Dose Ranging, Switch Study of Islatravir (ISL) and Ulonivirine (MK-8507) Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV-1) [MK-8591-013]

Study Overview
=================
Brief Summary
-----------------
This is a randomized, controlled, double-blind, study to evaluate the safety and tolerability of islatravir (ISL) + ulonivirine based on review of the accumulated safety data, in adult participants with human immunodeficiency virus type 1 (HIV-1) who have been virologically suppressed for ≥6 months on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) once-daily.

Detailed Description
-----------------
As of protocol amendment 2 (approved 01-Dec-2021), all participants are unblinded and discontinued from study therapy, and will be switched to non-study antiretroviral therapy. Participants who received ISL + ulonivirine will be followed for ≥6 months.

Official Title
-----------------
A Phase 2b, Randomized, Active-Controlled, Double-Blind, Dose-Ranging Clinical Study to Evaluate a Switch to Islatravir (ISL) and MK-8507 Once-Weekly in Adults With HIV-1 Virologically Suppressed on Bictegravir/Emtricitabine/Tenofovir Alafenamide (BIC/FTC/TAF) Once-Daily

Conditions
-----------------
HIV-1 Infection

Intervention / Treatment
-----------------
* Drug: Islatravir
* Drug: Ulonivirine
* Drug: BIC/FTC/TAF
* Drug: Placebo to ISL
* Drug: Placebo to Ulonivirine
* Drug: Placebo to BIC/FTC/TAF


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Is HIV-1 positive with plasma HIV-1 RNA <50 copies/mL at screening Has been virologically suppressed on BIC/FTC/TAF for ≥6 months Has a screening CD4+ T-cell count >200 cells/mm^3 (completed by the central laboratory) Is male or female, at least 18 years of age, at the time of signing the informed consent female participant 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 a contraceptive method that is highly effective (with a failure rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) 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 active hepatitis C virus (HCV) coinfection (defined as detectable HCV RNA) or hepatitis B virus (HBV) coinfection (defined as hepatitis B surface antigen [HBsAg]-positive or HBV deoxyribonucleic acid [DNA] positive) Has a current (active) diagnosis of acute hepatitis due to any cause 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 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 virological resistance to ulonivirine or nucleoside/nucleotide reverse transcriptase inhibitors (NNRTI) Is female and expecting to conceive or donate eggs at any time during the study

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: ISL 20 mg + Ulonivirine 100 mg<br>Participants receive ISL 20 mg (Parts 1-3) + ulonivirine 100 mg once weekly (QW) and placebo to BIC/FTC/TAF once daily (QD) [Part 1]. | Drug: Islatravir<br>* ISL capsule taken by mouth.<br>* Other names: MK-8591;Drug: Ulonivirine<br>* Ulonivirine tablet taken by mouth.<br>* Other names: MK-8507;Drug: Placebo to Ulonivirine<br>* Placebo tablet matched to ulonivirine taken by mouth.<br>Drug: Placebo to BIC/FTC/TAF<br>* Placebo tablet matched to BIC/FTC/TAF taken by mouth.<br>|
| Experimental: Group 2: ISL 20 mg + Ulonivirine 200 mg<br>Participants receive ISL 20 mg (Parts 1-3) + ulonivirine 200 mg QW and placebo to BIC/FTC/TAF QD (Part 1). | Drug: Islatravir<br>* ISL capsule taken by mouth.<br>* Other names: MK-8591;Drug: Ulonivirine<br>* Ulonivirine tablet taken by mouth.<br>* Other names: MK-8507;Drug: Placebo to Ulonivirine<br>* Placebo tablet matched to ulonivirine taken by mouth.<br>Drug: Placebo to BIC/FTC/TAF<br>* Placebo tablet matched to BIC/FTC/TAF taken by mouth.<br>|
| Experimental: Group 3: ISL 20 mg + Ulonivirine 400 mg<br>Participants receive ISL 20 mg (Parts 1-3) + ulonivirine 400 mg QW and placebo to BIC/FTC/TAF QD (Part 1). | Drug: Islatravir<br>* ISL capsule taken by mouth.<br>* Other names: MK-8591;Drug: Ulonivirine<br>* Ulonivirine tablet taken by mouth.<br>* Other names: MK-8507;Drug: Placebo to BIC/FTC/TAF<br>* Placebo tablet matched to BIC/FTC/TAF taken by mouth.<br>|
| Active Comparator: Group 4: BIC/FTC/TAF<br>Participants receive placebo to ISL + placebo to ulonivirine QW (Part 1) and BIC/FTC/TAF 50 mg/200 mg/25 mg QD (Parts 1 and 2). | Drug: BIC/FTC/TAF<br>* BIC/FTC/TAF tablet taken by mouth.<br>* Other names: BIKTARVY®;Drug: Placebo to ISL<br>* Placebo capsule matched to ISL taken by mouth.<br>Drug: Placebo to Ulonivirine<br>* Placebo tablet matched to ulonivirine taken by mouth.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with ≥1 adverse event (AE) | The percentage of participants with AEs will be determined. | Up to ≥96 weeks | 
| Percentage of participants discontinuing study intervention due to AE | The percentage of participants discontinuing due to AEs will be determined. | Up to ≥96 weeks |