Switch to Doravirine/Islatravir (DOR/ISL) in Human Immunodeficiency Virus 1 (HIV-1) Participants Treated With Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) (MK-8591A-018)

Study Overview
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Brief Summary
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This study will evaluate the safety and efficacy of a switch to MK-8591A (a fixed dose combination of doravirine and islatravir) in human immunodeficiency virus -1 (HIV-1)-infected participants virologically suppressed on a regimen of bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). The primary hypothesis is that a switch to MK-8591A will be non-inferior to continued treatment with BIC/FTC/TAF as assessed by the proportion of participants with HIV-1 ribonucleic acid (RNA) ≥50 copies/mL at Week 48. Participants who benefit from their assigned intervention (as determined by investigator) will be able to continue treatment through a 24-week study extension.

Official Title
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A Phase 3, Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate a Switch to Doravirine/Islatravir (DOR/ISL) Once-Daily in Participants With HIV-1 Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF)

Conditions
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HIV Infection

Intervention / Treatment
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* Drug: DOR/ISL
* Drug: BIC/FTC/TAF
* Drug: Placebo to BIC/FTC/TAF
* Drug: Placebo to FDC DOR/ISL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is HIV-1 positive with plasma Human Immunodeficiency Virus 1 (HIV-1) RNA <50 copies/mL at screening. Has been receiving BIC/FTC/TAF therapy with documented viral suppression (HIV-1 RNA <50 copies/mL) for ≥3 months prior to signing informed consent and has no history of prior virologic treatment failure on any past or current regimen. Female is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of childbearing potential (WOCBP); is a WOCBP and using an acceptable contraceptive method, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle; a WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] as required by local regulations) within 24 hours before the first dose of study intervention; if a urine test cannot be confirmed as negative (e.g. an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. Exclusion Criteria: Has HIV-2 infection. Has an active diagnosis of hepatitis due to any cause, including active Hepatitis B Virus (HBV) co-infection. Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or cutaneous Kaposi's sarcoma. Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or any prohibited therapies. Is currently participating in or has participated in a clinical study with an investigational compound or device from 45 days prior to Day 1 through the study treatment period. Has a documented or known virologic resistance to DOR. Female expects to conceive or donate eggs at any time during the study.

