Clinical trial NCT04665375
Conditions: Hiv Weight Gain
Keywords: weight gain HIV doravirine integrase inhibitor tenofovir alafenamide tenofovir disoproxil fumarate
Sponsor: University Health Network, Toronto
Start date: 2021-04-26; Completion date: 2024-03-31
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Weight gain with the integrase inhibitors and tenofovir alafenamide has been observed in observational cohorts and randomized controlled clinical trials. Although some risk factors have been identified, the cause is unknown and it remains to be determined if the changes are reversible. The weight gain is of concern to persons living with HIV. This pilot intervention study is designed to provide preliminary data on whether switching patients with weight gain on an INSTI-based regimen to a combination of doravirine/tenofovir disoproxil fumarate/lamivudine (DOR/3TC/TDF, an NNRTI-based regimen) for one year can slow down or even reverse weight gain. These data will then be used to inform the design and sample size of a larger switch study.

Detailed description:
Background and Importance: Lifelong antiretroviral treatment (ART) is recommended for all people living with HIV (PLWH) primarily with integrase strand inhibitor (INSTI)-based regimens. While weight gain following ART initiation was previously considered "return to health", recent studies have raised concerns of weight gain and increasing obesity in PLWH, most notably with INSTIs and possibly with tenofovir alafenamide (TAF), a preferred nucleoside backbone agent. The weight gain may be progressive and may increase cardiovascular risk. A critical unanswered question is whether weight gain and metabolic effects are permanent or reversible. This data is crucial to optimize ART therapy and health of PLWH.

Goal/Research Aims: No therapeutic alternatives are substantiated for ART-associated weight gain. Doravirine/lamivudine/tenofovir DF (DOR/3TC/TDF) is an attractive option to explore as it does not include an INSTI or TAF, is a well tolerated once daily single tablet, minimal drug interactions and has not been associated with significant weight gain to date. The investigators hypothesize that switching from an INSTI regimen to DOR/3TC/TDF will slow or reverse weight gain while maintaining viral suppression. Before embarking on a large randomized controlled study (RCT), the investigators propose this pilot study to determine the feasibility and acceptability and to obtain estimate measures of weight change to inform its design and sample size.

Methods: Open-label, exploratory pilot switch study. Patients who are virally suppressed on an INSTI regimen for \>1 year, without ART resistance, and have experienced significant weight gain will be approached to switch to DOR/3TC/TDF for 48 weeks. Weight, adherence, viral load, CD4, and other relevant labs will be measured every 3 months. A DXA body scan and body image questionnaires will be completed at baseline and 12 months. The anticipated sample size is 25 with an aim to recruit 50% male, 50% female.

The primary objective is to determine what proportion of clinic patients meet eligibility criteria, agree to participate, and complete the study. The secondary objective is to estimate the distribution of various weight-related outcomes while on DOR/3TC/TDF compared to previous INSTI regimens. Exploratory outcomes will address metabolic changes and body image impact.

Arms: arm 1: 100mg of doravirine (DOR), 300mg of lamivudine (3TC), and 300mg of tenofovir disoproxil fumarate (TDF)
Interventions: intervention 1: DOR/3TC/TDF
Intervention descriptions: intervention 1: switch antiretroviral regimen to doravirine/lamivudine/tenofovir disoproxil fumarate once daily for 1 year

Protocol documents:
Prot_SAP_000.pdf: 
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Study Title: 
Can the weight gain associated with use of integrase strand inhibitors be halted or reversed with 
a switch to doravirinE/lamivudine/TEnofovir DF (DeLiTE?) 
Protocol version: V 1.4 
Sponsor-Principal Investigator: Dr. Sharon Walmsley, University Health Network 
Funding:  Merck Canada Inc. 
 
Principal Investigator: 
Dr. Sharon Walmsley 
13EN room 214; 200 Elizabeth Street 
Toronto, Ontario, Canada, M5G2C4 
T: 416-340-5077 
F: 416-340-9105 
Email: sharon.walmsley@uhn.ca 
 
 
 


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GCP Statement 
This clinical study will be conducted in accordance with applicable Health Canada regulations, 
International Conference on Harmonisation (ICH) guidelines on current Good Clinical Practice 
(GCP), and the Declaration of Helsinki. 
 
Confidentiality Statement 
This clinical study protocol contains information which is of a confidential, trade-secret or 
proprietary nature. The protocol is for the use of Dr. Sharon Walmsley and her designated 
representatives participating in the investigational trial. It is not to be disclosed to any other 
person or party without the prior written approval of Dr. Sharon Walmsley 
 
 
 
 
 


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INVESTIGATOR AGREEMENT 
 
Protocol Title:  Can the weight gain associated with use of integrase strand inhibitors be halted 
or reversed with a switch to doravirinE/lamivudine/TEnofovir DF (DeLiTE? 
Protocol No.: version 1.4 
Date: October 19, 2021 
 
This clinical study will be conducted in accordance with applicable Health Canada, ICH guidelines 
on current GCP, and the Declaration of Helsinki. 
 
I confirm that I have read and understand this protocol and I agree to conduct this clinical study in 
accordance with the design and specific provisions of the protocol, with the exception of a change 
intended to eliminate an immediate hazard to participants. Any deviation from the study protocol 
will be documented in the case report form. 
 
I agree to promptly report to the applicable ethics boards any changes in the research activity and 
all unanticipated problems involving risks to human participants or others. Additionally, I will not 
make any changes in the research without prior ethics and sponsor approval, except where 
necessary to ensure the safety of study participants. 
 
 
 
 
 
 
 
 
Name  
Signature 
 
Date (dd-mmm-yyyy) 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS AND DEFINITIONS 
Acronym / Abbreviation 
Definition 
3TC 
AE 
ARV 
ASCVD 
AZT 
BMD 
BP 
cART 
CBC 
CrCl 
Lamivudine 
Adverse Event 
Antiretroviral 
Atherosclerotic cardiovascular disease 
Zidovudine  
Bone mineral density 
Blood pressure 
Combination antiretroviral therapy 
Combined blood count 
Creatinine Clearance 
DAIDS 
DM 
DOR 
DTG 
Division of Aids (table for grading severity of adverse events) 
Diabetes Mellitus 
Doravirine  
Dolutegravir 
DXA 
EACS 
EFV 
Dual Energy X-ray Absorptiometry 
European AIDS Clinical Society 
Efavirenz 
F/TAF or TAF/FTC 
FTC 
HATS 
HCV 
HIV 
INSTI 
LDL 
Tenofovir alafenamide – coformulated with Emtricitabine 
Emtricitabine 
HIV Adherence Treatment Scale 
Hepatitis C virus 
Human immunodeficiency virus 
Integrase strand inhibitor 
Low density lipoprotein 
NNRTI 
NRTI 
PI 
PLWH 
RAL 
Non-nucleoside reverse transcriptase inhibitor 
Nucleoside reverse transcriptase inhibitor 
Protease Inhibitor 
People living with HIV 
Raltegravir 
SAE 
TAF 
TDF 
 
 
Serious Adverse Event 
Tenofovir alafenamide 
Tenofovir disoproxil 
 


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Table of Contents 
 
1.0 
BACKGROUND AND SCIENTIFIC RATIONALE ......................................................... 8 
1.1 
Introduction ...................................................................................................................... 8 
1.2 
Study agent ....................................................................................................................... 9 
1.3  
Rationale for this Study .................................................................................................. 10 
1.4 
Potential risks and benefits to participants ..................................................................... 11 
2.0 
STUDY SYNOPSIS .......................................................................................................... 13 
3.0 
STUDY HYPOTHESIS ..................................................................................................... 13 
4.0 
STUDY OBJECTIVES ...................................................................................................... 13 
4.1 
Primary objective: .......................................................................................................... 13 
4.2.  Secondary Objective ...................................................................................................... 14 
5.0 
STUDY DESIGN............................................................................................................... 14 
5.1 
Study population: ........................................................................................................... 14 
5.2 
Intervention: ................................................................................................................... 14 
5.3 
Primary endpoint: ........................................................................................................... 14 
5.4 
Secondary endpoints ...................................................................................................... 14 
5.5 
Justification of Endpoints: .............................................................................................. 15 
6.0 
ELIGIBILITY CRITERIA ................................................................................................. 16 
6.1 
Inclusion Criteria ............................................................................................................ 16 
6.2 
Exclusion Criteria ........................................................................................................... 17 
7.0 
STUDY EVALUATIONS AND PROCEDURES ............................................................ 17 
7.1 
Clinical Evaluations ....................................................................................................... 17 
7.2 
Participant Identification Number Assignment .............................................................. 18 
7.3 
Imaging ........................................................................................................................... 18 
7.4 
Laboratory Evaluations .................................................................................................. 18 
7.5 
Stored Research Samples ............................................................................................... 18 
7.6 
Adherence ....................................................................................................................... 19 
7.7 
Questionnaires  ............................................................................................................... 19 
8.0 
STUDY VISITS ................................................................................................................. 19 
8.1 
Screening visit: ............................................................................................................... 19 


