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

• ClinicalTrials.gov Identifier: NCT03272347
• Recruitment Status: Completed
• First Posted: September 5, 2017
• Results First Posted: April 27, 2022
• Last Update Posted: March 29, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Study Description

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.

Condition or disease	Intervention/treatment	Phase
HIV-1 Infection	Drug: Islatravir; Drug: Placebo to Islatravir; Drug: Doravirine; Drug: Placebo to Doravirine; Drug: Lamivudine; Drug: Placebo to Lamivudine; Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; Drug: Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; Drug: Doravirine/Islatravir	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 123 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Masking Description: Masking in Part 1, including matching placebo. Masking only to dose in Part 2. No masking in Parts 3 and 4.
• Primary Purpose: Treatment
• Official Title: A Phase 2B, Randomized, Double-Blind, Active-Comparator-Controlled, Dose-Ranging Clinical Trial to Evaluate the Safety, Tolerability, Antiretroviral Activity, and Pharmacokinetics of MK-8591 Given in Combination With Doravirine (DOR) and Lamivudine (3TC) in HIV-1-Infected Treatment-Naïve Adults
• Actual Study Start Date: November 27, 2017
• Actual Primary Completion Date: March 8, 2021
• Actual Study Completion Date: March 9, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Islatravir 0.25 mg; 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; 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.; Other Name: MK-8591; Drug: Doravirine; Doravirine 100 mg is orally administered QD in tablet form for up to 144 weeks; Other Name: MK-1439; Drug: Lamivudine; Lamivudine 300 mg is orally administered QD in tablet form for up to 52 weeks; Other Name: 3TC; Drug: Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; Placebo to doravirine/lamivudine/tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 52 weeks; Drug: Doravirine/Islatravir; Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks; Other Name: MK-8591A
Experimental: Islatravir 0.75 mg; 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; 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.; Other Name: MK-8591; Drug: Doravirine; Doravirine 100 mg is orally administered QD in tablet form for up to 144 weeks; Other Name: MK-1439; Drug: Lamivudine; Lamivudine 300 mg is orally administered QD in tablet form for up to 52 weeks; Other Name: 3TC; Drug: Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; Placebo to doravirine/lamivudine/tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 52 weeks; Drug: Doravirine/Islatravir; Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks; Other Name: MK-8591A
Experimental: Islatravir 2.25 mg; 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; 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.; Other Name: MK-8591; Drug: Doravirine; Doravirine 100 mg is orally administered QD in tablet form for up to 144 weeks; Other Name: MK-1439; Drug: Lamivudine; Lamivudine 300 mg is orally administered QD in tablet form for up to 52 weeks; Other Name: 3TC; Drug: Placebo to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; Placebo to doravirine/lamivudine/tenofovir disoproxil fumarate is orally administered QD in tablet form for up to 52 weeks; Drug: Doravirine/Islatravir; Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks; Other Name: MK-8591A
Active Comparator: DOR/3TC/TDF; 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; Placebo to islatravir is orally administered QD in capsule form for up to 52 weeks; Drug: Placebo to Doravirine; Placebo to Doravirine is orally administered QD in tablet form for up to 52 weeks; Drug: Placebo to Lamivudine; Placebo to Lamivudine is orally administered QD in tablet form for up to 52 weeks; Drug: Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate; 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.; Other Name: MK-1439A; Drug: Doravirine/Islatravir; Fixed dose combination of islatravir 0.75 mg/doravirine 100 mg orally administered QD in tablet form for 48 weeks; Other Name: MK-8591A

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 24 [ Time Frame: 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.
2. Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 48 [ Time Frame: 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.
3. Number of Participants Experiencing Adverse Events (AEs) up to Week 144 [ Time Frame: Up to 144 weeks ]
   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.
4. Number of Participants Discontinuing Study Drug Due to AEs up to Week 144 [ Time Frame: Up to 144 weeks ]
   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.

Secondary Outcome Measures :

