Safety and Pharmacokinetics of Oral Islatravir (MK-8591) Once Monthly in Participants at Low Risk of Human Immunodeficiency Virus 1 (HIV-1) Infection (MK-8591-016)

• ClinicalTrials.gov Identifier: NCT04003103
• Recruitment Status: Active, not recruiting
• First Posted: July 1, 2019
• Last Update Posted: April 8, 2022
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: June 27, 2019
• First Posted Date: July 1, 2019
• Last Update Posted Date: April 8, 2022
• Actual Study Start Date: September 19, 2019
• Actual Primary Completion Date: March 18, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 8, 2020)

• Participants with an adverse event [ Time Frame: Up to Week 68 ]
  Percentage of participants with at least 1 adverse event (AE)
• Participants who discontinued from study therapy [ Time Frame: Up to week 20 ]
  Percentage of participants who discontinued from study therapy due to an AE
• Participants with a drug-related AE [ Time Frame: Up to Week 68 ]
  Percentage of participants with at least 1 drug-related AE
• Participants with a serious adverse event [ Time Frame: Up to Week 68 ]
  Percentage of participants with at least 1 serious AE (SAE)
• Participants with a Grade 3 to 5 AE [ Time Frame: Up to Week 68 ]
  Percentage of participants with at least 1 Grade 3 (severe AE) to 5 (death) AE
• Participants with a serious and drug-related AE [ Time Frame: Up to Week 68 ]
  Percentage of participants with at least 1 AE which is both serious and drug-related
• Participants with a Grade 3 to 5 and drug-related AE [ Time Frame: Up to Week 68 ]
  Percentage of participants with at least 1 AE which is both Grade 3 (severe AE) to 5 (death) AE and drug-related
• Participants with an AE resulting in death [ Time Frame: Up to Week 68 ]
  Percentage of participants with an AE which results in death

Original Primary Outcome Measures (submitted: June 27, 2019)

• Participants with an adverse event [ Time Frame: Up to Week 24 ]
  Percentage of participants with at least 1 adverse event (AE)
• Participants who discontinued from study therapy [ Time Frame: Up to week 20 ]
  Percentage of participants who discontinued from study therapy due to an AE
• Participants with a drug-related AE [ Time Frame: Up to Week 24 ]
  Percentage of participants with at least 1 drug-related AE
• Participants with a serious adverse event [ Time Frame: Up to Week 24 ]
  Percentage of participants with at least 1 serious AE (SAE)
• Participants with a Grade 3 to 5 AE [ Time Frame: Up to Week 24 ]
  Percentage of participants with at least 1 Grade 3 (severe AE) to 5 (death) AE
• Participants with a serious and drug-related AE [ Time Frame: Up to Week 24 ]
  Percentage of participants with at least 1 AE which is both serious and drug-related
• Participants with a Grade 3 to 5 and drug-related AE [ Time Frame: Up to Week 24 ]
  Percentage of participants with at least 1 AE which is both Grade 3 (severe AE) to 5 (death) AE and drug-related
• Participants with an AE resulting in death [ Time Frame: Up to Week 24 ]
  Percentage of participants with an AE which results in death

Current Secondary Outcome Measures (submitted: December 8, 2020)

• Area under the concentration-time curve of plasma islatravir [ Time Frame: Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 1, 2, 3, 21, 22, 23 and 24: collect at any time during the study visit. ]
  Area under the concentration-time curve (AUC) from time 0 to 672 hours post-dose of plasma islatravir
• Maximum concentration of plasma islatravir [ Time Frame: Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 1, 2, 3, 21, 22, 23 and 24: collect at any time during the study visit. ]
  Maximum concentration (Cmax) post-dose of plasma islatravir
• Trough concentration of plasma islatravir [ Time Frame: Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 1, 2, 3, 21, 22, 23 and 24: collect at any time during the study visit. ]
  Trough concentration (Ctrough) post-dose of plasma islatravir
• Apparent terminal half-life of plasma islatravir [ Time Frame: Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 1, 2, 3, 21, 22, 23 and 24: collect at any time during the study visit. ]
  Apparent terminal half-life (t1/2) post-dose of plasma islatravir
• Participants with an AE up to week 24 [ Time Frame: Up to week 24 ]
  Percentage of participants with at least 1 AE up to week 24
• Participants with a drug-related AE up to week 24 [ Time Frame: Up to week 24 ]
  Percentage of participants with at least 1 drug-related AE up to week 24
• Participants with a SAE up to week 24 [ Time Frame: Up to week 24 ]
  Percentage of participants with at least 1 SAE up to week 24
• Participants with Grade 3 to 5 AE up to week 24 [ Time Frame: Up to week 24 ]
  Percentage of participants with at least 1 Grade 3 to 5 AE up to week 24
• Participants with a serious and drug-related AE up to week 24 [ Time Frame: Up to week 24 ]
  Percentage of participants with at least 1 serious and drug-related AE up to week 24
• Participants with Grade 3 to 5 and drug-related AE up to week 24 [ Time Frame: Up to week 24 ]
  Percentage of participants with at least 1 Grade 3 to 5 and drug-related AE up to week 24
• Participants with an AE resulting in death up to week 24 [ Time Frame: Up to week 24 ]
  Percentage of participants with at least 1 AE resulting in death up to week 24

Original Secondary Outcome Measures (submitted: June 27, 2019)