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8.2 
Baseline Visit for Participants ........................................................................................ 19 
8.3 
Follow-up Visits for Participants ................................................................................... 20 
8.4 
Final Study Visit (Week 48 +/- 14 days) ....................................................................... 21 
8.5 
Early Termination .......................................................................................................... 21 
8.6 
Re-contact of Participants after Study Termination ....................................................... 21 
8.7  
Schedule of Procedures ...................................................................................................... 21 
9.0. STUDY DRUG ...................................................................................................................... 21 
9.1 Study Drug Accountability .................................................................................................. 22 
10. 
EARLY TERMINATION ................................................................................................. 22 
11. 
ASSESSMENT OF SAFETY ............................................................................................ 22 
11.1 Adverse Events (AEs) .................................................................................................... 22 
11.2 Recording/ Documentation of AEs ................................................................................ 23 
11.3 Serious Adverse Events (SAEs) ..................................................................................... 23 
11.4 AE/SAE Grading, Relationship Assignment and Reporting Procedures ....................... 24 
11.4.1  AE/SAE Grading .................................................................................................... 24 
11.4.2  Relationship Assessment ........................................................................................ 24 
11.4.3 
 SAE Reporting Procedures .................................................................................... 25 
11.5 AEs/SAEs monitoring .................................................................................................... 25 
11.6 Toxicities/ Adverse Event Management ........................................................................ 26 
11.7 Management of HIV Virologic failure. .......................................................................... 26 
11.8 Pregnancy Management ................................................................................................. 26 
11.9 Action to be taken if pregnancy occurs .......................................................................... 26 
12. 
TRIAL MANAGEMENT .................................................................................................. 26 
12.1 Local Coordination ......................................................................................................... 26 
13.0 DETAILS OF STATISTICAL ANALYSIS ...................................................................... 27 
13.1. 
Sample size considerations ......................................................................................... 27 
13.2 Primary analysis: ............................................................................................................ 27 
13.3  
Secondary analyses: .................................................................................................... 27 
14.0 QUALITY CONTROL AND QUALITY ASSURANCE ................................................. 28 
15. 
ETHICS AND PROTECTION OF HUMAN PARTICIPANTS....................................... 28 
15.1 ICH Guidance E6: .......................................................................................................... 28 
15.2 Research Ethics Board/ Institutional Review Board ...................................................... 28 


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15.3 Informed consent process ............................................................................................... 28 
15.4 Subject confidentiality .................................................................................................... 29 
15.5 Early Termination of the Protocol .................................................................................. 29 
15.6 Record Retention ............................................................................................................ 29 
16.0 PROTOCOL DEVIATIONS ............................................................................................. 29 
17.0 STUDY CONDUCT AND MONITORING ..................................................................... 30 
18.0 DATA MANAGEMENT RESPONSIBILITIES .............................................................. 30 
19.0 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA DOCUMENTS ........... 30 
20. 
DISCLOSURE AND PUBLICATION POLICY .............................................................. 30 
21. 
STUDY TEAM ROLES AND RESPONSIBILITIES ...................................................... 30 
22. REFERENCES ....................................................................................................................... 32 
 
 
 


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1.0 
BACKGROUND AND SCIENTIFIC RATIONALE 
1.1 
Introduction 
Advances in the field of HIV therapeutics have led to the universal recommendation of 
combination antiretroviral therapy (cART) in the treatment of people living with HIV (PLWH) 
(1). Effective utilization of cART has led to dramatic reductions in HIV-associated morbidity and 
mortality, improved quality of life, and declining risk of HIV transmission (1). Current guidelines 
recommend that most individuals with HIV, regardless of CD4 cell count, receive initial therapy 
with an integrase strand inhibitor (INSTI) based regimen (1). As the HIV therapeutic arsenal has 
expanded, and efficacy increased to >90% for antiretroviral naïve patients, there has been a 
renewed focus on differentiating therapy based on factors such as off-target effects and toxicities, 
convenience, and potential for drug interactions (1). One emerging differentiating factor appears 
to be weight gain, with early trials implicating an integrase class effect (2). 
Is weight gain the result of antiretroviral use?  
Whether weight gain is truly consequent to antiretroviral medication and if so, the mechanism for 
its development is under ongoing investigation. Some instances of weight gain can be attributed 
to a “return to health” effect amongst those who are underweight with higher viral burdens upon 
initiating therapy (2, 3). However, in those who are normal or overweight prior to initiating 
therapy, weight gain above a reasonable “return to health” threshold has been associated with an 
increase in metabolic and cardiovascular disease risk (2, 3). There is also some suggestion that 
there may be genetic, racial, or other factors that contribute to its development. For example, in 
the ADVANCE study the greatest weight gains were observed in African black females (4). 
Existing clinical trials vary widely in terms of sample size, demographics, interventions assessed, 
outcome measures, and follow-up periods (4-12). Integrase inhibitors are the most commonly 
implicated drug class, and the most clinically relevant due to their first line status (5). However, 
protease inhibitors (PIs) and more recently, tenofovir alafenamide (TAF) have also been 
implicated in causing clinically significant weight gain (2, 5, 6, 10). There may also be an 
interaction effect between the classes. In the recently published ADVANCE trial, triple therapy 
with dolutegravir (DTG) and emtricitabine (FTC) combined with either TAF or tenofovir 
disoproxil fumarate (TDF) was compared to the local standard of care regimen of 
efavirenz/FTC/TDF in a South African population (4). There was significantly more weight gain 
with DTG-containing regimens, especially in combination with TAF (4).  
Existing studies are difficult to compare. Outcome measures that have been utilized to assess 
weight gain include, but are not limited to, absolute and percent weight gain, BMI changes, and 
DXA-body composition (4-12). In studies that have employed DXA-body composition scans to 
assess the nature of weight gain, there have been mixed results (4, 7, 8, 12). In the recently 
published ADVANCE trial, DXA-body composition scans revealed that males gained mainly lean 
mass in both the trunk and limbs while females gained significantly more weight overall and a 
higher proportion of fat vs lean mass in both the trunk and limbs (4).  A table summarizing studies 
of INSTI and TAF-associated weight gain appears in Appendix A. 
Is this different than lipodystrophy?  


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With the introduction of the protease inhibitors, particularly indinavir, in the mid-1990s, a 
condition “lipodystrophy” was coined based on changes in body habitus that were observed, 
including central hypertrophy with peripheral atrophy. The central hypertrophy included increases 
in centripetal fat, often associated with the development of a buffalo hump. The body habitus 
changes were also associated with metabolic changes including hyperlipidemia, insulin resistance, 
and metabolic syndrome. The protease inhibitors were implicated but the exact mechanism never 
elucidated. 
With the introduction of the integrase inhibitors, comparator studies suggested these body habitus 
and metabolic changes were less common. The PROGRESS trial found significant increases in 
limb fat distribution but nonsignificant changes in trunk fat when comparing RAL to TDF/FTC 
(7). In contrast, the STARTMRK trial compared raltegravir (RAL) vs efavirenz (EFV) and found 
that mean overall fat gain for both trunk and limbs was 19% vs 31%, with the majority of patients 
in both groups gaining moderately more central fat than limb fat (8). 
Trajectory/pattern of weight gain  
In contrast to a number of ART-related adverse effects that generally occur during the first year of 
therapy then decline (i.e. decreased BMD with TDF); weight gain appears to follow a continuous 
upward trajectory (9). A substudy of the 96-week ADVANCE trial found that body weight gains 
with DTG/TAF/FTC did not plateau at 96 weeks but rather appeared to be progressively rising (9). 
While this continuous pattern of weight gain may in part be explained by background weight gain 
of 0.5-1kg per year associated with normal aging, the ADVANCE study found mean weight gain 
of 6.3kg in females taking DTG/TAF/FTC at just 48 weeks (4, 9). By week 96, 51% of women on 
this regimen had experienced a ≥10% body weight increase (4, 9).  Overall, aggregate data from 
existing trials suggests that weight gain is a class effect and that the nature of weight gain and 
metabolic changes is progressive throughout therapy (4-12).   
Metabolic effects 
Metabolic impacts of weight changes have been assessed through the measures of new-onset 
diabetes mellitus (DM), HbA1c, lipid values, and atherosclerotic cardiovascular disease (ASCVD) 
risk scores (10-12). Rebeiro et al. (2019) investigated ART effect on DM and found that INSTIs, 
namely raltegravir (RAL), and PIs are associated with an increased risk of incident DM compared 
to NNRTIs (10). Schafer et al. (2019) looked at virologically-suppressed PLWH switching from 
TDF to TAF as part of combination therapy and found significant increases in total cholesterol, 
LDL, and ASCVD risk scores (11). Blood pressure effects were investigated by KerchBerger et 
al. (2019), who found that there was a significant rise in systolic and diastolic blood pressure in 
PLWH who were switched to or received add-on therapy with an INSTI (12). Overall, numerous 
studies have shown that ART-related weight gain may impact metabolic parameters that have been 
implicated in increased risk of morbidity and mortality. This represents an area of growing focus 
in a cohort of PLWH that are living longer than ever before.      
1.2 
Study agent   
The agent for this study is Delstrigo, a combination product that contains 100mg of doravirine 
(DOR), 300mg of lamivudine (3TC), and 300mg of tenofovir disoproxil fumarate (TDF). 


