Comparison of Doravirine, Tenofovir, Lamivudine (MK-1439A) and ATRIPLA™ in Treatment-Naive Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Participants (MK-1439A-021)

Study Overview
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Brief Summary
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The purpose of this study is to compare the antiretroviral activity of doravirine, tenofovir, lamivudine (MK-1439A), a single-tablet, once-daily (q.d.) fixed-dose combination (FDC) containing doravirine (MK-1439) 100 mg + lamivudine 300 mg + tenofovir disoproxil fumarate 300 mg, with ATRIPLA™, a single-tablet FDC containing efavirenz 600 mg + emtricitabine 200 mg + tenofovir disoproxil fumarate 300 mg, in treatment-naive participants infected with human immunodeficiency virus (HIV). The primary hypothesis is that doravirine, tenofovir, lamivudine q.d. is non-inferior to ATRIPLA™ q.d. as assessed by the proportion of participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL (by the Abbott RealTime HIV-1 Assay) at Week 48. This study has a total duration of 192 weeks, including a 96-week double-blind period and a 96-week open-label period. The present results are based on the first 48 weeks of this ongoing study.

Detailed Description
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Participants in Australia, Colombia, Guatemala, Honduras, Israel, New Zealand, Peru, Russia, South Africa, and Thailand who are deriving benefit from doravirine, tenofovir, lamivudine are also eligible to continue receiving study drug during additional open-label extensions which will last for 2 years or until drug is available locally, whichever comes first.

Official Title
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A Phase III Multicenter, Double-Blind, Randomized, Active Comparator-Controlled Clinical Trial to Evaluate the Safety and Efficacy of MK-1439A Once-Daily Versus ATRIPLA™ Once-Daily in Treatment-Naïve HIV-1 Infected Subjects

Conditions
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Human Immunodeficiency Virus (HIV)

Intervention / Treatment
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* Drug: Doravirine, Tenofovir, Lamivudine
* Drug: ATRIPLA™
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is HIV-1 positive as determined by a positive result on an enzyme-immunoassay, has screening plasma HIV-1 RNA (determined by the central laboratory) ≥1000 copies/mL within 45 days prior to the treatment phase of this study, and has HIV treatment indicated based on physician assessment Has never received antiretroviral therapy (ART) Is highly unlikely to either become pregnant or impregnate a partner Exclusion Criteria: Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound results of the study Is a user of recreational or illicit drugs or has a recent history of alcohol/drug abuse Has been treated for a viral infection other than HIV-1 (e.g., hepatitis B) with an agent that is active against HIV-1 Has participated in a study with an investigational drug/device within 30 days prior to Screening 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 Has a current (active) diagnosis of acute hepatitis due to any cause (note: 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 synthetic function) Is a female who is pregnant, breastfeeding, or expecting to conceive Is a female and is expecting to donate eggs or is male and is expecting to donate sperm (investigators will provide appropriate guidance regarding egg and/or sperm donation after completion of the study treatment regimen) Has evidence of decompensated liver disease manifested by the presence of or a history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or other signs or symptoms of advanced liver diseases, or has liver cirrhosis and a Child-Pugh Class C score or Pugh-Turcotte (CPT) score > 9

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: Doravirine, Tenofovir, Lamivudine<br>Treatment-naive HIV-infected participants will receive doravirine, tenofovir, lamivudine, a single-tablet FDC containing doravirine 100 mg + lamivudine 300 mg + tenofovir disoproxil fumarate 300 mg, q.d. by mouth for 96 weeks. Participants will also take 1 placebo tablet matched to ATRIPLA™ q.d. by mouth for 96 weeks in order to maintain blinding. | Drug: Doravirine, Tenofovir, Lamivudine<br>* One doravirine, tenofovir, lamivudine tablet taken q.d. by mouth.<br>* Other names: MK-1439A;Drug: Placebo<br>* Placebo tablets matched to ATRIPLA® or Doravirine, Tenofovir, Lamivudine.<br>|
| Active Comparator: ATRIPLA™<br>Treatment-naive HIV-infected participants will receive ATRIPLA™, a single-tablet FDC containing efavirenz 600 mg + emtricitabine 200 mg + tenofovir disoproxil fumarate 300 mg (equivalent to 245 mg tenofovir disoproxil), q.d. by mouth for 96 weeks. Participants will also take 1 placebo tablet matched to doravirine, tenofovir, lamivudine q.d. by mouth for 96 weeks in order to maintain blinding. | Drug: ATRIPLA™<br>* One ATRIPLA™ tablet taken q.d. by mouth<br>Drug: Placebo<br>* Placebo tablets matched to ATRIPLA® or Doravirine, Tenofovir, Lamivudine.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/mL at Week 48 | The percentage of participants in each arm with HIV-1 RNA levels <50 copies/mL at Week 48 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 in which all missing data are considered treatment failures, regardless of the reason. | Week 48 | 
| Percentage of Participants With Tier-1 Neuropsychiatric Adverse Events (AEs) | The percentage of participants in each arm experiencing ≥1 pre-specified Tier-1 neuropsychiatric AEs was determined. The list of Tier-1 neuropsychiatric AE categories included dizziness, sleep disorders and disturbances, and altered sensorium (including disturbance in attention). | Up to Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 96 | The percentage of participants in each arm with HIV-1 RNA levels <50 copies/mL at Week 96 will be determined. Plasma HIV-1 RNA levels will be quantified with the Abbott RealTime HIV-1 Assay. The US Food and Drug Administration (FDA) snapshot approach (i.e., all missing data handled as treatment failures, regardless of the reason) will be used for efficacy analyses. | Week 96 | 
| Percentage of Participants With HIV-1 RNA <40 Copies/mL at Week 48 | The percentage of participants in each arm with HIV-1 RNA levels <40 copies/mL (including target detected and target not detected) at Week 48 was determined. Plasma HIV 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 in which all missing data are considered treatment failures, regardless of the reason. | Week 48 | 
| Percentage of Participants With HIV-1 RNA <40 Copies/mL at Week 96 | The percentage of participants in each arm with HIV-1 RNA levels <40 copies/mL (including target detected and target not detected) at Week 96 will be determined. Plasma HIV-1 RNA levels will be quantified with the Abbott RealTime HIV-1 Assay. The US Food and Drug Administration (FDA) snapshot approach (i.e., all missing data handled as treatment failures, regardless of the reason) will be used for efficacy analyses. | Week 96 | 
| Change From Baseline in CD4 Cell Counts at Week 48 | 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 prior to Week 48 due to lack of efficacy. Cell counts at Baseline and Week 48 were measured and expressed as cells/mm^3, and percent change was then calculated as [(Baseline counts - Week 48 counts)*100]. CD4 cell counts were quantified by a central laboratory using a commercially available assay. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in CD4 Cell Counts at Week 96 | The mean change from baseline in CD4 cell counts at Week 96 will be assessed using the Observed Failure (OF) approach. With the OF approach, baseline values will be carried forward for participants who discontinued prior to Week 96 due to lack of efficacy. Cell counts at Baseline and Week 96 will be measured and expressed as cells/mm^3, and percent change will then be calculated as [(Baseline counts - Week 96 counts)*100]. CD4 cell counts will be quantified by a central laboratory using a commercially available assay. | Baseline (Day 1) and Week 96 | 
| Percentage of Participants Experiencing ≥1 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 48 | 
| 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 48 | 
| Percentage of Participants With Tier-2 Neuropsychiatric AEs | The percentage of participants in each arm experiencing ≥1 pre-specified Tier-2 neuropsychiatric AEs was determined. The list of Tier-2 neuropsychiatric AE categories included depression and suicide/self-injury and psychosis and psychotic disorders. | Up to Week 48 | 
| Change From Baseline in Fasting LDL-C at Week 48 | The mean percent change from baseline in fasting (fast duration of ≥8 hours) LDL-C levels at Week 48 was determined for each arm. The Last Observation Carry Forward (LOCF) approach was applied to missing data and data collected after a participant initiated lipid-modifying therapy. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Fasting Non-HDL-C at Week 48 | The mean percent change from baseline in fasting (fast duration of ≥8 hours) non-HDL-C levels at Week 48 was determined for each arm. The LOCF approach was applied to missing data and data collected after a participant initiated lipid-modifying therapy. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Fasting Cholesterol at Week 48 | The mean percent change from baseline in fasting (fast duration of ≥8 hours) cholesterol levels at Week 48 was determined for each arm. The LOCF approach was applied to missing data and data collected after a participant initiated lipid-modifying therapy. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Fasting Triglycerides at Week 48 | The mean percent change from baseline in fasting (fast duration of ≥8 hours) triglycerides levels at Week 48 was determined for each arm. The LOCF approach was applied to missing data and data collected after a participant initiated lipid-modifying therapy. | Baseline (Day 1) and Week 48 | 
| Change From Baseline in Fasting HDL-C at Week 48 | The mean percent change from baseline in fasting (fast duration of ≥8 hours) HDL-C levels at Week 48 was determined for each arm. The LOCF approach was applied to missing data and data collected after a participant initiated lipid-modifying therapy. | Baseline (Day 1) and Week 48 | 
| Percentage of Participants With HIV-1 RNA Below the Limit of Quantification (BLoQ) at Week 48 | The percentage of participants in each arm with HIV-1 RNA levels BLoQ of 40 copies/mL and target not detected at Week 48 was determined. Plasma HIV RNA levels were quantified with the Abbott RealTime HIV-1 Assay. Data were handled as observed. | Week 48 | 
| Percentage of Participants With HIV-1 RNA BLoQ at Week 96 | The percentage of participants in each arm with HIV-1 RNA levels BLoQ of 40 copies/mL and target not detected at Week 96 will be determined. Plasma HIV RNA levels will be quantified with the Abbott RealTime HIV-1 Assay. Data will be handled as observed. | Week 48 | 
| Plasma Concentration of Doravirine at Week 48 | Plasma samples were collected for analysis of doravirine concentration at Week 48. A total of 2 samples were collected: 1 prior to dosing and 1 collected between 0.5 and 2 hours post-dose. | 0 hours post-dose and 2 hours post-dose on Week 48 |