Islatravir (MK-8591) With Doravirine and Lamivudine in Participants Infected With Human Immunodeficiency Virus Type 1 (MK-8591-011)

NCT03272347 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 8591-0112017-000437-32
• Study Type: interventional
• Target: 123
• Locations: 4 countries
• Sites: 26

Brief Summary

This study will evaluate the safety, tolerability, antiretroviral activity, and pharmacokinetics of 3 doses of islatravir (MK-8591) in combination with doravirine (DOR) and lamivudine (3TC) administered to antiretroviral treatment-naïve adult participants with human immunodeficiency virus type 1 (HIV-1) infection.

Conditions

HIV-1 Infection

Outcome Measures

Primary Outcomes (4)

• Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 24

  Blood samples were collected and plasma human immunodeficiency virus 1 (HIV-1) ribonucleic acid (RNA) were quantified using a real time polymerase chain reaction (PCR) assay with a lower limit of detection of 40 copies/mL. Missing values were counted as failure.

  Week 24

• Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 48

  Blood samples were collected and plasma HIV-1 RNA were quantified using a real time PCR assay with a lower limit of detection of 40 copies/mL. Missing values were counted as failure.

  Week 48

• Number of Participants Experiencing Adverse Events (AEs) up to Week 144

  An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.

  Up to 144 weeks

• Number of Participants Discontinuing Study Drug Due to AEs up to Week 144

  An AE is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study treatment.

  Up to 144 weeks

Secondary Outcomes (14)

• Percentage of Participants With HIV-1 RNA <50 Copies/mL up to 24 Weeks After 3TC and Placebo Are Discontinued From the Regimen

  Up to 24 weeks after 3TC and Placebo are discontinued from the regimen (up to approximately 60 weeks after initiating treatment)

• Percentage of Participants With HIV-1 RNA <50 Copies/mL up to 48 Weeks After 3TC and Placebo Are Discontinued From the Regimen

  Up to 48 weeks

• Percentage of Participants With HIV-1 RNA <50 Copies/mL up to 48 Weeks After Starting Open-label Doravirine/Islatravir Regimen (Part 4)

  Up to Week 192

• Change From Baseline in Mature T-helper (CD4+ T)-Cell Count at Week 24

  Baseline and Week 24

• Change From Baseline in CD4+ T-cell Count at Week 48

  Baseline and Week 48

Study Arms (4)

Islatravir 0.25 mg

EXPERIMENTAL

Participants will be treated once daily (QD) with 0.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) for a minimum of 24 weeks. Between week 24 through week 52, 3TC and placebo to DOR/3TC/TDF may be discontinued. Around Week 60, participants may be switched to a selected open label dose of islatravir and DOR 100 mg QD and continue treatment until Week 144. At Week 144 participants will receive the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and will continue treatment until Week 192.

Drug: Islatravir; Drug: Doravirine; Drug: Lamivudine; Drug: Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; Drug: Doravirine/Islatravir

Islatravir 0.75 mg

EXPERIMENTAL

Participants will be treated QD with 0.75 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. Between week 24 through week 52, 3TC and placebo to DOR/3TC/TDF may be discontinued. Around Week 60, participants may be switched to a selected open label dose of islatravir and DOR 100 mg QD and will continue treatment until Week 144. At Week 144 participants will receive the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and will continue treatment until Week 192.

Drug: Islatravir; Drug: Doravirine; Drug: Lamivudine; Drug: Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; Drug: Doravirine/Islatravir

Islatravir 2.25 mg

EXPERIMENTAL

Participants will be treated QD with 2.25 mg islatravir, 100 mg DOR, 300 mg 3TC, and placebo to DOR/3TC/TDF for a minimum of 24 weeks. Between week 24 through week 52, 3TC and placebo to DOR/3TC/TDF may be discontinued. Around Week 60, participants may be switched to a selected open label dose of islatravir and DOR 100 mg QD and will continue treatment until Week 144. At Week 144 participants will receive the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and will continue treatment until Week 192.

Drug: Islatravir; Drug: Doravirine; Drug: Lamivudine; Drug: Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; Drug: Doravirine/Islatravir

DOR/3TC/TDF

ACTIVE COMPARATOR

Participants will be treated QD with placebo to islatravir, placebo to DOR, placebo to 3TC, and a fixed dose combination of DOR/3TC/TDF consisting of 100 mg DOR + 300 mg 3TC + 300 mg TDF for a minimum of 24 weeks. Between week 24 through week 52 placebo treatments may be discontinued and participants will receive only DOR/3TC/TDF QD open label up to Week 144. At Week 144 participants will receive the fixed dose combination of doravirine (100mg)/islatravir (0.75mg) QD open label and will continue treatment until Week 192.

