 
also test for pregnancy during the study.  Females who become pregnant will stop the study ARVs. 
 
If [you have/your daughter has] had her period or [you are/your daughter is] sexually active, we will 
collect urine or blood to test for pregnancy to see if [you/she] qualifies for the study.  The pregnancy test 
must show that [you/she] is not pregnant to qualify for the study.  If [you/she] enter the study, [you/she] 
will be required to use two forms of birth control while in the study.  We will talk to [you/your child] 
about how to prevent pregnancy.   
 
During the study, we will collect blood or urine to test for pregnancy.  If [you/your child] becomes 
pregnant during the study, please let us know right away.  If [you/your child] becomes pregnant, 
[you/your child] will stop taking the study ARVs and leave the study early.   
 
[Sites may modify the following paragraph to include locally appropriate language regarding disclosure 
of pregnancy results to parents or legal guardians: We will talk over the test result as soon as it is 
available with [you/your child] in private without parents/guardians present.  [You/Your child] must give 
us permission before we can share these results with parents/guardians.  If [you are/your child is] 
pregnant, we will take [you/your child] off the study early.  This means that even if we did not tell your 
parent or guardian, they might find out you were pregnant.  If the test shows that [you are/she is] 
pregnant, we will give [you/your child] information on where medical care and other services can be 
received.]  
 
We will contact [you/your child] after [your/your child’s] last study visit to find out the outcome of the 
pregnancy.  We will also ask about any ARVs [you/your child] took during the pregnancy. 
 
7. We will tell you if [you/your child] qualifies. 
 
We will give you the results of all procedures and explain the results to you. 
 
If these procedures show that [you do/your child does] not qualify for the study, we will tell you this and 
[you/your child] will not be entered into the study.  We will give you information on where medical care 
and other needed services can be received. 
 
If these procedures show that [you do/your child does] qualify for the study, [you/your child] will be 
entered into the study. 
 
Being in the study 
 
8. If [you qualify/your child qualifies], [you/he or she] will enter the study.  Participants will have about 12 
scheduled visits over 2 years. 
 
Visits will be more frequent in the first year.  During this time, visits will be at entry, 2, 4, 8, 12, 16, 24, 
36, and 48 weeks.  After the first year, there will be at least three more visits, each four months apart.  
 
Some children and adolescents may need to stop the study early.  More information about this is given in 
#14 below. 
 
Each visit will take about 2 to 3 hours.  At these visits, we will: 
• 
Review medical records 
• 
Ask about ARVs 


IMPAACT 2014, FINAL Version 1.0 
Page 116 of 129 
7 September 2017 
 
• 
Do a physical exam.  At the first visit, this exam will include examination of your [child’s] genitals to 
see the stage of development. 
• 
Draw blood for tests.  We will take between 10 mL and 19 mL of blood at each visit (about 2 and less 
than 4 teaspoons).  At some visits, we will only do some of the tests.  At other visits, we will do all of 
the tests.  These tests may check:  
o Blood cells and the amount of fat in the blood 
o How well the liver and kidneys are working 
o How much HIV is in the blood 
o How many CD4 cells are in the blood.  CD4 cells are cells that fight infections  
o How much of the study ARVs are in the blood (see #9 below) 
o If [you have/your child has] never taken any ARVs for treatment, we will save some blood for 
later resistance testing 
o We will also save any extra blood for future testing after the study is over.  We will not tell you 
the results of any future tests.  We will ask you about saving these extra samples in a separate 
form. 
• 
Collect urine to check on how the kidneys are working.   
• 
We may also do a test to check if [you are/your child is] pregnant (see #6 above). 
 
[You/Your child] will also receive study ARVs at the entry, or first, visit.  We will show you [and your 
child] how to take the ARVs.  It is very important that [you/your child] takes the ARVs as instructed.  We 
will take as much time as needed for you [and your child] to understand the instructions and identify 
strategies that will help to take the ARVs are instructed.  After [you/your] child has been taking the study 
ARVs for two weeks, we will also ask how it felt to take the tablet or oral granules (for example, how 
DOR tasted, how easy or difficult it was to swallow the tablet, how easy or difficult it was to mix the 
granules). 
 
If [you were/your child was] taking ARVs for treatment before the study, we will ask [you/your child] to 
stop taking the ARVs from before the study and start taking the study ARVs on the same day. 
 
