Safety and Efficacy of a Switch to Doravirine, Tenofovir, Lamivudine (MK-1439A) in Human Immunodeficiency Virus (HIV-1)-Infected Participants Virologically Suppressed on an Anti-retroviral Regimen in Combination With Two Nucleoside Reverse Transcriptase Inhibitors (MK-1439A-024)

Study Overview
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Brief Summary
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The multicenter, open label, randomized study will evaluate the safety and efficacy of a switch to MK-1439A (MK-1439 [doravirine] plus lamivudine and tenofovir disoproxil fumarate) in HIV-1-infected participants virologically suppressed on a protocol-specified antiretroviral regimen. The primary hypothesis is that a switch to doravirine, tenofovir, lamivudine will be non-inferior to continuation of the regimen at Screening for 24 weeks, as assessed by the proportion of participants maintaining HIV-1 ribonucleic acid (RNA) <50 copies/mL. The Base Study results will be based on the first 48 weeks of this ongoing study.

Detailed Description
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Two optional study extensions are planned. Study Extension 1 will evaluate safety of the switch to doravirine, tenofovir, lamivudine for an additional 2 years beyond the Base Study. Study Extension 2 will evaluate safety of the switch to doravirine, tenofovir, lamivudine until doravirine, tenofovir, lamivudine becomes locally available, or 4 years beyond Study Extension 1, whichever comes first.

Official Title
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A Phase III Multicenter, Open-Label, Randomized Study to Evaluate a Switch to MK-1439A in HIV-1-Infected Subjects Virologically Suppressed on a Regimen of a Ritonavir-boosted Protease Inhibitor and Two Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: Doravirine, Tenofovir, Lamivudine
* Drug: Baseline regimen of ritonavir- or cobicistat-boosted protease inhibitor
* Drug: Baseline regimen of cobicistat-boosted elvitegravir
* Drug: Baseline regimen of a non-nucleoside reverse transcriptase inhibitor
* Drug: Baseline regimen of two nucleoside reverse transcriptase inhibitors


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 18 years of age on the day of signing the informed consent. Understand the study procedures and voluntarily agree to participate by giving written informed consent for the trial. Have plasma HIV-1 RNA levels below the limit of quantification (BLoQ) (<40 copies/mL by the Abbott RealTime HIV-1 Assay as determined by the central laboratory) at the screening visit. Receiving antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) or cobicistat-boosted elvitegravir or a NNRTI (specifically, efavirenz, nevirapine, or rilpivirine) in combination with 2 NRTIs (and no other antiretroviral therapy) continuously for >= 6 months. Receiving first or second retroviral regimen (participants receiving a NNRTI at Screening must be on their first retroviral regimen) No history of using an experimental NNRTI Has a genotype prior to starting his/her initial antiretroviral regimen and no known resistance to any of the study agents Not receiving lipid lowering therapy or on a stable dose of lipid lowering therapy at the time of enrollment Has the following laboratory values at screening within 30 days prior to the treatment phase of this study: Alkaline phosphatase ≤ 3.0 x upper limit of normal (ULN), Serum aspartate aminotransferase (AST) and serum alanine aminotransferase (ALT) ≤ 5.0 x ULN, and Hemoglobin ≥9.0 g/dL (if female) or ≥10.0 g/dL (if male) Has a calculated creatinine clearance at the time of screening ≥ 50 mL/min, based on the Cockcroft-Gault equation Male or female participant not of reproductive potential or, if of reproductive potential, agrees to avoid becoming pregnant or impregnating a partner while receiving study drug and for 14 days after the last dose of study drug by complying with one of the following: 1) practice abstinence from heterosexual activity, or 2) use acceptable contraception during heterosexual activity For inclusion in Study Extension 1 (optional): completed the Week 48 visit; considered to have derived benefit from study participation up to Week 48; considered to be a clinically appropriate candidate for an additional 2 years treatment with study drug For inclusion in Study Extension 2 (optional): completed the Week 144 visit; considered to have derived benefit from study participation up to Week 144; considered to be a clinically appropriate candidate for an additional 2 years treatment with study drug Exclusion Criteria: Uses recreational or illicit drugs or has a recent history of drug or alcohol abuse or dependence Received treatment for a viral infection other than HIV-1, such as hepatitis B, with an agent that is active against HIV-1 such as adefovir, emtricitabine, lamivudine, or tenofovir Has documented or known resistance to study drugs including doravirine, lamivudine, and/or tenofovir Participated in a study with an investigational compound or device within 30 days or anticipates doing so during the course of this study Used systemic immunosuppressive therapy or immune modulators within 30 days or anticipates needing them during the course of this study (short courses of corticosteroids will be allowed) Current, active diagnosis of acute hepatitis due to any cause (participants with chronic hepatitis B and C may enter the study as long as they fulfill all entry criteria, have stable liver function tests, and have no significant impairment of hepatic function) Has evidence of decompensated liver disease or has liver cirrhosis and a Child-Pugh Class C score or Pugh-Turcotte score >9 Pregnant, breastfeeding, or expecting to conceive at any time during the study Female and is expecting to donate eggs or male and is expecting to donate sperm during the study

