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)
- Conditions
- HIV-1 Infection
- Interventions
- Drug: DOR/ISL
- Registration Number
- NCT04295772
- Lead Sponsor
- Merck Sharp & Dohme LLC
- Brief Summary
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
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 42
- 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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description DOR/ISL DOR/ISL Pediatric participants with HIV-1 infection receive DOR/ISL for 96 weeks.
- Primary Outcome Measures
Name Time Method Maximum Plasma Concentration (Cmax) of ISL Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 The Cmax of ISL in plasma was determined at steady state.
C24 of ISL-TP in PBMCs 24 hours post-dose on Day 28 The C24 of ISL-TP in PBMCs was determined at steady state.
Number of Participants Discontinuing From Study Treatment Due to an AE Up to 24 weeks 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.
Apparent Total Clearance From Plasma (CL/F) of ISL Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 The CL/F of ISL from plasma was determined at steady state.
Apparent Volume of Distribution During Terminal Phase (Vz/F) of ISL Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 The Vz/F of ISL was determined at steady state.
AUC0-last of ISL-triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMCs) Pre-dose, and 4 and 24 hours post-dose on Day 28 The AUC0-24 of ISL-TP in PBMCs was determined at steady state.
Area Under the Plasma Drug Concentration-time Curve From 0 to 24 Hours Post-dose (AUC0-24) of Islatravir (ISL) Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 The AUC0-24 of ISL in plasma was determined at steady state.
Time to Reach Maximum Plasma Concentration (Tmax) of ISL Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 The Tmax of ISL in plasma was determined at steady state.
Apparent Plasma Terminal Half-life (t½) of ISL Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 The t½ of ISL in plasma was determined at steady state.
Cmax of ISL-TP in PBMCs Pre-dose, and 4, and 24 hours post-dose on Day 28 The Cmax of ISL-TP in PBMCs was determined at steady state.
Number of Participants Experiencing ≥1 Adverse Event (AE) Up to 24 weeks 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.
- Secondary Outcome Measures
Name Time Method Percentage of Virologically Suppressed (VS) Participants With HIV-1 Ribonucleic Acid (RNA) ≥50 Copies/mL Week 24 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.
Percentage of Treatment Naive (TN) Participants With HIV-1 RNA <50 Copies/mL Week 24 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.
Incidence of Viral Drug Resistance to ISL Up to 24 weeks The number of participants with viral drug resistance to ISL was determined.
Change From Baseline in Cluster of Differentiation 4+ (CD4+) T-cells in VS Participants Baseline (Day 1) and Week 24 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.
Change From Baseline in CD4+ T-cells in TN Participants Baseline (Day 1) and Week 24 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.
Incidence of Viral Drug Resistance to DOR Up to 24 weeks The number of participants with viral drug resistance to DOR was determined.
Palatability of DOR/ISL Tablet Baseline (Day 1), Week 4, and Week 24 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.
Percentage of VS Participants With HIV-1 RNA <50 Copies/mL Week 24 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.
Acceptability of DOR/ISL Tablet Baseline (Day 1), Week 4, and Week 24 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.
Trial Locations
- Locations (17)
Emory Children's Center ( Site 1805)
🇺🇸Atlanta, Georgia, United States
Johns Hopkins University ( Site 1800)
🇺🇸Baltimore, Maryland, United States
Children's National Medical Center ( Site 1816)
🇺🇸Washington, District of Columbia, United States
Azienda Ospedaliera Luigi Sacco ( Site 1300)
🇮🇹Milano, Italy
Duke University ( Site 1807)
🇺🇸Durham, North Carolina, United States
IRCCS Ospedale Pediatrico Bambino Gesu ( Site 1301)
🇮🇹Roma, Italy
FGU Republican Clinical Infectious Hospital of Roszdrav ( Site 1500)
🇷🇺Saint Petersburg, Sankt-Peterburg, Russian Federation
Krasnoyarsk Regional Center for Prevention and Control of AIDS ( Site 1507)
🇷🇺Krasnoyarsk, Krasnoyarskiy Kray, Russian Federation
Infectious Clinical Hospital #2 ( Site 1501)
🇷🇺Moscow, Moskva, Russian Federation
Saratov Regional Clinical Center for Prophylaxis and Control of AIDS ( Site 1505)
🇷🇺Saratov, Saratovskaya Oblast, Russian Federation
Perinatal HIV Research Unit ( Site 1902)
🇿🇦Johannesburg, Gauteng, South Africa
King Edward Hospital ( Site 1900)
🇿🇦Durban, Kwazulu-Natal, South Africa
Wits Reproductive Health and HIV Institute (WRHI) ( Site 1903)
🇿🇦Johannesburg, Gauteng, South Africa
Empilweni Services and Research Unit ( Site 1904)
🇿🇦Johannesburg, Gauteng, South Africa
Siriraj Hospital ( Site 1601)
🇹🇭Bangkok, Krung Thep Maha Nakhon, Thailand
Research Institute for Health Sciences ( Site 1603)
🇹🇭Chiang Mai, Thailand
Chulalongkorn University ( Site 1602)
🇹🇭Bangkok, Krung Thep Maha Nakhon, Thailand