Doravirine for Persons With Excessive Weight Gain on Integrase Inhibitors and Tenofovir Alafenamide

Study Overview
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Brief Summary
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The primary purpose of this study is to see if people with HIV who had a significant weight gain after starting INSTI (integrase strand transfer inhibitor)+TAF/FTC (tenofovir alafenamide/emtricitabine) (TAF/3TC (lamivudine)) regimen could either slow their rate of weight gain or lose weight within about 1 year if they switch to a regimen containing doravirine (DOR; a newer, non-nucleoside reverse transcriptase inhibitor medication). The study will also try to see if participants changing from TAF/FTC (or TAF/3TC) to TDF/FTC (or TDF/3TC) will experience less additional weight gain or a reduction in overall body weight at 48 weeks compared to persons continued on an INSTI + TAF/FTC (or TAF/3TC) combination. INSTINs assessed in A5391 include bictegravir (BIC), dolutegravir (DTG), or raltegravir (RAL). Additionally, the study will see whether a change in ART can affect things like waist circumference, metabolic and cardiovascular health, fat and lean mass body composition, bone health, and maintenance of virologic suppression. Finally, the study will look at the safety and tolerability of DOR plus either TAF/FTC (or TAF/3TC) versus TDF/FTC (or TDF/3TC).

Official Title
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Doravirine for Persons With Excessive Weight Gain on Integrase Inhibitors and Tenofovir Alafenamide (The Do IT Study)

Conditions
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HIV Infections

Intervention / Treatment
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* Drug: Doravirine 100 Mg
* Drug: Tenofovir alafenamide/emtricitabine
* Drug: tenofovir alafenamide/lamivudine
* Drug: Integrase strand transfer inhibitors
* Drug: tenofovir disproxil fumarate/emtricitabine
* Drug: tenofovir disproxil fumarate/lamivudine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability and willingness of participant or legal guardian/representative to provide informed consent. HIV-1, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, or plasma HIV-1 RNA viral load. If a rapid HIV test or any FDA-approved HIV-1 E/CIA test kit is not available, two HIV-1 RNA values ≥2000 copies/mL at least 24 hours apart may be performed by any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification or its equivalent, or by any non-US laboratory that is DAIDS Good Clinical Laboratory Practice (GCLP) compliant and, if performing HIV-1 RNA testing, is Virology Quality Assurance (VQA)-certified. NOTE: The term licensed refers to a US FDA-approved kit, or for sites located in countries other than the United States, a kit that has been certified or licensed by an oversight body within that country and validated internally. World Health Organization (WHO) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load. Currently, on a BIC (bictegravir), DTG (dolutegravir), or RAL (raltegravir) +TAF/FTC (or TAF/3TC) regimen with ≥48 weeks INSTI+TAF/FTC (or TAF/3TC) dosing prior to study entry. NOTE A: Participants who did not start TAF at the same time as they started an INSTI will be eligible if they started TAF/FTC (or TAF/3TC) ≥48 weeks prior to study entry. NOTE B: Participants who underwent within-INSTI class substitutions (including from EVG (elvitegravir) to BIC, DTG, or RAL) will be eligible if substitution occurred ≥24 weeks prior to study entry. NOTE C: Participants are permitted ART adherence gaps of ≤7 days (i.e., missed doses), with a maximum of 3 gaps in the 48 weeks prior to study entry. Ability to acquire NRTIs (TAF/FTC or TAF/3TC, and TDF/FTC or TDF/3TC) and INSTI through usual care for the duration of the study. A BMI ≥27.5 kg/m2 at screening. An unintentional >10% weight gain in the 1-3 years after initiating or switching to INSTI-based ART and with ≥48 weeks of TAF/FTC (or TAF/3TC) preceding enrollment, as ascertained from clinical records, with no other medically apparent reason to readily explain the weight gain (including, but not limited to, concomitant medication use [e.g., corticosteroids], Cushing's disease, recent prolonged hospitalization, etc.), in the opinion of the site investigator. No known plans to change or to initiate medications known to be associated with significant weight changes during study period. Agree to adhere to assigned ART during the study period At least one HIV-1 RNA level <50 copies/mL (or below the lower limit of HIV-1 RNA detection available at the site if the lower limit of detection is >50) performed in the 48 weeks prior (≤48 weeks) to study screening, and at least one HIV-1 RNA level <50 copies/mL ≥48 weeks prior to study