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immediate Switch to Doravirine, Tenofovir, Lamivudine<br>Participants receiving continuous antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) or cobicistat-boosted elvitegravir or a non nucleoside reverse transcriptase inhibitor (NNRTI) (specifically, efavirenz, nevirapine, or rilpivirine) in combination with 2 NRTIs for >=6 months with undetectable HIV-1 RNA will switch on Day 1 to doravirine, tenofovir, lamivudine single tablet by mouth once daily for 48 weeks in the Base Study and, optionally, for up to an additional 6 years in the Study Extensions | Drug: Doravirine, Tenofovir, Lamivudine<br>* Single tablet containing MK-1439 (doravirine) 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg<br>* Other names: MK-1439A;Drug: Baseline regimen of ritonavir- or cobicistat-boosted protease inhibitor<br>* Baseline regimen of antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) administered according to the product circular<br>Drug: Baseline regimen of cobicistat-boosted elvitegravir<br>* Baseline regimen of antiretroviral therapy with cobicistat-boosted elvitegravir administered according to the product circular<br>Drug: Baseline regimen of a non-nucleoside reverse transcriptase inhibitor<br>* Baseline regimen of antiretroviral therapy with a NNRTI (efavirenz, nevirapine, or rilpivirine) administered according to the product circular<br>Drug: Baseline regimen of two nucleoside reverse transcriptase inhibitors<br>* Baseline regimen of antiretroviral therapy with two NRTIs administered according to the product circular<br>|
| Active Comparator: Delayed Switch to Doravirine, Tenofovir, Lamivudine<br>Participants receiving continuous antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) or cobicistat-boosted elvitegravir or a NNRTI (specifically, efavirenz, nevirapine, or rilpivirine) in combination with 2 NRTIs for >=6 months with undetectable HIV-1 RNA will continue on this therapy until Week 24, at which time they will switch to doravirine, tenofovir, lamivudine single tablet by mouth once daily for 24 weeks in the Base Study and, optionally, for up to an additional 6 years in the Study Extensions | Drug: Doravirine, Tenofovir, Lamivudine<br>* Single tablet containing MK-1439 (doravirine) 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg<br>* Other names: MK-1439A;Drug: Baseline regimen of ritonavir- or cobicistat-boosted protease inhibitor<br>* Baseline regimen of antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) administered according to the product circular<br>Drug: Baseline regimen of cobicistat-boosted elvitegravir<br>* Baseline regimen of antiretroviral therapy with cobicistat-boosted elvitegravir administered according to the product circular<br>Drug: Baseline regimen of a non-nucleoside reverse transcriptase inhibitor<br>* Baseline regimen of antiretroviral therapy with a NNRTI (efavirenz, nevirapine, or rilpivirine) administered according to the product circular<br>Drug: Baseline regimen of two nucleoside reverse transcriptase inhibitors<br>* Baseline regimen of antiretroviral therapy with two NRTIs administered according to the product circular<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Maintaining Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) <50 Copies/mL | The percentage of participants in each arm achieving HIV-1 RNA levels <50 copies/mL was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) snapshot approach and all missing data were considered treatment failures, regardless of the reason. | Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Fasting Low-density Lipoprotein Cholesterol (LDL-C) | To evaluate the effect on fasting LDL-C of an immediate switch to DOR/3TC/TDF on Study Day 1 compared with continuation of a ritonavir-boosted, PI-based regimen, as measured by mean change from baseline in each treatment group. The Last Observation Carry Forward (LOCF) approach was applied to missing data and data collected after a participant initiated lipid-modifying therapy. | Baseline and Week 24 | 
