Clinical trial NCT04295772: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV-1 Infection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-03-04
Enrollment: 42
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Area Under the Plasma Drug Concentration-time Curve From 0 to 24 Hours Post-dose (AUC0-24) of Islatravir (ISL)
timeFrame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
measure: Maximum Plasma Concentration (Cmax) of ISL
timeFrame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
measure: Time to Reach Maximum Plasma Concentration (Tmax) of ISL
timeFrame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
measure: Apparent Plasma Terminal Half-life (t½) of ISL
timeFrame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
measure: Apparent Total Clearance From Plasma (CL/F) of ISL
timeFrame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
measure: Apparent Volume of Distribution During Terminal Phase (Vz/F) of ISL
timeFrame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28
measure: AUC0-last of ISL-triphosphate (ISL-TP) in Peripheral Blood Mononuclear Cells (PBMCs)
timeFrame: Pre-dose, and 4 and 24 hours post-dose on Day 28
measure: Cmax of ISL-TP in PBMCs
timeFrame: Pre-dose, and 4, and 24 hours post-dose on Day 28
measure: C24 of ISL-TP in PBMCs
timeFrame: 24 hours post-dose on Day 28
measure: Number of Participants Experiencing ≥1 Adverse Event (AE)
timeFrame: Up to 24 weeks
measure: Number of Participants Discontinuing From Study Treatment Due to an AE
timeFrame: Up to 24 weeks
Secondary outcomes:
measure: Percentage of Virologically Suppressed (VS) Participants With HIV-1 Ribonucleic Acid (RNA) ≥50 Copies/mL
timeFrame: Week 24
measure: Percentage of VS Participants With HIV-1 RNA <50 Copies/mL
timeFrame: Week 24
measure: Percentage of Treatment Naive (TN) Participants With HIV-1 RNA <50 Copies/mL
timeFrame: Week 24
measure: Change From Baseline in Cluster of Differentiation 4+ (CD4+) T-cells in VS Participants
timeFrame: Baseline (Day 1) and Week 24
measure: Change From Baseline in CD4+ T-cells in TN Participants
timeFrame: Baseline (Day 1) and Week 24
measure: Incidence of Viral Drug Resistance to DOR
timeFrame: Up to 24 weeks
measure: Incidence of Viral Drug Resistance to ISL
timeFrame: Up to 24 weeks
measure: Palatability of DOR/ISL Tablet
timeFrame: Baseline (Day 1), Week 4, and Week 24
measure: Acceptability of DOR/ISL Tablet
timeFrame: Baseline (Day 1), Week 4, and Week 24
Other outcomes:
Locations:
city: Washington
country: United States
facility: Children's National Medical Center ( Site 1816)
state: District of Columbia
city: Atlanta
country: United States
facility: Emory Children's Center ( Site 1805)
state: Georgia
city: Baltimore
country: United States
facility: Johns Hopkins University ( Site 1800)
state: Maryland
city: Durham
country: United States
facility: Duke University ( Site 1807)
state: North Carolina
city: Milano
country: Italy
facility: Azienda Ospedaliera Luigi Sacco ( Site 1300)
city: Roma
country: Italy
facility: IRCCS Ospedale Pediatrico Bambino Gesu ( Site 1301)
city: Krasnoyarsk
country: Russian Federation
facility: Krasnoyarsk Regional Center for Prevention and Control of AIDS ( Site 1507)
state: Krasnoyarskiy Kray
city: Moscow
country: Russian Federation
facility: Infectious Clinical Hospital #2 ( Site 1501)
state: Moskva
city: Saint Petersburg
country: Russian Federation
facility: FGU Republican Clinical Infectious Hospital of Roszdrav ( Site 1500)
state: Sankt-Peterburg
city: Saratov
country: Russian Federation
facility: Saratov Regional Clinical Center for Prophylaxis and Control of AIDS ( Site 1505)
state: Saratovskaya Oblast
city: Johannesburg
country: South Africa
facility: Perinatal HIV Research Unit ( Site 1902)
state: Gauteng
city: Johannesburg
country: South Africa
facility: Wits Reproductive Health and HIV Institute (WRHI) ( Site 1903)
state: Gauteng
city: Johannesburg
country: South Africa
facility: Empilweni Services and Research Unit ( Site 1904)
state: Gauteng
city: Durban
country: South Africa
facility: King Edward Hospital ( Site 1900)
state: Kwazulu-Natal
city: Bangkok
country: Thailand
facility: Chulalongkorn University ( Site 1602)
state: Krung Thep Maha Nakhon
city: Bangkok
country: Thailand
facility: Siriraj Hospital ( Site 1601)
state: Krung Thep Maha Nakhon
city: Chiang Mai
country: Thailand
facility: Research Institute for Health Sciences ( Site 1603)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: