Comparison of MK-1439A and ATRIPLA™ in Treatment-Naive Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Participants (MK-1439A-021) (DRIVE-AHEAD)

• ClinicalTrials.gov Identifier: NCT02403674
• Recruitment Status: Active, not recruiting
• First Posted: March 31, 2015
• Results First Posted: April 30, 2018
• Last Update Posted: April 24, 2020
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Study Description

Brief Summary:

The purpose of this study is to compare the antiretroviral activity of 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 MK-1439A 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.

Condition or disease	Intervention/treatment	Phase
Human Immunodeficiency Virus (HIV)	Drug: MK-1439A; Drug: ATRIPLA™; Drug: Placebo	Phase 3

Detailed Description:

Participants in Australia, Colombia, Guatemala, Honduras, Israel, New Zealand, Peru, Russia, South Africa, and Thailand who are deriving benefit from MK-1439A 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 734 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: June 5, 2015
• Actual Primary Completion Date: March 20, 2017
• Estimated Study Completion Date: November 18, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: MK-1439A; Treatment-naive HIV-infected participants will receive MK-1439A, 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: MK-1439A; One MK-1439A tablet taken q.d. by mouth.; Drug: Placebo; Placebo tablets matched to ATRIPLA® or MK-1439A.
Active Comparator: ATRIPLA™; 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 MK-1439A q.d. by mouth for 96 weeks in order to maintain blinding.	Drug: ATRIPLA™; One ATRIPLA™ tablet taken q.d. by mouth; Drug: Placebo; Placebo tablets matched to ATRIPLA® or MK-1439A.

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With HIV-1 Ribonucleic Acid (RNA) <50 Copies/mL at Week 48 [ Time Frame: 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.
2. Percentage of Participants With Tier-1 Neuropsychiatric Adverse Events (AEs) [ Time Frame: Up to Week 48 ]
   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).

Secondary Outcome Measures :

1. Percentage of Participants With HIV-1 RNA <50 Copies/mL at Week 96 [ Time Frame: 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.
2. Percentage of Participants With HIV-1 RNA <40 Copies/mL at Week 48 [ Time Frame: 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.
3. Percentage of Participants With HIV-1 RNA <40 Copies/mL at Week 96 [ Time Frame: 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.
4. Change From Baseline in CD4 Cell Counts at Week 48 [ Time Frame: Baseline (Day 1) and 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.
5. Change From Baseline in CD4 Cell Counts at Week 96 [ Time Frame: Baseline (Day 1) and 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.
6. Percentage of Participants Experiencing ≥1 AE [ Time Frame: Up to Week 48 ]
   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.
7. Percentage of Participants Discontinuing From Study Medication Due to an AE(s) [ Time Frame: Up to Week 48 ]
   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.
8. Percentage of Participants With Tier-2 Neuropsychiatric AEs [ Time Frame: Up to Week 48 ]
   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".
9. Change From Baseline in Fasting LDL-C at Week 48 [ Time Frame: Baseline (Day 1) and 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.
10. Change From Baseline in Fasting Non-HDL-C at Week 48 [ Time Frame: Baseline (Day 1) and 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.
11. Change From Baseline in Fasting Cholesterol at Week 48 [ Time Frame: Baseline (Day 1) and 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.
12. Change From Baseline in Fasting Triglycerides at Week 48 [ Time Frame: Baseline (Day 1) and 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.
13. Change From Baseline in Fasting HDL-C at Week 48 [ Time Frame: Baseline (Day 1) and 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.
14. Percentage of Participants With HIV-1 RNA Below the Limit of Quantification (BLoQ) at Week 48 [ Time Frame: 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.
15. Percentage of Participants With HIV-1 RNA BLoQ at Week 96 [ Time Frame: 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 96 will be determined. Plasma HIV RNA levels will be quantified with the Abbott RealTime HIV-1 Assay. Data will be handled as observed.
16. Plasma Concentration of Doravirine at Week 48 [ Time Frame: 0 hours post-dose and 2 hours post-dose on 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.

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:

• 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

Contacts and Locations

Sponsors and Collaborators

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

  Study Documents (Full-Text)

Documents provided by Merck Sharp & Dohme Corp.:

Study Protocol and Statistical Analysis Plan  [PDF] November 8, 2016

More Information

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

Orkin C, Molina JM, Lombaard J, DeJesus E, Rodgers A, Kumar S, Martin E, Hanna G, Hwang C. Once-daily Doravirine in Human Immunodeficiency Virus Type 1-Infected, Antiretroviral-naive Adults: An Integrated Efficacy Analysis. Clin Infect Dis. 2020 Mar 17;70(7):1344-1352. doi: 10.1093/cid/ciz424. Erratum in: Clin Infect Dis. 2020 Jan 2;70(2):360.

Orkin C, Squires KE, Molina JM, Sax PE, Wong WW, Sussmann O, Kaplan R, Lupinacci L, Rodgers A, Xu X, Lin G, Kumar S, Sklar P, Nguyen BY, Hanna GJ, Hwang C, Martin EA; DRIVE-AHEAD Study Group. Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate is Non-inferior to Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate in Treatment-naive Adults With Human Immunodeficiency Virus-1 Infection: Week 48 Results of the DRIVE-AHEAD Trial. Clin Infect Dis. 2019 Feb 1;68(4):535-544. doi: 10.1093/cid/ciy540.

• Responsible Party: Merck Sharp & Dohme Corp.
• ClinicalTrials.gov Identifier: NCT02403674
• Other Study ID Numbers: 1439A-021; 2014-003382-17 ( EudraCT Number ); MK-1439A-021 ( Other Identifier: Merck Protocol Number )
• First Posted: March 31, 2015
• Results First Posted: April 30, 2018
• Last Update Posted: April 24, 2020
• Last Verified: April 2020

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

Additional relevant MeSH terms:

Acquired Immunodeficiency Syndrome; HIV Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Slow Virus Diseases; Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents; Anti-HIV Agents