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Doravirine (DOR) is a novel NNRTI that has established efficacy in treatment-naïve adults with 
HIV-1 (13,14). In addition, as demonstrated by the DRIVE-SHIFT trial, doravirine as part of a 
fixed dose combination tablet with 3TC and TDF (Delstrigo) has demonstrated noninferiority to a 
regimen of 2 NRTIs plus an NNRTI, boosted PI, or boosted ETG (13). Delstrigo contains TDF 
and has the advantage of easy administration owing to once-daily dosing, no evidence of CYP 
enzyme induction/inhibition, and no food, gastric pH, or chelation interactions (14,15). Within the 
above study, Delstrigo was shown to have a favorable safety profile over 48 weeks of follow-up 
and was associated with a substantially significant decrease in fasting lipid levels (including total 
cholesterol, LDL, and triglycerides) compared to baseline regimens that included a PI (13).  
Doravirine-based regimens are now included in the European AIDS Clinical Society (EACS) 
treatment guidelines for antiretroviral-naïve adults, with no restrictions in terms of baseline CD4 
or viral load (https://eacs.sanfordguide.com/art/initial-regimens-arv-naive-adults).   Doravirine-
based combinations are also classified by the U.S. Department of Health and Human Services as 
a 
recommended 
initial 
regimen 
in 
certain 
clinical 
situations.( 
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/11/what-to-start) 
 
1.3  
Rationale for this Study 
A primary question that remains unaddressed by existing trials is whether weight gain and 
metabolic effects are permanent or reversible. Furthermore, the significance of these effects as 
they apply to medication adherence, quality of life, and clinical outcomes has yet to be assessed. 
Trials suggest that weight gain may be progressive throughout therapy and may increase risk of 
cardiovascular events in an aging HIV+ cohort by increasing risk factors (i.e. elevated lipids, BP, 
and blood glucose). The trajectory of weight gain has yet to be quantified and no therapeutic 
alternatives have been substantiated in those who experience extreme weight gain and 
associated morbidity. While all clinicians may concede that extreme weight gain is an undesirable 
adverse effect of therapy, without evidence to suggest that it impacts clinical outcomes or quality 
of life for patients, there may be hesitation to switch from otherwise effective, stable therapy. This 
hesitation may be compounded by the fact that there is no good evidence to suggest that any 
particular alternative agent may successfully change or reverse the trajectory of drug-associated 
weight gain. 
A key benefit of Delstrigo for the purposes of investigating (and potentially slowing/reversing) 
antiretroviral-associated weight gain in PLWH is that it excludes drug classes previously 
implicated in causing weight gain, namely INSTIs, PIs, and TAF. In a recent pooled analysis of 3 
doravirine studies, the proportion of participants with ≥10% increase in body weight was not 
significantly different in the doravirine group as compared to those in the darunavir and efavirenz 
arms (16). Median changes in weight were also not significantly different among the groups, with 
an increase of 1.5kg in DOR, 0.7kg in DRV, and 1.0 in EFV through 96 weeks (16).       
Although there could be hesitation with switching to a TDF-containing regimen due to concerns 
of increased nephrotoxicity compared to TAF, we argue that this is low risk in light of the meta-
analysis by Hill et al. (2018). In this analysis of 11 randomized head-to-head studies comparing 
TDF versus TAF, it was found that risks associated with TDF are higher only when TDF is used 


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in a boosted regimen including ritonavir or cobicistat (14). No significant differences in HIV RNA 
suppression rates or clinical safety endpoints were demonstrated between unboosted TAF and 
unboosted TDF (14). 
1.4 
Potential risks and benefits to participants 
In a study that compared Delstrigo to efavirenz/emtricitabine/tenofovir DF over the course of 96 
weeks, the most frequent side effects (>1%) shown in the DRIVE-AHEAD trial among 364 
participants who took Delstrigo were: 
• Nausea (5%) 
• Diarrhea (3%) 
• Vomiting (2%) 
• Tiredness (4%) 
• Dizziness (7%) 
• Headache (4%) 
• Drowsiness (3%) 
• Abnormal dreams (5%) 
• Insomnia (4%) 
• Nightmares (2%) 
• Rash (2%) 
Some other rare but possible side effects with Delstrigo include: 
• Bone loss 
• New onset or worsening kidney impairment (and Fanconi syndrome) 
• Lactic acidosis 
• Severe hepatomegaly with steatosis  
• Pure red cell aplasia 
• Severe acute exacerbation of hepatitis B in patients co-infected with HIV-1 and HBV 
• Immune reconstitution inflammatory syndrome  
Immune reconstitution inflammatory syndrome can occur during the initial phase of combined 
antiretroviral treatment. Patients may develop an inflammatory response to indolent or residual 
opportunistic infections. Patients may necessitate further evaluation and treatment. As this is a 
switch study, patients will not be in the initial phase of cART. Therefore this reaction is unlikely. 
 
Lamivudine (3TC) 
In clinical studies of lamivudine in combination with zidovudine and efavirenz (EFV) in patients 
with HIV-1, the most frequent adverse events reported include: 
• Malaise and fatigue 
• Headache 
• Abdominal 
discomfort 
and pain 
• Nasal 
signs 
and 
symptoms 


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• Viral respiratory infection 
• Dizziness 
• Sleep disorders 
• Musculoskeletal pain 
• Myalgia 
• Diarrhea  
• Cough  
• Skin Rashes 
• Depressive disorders 
• Nausea and vomiting 
• Throat and tonsil 
discomfort and pain 
• Fever or chills 
• Arthralgia 
 
Other common (1-10%) adverse effects from lamivudine, zidovudine and efavirenz treatment 
include: 
dyspepsia, 
hyposalivation, 
oral 
ulceration, 
muscle 
pain, 
muscle 
atrophy/weakness/tiredness, mood disorders, taste disturbances, sexual function disturbances, 
temperature regulation disturbances, sweating, rash, and pruritus.  
 
Tenofovir DF (TDF, Viread®) 
Tenofovir DF has been studied in more than 12,000 HIV-infected adults for as long as 480 weeks 
in some patients. Common potential side effects identified in patients who received at least 
one dose of tenofovir DF 300 mg include diarrhea, nausea, vomiting, flatulence (intestinal gas), 
and dizziness.  Those side effects were often mild or moderate in severity, and did not lead to 
discontinuation of tenofovir DF.33  
 
In addition to side effects reported from clinical trials the following side effects have also been 
identified after tenofovir DF was approved by the FDA and Health Canada in HIV-infected 
patients treated with combination therapy that has included tenofovir DF and other anti-HIV drugs. 
Because post marketing (after regulatory licensing) reactions are reported voluntarily from a 
patient population of uncertain size, it is not always possible to reliably estimate how frequently 
these side effects occurred, or establish a causal relationship to tenofovir DF. The side effects 
which have been reported with tenofovir DF when taken with other anti-HIV drugs include:   
• allergic reaction  
• rash 
• abdominal pain 
• pancreatitis  
• shortness of breath 
• weakness 
• abnormalities of hepatic (liver) 
function 
and 
hepatitis 
(inflammation of liver). 
 
Cases of lactic acidosis, hepatosteatosis, including fatal cases, were reported in HIV-infected 
patients treated with anti-retroviral agents similar to tenofovir DF. The symptoms of lactic acidosis 
include weakness, nausea, vomiting, and unexpected and uncommon abdominal pain.  
 
Symptoms of liver problems include: 
• yellowing of the skin 
or whites of the eyes 
• light colored bowel 
movements 
• loss of appetite 
• dark urine 
• nausea 
• lower abdominal pain 
 
Cases of kidney damage have been reported in patients taking tenofovir DF who already have 
atherosclerosis, or specific kidney disease, and patients who, while receiving tenofovir DF, were 
also taking medications that may cause damage to the kidneys. Kidney damage has also been 
reported in patients without any of these factors.   In addition, continuous or sudden kidney failure, 
abnormal kidney function, inflammation of the kidneys, protein in the urine, excessive urination, 


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nephrogenic diabetes insipidus, and increased creatinine have also been reported in patients taking 
tenofovir DF. 
Bone toxicity, including a decrease in bone mineral density was seen in animals following 
treatment with tenofovir DF. Decreases in bone mineral density have been seen in humans. The 
risk of bone fractures associated with these types of changes is unknown. 
Because these events have been reported voluntarily from a population of unknown size, estimates 
of frequency cannot be made. 
Allergic Reaction Risks 
As with taking any drug, there is a risk of allergic reaction.  
Blood Draws 
Drawing blood from a vein may cause local pain, bruising, occasional light-headedness, fainting, 
and very rarely, infection at the site of the blood draw. 
DXA 
Changes in body fat composition have been observed in HIV-infected patients taking certain 
antiretrovirals. An X-Ray called dual energy X-ray absorptiometry, or a DXA scan, will be 
performed on the abdomen to measure changes in body fat. The radiation exposure is lower than 
with a chest x-ray. The DXA scans are considered, in general, less harmful than a standard x-ray.31 
A DXA scan usually takes about 30 minutes. 
2.0 
STUDY SYNOPSIS 
This pilot intervention study is designed to provide preliminary data on whether switching patients 
with weight gain on an INSTI-based regimen to a combination of doravirine/tenofovir disoproxil 
fumarate/lamivudine (DOR/3TC/TDF, an NNRTI-based regimen) for one year can slow down or 
even reverse weight gain.  Combined these data will then be used to inform the design and sample 
size of a larger switch study. This study will be conducted at the University Health Network 
Toronto General Immunodeficiency Clinic.  
3.0 
STUDY HYPOTHESIS  
We hypothesize that switching from an INSTI-containing regimen to Delstrigo will stabilize or 
even reverse the trajectory of weight gain in virally-suppressed PLWH. 
4.0 
STUDY OBJECTIVES 
4.1 
Primary objective:  
To determine how many active patients in our clinic who have gained ≥10% body weight on a 
current INSTI-containing regimen would be eligible for our proposed switch study to 
DOR/TDF/3TC. We will determine how many of those approached accept enrollment and 
complete the protocol.  


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4.2.  
Secondary Objectives   
To determine changes in absolute weight, weight trajectory, BMI and waist circumference after 1 
year following regimen switch. To determine nature of weight gain (lean vs fat mass), impact of 
weight gain on body image and medication adherence, and impact of weight gain on fasting 
glucose, insulin resistance (HOMA), and lipid values.  To determine efficacy, safety, and 
tolerability of DOR/TDF/3TC as a switch strategy in virally suppressed patients who have gained 
≥10% body weight on a current INSTI-containing regimen. 
5.0 
STUDY DESIGN 
This study is an open-label, exploratory switch study from INSTI-containing regimens to 
DOR/TDF/3TC.  
5.1 
Study population:   
Participants will be selected from the patient population of the Toronto General Hospital 
Immunodeficiency Clinic. The charts of active patients currently on INSTI-containing regimens 
and experiencing a ≥10% weight gain identified will be further reviewed to determine the 
proportion that meet the remainder of the eligibility criteria for the intervention study.  A current 
version of the consent form is included in Appendix B.  
5.2 
Intervention: 
Switch from current INSTI based ARV to Delstrigo (doravirine, 3TC, TDF) for 12 months. 
5.3 
Primary endpoints:  
1. 
Identify number of active patients in our clinic who meet eligibility criteria, and of 
those approached, how many accepted enrollment and completed the study protocol.   
2. 
Identify reasons for study ineligibility/study refusal among clinic patients on INSTI-
containing regimen who have experienced weight gain. 
3. 
Identify factors associated with early study discontinuation. 
5.4 
Secondary endpoints  
1. To determine the change in absolute weight, relative weight change per year (i.e. weight 
trajectory), waist circumference, and BMI category from baseline to one year following 
the switch from the INSTI-containing regimen to DOR/TDF/3TC. 
2. To determine the proportion of participants who maintain viral suppression (HIV RNA < 
50 copies/ml) after a switch to DOR/TDF/3TC. 
3. To assess safety and tolerability of the DOR/TDF/3TC combination. 
5.5  
Exploratory endpoints  
To determine the impact from baseline to one year following the switch from the INSTI-
containing regimen to DOR/TDF/3TC on DXA body scans, body image questionnaires, fasting 
glucose, insulin resistance (HOMA), and lipid values.  
 


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5.6 
Justification of endpoints: 
 
Absolute weight, BMI, waist circumference, metabolic effects: 
Patients who experience weight gain while on an INSTI-based regimen have generally shown an 
increasing and progressive increase in weight, with some studies showing increases up to 96 weeks 
with no plateau (9). Absolute weight change over the course of the trial will be compared to weight 
change from baseline while on the INSTI-based regimen to examine if the patient’s rate of weight 
gain is altered. 
BMI category increases are significantly associated with cardiovascular mortality. A shift to a 
lower BMI category would demonstrate a change in overall health and cardiovascular risk in these 
patients who have been put at an increased risk due to their ART.  
Measurement of waist circumference is recommended as an important vital sign in clinical 
practice, and provides additional information for assessment and management of cardiometabolic 
risk associated with increased adiposity in adults. 
The metabolic effects of ART-related weight gain include increased lipid values, atherosclerotic 
cardiovascular disease (ASCVD) risk scores, blood pressure, incident diabetes mellitus, and 
hemoglobin A1c values (10-12). These metabolic parameters are associated with increased risk of 
morbidity and mortality. 
Use of DXA body composition scan: 
The whole-body DXA scan allows for rapid and non-invasive assessment of body composition—
including fat mass, lean mass, and bone mineral mass—with relatively low radiation exposure 
(28). DXA body scans have been used in numerous studies investigating ART-related weight gain 
in PLWH in order to quantify the nature of the weight gained (4, 7, 8). This information is vital to 
determining clinical relevance as raw changes in weight do not directly translate into increased 
risk of adverse clinical outcomes (i.e. diabetes, CVD) (28, 29).  Srikanthan et al. (2016) performed 
DXA body scans of 6,541 participants with CVD (defined by confirmation of coronary artery 
disease, cerebrovascular disease, hypertension, or congestive heart failure) to determine how body 
composition and CVD might be linked. In assessing both cardiovascular mortality outcomes and 
death from natural causes, they found that risk was significantly lower in participants with a high 
muscle/low fat composition as compared to those with a low muscle/low fat composition (29). 
Across the board, a higher proportion of lean mass was associated with lower risk of morbidity 
and mortality, even in those considered “overweight” or “obese” according to their BMI (29). If 
Delstrigo is able to change or reverse the trajectory of weight gain in PLWH, it will be valuable to 
assess change in body composition and how it may ultimately impact clinical outcomes. 
Use of body image questionnaires: 
In order to obtain a complete picture of ART-related weight gain in PLWH, impact on quality of 
life must be considered. While the degree and nature of weight gain may impact clinical outcomes, 
it may also have a significant bearing on patient satisfaction with therapy. Few studies looking at 