9. At some visits, we will look to see how much of the study ARVs are in your [child’s] blood. 
 
[You/Your child] will also have blood drawn to measure the amount of study ARVs in the blood.  This is 
called a pharmacokinetic evaluation, or PK evaluation.   
 
At 6 visits, we will take about 3.5 – 7 mL of blood drawn (less than 2 teaspoons).  This blood will be 
drawn in the same way that other blood for the study is drawn.   
 
At 4, 24, and 48 weeks after [you start/your child starts] the study, we may ask [you/your child] to take 
the study ARVs while at the study clinic so we can note the time [you/your child] took the study ARVs.  
On the day of this visit, we may ask [you/your child] to not take the study ARVs at home. We will help 
you remember this before each visit. 
 
At 24 weeks and 48 weeks after [you start/your child starts] the study, we will draw blood two times at 
least 30 minutes apart.  
 


IMPAACT 2014, FINAL Version 1.0 
Page 117 of 129 
7 September 2017 
 
10. For the first 10 participants in this part of the study: there will be an extra visit about one week after [you 
start/your child starts] the study where we will look very closely at the amount of study ARVs in the 
blood.  
 
About one week after [you start/your child starts] the study, [you/your child] will have blood drawn to 
very closely measure the amount of study ARVs in the blood and how long it stays.  This is called an 
intensive pharmacokinetic (PK) evaluation.   
 
At this visit, we will ask you [and your child] when she or he took the study ARVs in the past three days.  
For three days before this visit, you must be sure that the child takes the study ARVs on time.  This is 
very important.  We will help you remember this before the visit. 
 
On the day of this visit, do not [take/give] the medicine [to your child] at home.  [You/Your child] will 
take the study ARVs while at the study clinic so that we know the time [you/your child] took the study 
ARVs.     
  
[You/Your child] will then stay at the clinic or hospital for up to 24 hours.  [sites: modify language as 
appropriate to indicate procedures for overnight stays – If the study clinic is able, you and your child 
may be allowed to stay at the clinic the night before and during your first PK visit.] 
 
[Sites: modify language as appropriate to indicate procedures for the intensive PK collection.  A small 
plastic tube (like a “drip”) will be placed in your [child’s] arm to draw blood samples.  This tube is 
attached to a plastic needle so that we can draw blood several times.  We will not need to stick your child 
with a needle each time.  The plastic tube may stay in place until all the blood samples are drawn.]  
 
We will draw about 2.5 – 3.5 mL (less than 1 teaspoon) of blood at six different time points during the 
first day for the PK test and at one time point during the second day of the PK test (a total of about 22.5 
mL or less than 5 teaspoons).  We will look at the amount of ARVs in your [child’s] blood at each of 
these times.   
 
11. Children and adolescents will have an extra visit if their HIV is not controlled. 
 
Participants will have viral load tests at all visits.  If the study ARVs are your [child’s] first anti-HIV 
medicine, your [child’s] viral load should be very low after about four months.  If tests show that the viral 
load is higher than expected after four months, [you/your child] will have an extra visit.  If [you 
were/your child was] on other ARVs before starting the study, your [child’s] viral load should stay very 
low during the study.  If tests show that the viral load is higher than expected at any time during the study, 
[you/your child] will have an extra visit.  If your [child’s] viral load is high at the last study visit, we will 
ask you to come back to the clinic after that to have an extra visit. 
 
These extra visits will take about one hour.  At these visits we will: 
• 
Review medical records 
• 
Ask about your [child’s] health, ARVs, and other medicines 
• 
Do a physical exam 
• 
Draw blood (up to 13 mL or less than 3 teaspoons) for tests.  The tests will check the HIV viral load.  
We will save some blood for later resistance testing. 
• 
Give you additional supplies of ARVs as needed 
 
If the repeat test also shows the high numbers of HIV in your [child’s] blood, we will talk with you about 
whether [you/your child] should stay on the study ARVs.   


IMPAACT 2014, FINAL Version 1.0 
Page 118 of 129 
7 September 2017 
 
 
12. The tests for the amount of ARVs in your [child’s] blood will be done at different laboratories. 
 
We will do most of the blood tests here at our laboratory.  Some of the blood tests will be done in the U.S. 
or other countries.  We will give you the results of most of these tests at the next scheduled visit, or 
sooner, if necessary.  We will explain the results and give you counseling and referrals as needed.   
 