1. Percentage of Participants With HIV-1 RNA <50 Copies/mL up to 24 Weeks After 3TC and Placebo Are Discontinued From the Regimen [ Time Frame: Up to 24 weeks after 3TC and Placebo are discontinued from the regimen (up to approximately 60 weeks after initiating treatment) ]
   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, and missing values were counted as failure. 3TC and placebo are discontinued from the regimen from Week 24 up to Week 52.
2. Percentage of Participants With HIV-1 RNA <50 Copies/mL up to 48 Weeks After 3TC and Placebo Are Discontinued From the Regimen [ Time Frame: Up to 48 weeks ]
   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, and missing values were counted as failure. 3TC and placebo are discontinued from the regimen from Week 24 up to Week 52.
3. Percentage of Participants With HIV-1 RNA <50 Copies/mL up to 48 Weeks After Starting Open-label Doravirine/Islatravir Regimen (Part 4) [ Time Frame: Up to Week 192 ]
   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. The percentage of participants with HIV-1 RNA <50 copies in Part 4 are reported.
4. Change From Baseline in Mature T-helper (CD4+ T)-Cell Count at Week 24 [ Time Frame: Baseline and Week 24 ]
   Blood samples were collected and cluster of differentiation (CD4)+ T-cell counts were performed, where baseline measurements are defined as the Day 1 value, and baseline values were carried forward for participants who discontinue due to lack of efficacy. Post-baseline data were collected after the first dose of study medication through 14 days after the last dose of study medication.
5. Change From Baseline in CD4+ T-cell Count at Week 48 [ Time Frame: Baseline and Week 48 ]
   Blood samples were collected and CD4+ T-cell counts were performed, where baseline measurements are defined as the Day 1 value, and baseline values were carried forward for participants who discontinue due to lack of efficacy. Post-baseline data were collected after the first dose of study medication through 14 days after the last dose of study medication.
6. Change From Baseline in CD4+ T-cell Count at Week 96 [ Time Frame: Baseline and Week 96 ]
   Blood samples were collected and CD4+ T-cell counts were performed, where baseline measurements are defined as the Day 1 value, and baseline values were carried forward for participants who discontinue due to lack of efficacy. Post-baseline data were collected after the first dose of study medication through 14 days after the last dose of study medication.
7. Change From Baseline in CD4+ T-cell Count at Week 144 [ Time Frame: Baseline and Week 144 ]
   Blood samples were collected and CD4+ T-cell counts were performed, where baseline measurements are defined as the Day 1 value, and baseline values were carried forward for participants who discontinue due to lack of efficacy. Post-baseline data were collected after the first dose of study medication through 14 days after the last dose of study medication.
8. Change From Baseline in CD4+ T-cell Count at Week 192 (Part 4) [ Time Frame: Baseline and Week 192 ]
   Blood samples were collected and CD4+ T-cell counts were performed, where baseline measurements are defined as the Week 144 value. The change from baseline in CD4+ T-cell count at Week 192 (Part 4) are reported.
9. Number of Participants Experiencing AEs Through 24 Weeks After 3TC and Placebo Are Discontinued From the Regimen [ Time Frame: Up to 24 weeks ]
   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. 3TC and placebo are discontinued from the regimen from Week 24 up to Week 52.
10. Number of Participants Discontinuing Study Drug Due to AEs Through 24 Weeks After 3TC and Placebo Are Discontinued From the Regimen [ Time Frame: Up to 24 weeks ]
    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. 3TC and placebo are discontinued from the regimen from Week 24 up to Week 52.
11. Number of Participants Experiencing AEs From Week 96 Through Study Duration [ Time Frame: Week 96 up to Week 192 ]
    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.
12. Number of Participants Discontinuing Study Drug Due to AEs From Week 96 Through Study Duration [ Time Frame: Week 96 up to Week 192 ]
    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.
13. Number of Participants Experiencing AEs During Open Label Doravirine/Islatravir Treatment After Week 144 up to Week 192 (Part 4) [ Time Frame: Week 144 up to Week 192 ]
    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. The number of participants who experienced AEs during Part 4 are reported.
14. Number of Participants Discontinuing Study Drug Due to AEs During Open Label Doravirine/Islatravir Treatment After Week 144 up to Week 192 (Part 4) [ Time Frame: Week 144 up to Week 192 ]
    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. The number of participants who discontinued the study drug due to AEs in Part 4 are reported.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Contacts and Locations

Locations

United States, Arizona

Pueblo Family Physicians ( Site 0119)

Phoenix, Arizona, United States, 85015

United States, California

University California / Davis ( Site 0101)

Sacramento, California, United States, 95817

United States, District of Columbia

Whitman Walker Clinic ( Site 0108)

Washington, District of Columbia, United States, 20005

United States, Florida

Orlando Immunology Center (OIC) ( Site 0105)

Orlando, Florida, United States, 32803

United States, Illinois

Northstar Medical Center ( Site 0102)

Chicago, Illinois, United States, 60657

United States, Missouri

Kansas City CARE Clinic ( Site 0106)

Kansas City, Missouri, United States, 64111

United States, Texas

Saint Hope Foundation, Inc. ( Site 0116)

Bellaire, Texas, United States, 77401

North Texas Infectious Diseases Consultants, PA ( Site 0103)

Dallas, Texas, United States, 75246

Tarrant County Infectious Disease Associates ( Site 0112)

Fort Worth, Texas, United States, 76104

The Crofoot Research Center, Inc. ( Site 0118)

Houston, Texas, United States, 77098

Chile

Clinica Arauco Salud ( Site 0200)

Santiago, RM, Chile

Biomedica Research Group ( Site 0202)

Santiago, Chile

Hospital Dr. Hernan Henriquez Aravena ( Site 0203)

Temuco, Chile

France

Hopital Avicenne ( Site 2302)

Bobigny, France

Hopital Saint-Andre ( Site 2307)

Bordeaux, France

CHU Hotel Dieu ( Site 2308)

Nantes, France

CHU de Nice Hopital Archet 1 ( Site 2303)

Nice, France

Hopital Bichat - Claude Bernard ( Site 2309)

Paris, France

Hopital Pitie Salpetriere ( Site 2305)

Paris, France

Hopital Saint Louis ( Site 2306)

Paris, France

Centre Hospitalier de Tourcoing ( Site 2301)

Tourcoing, France

United Kingdom

Brighton and Sussex University Hospitals NHS Trust ( Site 2105)

Brighton, East Sussex, United Kingdom

Chelsea and Westminster Hospital ( Site 2101)

London, United Kingdom

Royal London Hospital ( Site 2103)

London, United Kingdom

The Royal Free London NHS Foundation Trust ( Site 2102)

London, United Kingdom

North Manchester General Hospital ( Site 2104)

Manchester, United Kingdom

Sponsors and Collaborators

Merck Sharp & Dohme LLC

Investigators

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

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme LLC:

Study Protocol and Statistical Analysis Plan  [PDF] July 6, 2020

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

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.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT03272347
• Other Study ID Numbers: 8591-011; 2017-000437-32 ( EudraCT Number )
• First Posted: September 5, 2017
• Results First Posted: April 27, 2022
• Last Update Posted: March 29, 2023
• Last Verified: February 2023

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

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

Additional relevant MeSH terms:

Tenofovir; Lamivudine; Islatravir; Antiviral Agents; Anti-Infective Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-HIV Agents; Anti-Retroviral Agents