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ART-related weight gain have assessed self-reported weight gain and none have assessed impact 
on body image, self-esteem, and overall quality of life. Bhagwat et al. (2018) used a subjective 
measure of self-reported abdominal change (“gained a lot”/“gained some”/“no change or lost in 
size”) in addition to objective measures of weight gain (i.e. waist circumference) in an effort to 
add context to raw weight gain data (30). In a similar vein, the FRAM study provided participants 
with a self-administered questionnaire on body fat changes  to compare self-perceived changes 
with those identified by research associates upon examination (31).  Since this was originally 
applied to investigation of ART-associated “lipodystrophy” in the early 2000’s, we will adapt it to 
be relevant to modern concerns of fat change in the context of significant weight gain with 
implicated ARTs. Assessing how self-reported weight gain influences factors related to quality of 
life is complicated by the lack of body image questionnaires that have been validated for use in 
HIV positive populations. However, the body weight, image, and self-esteem (B-WISE) evaluation 
questionnaire has been validated for the assessment of weight gain associated with psychotropic 
drug use (32). This 12-item, self-administered questionnaire can be applied for our purposes to 
obtain a more holistic picture of the impact of weight gain in PLWH. It may also be of benefit for 
monitoring the impact of switching to Delstrigo to see if any potential effect on trajectory of weight 
gain may also influence participant body image and self-esteem.  Both questionnaires will be short 
(Appendix D). 
6.0 
ELIGIBILITY CRITERIA 
6.1 
Inclusion Criteria – all criteria must be met 
1. 
Age 18 years or older 
2. 
Documented HIV-1 infection  by means of any one of the following: 
i. Documentation of HIV diagnosis in the medical record by a licensed 
health care provider;  
 
ii. OR HIV-1 RNA detection by a licensed HIV-1 RNA assay 
demonstrating >1000 RNA copies/mL; 
 
iii. OR any licensed HIV screening antibody and/or HIV antibody/antigen 
combination assay confirmed by a second licensed HIV assay such as a 
HIV-1 Western blot confirmation or HIV rapid Multispot antibody 
differentiation assay. 
 
3. 
On current Integrase Strand Transfer Inhibitor (INSTI) based regimen for at least 1 year 
and less than 5 years prior to screening 
4. 
Significant weight gain since initiation of the current INSTI-based regimen (>10% of 
baseline body weight) 
5. 
Viral load of <200 copies/mL for > 6 consecutive months prior to screening (single viral 
blips <200 copies/mL accepted if re-suppressed) 
6. 
Documentation of weight, glycemia, cholesterol, and blood pressure (BP) history within 
the last year. 


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7. 
Signed Informed Consent Form (Appendix B) and willing to comply with the protocol.  
8. 
Using proper contraception if of child bearing age and potential. 
 
6.2 
Exclusion Criteria - if any are present the participant cannot be included  
1. 
Pregnancy or desire to become pregnant within the next year 
2. 
Failure to use adequate contraception during the study if of child-bearing potential. 
3. 
Any underlying documented ART resistance to doravirine, tenofovir disoproxil 
fumarate, or lamivudine 
4. 
Prior virologic failure 
5. 
Concomitant drugs that interact with doravirine 
6. 
Initiated on concomitant drugs known to cause weight gain within the last 6 months 
(i.e. antidepressants and antipsychotics) 
7. 
Concomitant drugs known to cause nephrotoxicity 
8. 
History of renal toxicity or renal events while on TDF therapy. 
9. 
Creatinine clearance (CrCL) < 50 mL/min 
10. 
Inability to read/understand English 
7.0 
STUDY EVALUATIONS AND PROCEDURES 
7.1 
Study Eligibility and Participation 
A screening log and enrollment log will be used to record all subjects screened for 
eligibility.  Information recorded will include Subject ID, date of screening, eligibility for 
enrollment.  Of those eligible who consent to enrollment, the date of consent and version 
of the Informed Consent Form will be recorded.  Reasons for ineligibility or declining to 
participate in the study will be recorded.  The screening log will not contain any 
identifying information.  Subjects will be tracked separately on logs which are only 
accessed by the research coordinator and the principle investigator. 
7.2 
Clinical Evaluations 
Once a candidate for screening has been identified, study details will be carefully discussed 
with the potential participant. The participant will be asked to read and sign the approved 
informed consent form (Appendix B) prior to any assessments being performed. 
Medical history, documented HIV test results, and demographic information will be 
obtained at the screening visit. Data will be collected on age, race, HIV risk factor, smoking 
history, diet, exercise habits (Appendix K), illicit drug use, alcohol, steroid use, ARV 
history, past medical illness, medications, weight, and body mass index. Weight and waist 
circumference will be measured according to protocols defined in Appendices F and G, 
respectively. 
Routine investigations will include viral load, CD4, CD8, haematology, biochemistry, 
lipids, endocrinology, renal monitoring. Hepatitis B and C status will be recorded. 


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A complete physical exam, including vital signs will also be performed at the screening 
visit.  A brief targeted physical exam, including vital signs, will be performed at subsequent 
visits. Information pertaining to medication review and adverse events will be collected as 
indicated in Appendix C. 
A complete history of antiretroviral therapy including time of starting ART and type of 
drugs will be recorded. While on the study, ART switching, adherence to ART (Appendix 
E) or stopping ART for any reasons will also be documented. 
7.3 
Participant Identification Number Assignment 
Participant Identification (ID) numbers will be assigned sequentially to each participant 
who is eligible to participate in the study. Participants who are not eligible for the study 
will not be assigned a Participant ID Number. The Participant ID Number will consist of a 
three digit number according to chronological order of entry. Details for assigning 
Participant ID Numbers will be provided in the Operations Manual. Log(s) should be 
completed to capture all participants who have consented and who have been assigned a 
participant identification number. If a patient discontinues from the study the Participant 
ID Number will not be reused. 
The Participant ID Numbers will be used for identification of participants in the source 
documentation, CRFs, and laboratory samples. This will ensure that participant data and 
laboratory samples will be identified and tracked. 
7.4 
Imaging 
Participants will complete DXA scans at the UHN site. 
7.5 
Laboratory Evaluations  
Blood samples will be obtained for clinical laboratory evaluations on the days specified in 
Appendix C. Routine investigations will include HIV viral load, CD4 cell counts, complete 
blood count (CBC) with differential and measurements of hepatic (AST, ALT, ALP, GGT, 
bilirubin, albumin) and renal function (creatinine, GFR, urinalysis, urine albumin, Ur 
albumin/Cr, and Ur Protein/cr), urine and serum phosphate), calcium, fasting glucose, 
hemoglobin A1c, and lipid profiles (triglyceride, LDL, HDL, TC/HDL). Plasma HIV RNA 
levels will be measured at local laboratories with a lower limit of detection as per current 
assays. (This may be < 50/ml, < 40/ml or viral load not detected). Clinical laboratory 
evaluations for hematology, biochemistry, CD4/CD8, viral load and serology will be 
performed at the UHN laboratory.  
7.6 
Stored Research Samples 
Blood samples will be aliquoted, frozen and stored in order to perform biomarker testing 
at a later date. As this field is rapidly evolving, not all tests are currently known or 
developed but the frozen samples will be used only for HIV research purposes and testing 
related to this study. The samples will not be made available to any commercial enterprise. 
Stored samples will be identified only by a code number and will be destroyed after 10 


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years. A separate consent form for the collection and storage of these samples will be 
obtained. 
7.7 
Adherence  
For self-reports of adherence will use the Visual Analogue Scale44 (VAS last week and/or 
last month) which measures item ratings by participants in percentile terms from 0 to 100% 
and using a descriptor, for subjective perception of adherence in the last day, week, two 
weeks, and month (Appendix E). We will corroborate self-reported measure with objective 
outcome measurements such as returned pill counts. 
7.8 
Body Image Questionnaires (Appendix D) 
• Body Weight, Image, and Self-Esteem (B-WISE) evaluation questionnaire 
• Adjusted questionnaire from the FRAM study 
8.0 
STUDY VISITS 
8.1 
Screening visit:  
The screening visit is anticipated to require 1-2 hours of the participant’s time. 
During this visit the following will take place: 
• Informed Consent 
• Assign Participant ID Number 
• Demographic Information 
• Medical History 
• Physical Exam 
• Vital Signs including height, weight and determination of BMI 
• HIV Viral load (within 1 month of screening date) 
• CD4 and CD8 levels 
• Serum Pregnancy test 
• Hepatitis B and C (only if not previously tested) 
• Hematology and biochemistry: CBC with differential, liver profile (AST, ALT, serum 
creatinine, Urinalysis, GFR, Urine albumin/creatinine, urine protein/creatinine), lipid 
profile (within 1 month of screening date) 
• Medication Review 
• Review of Eligibility Criteria 
• DXA scan will be scheduled before baseline visit. (DXA scan should be completed prior 
to Baseline Visit). 
8.2 
Baseline Visit for Participants  
Day 1- Week 0 (no more than 30 days after screening visit date) 
This visit must occur within 30 days of the screening visit. (Note: If baseline visit is within 
2 weeks of screening lab work, then available screening lab results may be used and 
duplicate lab work need not be recollected).  This visit is anticipated to require 1 hour of 


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the participant’s time. A baseline visit should be scheduled if the eligibility criteria met, at 
which the following events will take place: 
• Confirmation that eligibility criteria have been met 
• Confirm DXA Scan has been completed.  
• Urine Pregnancy test (if premenopausal) and FSH if postmenopausal 
• Targeted Physical Exam including waist circumference 
• Vital Signs 
• Diet & exercise habits over the previous 3 months (Appendix K) 
• Framingham Cardiovascular Risk Score 
• Hematology and biochemistry: CBC with differential and liver profile (AST, ALT), 
serum creatinine, calcium, phosphate, Urinalysis, GFR, Urine albumin/creatinine, urine 
protein/creatinine, lipids- cholesterol, LDL, HDL, TG, fasting glucose, hemoglobin 
A1c) 
• CD4/CD8 
• HIV Viral Load 
• Research Blood Sample 
• Study Drug dispensation 
• Body image questionnaires (Appendix D)  
• Medication review 
• Body composition (lean mass, fat mass, and bone mineral mass) will be determined 
from the screening DXA 
8.3 
Follow-up Visits for Participants 
Follow-up visits will occur at weeks 12, 24, 36, and a final visit at week 48. Accepted 
windows around study visits are +/- 7 days.  Patient weight and waist circumference will 
be measured every 3 months until study completion at 12 months according to the protocols 
outlined in Appendix F & Appendix G. Routine laboratory work will also be done every 3 
months, including HIV RNA, CD4, CD8, liver transaminases, renal function, fasting 
glucose, hemoglobin A1c and a standard lipid panel. Medication adherence will be 
assessed every 3 months using the Visual Analogue Scale (VAS) (Appendix E) and AE 
based on DAIDS criteria (Appendix H) will be documented as well as any changes in 
clinical conditions, diet or exercise habits or medications over the past 3 months (Appendix 
K), and pill counts of returned study drug. The procedures will last about 60 minutes per 
visit. 
 
Drug dispensation will be done every 3 months during the regular visits at W0, W12, W24, 
and W36.  


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8.4 
Final Study Visit (Week 48 +/- 14 days) 
The duration of the study is 1 year per participant. Participants will be recruited during the 
first year of the study and will be followed for 48 weeks. The final visit will be the 
participant’s last follow-up visit and the following assessments will take place: 
• Complete Physical Exam including weight and waist circumference 
• Vital Signs 
• Hematology and biochemistry: CBC with differential and liver profile (AST, ALT), 
serum creatinine, calcium, phosphate, Urinalysis, GFR, Urine albumin/creatinine, urine 
protein/creatinine, lipids- cholesterol, LDL, HDL, TG, fasting glucose, hemoglobin 
A1c, CD4/CD8 
• HIV Viral Load 
• Research Blood Samples 
• Documentation of any changes in clinical conditions, diet or exercise habits over the 
past 3 months (Appendix K) 
• Medication review: ART and Other Concomitant Medications 
• Adherence questionnaire (Appendix E) 
• DXA imaging 
• Body image questionnaires (Appendix D) 
To collect any information on potential adverse event reaction, patients will be called 4 
weeks after their last visit at 48 weeks +/- 7 days. 
8.5 
Early Termination 
If a participant withdraws from the study early, documentation for reason of early 
termination is required. Investigations will be completed as per final visit.  If they agree, 
participants will continue to be followed even if they decide to stop the study medication 
8.6 
Re-contact of Participants after Study Termination 
Study results will be made known to the investigators. As per UHN practices and IRB/REB 
requirements, investigators will be responsible for disseminating the information to 
participants who participated in the study. 
8.7  
Schedule of Procedures 
Please refer to Appendix C.  
9.0. STUDY DRUG 
Participants will take a single tablet of Delstrigo (DOR 100 mg, 3TC 300mg, TDF 300mg) 
once daily orally.  
Study drug will be donated by Merck. Study drug will be packaged in bottles containing 
30 tablets, silica gel desiccant and polyester packing material. Each bottle will be enclosed 
with a polypropylene screw cap. To ensure stability the drug should not be stored in any 


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other container than that supplied. The study drug bottles will be labelled to meet all the 
applicable requirements of the EU guidelines to good manufacturing practice, Health 
Canada and the US food and drug administration. The bottles should be stored at a 
controlled room temperature of 25C (77F) with excursions permitted to between 15C and 
30C).  Storage conditions will be specified on the labels. 
Until dispensed to participants, all bottles of study drug will be stored in a securely locked 
area, accessible only to authorized study personnel. 
9.1 Study Drug Accountability 
The investigator is responsible to ensure adequate accountability of all used and unused 
study products. The investigator or designated central pharmacy will acknowledge receipt 
of the study drugs from Merck after reviewing the shipment’s content and condition. The 
investigator or designee will be responsible for maintaining an accurate inventory of the 
dates and quantities of all study drugs received, dispensed and returned. Each dose of the 
study drug administered by the qualified study centre personnel will be accurately recorded 
on logs which indicate the date and quantity of all doses dispensed.  These logs will be 
available for inspection by study monitors.  Study medication supplies must be accounted 
for by the study monitor prior to destruction or return. 
10. 
EARLY TERMINATION 
Participation in the study will be terminated early if: the participant refuses further 
treatment and/or follow-up evaluations; the study staff or participant’s medical provider 
determines that further participation in the study would be detrimental to the participant’s 
health or well-being; the participant is non-compliant with the study requirements in a 
manner that is either detrimental to her health or interferes with the validity of the study 
results; the patient has viral failure and requires an alternative antiretroviral regimen (the 
viral load that requires a change in therapy will be at discretion of the investigator); the 
patient becomes pregnant; or the sponsor terminates the study.  
11. 
ASSESSMENT OF SAFETY 
11.1 
Adverse Events (AEs) 
Adverse events (AEs) are defined as any untoward medical occurrence in a participant that 
does not necessarily have a causal relationship with the study medication/intervention. An 
AE can therefore be any unfavourable and unintended sign (including abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study 
drug/intervention, whether or not it is related to the medication/intervention. 
Toxicities will be graded on a 4-point scale according to standard guidelines outlined in 
the “Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse 
Events” 48[Appendix H]. In general, grade 1 and 2 events will not be considered adverse 


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events, but details should be documented in the source documents. Fractures will be 
considered and captured as an adverse event regardless of grading. 
Stable chronic conditions which are present prior to clinical study entry and do not worsen 
are not considered adverse events and will be accounted for in the participant’s medical 
history. 
Participants who have an adverse event should be followed and treated by the Investigator 
until the abnormal parameter or symptom has resolved or stabilized. It is up to the clinician 
to determine that the AE is either resolved or that is has reached a stable state, after which 
no further follow-up is necessary. There should also be source documentation to support 
this determination. 
There are no recorded moderate to severe intensity adverse reactions that occur ≥2%  in 
those receiving Delstrigo. 
11.2 
Recording/ Documentation of AEs 
At each contact with the participant, information regarding adverse events will be elicited 
by appropriate questioning and examinations, and will be recorded immediately on a source 
document (e.g., progress notes, laboratory reports, survey tools, and data collection tools). 
The start date, stop date, severity of each reportable event, and the PI’s judgment of the 
AE’s relationship to the study medication/intervention will also be recorded in the case 
report form (CRF). 
11.3 
Serious Adverse Events (SAEs) 
A Serious Adverse Event is defined as an AE meeting one of the following: 
• 
Death during the period of protocol-defined surveillance 
• 
Life Threatening Event (immediate risk of death at the time of the event) 
• 
In-patient hospitalization or prolongation of existing hospitalization during the 
period of protocol-defined surveillance 
• 
Results in congenital anomaly or birth defect 
• 
Results in a persistent or significant disability/incapacity 
• 
Any other important medical event that may not result in one of the above outcomes 
may be considered a serious adverse event when: based upon appropriate medical 
judgment, the event may jeopardize the participant, and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias, or convulsions that do not result in in-patient hospitalization, or 
the development of drug dependency or drug abuse or any event of possible drug-induced 
liver injury with hyperbilirubinemia defined as ALT>3xULN and bilirubin >2xULN 
(>35% direct)  
Any AE that occurs between baseline and 30 days following the last study visit at Week 
48 (or at the time of early discontinuation of the participant from the study for any reason) 