We will also draw blood to check the amount of ARVs in your [child’s] blood here in the clinic.  The test 
will be done at laboratories in the U.S. or other countries.   
 
Some tests may be done while the study is ongoing; others after the study is done.  We will not give you 
the results of the pharmacokinetic tests during the study.   
 
13. We may stop your [child’s] study ARVs or take [you/your child] off the study early.  
 
We may take your child off the study ARVs if: 
• 
[You are/Your child is] not able to come to the study visits or we determine that [you/your child] 
cannot meet the study requirements. 
• 
[You are/Your child is] not able to take the study ARVs. 
• 
The study ARVs are not controlling the HIV in your [child’s] blood. 
• 
[You/Your child] becomes pregnant (see #6 above). 
• 
Continuing the study ARVs may be harmful to [you/your child]. 
• 
You request to stop the study ARVs [for your child]. 
 
If [you stop/your child stops] the study ARVs, [you/your child] will stop the study early.  We will ask you 
to come back to the clinic [with your child] about four weeks after [you stop/your child stops] the study 
ARVs.  [You/Your child] will not have any other visits after this. 
 
We may also take [you/your child] off the study early if the study is stopped for any reason.  
 
The study cannot provide other types of ARVs, but we will give information, counseling, and referrals to 
where children can get care and treatment they need.  We will help make sure [you/your child] can get 
ARVs from outside of the study. If the study stops early, every effort would be made to make certain that 
there is no interruption in your [child’s] therapy.   
 
14. Please tell us if you want [your child] to leave the study. 
 
[You are/Your child is] free to leave the study at any time for any reason.  The care that [you receive/your 
child receives] at this clinic will not be affected, but it is important for us to know about your decision.  
We will ask you to [come/bring your child] to the clinic for one last visit.  At this visit, we will do the 
same types of procedures listed in #8 (see above).  We will answer any questions you may have and give 
you information on how to contact us in the future, if you wish. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 119 of 129 
7 September 2017 
 
After the study 
 
15. Receiving the study ARVs after the study is over.  
 
As [you come/your child comes] to the end of the study, we will work with you to plan for your [child’s] 
care and treatment outside the study.  It is important that we plan for this in advance, so that there is no 
gap in your [child’s] taking ARVs as [you finish/he or she finishes] the study.  Taking ARVs without 
interruption is the best-known way for [you/your child] to stay healthy.  
 
We will tell you where [you/your child] can go to receive needed care and treatment after [you finish/he 
or she finishes] the study.  If [you are/your child is] gaining benefit from the ARVs given in the study, the 
company that is providing these ARVs (Merck) will try to provide these ARVs to your child.  They will 
be provided until they are otherwise available locally, until [you are/your child is] no longer gaining 
benefit, or if the company decides to stop studying the ARVs.  However, there is no guarantee this will be 
possible.  If this is not possible, [you/your child] will need to switch to other ARVs that are available 
locally.  We will explain the options to you and help ensure your [child’s] access to ARVs outside the 
study.  We will also contact you again within the first four weeks after [you finish/your child finishes] the 
study to confirm that [you are/he or she is] receiving ARVs. 
 
Risks of the study 
 
16. There is little risk from the study procedures. 
 
Most procedures done in this study are routine medical procedures, with little risk to [you/your child].  
Drawing blood can cause pain, swelling, bruising, or bleeding where the needle is inserted.  Rarely, 
drawing blood can cause fainting or infection. 
 
17. There are some risks from the study ARVs. 
 
All ARVs can cause side effects, whether taken along or when taken in combination.  This includes any 
ARVs that you would receive outside the study.  The study ARVs, doravirine, lamivudine, and tenofovir 
disoproxil fumarate, may have side effects.  Some of the most common or most serious effects are listed 
below.  There may also be unknown side effects because this is the first time DOR will be studied in 
children.  The lists do not include all the possible side effects.  If you have questions about side effects not 
included in these lists, you can ask us. 
 
Each of the study ARVs can cause side effects, when taken alone or when taken in combination.  Some 
side effects are minor; others can be severe.  Some are common and some are rare.  Some people who 
take the study ARVs have some of these effects.  Some people have different side effects.  We do not 
expect to see different side effects if the ARVs are combined or if they are given separately.   
 
