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Safety and Efficacy of a Switch to 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) (DRIVE-SHIFT)

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ClinicalTrials.gov Identifier: NCT02397096
Recruitment Status : Active, not recruiting
First Posted : March 24, 2015
Results First Posted : April 3, 2019
Last Update Posted : February 11, 2020
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Tracking Information
First Submitted Date  ICMJE March 18, 2015
First Posted Date  ICMJE March 24, 2015
Results First Submitted Date  ICMJE February 4, 2019
Results First Posted Date  ICMJE April 3, 2019
Last Update Posted Date February 11, 2020
Actual Study Start Date  ICMJE June 9, 2015
Actual Primary Completion Date February 22, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 13, 2019)
Percentage of Participants Maintaining Human Immunodeficiency Virus-1 Ribonucleic Acid (HIV-1 RNA) <50 Copies/mL [ Time Frame: Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24 ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: March 18, 2015)
Percentage of Participants Maintaining HIV-1 RNA <50 Copies/mL [ Time Frame: Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2019)
  • Mean Change From Baseline in Fasting Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline and Week 24 ]
    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.
  • Mean Change From Baseline in Fasting Non-high-density Lipoprotein Cholesterol (Non-HDL-C) [ Time Frame: Baseline and Week 24 ]
    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.
  • Percentage of Participants Maintaining HIV-1 RNA <50 Copies/mL [ Time Frame: Week 24 ]
    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.
  • Mean Change From Baseline in Cluster of Differentiation (CD4) Cell Counts [ Time Frame: Immediate Switch to MK-1439A arm: Baseline and Week 48; Delayed Switch to MK-1439A arm: Baseline and Week 24 ]
    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.
  • Mean Change From Baseline in Cluster of Differentiation (CD4) Cell Counts [ Time Frame: Baseline and Week 24 ]
    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.
  • Percentage of Participants Maintaining HIV-1 RNA <40 Copies/mL [ Time Frame: Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24 ]
    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.
  • Percentage of Participants Maintaining HIV-1 RNA <40 Copies/mL [ Time Frame: Immediate Switch to MK-1439A arm: Week 24; Delayed Switch to MK-1439A arm: Week 24 ]
    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.
  • Percentage of Participants With HIV-1 RNA >=50 Copies/mL [ Time Frame: Immediate Switch to MK-1439A arm: Week 48; Delayed Switch to MK-1439A arm: Week 24 ]
    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.
  • Percentage of Participants Experiencing ≥1 Adverse Event (AE) [ Time Frame: Up to week 24 ]
    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.
  • Percentage of Participants Experiencing ≥1 Serious Adverse Event (SAE) [ Time Frame: Up to 24 weeks ]
    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.
  • Percentage of Participants Discontinuing From Study Medication Due to an AE(s) [ Time Frame: Up to Week 24 ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2015)
  • Change from Baseline in Fasting Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Both arms: Baseline and Week 24 ]
  • Change from Baseline in Fasting Non-high-density Lipoprotein Cholesterol (non-HDL-C) [ Time Frame: Both arms: Baseline and Week 24 ]
  • Percentage of Participants Maintaining HIV-1 RNA <50 Copies/mL [ Time Frame: Both arms: Week 24 ]
  • Change from Baseline in Cluster of Differentiation (CD4) Cell Counts [ Time Frame: Immediate Switch to MK-1439A arm: Baseline and Week 48; Both arms: Baseline and Week 24 ]
  • Percentage of Participants Maintaining HIV-1 RNA <40 Copies/mL [ Time Frame: Immediate Switch to MK-1439A arm: Week 48; Both arms: Week 24 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy of a Switch to 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  ICMJE 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)
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 MK-1439A 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 Two optional study extensions are planned. Study Extension 1 will evaluate safety of the switch to MK-1439A for an additional 2 years beyond the Base Study. Study Extension 2 will evaluate safety of the switch to MK-1439A until MK-1439A becomes locally available, or 4 years beyond Study Extension 1, whichever comes first.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE HIV-1 Infection
Intervention  ICMJE
  • Drug: MK-1439A
    Single tablet containing MK-1439 (doravirine) 100 mg, lamivudine 300 mg, and tenofovir disoproxil fumarate 300 mg
    Other Names:
    • Doravirine (PIFELTRO™)
    • Doravirine/Lamivudine/Tenofovir disoproxil fumarate (DELSTRIGO™)
  • Drug: Baseline regimen of ritonavir- or cobicistat-boosted protease inhibitor
    Baseline regimen of antiretroviral therapy with a ritonavir- or cobicistat-boosted protease inhibitor (atazanavir, darunavir, or lopinavir) administered according to the product circular
  • Drug: Baseline regimen of cobicistat-boosted elvitegravir
    Baseline regimen of antiretroviral therapy with cobicistat-boosted elvitegravir administered according to the product circular
  • Drug: Baseline regimen of a non-nucleoside reverse transcriptase inhibitor
    Baseline regimen of antiretroviral therapy with a NNRTI (efavirenz, nevirapine, or rilpivirine) administered according to the product circular
  • Drug: Baseline regimen of two nucleoside reverse transcriptase inhibitors
    Baseline regimen of antiretroviral therapy with two NRTIs administered according to the product circular
Study Arms  ICMJE
  • Experimental: Immediate Switch to MK-1439A
    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 MK-1439A 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
    Interventions:
    • Drug: MK-1439A
    • 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
  • Active Comparator: Delayed Switch to MK-1439A
    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 MK-1439A 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
    Interventions:
    • Drug: MK-1439A
    • 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
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: December 20, 2017)
673
Original Estimated Enrollment  ICMJE
 (submitted: March 18, 2015)
660
Estimated Study Completion Date  ICMJE August 26, 2022
Actual Primary Completion Date February 22, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 MK-1439, 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Not Provided
Removed Location Countries Argentina,   Australia,   Austria,   Belgium,   Canada,   Colombia,   Denmark,   France,   Germany,   Guatemala,   Israel,   Italy,   Korea, Republic of,   Mexico,   New Zealand,   Peru,   Poland,   Puerto Rico,   Russian Federation,   Spain,   Switzerland,   United Kingdom,   United States
 
Administrative Information
NCT Number  ICMJE NCT02397096
Other Study ID Numbers  ICMJE 1439A-024
2014-005550-18 ( EudraCT Number )
MK-1439A-024 ( Other Identifier: Merck )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
URL: http://engagezone.msd.com/ds_documentation.php
Responsible Party Merck Sharp & Dohme Corp.
Study Sponsor  ICMJE Merck Sharp & Dohme Corp.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Merck Sharp & Dohme Corp.
PRS Account Merck Sharp & Dohme Corp.
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP