Clinical trial NCT02397096: 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)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV-1 Infection
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2015-03-24
Enrollment: 673
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: Three 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 Extensions 2 and 3 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.

Eligibility criteria: Inclusion Criteria:

Inclusion Criteria include, but are not limited to:

* Have plasma Human Immunodeficiency Virus-1 Ribonucleic Acid (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 Nucleoside Reverse Transcriptase Inhibitor (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
* For inclusion in Study Extension 3 (optional): completed the Week 240 visit; considered to have derived benefit from study participation up to Week 240; considered to be a clinically appropriate candidate for an additional 2 years treatment with study drug

Exclusion Criteria:

Exclusion Criteria include, but are not limited to:

* 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

Primary outcomes:
measure: Percentage of Participants Maintaining Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) <50 Copies/mL
timeFrame: Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24
Secondary outcomes:
measure: Mean Change From Baseline in Fasting Low-density Lipoprotein Cholesterol (LDL-C)
timeFrame: Baseline and Week 24
measure: Mean Change From Baseline in Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C)
timeFrame: Baseline and Week 24
measure: Percentage of Participants Maintaining HIV-1 RNA <50 Copies/mL
timeFrame: Week 24
measure: Mean Change From Baseline in Cluster of Differentiation (CD4) Cell Counts
timeFrame: Immediate Switch to MK-1439A arm: Baseline and Week 48; Delayed Switch to MK-1439A arm: Baseline and Week 24
measure: Mean Change From Baseline in Cluster of Differentiation (CD4) Cell Counts
timeFrame: Baseline and Week 24
measure: Percentage of Participants Maintaining HIV-1 RNA <40 Copies/mL
timeFrame: Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24
measure: Percentage of Participants Maintaining HIV-1 RNA <40 Copies/mL
timeFrame: Immediate Switch to MK-1439A arm: Week 24; Delayed Switch to MK-1439A arm: Week 24
measure: Percentage of Participants With HIV-1 RNA >=50 Copies/mL
timeFrame: Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24
measure: Percentage of Participants Experiencing ≥1 Adverse Event (AE)
timeFrame: Up to week 24
measure: Percentage of Participants Experiencing ≥1 Serious Adverse Event (SAE)
timeFrame: Up to 24 weeks
measure: Percentage of Participants Discontinuing From Study Medication Due to an AE(s)
timeFrame: Up to Week 24
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Kumar P, Johnson M, Molina JM, Rizzardini G, Cahn P, Bickel M, Wan H, Xu ZJ, Morais C, Sklar P, Greaves W; DRIVE-SHIFT Study Group. Brief Report: Switching to DOR/3TC/TDF Maintains HIV-1 Virologic Suppression Through Week 144 in the DRIVE-SHIFT Trial. J Acquir Immune Defic Syndr. 2021 Jun 1;87(2):801-805. doi: 10.1097/QAI.0000000000002642.
citation: Vaddady P, Kandala B, Yee KL. Population Pharmacokinetic and Pharmacodynamic Analysis To Evaluate a Switch to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate in People Living with HIV-1. Antimicrob Agents Chemother. 2020 Oct 20;64(11):e00590-20. doi: 10.1128/AAC.00590-20. Print 2020 Oct 20.
citation: Johnson M, Kumar P, Molina JM, Rizzardini G, Cahn P, Bickel M, Mallolas J, Zhou Y, Morais C, Kumar S, Sklar P, Hanna GJ, Hwang C, Greaves W; DRIVE-SHIFT Study Group. Switching to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintains HIV-1 Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT Trial. J Acquir Immune Defic Syndr. 2019 Aug 1;81(4):463-472. doi: 10.1097/QAI.0000000000002056.