If [you join/your child joins] the study, we will tell you about the side effects of the study ARVs that 
[you/your child] will take.  We will also check for any side effects during the visits and tell you what to 
do if [you have/your child has] any side effects. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 120 of 129 
7 September 2017 
 
18. We will tell you about the most severe side effects first. 
 
First, you should know about the possible severe side effects.  These effects are rare, but they can cause 
serious health problems and can result in death: 
 
• 
Liver problems.  The liver is an organ near the stomach.  If there are liver problems, [you/your child] 
might have yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale colored stools; 
upset stomach or vomiting; loss of appetite; pain, aching or tenderness of the right side below the 
ribs; or itchy skin.  This can be caused by DOR, 3TC, and TDF. 
 
• 
Build-up of acid in blood, called lactic acidosis, very enlarged liver, fatty liver, or death have been 
reported.  If [you have/your child has] these problems, [you/your child] might have unexplained 
weight loss, stomach discomfort, nausea, vomiting, fatigue, cramps, muscle pain, weakness, 
dizziness, and shortness of breath.  This can be caused by 3TC and TDF. 
 
• 
Pancreas problems.  The pancreas is an organ near the stomach.  If your [child’s] pancreas becomes 
inflamed, [you/your child] may have stomach pain, upset stomach or vomiting, or more fats in the 
blood.  This can be caused by 3TC. 
 
• 
Kidney problems.  The kidneys are organs near the middle of the back (one on each side).  Doctors 
usually find out about kidney problems from tests of the blood.  These effects can be caused by TDF.   
 
19. There are also more common and not severe side effects from the study ARVs. 
 
You should also know about the more common side effects.  These side effects are not severe.  There are 
many possible mild and moderate side effects.  The most common ones are listed below: 
 
Overall Body Effects 
• Changes in the placement of body fat 
(increasing around the stomach, neck, or breast 
or decreasing in the arms, legs, or cheeks) 
• Overall weakness 
• Headache 
• Back pain 
• Stuff, runny, or uncomfortable nose 
• Allergic reaction 
• Numbing, tingling, or pain in the hands and feet 
• Fever 
Effects on Blood 
• Decrease in the blood cells that fight infection 
• Other changes in the blood tests that may show 
problems with the liver or pancreas.  The blood 
tests may show how well these organs are 
working, or they may look for substances made 
by the organs, or they may look for fats in the 
blood. 
Effects on Skin 
• Rash 
Effects on the Chest 
• Shortness of breath 
Effects on Muscle and Bones 
• Aches and pains 
• Loss of muscle 
• Bone thinning or softening (which could 
increase the chance of breaking a bone) 
Effects on Activity 
• Drowsiness and tiredness 
• Trouble sleeping 
• Dizziness 
• Abnormal dreams, hallucinations and 
nightmares 
• Clumsiness or lack of coordination 
• Feeling of deep sadness or unworthiness 
(depression) 
Effects on Stomach 
• Pain or upset stomach 
• Loose or watery stools 
• Vomiting 
• Gas 
 


IMPAACT 2014, FINAL Version 1.0 
Page 121 of 129 
7 September 2017 
 
20. There may be other possible risks from the study ARVs. 
 
Possible effects on pregnancy or unborn babies 
 
HIV and ARVs may lead to some pregnancy complications, like early delivery or low weight of the baby 
at birth.  We do not know if some ARVs are more likely to cause these effects than others.  We do not yet 
know if this combination of ARVs with DOR is safe in pregnancy.  There were no pregnancy 
complications seen when DOR was given in animals.    
 
If [you/your child] becomes pregnant during the study, please let us know right away. 
 
Immune reconstitution syndrome 
 
In some people with advanced HIV infection, signs and symptoms from other infections or certain 
diseases may occur soon after starting combination ARVs but can also occur later.  Some of these 
symptoms may be life threatening.  If [you start/your child starts] having new symptoms, or if you notice 
that any existing symptoms are getting worse after starting the ARVs, tell your doctor immediately. 
 
Hepatitis B 
 
Some ARVs are active against hepatitis B.  For children who have hepatitis B, and take ARVs that are 
active against hepatitis B, stopping the ARVs could cause the hepatitis B to worsen.  If this happens, most 
children get better quickly without treatment, but in rare cases this has resulted in death. 
 
Risk of resistance 
 
All ARVs can cause some resistance.  Resistance means that the ARVs may not work against HIV if it is 
taken again in the future.  To stop resistance, it is important that [you take/give your child] the ARVs as 
instructed, and do not miss any doses.   
 
Risk related to stopping study ARVs 
 
If the study is unexpectedly stopped early or if you reach the end of the study and it is not possible to 
continue the study ARVs and you therefore need to change to different anti-HIV medicines, there is a risk 
that the new ARVs would not work as well as the study ARVs.  
 
[Sites should include for participants who are ART-experienced: Risk of switching ARVs 
 
If [you are/your child is] switching to study ARVs from different anti-HIV medicines, there is a 
possibility that the study ARVs will not work as well as your [child’s] current anti-HIV medicines.  We 
will test the viral load during the study to check (see #8 above).] 
 
21. There could be risks of disclosure of your [child’s] information. 
 
We will make every effort to keep your [child’s] information private and confidential.  Study records and 
specimens will be kept in secure locations.  All specimens and most records will be labeled only with a 
code number.  However, your [and your child’s] names will be written on some records.   
 
Despite our best efforts to keep your [child’s] information private, it is possible that the information could 
be obtained by someone who should not have it.  If this were to happen, [you/your child] could be treated 
badly or unfairly.  You could feel stress or embarrassment.   


IMPAACT 2014, FINAL Version 1.0 
Page 122 of 129 
7 September 2017 
 
 
[To be included at US sites:] To help us protect your [child’s] privacy, we have obtained a Certificate of 
Confidentiality that protects us from being forced to release information that may identify [you/your 
child], such as by the courts or police.  The certificate cannot be used in all situations, but it can be used 
to resist demands for information that would identify [you/your child].  The certificate does not protect 
against requests for information from the US federal government or from the US Food and Drug 
Administration. Regardless of the certificate, you can release information about your [child’s] 
participation in the study to others, if you wish. 
 
Benefits of the study 
 
22. There may be no benefit to [you/your child from being in the study. 
 
By joining the study, [you/your child] will be part of the search for ARVs that may be better for children.  
We do not know if being in the study will benefit [you/your child] in any way.  There may be a direct 
benefit to [you/your child] by taking part in this study, but no guarantee can be made.  For example, the 
study drugs may lower the amount of HIV in the blood.  There may also be benefit if the results from this 
study lead to a safe and effective dose of the study drugs for children.  It is also possible that [you/your 
child] may receive no direct benefit from this study.  Information learned from this study may help other 
children who have HIV. 
 
[You/Your child] will have regular visits here and frequent checks on your [child’s] health, including tests 
for amount of HIV in your [child’s] blood, called viral load, and for the amount of cells that fight HIV, 
called CD4.  It is possible that the study ARVs will slow your [child’s] HIV infection.  Information 
learned from this study may help other children with HIV. 
 
Other information about the study 
 
23. There are no costs to you from [you/your child] being in the study. 
 
There are no costs to you for study visits, study ARVs, or procedures.  
 
[Insert information about compensation/reimbursement here, e.g., You will be reimbursed for the cost of 
transport to study visits.  For each visit, you will be given (specify amount).] 
 
24. Study records may be reviewed by study staff and groups that oversee the study. 
 
Groups that oversee the study include:  
• 
[insert name of site IRB/EC] 
• 
[insert name of site drug regulatory authority] 
• 
[insert name of other site regulatory entities] 
• 
The United States National Institutes of Health and its study monitors 
• 
The United States Food and Drug Administration 
• 
The United States Office for Human Research Protections 
• 
The IMPAACT Network that is coordinating the study 
• 
Merck Ltd. (the company that makes the study ARVs) 
 
The study staff and these groups are required to keep study records private and confidential.   
 


IMPAACT 2014, FINAL Version 1.0 
Page 123 of 129 
7 September 2017 
 
The results of the study may be presented publicly or published.  However, no presentation or publication 
will not use your [child’s] name or identify [you/your child] personally.   
 
A description of this study will be available on ClinicalTrials.gov.  This website will not include 
information that can identify you or your child.  At most, the website will include a summary of the 
results.  You can search this website at any time. 
 
Your [child’s] study information may be disclosed to other authorities if required by law. 
 
25. If [you take/your child takes] any new medication or uses alcohol or recreational drugs, please inform 
your study doctor. 
 
Some medications, including herbal medications, may make the ARVs not work as well or be less 
safe.  Please let the study doctor know if [you start/your child starts] any new medicines.  Use of alcohol 
or intravenous drugs may increase the risk of side effects from the ARVs. [Please discuss with the study 
doctor if [you are/your child is] using intravenous drugs or drinking alcohol]. 
 
26. If [you get/your child gets] sick or injured, contact us immediately. 
 
Your [child’s] health is important to us.  We will make every effort to protect your [child’s] well-being 
and minimize risks to [you/your child].  It is possible, however, that [you/your child] could have an 
illness or injury that is study-related.  This means that the illness or injury occurred as a direct result of 
the study procedures.  
 
[Sites may modify this paragraph to reflect local institutional policies; information regarding coverage 
available through clinical trial insurance obtained by the site should be included if applicable; the 
statement regarding no program for compensation through the NIH may not be removed.]  If a study-
related illness or injury occurs, we will treat [you/your child] or tell you were you can get the treatment 
your child needs.  The cost for this treatment may be charged to you or your insurance company.  There is 
no program for compensation either through [site name or] the National Institutes of Health.  
 
Whom to contact 
 
27. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about the study:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you have questions about your [child’s] rights as research participants or concerns about how [you 
are/your child is] being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization] 
 
• 
If [you have/your child has] any health or other problems that may be related to study participation:  
[insert name and telephone number of investigator or other study staff] 
 
• 
If you want [your child] to leave the study:  
[insert name and telephone number of investigator or other study staff] 
 


IMPAACT 2014, FINAL Version 1.0 
Page 124 of 129 
7 September 2017 
 
Signatures 
 
If you agree to [let your child] participate in this study, please sign or make your mark below. 
 
Before deciding whether to [let your child] participate in this study, make sure you have read this form, or 
had it read to you, and that all your questions have been answered.  You should feel that you understand 
the study, its risks and benefits, and what is expected of you [and your child] if you decide [allow your 
child] to join.  
 
If you decide to [allow your child to] join, we will tell you any new information from this study or other 
studies that may affect your willingness [for your child] to stay in the study.  You are welcome to ask 
questions or request more information at any time.   
 
You do not give up any rights by signing this form. 
 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 125 of 129 
7 September 2017 
 
[Insert signature blocks as required by site IRB/EC policies.] 
 
Signature blocks for participants below legal age to provide independent informed consent 
 
 
Participant Assent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
Parent/Guardian Consent 
 
 
_______________________________  
___________________________________ 
Parent/Guardian Name (print) 
 
 
Parent/Guardian Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 
Signature page for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 126 of 129 
7 September 2017 
 
Appendix IV: Sample Informed Consent Form 
for Specimen Storage and Future Use 
 
IMPAACT 2014 
Phase I/II Study of the Pharmacokinetics, Safety and Tolerability of  
Doravirine (MK-1439) and Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (MK-1439A)  
in HIV-1-infected Children and Adolescents 
 
Version 1.0, 7 September 2017 
 
You have decided [to allow your child] to join the study named above.  As part of the study, [your/your 
child] will have blood and urine collected.  After these samples are tested for the study, some samples 
may be left over.  We call these extra samples.  The IMPAACT Network would like to keep these extra 
samples and use them for other research in the future. 
 
This form gives information about use of extra samples.  Please read it, or have it read to you, and ask any 
questions you may have.  After we discuss the information with you, you will record your decisions on 
use of extra samples at the end of the form.  
 
1. It is your decision whether or not to allow the extra samples to be used.  
 
You are free to say yes or no, and to change your mind at any time.  Your decision will not affect 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.  
 
[Sites should insert one of the two options shown below.  Choose/adapt the second option if local 
regulations do not permit storage of samples for future research use in the United States.] 
 
A repository is a secure facility that is used to store samples.  The IMPAACT Network repository is in the 
United States.  If you agree to have extra samples stored, the samples will be kept in this repository.  
There is no limit on how long the samples will be kept [sites may insert time limits or additional site-
specific requirements here if required by local authorities]. 
 
A repository is a secure facility that is used to store samples.  The IMPAACT Network has a repository in 
the United States.  However, our local regulations require that extra samples be stored in our country.  
Therefore, we will keep the samples here at our laboratory.  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 [child’s] genes.  Genes 
are passed to children from their birth parents.  They affect how people look and how their bodies work.  
Differences in people’s genes can help explain why some people get a disease while others do not.  Your 
[child’s] samples would only be used to look at genes related to HIV and the immune system. 
 


IMPAACT 2014, FINAL Version 1.0 
Page 127 of 129 
7 September 2017 
 
Any research done with the extra samples must be reviewed and approved by the IMPAACT Network.  
The research must also be approved by an ethics committee.  The role of an ethics committee is to review 
the research plan and protect the rights and well-being of the people whose samples will be used.   
 
The research done with extra samples is not expected to give any information relevant to your [child’s] 
health.  Therefore, the results will not be given to the study staff or to you.  The results also will not be 
placed in your [child’s] study records. 
 
4. There is little risk to your child.  
 
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 the ARVs your child received in the 
study may also be linked to the samples.  
 
There may be some risks from tests of your [child’s] genes.  If others found out the results of these tests, 
they could treat [you/your child] badly or unfairly.  However, this is almost impossible because the results 
will not be given to the study staff, or to you, [or to your child] and will not be in your [child’s] study 
records. 
 
5. There may be no benefit to [you/your child].  
 
By allowing extra samples to be used for research, [you/your child] will be part of the search for new 
information that may benefit people with HIV in the future.  However, the research done with the extra 
samples is not expected to directly benefit [you/your child] in any way.  
 
6. You will not be paid for use of 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/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  
 
The people who do research with the extra samples and the groups listed above are required to make 
efforts to keep information private and confidential. 
 
The results of research done with the extra samples may be presented publicly or published.  However, no 
presentation or publication will use your [child’s] name or identify [you/your child] personally.   
 


IMPAACT 2014, FINAL Version 1.0 
Page 128 of 129 
7 September 2017 
 
8. If you have questions, concerns, or problems at any time, use these contacts. 
 
• 
If you have questions about use of your [child’s] extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you later change your mind about use of your [child’s] extra samples:  
[insert name and telephone number of investigator or other study staff].  
 
• 
If you have questions about your [child’s] rights as a research participant or concerns about how [you 
are/your child is] being treated in the study:  
[insert name and telephone number of IRB/EC contact person or other appropriate 
person/organization].  
 
Signatures 
 
Before deciding whether [your/to allow your child’s] extra samples [can/to] be used for research, make 
sure you have read this form, or had it read to you.  Make sure all your questions have been answered.  
You should feel that you understand your options and the possible risks and benefits before making your 
decision. 
 
You do not give up any rights by signing this form. 
 
[Insert initial and signature blocks as required by site IRB/EC policies and the IRB/EC determination if 
the level of risk to children in the categories specified in 45 CFR 46.404-407.  Separate consent decisions 
must be documented for genetic testing]. 
 
For YOUR [CHILD’s] extra samples, write your initials or make your mark next to your choice.  
 
__________ 
I allow my [child’s] extra samples to be used for research on HIV, the immune system, 
ARVs, and other diseases.  I also allow my [child’s] samples to be used for tests of his or 
her genes.   
 
__________ 
I allow my [child’s] extra samples to be used for research on HIV, the immune system, 
ARVs, 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 [child’s] extra samples to be used for any research.   
 
 
 


IMPAACT 2014, FINAL Version 1.0 
Page 129 of 129 
7 September 2017 
 
Signature blocks for participants below legal age to provide independent informed consent 
 
Participant Assent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
Parent/Guardian Consent 
 
 
_______________________________  
___________________________________ 
Parent/Guardian Name (print) 
 
 
Parent/Guardian Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate) 
 
 
 
Signature blocks for participants of legal age to provide independent informed consent 
 
 
_______________________________  
___________________________________ 
Participant’s Name (print) 
 
 
Participant’s Signature and Date 
 
 
_______________________________  
___________________________________ 
Study Staff Conducting  
 
 
Study Staff Signature and Date 
Consent Discussion (print)  
 
 
_______________________________  
___________________________________ 
Witness’s Name (print)  
 
 
Witness’s Signature and Date 
 
 
(As appropriate)