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DOR/ISL<br>A fixed dose combination (FDC) of 100 mg doravirine (DOR)/0.75 mg islatravir (ISL) for 144 weeks; and placebo to Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) for 96 weeks. | Drug: DOR/ISL<br>* 100 mg DOR/ 0.75 ISL FDC tablet taken orally once daily<br>* Other names: MK-8591A;Drug: Placebo to BIC/FTC/TAF<br>* Placebo to BIC/FTC/TAF in a single tablet taken orally, once daily<br>|
| Active Comparator: BIC/FTC/TAF<br>50 mg bictegravir (BIC), 200 mg emtricitabine (FTC), 25 mg tenofovir alafenamide (TAF) for 144 weeks, and placebo to FDC DOR/ISL for 96 weeks. Participants will be offered the option to receive open-label FDC DOR/ISL from Week 144 to Week 156. | Drug: DOR/ISL<br>* 100 mg DOR/ 0.75 ISL FDC tablet taken orally once daily<br>* Other names: MK-8591A;Drug: BIC/FTC/TAF<br>* 50 mg BIC, 200 mg FTC, and 25 mg TAF combined in a single tablet, taken orally once daily<br>Drug: Placebo to FDC DOR/ISL<br>* Placebo to FDC DOR/ISL in a tablet taken orally, once daily<br>* Other names: Placebo to MK-8591A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Human Immunodeficiency Virus 1 Ribonucleic Acid (HIV-1 RNA) ≥50 Copies/mL at Week 48 | The Abbott RealTime PCR assay with a reliable lower limit of quantification of 40 copies/mL was used to measure the HIV-1 RNA level in blood samples obtained at each visit. The percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 48 is presented using the FDA Snapshot missing data approach. | Week 48 | 
| Percentage of Participants With One or More Adverse Events (AEs) up to Week 48 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who experienced an AE up to week 48 is presented. | Up to 48 weeks | 
| Percentage of Participants Who Discontinued Study Intervention Due to an AE up to Week 48 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The percentage of participants who discontinued study intervention due to an AE up to week 48 is presented. | Up to 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With HIV-1 RNA ≥50 Copies/mL at Week 96 | The Abbott RealTime PCR assay with a reliable lower limit of quantification of 40 copies/mL was used to measure the HIV-1 RNA level in blood samples obtained at each visit. The percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 96 is presented. | Week 96 | 
| Participants With HIV-1 RNA ≥50 Copies/mL at Week 144 | The Abbott RealTime PCR assay with a reliable lower limit of quantification of 40 copies/mL was used to measure the HIV-1 RNA level in blood samples obtained at each visit. The percentage of participants with HIV-1 RNA ≥50 copies/mL at Week 144 is presented. | Week 144 | 
| Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 48 | The Abbott RealTime PCR assay with a reliable lower limit of quantification of 40 copies/mL was used to measure the HIV-1 RNA level in blood samples obtained at each visit. The percentage of participants with HIV-1 RNA <50 copies/mL at Week 48 is presented using the FDA snapshot missing data approach | Week 48 | 
| Percentage of Participants With HIV-1 RNA <40 Copies/mL at Week 48 | The Abbott RealTime PCR assay with a reliable lower limit of quantification of 40 copies/mL was used to measure the HIV-1 RNA level in blood samples obtained at each visit. The percentage of participants with HIV-1 RNA <40 copies/mL at Week 48 is presented using the FDA snapshot missing data approach. | Week 48 | 
| Participants With HIV-1 RNA <40 or <50 Copies/mL at Week 96 | The Abbott RealTime PCR assay with a reliable lower limit of quantification of 40 copies/mL was used to measure the HIV-1 RNA level in blood samples obtained at each visit. The percentage of participants with HIV-1 RNA <40 or <50 copies/mL at Week 96 is presented. | Week 96 | 
| Participants With HIV-1 RNA <40 or <50 Copies/mL at Week 144 | The Abbott RealTime PCR assay with a reliable lower limit of quantification of 40 copies/mL was used to measure the HIV-1 RNA level in blood samples obtained at each visit. The percentage of participants with HIV-1 RNA <40 or <50 copies/mL at Week 144 is presented. | Week 144 | 
| Change From Baseline in Cluster of Differentiation-positive (CD4+) T-cell Count at Week 48 | Blood samples were used to measure CD4+ T-cell count. Baseline measurement of CD4+ T-cell count is defined as the day 1 value for each participant. Change from baseline in CD4+ T-cell count at week 48 using the data as observed (DAO) approach is presented. A negative value indicates a mean decrease in CD4+ T-cell count from baseline and a positive value indicates a mean increase in CD4+ T-cell count from baseline. | Baseline and Week 48 | 
| Change From Baseline in CD4+ T-cell Count at Week 96 | Blood samples were used to measure CD4+ T-cell count. Baseline measurement of CD4+ T-cell count is defined as the day 1 value for each participant. Change from baseline in CD4+ T-cell count at week 96 using the data as observed (DAO) approach is presented. A negative value indicates a mean decrease in CD4+ T-cell count from baseline and a positive value indicates a mean increase in CD4+ T-cell count from baseline. | Baseline and Week 96 | 
| Change From Baseline in CD4+ T-cell Count at Week 144 | Blood samples were used to measure CD4+ T-cell count. Baseline measurement of CD4+ T-cell count is defined as the day 1 value for each participant. Change from baseline in CD4+ T-cell count at week 144 using the data as observed (DAO) approach is presented. A negative value indicates a mean decrease in CD4+ T-cell count from baseline and a positive value indicates a mean increase in CD4+ T-cell count from baseline. | Baseline and Week 144 | 
| Participants With Viral Drug Resistance-associated Substitutions at Week 48 | Viral drug resistance is defined as participants with confirmed HIV-1 RNA ≥400 copies/mL having genotypic or phenotypic evidence of resistance to the study drug administered. The number of participants who demonstrate drug resistance is presented. | Week 48 | 
| Participants With Evidence of Viral Drug Resistance-associated Substitutions at Week 96 | Viral drug resistance is defined as participants with confirmed HIV-1 RNA ≥400 copies/mL and/or genotypic or phenotypic analysis of data showing evidence of resistance to the study drug administered. The number of participants who demonstrate drug resistance is presented. | Week 96 | 
| Participants With Evidence of Viral Drug Resistance-associated Substitutions at Week 144 | Viral drug resistance is defined as participants with confirmed HIV-1 RNA ≥400 copies/mL and/or genotypic or phenotypic analysis of data showing evidence of resistance to the study drug administered. The number of participants who demonstrate drug resistance is presented. | Week 144 | 
| Change From Baseline in Body Weight at Week 48 | Body weight was measured and recorded at baseline and week 48. Participants removed their shoes and wore a single layer of clothing at each measurement. The mean change from baseline in body weight at week 48 is presented. | Baseline and Week 48 | 
| Change From Baseline in Body Weight at Week 96 | Body weight was measured and recorded at baseline and week 96. Participants removed their shoes and wore a single layer of clothing at each measurement. | Baseline and Week 96 | 
| Change From Baseline in Body Weight at Week 144 | Body weight was measured and recorded at baseline and week 144. Participants removed their shoes and wore a single layer of clothing at each measurement. | Baseline and Week 144 | 
| Percentage of Participants With One or More AEs up to Week 144 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. | Up to Week 144 | 
| Percentage of Participants Who Discontinued Study Intervention Due to an AE up to Week 144 | An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. | Up to Week 144 |