Doravirine/Islatravir (DOR/ISL) in Pediatric Participants With Human Immunodeficiency Virus Type 1 (HIV-1) Who Are <18 Years of Age and Weigh ≥35 kg (MK-8591A-028)

Study Overview
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Brief Summary
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This is a phase 2, single-group, multi-site, open-label study of an islatravir/doravirine (ISL/DOR, MK-8591A) fixed dose combination (FDC) for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in pediatric participants who are virologically suppressed (VS) on antiretroviral therapy (ART) for ≥3 months or are treatment-naive (TN). The primary purposes of the study are 1) to examine the steady-state pharmacokinetics (PK) of ISL in plasma; 2) the steady-state PK of ISL-triphosphate (ISL-TP) in peripheral blood mononuclear cells (PBMCs); and 3) to examine the safety and tolerability of ISL/DOR.

Detailed Description
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As of protocol amendment 03 (approved 08-Feb-2022), all participants have been discontinued from study therapy and will be switched to non-study antiretroviral therapy and monitored for safety. The present results cover data obtained through the cut-off date of 30-Mar-2022, and will be updated once monitoring is completed.

Official Title
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A Phase 2 Clinical Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Doravirine/Islatravir in Pediatric Participants With HIV-1 Infection Who Are Virologically Suppressed or Treatment-Naïve, Are Less Than 18 Years of Age, and Weigh Greater Than or Equal to 35 kg

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: DOR/ISL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is HIV-1 positive, is <18 years of age, and weighs ≥35 kg at screening. VS Participants: Is HIV-1 positive at Screening with plasma HIV-1 RNA <50 copies/mL and has been receiving continuous, stable oral 2-drug or 3-drug combination ART ± PK booster with documented viral suppression for ≥3 months prior to providing documented informed consent/assent and has no history of prior virologic treatment failure on any past or current regimen. TN Participants: Is HIV-1 positive at Screening with plasma HIV-1 RNA ≥500 copies/mL and is naive to ART defined as having received <=10 days of prior therapy with any antiretrovirals following HIV-1 diagnosis other than pre-exposure prophylaxis (PrEP) or potentially exposed person (PEP). If female, is not pregnant or breastfeeding, and is either 1) not a woman of childbearing potential (WOCBP) or 2) is a WOCBP and is using acceptable contraception or is abstinent. Exclusion Criteria: Has HIV-2 infection. Has hypersensitivity or other contraindication to any of the components of the study drugs as determined by the investigator. Has an active diagnosis of hepatitis due to any cause, including active hepatitis B virus (HBV) infection (defined as hepatitis B surface antigen [HBsAg]-positive or HBV deoxyribonucleic acid [DNA] positive). Has a history of malignancy ≤5 years prior to providing documented 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, such that it is not in the best interest of the participant to participate. Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or any prohibited therapies from 45 days prior to Day 1 through the study treatment period. Is currently taking long-acting cabotegravir-rilpivirine. Is currently participating in or has participated in an interventional 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/ISL (DOR resistance substitutions in reverse transcriptase: V106A/M, V108I, Y188L, H221Y, P225H, F227C/L, M230I/L, L234I, P236L, or Y318F; ISL resistance substitution in reverse transcriptase: M184V/I). Has exclusionary laboratory values. Is female and expecting to conceive or donate eggs at any time during the study.

Ages Eligible for Study
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Maximum Age: 17 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DOR/ISL<br>Pediatric participants with HIV-1 infection receive DOR/ISL for 96 weeks. | Drug: DOR/ISL<br>* 100 mg DOR/0.75 mg ISL FDC tablet taken once daily by mouth.<br>* Other names: Doravirine/islatravir;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Plasma Drug Concentration-time Curve From 0 to 24 Hours Post-dose (AUC0-24) of Islatravir (ISL) | The AUC0-24 of ISL in plasma was determined at steady state. | Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 | 
| Maximum Plasma Concentration (Cmax) of ISL | The Cmax of ISL in plasma was determined at steady state. | Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 | 
| Time to Reach Maximum Plasma Concentration (Tmax) of ISL | The Tmax of ISL in plasma was determined at steady state. | Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 | 
| Apparent Plasma Terminal Half-life (t½) of ISL | The t½ of ISL in plasma was determined at steady state. | Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 | 
| Apparent Total Clearance From Plasma (CL/F) of ISL | The CL/F of ISL from plasma was determined at steady state. | Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 | 
| Apparent Volume of Distribution During Terminal Phase (Vz/F) of ISL | The Vz/F of ISL was determined at steady state. | Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 | 
| AUC0-last of ISL-triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMCs) | The AUC0-24 of ISL-TP in PBMCs was determined at steady state. | Pre-dose, and 4 and 24 hours post-dose on Day 28 | 
| Cmax of ISL-TP in PBMCs | The Cmax of ISL-TP in PBMCs was determined at steady state. | Pre-dose, and 4, and 24 hours post-dose on Day 28 | 
| C24 of ISL-TP in PBMCs | The C24 of ISL-TP in PBMCs was determined at steady state. | 24 hours post-dose on Day 28 | 
| Number of Participants Experiencing ≥1 Adverse Event (AE) | 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. | Up to 24 weeks | 
| Number of Participants Discontinuing From Study Treatment Due to an AE | 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. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Virologically Suppressed (VS) Participants With HIV-1 Ribonucleic Acid (RNA) ≥50 Copies/mL | The percentage of VS participants with HIV-1 RNA ≥50 copies/mL was determined at the central laboratory with an Abbott Real Time Polymerase Chain Reaction (PCR) assay with a lower limit of detection (LLOD) of 40 copies/mL. | Week 24 | 
| Percentage of VS Participants With HIV-1 RNA <50 Copies/mL | The percentage of VS participants with HIV-1 RNA <50 copies/mL will be determined at the central laboratory with an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. | Week 24 | 
| Percentage of Treatment Naive (TN) Participants With HIV-1 RNA <50 Copies/mL | The percentage of TN participants with HIV-1 RNA <50 copies/mL will be determined at the central laboratory with an Abbott Real Time PCR assay with a LLOD of 40 copies/mL. | Week 24 | 
| Change From Baseline in Cluster of Differentiation 4+ (CD4+) T-cells in VS Participants | CD4+ T-cell counts were measured by a central laboratory. Negative and positive results represent a decrease and increase, respectively, from baseline CD4+ T-cell counts. | Baseline (Day 1) and Week 24 | 
| Change From Baseline in CD4+ T-cells in TN Participants | CD4+ T-cell counts were measured by a central laboratory. Negative and positive results represent a decrease and increase, respectively, from baseline CD4+ T-cell counts. | Baseline (Day 1) and Week 24 | 
| Incidence of Viral Drug Resistance to DOR | The number of participants with viral drug resistance to DOR was determined. | Up to 24 weeks | 
| Incidence of Viral Drug Resistance to ISL | The number of participants with viral drug resistance to ISL was determined. | Up to 24 weeks | 
| Palatability of DOR/ISL Tablet | The palatability of the DOR/ISL tablet (whole or split) was assessed with a modified 5-point facial hedonic scale. Responses ranged from 1 (very bad) to 5 (very good). Data show the number of VS and TN participants responding at each score at the designated time points. | Baseline (Day 1), Week 4, and Week 24 | 
| Acceptability of DOR/ISL Tablet | The acceptability of the DOR/ISL tablet (whole or split) was assessed. Acceptability was assessed by monitoring for refusing the tablet, throwing up or spitting out the tablet, and gagging on the tablet. Data show the number of VS and TN participants responding at each score at the designated time points. | Baseline (Day 1), Week 4, and Week 24 |