A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral Intensification With Maraviroc and Dolutegravir With No Intensification or Intensification With Dolutegravir Alone for the Treatment of Cognitive Impairment in HIV
Phase: PHASE4
Conditions: HIV Infections
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
 
 
A5324, Version 2.0 LOA #2 (06/04/18) 
IND Number: 126,854 
 
 
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ACTG Network Coordinating Center 
Social & Scientific Systems, Inc. 
 
 
 
 
Telephone: 301-628-3000 
8757 Georgia Avenue, 12th Floor 
 
 
 
 
Fax: 
301-628-3302 
Silver Spring, MD  20910 
 
 
LETTER OF AMENDMENT 
 
 
DATE:  
June 4, 2018 
 
TO: 
 
ACTG CTU Principal Investigators, CRS Leaders, and CTU/CRS Coordinators 
 
FROM: 
A5324 Protocol Team  
 
SUBJECT: 
Letter of Amendment #2 for Protocol A5324, Version 2.0, 08/25/17, entitled “A 
Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or 
Intensification with Dolutegravir Alone for the Treatment of Cognitive Impairment 
in HIV” 
 
 
The following information impacts the A5324 study and must be forwarded to your 
institutional review board (IRB)/ethics committee (EC) as soon as possible for their 
information and review. To eliminate apparent immediate hazards to study participants, 
this LOA may be implemented before receiving your IRB/EC approval.  
 
The following information also impacts the Sample Informed Consent. Your IRB/EC is 
responsible for determining the process of informing participants of the contents of this 
LOA.   
 
Sites are still required to submit an LOA registration packet to the DAIDS Protocol 
Registration Office (PRO) at the Regulatory Support Center. Sites will receive a 
registration notification for the LOA once the DAIDS PRO verifies that all required LOA 
registration documents have been received and are complete. An LOA registration 
notification from the DAIDS PRO is not required prior to implementing the LOA. A copy 
of the LOA registration notification, along with this letter and any IRB/EC 
correspondence, should be retained in the site’s regulatory files. 
 
The World Health Organization (WHO), U.S. Food and Drug Administration (FDA), and 
European Medicines Agency (EMA) released a safety announcement on May 18, 2018, 
regarding a recent unplanned analysis of an ongoing study in Botswana of pregnant HIV-
positive women on antiretroviral therapy. In that analysis, investigators noted 4 neural tube 
defects in infants born to 426 women who conceived while on dolutegravir (0.9%). This was 
compared with 0.1% of infants (14 of 11,173) treated with other antiretroviral agents. This has 
prompted regulatory agencies and the WHO to issue advice to health care professionals and 

 
 
 
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HIV-positive patients that includes avoiding dolutegravir in HIV-positive women who are 
contemplating pregnancy, testing for pregnancy prior to starting dolutegravir, and ensuring 
adequate birth control use among women taking dolutegravir. Based on discussions within the 
U.S. Division of AIDS (DAIDS) and regulatory groups, changes to the A5324 study are needed 
to revise the pregnancy/contraception language for HIV-infected women of reproductive 
potential who receive study treatment. It should be noted that enrollment of HIV-infected women 
of reproductive potential is permissible as long as the pregnancy/contraception inclusion criteria 
of the protocol are met. Of note, birth control is already required of all females of reproductive 
potential who participate in the trial. 
 
The main reasons for this LOA are to update the pregnancy/contraception requirements and 
dolutegravir risk information in the protocol and the sample informed consent form.  
 
 
 

 
 
 
A5324, Version 2.0 LOA #2 (06/04/18) 
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TABLE OF CONTENTS 
 
1. Section 2.1, Background/Rationale ................................................................................. 4 
2. Section 4.1.9 .................................................................................................................. 4 
3. Section 6.1, Schedule of Evaluations ............................................................................. 5 
4. Section 6.2.2, Entry Evaluations ..................................................................................... 5 
5. Section 6.2.4, Discontinuation Evaluations ..................................................................... 5 
6. Section 6.3.11, Study Medication Dispensing ................................................................. 5 
7. Section 6.3.12, Laboratory Evaluations .......................................................................... 6 
8. Section 7.3, Pregnancy .................................................................................................. 6 
9. Section 8.1, Premature Treatment Discontinuation ......................................................... 6 
10. Appendix I, Sample Informed Consent, ‘WHAT DO I HAVE TO DO IF I AM IN THIS 
STUDY?’ ........................................................................................................................ 7 
11. Appendix I, Sample Informed Consent, ‘WHY WOULD THE DOCTOR TAKE ME OFF 
THIS STUDY EARLY?’ ................................................................................................... 7 
12. Appendix I, Sample Informed Consent, ‘WHAT ARE THE RISKS OF THE STUDY?’ ..... 7 
13. Appendix I, Sample Informed Consent, ‘ARE THERE RISKS RELATED TO 
PREGNANCY’ ................................................................................................................ 9 
14. Protocol Signature Page ................................................................................................10 
 
 
 

 
 
 
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The specific updates that are being made via this LOA #2 to A5324, Final Version 2.0, 08/25/17, 
are listed below. An italicized statement provides the location of the update within the identified 
section of the protocol. New text resulting from this LOA appears in bold; deleted text is shown 
in strikethrough. Changes that were made in the excerpted text shown below when the protocol 
was amended to Version 2.0 and in LOA #1 are no longer presented in bold. 
 
1. Section 2.1, Background/Rationale 
 
The following has been added as the last paragraph in the DTG (Tivicay) sub-section: 
 
In May 2018, ViiV Healthcare became aware of a potential safety issue related to 
neural tube defects (NTDs) in infants born to women with exposure to dolutegravir 
at the time of conception that was identified from a preliminary unscheduled 
analysis of a study conducted among pregnant women in Botswana (Tsepamo 
study, 4 NTDs among 426 pregnancies on dolutegravir). This represented an 
incidence of about 0.9% with an expected background rate of about 0.1%. In the 
reproductive toxicology studies, including embryo-fetal development studies 
performed in animals prior to drug licensure, there were no adverse development 
outcomes, including NTDs, but dolutegravir was found to cross the placenta. Up 
to now, data from the Antiretroviral Pregnancy Registry (APR), clinical trials, and 
postmarketing use have not indicated a potential safety issue, but data from these 
sources are limited. The FDA recommends that women of childbearing potential 
have a pregnancy test before starting dolutegravir, and that women of 
childbearing age who decide to take a dolutegravir-containing regimen 
consistently use effective contraception while on HIV treatment (www.fda.gov). 
 
2. Section 4.1.9 
 
The following changes have been made to the list of acceptable forms of contraception:  
 
Females of reproductive potential must agree not to participate in the conception 
process (i.e., active attempt to become pregnant, in vitro fertilization), and if participating 
in sexual activity that could lead to pregnancy, must use at least one reliable form of 
contraception. Female participants must use contraceptives while receiving study 
treatment and for 6 weeks after stopping study treatment. 
 
Acceptable forms of contraception include: 
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) or intrauterine system 
• 
Hormonal contraceptive (contraceptive subdermal implant, combined estrogen 
and progestogen oral contraceptive, injectable progestogen, contraceptive 
vaginal ring, and percutaneous contraceptive patches) 
 

 
 
 
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Females who are not of reproductive potential or whose male partner(s) has 
documented azoospermia are not required to use contraceptives. Any statement of self-
reported sterility or that of her partner’s must be entered in the source documents.  
NOTE: Acceptable documentation of lack of reproductive potential is oral or written 
documentation from the participant. 
 
3. Section 6.1, Schedule of Evaluations 
 
The schedule of pregnancy testing has been changed to: 
 
Evaluation 
Screening Pre-
Entry  Entry 
Post-Entry Evaluations 
(Weeks) 
Confirmation  
of  VF 
Premature 
Study/Treatment 
Discontinuation 
2 
4 12 24 36 48 60 72 84 96 
Pregnancy 
Testing 
X 
 
X 
Whenever pregnancy is suspected 
 
If pregnancy is 
suspected  
X 
X X X X X X X X X 
X 
 
4. Section 6.2.2, Entry Evaluations 
 
The following change has been made to this section: 
 
Entry evaluations must occur at least 24 hours after pre-entry unless otherwise 
specified. Participant must begin treatment within 3 days after randomization. Refer to 
section 6.3.12 Laboratory Evaluations, Pregnancy Test sub-section, for the 
pregnancy test requirement for females of reproductive potential if treatment 
cannot be started on the same day as randomization. 
 
5. Section 6.2.4, Discontinuation Evaluations 
 
The following paragraph has been added as the last paragraph in the Premature Treatment 
Discontinuation Evaluations sub-section: 
 
Refer to section 7.3 Pregnancy, Pregnancy Outcomes and Reporting sub-section, 
for additional guidance for monitoring women who become pregnant while on 
study and prematurely discontinue study treatment. 
 
6. Section 6.3.11, Study Medication Dispensing 
 
The following change has been made to this section: 
 
At study entry, dispense either a 12-week supply of study medication or a sufficient 
quantity to last until the participant’s next visit. Beginning with the week 12 visit, study 
medications will be dispensed every 12 weeks. At weeks 36, 60, and 84, participants will 
return for study medication dispensing only. No other study evaluations will be 
performed. 
 

 
 
 
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7. Section 6.3.12, Laboratory Evaluations 
 
The following changes have been made to the second paragraph in the Pregnancy Test 
sub-section: 
 
Negative pregnancy test must be obtained within 48 hours prior to study entry 
randomization for females of reproductive potential as defined in section 4.1.8. If study 
treatment cannot be started within 72 hours of obtaining the negative pregnancy 
test for randomization, a repeat test must be performed and must be negative 
before starting treatment. After entry, perform a pregnancy test when pregnancy is 
suspected. Refer to section 7.3 for pregnancy and pregnancy outcome reporting 
requirements. 
 
After entry, perform a pregnancy test in females of reproductive potential as 
indicated in section 6.1. Refer to section 7.3 for pregnancy and pregnancy 
outcomes reporting requirements. 
 
8. Section 7.3, Pregnancy 
 
The following changes have been made to the first paragraph in the Pregnancy Outcomes 
and Reporting sub-section: 
 
The core team (actg.corea5324@fstrf.org) should be notified immediately if a participant 
becomes pregnant after study entry. Study medications must be discontinued and the 
underlying ART regimen continued at the discretion of the site investigator. Participants 
will come in for a premature treatment discontinuation evaluation visit within 14 days 
after stopping study medications. Participants who choose should be encouraged to 
stay on study will continue to be followed for on study/off study treatment follow-up 
visits, but will not have blood drawn for PK studies and stored plasma/PBMCs. They 
also will not have to complete the adherence questionnaire. The investigator must 
ensure that participants are referred and enrolled into appropriate obstetrical care. 
 
9. Section 8.1, Premature Treatment Discontinuation 
 
The following has been added to the criteria for premature treatment discontinuation 
(inserted as second and third bullets in this section): 
 
• 
Actively trying to get pregnant 
• 
Female participant of reproductive potential refuses to use one of the required 
contraception methods while on study treatment 
 

 
 
 
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10. Appendix I, Sample Informed Consent, ‘WHAT DO I HAVE TO DO IF I AM IN THIS 
STUDY?’ 
 
The following change has been made to the last paragraph in the At Study Entry Visit sub-
section: 
 
You will continue taking the anti-HIV drugs that you are currently taking. You will also be 
given a combination of MVC, DTG or placebo based on the group that you are randomly 
assigned to. You must start the new medications within three days after you are 
randomized. If you will start taking the new medications after the day you are 
randomized, you may need another pregnancy test before starting. If you are 
pregnant you cannot start the new medications. 
 
The following changes have been made to the second to the last paragraph in the After 
Entry sub-section: 
 
At weeks 36, 60, and 84, you will return for refill of your study drugs. If you are a 
woman and able to become pregnant, you will also have a pregnancy test. These 
refills visits should take about 30 minutes or less. No other evaluations will be done. 
 
