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 Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
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. Certain participants may be followed for up to 6 months, if they met specified criteria for extended monitoring.
Study Design
Arms and Interventions
| 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:
|
Outcome Measures
Primary Outcome Measures
- 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 will be determined at steady state.
- 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 will be 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 will be determined at steady state.
- 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 will be 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 will be 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 will be determined at steady state.
- AUC0-24 of ISL-triphosphate (ISL-TP) in PBMCs [Pre-dose, and 4 and 24 hours post-dose on Day 28]
The AUC0-24 of ISL-TP in PBMCs will be determined at steady state.
- Cmax of ISL-TP in PMBCs [Pre-dose, and 4, and 24 hours post-dose on Day 28]
The Cmax of ISL-TP in PBMCs will be determined at steady state.
- C24 of ISL-TP in PBMCs [24 hours post-dose on Day 28]
The C24 of ISL-TP in PBMCs will be determined at steady state.
- Percentage 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.
- Percentage 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.
Secondary Outcome Measures
- 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 will be 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 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.
- Percentage of 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.
- Change from baseline in cluster of differentiation 4+ (CD4+) T-cells in VS participants [Baseline (Day 1) and Week 24]
CD4+ T-cell counts will be measured by a central laboratory.
- Change from baseline in CD4+ T-cells in TN participants [Baseline (Day 1) and Week 24]
CD4+ T-cell counts will be measured by a central laboratory.
- Incidence of viral drug resistance to DOR [Up to 24 weeks]
The incidence of viral drug resistance to DOR will be determined.
- Incidence of viral drug resistance to ISL [Up to 24 weeks]
The incidence of viral drug resistance to ISL will be determined.
- Mean score on a 5-point visual analog facial hedonic scale assessing ease or difficulty associated with swallowing the DOR/ISL whole tablet [Day 1 and Day 28]
The palatability and acceptability of the DOR/ISL whole tablet will be measured by a 5-point facial hedonic scale depicting various degrees of pleasure/displeasure that was modified from a Wong-Baker scale. Scores range from 1 ("worst swallowability/most discomfort") to 5 ("easiest swallowability/no discomfort at all"). Scores will be determined on Days 1 and 28.
- Mean score on a 5-point visual analog facial hedonic scale assessing ease or difficulty associated with swallowing the DOR/ISL split tablet [Week 24]
The palatability and acceptability of the DOR/ISL split tablet will be measured by a 5-point facial hedonic scale depicting various degrees of pleasure/displeasure that was modified from a Wong-Baker scale. Scores range from 1 ("worst swallowability/most discomfort") to 5 ("easiest swallowability/no discomfort at all"). Scores will be determined on Week 24.
Eligibility Criteria
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.
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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.
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Is currently taking long-acting cabotegravir-rilpivirine.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's National Medical Center ( Site 1816) | Washington | District of Columbia | United States | 20010 |
| 2 | Emory Children's Center ( Site 1805) | Atlanta | Georgia | United States | 30322 |
| 3 | Johns Hopkins University ( Site 1800) | Baltimore | Maryland | United States | 21287 |
| 4 | Duke University ( Site 1807) | Durham | North Carolina | United States | 27705 |
| 5 | Azienda Ospedaliera Luigi Sacco ( Site 1300) | Milano | Italy | 20157 | |
| 6 | IRCCS Ospedale Pediatrico Bambino Gesu ( Site 1301) | Roma | Italy | 00165 | |
| 7 | Krasnoyarsk Regional Center for Prevention and Control of AIDS ( Site 1507) | Krasnoyarsk | Krasnoyarskiy Kray | Russian Federation | 660049 |
| 8 | Infectious Clinical Hospital #2 ( Site 1501) | Moscow | Moskva | Russian Federation | 105275 |
| 9 | FGU Republican Clinical Infectious Hospital of Roszdrav ( Site 1500) | Saint Petersburg | Sankt-Peterburg | Russian Federation | 196645 |
| 10 | Saratov Regional Clinical Center for Prophylaxis and Control of AIDS ( Site 1505) | Saratov | Saratovskaya Oblast | Russian Federation | 410009 |
| 11 | Perinatal HIV Research Unit ( Site 1902) | Johannesburg | Gauteng | South Africa | 1864 |
| 12 | Wits Reproductive Health and HIV Institute (WRHI) ( Site 1903) | Johannesburg | Gauteng | South Africa | 2000 |
| 13 | Empilweni Services and Research Unit ( Site 1904) | Johannesburg | Gauteng | South Africa | 2093 |
| 14 | King Edward Hospital ( Site 1900) | Durban | Kwazulu-Natal | South Africa | 4001 |
| 15 | Chulalongkorn University ( Site 1602) | Bangkok | Krung Thep Maha Nakhon | Thailand | 10330 |
| 16 | Siriraj Hospital ( Site 1601) | Bangkok | Krung Thep Maha Nakhon | Thailand | 10700 |
| 17 | Research Institute for Health Sciences ( Site 1603) | Chiang Mai | Thailand | 50200 |
Sponsors and Collaborators
- Merck Sharp & Dohme LLC
Investigators
- Study Director: Medical Director, Merck Sharp & Dohme LLC
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 8591A-028
- MK-8591A-028
- 2019-003597-10