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is to be recorded in the source documentation (patient will be called). Surveillance for AEs 
will end at 30 days following Week 48. If an SAE is ongoing at the time a participant 
discontinues/completes the trial the SAE will be followed until the Investigator agrees that 
the event is satisfactorily resolved, becomes chronic, or that no further follow-up is 
required. 
11.4 
AE/SAE Grading, Relationship Assignment and Reporting Procedures 
11.4.1  AE/SAE Grading  
The intensity (severity) of each adverse/serious event will be graded according to the 
toxicity table and toxicity guidelines provided by the Division of AIDS (DAIDS) Table for 
Grading the Severity of Adult and Pediatric Adverse Events (Appendix H).  The DAIDS 
Table will be provided with the Operations Manual. 
11.4.2  Relationship Assessment 
For all collected AEs (including SAEs), the clinician who examines and evaluates the 
participant will determine the AE’s causality based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the 
categories below: 
Definitely Related: There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to drug administration and 
cannot be explained by concurrent disease or other drugs or chemicals. The response to 
withdrawal of the drug (de-challenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory re-
challenge procedure if necessary. 
Probably Related: There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event, including an abnormal laboratory test result, 
occurs within a reasonable time sequence to administration of the drug, is unlikely to be 
attributed to concurrent disease or other drugs or chemicals, and follows a clinically 
reasonable response on withdrawal (de-challenge). Re-challenge information is not 
required to fulfill this definition. 
Possibly Related: There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, 
the influence of other factors may have contributed to the event (e.g., the participant’s 
clinical condition, other concomitant events). Although an adverse drug event may rate 
only as “possibly related” soon after discovery, it can be flagged as requiring more 
information and later be upgraded to “probably related” or “definitely related”, as 
appropriate. 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event 
did not occur within a reasonable time after administration of the trial medication) and in 


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which other drugs or chemicals or underlying disease provides plausible explanations (e.g., 
the participant’s clinical condition, other concomitant treatments). 
Not related: The AE is completely independent of study drug administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
11.4.3  
SAE Reporting Procedures 
The Investigator or designee must report any SAE occurring in a patient receiving study 
drug to the Sponsor within 24 hours, even if the SAE is not drug-related. This should be 
done by telephone and by sending a faxed or emailed copy of the Serious Adverse Event 
form plus other supporting documentation, as required. 
SAEs will be reported to: 
Immunodeficiency Clinic 
University Health Network 
Attention: Rosemarie Clarke, Research Nurse Manager 
Phone: 416-340-4800 ext. 6723 or 416-340-5077  
Fax:  416-340-9105 
E-mail: rosemarie.clarke@uhn.ca 
All additional follow-up evaluations must also be reported as soon as possible in the same 
manner. All SAEs will be followed until the Investigator agrees that the event is 
satisfactorily resolved, becomes chronic, or that no further follow-up is required. 
The Sponsor or designee will be responsible for notifying the relevant authorities of any 
reportable SAE as outlined in the Canadian Food and Drug Regulations and ICH 
Guidelines.  
11.5 
AEs/SAEs monitoring 
Any AE/SAE that occurs between baseline and the time the participant departs the study 
at the end of the final follow-up visit (or at the time of early discontinuation of the 
participant from the study for any reason) will be captured and recorded in the source 
documentation. At each contact with the participant, the investigator (or designate) must 
seek information on adverse events by specific questioning and, as appropriate, by 
examination.  
Adverse events that had previously been reported by the study participant will also be 
reassessed for duration, intensity and possible reoccurrence. Assessment of safety will 
include clinical observation and monitoring of routine hematology and biochemistry. 
Surveillance for AEs will end 30 days post Week 48 (or at the time of early discontinuation 
of the participant from the study for any reason). If an SAE is ongoing at the time a 
participant discontinues/completes the study, the SAE will be followed up until the 


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Investigator agrees that the event is satisfactorily resolved, becomes chronic, or that no 
further follow-up is required. 
11.6 
Toxicities/ Adverse Event Management  
In the event of a discontinuation of Delstrigo for suspected renal impairment, or other 
clinically significant chemistry elevations, participants should not restart Delstrigo due to 
the risk of a recurrent reaction; such participants should be withdrawn from study and 
seek/be reviewed for alternative antiretroviral therapy. If they agree, participants will 
continue to be followed for the duration of the study. 
11.7 
Management of HIV Virologic failure. 
Virologic failure must be considered for any patient with plasma HIV RNA ≥50 c/mL at 
any time following randomization. For the purposes of clinical management in this study, 
virologic failure is defined as: 
Two consecutive plasma HIV RNA ≥50 c/mL within four weeks of the initial suspected 
virologic failure. 
Cases of confirmed virologic failure will trigger genotypic virologic resistance testing, 
including non-nucleoside reverse transcriptase resistance testing, when plasma HIV RNA 
>400c/mL. The virologic failure definition is intended for guidance and Investigators 
should use their discretion as to the most appropriate clinical management of their patients. 
The choice of antiretroviral therapy will be left to the discretion of the treating physician. 
In some cases, e.g. if there is no evidence of acquired resistance to the current regimen, 
treatment may be continued with increased efforts at adherence support. 
11.8 
Pregnancy Management 
Patients who are pregnant will be excluded from the study, as pregnancy is associated with 
weight gain which would be a confounder for this study. Additionally, the safety of the 
study drug in pregnancy is unknown. There is no data are available on the placental transfer 
of DOR in humans, and insufficient data to assess for teratogenicity in humans. 
11.9 
Action to be taken if pregnancy occurs 
Any participant who becomes pregnant during the study must be immediately withdrawn 
from the study because, as stated above, weight gain in pregnancy would be a confounding 
factor and the effects of the drug during pregnancy are not known. Management of the 
patient after removal from the study will handled by their treating physician. 
12. 
TRIAL MANAGEMENT 
12.1 
Local Coordination 
The principal investigator will be responsible for recruiting study personnel, obtaining 
UHN  REB/IRB approval, ensuring clinic staff are informed about the study, and 
supervising  study activities. The study personnel will be responsible for: identifying 
participants; obtaining informed consent; conducting study visits; ensuring participants 


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have regular follow-up; encouraging attendance at visits; telephoning participants if visits 
are missed; and collecting participant data. A study manual will outline methods for CRF 
completion and record management. Personnel will also be trained on study procedures 
prior to and during the study.  
13.0 
DETAILS OF STATISTICAL ANALYSIS 
13.1. Sample size considerations 
As this is a pilot study it is not powered to meet statistical significance for the primary or 
secondary endpoints but is chosen as a convenience sample upon which preliminary data 
can be obtained.  We estimate 800 active patients currently on an INSTI-containing 
regimen at our clinic. If we approach 40 eligible patients, we estimate 70% acceptance rate 
with a 95% confidence interval (CI) of +/- 14%.  Reaching our target enrollment of 25 
patients means that we will be able to estimate a 90% completion rate with a 95% CI of +/- 
12%. 
13.2 
Primary analysis:   
The following proportions and their 95% confidence intervals will be calculated: 1) the 
proportion of patients on INSTI-containing regimens that are eligible for the study, 2) the 
proportion of eligible patients approached who agree to participate, and 3) the proportion 
of those who sign consent who complete the protocol. 
13.3  Secondary analyses:   
 Wilcoxon Signed Rank Tests will be used to compare patients’ absolute weight and 
waist circumference between baseline and 12 months on DOR/TDF/3TC.  Relative 
weight change per year (i.e. weight trajectory) while on INSTI and while on 
DOR/TDF/3TC will be calculated and compared using a Wilcoxon Signed Rank Test.  
McNemar’s test will be used to compare BMI categories between baseline and 12 months 
on DOR/TDF/3TC. Retrospective (from Part 1) and prospective measures of weight will 
be used in univariable GEE models to estimate weight change over time before and after 
switching to DOR/TDF/3TC. GEE models are flexible to different follow-up schedules 
and thus allow for missed visits and loss to follow up. The number of participants with 
viral failure will be recorded. 
Exploratory analyses: For the following outcomes with repeated measures, univariable 
GEE models will be used to estimate the trajectory of change after switching to 
DOR/TDF/3TC: CD4 count, CD8 count, liver transaminases, renal function, fasting 
glucose, insulin resistance (HOMA) and a standard lipid panel. Wilcoxon Signed Rank 
Tests will be used to compare DXA body scan results and body image questionnaires 
between baseline and 12 months on DOR/TDF/3TC. 
13.4. Interim analysis:  no interim analyses are planned 


