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)

• ClinicalTrials.gov Identifier: NCT04295772
• Recruitment Status: Recruiting
• First Posted: March 4, 2020
• Last Update Posted: February 15, 2021
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Tracking Information

• First Submitted Date: March 3, 2020
• First Posted Date: March 4, 2020
• Last Update Posted Date: February 15, 2021
• Actual Study Start Date: November 26, 2020
• Estimated Primary Completion Date: July 29, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 9, 2020)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Original Primary Outcome Measures (submitted: March 3, 2020)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• AUC0-24 of doravirine (DOR) [ Time Frame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 ]
  The AUC0-24 of DOR in plasma will be determined at steady state.
• Cmax of DOR [ Time Frame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 ]
  The Cmax of DOR in plasma will be determined at steady state.
• Plasma concentration at 24 hours post-dose (C24) of DOR [ Time Frame: 24 hours post-dose on Day 28 ]
  The C24 of DOR in plasma will be determined at steady state.
• Tmax of DOR [ Time Frame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 ]
  The Tmax of DOR in plasma will be determined at steady state.
• CL/F of DOR [ Time Frame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 ]
  The CL/F of DOR in plasma will be determined at steady state.
• Vz/F of DOR [ Time Frame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 ]
  The Vz/F of DOR in plasma will be determined at steady state.
• t½ of DOR [ Time Frame: Pre-dose, and 0.5, 1, 2, 4, 8, 12, and 24 hours post-dose on Day 28 ]
  The t½ of DOR in plasma will be determined at steady state.
• 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.
• 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.
• 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.
• 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.
• 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.

Current Secondary Outcome Measures (submitted: September 9, 2020)

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Mean score on a 5-point visual analog facial hedonic scale assessing ease or difficulty associated with swallowing the DOR/ISL tablet [ Time Frame: Day 1 and Day 28 ]
  The palatability and acceptability of the DOR/ISL 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.

Original Secondary Outcome Measures (submitted: March 3, 2020)

• 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.
• 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.
• Percentage of participants with human immunodeficiency virus type 1 (HIV-1) ribonucleic acid (RNA) ≥50 copies/mL [ Time Frame: Week 24 ]
  The percentage of 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 participants with HIV-1 RNA ≥50 copies/mL [ Time Frame: Week 48 ]
  The percentage of 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 participants with HIV-1 RNA <50 copies/mL [ Time Frame: Week 24 ]
  The percentage of 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 participants with HIV-1 RNA <50 copies/mL [ Time Frame: Week 48 ]
  The percentage of 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 [ Time Frame: Baseline (Day 1) and Week 24 ]
  CD4+ T-cell counts will be measured by a central laboratory.
• Change from baseline in CD4+ T-cells [ Time Frame: Baseline (Day 1) and Week 48 ]
  CD4+ T-cell counts will be measured by a central laboratory.
• 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.
• 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: HIV-1 Infection

Intervention

Drug: DOR/ISL

100 mg DOR/0.75 mg ISL FDC tablet taken once daily by mouth.

Other Names:

• MK-8591A
• Doravirine/islatravir

Study Arms

Experimental: DOR/ISL

Pediatric participants with HIV-1 infection receive DOR/ISL for 96 weeks.

Intervention: Drug: DOR/ISL

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 9, 2020): 45
• Original Estimated Enrollment (submitted: March 3, 2020): 30
• Estimated Study Completion Date: January 26, 2024
• Estimated Primary Completion Date: July 29, 2022 (Final data collection date for primary outcome measure)

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 signing informed consent/assent
• 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 signing 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.
• Has exclusionary laboratory values.
• Is female and expecting to conceive or donate eggs at any time during the study.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: up to 17 Years (Child)
• Accepts Healthy Volunteers: No

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

• Listed Location Countries: Italy, Russian Federation, Thailand, United States

Administrative Information

• NCT Number: NCT04295772
• Other Study ID Numbers: 8591A-028; 2019-003597-10 ( EudraCT Number ); MK-8591A-028 ( Other Identifier: Merck Protocol Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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

• Responsible Party: Merck Sharp & Dohme Corp.
• Study Sponsor: Merck Sharp & Dohme Corp.
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

• PRS Account: Merck Sharp & Dohme Corp.
• Verification Date: February 2021