| Mean Change From Baseline in Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) | Serum non-HDL-C was determined after an overnight fast. Change from Baseline was analyzed using ANCOVA models with terms for Baseline lipid level and treatment group. The Last Observation Carry Forward (LOCF) approach was applied for missing data or data collected after modifying lipid lowering therapy. | Baseline and Week 24 | 
| Percentage of Participants Maintaining HIV-1 RNA <50 Copies/mL | The percentage of participants in each arm achieving HIV-1 RNA levels <50 copies/mL was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) snapshot approach and all missing data were considered treatment failures, regardless of the reason. | Week 24 | 
| Mean Change From Baseline in Cluster of Differentiation (CD4) Cell Counts | The mean change from baseline in CD4 cell counts was assessed using the Observed Failure (OF) approach. With the OF approach, baseline values were carried forward for participants who discontinued due to lack of efficacy. Cell counts were measured and expressed as cells/mm^3, and percent change was then calculated. CD4 cell counts were quantified by a central laboratory using a commercially available assay. | Immediate Switch to MK-1439A arm: Baseline and Week 48; Delayed Switch to MK-1439A arm: Baseline and Week 24 | 
| Mean Change From Baseline in Cluster of Differentiation (CD4) Cell Counts | The mean change from baseline in CD4 cell counts at Week 48 was assessed using the Observed Failure (OF) approach. With the OF approach, baseline values were carried forward for participants who discontinued due to lack of efficacy. Cell counts were measured and expressed as cells/mm^3, and percent change was then calculated. CD4 cell counts were quantified by a central laboratory using a commercially available assay. | Baseline and Week 24 | 
| Percentage of Participants Maintaining HIV-1 RNA <40 Copies/mL | The percentage of participants in each arm achieving HIV-1 RNA levels <40 copies/mL was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) snapshot approach and all missing data were considered treatment failures, regardless of the reason. | Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24 | 
| Percentage of Participants Maintaining HIV-1 RNA <40 Copies/mL | To evaluate the immunological effect of an immediate switch to MK -1439A on Study Day 1 compared with continuation of a ritonavir boosted, PI-based regimen, as measured by the proportion of subjects maintaining HIV-1 RNA below the limit of quantification (BLoQ) by the Abbott RealTime HIV-1 Assay (<40 copies/mL) in both treatment groups. | Immediate Switch to MK-1439A arm: Week 24; Delayed Switch to MK-1439A arm: Week 24 | 
| Percentage of Participants With HIV-1 RNA >=50 Copies/mL | The percentage of participants in each arm achieving HIV-1 RNA levels >=50 copies/mL was determined. Plasma HIV-1 RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled according to the US Food and Drug Administration (FDA) snapshot approach. | Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24 | 
| Percentage of Participants Experiencing ≥1 Adverse Event (AE) | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to week 24 | 
| Percentage of Participants Experiencing ≥1 Serious Adverse Event (SAE) | A serious adverse event is an AE that results in death, is life threatening, results in persistent or significant disability or incapacity, results in or prolongs a hospitalization, is a congenital anomaly or birth defect, is a cancer, is associated with an overdose, or is another important medical event. The percentage of participants with any SAE was assessed. | Up to 24 weeks | 
| Percentage of Participants Discontinuing From Study Medication Due to an AE(s) | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to Week 24 |