screening, using an FDA-approved assay performed by any US laboratory that has a CLIA certification or its equivalent, or at any network-approved non-US laboratory that is VQA certified. HIV-1 RNA values prior to the screening visit will be assessed for eligibility by the site and assay dates and values do not need to be entered on an eCRF. Screening HIV-1 RNA <50 copies/mL (or below the lower limit of HIV-1 RNA detection available if the lower limit of detection is >50) performed within 45 days prior to study entry by any US laboratory that possesses a CLIA certification or its equivalent, or at any network-approved non-US laboratory that is VQA certified. For participants capable of becoming pregnant, negative serum or urine pregnancy test within 45 days prior to study entry by any US clinic or laboratory that has a CLIA certification or its equivalent, or is using a point of care (POC)/ CLIA-waived test, or at any network-approved non-US laboratory or clinic that operates in accordance with GCLP and participates in appropriate external quality assurance programs. NOTE: Participants capable of becoming pregnant are defined as individuals who were assigned a female sex at birth and of reproductive potential; (i.e., have reached menarche and who have not been post-menopausal for at least 24 consecutive months, and have not undergone surgical sterilization such as hysterectomy, bilateral oophorectomy, tubal ligation, or salpingectomy). This includes transgender men who could become pregnant if menstruation were not suppressed. Participant-reported history is acceptable documentation of menopause. Participants engaging in sexual activity and capable of becoming pregnant must agree to use contraception while on study drug (approximately 48 weeks) and for 8 weeks after the end of the study. At least one of the following contraceptive methods must be used: Intrauterine device (IUD) Hormone-based contraceptive Partner sterilization (i.e., vasectomy) and is the sole partner for the participant. NOTE: Participant report of partner sterilization is acceptable. Transgender participants who are currently taking hormones must be on a stable hormone dose for >12 weeks prior to study entry. Transgender participants should not have active plans to change their hormone regimen or dose during the study period. NOTE: As some transgender participants may also use hormones purchased outside of the medical system (e.g., street hormones), the medication history should include questions about the use of these agents. The following laboratory values obtained within 45 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent, or at any network-approved non-US laboratory that operates in accordance with GCLP and participates in appropriate external quality assurance programs: Absolute neutrophil count (ANC) >750 cells/mm3 Hemoglobin >10 g/dL for males and >9 g/dL for females (based on sex at birth) Calculated creatinine clearance ≥50 mL/min as estimated by the CKD-EPI equation (a calculator is available at: https://qxmd.com/calculate/calculator_251/egfr-using-ckd-epi) Aspartate aminotransferase (AST) (SGOT) <3x ULN Alanine aminotransferase (ALT) (SGPT) <3x ULN Exclusion Criteria: Historical or current evidence of the K65R/E/N or M184V/I mutations (for participants who have undergone HIV-1 genotyping), due to the potential for viral rebound after switch from an INSTI- to NNRTI-based regimen. Historical or current evidence of major mutations associated with any NNRTI resistance. NOTE: Refer to the IAS-USA 2019 mutations list, including significant substitutions at positions 100, 101, 103, 106, 138, 179, 181, 188, 190, 221, 225, 227, 230, or 234 [22]. History of prior virologic failure in the opinion of the site investigator. For example, a confirmed plasma HIV-1 RNA >1000 copies/mL after having achieved viral suppression. Prior exposure to single-dose nevirapine for the prevention of parent-to-child transmission of HIV. Any history of significant renal toxicity while taking TDF (as determined by site investigator). Currently breast-feeding or pregnant, or intending to become pregnant during the duration of the study. Anticipated start or cessation of any of the following drugs during study period: Antipsychotics (e.g., clozapine, olanzapine, risperidone, etc.) and antidepressants (tricyclic antidepressants, e.g., amitriptyline, nortriptyline, etc.; selective serotonin reuptake inhibitors, e.g., fluoxetine, paroxetine, sertraline, etc.; and monoamine oxidase inhibitors, e.g., selegiline) associated with weight gain Anticonvulsants/mood stabilizers associated with weight gain (e.g., lithium, valproic acid) or weight loss (e.g., topiramate) Thyroid replacement hormones Anti-diabetic agents known to cause weight loss (e.g., GLP-1 