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13.5 
Feasibility:   Of approximately 1500 active patients at the Immunodeficiency Clinic, 98% 
are currently on antiretroviral treatment, and 91% have a viral load below 40 copies/mL.  Over 
1000 patients (over 2/3) are on treatment with an INSTI. 
13.6 
Timeline:    6-12 months for start- up and ethics approval, 6-9 months for enrollment; 12 
months for follow-up; 6 months for analysis/write-up (Appendix I) 
13.7.  Loss to follow-up: We expect that 10% of patients will drop out before 48 weeks. Primary 
analyses will be conducted assuming data are missing at random. Pattern mixture models and 
selection models will be used as sensitivity analyses to determine the range of possible treatment 
effects under the assumption of not missing at random.50 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
Checks will be built into the database to alert the data manager to inconsistent data at the 
time of data entry. Site personnel will then be prompted to double-check the data. Source 
documentation will not be verified by an on-site monitor visit during the study. It is the 
responsibility of the Sponsor Investigator to assure the quality of computerized data for 
this study. 
15. 
ETHICS AND PROTECTION OF HUMAN PARTICIPANTS 
15.1 
ICH Guidance E6:  
Good Clinical Practice: Consolidating Guideline/ Declaration of Helsinki.  The conduct of 
this study will conform to the International Conference for Harmonization and Good 
Clinical Practice (ICH-GCP) regulations and guidelines and the current revision of the 
Declaration of Helsinki. 
15.2 
Research Ethics Board/ Institutional Review Board 
A copy of the protocol (including protocol amendments), all versions of the informed 
consents, other information to be completed by participants such as questionnaires, and 
any proposed advertising/ recruitment materials must be reviewed and approved by the 
REB/IRB prior to implementation of the study. The principal investigator will be 
responsible for obtaining REB/IRB approval of the annual Continuing Review throughout 
the duration of the study.  The principal investigator will notify the REB/IRB of violations 
from the protocol and serious adverse events.   
15.3 
Informed consent process 
All participants will be given detailed oral and written information about the study. Consent 
forms describing in detail the study medications/intervention(s), study procedures, 
anticipated benefits and potential risks will be given to each participant and written 
documentation of informed consent is required prior to starting the study. Participants must 
voluntarily sign and date an informed consent document that has been approved by UHN’s 
REBprior to any procedures being done specifically for the trial. Each participant should 
have sufficient opportunity to discuss the study and consider the information in the consent 


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process prior to agreeing to participate. Participants may withdraw consent at any time 
during the course of the trial. The informed consent will be signed and dated by the 
participant, the person who conducted the informed consent discussion and the 
investigator. The original signed informed consent form will be retained in the participant’s 
study files and a copy will be provided to the subject.       
15.4 
Subject confidentiality 
All participant related information including the CRFs, laboratory samples, evaluation 
forms, etc. will be kept strictly confidential. All records will be kept in a secure, locked 
location and only research staff will have access to the records. Participants will be 
identified only by means of a coded number specific to each participant, and a participant 
letter code. All computerized databases will identify participants by numeric codes only, 
and will be password protected. Upon request, clinical information may be reviewed by or 
released to study monitors, auditors, or regulatory agencies.   
15.5 
Early Termination of the Protocol 
The REB/IRB or other government organizations, as part of their duties to ensure that 
research participants are protected may discontinue the study at any time. Regulatory 
authorities and the study Sponsor retain the authority to suspend additional enrollment for 
the entire study as applicable.  
15.6 
Record Retention 
The Investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for 25 years, in accordance with 
applicable regulatory requirement(s). If the Investigator withdraws from the responsibility 
of keeping the study records, custody must be transferred to a person willing to accept the 
responsibility and the Sponsor notified. The Investigator should ensure that no destruction 
of medical records occurs without the written approval of the Sponsor. 
Samples collected and sent to the UHN laboratory will be retained for 10 years, after which 
they will be destroyed.   
16.0 
PROTOCOL DEVIATIONS 
No deviations from this protocol will be permitted without the prior written approval of the 
Sponsor, except when the modification is needed to eliminate an immediate hazard or 
hazards to participants. Any deviations that may affect a participant’s treatment or 
informed consent, especially those increasing potential risks, must receive prior approval 
from the REB unless performed to remove an immediate safety risk to the participants. In 
this case it will be reported to the REB and the Sponsor immediately thereafter. Any 
departures from the protocol must be documented. 


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17.0 
STUDY CONDUCT AND MONITORING 
Limited monitoring will be done by the Principal Investigator and will include clinical and 
operational data reviewed for outliers and trends.  
18.0 
DATA MANAGEMENT RESPONSIBILITIES 
It is the responsibility of the Data Management Centre to assure the quality of computerized 
data for this study. This role extends from protocol development to generation of the final 
study databases. 
19.0 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA DOCUMENTS 
Appropriate medical and research records will be maintained for this study and regulatory/ 
institutional requirements for the protection of confidentiality of study participants. The 
Principal Investigator is responsible for assuring that the data collected are complete, 
accurate, and recorded in a timely manner.  
Study data will be collected on study specific CRFs. Source documentation should support 
the data collected on the CRFs. Source documents include all recordings of observations 
or notations of clinical activities and all reports and records necessary for the evaluation 
and reconstruction of the clinical trial. Data for CRFs will be collected during participant 
visits, phone calls with participants and health care providers, completed questionnaires 
and abstracted from the participant’s medical records. It is not acceptable for the CRF to 
be the only record of participation in the trial. 
Clear and detailed instruction explaining CRF completion and where, when and how CRFs 
are to be sent to the data centre will be included in the study Operations Manual.  
20. 
DISCLOSURE AND PUBLICATION POLICY 
Publication of the final study report is planned. The Sponsor-Investigator (Dr. Walmsley) 
will determine authorship for each manuscript based on contributions to the study design, 
study execution, and manuscript completion. No author will be included without prior 
authorization but the intention is to be broadly inclusive of all study investigators who 
make active contributions as outlined by the ICJME criteria for authorship (Authorship 
credit should be based on 1) substantial contributions to conception and design, acquisition 
of data, or analysis and interpretation of data; 2) drafting the article or revising it critically 
for important intellectual content; and 3) final approval of the version to be published. 
Authors should meet conditions 1, 2, and 3). 
21. 
STUDY TEAM ROLES AND RESPONSIBILITIES 
Dr. Walmsley, MD is a clinician investigator with a strong and sustained (over 25 year) 
track record in the conduct of multicentre RCT in clinic HIV management. Her interest and 
knowledge translation in the field of HIV, aging and women, and her clinical practice 
which includes HIV infected aging women on therapy will strengthen recruitment and 


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interest in this study. She directs a clinical research team who will conduct this study at the 
Immunodeficiency Clinic in Toronto. The team has participated in over 150 HIV related 
studies and have excellent recruitment and retention records. 
Dr. Alice Tseng, PharmD is a specialist consultant at the TGH Immunodeficiency Clinic, 
co-investigator on several CIHR grants and cofounder of the Canadian HIV/AIDS 
Pharmacists Network. She will provide pharmaceutical expertise. She will be responsible 
for reviewing the potential participants for eligibility including the previous ART 
regimens, resistance profiles, drug interactions etc. She will review the new regimen with 
each participant and assess any potential adverse drug events. Estimated ½ day per week 
on the project. 
Dr. Melody Ren, MD is a second year infectious diseases fellow under the supervision 
and mentorship of Dr. Walmsley.  She has expressed interest in pursuing a career in HIV 
related research. She will be involved in the recruitment and follow up of the participants 
and in assisting in the analysis. This will enable her to expand her knowledge around 
clinical trials and assist with future career opportunities. She will be responsible for 
recruiting and following patients. She will write the initial draft of the manuscript. She will 
commit one day per week to the project. 
Dr. Ella Huszti PhD is a Biostatistician at the Biostatistics Research Unit at TGH who has 
been conducting analyses for HIV research. She will provide biostatistics expertise and 
oversee the statistician conducting the analysis. She will commit ½ day per week to the 
project.  
 


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