Safety and Efficacy of Doravirine (MK-1439) in Participants With Human Immunodeficiency Virus 1 (HIV-1) (MK-1439-018) (DRIVE-FORWARD)

A Phase 3 Multicenter, Double-Blind, Randomized, Active Comparator-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Doravirine (MK-1439) 100 mg Once Daily Versus Darunavir 800 mg Once Daily Plus Ritonavir 100 mg Once Daily, Each in Combination With TRUVADA™ or EPZICOM™/KIVEXA™, in Treatment-Naïve HIV-1 Infected Subjects

To establish a new treatment option for treatment-naïve participants with HIV-1, the efficacy and safety of doravirine will be determined relative to a protease inhibitor (PI). Participants will receive double-blind treatment during the 96-week Base Study. Eligible participants in either of the Base Study groups will continue to receive the doravirine-containing regimen open label for an additional 96 weeks in the Study Extension 1. Eligible participants who are deriving benefit will continue in Study Extension 2 to receive the doravirine-containing regimen open label until doravirine becomes locally available or for an additional 96 weeks, whichever comes first. The primary hypothesis is that doravirine 100 mg once a day (q.d.) is non-inferior to darunavir/ritonavir (800 mg/100 mg) q.d., each in combination with TRUVADA™ or EPZICOM™/KIVEXA™, as assessed by the proportion of participants with HIV-1 ribonucleic acid (RNA) <50 copies/mL at Week 48. If non-inferiority is established, then the superiority of doravirine 100 mg q.d. compared to darunavir/ ritonavir (800 mg/100 mg) q.d. will be assessed.

Study Overview

• Status: Completed
• Conditions: HIV-1
• Intervention / Treatment: Drug: Doravirine; Drug: TRUVADA™ or EPZICOM™/KIVEXA™; Drug: Darunavir; Drug: Ritonavir

Detailed Description

Participants in Australia, Russia, and South Africa who are deriving benefit from MK-1439A are also eligible to continue receiving study drug during Study Extension 3, which will last for 2 years or until drug is available locally, whichever comes first.

• Study Type: Interventional
• Enrollment (Actual): 769
• Phase: Phase 3

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Is HIV-1 positive and has HIV treatment indicated based on physician assessment.
• Has received no (0 days of) antiretroviral therapy (ART), including investigational antiretroviral agents.
• Is considered clinically stable with no signs or symptoms of active infection for at least 2 weeks prior to the start of treatment.
• Female is highly unlikely to become pregnant, or male is highly unlikely to impregnate a partner because they are not of reproductive potential, or agree to practice abstinence or use acceptable contraception for up to 14 days after the last dose of study drug.
• Eligibility for the Study Extension 1 at the Week 96 visit: 1) completed the Week 96 visit, 2) derived benefit from participation through Week 96 in the opinion of the investigator, 3) is a clinically-appropriate candidate for an additional 96 weeks of treatment with the Study Extension regimen.
• Eligibility for the Study Extension 2 at the Week 192 visit: 1) completed the Week 192 visit, 2) derived benefit from participation through Week 192 in the opinion of the investigator, 3) is a clinically-appropriate candidate for 96 weeks of treatment with the Study Extension regimen.

Exclusion Criteria:

• Uses or has had a recent history of using recreational or illicit drugs.
• 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 documented or known resistance to study drugs including doravirine, darunavir, ritonavir, emtricitabine, tenofovir, abacavir and/or lamivudine.
• Has participated in a study with an investigational compound/device within the prior month, or anticipates doing so during this study.
• Has used systemic immunosuppressive therapy or immune modulators within the prior 30 days, or anticipates doing so during this study.
• Has significant hypersensitivity or other contraindication to any of the components of the study drugs.
• Has a current (active) diagnosis of acute hepatitis due to any cause.
• Is pregnant, breastfeeding or expecting to conceive at any time during the study.
• Female who expects to donate eggs, or male who expects to donate sperm at any time during the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Doravirine 100 mg; Double-blind Doravirine 100 mg administered orally (p.o.) once daily (q.d.) + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks in the Base Study. Eligible participants may continue in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o., q.d. for an additional 96 weeks. Eligible participants may continue to receive the Doravirine regimen in Study Extension 2 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first. Eligible participants may continue to receive the Doravirine regimen in Study Extension 3 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first.	Drug: Doravirine; Doravirine 100 mg tablet administered p.o. q.d.; Drug: TRUVADA™ or EPZICOM™/KIVEXA™; The investigator selects either TRUVADA™, a tablet containing 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate p.o. q.d. or EPZICOM™/KIVEXA™, a tablet containing 600 mg abacavir sulfate and 300 mg lamivudine, p.o. q.d.
Active Comparator: Darunavir 800 mg and Ritonavir 100 mg; Double-blind Darunavir 800 mg and Ritonavir 100 mg administered p.o. q.d. + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for 96 weeks. Eligible participants may continue in Study Extension 1 with open-label Doravirine 100 mg administered p.o. q.d. + investigator selected TRUVADA™ or EPZICOM™/KIVEXA™ administered p.o. q.d. for an additional 96 weeks. Eligible participants may continue to receive the Doravirine regimen in Study Extension 2 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first. Eligible participants may continue to receive the Doravirine regimen in Study Extension 3 until Doravirine becomes locally available, or for an additional 96 weeks, whichever comes first.	Drug: Doravirine; Doravirine 100 mg tablet administered p.o. q.d.; Drug: TRUVADA™ or EPZICOM™/KIVEXA™; The investigator selects either TRUVADA™, a tablet containing 200 mg emtricitabine and 300 mg tenofovir disoproxil fumarate p.o. q.d. or EPZICOM™/KIVEXA™, a tablet containing 600 mg abacavir sulfate and 300 mg lamivudine, p.o. q.d.; Drug: Darunavir; Darunavir 800 mg tablet administered p.o. q.d.; Drug: Ritonavir; Ritonavir 100 mg tablet administered p.o. q.d.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Plasma HIV-1 RNA <50 Copies/mL at Week 48	The percentage of participants in each arm achieving 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 and all missing data were considered treatment failures, regardless of the reason.	Week 48

