A Phase 3, Randomized, Active-controlled, Double-blind Study to Evaluate Efficacy and Safety of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Once Daily Fixed Dose Combination Regimen Versus a Regimen Consisting of Darunavir/Cobicistat Fixed Dose Combination Coadministered With Emtricitabine/Tenofovir Disoproxil Fumarate Fixed Dose Combination in Antiretroviral Treatment-naive Human Immunodeficiency Virus Type 1 Infected Subjects
Trial Snapshot
- Phase
- Phase 3
- Status
- Completed
- Sponsor
- Janssen Sciences Ireland UC
- Enrollment
- 725
- Primary Endpoint
- Percentage of Participants With Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Less Than (<) 50 Copies Per Milliliter (Copies Per mL) (Virologic Response) at Week 48 Defined by Food and Drug Administration (FDA) Snapshot Approach
Study Overview
Brief Summary
The purpose of this study is to demonstrate non-inferiority in efficacy of a darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) fixed dose combination (FDC) tablet versus Darunavir/Cobicistat (DRV/COBI) FDC coadministered with Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) FDC in human immunodeficiency virus-1 (HIV-1) infected, antiretroviral (ARV) treatment naive adult participants.
Detailed Description
This is a Phase 3, multicenter (when more than one hospital or medical school team work on a medical research study), randomized (study drug assigned by chance), double-blind (a medical research study in which neither the researchers nor the participant know what treatment the participant is receiving), active-controlled (study in which the experimental treatment or procedure is compared to a standard [control] treatment or procedure) study. The study consists of 5 periods: a Screening period, Double-blind treatment period, Single-arm treatment period, Extension period and a Follow-up period. Participants will receive either darunavir (DRV)/ cobicistat (COBI)/emtricitabine (FTC) /tenofovir alafenamide (TAF) fixed dose combination (D/C/F/TAF FDC) or DRV/COBI FDC along with FTC/TDF FDC. Primarily percentage of participants with human immunodeficiency virus (HIV) -1 Ribonucleic acid (RNA) less than (<) 50 copies per milliliter (copies/ml) defined by snapshot analysis will be evaluated. Participants' safety will be monitored throughout the study.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Subject must be antiretroviral (ARV) treatment-naive (never treated with an ARV including post-exposure prophylaxis and pre-exposure prophylaxis); no prior use of any approved or experimental anti- human immunodeficiency virus (anti-HIV) drug for any length of time
- •Screening plasma HIV-1 ribonucleic acid (RNA) level greater than or equal to >=1,000 copies per milliliter (copies/mL)
- •Cluster of Differentiation 4+ (CD4+) cell count >50 cells/microliter (cells/mcL)
- •Screening HIV-1 genotype report must show full sensitivity to DRV, TDF and FTC
- •Screening eGFRcreatinine >=70 mL/min according to the Cockcroft-Gault formula for creatinine clearance
Exclusion Criteria
- •Subject has been diagnosed with a new acquired immunodeficiency syndrome (AIDS)-defining condition within the 30 days prior to screening
- •Subject has proven or suspected acute hepatitis within 30 days prior to screening
- •Subject is hepatitis C or hepatitis B positive
- •Subject has a history of cirrhosis
Arms & Interventions
Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide
Subject will receive a single oral tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF fixed dose combination [FDC]) once daily along with DRV/COBI FDC-matching and FTC/TDF FDC-matching placebo tablets once daily up to Week 48 analysis unblinding visit (i.e. after last subject has reached Week 48). After Week 48 analysis unblinding visit, subjects will receive a single tablet containing D/C/F/TAF FDC once daily up to Week 96.
Intervention: Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide FDC (Drug)
Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide
Subject will receive a single oral tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF fixed dose combination [FDC]) once daily along with DRV/COBI FDC-matching and FTC/TDF FDC-matching placebo tablets once daily up to Week 48 analysis unblinding visit (i.e. after last subject has reached Week 48). After Week 48 analysis unblinding visit, subjects will receive a single tablet containing D/C/F/TAF FDC once daily up to Week 96.
Intervention: FTC/TDF FDC Matching Placebo (Drug)
Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide
Subject will receive a single oral tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF fixed dose combination [FDC]) once daily along with DRV/COBI FDC-matching and FTC/TDF FDC-matching placebo tablets once daily up to Week 48 analysis unblinding visit (i.e. after last subject has reached Week 48). After Week 48 analysis unblinding visit, subjects will receive a single tablet containing D/C/F/TAF FDC once daily up to Week 96.
Intervention: DRV/COBI FDC Matching Placebo (Drug)
DRV/COBI fixed dose combination (FDC) and FTC/TDF FDC
Subject will receive DRV 800 mg/COBI 150 mg FDC and FTC 200 mg/TDF 300 mg FDC along with D/C/F/TAF FDC-matching placebo tablet once daily up to Week 48 analysis unblinding (i.e. after last subject has reached Week 48). After Week 48 analysis unblinding, subjects will receive a single tablet containing D/C/F/TAF FDC once daily up to Week 96.
Intervention: DRV/COBI FDC (Drug)
DRV/COBI fixed dose combination (FDC) and FTC/TDF FDC
Subject will receive DRV 800 mg/COBI 150 mg FDC and FTC 200 mg/TDF 300 mg FDC along with D/C/F/TAF FDC-matching placebo tablet once daily up to Week 48 analysis unblinding (i.e. after last subject has reached Week 48). After Week 48 analysis unblinding, subjects will receive a single tablet containing D/C/F/TAF FDC once daily up to Week 96.
Intervention: FTC/TDF FDC (Drug)
DRV/COBI fixed dose combination (FDC) and FTC/TDF FDC
Subject will receive DRV 800 mg/COBI 150 mg FDC and FTC 200 mg/TDF 300 mg FDC along with D/C/F/TAF FDC-matching placebo tablet once daily up to Week 48 analysis unblinding (i.e. after last subject has reached Week 48). After Week 48 analysis unblinding, subjects will receive a single tablet containing D/C/F/TAF FDC once daily up to Week 96.
Intervention: D/C/F/TAF FDC - Matching Placebo (Drug)
Outcomes
Primary Outcomes
Percentage of Participants With Human Immunodeficiency Virus (HIV)-1 Ribonucleic Acid (RNA) Less Than (<) 50 Copies Per Milliliter (Copies Per mL) (Virologic Response) at Week 48 Defined by Food and Drug Administration (FDA) Snapshot Approach
Time Frame: At Week 48
Percentage of participants with a HIV-1 RNA \< 50 copies per mL were assessed using FDA snapshot approach which defines a participant's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. The snapshot approach classified participants into 3 outcome categories: 1) virologic success (HIV RNA \< 20/50/200 copies per mL at Week 48), 2) virologic failure (HIV RNA greater than or equal to \[\>=\] 20/50/200 copies per mL at Week 48), 3) no viral load data in the Week 48 visit window (discontinued due to adverse event/death/other reason). The missing HIV-1 RNA is considered as non-response.
Secondary Outcomes
- Percentage of Participants With HIV-1 RNA <20 and 200 Copies Per mL at Weeks 48 and 96 Defined by FDA Snapshot Approach(At Weeks 48 and 96)
- Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula at Week 48(Baseline and Week 48)
- Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) at Week 48(Baseline and Week 48)
- Percent Change From Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Week 48(Baseline and Week 48)
- Area Under the Plasma Concentration-Time Curve From Time of Administration to 24 Hours Post-dose (AUC0-24h) of Darunavir(0 to 24 hours post dose)
- Predose (Trough) Plasma Concentration (C0h) of Darunavir(30 minutes to 4 hours postdose at Weeks 2, 4, 12, 24 and 48 and at 2 timepoints with at least 2.5 hours in between sampling at Week 8 and 36 (first sample between 1 and 4 hours postdose))
- Percentage of Participants With HIV-1 RNA < 20, 50, and 200 Copies Per mL at Week 48 and 96 Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm(At Week 48 and 96)
- Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Formula at Week 48(Baseline and Week 48)
- Percentage of Participants With Grade 3 and 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Premature Discontinuations Due to Adverse Events Through Week 48(Up to Weeks 48)
- Area Under the Plasma Concentration Time Curve Across the Dosing Interval (AUCtau) of Tenofovir Alafenamide(30 minutes to 4 hours postdose at Weeks 2, 4, 12, 24 and 48 and at 2 timepoints with at least 2.5 hours in between sampling at Week 8 and 36 (first sample between 1 and 4 hours postdose))
- Change From Baseline in Levels of Serum Procollagen 1 N-Terminal Propeptide (P1NP) at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- Percentage of Participants With HIV-1 RNA <50 Copies Per mL at Week 96 Defined by FDA Snapshot Approach(At Week 96)
- Percentage of Participants With Grade 3 and 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Premature Discontinuations Due to Adverse Events Through Week 96(Up to Week 96)
- Change From Baseline in log10 HIV-1 RNA Levels at Week 48(Baseline and Week 48)
- Change From Baseline in Cluster of Differentiation-4 (CD4+) Cell Count at Week 48(Baseline and Week 48)
- Change From Baseline in Serum Creatinine at Week 48(Baseline and Week 48)
- Plasma Concentrations 2 Hours After Dosing (C0-2h) of Tenofovir Alafenamide(0 to 2 hours post dose)
- Change From Baseline in BMD T-score of Hip and Spine(Baseline, Weeks 24 and 48)
- Change From Baseline in Alkaline Phosphatase (ALP) Levels at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- Change From Baseline in Levels of Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine by Cockcroft-Gault Formula(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in UPCR(From Reference 1 to Week 96 for D/C/F/TAF+ FTC/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in UB2MGCR(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in BMD T-score of Hip and Spine at Week 96(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine by (Cockcroft-Gault Formula) at Week 48(Baseline and Week 48)
- Change From Baseline in Urine Protein to Creatinine Ratio (UPCR) at Week 48(Baseline and Week 48)
- Change From Baseline in Urine Retinol Binding Protein To Creatinine Ratio (URBPCR) at Week 48(Baseline and Week 48)
- Change From Baseline in Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Week 48(Baseline and Week 48)
- Percent Change From Baseline in Hip and Spine Bone Mineral Density (BMD)(Baseline, Weeks 24 and 48)
- Change From Baseline in Levels of 25-Hydroxyvitamin D (25-OH Vitamin D), at Week 24 and 48(Baseline, Weeks 24 and 48)
- Change From Baseline in Levels of Parathyroid Hormone (PTH) at Weeks 24 and 48(Baseline, Weeks 24 and 48)
- Change From Reference in log10 HIV-1 RNA Levels at Week 96(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in URBPCR(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Percent Change From Reference in Hip and Spine BMD(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in ALP Levels(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in Levels of Serum CTX(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in CD4+ Cell Count at Week 96(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in Levels of PTH(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Percentage of Participants With Non-PDVF by Kaplan-Meier Estimates(From Week 96 to end of extension (up to 2 years and 6 months))
- Percentage of Participants With Time to Treatment Failure by Kaplan-Meier Estimates(From Week 96 to end of extension (up to 3 years))
- CD4+ Cell Count Post-Week From 96 to End of Extension(Week 96 to end of extension (up to 3 years))
- Percentage of Participants With >95% Treatment Adherence Assessed by Drug Accountability(Baseline to Switch and switch to EOE to Open-Label D/C/F/TAF (Up to 3 years))
- Change From Reference in Serum Creatinine(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in eGFRcr by CKD-EPI Formula(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in Levels of 25-OH Vitamin D(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Percentage of Participants With HIV RNA <50, <20, and <200 Copies/mL Post-week 96 to End of Extension(Week 96 to end of extension (up to 3 years))
- Percentage of Participants With Protocol-defined Virologic Failure (PDVF)(From Baseline up to Week 96)
- Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in UACR(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Percent Change From Reference in Urine FEPO4(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Change From Reference in Levels of Serum P1NP(From Reference 1 to Week 96 for D/C/F/TAF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF)
- Percentage of Participants With PDVF Post-week 96 to End of Extension(Week 96 to end of extension (up to 3 years))
- Number of Participants With ARV Resistance(Baseline to end of extension (up to 4 years))
- Percentage of Participants With Grade 3 and 4 AEs, SAEs, and Premature Discontinuations Due to Adverse Events Post-Week 96 to End of Extension(From Week 96 to end of extension (up to 3 years))