receptor agonists such as exenatide, dulaglutide, semaglutide, metformin, and SGLT-2 inhibitors such as canagliflozin, dapagliflozin, etc.). NOTE A: Participants currently receiving antipsychotics, antidepressants, anticonvulsants/mood stabilizers, and thyroid replacement hormones with no dose modifications for at least 12 weeks prior to entry are eligible. NOTE B: Participants currently receiving anti-diabetic agents known to cause weight loss with no dose modifications for at least 24 weeks prior to entry are eligible. Planning to undergo bariatric surgery or initiate significant dietary or exercise changes within the study period (e.g., structured weight loss programs such as Weight Watchers), as determined by participant report. Known allergy/sensitivity or any hypersensitivity to components of study drug or its formulation. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with ability to adhere to study requirements, or cessation of routine methamphetamine use within 60 days prior to study entry. NOTE: Routine methamphetamine use is considered >4 days per week. Acute or serious illness requiring systemic treatment and/or hospitalization within 30 days prior to entry. A history of a diagnosis of osteoporosis or osteopenia.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DOR 100 mg + TAF/FTC (or TAF/3TC, depending on location)<br>By mouth daily with or without food | Drug: Doravirine 100 Mg<br>* Participants will receive 100 mg tablet by mouth daily with or without food.<br>Drug: Tenofovir alafenamide/emtricitabine<br>* NRTIs for all arms (TAF/FTC, TAF/3TC, TDF/FTC, or TDF/3TC) and INSTIs for Arm 3 will be acquired through standard of care locally.<br>Drug: tenofovir alafenamide/lamivudine<br>* NRTIs for all arms (TAF/FTC, TAF/3TC, TDF/FTC, or TDF/3TC) and INSTIs for Arm 3 will be acquired through standard of care locally.<br>|
| Experimental: DOR 100 mg + TDF/FTC (or TDF/3TC, depending on location)<br>By mouth daily with or without food | Drug: Doravirine 100 Mg<br>* Participants will receive 100 mg tablet by mouth daily with or without food.<br>Drug: tenofovir disproxil fumarate/emtricitabine<br>* NRTIs for all arms (TAF/FTC, TAF/3TC, TDF/FTC, or TDF/3TC) and INSTIs for Arm 3 will be acquired through standard of care locally.<br>Drug: tenofovir disproxil fumarate/lamivudine<br>* NRTIs for all arms (TAF/FTC, TAF/3TC, TDF/FTC, or TDF/3TC) and INSTIs for Arm 3 will be acquired through standard of care locally.<br>|
| Experimental: Continuation of entry INSTI+TAF/FTC (or TAF/3TC)<br> | Drug: Tenofovir alafenamide/emtricitabine<br>* NRTIs for all arms (TAF/FTC, TAF/3TC, TDF/FTC, or TDF/3TC) and INSTIs for Arm 3 will be acquired through standard of care locally.<br>Drug: tenofovir alafenamide/lamivudine<br>* NRTIs for all arms (TAF/FTC, TAF/3TC, TDF/FTC, or TDF/3TC) and INSTIs for Arm 3 will be acquired through standard of care locally.<br>Drug: Integrase strand transfer inhibitors<br>* NRTIs for all arms (TAF/FTC, TAF/3TC, TDF/FTC, or TDF/3TC) and INSTIs for Arm 3 will be acquired through standard of care locally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change (percent) in body weight (kg) from entry to week 48 |  | Day 0 to week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change (percent) in body weight (kg) from entry to week 24 |  | Day 0 to week 24 | 
| Change (absolute) in waist circumference from entry to weeks 24 and 48 |  | Day 0 to weeks 24 and 48 | 
| Change (absolute) in fasting cardiometabolic parameters (glucose, insulin, HOMA-IR, triglycerides, LDL, HDL) from entry to weeks 24 and 48 |  | Day 0 to weeks 24 and 48 | 
| Occurrence of confirmed plasma HIV-1 RNA >200 copies/mL | Proportion of participants with confirmed plasma HIV-1 RNA >200 copies/mL | At day 0, weeks 4, 12, 24, and 48 | 
| Occurrence of Grade ≥3 AEs or >10% reduction in CrCl as estimated by the CKD-EPI equation | Proportion of participants with Grade ≥3 AEs or >10% reduction in CrCl as estimated by the CKD-EPI equation | Day 0 to week 48 | 
| Occurrence of premature discontinuation of study treatment | Proportion of participants who prematurely discontinued study treatment | Day 0 to week 48 | 
| Change (percent) in total fat from entry to week 48, measured by DEXA. |  | Day 0 to week 48 | 
| Change (percent) in lean mass from entry to week 48, measured by DEXA. |  | Day 0 to week 48 | 
| Change (percent) in trunk fat from entry to week 48, measured by DEXA. |  | Day 0 to week 48 | 
| Change (percent) in limb fat from entry to week 48, measured by DEXA. |  | Day 0 to week 48 | 
| Change (percent) in appendicular lean mass from entry to week 48, measured by DEXA. |  | Day 0 to week 48 | 
| Change (percent) in DEXA hip and lumbar spine bone mineral density from entry to week 48 |  | Day 0 to week 48 |