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Plasma HIV-1 RNA <50 Copies/mL at Week 96	The percentage of participants in each arm achieving HIV-1 RNA levels <50 copies/mL at Week 96 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 96
Change From Baseline in Mean CD4+ T-cell Count at Week 48	CD4+ T-cell counts were quantified by a central laboratory using a commercially available assay.	Baseline and Week 48
Change From Baseline in Mean CD4+ T-cell Count at Week 96	CD4+ T-cell counts were quantified by a central laboratory using a commercially available assay.	Baseline and Week 96
Mean Change From Baseline in Fasting Low Density Lipoprotein Cholesterol (LDL-C) at Week 48	Serum LDL-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 48
Mean Change From Baseline in Fasting Non-High Density Lipoprotein Cholesterol (Non-HDL-C) at Week 48	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 LOCF approach was applied for missing data or data collected after modifying lipid-lowering therapy.	Baseline and Week 48
Mean Change From Baseline in Fasting High Density Lipoprotein Cholesterol (HDL-C) at Week 48	Serum 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 LOCF approach was applied for missing data or data collected after modifying lipid-lowering therapy.	Baseline and Week 48
Mean Change From Baseline in Fasting Total Cholesterol at Week 48	Serum total cholesterol was determined after an overnight fast. Change from Baseline was analyzed using ANCOVA models with terms for Baseline lipid level and treatment group. The LOCF approach was applied for missing data or data collected after modifying lipid-lowering therapy.	Baseline and Week 48
Mean Change From Baseline in Fasting Triglyceride at Week 48	Serum triglyceride was determined after an overnight fast. Change from Baseline was analyzed using ANCOVA models with terms for Baseline lipid level and treatment group. The LOCF approach was applied for missing data or data collected after modifying lipid-lowering therapy.	Baseline and Week 48
Percentage of Participants With Any Adverse Event	An adverse event (AE) is defined as any untoward medical occurrence in a study participant and which does not necessarily have to have a causal relationship to treatment. An adverse event can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the study treatment or protocol-specified procedure, whether or not considered related to study treatment or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the study treatment is also an AE. The percentage of participants with any AE was assessed.	Up to 98 weeks
Percentage of Participants With Any Serious Adverse Event	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 98 weeks
Percentage of Participants With Any Drug-related Adverse Event	The investigator was to determine if an AE had a reasonable possibility of a relationship to the study drug. The percentage of participants with any drug-related AE was assessed.	Up to 98 weeks
Percentage of Participants With Any Drug-related Serious Adverse Event	The percentage of participants with any drug-related SAE was assessed.	Up to 98 weeks
Percentage of Participants Who Discontinued Study Treatment Due to an Adverse Event	The percentage of participants who discontinued study treatment due to an AE was assessed.	Up to 96 weeks
Percentage of Participants Achieving Plasma HIV-1 RNA <40 Copies/mL at Week 48	The percentage of participants in each arm achieving HIV-1 RNA levels <40 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 and all missing data were considered treatment failures, regardless of the reason.	Week 48
Percentage of Participants Achieving Plasma HIV-1 RNA <40 Copies/mL at Week 96	The percentage of participants in each arm achieving HIV-1 RNA levels <40 copies/mL at Week 96 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 96

Collaborators and Investigators

• Sponsor: Merck Sharp & Dohme LLC
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• Thompson M, Orkin C, Molina JM, Sax P, Cahn P, Squires K, Xu X, Rodgers A, Kumar S, Teppler H, Martin E, Hanna G, Hwang C. Once-daily Doravirine for Initial Treatment of Adults Living With Human Immunodeficiency Virus-1: An Integrated Safety Analysis. Clin Infect Dis. 2020 Mar 17;70(7):1336-1343. doi: 10.1093/cid/ciz423.
• Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, Lai MT, Rodgers A, Lupinacci L, Kumar S, Sklar P, Hanna GJ, Hwang C, Martin EA; DRIVE-FORWARD trial group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double-blind, non-inferiority, phase 3 trial. Lancet HIV. 2020 Jan;7(1):e16-e26. doi: 10.1016/S2352-3018(19)30336-4. Epub 2019 Nov 15.
• Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, Lai MT, Xu X, Rodgers A, Lupinacci L, Kumar S, Sklar P, Nguyen BY, Hanna GJ, Hwang C; DRIVE-FORWARD Study Group. Doravirine versus ritonavir-boosted darunavir in antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018 May;5(5):e211-e220. doi: 10.1016/S2352-3018(18)30021-3. Epub 2018 Mar 25.
• 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. doi: 10.1093/cid/ciz1094.

Helpful Links

• Merck Clinical Trials Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2014
• Primary Completion (Actual): September 29, 2016
• Study Completion (Actual): March 6, 2023

Study Registration Dates

• First Submitted: October 23, 2014
• First Submitted That Met QC Criteria: October 23, 2014
• First Posted (Estimated): October 27, 2014

Study Record Updates

• Last Update Posted (Actual): October 1, 2024
• Last Update Submitted That Met QC Criteria: September 10, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Darunavir
• Other Study ID Numbers: 1439-018; MK-1439-018 (Other Identifier: MSD Protocol Number); 2014-001127-69 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf