Conditions: HIV-1-infection
Keywords: multi-drug resistant
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
The current study proposal is an open label observational trial for maintenance of virologic suppression, and is designed as a non- inferiority switch trial. The study will involve approximately 30 patients, which includes a PK arm of approximately 10 patients. The study will also include secondary outcomes of quality of life (QOL) and weight changes

Hypothesis:

Patients with prior NUC or NNRTI resistance (but not to rilpivirine or doravirine) will maintain their virologic suppression after a drug regimen switch from rilpivirine/emtricitabine/tenofovir alafenamide in combination with dolutegravir, to bictegravir/emtricitabine/tenofovir alafenamide in combination with doravirine. The switch therapy will avoid food interactions, and will be well tolerated by subjects.

Detailed description:

Arms:
arm 1: bictegravir 50mg/emtricitabine 200mg/tenofovir alafenamide 25mg tablets + doravirine 100mg tablets taken orally once per day

Interventions: intervention 1: Bictegravir/emtricitabine/tenofovir alafenamide + Doravirine switch
Intervention descriptions: intervention 1: Safety and efficacy of switching from rilpivirine/emtricitabine/tenofovir alafenamide in combination with dolutegravir, to bictegravir/emtricitabine/tenofovir alafenamide in combination with doravirine in male, 45+ year old subjects. The study will also include secondary outcomes of quality of life (QOL) and weight changes.

Protocol document:
ICF_001.pdf: 
 
 
Bictegravir/emtricitabine/tenofovir alafenamide plus 
doravirine in highly treatment-experienced men with 
mulƟdrug-resistant HIV 
 
 
 
 
 
NCT04538040 
2023 


Quest Clinical Research / Protocol Number BETD-001
Page 1 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
INFORMED CONSENT DOCUMENT 
AGREEMENT TO BE IN A RESEARCH STUDY AND  
AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
 
 
Sponsor / Study Title: 
  
Quest Clinical Research / “An open label study evaluating the 
safety and efficacy of switching from 
rilpivirine/emtricitabine/tenofovir alafenamide in combination 
with dolutegravir, to bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine, in male HIV+ 
subjects > 45 years with multi-drug resistant virus and virologic 
suppression (documented with at least one viral load result < 50 
copies per mL) during the last 6 months on current therapy” 
 
Protocol Number: 
 
BETD-001 
Principal Investigator: 
(Study Doctor) 
 
F. Lisa Sterman, M.D., M.P.H. 
 
Telephone: 
 
415-353-0800  
415-863-3366 (24 Hour) 
 
Address: 
Quest Clinical Research 
2300 Sutter Street, suites 202 & 208  
San Francisco, CA  94115 
 
SFOMG Private Practice, Internal Medicine and HIV Medicine 
45 Castro Street Suite 325  
San Francisco, CA   94114 
 
 
INTRODUCTION 
 
You are invited to take part in a Phase IV research study.  This study is studying the effect of switching 
your current HIV treatment from the combination of rilpivirine/emtricitabine/tenofovir alafenamide 
(ODEFSEY) in combination with dolutegravir (TIVICAY) to bictegravir/emtricitabine/tenofovir 
alafenamide (BIKTARVY) and Doravirine (PIFELTRO). 
 
These medications are approved by the FDA for treatment of HIV and are used in combination with other 
HIV-1 medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults.  
 
Quest Clinical Research is sponsoring this research study. 
 
Please read this form carefully. Take your time to ask the study doctor or study staff as many questions 
about the study as you would like. The study doctor or study staff can explain words or information that 
you do not understand. Reading this form and talking to the study doctor or study staff may help you decide 
whether to take part or not. If you decide to take part in this study, you must sign your name at the end of 
this form and date it.  
 
You must be honest with the study doctor about your health history or it may not be safe for you to be in 
this study. 
 


Quest Clinical Research / Protocol Number BETD-001
Page 2 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
BACKGROUND AND PURPOSE  
 
You are being asked to participate in this study because you are a male, 45 years or older and have been 
diagnosed 
with 
HIV 
and 
receiving 
a 
combination 
of 
antiretroviral 
treatment 
(rilpivirine/emtricitabine/tenofovir alafenamide (ODEFSEY) in combination with dolutegravir 
(TIVICAY)) for more than 12 months. Antiretroviral drugs prevent HIV from inserting its genetic code 
into the DNA of an infected cell. They do this by blocking enzymes that HIV needs to hijack the host's 
DNA. HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).  
 
The new combination of study drugs should maintain the HIV virologic suppression and is designed with 
the goal of not being inferior to your current medication combination. It is not anticipated that this switch 
will place you at a greater risk than your current therapy. 
 
The purpose of this research study is to:  
 
 
Test the safety and effectiveness of the combination drug 
 
Monitor for any improvement in well-being, weight changes and sleep pattern  
 
About 30 subjects will participate in this study including 10 subjects who will participate in the PK portion 
(evaluation of the amount of drug in the body) of the study.  
 
WHAT WILL HAPPEN DURING THE STUDY 
 
Your participation in this study will last approximately 48 weeks and will include approximately 6 study 
visits to the study center.  You may be asked to return to the clinic for an unscheduled visit to complete or 
retest a PK evaluation after completing the 6 study visits. 
 
Screening/Baseline: 
 
Before any study-related tests and procedures are performed, you will be asked to read and sign this consent 
document.   
 
 
Obtaining informed consent for participation in the study 
 
Review of your demographic (personal) information such as date of birth, sex, ethnicity, race, and year 
of HIV diagnosis 
 
A physical examination including height, weight and BMI (body mass index) 
 
Your quality and pattern of sleep will be measured 
 
You will be asked to complete a questionnaire to check the effect of your health problems on your 
ability to work and perform regular activities 
 
Check your HIV virus count 
 
Check your CD4 count (less than 3 months of study entry) 
 
Your vital signs (temperature, respiratory rate, resting pulse and blood pressure) will be measured 
 
Collection of blood for safety lab tests 
 
Collection of a urine sample for routine lab tests  
 
You will be asked if you have had any recent illnesses or changes in your condition  
 
Inclusion and exclusion criteria will be reviewed to see if you qualify for the study 
 
If you qualify for the study, you will start taking your new drug regimen 
 
 
 


Quest Clinical Research / Protocol Number BETD-001
Page 3 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
Study Treatment:  
 
You will have the following study visits and undergo the following procedures: 
 
Visit 2 (Month 1 (give or take 14 days))  
 
 
Your blood may be collected to measure the amount of study drug in your blood if you participate in 
the PK portion of the study  
 
You will be asked if you have had any recent illnesses or changes in your condition 
 
A physical examination  
 
Your weight & vital signs (temperature, respiratory rate, and resting pulse and blood pressure) will be 
measured 
 
Collection of blood for safety lab tests 
 
Check your HIV virus count 
 
Collection of a urine sample for routine lab tests 
 
Visit 3 (Week 12 (give or take 14 days)), Visit 4 (Week 24 (give or take 14 days)), Visit 5 (Week 36 
(give or take 14 days)) 
 
 
A physical examination  
 
Your weight & vital signs (temperature, respiratory rate, and resting pulse and blood pressure) will be 
measured 
 
Collection of blood for safety lab tests 
 
Check your HIV virus count 
 
Collection of a urine sample for routine lab tests 
 
You will be asked if you have had any recent illnesses or changes in your condition  
 
Visit 6 (End of Study, Week 48 (give or take 14 days))  
 
 
A physical examination including weight and BMI 
 
Your quality and pattern of sleep will be measured 
 
You will be asked to complete a questionnaire to check the effect of your health problems on your 
ability to work and perform regular activities 
 
Your vital signs (temperature, respiratory rate, and resting pulse and blood pressure) will be measured 
 
Collection of blood for safety lab tests 
 
Check your HIV virus count 
 
Check your CD4 count 
 
Collection of a urine sample for routine lab tests 
 
You will be asked if you have had any recent illnesses or changes in your condition  
 
PK Test/Retest 
 
 
You will be asked to take your study drug in the morning on the day before the PK sampling and record 
the time it was taken so you can let your study coordinator know 
 
On the day of PK sampling, you should not take your study drug until after you come to the clinic and 
your blood is drawn. 
 
Your blood will be collected to measure the amount of study drug in your blood at the following time 
points (in hours): -0.5, 0.5, 1, 2, 4, 6, 8, 12, & 24 
 
You will be asked to wait to take the study drug until after your blood has been drawn at the clinic on 
your hour 24 blood draw (the day after the PK sampling)  
 


Quest Clinical Research / Protocol Number BETD-001
Page 4 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
EXPECTATIONS  
 
If you participate in this study, you will be expected to:  
 
 
Attend each visit at the study center  
 
Follow the instructions given by the study doctor 
 
Have all procedures done to you 
 
Notify the study doctor if you experience any health problems or illnesses during the study 
 
RISKS, SIDE EFFECTS, AND/OR DISCOMFORTS  
 
You must tell the investigator or study staff about all side effects that you have. If you are not honest about 
your side effects, you may harm yourself by staying in this study. 
 
If you don't understand what any of these side effects mean, please ask the investigator or study staff to 
explain these terms to you. 
 
The study drugs can cause serious, life-threatening side effects. These include a buildup of lactic acid in 
the blood (lactic acidosis) and severe liver problems.  
 
For bictegravir/emtricitabine/tenofovir alafenamide (BIKTARVY):  
 
Possible 
 
 
Change in your immune system 
 
Kidney problems including kidney failure 
 
Too much lactic acid in the blood 
 
Severe liver problems 
 
Worsening of Hepatitis B virus infection 
 
Diarrhea 
 
Nausea 
 
Headache 
 
Tiredness 
 
Abnormal dreams  
 
Dizziness 
 
Insomnia 
  
For Doravirine (PIFELTRO): 
 
Possible 
 
 
Nausea 
 
Dizziness 
 
Headache 
 
Tiredness 
 
Diarrhea 
 
Stomach pain 
 
Abnormal dreams 
 
Rash 
 
Insomnia 
 
Altered state of consciousness 
 


Quest Clinical Research / Protocol Number BETD-001
Page 5 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
When you take more than one drug at a time, the side effects can be worse or different than if you take 
either drug by itself.  
 
Until you know how the drug(s) will affect you, you should use caution by avoiding stairs, not driving a 
car or working with machinery. 
 
RISKS OF STUDY PROCEDURES 
 
 
Blood samples: Possible side effects from blood drawing include faintness, inflammation of the vein, 
pain, bruising, or bleeding at the site of puncture. There is also a slight possibility of infection. 
 
Questionnaires: The questionnaires used in this study may be upsetting. You do not need to answer any 
questions that you are not comfortable with.  
 
Blood Samples  
 
Blood samples will be taken by single needle-sticks or by a tube that is left in your arm.  You cannot choose 
how the blood is taken. 
 
There will be about 9 time points during the PK collection.  The total amount of blood drawn will be about 
36 ml.  For comparison, the standard blood donation is about 480 mL (two cups).   
 
UNFORESEEN RISKS  
 
There may be other risks for the study drugs, especially when given in combination with each other, that 
are unknown at this time. Additionally, there may be unknown risks to a pregnancy, embryo, or fetus if 
your female partner becomes pregnant. 
  
ALTERNATIVES TO PARTICIPATION  
 
You do not have to be in this study to receive treatment for your HIV. Your options may include continuing 
your current therapy or standard of care.    
 
Please talk to the study doctor about your options before you decide whether or not you will take part in 
this study. 
 
NEW FINDINGS  
 
Any new important information that is discovered during the study and which may influence your 
willingness to continue participation in the study will be provided to you. 
 
BENEFITS 
 
You may benefit as a result of your participation in this study. There is, however, no guarantee that you 
will benefit from your participation in this study. Information learned from the study may help other people 
in the future. You may maintain your weight and you may maintain your quality of life or may have 
improvement in your quality of life. 
 
 
 


Quest Clinical Research / Protocol Number BETD-001
Page 6 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
COMPENSATION FOR PARTICIPATION  
 
You will be paid up to a total of $300.00 if you complete this study or $550.00 if you also participate in the 
intensive PK evaluation. You will be paid for the visits you complete according to the following schedule: 
 
$50.00 for Visits Screening/Baseline, Month 1, 3, 6, 9, 12.  
$300.00 for Visit Month 1 if you participate in PK evaluation.  
$300.00 for PK evaluations performed after Month 1. 
 
If you do not complete the study, for any reason, you will be paid for each study visit you do complete.  
 
You will be paid after each visit.  
 
CONFIDENTIALITY   
 
Records of your participation in this study will be held confidential except when sharing the information is 
required by law or as described in this informed consent. The Investigator, the sponsor or persons working 
on behalf of the sponsor, and under certain circumstances, the United States Food and Drug Administration 
(FDA) and other state or federal regulatory agencies and the Institutional Review Board (IRB) will be able 
to inspect and copy confidential study-related records which identify you by name. This means that absolute 
confidentiality cannot be guaranteed. If the results of this study are published or presented at meetings, you 
will not be identified. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include a 
summary of the results. You can search this Web site at any time. 
 
COMPENSATION FOR INJURY  
 
If you become ill or are injured while you are in the study, get the medical care that you need right away. 
You should inform the healthcare professional treating you that you are participating in this study. If you 
tell the study staff that you think you have been injured then they will help you get the care you need.  
 
If you are injured as a result of taking the study drug(s) or from procedures done for the purpose of this 
study, the sponsor will pay for those medical expenses necessary to treat your injury that are not covered 
by your medical insurance or any other third-party coverage. Please be aware that some insurance plans 
may not pay for research-related injuries. You should contact your insurance company for more 
information. You will not lose any of your legal rights or release the sponsor, the Investigator, the study 
staff, or study site from liability for mistakes by signing this consent document. 
 
To pay medical expenses, the sponsor will need to know some information about you like your name, date 
of birth, and Medicare Beneficiary Identifier (MBI). This is because the sponsor has to check to see if you 
receive Medicare and if you do, report the payment it makes to Medicare.  
 
COSTS  
 
There will be no charge to you for your participation in this study. The study drug, study-related procedures, 
and study visits will be provided at no charge to you.  Most of you will obtain your drugs through insurance, 
but we may be able to provide the drugs for you if insurance does not cover the cost. 
 
 
 


Quest Clinical Research / Protocol Number BETD-001
Page 7 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
WHOM TO CONTACT ABOUT THIS STUDY 
 
During the study, if you experience any medical problems, suffer a research-related injury, or have 
questions, concerns or complaints about the study, please contact the Investigator at the telephone number 
listed on the first page of this consent document. If you seek emergency care, or hospitalization is required, 
alert the treating physician that you are participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the rights of 
research subjects. If you have any questions about your rights as a research subject, and/or concerns or 
complaints regarding this research study, contact: 
 
 
By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
 
or call toll free:    877-992-4724 
 
or by email:          adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00052105. 
 
CONSENT FOR OPTIONAL SUB-STUDY  
 
You are also being asked to participate in an optional sub-study to measure the amount of study drug in 
your blood.  
 
You may decide not to participate in the optional sub-study. If you decide not to participate in the sub-
study, your decision will have no impact on your ability to participate in the main study and will have no 
impact on any other benefits to which you would otherwise be entitled.  
 
Please indicate your preference below: 
 
YES _____ (initials) I agree to participate in the sub-study described above. 
 
NO _____ (initials) I do not agree to participate in the sub-study described above. 
 
VOLUNTARY PARTICIPATION / WITHDRAWAL  
 
Your decision to participate in this study is voluntary. You may choose to not participate or you may 
withdraw from the study for any reason without penalty or loss of benefits to which you are otherwise 
entitled and without any effect on your future medical care. However, please note that the FDA requires 
that any information collected up to the point of your withdrawal cannot be removed from the study. 
 
If you leave the study for any reason, the study doctor may ask you to come back for a follow-up visit 90 
days after you discontinue treatment to have some end-of-study tests for your safety. 
 
 
 


Quest Clinical Research / Protocol Number BETD-001
Page 8 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
The Investigator or the sponsor can stop your participation at any time without your consent for the 
following reasons: 
 
 
If it appears to be medically harmful to you; 
 
If you fail to follow directions for participating in the study; 
 
If it is discovered that you do not meet the study requirements; 
 
If the study is canceled; or  
 
For administrative reasons. 
 
If you leave the study for any reason, the Investigator may ask you to have some end-of-study tests for your 
safety.  
 
PRIMARY HEALTH CARE PROVIDER NOTIFICATION OPTION 
 
I consent to having my family doctor or primary health care provider notified by the study site of my 
participation in this study and/or any significant findings related to my health (please check yes or no). 
 
YES (If yes, please complete the information below) 
 
NO  
 
Name and address of family doctor 
or primary health care provider: 
Name: 
Address: 
 
Telephone and Fax Number: 
Tel: 
Fax: 
 
SUBJECT’S BILL OF RIGHTS 
 
If you have not already been given a separate copy of the California Experimental Research Subject’s Bill 
of Rights, you will be given one at your visit.  If you have not received a copy of this document, please 
notify study staff. 
 
 
 


Quest Clinical Research / Protocol Number BETD-001
Page 9 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
CONSENT  
 
I have read and understand the information in this informed consent document. I have had an opportunity 
to ask questions and all of my questions have been answered to my satisfaction. I voluntarily agree to 
participate in this study until I decide otherwise. I do not give up any of my legal rights by signing this 
consent document. I will receive a copy of this signed and dated consent document. 
 
 
________________________________________ 
 
 
Subject’s Printed Name  
 
 
________________________________________ 
 
___________  
Subject’s Signature 
 
 
 
 
 
Date 
 
 
________________________________________ 
 
 
Printed Name of the Person Conducting the  
 
 
 
Consent Discussion  
 
 
________________________________________ 
 
___________ 
Signature of the Person Conducting the   
 
 
Date 
 
Consent Discussion  
 
 
 
 
 
 
 
 
 
 


Quest Clinical Research / Protocol Number BETD-001
Page 10 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
AUTHORIZATION TO USE AND DISCLOSE 
PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and research team will use and 
share health data about you to conduct the study. Health data may include: 
 
 Your name. 
 Address. 
 Phone number. 
 Date of birth. 
 Medical history. 
 Information from your study visits, including all test results.  
 
Health data may come from your study records or from existing records kept by your 
doctor or other health care workers.  
 
For this study, the research team may share health data about you with authorized 
users. Authorized users may include 
 
 Representatives of Quest Clinical Research. 
 Representatives of DP Clinical Inc. 
 Representatives of Advarra IRB (an Institutional Review Board that reviews this 
study). 
 The Food and Drug Administration (FDA) and other US federal and state 
agencies. 
 Government agencies to whom certain diseases (like HIV, hepatitis, and STDs) 
must be reported. 
 Governmental agencies of other countries. 
 Outside individuals and companies, such as laboratories and data storage 
companies, that work with the researchers and sponsor and need to access your 
information to conduct this study. 
 Other research doctors and medical centers participating in this research, if 
applicable.  
 
 
 


Quest Clinical Research / Protocol Number BETD-001
Page 11 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
Your health data will be used to conduct and oversee the research, including for 
instance: 
 
 To see if the drug combination works and is safe and effective 
 To compare the drug combination to rilpivirine/emtricitabine/tenofovir 
alafenamide (RPF/FTC/TAF) in combination with dolutegravir.  
 For other research activities related to the bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine. 
 
Once your health data has been shared with authorized users, it may no longer be 
protected by federal privacy law and could possibly be used or disclosed in ways 
other than those listed here.  
 
Your permission to use and share health data about you will end in 50 years unless 
you revoke it (take it back) sooner.  
 
You may revoke (take back) your permission to use and share health data about you 
at any time by writing to the study doctor. If you do this, you will not be able to stay 
in this study. No new health data that identifies you will be gathered after your 
written request is received. However, health data about you that has already been 
gathered may still be used and given to others as described in this form.  
 
Your right to access your health data in the study records will be suspended during 
the study to keep from changing the study results. When the study is over, you can 
access your study health data. 
 
If you decide not to sign this form, you will not be able to take part in the study. 
 
 
 


Quest Clinical Research / Protocol Number BETD-001
Page 12 of 12
 
F. Lisa Sterman, M.D., M.P.H. 
Advarra IRB Approved Version 13 Jul 2021
 
STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained. My questions have been 
answered. I voluntarily agree to allow study staff to collect, use and share my health 
data as specified in this form. I will receive a signed and dated copy of this form for 
my records. I am not giving up any of my legal rights by signing this form.  
 
 
__________________________________ 
Printed Name of Subject 
 
 
__________________________________ 
 
 
__________ 
Signature of Subject 
 
 
 
 
 
Date 
 
 
__________________________________ 
Printed Name of the Person Obtaining the  
Authorization 
 
 
__________________________________ 
 
 
__________ 
Signature of the Person Obtaining the 
 
 
 
Date 
Authorization  
 

Prot_SAP_002.pdf: 
 
 
Bictegravir/emtricitabine/tenofovir alafenamide plus 
doravirine in highly treatment-experienced men with 
mulƟdrug-resistant HIV 
 
 
 
 
 
NCT04538040 
2023 


Protocol No. BETD-001 
Version 3 / Date (25-Jun-2021) 
Quest Clinical Research 
-CONFIDENTIAL-
Page 1 of 48
 
 
 
 
 
 
 
 
 
 
Protocol Title: 
An open label study evaluating the safety and efficacy of switching 
from 
rilpivirine/emtricitabine/tenofovir 
alafenamide 
in 
combination 
with 
dolutegravir, 
to 
bictegravir/emtricitabine/tenofovir alafenamide in combination 
with doravirine, in male HIV+ subjects > 45 years with multi-drug 
resistant virus and virologic suppression (documented with at least 
one viral load result < 50 copies per mL) during the last 6 months on 
current therapy. 
 
Switch Therapy: 
Bictegravir/emtricitabine/tenofovir alafenide plus doravirine: 
Investigator: 
F. Lisa Sterman MD, MPH 
Phase: 
IV 
Protocol Number: 
BETD-001 
Version No.: 
3.0 
Date: 
06-25-2021 
 
 
 
 
 
 
 
STATEMENT OF CONFIDENTIALITY 
The information contained in this protocol is confidential and is intended for the use of clinical Investigators. It is the 
property of Quest Clinical Research and should not be copied or distributed to persons not involved in the clinical 
investigation, unless such persons are bound by a confidentiality agreement with Quest Clinical Research. 


