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)

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

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.

Study Overview

• Status: Completed
• Conditions: HIV-1 Infection
• Intervention / Treatment: Drug: DOR/ISL

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20157
    • Azienda Ospedaliera Luigi Sacco ( Site 1300)
  • Roma, Italy, 00165
    • IRCCS Ospedale Pediatrico Bambino Gesu ( Site 1301)
• Russian Federation
  • Krasnoyarskiy Kray
    • Krasnoyarsk, Krasnoyarskiy Kray, Russian Federation, 660049
      • Krasnoyarsk Regional Center for Prevention and Control of AIDS ( Site 1507)
  • Moskva
    • Moscow, Moskva, Russian Federation, 105275
      • Infectious Clinical Hospital #2 ( Site 1501)
  • Sankt-Peterburg
    • Saint Petersburg, Sankt-Peterburg, Russian Federation, 196645
      • FGU Republican Clinical Infectious Hospital of Roszdrav ( Site 1500)
  • Saratovskaya Oblast
    • Saratov, Saratovskaya Oblast, Russian Federation, 410009
      • Saratov Regional Clinical Center for Prophylaxis and Control of AIDS ( Site 1505)
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 1864
      • Perinatal HIV Research Unit ( Site 1902)
    • Johannesburg, Gauteng, South Africa, 2000
      • Wits Reproductive Health and HIV Institute (WRHI) ( Site 1903)
    • Johannesburg, Gauteng, South Africa, 2093
      • Empilweni Services and Research Unit ( Site 1904)
  • Kwazulu-Natal
    • Durban, Kwazulu-Natal, South Africa, 4001
      • King Edward Hospital ( Site 1900)
• Thailand
  • Chiang Mai, Thailand, 50200
    • Research Institute for Health Sciences ( Site 1603)
  • Krung Thep Maha Nakhon
    • Bangkok, Krung Thep Maha Nakhon, Thailand, 10330
      • Chulalongkorn University ( Site 1602)
    • Bangkok, Krung Thep Maha Nakhon, Thailand, 10700
      • Siriraj Hospital ( Site 1601)
• United States
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center ( Site 1816)
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory Children's Center ( Site 1805)
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University ( Site 1800)
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University ( Site 1807)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 17 years (Child)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: DOR/ISL; Pediatric participants with HIV-1 infection receive DOR/ISL for 96 weeks.	Drug: DOR/ISL; 100 mg DOR/0.75 mg ISL FDC tablet taken once daily by mouth.; Other Names: MK-8591A; Doravirine/islatravir

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

Helpful Links

• Merck Clinical Trials Information

Study record dates

Study Major Dates

• Study Start (Actual): November 26, 2020
• Primary Completion (Actual): December 21, 2021
• Study Completion (Actual): January 25, 2023

Study Registration Dates

• First Submitted: March 3, 2020
• First Submitted That Met QC Criteria: March 3, 2020
• First Posted (Actual): March 4, 2020

Study Record Updates

• Last Update Posted (Actual): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 9, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Retroviral Agents; Islatravir
• Other Study ID Numbers: 8591A-028; MK-8591A-028 (Other Identifier: Merck Protocol Number); 2019-003597-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No