Study of Doravirine/Islatravir (DOR/ISL 100 mg/0.75 mg) to Evaluate the Antiretroviral Activity, Safety, and Tolerability in Treatment-Naïve Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Infection (MK-8591A-020)

Study Overview
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Brief Summary
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This is a phase 3, randomized, controlled, double-blind, multisite clinical study of a once-daily fixed dose combination (FDC) of 100 mg doravirine/0.75 mg islatravir (DOR/ISL [also known as MK-8591A]) in treatment-naïve participants with human immunodeficiency virus type-1 (HIV-1) infection. The primary objectives are to evaluate the antiretroviral activity, safety, and tolerability of DOR/ISL compared to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF). The primary hypothesis is that DOR/ISL is noninferior or superior to BIC/FTC/TAF treatment based on the percentage of participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48.

Detailed Description
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Double-blind treatment with the assigned intervention occurs from Day 1 to Week 96, followed by an open-label portion up to Week 144. Participants who benefit from treatment in the opinion of the Investigator may continue their assigned intervention up to Week 168 (or until they have the option to enroll in a DOR/ISL 100 mg/0.25 mg study, whichever is sooner).

Official Title
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A Phase 3 Randomized, Active-Controlled, Double-Blind Clinical Study to Evaluate the Antiretroviral Activity, Safety, and Tolerability of Doravirine/Islatravir Once-Daily in HIV-1 Infected Treatment-Naïve Participants

