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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)

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ClinicalTrials.gov Identifier: NCT04295772
Recruitment Status : Active, not recruiting
First Posted : March 4, 2020
Last Update Posted : December 22, 2021
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Study Description
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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
HIV-1 Infection Drug: DOR/ISL Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 45 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : November 26, 2020
Estimated Primary Completion Date : July 29, 2022
Estimated Study Completion Date : January 26, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS
Drug Information available for: Doravirine

Arms and Interventions
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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


Outcome Measures
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Primary Outcome Measures :
  1. Area under the plasma drug concentration-time curve from 0 to 24 hours post-dose (AUC0-24) of islatravir (ISL) [ Time Frame: 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.

  2. Maximum plasma concentration (Cmax) of ISL [ Time Frame: 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.

  3. Time to reach maximum plasma concentration (Tmax) of ISL [ Time Frame: 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.

  4. Apparent total clearance from plasma (CL/F) of ISL [ Time Frame: 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.

  5. Apparent volume of distribution during terminal phase (Vz/F) of ISL [ Time Frame: 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.

  6. Apparent plasma terminal half-life (t½) of ISL [ Time Frame: 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.

  7. AUC0-24 of ISL-triphosphate (ISL-TP) in PBMCs [ Time Frame: 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.

  8. Cmax of ISL-TP in PMBCs [ Time Frame: 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.

  9. C24 of ISL-TP in PBMCs [ Time Frame: 24 hours post-dose on Day 28 ]
    The C24 of ISL-TP in PBMCs will be determined at steady state.

  10. Percentage of participants experiencing ≥1 adverse event (AE) [ Time Frame: 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.

  11. Percentage of participants discontinuing from study treatment due to an AE [ Time Frame: 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 :
  1. Percentage of participants experiencing ≥1 adverse event (AE) [ Time Frame: Up to at least 48 weeks (through study duration) ]
    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.

  2. Percentage of participants discontinuing from study treatment due to an AE [ Time Frame: Up to at least 48 weeks (through study duration) ]
    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.

  3. Percentage of VS participants with HIV-1 ribonucleic acid (RNA) ≥50 copies/mL [ Time Frame: 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.

  4. Percentage of VS participants with HIV-1 RNA ≥50 copies/mL [ Time Frame: Week 48 ]
    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.

  5. Percentage of VS participants with HIV-1 RNA ≥50 copies/mL [ Time Frame: Week 96 ]
    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.

  6. Percentage of VS participants with HIV-1 RNA <50 copies/mL [ Time Frame: 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.

  7. Percentage of VS participants with HIV-1 RNA <50 copies/mL [ Time Frame: Week 48 ]
    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.

  8. Percentage of VS participants with HIV-1 RNA <50 copies/mL [ Time Frame: Week 96 ]
    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.

  9. Percentage of TN participants with HIV-1 RNA <50 copies/mL [ Time Frame: 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.

  10. Percentage of TN participants with HIV-1 RNA <50 copies/mL [ Time Frame: Week 48 ]
    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.

  11. Percentage of TN participants with HIV-1 RNA <50 copies/mL [ Time Frame: Week 96 ]
    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.

  12. Change from baseline in cluster of differentiation 4+ (CD4+) T-cells in VS participants [ Time Frame: Baseline (Day 1) and Week 24 ]
    CD4+ T-cell counts will be measured by a central laboratory.

  13. Change from baseline in CD4+ T-cells in VS participants [ Time Frame: Baseline (Day 1) and Week 48 ]
    CD4+ T-cell counts will be measured by a central laboratory.

  14. Change from baseline in CD4+ T-cells in VS participants [ Time Frame: Baseline (Day 1) and Week 96 ]
    CD4+ T-cell counts will be measured by a central laboratory.

  15. Change from baseline in CD4+ T-cells in TN participants [ Time Frame: Baseline (Day 1) and Week 24 ]
    CD4+ T-cell counts will be measured by a central laboratory.

  16. Change from baseline in CD4+ T-cells in TN participants [ Time Frame: Baseline (Day 1) and Week 48 ]
    CD4+ T-cell counts will be measured by a central laboratory.

  17. Change from baseline in CD4+ T-cells in TN participants [ Time Frame: Baseline (Day 1) and Week 96 ]
    CD4+ T-cell counts will be measured by a central laboratory.

  18. Incidence of viral drug resistance to DOR [ Time Frame: Up to at least 48 weeks (through study duration) ]
    The incidence of viral drug resistance to DOR will be determined.

  19. Incidence of viral drug resistance to ISL [ Time Frame: Up to at least 48 weeks (through study duration) ]
    The incidence of viral drug resistance to ISL will be determined.

  20. Mean score on a 5-point visual analog facial hedonic scale assessing ease or difficulty associated with swallowing the DOR/ISL whole tablet [ Time Frame: 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.

  21. Mean score on a 5-point visual analog facial hedonic scale assessing ease or difficulty associated with swallowing the DOR/ISL split tablet [ Time Frame: 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
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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04295772


Locations
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Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.
More Information
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT04295772    
Other Study ID Numbers: 8591A-028
2019-003597-10 ( EudraCT Number )
MK-8591A-028 ( Other Identifier: Merck Protocol Number )
First Posted: March 4, 2020    Key Record Dates
Last Update Posted: December 22, 2021
Last Verified: December 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Infections
Islatravir
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
 Molecular Mechanisms of Pharmacological Action
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Anti-Retroviral Agents