• Area under the concentration-time curve of plasma MK-8591 [ Time Frame: Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 2, 3, 21, 22, 23 and 24: collect at any time during the study visit. ]
  Area under the concentration-time curve (AUC) from time 0 to 672 hours post-dose of plasma MK-8591
• Maximum concentration of plasma MK-8591 [ Time Frame: Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 2, 3, 21, 22, 23 and 24: collect at any time during the study visit. ]
  Maximum concentration (Cmax) post-dose of plasma MK-8591
• Trough concentration of plasma MK-8591 [ Time Frame: Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 2, 3, 21, 22, 23 and 24: collect at any time during the study visit. ]
  Trough concentration (Ctrough) post-dose of plasma MK-8591
• Apparent terminal half-life of plasma MK-8591 [ Time Frame: Day 1 and Week 20, collect predose and 30-min postdose. On Day 2 collect ~24 hours after Day 1 dose. On Weeks 4, 8, 12 and 16, collect predose. Weeks 2, 3, 21, 22, 23 and 24: collect at any time during the study visit. ]
  Apparent terminal half-life (t1/2) post-dose of plasma MK-8591
• AUC of MK-8591-triphosphate in peripheral blood mononuclear cells [ Time Frame: Day 1, Day 2, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 21, 22, 23, 24, 44, 52, 60, and 68 ]
  AUC from time 0-672 hours post-dose of MK-8591-triphosphate in peripheral blood mononuclear cells (PBMCs)
• Maximum concentration of MK-8591-triphosphate in PBMCs [ Time Frame: Day 1, Day 2, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 21, 22, 23, 24, 44, 52, 60, and 68 ]
  Maximum concentration (Cmax) post-dose of MK-8591-triphosphate in PBMCs
• Trough concentration of MK-8591-triphosphate in PBMCs [ Time Frame: Day 1, Day 2, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 21, 22, 23, 24, 44, 52, 60, and 68 ]
  Trough concentration (Ctrough) post-dose of MK-8591-triphosphate in PBMCs
• Apparent terminal half-life of MK-8591-triphosphate in PBMCs [ Time Frame: Day 1, Day 2, Weeks 1, 2, 3, 4, 8, 12, 16, 20, 21, 22, 23, 24, 44, 52, 60, and 68 ]
  Apparent terminal half-life (t1/2) post-dose of MK-8591-triphosphate in PBMCs

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

Descriptive Information

• Brief Title: Safety and Pharmacokinetics of Oral Islatravir (MK-8591) Once Monthly in Participants at Low Risk of Human Immunodeficiency Virus 1 (HIV-1) Infection (MK-8591-016)
• Official Title: A Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral MK-8591 Once-Monthly in Participants at Low- Risk for HIV-1 Infection
• Brief Summary: This study will evaluate the safety, tolerability and pharmacokinetics (PK) of 6 once-monthly doses of oral islatravir (60 mg and 120 mg) compared with placebo in adults at low risk of HIV-1 infection
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Prevention
• Condition: HIV-1 Infection

Intervention

• Drug: Islatravir
  Islatravir administered orally in capsule form swallowed whole once monthly for 24 weeks
  Other Name: MK-8591
• Drug: Placebo
  Placebo for islatravir administered orally in capsule form swallowed whole once monthly for 24 weeks

Study Arms

• Experimental: Islatravir 60 mg
  60 mg islatravir + placebo for islatravir administered once monthly, orally in capsule form for 24 weeks
  Interventions:

  • Drug: Islatravir
  • Drug: Placebo
• Experimental: Islatravir 120 mg
  120 mg islatravir administered once monthly, orally in capsule form for 24 weeks
  Intervention: Drug: Islatravir
• Placebo Comparator: Placebo
  Placebo for islatravir administered once monthly, orally in capsule form for 24 weeks
  Intervention: Drug: Placebo

• Publications *: Devanathan AS, Cottrell ML. Pharmacology of HIV Cure: Site of Action. Clin Pharmacol Ther. 2021 Apr;109(4):841-855. doi: 10.1002/cpt.2187. Epub 2021 Mar 5. Review.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: April 7, 2022): 242
• Original Estimated Enrollment (submitted: June 27, 2019): 250
• Estimated Study Completion Date: March 30, 2023
• Actual Primary Completion Date: March 18, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Is in general good health with acceptable laboratory values at screening
• Is confirmed HIV-uninfected based on negative HIV-1/HIV-2 test result before randomization
• Has low risk of HIV infection, within 12 months prior to screening visit or the rescreening visit (if applicable)
• Use contraceptives consistent with local regulations
• Female is not pregnant or breastfeeding, and is not a woman of childbearing potential (WOCBP)
• A WOCBP is using an acceptable contraceptive method, or is abstinent from heterosexual intercourse as their preferred and usual lifestyle; or has a negative pregnancy test.

Exclusion Criteria:

• Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator
• Has an active diagnosis of hepatitis due to any cause
• Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer.

• Is taking or is anticipated to require systemic immunosuppressive therapy, immune modulators, or any prohibited therapies from 30 days prior to Day

  1 through the duration of the study.

• Is currently participating in or has participated in an interventional clinical study with an investigational compound or device within 30 days prior to Day1 through the duration of the study.
• Has previously been randomized in a study and received islatravir (MK-8591).
• Female is expecting to conceive or donate eggs at any time during the study
• Has QTc interval (using Fridericia correction) >450 msec (for males) or >460 msec (for females) or deemed clinically abnormal by the investigator.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Israel, South Africa, United States

Administrative Information

• NCT Number: NCT04003103
• Other Study ID Numbers: 8591-016; Merck Protocol Number ( Other Identifier: MK-8591-016 ); 2019-001704-38 ( EudraCT Number )
• Has Data Monitoring Committee: No

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

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: April 2022