Protocol No.: BETD-001 
Version 3 / Date (25-Jun-2021) 
Quest Clinical Research 
-CONFIDENTIAL-
Page 2 of 48
 
 
 
PROTOCOL APPROVAL – SPONSOR SIGNATURE PAGE 
 
This study protocol entitled: 
 
An 
open 
label 
study 
evaluating 
the 
safety 
and 
efficacy 
of 
switching 
from 
rilpivirine/emtricitabine/tenofovir alafenamide in combination with dolutegravir, to 
bictegravir/emtricitabine/tenofovir alafenamide in combination with doravirine, in male HIV+ 
subjects > 45 years with multi-drug resistant virus and HIV virologic suppression ( documented 
with at least one viral load result < 50 copies per mL) during the last 6 months on current 
therapy. 
 
The information this protocol contains is consistent with the current risk/benefit evaluation of the 
study drug as well as with the moral, ethical, and scientific principles governing clinical research as 
set out in the Declaration of Helsinki and the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) guidelines on Good Clinical Practice (GCP). 
 
This protocol is approved by: 
 
Name:     
 
 
 
 
Signature:    
 
 
 
Date: 
/ 
/ 
(DD/MMM/YYYY) 


Protocol No.: BETD-001 
Version 3 / Date (25-Jun-2021) 
Quest Clinical Research 
-CONFIDENTIAL-
Page 3 of 48
 
 
 
TABLE OF CONTENTS 
1.0 
GLOSSARY ............................................................................................................................... 7 
2.0 
PROTOCOL SYNOPSIS ............................................................................................................... 9 
3.0 
BACKGROUND INFORMATION ............................................................................................... 12 
3.1 
Study Rationale ......................................................................................................... 12 
3.2 
Anticipated Risks and Safety concerns for the switch ................................................. 12 
4.0 
STUDY OBJECTIVES ................................................................................................................ 13 
5.0 
INVESTIGATIONAL PLAN ........................................................................................................ 13 
5.1 
Overall Study Design and Plan ................................................................................... 13 
5.2 
Duration of Study Participation ................................................................................. 14 
5.2.1 
Study Procedures ................................................................................................. 14 
5.2.2 
Screening/Baseline ............................................................................................... 14 
5.2.3 
28 Days (+/- 14 days) ........................................................................................... 15 
5.2.4 
Week 12 (+/- 14 days) .......................................................................................... 15 
5.2.5 
Week 24 (+/- 14 days) .......................................................................................... 15 
5.2.6 
Week 36 (+/- 14 days) .......................................................................................... 15 
5.2.7 
Week 48/End-of-treatment (EOT)/Early Termination Visit +/- 14 days) ............. 16 
5.3 
Randomisation and Blinding ...................................................................................... 16 
5.4 
Source Data ............................................................................................................... 16 
6.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ......................................................................... 17 
6.1 
Subject Inclusion Criteria ........................................................................................... 17 
6.2 
Subject Exclusion Criteria .......................................................................................... 17 
7.0 
SUBJECT WITHDRAWAL CRITERIA .......................................................................................... 17 
7.1 
Removal of Subjects from Assessment ....................................................................... 17 
7.2 
Handling of Withdrawals ........................................................................................... 18 
7.3 
Termination of Study ................................................................................................. 18 
7.3.1 
Regular Termination of Study .............................................................................. 19 
7.3.2 
Premature Termination of Study ......................................................................... 19 
8.0 
TREATMENT OF SUBJECTS ...................................................................................................... 19 
8.1 
Treatments Administered .......................................................................................... 19 
8.2 
Assessment of Compliance and procedures ............................................................... 20 
9.0 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS ............................................. 20 


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9.1 
Pharmacokinetic Analyses ......................................................................................... 20 
10.0 
ASSESSMENT OF SAFETY ........................................................................................................ 20 
10.1 
Safety Parameters ..................................................................................................... 20 
10.1.1 Adverse Events ..................................................................................................... 20 
10.1.2 Adverse Event Definition ...................................................................................... 20 
10.1.3 Laboratory investigations criteria for AE ............................................................. 21 
10.1.4 Intensity of Adverse Events .................................................................................. 23 
10.1.5 Treatment-Emergent Adverse Events .................................................................. 23 
10.1.6 Serious Adverse Events ......................................................................................... 23 
10.1.7 AE or SAE Exceptions ............................................................................................ 24 
10.1.8 Laboratory Evaluation .......................................................................................... 24 
10.1.8.1 
Safety Laboratory Parameters ............................................................ 24 
10.1.9 Other Safety Parameters ..................................................................................... 24 
10.1.9.1 
Vital Signs ............................................................................................ 24 
10.1.9.2 
Physical Examination .......................................................................... 24 
10.2 
Recording and Reporting Adverse Event/Intercurrent Illnesses .................................. 25 
10.3 
Adverse Event Follow-up Procedures ......................................................................... 25 
11.0 
STATISTICAL METHODS .......................................................................................................... 25 
11.1 
General Methods ...................................................................................................... 25 
11.2 
Demographics and baseline characteristics ................................................................ 26 
11.3 
Analysis of Primary endpoints ................................................................................... 26 
11.3.1 Safety and Tolerability ......................................................................................... 26 
11.3.1.1 
Adverse Events ................................................................................... 26 
11.3.1.2 
Clinical Laboratory Tests ..................................................................... 27 
11.3.1.3 
Vital Signs ............................................................................................ 27 
11.3.1.4 
Physical Examination .......................................................................... 27 
11.3.1.5 
Tolerability .......................................................................................... 27 
11.3.1.6 
Pharmacokinetic Analyses .................................................................. 27 
11.3.2 Safety and Tolerability ......................................................................................... 28 
11.3.3 Pharmacokinetics Analyses .................................................................................. 28 
11.3.4 Preliminary Assessment of Clinical Activity .......................................................... 28 
11.5 
Interim analysis ......................................................................................................... 29 
11.6 
Statistical Considerations .......................................................................................... 29 
11.7 
Procedure For Accounting for Missing, Unused, and Spurious Data ............................ 29 
11.8 
Derived And Transformed Data ................................................................................. 29 
11.9 
Deviations From The Original Statistical Plan ............................................................. 30 


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11.10 Subject Selection For Analyses ................................................................................... 30 
12.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .................................................................... 30 
12.1 
Source Data ............................................................................................................... 31 
12.2 
Source Documents ..................................................................................................... 31 
12.3 
Direct Access ............................................................................................................. 31 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE ...................................................................... 31 
13.1 
Quality Control .......................................................................................................... 31 
13.2 
Quality Assurance...................................................................................................... 32 
13.2.1 Inspection ............................................................................................................. 32 
13.2.2 Audit ..................................................................................................................... 32 
14.0 
ETHICS ................................................................................................................................... 32 
14.1 
Ethical Conduct of the Study ...................................................................................... 32 
14.2 
Institutional Review Board/Independent Ethics Committee Approval ........................ 33 
14.3 
Informed Consent ...................................................................................................... 33 
14.4 
Modification of Protocol ............................................................................................ 34 
15.0 
INVESTIGATOR OBLIGATIONS ................................................................................................ 35 
15.1 
Confidentiality ........................................................................................................... 35 
15.2 
Investigator Documentation ...................................................................................... 35 
15.3 
Study Conduct ........................................................................................................... 36 
15.4 
Adherence to Protocol ............................................................................................... 36 
15.5 
Adverse Events and Study Report Requirements ....................................................... 36 
15.6 
Investigator’s Final Report ............................................................................................... 36 
16.0 
DATA HANDLING AND RECORD KEEPING ............................................................................... 36 
16.1 
Completion of Case Report Forms .............................................................................. 36 
16.2 
Archiving ................................................................................................................... 37 
17.0 
FINANCING AND INSURANCE ................................................................................................. 37 
18.0 
PUBLICATION POLICY ............................................................................................................. 37 
19.0 
REFERENCES .......................................................................................................................... 37 
APPENDICES ....................................................................................................................................... 40 
APPENDIX 1: STUDY SCHEDULE OF EVENTS ........................................................................................ 41 
APPENDIX 2: INVESTIGATOR SIGNATURE PAGE .................................................................................. 43 
APPENDIX 3: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) .............................. 44 


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APPENDIX 4: DATA SHEET FOR BICTEGRAVIR/EMTRICITABINE/TENOFOVIR ALAFENAMIDE (BIKTARVY®) 
45 
APPENDIX 5: DATA SHEET FOR DORAVIRINE (PIFELTRO ®) .................................................................. 46 
APPENDIX 6: PITTSBURGH SLEEP QUALITY INDEX ............................................................................... 47 
APPENDIX 7: WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE ............................ 48 


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1.0 
GLOSSARY 
 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
AST 
Aspartate aminotransferase 
AUC0-inf 
Area under the plasma concentration curve from time 0 to infinity 
AUClast 
Area under the plasma concentration curve from time 0 to the last
observable concentration 
AUC0-t 
Area under the plasma concentration versus time curve, from time 0 
to the last measurable concentration 
BLQ 
Below the limit of quantification 
BIC/FTC/TAF + DOR 
Bictegravir/emtricitabine/tenofovir alafenamide in combination with 
doravirine 
bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CK 
Creatine kinase 
CL 
Total clearance 
Cmax 
Maximum plasma concentration 
CRF 
Case report form 
CV 
Coefficient of variation 
EOT 
End-of-treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transpeptidase 
GLP 
Good Laboratory Practices 
h 
Hour 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council on Harmonisation 
IRB 
Institutional review board 
kel 
First-order rate constant for elimination of drug 


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LDH 
Lactate dehydrogenase 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
Pharmacokinetic 
RBC 
Red blood cell (count) 
RNA 
Ribonucleic Acid 
RPV/FTC/TAF + DTG 
Rilpivirine/emtricitabine/tenofovir alafenamide in combination with 
dolutegravir 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOP 
Standard operating procedure 
t1/2 
Half-life 
TEAE 
Treatment-emergent adverse event 
TRAE 
Treatment-related adverse event 
tlag 
Time between drug administration and first observed concentration 
above lower limit if quantitation in plasma 
tmax 
Time to maximum concentration 
ULN 
Upper limit of normal 
US 
United States 
Vd 
Volume of distribution 
WBC 
White blood cell (count) 
WHO 
World Health Organization 


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2.0 
PROTOCOL SYNOPSIS 
 
 
 
 
Title 
An open label study evaluating the safety and efficacy of switching 
from rilpivirine/emtricitabine/tenofovir alafenamide in combination 
with dolutegravir, to bictegravir/emtricitabine/tenofovir alafenamide 
in combination with doravirine, in male HIV+ subjects > 45 years with 
multi-drug resistant virus and virologic suppression (documented with 
at least one viral load result < 50 copies per mL) during the last 6 
months on current therapy. 
Protocol Number 
BETD-001 
Switch therapy 
Bictegravir/emtricitabine/tenofovir alafenide plus doravirine 
Number of Sites and 
Countries 
One site, US 
Phase 
Phase IV 
 
 
Indication 
Male HIV+ subjects over 45 years old with prior multidrug resistance 
to HIV therapy, with a prior positive response to 
rilpivirine/emtricitabine/tenofovir alafenamide in combination with 
dolutegravir, and switching to bictegravir/emtricitabine/ tenofovir 
alafenamide in combination with doravirine. 
Study Design 
The current study proposal is an open label observational trial for 
maintenance of virologic suppression, and is designed as a non- 
inferiority switch trial. The study will involve approximately 30 patients, 
which includes a PK arm of approximately 10 patients. The study will 
also include secondary outcomes of quality of life (QOL) and weight 
changes 
Hypothesis: 
Patients with prior NUC or NNRTI resistance (but not to rilpivirine or 
doravirine) will maintain their virologic suppression after a drug 
regimen switch from rilpivirine/emtricitabine/tenofovir alafenamide in 
combination with dolutegravir, to bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine. The switch therapy will 
avoid food interactions, and will be well tolerated by subjects. 
Primary Endpoint 
1. Percentage of patients with viral HIV load (VL) <50 and <200 
copies/mL at 48 weeks 
Secondary 
Endpoints 
1. Tolerability 
2. Changes in body mass index (BMI) from baseline to 48 weeks 


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3. Provide data on heavily treatment experienced (HTE) patients, 
switching to a bictegravir/emtricitabine/tenofovir alafenamide in 
combination with doravirine containing-regimen. 
4. Confirm absence of drug/drug interactions between 
bictegravir/emtricitabine/tenofovir alafenamide in combination 
with doravirine based on 24-hour PK at week 4 (+/- 14 days) with 
time points at predose (-0.5 hr), 0.5, 1, 2, 4, 6, 8, 12, and 24 hours 
for a subset of 10 subjects. 
5. Assess AE’s of any grade and relationship to the drug combination 
occurring in at least 5% of participants or more. 
6. Improvement in well-being and sleep inventory as measured by 
The Pittsburgh Sleep Quality Index (PSQI) & The Work 
Productivity and Activity Impairment Questionnaire (WPAI). 
Study Duration 
1. Duration of enrolment period: 12 months 
2. Subjects entering treatment per month: 10 patients 
3. First subject in to 50% enrolment: 3 months 
4. 50% enrolment to last subject in: 6 months (100% at 6 months) 
Number of Subjects 
30 (10 PK subjects as a subset) 
Subject Population 
Male HIV+ subjects over 45 years old with stable effective antiviral 
response (HIV RNA copies less than 50/mL on at least one occasion in 
the six months prior to switching therapy) with 
rilpivirine/emtricitabine/tenofovir alafenamide in combination with 
dolutegravir switching to bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine 
Inclusion Criteria 
1. HIV positive Males, age 45 or older 
2. Any genotypic or phenotypic resistance except k65R, 69 insertion, 
integrase resistance, or resistance to rilpivarine or doravirine. 
3. Receiving combination antiretroviral regimen of 
rilpivirine/emtricitabine/tenofovir alafenamide in combination 
with dolutegravir > 12 months and with viral load <50 copies/ mL 
on at least one occasion within the six months prior to switch. 
4. Suppressed viral load as defined by one plasma HIV RNA level < 
50 copies/mL within previous 6 months. 
5. Capable of providing informed consent 
Exclusion Criteria 
1. Any current or prior integrase inhibitor resistance 


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2. Nucleoside reverse transcriptase (NRTI) mutation 69 insertion or 
k65R mutation 
3. Documented second generation non-nucleoside reverse 
transcriptase inhibitor (NNRTI) resistance (rilpivirine or 
doravirine) 
Statistical Methods 
In this study, subjects will have stable prior antiretroviral therapy (HIV 
RNA copies <50/mL on at least one occasion in the 6 months prior to 
the study), and the aim is to determine if the protocol therapy will 
continue to suppress HIV activity. The goal is to determine the 
number of subjects who have 1) less than 50 copies/mL and 2) less 
than 200 copies/mL HIV at week 48. 
The secondary objective of the study is to determine the quality of life 
and weight stabilization provided by the switch therapy as measured 
by the Pittsburgh Sleep Quality Index (PSQI), The Work Productivity 
and Activity Impairment Questionnaire (WPAI) and BMI assessment. 
Values will be compared at baseline and at 48 weeks. 


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3.0 
BACKGROUND INFORMATION 
 
3.1 
Study Rationale 
 
In recent years with the advent of high barrier integrase strand transfer inhibitors 
(INSTI) and the aging HIV/AIDS population, providers have initiated proactive anti- 
retroviral (ARV) switches away from protease inhibitors, for minimization of 
coronary artery disease (CAD) risk associated with protease inhibition (1). Many 
legacy HIV patients have 2 and 3 class resistant viruses. Common regimens that 
were used for switch to overcome resistant virus and maintain un-detectability off 
protease regimens included a switch to rilpivirine, emtricitabine, tenofovir 
alafenamide 
plus 
dolutegravir. 
With 
the 
approval 
of 
bictegravir/emtricitabine/tenofovir alafenamide and doravirine, both very high 
genetic barrier antivirals, and with this regimen being two single small daily 
tablets, both with the advantage of elimination of need for food requirement in 
an antiviral regimen and fewer drug/drug/interactions (DDI), switching from 
rilpivirine/emtricitabine/tenofovir alafenamide plus dolutegravir to bictegravir/ 
emtricitabine/ tenofovir alafenamide plus doravirine is a very attractive current 
option. There are no theoretical pharmacokinetic (PK) interactions between these 
medications, but there exists a data gap as they have not been studied in 
combination for safety and efficacy. The current study proposal is an open label 
observational trial for maintenance of virologic suppression, and is designed as a 
non-inferiority switch trial. The study will involve approximately 30 patients, 
which includes a PK arm of approximately 10 patients. Given known incidence of 
adverse events with dolutegravir, including CNS toxicities(9), it might be expected 
that the switch regimen will have an improved adverse event profile. There is 
increasing evidence of weight gain challenges with integrase inhibitor class 
(including dolutegravir) containing regimens, but bictegravir containing regimens 
appear to offer equivalent weight gain compared with dolutegravir(10). The 
study will also include secondary outcomes of quality of life (QOL) as measured by 
the Pittsburgh Sleep Quality Index (PSQI) and The Work Productivity and Activity 
Impairment Questionnaire (WPAI), and subject weight as measured by Body Mass 
Index at baseline and 48 weeks. 
 
3.2 
Anticipated Risks and Safety concerns for the switch 
 
There are known risks associated with bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine (see data information for the 
combination in the product prescribing information in Appendices 4 and 5). 
It is not anticipated that the switch will place subjects at greater risk than their 
current therapy. 


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If subjects participate in the PK evaluation, there are minor risks associated with 
blood sampling. 
4.0 
STUDY OBJECTIVES 
Primary objectives: 
1. Percentage of patients with viral HIV load (VL) <50 and <200 copies/mL at 48 weeks 
 
Secondary objectives: 
1. Tolerability 
2. Changes in body mass index (BMI) from baseline to 48 weeks 
3. Provide 
safety 
and 
pharmacokinetic 
data 
on 
subjects 
switching 
to 
a 
bictegravir/emtricitabine/tenofovir alafenamide in combination with doravirine 
regimen. 
4. Confirm 
absence 
of 
drug/drug 
interaction 
between 
bictegravir/emtricitabine/tenofovir alafenamide in combination with doravirine 
based on 24 hour PK at week 4 (+/- 14 days) with time points at predose (-0.5 hr), 0.5, 
1, 2, 4, 6, 8, 12, and 24 hours for n=10. 
5. Improvement in well-being and sleep inventory as measured by the Pittsburgh Sleep 
Quality Index (PSQI) and The Work Productivity and Activity Impairment 
Questionnaire (WPAI). 
 
 
5.0 
INVESTIGATIONAL PLAN 
 
5.1 
Overall Study Design and Plan 
 
The current study proposal is an open label observational trial for maintenance of 
virologic suppression, and is designed as a non-inferiority switch trial. The study 
will involve approximately 30 patients, which includes a PK arm of approximately 
10 patients. The study will also include secondary outcomes of quality of life (QOL) 
as measured by the Pittsburgh Sleep Quality Index (PSQI) and The Work 
Productivity and Activity Impairment Questionnaire (WPAI), and weight changes 
measured by body mass index (BMI) over the 48 week study period. 
 
Hypothesis: 
HIV+ male patients 45 years and older with prior NUC or NNRTI resistance (but not 
to rilpivirine or doravirine) will maintain their virologic suppression after a drug 
regimen 
switch 
from 
rilpivirine/emtricitabine/tenofovir 
alafenamide 
in 
combination with dolutegravir to bictegravir/emtricitabine/tenofovir alafenamide 


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in combination with doravirine. Subjects will maintain weight, and will tolerate the 
switch therapy. Subject's quality of life will be maintained or improved. 
 
5.2 
Duration of Study Participation 
 
For each Subject, the study duration will span from the date of signed, written 
informed consent through the end of treatment (EOT) visit, expected to be about 
48 weeks with the option of returning for additional unscheduled visits if retests 
are required. 
 
Subjects who have signed the informed consent form and subsequently fail to 
meet the inclusion and/or exclusion criteria are defined as screen failures. For all 
screen failures, the Investigator is to maintain a screening log that documents the 
Subject initials and reason(s) for screen failure. A copy of the log should be 
retained in the Investigator's study files. Instructions on how to handle Subject 
screening, screen failure, and recruitment will be provided in a dedicated 
document. 
 
5.2.1 Study Procedures 
 
The procedures to be performed at each study visit are outlined below. 
 
5.2.2 Screening/Baseline 
 
The following activities will be performed at baseline: 
 Informed consent (prior to any study-specific procedures). 
 Study inclusion/exclusion criteria. 
 Collect year of HIV diagnosis 
 Demographic information (age, gender, race, ethnicity, as allowed 
by local regulation). 
 Height and weight, body mass index (BMI). 
 Pittsburgh Sleep Quality Index (PSQI) 
 The Work Productivity and Activity Impairment Questionnaire 
(WPAI) 
 HIV viral load 
 CD4 count within 3 months of study entry 
 Physical examination 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology: complete blood cell count (CBC) 
 Serum chemistry 
 Urinalysis 
 Adverse events reported after the Subject provides informed 


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consent. 


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 Treatment switch initiated 
5.2.3 28 Days (+/- 14 days) 
 
 Pharmacokinetic sampling (subset of 10 subjects) 
 Physical examination 
 Weight & Body Mass Index (BMI) 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology for CBC assessment 
 HIV viral load 
 Serum chemistry 
 Urinalysis 
 Adverse event updates. 
 
5.2.4 Week 12 (+/- 14 days) 
 
 Physical examination 
 Weight & Body Mass Index (BMI) 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology: for CBC assessment 
 HIV viral load 
 Serum chemistry 
 Urinalysis 
 Adverse event updates. 
5.2.5 Week 24 (+/- 14 days) 
 
 Physical examination 
 Weight & Body Mass Index (BMI) 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology: for CBC assessment 
 HIV viral load 
 Serum chemistry 
 Urinalysis 
 Adverse event updates. 
5.2.6 Week 36 (+/- 14 days) 


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 Physical examination 
 Weight & Body Mass Index (BMI)Vital signs, including HR, systolic 
and diastolic blood pressure, respiratory rate, and body 
temperature. 
 Hematology: for CBC assessment 16aematocrit16aematocrit 
 HIV viral load 
 Serum chemistry: 
 Adverse event updates. 
5.2.7 Week 48/End-of-treatment (EOT)/Early Termination Visit (+/- 14 days) 
 
The following procedures will be performed at the EOT visit: 
 Weight & Body Mass Index (BMI) 
 Pittsburgh Sleep Quality Index (PSQI) 
 The Work Productivity and Activity Impairment Questionnaire 
(WPAI). 
 Physical examination 
 Vital signs, including HR, systolic and diastolic blood pressure, 
respiratory rate, and body temperature. 
 Hematology: for CBC assessment 
 HIV viral load 
 CD4 count 
 Serum chemistry: 
 Urinalysis 
 Adverse event updates. 
5.3 
Randomisation and Blinding 
 
Not applicable. 
 
 
5.4 
Source Data 
 
Source documents (including all demographic and medical information, CRFs, and 
a copy of the signed informed consent form [ICF] indicating the study number and 
title) for each Subject in the study will be maintained by the Investigator (generally 
in the Subject’s files), and all information in the CRFs must be traceable to the 
source documents. 
 
All data should be recorded directly into the Subject’s medical record as source 
data. It will be confirmed at an initiation visit which documents will be considered 


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as source data for the site. These will be documented and reviewed by the monitor 
at each monitoring visit. 
 
Source documents must be available to document the participation of the Subject 
and substantiate the integrity of study data collected. 
 
6.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
 
6.1 
Subject Inclusion Criteria 
 
Each Subject (male) must meet all of the following criteria to be enrolled in this 
study: 
1. HIV positive Males, age 45 or older 
2. Any genotypic or phenotypic resistance except k65R, 69 insertion, 
integrase resistance, or resistance to rilpivarine or doravirine. 
3. Receiving 
combination 
antiretroviral 
regimen 
of 
rilpivirine/emtricitabine/tenofovir alafenamide in combination with 
dolutegravir > 12 months and with viral load <50 copies/ mL on at least 
one occasion within the previous 6 months. 
4. Suppressed viral load as defined by one or more plasma HIV RNA levels < 
50 copies/mL within previous 6 months. 
5. Capable of providing informed consent. 
 
 
6.2 
Subject Exclusion Criteria 
 
Subjects meeting any of the following criteria will be excluded from the study: 
1. Any current or prior integrase inhibitor resistance 
2. Nucleoside reverse transcriptase (NRTI) mutation 69 insertion or k65 
mutation 
3. Documented second generation non-nucleoside reverse transcriptase 
inhibitor (NNRTI) resistance (rilpivirine or doravirine) 
 
7.0 
SUBJECT WITHDRAWAL CRITERIA 
 
7.1 
Removal of Subjects from Assessment 
 
A Subject may withdraw (or be withdrawn) from the study prematurely for the 
following reasons: 


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 Subject voluntarily discontinues participation in the study (consent 
withdrawal) 
 Toxicity-related criteria 
 Any clinically relevant signs or symptoms that, in the opinion of the 
Investigator, warrant Subject withdrawal. 
 Protocol deviation (including non-compliance). 
 Disease progression or relapse 
 Lost to follow-up 
 The Investigator determines it is in the best interest of the Subject to 
discontinue the Subject’s participation in the study 
 
The Investigator will also withdraw a Subject if the Investigator terminates the 
study. If a Subject is discontinued because of an AE, the event will be followed 
until it is resolved, resolved with sequelae, not recovered (death due to another 
cause), or death (due to an SAE). 
 
Reasonable effort should be made to contact any Subject lost to follow-up during 
the course of the study in order to complete assessments. 
 
7.2 
Handling of Withdrawals 
 
Subjects who discontinue study drug or active participation in the study will no 
longer receive study drugs. When a Subject withdraws from the study, the 
reason(s) for withdrawal shall be recorded by the Investigator on the relevant 
page of the case report form (CRF). Whenever possible, all Subjects who 
discontinue study drug will undergo all the assessments at the EOT visit. Subjects 
who fail to return for final assessments will be contacted by the site in an attempt 
to have them comply with the protocol. Following a minimum of two documented 
unsuccessful telephone calls, a registered letter will be sent to the Subject in a 
final attempt to ensure protocol compliance. 
 
It is vital to obtain follow-up data on any Subject withdrawn because of an AE or 
SAE. In every case, efforts must be made to undertake protocol-specified, safety 
follow-up procedures. 
 
7.3 
Termination of Study 
 
The Investigator can terminate the study at any time for significant deviations 
from the protocol or due to difficulties experienced in running the study. 
 
The Investigator may terminate this study for any of the following reasons: 


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 Non-compliance with protocol, GCP, and/or regulatory requirements 
 Observation of unexpected, significant, or unacceptable risk to Subjects. 
 An adequate number of Subjects cannot be recruited 
 False documentation in the CRF 
 Other administrative reasons. 
 
Should the study be discontinued prematurely, all study materials must be 
returned to the Investigator or Investigator’s designee. 
 
7.3.1 Regular Termination of Study 
 
The end of this study is defined as the date of the last visit of the last 
Subject participating in the study. Within 90 days of the end of the study, 
the Investigator will notify the institutional review board/independent 
ethics committee (IRB/IEC) and the relevant regulatory authorities about 
the regular termination of the study as required according to national laws 
and regulations. If the study has to be terminated early, this period shall 
be reduced to 15 days and the reasons clearly explained. 
 
7.3.2 Premature Termination of Study 
 
The study may be terminated prematurely for any reason and at any time 
by the Investigator, IRB/IEC or regulatory authorities. The IRB/IEC and the 
relevant regulatory authorities will be informed about reason and time of 
termination according to the applicable laws and regulations. 
 
8.0 
TREATMENT OF SUBJECTS 
 
8.1 
Treatments Administered 
 
Orally administered (single doses daily) bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine at physician prescribed doses. 
 
50 mg of bictegravir (equivalent to 52.5 mg of bictegravir sodium), 200 mg of 
emtricitabine, and 25 mg of tenofovir alafenamide (equivalent to 28 mg of 
tenofovir alafenamide fumarate) as a single tablet daily. 
 
Doravirine 100mg tablet daily. 


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8.2 
Assessment of Compliance and procedures 
 
Investigator or designee will record time of administration of study drugs in the 
CRF on the day prior to PK sampling, the day of PK sampling, and the day after PK 
sampling for subjects participating in the PK portion of the study.  Study drug 
should be taken in the morning on the day prior to PK sampling, the day of PK 
sampling, and after the 24 hour PK draw on the day after PK sampling.  
 
9.0 
PHARMACOKINETIC AND PHARMACODYNAMIC ASSESSMENTS 
 
9.1 
Pharmacokinetic Analyses 
 
Full PK assessments will be taken pre-dose (-0.5 hr), and at 0.5, 1, 2, 4, 6, 8, 12, 
and 24 hours after dosing on day 28 (+/- 14 days).  Subjects may be asked to 
return for an unscheduled visit to test/retest PK samples if the initial data is 
found to be invalid 
 
The PK parameters to be calculated will include, but are not limited to, AUC0-inf, 
AUC0-t, Cmax, kel, tmax, tlag, CL, Vd and t½. The PK parameters and concentrations will 
be summarised by dose levels among the PK evaluable Subjects. Plots of mean 
plasma concentration of bictegravir and doravirine over time will be provided. 
 
10.0 
ASSESSMENT OF SAFETY 
 
The Investigator is responsible for the detection and documentation of events meeting 
the criteria and definition of an AE or SAE, as provided in this protocol. 
 
Follow-Up for Toxicities 
Subjects whose treatment is interrupted or permanently discontinued due to an AE or 
clinically significant laboratory value must be followed at least once a week for 4 weeks, 
and subsequently at 4 week intervals, until resolution or stabilisation of the event, 
whichever comes first. All Subjects must be followed up for AEs and SAEs for 30 days 
following the last dose of study therapy. 
 
10.1 
Safety Parameters 
 
10.1.1 Adverse Events 
 
Adverse events are continuously monitored beginning at enrolment (date 
of signed informed consent) and up to 30 days after the last dose of the 
study drug. Adverse events will be graded using CTCAE version 5.0 
 
10.1.2 Adverse Event Definition 
 


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An AE is any untoward medical occurrence in a Subject or clinical 
investigation. Subject will have been administered a pharmaceutical 


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product, which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavourable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational product, whether 
or not related to the investigational product. 
 
10.1.3 Laboratory investigations criteria for AE 
 
Any abnormal laboratory results (hematology, clinical chemistry, or 
urinalysis) or other safety parameters (e.g., radiological scans, ECGs, and 
vital sign measurements, etc), felt to be clinically significant in the medical 
and scientific judgement of the Investigator are considered AEs. Examples 
of criteria for determining whether an abnormal finding is clinically 
significant and should be reported as an AE are: 
 CTCAE Grade 4
 Laboratory result is associated with accompanying symptoms or 
signs
 Laboratory result requires additional diagnostic testing or 
medical/surgical intervention
 Laboratory result leads to a change in study dosing or 
discontinuation from the study significant additional concomitant 
drug treatment, or other therapy
 Laboratory results worsen from baseline
 Laboratory result is considered to be an AE by the Investigator or 
Sponsor.
 
However, merely repeating an abnormal test, in the absence of any of the 
above conditions, does not constitute an AE. Any abnormal test result that 
is determined to be an error does not require reporting as an AE. Any 
clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the Investigator to be more severe 
than expected for the Subject population and Subject’s individual 
condition, are not to be reported as AEs. 
 
Laboratory and other safety assessments can be considered SAEs when 
criteria apply 
 
Relationship of Adverse Events 
 
Not related: 
An AE for which there is no reasonable temporal 
association between its onset and administration of 


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the investigational drug, or that can reasonably be 
explained by other factors, including underlying 
disease, complications, concomitant drugs or 
concurrent treatment. 
Note: Even if the Investigator feels there was no 
relationship to study medication, the AE experience 
is to be reported. 
Unlikely to be related: 
A clinical event, including laboratory test 
abnormality, with a temporal relationship to drug 
administration which makes a causal relationship 
improbable, and in which other drugs, chemicals or 
underlying disease provide plausible explanations. 
Possibly related:         An AE for which there is  a reasonable temporal 
association between its onset and administration of 
the investigational drug (including the course of 
treatment after withdrawal of the drug), for which 
other causal factors may not be excluded. 
Probably related:       An AE for which there is  a reasonable temporal 
association 
between 
its 
onset 
and 
the 
administration of the investigational drug, including 
the course after treatment withdrawal, and which is 
more likely to be explained by the test drug than by 
any 
other 
cause 
(e.g., 
underlying 
disease, 
complications, concomitant drugs or concurrent 
treatment). 
Definitely related: An AE that is judged as undeniably related to the 
administration of study medication. Factors taken 
into consideration when a definite relationship is 
assigned include whether the AE: 
 Followed a clear temporal sequence from 
administration of study medication. 
 Could not be possibly explained by the known 
characteristics of the Subject’s clinical state, 
environmental or toxic factors, other modes of 
therapy administered to the Subject. 
 Disappeared or decreased on cessation or 
reduction in dose of study medication. 
 Reappeared 
or 
worsened 
when 
study 
medication was re-administered. 


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 Followed a response pattern known to be 
associated 
with 
administration 
of 
study 
medication. 
 
10.1.4 Intensity of Adverse Events 
 
For grading the intensity of an AE, the following CTCAE categories will be 
applied: 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
Grade 2 Moderate; minimal, local or non-invasive intervention 
indicated. 
Grade 3 Severe or medically significant but not immediately life- 
threatening; hospitalisation or prolongation of hospitalisation 
indicated; disabling; limiting self-care. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 
 
10.1.5 Treatment-Emergent Adverse Events 
 
An AE is defined as treatment-emergent adverse event (TEAE) if first onset 
or worsening is after first intake of study drugs. 
 
10.1.6 Serious Adverse Events 
 
An SAE is an AE that suggests a significant hazard, contraindication, side-
effect, or precaution. With respect to human clinical experience, this 
includes any event that: 
 
Results in death.
 
Is life-threatening.*
 
Requires in-Subject hospitalisation or prolongation of existing 
hospitalisation.
 
Results in persistent or significant disability/incapacity.
 
Is a congenital anomaly/birth defect.
 
Other medically important condition.
* Life-threatening in the definition of a SAE or adverse reaction 
refers to an event in which the Subject was at risk of death at the 
time of event; it does not refer to an event that hypothetically 
might have caused death if it were more severe. 


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All of the above criteria apply to the case as a whole and should not be 
confused with the outcomes of individual reactions/events. More than one 
of the above criteria can be applicable to the one event. 
 
10.1.7 AE or SAE Exceptions 
 
The following events must not be reported as AEs or SAEs: 
 Admissions to the hospital, not associated with deterioration in 
condition, for the following:
o supportive therapy, e.g., respite care, 
o standard procedures, e.g., pre-planned treatments, 
o elective procedures, e.g., a previously scheduled surgical 
procedure, 
o disease-related investigations, e.g., pre-planned laboratory or 
instrumental assessments. 
 
10.1.8 Laboratory Evaluation 
 
10.1.8.1 Safety Laboratory Parameters 
 
The following safety laboratory tests will be performed: 
Hematology (peripheral blood) 
 
Serum chemistry (peripheral blood): 
 
 
Urine Testing 
 
10.1.9 Other Safety Parameters 
 
10.1.9.1 Vital Signs 
 
Vital signs, including HR, systolic and diastolic blood pressure, respiratory 
rate, and body temperature will be recorded throughout the study as 
noted in Section 5.2.1 and Appendix 1. 
 
10.1.9.2 Physical Examination 
 
Physical examinations will be performed as noted in Section 5.2.1 and 
Appendix 1. The physical examination will consist of the following: 
evaluation of the general appearance, head, eyes, ears, nose, throat, 


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lymph nodes, heart/cardiovascular, respiratory, abdomen, genitourinary, 
musculoskeletal/extremities, neurological status, and dermatology. 
 
Body weight (with BMI) and height will be measured at as noted in Section 
5.2.1 and Appendix 1. 
 
10.2 
Recording and Reporting Adverse Event/Intercurrent Illnesses 
 
It is the responsibility of the Investigator to document all AEs that occur during the 
study. All AEs observed during the study from the time the Subject signs the ICF 
through 30 days after the last dose of the study drug on the AE page of the CRF. 
Information to be collected includes: event term, date of onset , pattern of AE 
(intermittent or continuous), outcome of the event, Investigator-specified 
assessments of severity, seriousness, relationship to study drug, date of resolution 
of the event, any required treatment or evaluations, and whether the event 
caused study discontinuation. 
 
Adverse events resulting from concurrent illnesses, reactions to concurrent 
illnesses, or reactions to concurrent medications must also be reported. 
 
Adverse events will be elicited by asking the Subject a non-leading question, for 
example “Have you experienced or are you experiencing any new or changed 
symptoms since we last asked/since your last visit?” Adverse events should be 
reported on the appropriate page of the CRF. 
 
10.3 
Adverse Event Follow-up Procedures 
 
All AEs must be followed-up until the event has resolved or stabilised or the 
relationship to study medication is clarified. 
 
11.0 
STATISTICAL METHODS 
 
11.1 
General Methods 
 
A SAP will be prepared as a separate document that will include a detailed 
description of statistical analyses and summarisation procedures (including 
templates for tables, listings, and figures). The SAP will be finalised before 
initiating any statistical analysis. 
 
All statistical tests will be two-sided with a significance level of α=0.05, unless 
specified otherwise, and will be performed using SAS® Version 9.2 or higher. All 


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summaries, listings, figures, and analyses will be performed by dose 
level/schedule (as applicable). 
 
Data will be summarised using descriptive statistics (number of Subjects, mean, 
standard deviation [SD], median, minimum, and maximum) for continuous 
variables and using frequency and percentage for discrete variables. 
 
Plasma concentration data at each time point will be summarised with number of 
Subjects, mean, median, minimum, maximum, SD, and coefficient of variation (CV; 
%) for each dose level/schedule (as applicable). All PK parameters will be 
summarised with number of Subjects, mean, standard deviation, median, 
minimum, maximum, geometric mean, CV (%), and log-transformed SD. 
 
All data will be provided in by-Subject listings. 
 
11.2 
Demographics and baseline characteristics 
 
Demographic and baseline disease characteristic data will be summarised by dose. 
 
 
11.3 
Analysis of Primary endpoints 
 
11.3.1 Safety and Tolerability 
 
The safety of the therapies will be assessed by monitoring incidence of AEs, 
clinical laboratory tests, vital signs, and physical examination. Safety will 
be monitored throughout the study for all Subjects. Safety data will be 
summarised by dose level/schedule (as applicable). Safety summaries will 
contain only data collected during on-treatment period, unless specified 
otherwise. 
 
11.3.1.1 Adverse Events 
 
The verbatim terms used in the CRF by the Investigator to identify AEs will 
be coded by system organ class and preferred terms using MedDRA 
(current version). All reported TEAEs will be included in the analysis. 
AEs will be summarised by system organ class and preferred term. 
The following summaries will be produced: 
 All TEAEs 
 Treatment related TEAEs 


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 Grade 3 or higher TEAEs 
 Most commonly reported TEAEs (i.e., those events reported by ≥ 5% 
of all Subjects) 
 SAEs 
 Discontinuations due to AEs. 
By-Subject listings will be provided for all AEs, SAEs, AEs leading to 
discontinuation of treatment, and deaths. 
 
11.3.1.2 Clinical Laboratory Tests 
 
Safety laboratory data (hematology, serum chemistry and urinalysis) will 
be summarised for each laboratory parameter. 
 
In addition to the above-mentioned tables and listings, graphical displays 
of key safety parameters, such as scatter plots of actual or change in 
laboratory tests over time or box plots may be specified in the SAP. 
 
11.3.1.3 Vital Signs 
 
The vital signs parameters that will be summarised are pulse, blood 
pressure (systolic and diastolic), respiratory rate, and body temperature. 
 
Descriptive statistics for the actual values and changes from baseline in 
vital signs data for each dose level over time will be summarised. 
 
11.3.1.4 Physical Examination 
 
A data listing of Subjects with abnormal physical examination results will 
be provided. 
 
11.3.1.5 Tolerability 
 
Tolerability of study drugs will be assessed by summarising the number of 
AE/SAE occurring during the study. 
 
11.3.1.6 Pharmacokinetic Analyses 
 
Individual Subject plasma concentration-time data of bictegravir and 
doravirine will be determined as listed in the protocol. 
The PK parameters to be calculated will include, but are not limited to, 
AUC0-inf, AUC0-t, Cmax, kel, tmax, tlag, CL, Vd and t½. The PK parameters and 
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Subjects. Plots of individual and mean plasma concentration of over time, 
data summaries, and data listings will be provided for the PK analysis set. 
 
The SAP will provide details of the analysis and presentation of the results. 
 
11.3.2 Safety and Tolerability 
 
Safety and tolerability of the new dosing regimen will be assessed by 
evaluation of the AE/SAE events occurring after the switch. 
 
11.3.3 Pharmacokinetics Analyses 
 
Individual Subject plasma concentration-time data of bictegravir and 
doravirine will be analysed using non-compartmental model (WinNonlin®). 
 
In the 10 subject sub-cohort, the plasma samples of bictegravir and doravirine 
for PK assessments will be taken prior to dosing (-0.5 hr), and at 0.5, 1, 2, 4, 6, 8, 
12, and 24 hours on day 28 (+/- 14 days). Subjects may be asked to return for an 
unscheduled visit to test/retest PK samples if the initial data is found to be 
invalid.  All calculations will be based on actual sampling times. 
 
The PK parameters to be calculated will include, but are not limited to, 
AUC0-inf, AUC0-t, Cmax, kel, tmax, tlag, CL, Vd and t½. The PK parameters and 
concentrations will be summarised by dose levels among the PK evaluable 
Subjects. Plots of individual and mean plasma concentration of over time, 
data summaries, and data listings will be provided for the PAS. 
 
The PK parameters will be Log (e) transformed prior to analysis. 
 
The SAP will provide details of the analysis and presentation of the results. 
 
11.3.4 Preliminary Assessment of Clinical Activity 
 
In this study, subjects will have stable prior antiretroviral therapy (HIV RNA 
copies <50/mL on at least one occasion in the 6 months prior to the 
switch), and the aim is to determine if the protocol therapy will continue 
to suppress HIV activity. The goal is to determine the number of subjects 
who have 1) < 50 copies/mL and 2) less than 200 copies/mL HIV at week 
48. 
 
The secondary objective of the study is to determine the quality of life and 
weight stabilization provided by the switch therapy. 


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11.4 
interim analysis 
 
No formal interim analyses are planned. 
 
11.5 
Statistical Considerations 
 
The target sample size for the study is 30 subjects. 
 
Number of subjects maintaining HIV suppression (either <50 copies/mL or <200 
copies/mL) will be tabulated. 
 
Descriptive analyses will be tabulated for subject weight and body mass index 
(BMI) prior to commencing therapy and at 48 weeks after dosing commences. 
 
Quality of life analysis will be determined by comparison of baseline QOL scores 
(Improvement in well-being and sleep inventory as measured by The Pittsburgh 
Sleep Quality Index (PSQI) & The Work Productivity and Activity Impairment 
Questionnaire (WPAI)) with scores at 48 weeks. 
 
11.6 
Procedure For Accounting for Missing, Unused, and Spurious Data 
 
In general, the values for missing data will not be imputed. For laboratory data the 
missing baseline values will be replaced by Screening value if available, otherwise 
it will be treated as normal for summary of graded laboratory of abnormalities. 
Subjects may be asked to return to the clinic to test or retest PK values if the 
initial results are found to be invalid.   
 
The values will not be imputed for missing vital signs and other safety data, 
however, missing baseline values will be replaced by Screening values if available. 
Also, missing relationship between AE and study medication will be considered as 
related to treatment and missing severity of an AE will be summarised as severe 
AE, following conservative principle. 
 
All available data for a Subject who do not complete the study will be included in 
the data listing. 
 
11.7 
Derived And Transformed Data 
 
Pharmacokinetic concentration values below the limit of quantification (BLQ) will 
be treated as zero for the determination of summary and order statistics. 
Individual values that are BLQ will be presented as “BLQ” in the concentration data 
listing. For the presentation of summary and order statistics, if at least 1 Subject 
has a concentration value BLQ for the time point, then the minimum value will be 


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displayed as BLQ. If more than 50% of the Subjects have a concentration data 
value BLQ for the time point, then the minimum and median values will be 
displayed as BLQ. If all Subjects have concentration data values BLQ for the time 
point, then all order statistics (minimum, first quartile, median, third quartile, 
maximum) will be displayed as BLQ. 
 
PK parameters selected for statistical analysis will be log transformed. 
Concentration values that are BLQ will be considered missing for any ratio or 
natural-log transformed statistical analyses. 
 
Laboratory data that are continuous in nature, but are less than the lower limit of 
quantification or above the upper limit of quantification, will be imputed to the 
value of the lower or upper limit minus or plus 1 significant digit, respectively (e.g., 
if the result of a continuous laboratory test is < 20, a value of 19 will be assigned). 
 
11.8 
Deviations From The Original Statistical Plan 
 
Any deviations from the original SAP as described in this protocol will be agreed 
to by the Investigator, documented, and justified in an amendment, the final SAP, 
or the final study report, as appropriate. 
 
11.9 
Subject Selection For Analyses 
 
The following analysis sets will be evaluated and used for presentation of data: 
 Dose Determining Set (DDS): All Subjects who complete at least 28 days 
dosing. Subjects in this set will be denoted as evaluable for safety 
assessment. 
 Safety Analysis Set (SAS): All Subjects who are enrolled and receive at least 
one dose of study treatment. Subjects will be classified according to the 
treatment received. The SAS will be the primary set for the analysis of 
safety data. 
 Full Analysis Set (FAS): All Subjects who are enrolled and receive at least 
one dose of study treatment. Subjects will be classified according to the 
assigned dose level and schedule. The FAS will be the primary analysis set 
for efficacy analysis and the default analysis set for all other analyses, 
unless otherwise specified. 
 PK Analysis Set (PAS): All Subjects who have at least one blood sample 
providing evaluable PK data. The PAS will be used for PK analyses. 
 
12.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 


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The clinical monitor(s) should be given direct access to primary subject data (i.e., source 
data) which supports the data on the CRFs for the study, i.e., general practice charts, 
hospital notes, appointment books, original laboratory records etc. Because this enters 
into the realm of subject confidentiality, this fact must be included in the ICF that the 
subject signs. Other authorised persons such as auditors may need to have direct access 
to this source data. 
 
12.1 
Source Data 
 
Source data is defined as all information in original records and certified copies of 
original records of clinical findings, observations or other activities in a clinical 
study necessary for the reconstruction and evaluation of the study. Source data 
are contained in source documents (original records or certified copies). 
 
12.2 
Source Documents 
 
Source documents are defined as original documents, data and records (e.g., 
hospital records, clinical and office charts, laboratory notes, memoranda, or 
evaluation check lists, pharmacy dispensing records, recorded data from 
automated instruments, copies or manuscripts certified after verification as being 
accurate copies, microfiches, photographic negatives, microfilm or magnetic 
media, X-rays, Subject files, records kept at the pharmacy, at the laboratories and 
at medico-technical departments involved in the clinical study). 
 
12.3 
Direct Access 
 
Direct access is defined as the permission to examine, analyse, verify and 
reproduce any records and reports that are important to evaluation of a clinical 
study. Any party (e.g., domestic and foreign regulatory authorities) with direct 
access should take all reasonable precautions within the constraints of the 
applicable regulatory requirements to maintain the confidentiality of Subject 
identities. 
 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
 
An independent audit at the study site may take place at any time during or after the 
study. The independent audit can be carried by the Quality Assurance (QA) department 
of a regulatory authority. 
 
13.1 
Quality Control 


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Quality control is defined as the operational techniques and activities undertaken 
within the quality assurance system to verify that the requirements for quality of 
the study related activities have been fulfilled. 
 
Quality control should be applied to each stage of data handling to ensure that all 
data are reliable and have been processed correctly. 
 
13.2 
Quality Assurance 
 
Quality Assurance is defined as the planned and systematic actions that are 
established to ensure that the study is performed and the data are generated, 
documented (recorded) and reported in compliance with GCP and the applicable 
regulatory requirements. 
 
13.2.1 Inspection 
 
An inspection is defined as the act by a regulatory authority of conducting 
an official review of documents, facilities, records and any other resources 
that are deemed by the authorities to be related to the clinical study and 
that may be located at the site of the study, or at any other establishments 
deemed appropriate by the regulatory authorities. 
 
13.2.2 Audit 
 
An audit is a systematic and independent review of study related activities 
and documents to determine whether the validated study related 
activities were conducted and the data were recorded, analysed and 
accurately reported according to the protocol, designated standard 
operating procedures (SOPs), GCP and the applicable regulatory 
requirements. 
 
14.0 
ETHICS 
 
14.1 
Ethical Conduct of the Study 
 
This clinical study will be conducted in compliance to this protocol, and in 
accordance with ICH GCP, the provisions of the guidelines of the World Medical 
Association Declaration of Helsinki in its revised edition (Fortaleza, Brazil, 2013), 
designated SOPs, and with local laws and regulations relevant to the use of new 
therapeutic agents in the country of conduct. The IRB/IEC must be constituted 
according to the local laws/guidelines. 


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14.2 
Institutional Review Board/Independent Ethics Committee Approval 
 
Before initiating a study, the Investigator will have the written and dated 
approval/favorable opinion from the relevant IRB/IEC for the study protocol (and 
any   amendments),   ICF,   ICF   updates,   Subject   recruitment    procedures 
(e.g., advertisements), and any other written information to be provided to 
Subjects. Approval will be indicated in writing with reference to the final protocol 
number and date. Details of the IRB/IEC’s constitution, including names of its 
members and what function they perform on the committee (e.g., chairman, 
specialist, lay-member) should be documented by the Investigator. 
 
During the study the Investigator should provide to the IRB/IEC all documents that 
are subject to review. 
The Investigator will submit the protocol to the IRB/IEC and their written 
unconditional approval will be obtained before the start of the study. 
 
The Investigator will provide all supportive literature (product data sheets) to the 
IRB/IEC for the protocol’s review and approval. Verification of the IRB/IEC’s 
unconditional approval of the protocol will be transmitted to the Investigator prior 
to the start of the study. This approval must refer to the study by exact protocol 
title and number, identify the documents reviewed, and state the date of review. 
 
The IRB/IEC must be informed by the Investigator of all subsequent protocol 
amendments and of unexpected SAEs occurring during the study that are likely to 
affect the safety of the Subjects or the conduct of the study. Approval for protocol 
amendments must be transmitted in writing by the Investigator. 
 
The Investigator should provide the IRB/IEC with all relevant amendments or 
updates of the protocol and product information guidance. Also, the Investigator 
should provide written reports to the IRB/IEC annually or more frequently if 
requested on any change significantly affecting the conduct of the study and/or 
increasing risk to the Subjects. A final report of study outcome, if required, should 
also be submitted by the Investigator to the IRB/IEC. 
 
14.3 
Informed Consent 
 
The principles of informed consent in the Declaration of Helsinki should be 
implemented in this clinical study before protocol-specified procedures are 
carried out. Information should be given in both oral and written form whenever 
possible and deemed appropriate by the IRB/IEC. Subjects, their relatives, or, if 
necessary, their legal representatives must be given ample opportunity to inquire 
about details of the study. 


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The Investigator or designee will explain the nature, purpose and risks of the study 
and provide the Subject with a copy of the study information sheet. The Subject 
will be given sufficient time to consider the study’s implications before deciding 
whether to participate. Should the Investigators choose to produce their own 
information sheet, then the detail provided by the Sponsor information sheet 
should be regarded as the minimum written explanation required. 
 
Consent forms must be in a language fully comprehensible to the prospective 
Subject. Informed consent will be documented by the use of an ICF approved by 
the IRB/IEC and signed by the Subject and the Investigator obtaining the consent. 
The ICF will also be annotated with the study Subject number. 
 
The written consent document will embody the elements of informed consent as 
described in the Declaration of Helsinki and will also comply with local regulations. 
Consent must be documented by the Subject’s dated signature. The signature 
confirms the consent is based on information that has been understood. Each 
Subject’s signed ICF must be kept on file by the Investigator for possible inspection 
by regulatory authorities. 
 
Should there be any amendments to the protocol that would directly affect the 
Subject’s participation in the study, e.g., a change in any procedure, the ICF must 
be amended to incorporate this modification and the Subject must agree to sign 
this amended form indicating re-consent to participate in the study. 
 
Subjects will be instructed that they are free to obtain further information from 
the Investigator at any time and that they are free to withdraw their consent/ 
assent and discontinue participation in the project at any time without prejudice. 
 
The Subject will also be advised that access to medical records will be required 
and his/her general practitioner will be informed of the Subject’s intention to 
participate in this study 
 
14.4 
Modification of Protocol 
 
The Investigator should not implement any deviation from, or changes of, the 
protocol without documented approval/favourable opinion from the IRB/IEC of an 
amendment. The only exceptions are where necessary to eliminate an immediate 
hazard(s) to study Subjects, or when the change(s) involves only logistical or 
administrative aspects of the study (e.g., change in monitor[s], change of 
telephone number[s]). Non-substantial protocol amendments may or may not be 


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required to be submitted for approval/notification to the IRBs and regulatory 
agencies. 
 
As soon as possible, the implemented deviation or change, the reasons for it, and, 
if appropriate, the proposed protocol amendment(s) should be submitted 
(according to national legislation): 
 to the IRB for review and approval/favourable opinion, 
 to the regulatory authority(ies). 
 
The party initiating an amendment must confirm it clearly in writing and it must 
be signed and dated by the Investigator. The Investigator will submit protocol 
amendments, as necessary, to the appropriate IRB/IEC. 
 
All protocol amendments must be clearly documented using standard procedures 
and must be signed and dated by the Investigator. 
 
15.0 
INVESTIGATOR OBLIGATIONS 
 
The following administrative items are meant to guide the Investigator in the conduct of 
the study, but may be subject to change based on industry and government standard 
operating procedures, working practice documents, or guidelines. Changes will be 
reported to the IRB/IEC, but will not result in protocol amendments. 
 
15.1 
Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records will be 
identified in a manner designed to maintain Subject confidentiality. All records will 
be kept in a secure storage area with limited access. Clinical information will not 
be released without the written permission of the Subject (or the Subject’s legal 
guardian), except as necessary for monitoring and auditing by the FDA or the 
IRB/IEC. 
 
The Investigator and all employees and co-workers involved with this study may 
not disclose or use for any purpose other than performance of the study any data, 
record, or other unpublished, confidential information disclosed to those 
individuals for the purpose of the study. Prior written agreement from the Sponsor 
or its designee must be obtained for the disclosure of any said confidential 
information to other parties. 
 
15.2 
Investigator Documentation 


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Prior to beginning the study, the Investigator will be asked to comply with ICH 
E6(R2) 8.2 and 21 CFR by providing the following essential documents, including 
but not limited to: 
 IRB/IEC approval 
 Original Investigator-signed Investigator agreement page of the protocol 
 IRB/IEC-approved informed consent, samples of site advertisements for 
recruitment for this study, and any other written information regarding 
this study that is to be provided to the Subject or legal guardian 
 
15.3 
Study Conduct 
 
The Investigator agrees that the study will be conducted according to the 
principles of ICH E6(R2). The Investigator will conduct all aspects of this study in 
accordance with all national, state, and local laws or regulations. Study 
information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of Subjects begins. 
 
15.4 
Adherence to Protocol 
 
The Investigator agrees to conduct the study as outlined in this protocol in 
accordance with ICH E6(R2) and all applicable guidelines and regulations. 
 
15.5 
Adverse Events and Study Report Requirements 
 
By participating in this study, the Investigator agrees to submit reports of AEs and 
SAEs according to the time line and method outlined in the protocol. In addition, 
the Investigator agrees to submit annual reports to the study site IRB/IEC as 
appropriate. 
 
15.6 
Investigator’s Final Report 
 
Upon completion of the study, the Investigator should provide the IRB/IEC with a 
summary of the study’s outcome and the regulatory authority(ies) with any 
reports required. 
 
16.0 
DATA HANDLING AND RECORD KEEPING 
 
16.1 
Completion of Case Report Forms 
 
The Investigator will be provided with detailed CRF completion guidelines that will 
identify the required data points to be collected, how to document them, and 
when the data should be documented. 


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It is the responsibility of the Investigator to maintain adequate and accurate CRFs 
to record (according to the CRF completion guidelines) all observations and other 
data pertinent to the clinical trial obtained during scheduled or unscheduled visits. 
All CRFs should be fully completed to ensure accurate data interpretation. 
 
16.2 
Archiving 
 
According to ICH-GCP, the documents which should be archived are ‘essential 
documents’ which individually and collectively permit the evaluation of the 
conduct of a study and the quality of the data produced. 
 
Source documentation must also be archived. This may include observations and 
source data contained in medical records (certified copies or originals are 
acceptable for archiving purposes), data collection forms or CRFs and research 
related records held in support departments. All hard copies of source documents 
must be retained. If electronic records of documents exist these must be backed 
up and retained with the hard copies. 
 
17.0 
FINANCING AND INSURANCE 
 
The costs necessary to perform the study will be the responsibility of the Investigator and 
Sponsor 
 
18.0 
PUBLICATION POLICY 
 
Study data may be considered for reporting at a scientific meeting or for publication in a 
scientific journal. In these cases, the Investigator will be responsible for these activities 
and will determine how the manuscript is written and edited, the number and order of 
authors, the publication to which it will be submitted, and other related issues. 
 
19.0 
REFERENCES 
 
1. Alvi et al. Protease Inhibitors and Cardiovascular Outcomes in Patients with HIV and 
Heart 
Failure. 
J 
Am 
Coll 
Cardiol. 
2018 
Jul 
31;72(5):518-530. 
doi: 
10.1016/j.jacc.2018.04.083. 
 
2. Lake JE et al. Risk factors for excess weight gain following switch to integrase 
inhibitor–basedART. Poster abstract 669. 
https://www.croiconference.org/sessions/risk-factors-excess-weight-gain-following- 
switch-integrase-inhibitor–based-art (abstract) 
https://www.croiconference.org/sites/default/files/posters- 


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2019/1430_Lake_0669.pdf (poster) 
http://www.croiwebcasts.org/p/2019croi/669 (webcast) 
 
3. Bourgi K et al. Greater weight gain among treatment-naive persons starting 
integrase inhibitors. Poster abstract 670. 
https://www.croiconference.org/sessions/greater-weight-gain-among-treatment- 
naive-persons-starting-integrase-inhibitors (abstract) 
https://www.croiconference.org/sites/default/files/posters- 
2019/1430_Bourgi_0670.pdf (poster) 
http://www.croiwebcasts.org/p/2019croi/670 (webcast) 
 
4. McComsey GA et al. Weight gain during treatment among 3,468 treatment- 
experienced adults with HIV. Poster abstract 671. 
https://www.croiconference.org/sessions/weight-gain-during-treatment-among- 
3468-treatment-experienced-adults-hiv (abstract) 
https://www.croiconference.org/sites/default/files/posters- 
2019/1430_McComsey_0671.pdf (poster) 
http://www.croiwebcasts.org/p/2019croi/671 (webcast) 
 
5. Palella FJ et al. Weight gain among virally suppressed persons who switch to InSTI- 
based ART. Poster abstract 674. 
https://www.croiconference.org/sessions/weight-gain-among-virally-suppressed- 
persons-who-switch-insti-based-art (abstract) 
https://www.croiconference.org/sites/default/files/posters- 
2019/1430_Palella_0674.pdf (poster) 
 
6. Bedimo R et al. Differential BMI changes following PI- and InSTI-based ART initiation 
by sex and race. Poster abstract 675. 
https://www.croiconference.org/sessions/differential-bmi-changes-following-pi- 
and-insti-based-art-initiation-sex-and-race (abstract) 
https://www.croiconference.org/sites/default/files/posters- 
2019/1430_Bedimo_0675.pdf (poster) 
 
7. Landovitz RJ et al. Cabotegravir is not associated with weight gain in HIV-negative 
individuals: HPTN 077. Oral abstract 34. 
https://www.croiconference.org/sessions/cabotegravir-not-associated-weight-gain- 
hiv-negative-individuals-hptn-077 (abstract) 
 
8. Hill A et al. Are new antiretroviral treatments increasing the risks of clinical obesity? 
Journal of Virus Eradication 2019;5: e45–e47. 


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http://viruseradication.com/journal- 
details/Are_new_antiretroviral_treatments_increasing_the_risks_of_clinical_obesity 
 
9. Hill AM, Mitchell N, Hughes S, Pozniak AL. Risks of cardiovascular or central nervous 
system adverse events and immune reconstitution inflammatory syndrome, for 
dolutegravir versus other antiretrovirals: meta-analysis of randomized trials. 
Curr Opin HIV AIDS. 2018 Mar;13(2):102-111. 
 
10. Sax PE et al. Weight Gain Following Initiation of Antiretroviral Therapy: Risk Factors 
in Randomized Comparative Clinical Trials 
Clinical Infectious Diseases, ciz999, https://doi.org/10.1093/cid/ciz999 


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APPENDICES 
 
Appendix 1 
Study Schedules of Events 
Appendix 2 
Investigator Signature Page 
Appendix 3 
Common Terminology Criteria for Adverse Events (CTCAE) 
Appendix 4 
Product Information for bictegravir/emtricitabine/tenofovir alafenamide 
(Biktarvy®) 
Appendix 5 
Product Information for doravirine (Pifeltro®) 
Appendix 6 
Pittsburgh Sleep Quality Index 
Appendix 7 
Work Productivity and Activity Impairment Questionnaire 


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APPENDIX 1: STUDY SCHEDULE OF EVENTS 
 
Schedule of Events: 
 
Evaluations 
Screening/ 
Baseline 
Day 28 (+/-14 days) Week 12 
(+/- 14 
days) 
Week 24
(+/- 14 
days) 
Week 36
(+/- 14 
days) 
Week 
48/EOS/Early 
Termination 
(+/- 14 days) 
Inclusion/exclusion criteria 
X
 
 
 
 
 
Demographya 
X 
 
 
 
 
 
HIV viral load 
X
X
X
X
X
X
CD4 count 
X (within 3 
months) 
 
 
 
 
X 
Height, Weight, BMIb 
X
X
X
X
X
X
Physical examination, including other signs
and symptoms 
X 
X 
X 
X 
X 
X 
Vital signsc 
X
X
X
X
X
X
Hematology (CBC 
with differential) 
X 
X 
X 
X 
X 
X 
Serum chemistry 
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
Blood sampling for PKd 
 
X
 
 
 
 
Adverse eventse 
X
X
X
X
X
X
Pittsburgh Sleep Quality Index 
X
 
 
 
 
X
WPAI Questionnaire 
X
 
 
 
 
X
Drug Treatment Switch 
X
 
 
 
 
 
a Demographic information consists of age, gender, race, year of HIV diagnosis and ethnicity 


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b Subject’s height must be recorded at Screening; weight should be recorded at every examination and body mass index (BMI) 
calculated. 
c Vital signs include pulse, systolic and diastolic blood pressure, respiratory rate, and body temperature. 
dPlasma samples for PK assessments will be collected before dosing at -0.5 hr (time 0) and at 0.5, 1, 2, 4, 6, 8, 12, and 24 
hours after dosing on day 28 (+/- 14 days) in the PK cohort.  Subjects may be asked to return for an unscheduled visit to 
test/retest PK samples if the initial data is found to be invalid 
 
e Adverse events will be assessed beginning at enrolment (date of signed informed consent) and up to last dose of study drug. 
Treatment-emergent AEs will be assessed during the dosing period. 


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APPENDIX 2: INVESTIGATOR SIGNATURE PAGE 
 
 
INVESTIGATOR STUDY ACKNOWLEDGEMENT / PROTOCOL SIGNATURE PAGE 
 
Investigator’s Statement: 
 
I have read and understand the foregoing clinical study protocol entitled, “An open label study 
evaluating the safety and efficacy of switching from rilpivirine/emtricitabine/tenofovir 
alafenamide in combination with dolutegravir, to bictegravir/emtricitabine/tenofovir 
alafenamide in combination with doravirine, in male HIV+ subjects > 45 years with multi-drug 
resistant virus and virologic suppression (documented with at least one viral load result < 50 
copies per mL) during the last 6 months on current therapy. Protocol No.: BETD-001. 
 
I understand and recognize its confidentiality and agree to conduct this study as described in the 
protocol, in compliance with Good Clinical Practices (GCP), designated standard operating 
procedures, all applicable regulations of the country in which the study is being conducted, and 
within the principles of the current version of the Declaration of Helsinki. 
 
 
 
 
 
Investigator’s Name (please print) 
 
Investigator’s Title 
Date (dd-mm-yyyy) 
 
Investigator’s Signature


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APPENDIX 3: COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) 
 
 
The United States of America (USA) Common Terminology Criteria for Adverse Events, version 
5.0 can be found online at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_ 
Reference_5x7.pdf 


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APPENDIX 4: DATA SHEET FOR BICTEGRAVIR/EMTRICITABINE/TENOFOVIR ALAFENAMIDE 
(BIKTARVY®) 
 
https://www.gilead.com/~/media/files/pdfs/medicines/hiv/biktarvy/biktarvy_pi.pdf 


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APPENDIX 5: DATA SHEET FOR DORAVIRINE (PIFELTRO ®) 
 
https://www.merck.com/product/usa/pi_circulars/p/pifeltro/pifeltro_pi.pdf 


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APPENDIX 6: PITTSBURGH SLEEP QUALITY INDEX 
 
https://www.opapc.com/uploads/documents/PSQI.pdf 


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APPENDIX 7: WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE 
 
http://oml.eular.org/sysModules/obxOML/docs/id_98/WPAI-GH_English_US_V2.pdf