Drug: Placebo to Islatravir; Drug: Placebo to Doravirine; Drug: Placebo to Lamivudine; Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; Drug: Doravirine/Islatravir

Interventions

Islatravir DRUG

Islatravir at 0.25 mg, 0.75 mg or 2.25 mg is orally administered QD in capsule form for up to 52 weeks. After Week 60 a selected open label dose may be administered.

Also known as: MK-8591

Islatravir 0.25 mg; Islatravir 0.75 mg; Islatravir 2.25 mg

Placebo to Islatravir DRUG

Placebo to islatravir is orally administered QD in capsule form for up to 52 weeks

DOR/3TC/TDF

Doravirine DRUG

Doravirine 100 mg is orally administered QD in tablet form for up to 144 weeks

Also known as: MK-1439

Islatravir 0.25 mg; Islatravir 0.75 mg; Islatravir 2.25 mg

Placebo to Doravirine DRUG

Placebo to Doravirine is orally administered QD in tablet form for up to 52 weeks

DOR/3TC/TDF

Lamivudine DRUG

Lamivudine 300 mg is orally administered QD in tablet form for up to 52 weeks

Also known as: 3TC

Islatravir 0.25 mg; Islatravir 0.75 mg; Islatravir 2.25 mg

Placebo to Lamivudine DRUG

Placebo to Lamivudine is orally administered QD in tablet form for up to 52 weeks

DOR/3TC/TDF

Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate DRUG

Fixed dose combination of 100 mg doravirine + 300 mg lamivudine + 300 mg tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 144 weeks.

Also known as: MK-1439A

DOR/3TC/TDF

Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate DRUG

Placebo to doravirine/lamivudine/tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 52 weeks

Islatravir 0.25 mg; Islatravir 0.75 mg; Islatravir 2.25 mg

Doravirine/Islatravir DRUG

Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks

Also known as: MK-8591A

DOR/3TC/TDF; Islatravir 0.25 mg; Islatravir 0.75 mg; Islatravir 2.25 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has HIV-1 infection
• Is naïve to anti-retroviral therapy (ART).
• Is clinically stable, with no signs or symptoms of acute infection, at the time of entry into the study
• Female is not pregnant, not breastfeeding, not a woman of childbearing potential (WOCBP); but if WOCBP agrees to follow the contraceptive guidance
• All participants, male and female, agree to use barrier methods of contraception when engaged in any sexual activity during treatment and for 6 weeks following treatment.

You may not qualify if:

• Is a user of recreational or illicit drugs or has had a history of drug or alcohol abuse or dependence that may interfere with trial participation
• Has significant hypersensitivity or other contraindication to any of the components of the study drugs
• Has a history of malignancy ≤5 years prior
• Female expects to donate eggs at any time during the study
• Is breastfeeding or expecting to conceive
• A WOCBP who has a positive urine pregnancy test on Day 1 before the first dose of study treatment
• Has been treated for a viral infection other than HIV-1, such as hepatitis B, with an agent that is active against HIV-1
• Has used systemic immunosuppressive therapy or immune modulators within 30 days prior to treatment in this study or is anticipated to need them during the course of the study
• Requires any of the following prohibited medications: Carbamazepine, Phenobarbital, Phenytoin, Rifabutin, Rifampin, Herbal remedies, St. John's Wort, Modafinil, Bosentan, Nafcillin, Pentostatin
• Is currently participating in or has participated in an interventional clinical trial with an investigational compound or device within 30 days of signing informed consent to participate in this current trial
• Has a documented or known virologic resistance to any approved HIV-1 reverse transcriptase inhibitor, protease inhibitor, integrase inhibitor
• Has active hepatitis C virus (HCV) coinfection defined as detectable HCV RNA or HBV co-infection defined as hepatitis B surface antigen \[HBsAg\]-positive
• Has a current (active) diagnosis of acute hepatitis due to any cause
• Has previously been randomized in a study and received islatravir (MK-8591), DOR, Doravirine, Tenofovir, Lamivudine, or 3TC.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Study Sites (26)

Pueblo Family Physicians ( Site 0119)

Phoenix, Arizona, 85015, United States

Location

University California / Davis ( Site 0101)

Sacramento, California, 95817, United States

Location

Whitman Walker Clinic ( Site 0108)

Washington D.C., District of Columbia, 20005, United States

Location

Orlando Immunology Center (OIC) ( Site 0105)

Orlando, Florida, 32803, United States

Location

Northstar Medical Center ( Site 0102)

Chicago, Illinois, 60657, United States

Location

Kansas City CARE Clinic ( Site 0106)

Kansas City, Missouri, 64111, United States

Location

Saint Hope Foundation, Inc. ( Site 0116)

Bellaire, Texas, 77401, United States

Location

North Texas Infectious Diseases Consultants, PA ( Site 0103)

Dallas, Texas, 75246, United States

Location

Tarrant County Infectious Disease Associates ( Site 0112)

Fort Worth, Texas, 76104, United States

Location

The Crofoot Research Center, Inc. ( Site 0118)

Houston, Texas, 77098, United States

Location

Clinica Arauco Salud ( Site 0200)

Santiago, RM, Chile

Location

Biomedica Research Group ( Site 0202)

Santiago, Chile

Location

Hospital Dr. Hernan Henriquez Aravena ( Site 0203)

Temuco, Chile

Location

Hopital Avicenne ( Site 2302)

Bobigny, France

Location

Hopital Saint-Andre ( Site 2307)

Bordeaux, France

Location

CHU Hotel Dieu ( Site 2308)

Nantes, France

Location

CHU de Nice Hopital Archet 1 ( Site 2303)

Nice, France

Location

Hopital Bichat - Claude Bernard ( Site 2309)

Paris, France

Location

Hopital Pitie Salpetriere ( Site 2305)

Paris, France

Location

Hopital Saint Louis ( Site 2306)

Paris, France

Location

Centre Hospitalier de Tourcoing ( Site 2301)

Tourcoing, France

Location

Brighton and Sussex University Hospitals NHS Trust ( Site 2105)

Brighton, East Sussex, United Kingdom

Location

Chelsea and Westminster Hospital ( Site 2101)

London, United Kingdom

Location

Royal London Hospital ( Site 2103)

London, United Kingdom

Location

The Royal Free London NHS Foundation Trust ( Site 2102)

London, United Kingdom

Location

North Manchester General Hospital ( Site 2104)

Manchester, United Kingdom

Location

Related Publications (2)

• Molina JM, Yazdanpanah Y, Afani Saud A, Bettacchi C, Chahin Anania C, Klopfer SO, Grandhi A, Eves K, Hepler D, Robertson MN, Hwang C, Hanna GJ, Correll T. Brief Report: Efficacy and Safety of Oral Islatravir Once Daily in Combination With Doravirine Through 96 Weeks for Treatment-Naive Adults With HIV-1 Infection Receiving Initial Treatment With Islatravir, Doravirine, and Lamivudine. J Acquir Immune Defic Syndr. 2022 Sep 1;91(1):68-72. doi: 10.1097/QAI.0000000000002879. Epub 2021 Dec 8.

  PMID: 35972855 DERIVED

• Molina JM, Yazdanpanah Y, Afani Saud A, Bettacchi C, Chahin Anania C, DeJesus E, Olsen Klopfer S, Grandhi A, Eves K, Robertson MN, Correll T, Hwang C, Hanna GJ, Sklar P. Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial. Lancet HIV. 2021 Jun;8(6):e324-e333. doi: 10.1016/S2352-3018(21)00021-7. Epub 2021 May 14.

  PMID: 34000227 DERIVED

MeSH Terms

Interventions

islatravir; doravirine; Lamivudine

Intervention Hierarchy (Ancestors)

Zalcitabine; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Dideoxynucleosides

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Masking in Part 1, including matching placebo. Masking only to dose in Part 2. No masking in Parts 3 and 4.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 1, 2017
• First Posted: September 5, 2017
• Study Start: November 27, 2017
• Primary Completion: March 8, 2021
• Study Completion: March 9, 2022
• Last Updated: March 29, 2023
• Results First Posted: April 27, 2022

Record last verified: 2023-02

Data Sharing

• IPD Sharing: Will share

Locations

US (10); GB (5); CL (3); FR (8)