11. Appendix I, Sample Informed Consent, ‘WHY WOULD THE DOCTOR TAKE ME OFF THIS 
STUDY EARLY?’ 
 
The following addition has been made to the reasons the study doctor may take a 
participant off the study drugs without permission of the participant: 
 
The study doctor may need to take you off the study drugs without your permission if: 
• 
you become pregnant or start breastfeeding 
• 
you decide that you want to become pregnant or actively try to get pregnant 
• 
you do not want to use one of the required birth control methods while on the 
study treatment 
• 
continuing the study drug(s) may be harmful to you 
• 
you need a treatment that you may not take while on the study 
• 
you are not able to take the study drug(s) as required by the study 
 
12. Appendix I, Sample Informed Consent, ‘WHAT ARE THE RISKS OF THE STUDY?’ 
 
The following changes have been made to this section: 
 
The drugs used in this study may have side effects, some of which are listed below. 
Please note that these lists do not include all the side effects seen with these drugs. 
These lists include the more serious or common side effects with a known or possible 
relationship. It is very important that you tell your study doctor of any changes in 
your medical condition while taking part in the study. If you have questions 
concerning the additional study drug side effects please ask the medical staff at your 
site. At any time during the study, if you believe you are experiencing any of these 
side effects, you have the right to ask questions on possible and/or known risks. 

 
 
 
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There is a risk of serious and/or life-threatening side effects when non-study drugs are 
taken with the study drugs. For your safety, you must tell the study doctor or nurse about 
all drugs you are taking (including non-prescription drugs, vitamins and herbal 
supplements) before you start the study and you must ask for approval for taking also 
before starting any new drugs while you are on the study. You must also tell the study 
doctor or nurse before enrolling in any other clinical trials while on this study. 
 
The following changes have been made to the Risks of DTG (Tivicay) sub-section: 
 
The following serious side effects have been associated with the use of DTG. These 
include allergic (hypersensitivity) reactions and liver problems, which may be life-
threatening. 
 
Contact the study doctor or your healthcare provider right away if you develop a rash 
while taking DTG, especially if it is associated with any of the symptoms listed below, 
which could be signs of an allergic reaction. Stop taking DTG and get medical help 
right away if you develop a rash with any of the following signs or symptoms:  
• 
Fever 
• 
Generally General ill feeling 
• 
Extreme tiredness 
• 
Muscle or joint aches 
• 
Blisters or sores in mouth 
• 
Blisters or peeling of the skin 
• 
Redness or swelling of the eyes 
• 
Swelling of the mouth, face, lips, or tongue 
• 
Problems breathing 
 
Contact the study doctor or your healthcare provider if you have any of the following 
symptoms that could be signs of liver problems:  
• 
Yellowing of the skin or whites of the eyes (jaundice) 
• 
Dark or tea-colored urine 
• 
Pale-colored stools or bowel movements 
• 
Nausea or vomiting 
• 
Loss of appetite 
• 
Pain, aching, or tenderness on the right side below the ribs 
• 
Changes in liver test results, more common in people with hepatitis B or C 
 
People with a pre-existing history of depression or other mental health illness may be at 
greater risk for suicidal thoughts, or attempts, which may lead to death. If your mental 
health illness worsens, or if you develop suicidal thoughts, call the study doctor or your 
healthcare provider right away. 
 
Other side effects of DTG include: 
• 
Changes in liver test results, more common in people with hepatitis B or C 
• 
Trouble sleeping 

 
 
 
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• 
Abnormal dreams 
• 
Tiredness 
• 
Headache 
• 
Anxiety (fear, worry) 
• 
Dizziness 
• 
Abdominal pain  
• 
Flatulence (gas in the abdomen) 
• 
Nausea/Vomiting 
• 
Muscle and joint aches 
 
Dolutegravir and Pregnancy: 
Early results from a large study in Botswana of pregnant women showed a 
possible increased risk of certain types of serious birth defects involving the brain 
and spinal cord in babies born to women who received DTG for HIV treatment at 
the time of becoming pregnant or early in their pregnancy. No cases of babies 
born with these types of birth defects have been reported among women who 
started DTG later in pregnancy. 
  
Tell the study doctor or your healthcare provider about any side effect that bothers you 
or that does not go away. 
 