Conditions
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HIV-1 Infection

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is human immunodeficiency virus type 1 (HIV-1) positive Is naïve to antiretroviral therapy (ART) defined as having received ≤10 days of prior therapy with any antiretroviral agent following a diagnosis of HIV-1 infection including prevention of mother-to-child transmission up to 1 month prior to screening. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: 1) Is not a woman of childbearing potential (WOCBP); 2) Is a WOCBP and using an acceptable contraceptive method, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis); 3) 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; 4) If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required Exclusion Criteria: Has HIV-2 infection Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator Has an active diagnosis of hepatitis due to any cause, including active HBV infection (defined as hepatitis B surface antigen [HBsAg]-positive or hepatitis B virus deoxyribonucleic acid [HBV DNA]-positive) 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 Has a history or current evidence of any condition (including active tuberculosis infection), therapy, laboratory abnormality or other circumstance (including drug or alcohol use or dependence) that might, in the opinion of the investigator, confound the results of the study or interfere with the participant's participation for the full duration of the study Has been treated for a viral infection other than HIV-1, such as hepatitis B, with an agent that is active against HIV-1 Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or any prohibited therapy from 45 days prior to Day 1 through the study intervention period 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 intervention period Has a documented or known virologic resistance to any approved HIV-1 reverse transcriptase inhibitor, or any study intervention Has exclusionary laboratory values within 45 days prior to Day 1 Is female and is expecting 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: Group 1: DOR/ISL<br>Treatment-naïve participants with HIV-1 receive blinded DOR/ISL and placebo to BIC/FTC/TAF once daily (QD) from Day 1 to Week 96, and open-label DOR/ISL up to Week 144. Participants who are benefitting from treatment are then eligible to continue on open-label DOR/ISL up to Week 168. | Drug: DOR/ISL<br>* 100 mg DOR/0.75 mg ISL FDC tablet taken once daily by mouth.<br>* Other names: Doravirine/islatravir;Drug: Placebo to BIC/FTC/TAF<br>* Placebo tablet matched to BIC/FTC/TAF taken by mouth.<br>|
| Active Comparator: Group 2: BIC/FTC/TAF<br>Treatment-naïve participants with HIV-1 receive blinded BIC/FTC/TAF and placebo to DOR/ISL QD from Day 1 to Week 96, and open-label BIC/FTC/TAF up to Week 144. Participants who are benefitting from treatment are then eligible to continue on open-label BIC/FTC/TAF up to Week 168. | Drug: BIC/FTC/TAF<br>* BIC/FTC/TAF 50/200/25 mg FDC tablet taken once daily by mouth.<br>* Other names: Bictegravir/emtricitabine/tenofovir alafenamide;Drug: Placebo to DOR/ISL<br>* Placebo tablet matched to DOR/ISL taken by mouth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) <50 Copies/mL at Week 48 | HIV-1 RNA levels in blood samples taken at each visit were measured by the Abbott Real Time polymerase chain reaction (PCR) assay with a reliable lower limit of quantification of 40 copies/mL. The percentage of participants with HIV-1 RNA <50 copies/mL at Week 48 was presented using the FDA Snapshot missing data approach. | Week 48 | 
| Percentage of Participants Who Experienced an Adverse Event (AE) up to Week 48 | An AE is any untoward medical occurrence in a study participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The percentage of participants who experience an AE was reported. | Up to approximately 48 weeks | 
| Percentage of Participants Who Discontinued Study Treatment Due to an AE up to Week 48 | An AE is any untoward medical occurrence in a study participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The percentage of participants who discontinued study treatment due to an AE were reported. | Up to approximately 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 96 | The percentage of participants with HIV-1 RNA <50 copies/mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The percentage of participants with HIV-1 RNA <50 copies/mL at Week 96 will be presented using the FDA Snapshot missing data approach. | Week 96 | 
| Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 144 | The percentage of participants with HIV-1 RNA <50 copies/mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The percentage of participants with HIV-1 RNA <50 copies/mL at Week 144 will be presented using the FDA Snapshot missing data approach. | Week 144 | 
| Percentage of Participants With HIV-1 RNA <40 Copies/mL at Week 48 | The percentage of participants with HIV-1 RNA <40 copies/mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The percentage of participants with HIV-1 RNA <40 copies/mL at Week 48 will be presented using the FDA Snapshot missing data approach. | Week 48 | 
| Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 48 | The percentage of participants with HIV-1 RNA <200 copies/mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The percentage of participants with HIV-1 RNA <200 copies/mL at Week 48 will be presented using the FDA Snapshot missing data approach. | Week 48 | 
| Percentage of Participants With HIV-1 RNA <40 Copies/mL at Week 96 | The percentage of participants with HIV-1 RNA <40 copies/mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The percentage of participants with HIV-1 RNA <40 copies/mL at Week 96 will be presented using the FDA Snapshot missing data approach. | Week 96 | 
| Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 96 | The percentage of participants with HIV-1 RNA <200 copies/mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The percentage of participants with HIV-1 RNA <200 copies/mL at Week 96 will be presented using the FDA Snapshot missing data approach. | Week 96 | 
| Percentage of Participants With HIV-1 RNA <40 Copies/mL at Week 144 | The percentage of participants with HIV-1 RNA <40 copies/mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The percentage of participants with HIV-1 RNA <40 copies/mL at Week 144 will be presented using the FDA Snapshot missing data approach. | Week 144 | 
| Percentage of Participants With HIV-1 RNA <200 Copies/mL at Week 144 | The percentage of participants with HIV-1 RNA <200 copies/mL will be determined. The central laboratory will measure plasma HIV-1 RNA using an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. The percentage of participants with HIV-1 RNA <200 copies/mL at Week 144 will be presented using the FDA Snapshot missing data approach. | Week 144 | 
| Change From Baseline in Cluster of Differentiation 4+ (CD4+) T-Cell Counts at Week 48 | Plasma CD4+ T-cell count was measured in cells/mm^3 for baseline and 48 weeks by a central laboratory. Baseline measurements were defined as the Day 1 value of each participant. The mean change from baseline in CD4+ T-cell count at Week 48 was presented. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Cluster of Differentiation 4+ (CD4+) T-Cell Counts at Week 96 | Plasma CD4+ T-cell count will be measured in cells/mm^3 for baseline and 96 weeks by a central laboratory. Baseline measurements were defined as the Day 1 value of each participant. The mean change from baseline in CD4+ T-cell count at Week 96 will be presented. | Baseline (Day 1) and Week 96 | 
| Change From Baseline in Cluster of Differentiation 4+ (CD4+) T-Cell Counts at Week 144 | Plasma CD4+ T-cell count will be measured in cells/mm^3 for baseline and 144 weeks by a central laboratory. Baseline measurements were defined as the Day 1 value of each participant. The mean change from baseline in CD4+ T-cell count at Week 144 will be presented. | Baseline (Day 1) and Week 144 | 
| Incidence of Viral Resistance-Associated Substitutions (RASs) at Week 48 | RASs was defined as participants with confirmed HIV-1 RNA ≥200 copies/mL and/or genotypic or phenotypic analysis of data showing evidence of resistance to the study drug administered. The number of participants who demonstrated RASs at Week 48 was presented. | Week 48 | 
| Incidence of Viral RASs at Week 96 | RASs was defined as participants with confirmed HIV-1 RNA ≥200 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 viral RASs at Week 96 will be presented. | Week 96 | 
| Incidence of Viral RASs at Week 144 | RASs was defined as participants with confirmed HIV-1 RNA ≥200 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 viral RASs at Week 144 will be presented. | Week 144 | 
| Change From Baseline in Body Weight at Week 48 | Body weight was measured at baseline and at Week 48. Baseline measurements were defined as the Day 1 value of each participant. The change from baseline in body weight at Week 48 was presented. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Body Weight at Week 96 | Body weight was measured at baseline and at Week 96. Baseline measurements were defined as the Day 1 value of each participant. The change from baseline in body weight at Week 96 will be presented. | Baseline (Day 1) and Week 96 | 
| Change From Baseline in Body Weight at Week 144 | Body weight was measured at baseline and at Week 144. Baseline measurements were defined as the Day 1 value of each participant. The change from baseline in body weight at Week 144 will be presented. | Baseline (Day 1) and Week 144 | 
| Percentage of Participants Who Experienced an Adverse Event (AE) up to Week 156 | An AE is any untoward medical occurrence in a study participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The percentage of participants who experience an AE will be reported. | Up to approximately 156 weeks | 
| Percentage of Participants Who Discontinued Study Treatment Due to an AE up to Week 156 | An AE is any untoward medical occurrence in a study participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The percentage of participants who discontinued study treatment due to an AE will be reported. | Up to approximately 156 weeks |