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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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HIV-1 Infection

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HIV-1 RNA <50 Copies/mL up to 24 Weeks After 3TC and Placebo Are Discontinued From the Regimen | 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. | 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 | 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. | 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) | 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. | Up to Week 192 | 
| Change From Baseline in Mature T-helper (CD4+ T)-Cell Count at 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. | Baseline and Week 24 | 
| Change From Baseline in CD4+ T-cell Count at 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. | Baseline and Week 48 | 
| Change From Baseline in CD4+ T-cell Count at 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. | Baseline and Week 96 | 
| Change From Baseline in CD4+ T-cell Count at 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. | Baseline and Week 144 | 
| Change From Baseline in CD4+ T-cell Count at Week 192 (Part 4) | 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. | Baseline and Week 192 | 
| Number of Participants Experiencing AEs Through 24 Weeks After 3TC and Placebo Are Discontinued From the Regimen | 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. | Up to 24 weeks | 
| Number of Participants Discontinuing Study Drug Due to AEs Through 24 Weeks After 3TC and Placebo Are Discontinued From the Regimen | 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. | Up to 24 weeks | 
| Number of Participants Experiencing AEs From Week 96 Through Study Duration | 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. | Week 96 up to Week 192 | 
| Number of Participants Discontinuing Study Drug Due to AEs From Week 96 Through Study Duration | 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. | Week 96 up to Week 192 | 
| Number of Participants Experiencing AEs During Open Label Doravirine/Islatravir Treatment After Week 144 up to Week 192 (Part 4) | 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. | Week 144 up to Week 192 | 
| Number of Participants Discontinuing Study Drug Due to AEs During Open Label Doravirine/Islatravir Treatment After Week 144 up to Week 192 (Part 4) | 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. | Week 144 up to Week 192 |