13. Appendix I, Sample Informed Consent, ‘ARE THERE RISKS RELATED TO PREGNANCY’  
 
The following changes have been made to this section: 
 
Recently, some new information about DTG from another study being done in 
Botswana was reported. This study found that women taking DTG when they 
became pregnant appeared to be more likely to have babies with an abnormality 
called a neural tube defect than women who were taking other HIV medicines 
when they became pregnant. A neural tube defect is an abnormality of the spine 
or brain that can be severe. This abnormality can cause babies to die. Neural tube 
defects usually happen in about 1 out of every 1000 babies. In the Botswana 
study, neural tube defects were found in about 1 out of every 100 babies born to 
women who were taking DTG when they became pregnant. A baby’s neural tube is 
formed in the first 4 weeks after conception. In the Botswana study, no neural 
tube defects were found in babies born to women who started taking DTG during 
pregnancy, after the neural tube had formed. The drug company and regulatory 
authorities and different researchers are looking into this issue to see if DTG 
really does cause neural tube defects. In the meantime, the U.S. FDA and other 
groups have recommended that women who are going to start taking DTG have a 
pregnancy test first. They also recommend that women use birth control to 
prevent pregnancy while taking DTG. HIV-infected women who are able to become 
pregnant are allowed to participate in this study, but they must use birth control 
(intrauterine device [IUD] or hormone-based contraceptive) in order to not become 
pregnant while in this study. If you do become pregnant while on study and taking 
the study drugs, you must call the study doctor right away. 
 

 
 
 
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The drugs used in this study may be unsafe for unborn babies. If you are having sex that 
could lead to pregnancy, you must agree not to become pregnant. Because of the risk 
involved, you must use at least one method of birth control. You must continue to use 
birth control for 6 weeks after stopping your medicines. You must choose one of the birth 
control methods listed below:  
• 
Condoms (male or female) with or without a spermicidal agent 
• 
Diaphragm or cervical cap with spermicide 
• 
Intrauterine device (IUD) or intrauterine system 
• 
Hormone-based contraceptive (contraceptive subdermal implant, combined 
estrogen and progestogen oral contraceptive, injectable progestogen, 
contraceptive vaginal ring, and percutaneous contraceptive patches) 
 
If you do not want to use one of the birth control methods listed above, you will be 
taken off the study treatment, but asked to continue the study evaluations. 
 
If you can become pregnant, you must have a pregnancy test before you enter this 
study. The test must show that you are not pregnant. Women who can become 
pregnant will have testing for pregnancy at every study visit. If you think you may 
be pregnant at any time during the study, tell your study staff right away. If you decide 
at any time while you are in this study that you want to become pregnant and start 
trying to become pregnant, you must tell your study staff right away. If you are 
pregnant or trying to become pregnant, you will be taken off the study treatment, but 
asked to continue the study evaluations. The study staff will talk to you about your 
choices.  
 
If you become pregnant while on study, the study staff would like to obtain information 
from you about the outcome of the pregnancy (even if it is after your participation in the 
study ends). If you are taking anti-HIV drugs when you become pregnant, your 
pregnancy will be reported to an international database that collects information about 
pregnancies in women taking anti-HIV drugs. This report will not use your name or other 
information that could be used to identify you. 
 
NOTE: It is not known whether the study drug passes through breast-milk and may 
cause harm to your baby. If you are breastfeeding, you cannot take part in this study. 
 
14. Protocol Signature Page 
 
Per a new regulatory requirement by the Division of AIDS (DAIDS), a Protocol Signature 
Page (PSP) is appended for submission to the DAIDS Protocol Registration System (DPRS) 
as part of the LOA registration packet. 
 
 
The information above will be incorporated into the next protocol version as necessary if the 
protocol is amended.

 
 
 
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A Randomized, Double-Blinded, Placebo-Controlled Trial Comparing Antiretroviral 
Intensification with Maraviroc and Dolutegravir with No Intensification or Intensification 
with Dolutegravir Alone for the Treatment of Cognitive Impairment in HIV 
Version 2.0, 08/25/17 
 
 
SIGNATURE PAGE 
 
 
I will conduct the study in accordance with the provisions of this protocol and all applicable 
protocol-related documents. I agree to conduct this study in compliance with United States (US) 
Health and Human Service regulations (45 CFR 46); applicable U.S. Food and Drug 
Administration regulations; standards of the International Conference on Harmonization 
Guideline for Good Clinical Practice (E6); Institutional Review Board/Ethics Committee 
determinations; all applicable in-country, state, and local laws and regulations; and other 
applicable requirements (e.g., US National Institutes of Health, Division of AIDS) and 
institutional policies. 
 
 
 
 
 
Principal Investigator: _____________________________________________________ 
 
Print/Type 
 
 
 
 
 
Signed: _______________________________________________Date: _____________ 
 
Name/Title