Clinical trial NCT02431247: A Study to Evaluate Efficacy and Safety of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Fixed Dose Combination (FDC) Versus a Regimen Consisting of Darunavir/Cobicistat FDC With Emtricitabine/Tenofovir Disoproxil Fumarate FDC in Treatment-naive HIV Type 1 Infected Subjects
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Immunodeficiency Virus Type 1, Human
Keywords: Immunodeficiency Virus Type 1, Human
Darunavir
Cobicistat
Tenofovir Alafenamide
Emtricitabine
Tenofovir Disoproxil Fumarate
Lead sponsor: Janssen Sciences Ireland UC
Sponsor class: INDUSTRY
First posted: 2015-04-30
Enrollment: 725
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 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.

Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: At Week 48
Secondary outcomes:
measure: Percentage of Participants With HIV-1 RNA <20 and 200 Copies Per mL at Weeks 48 and 96 Defined by FDA Snapshot Approach
timeFrame: At Weeks 48 and 96
measure: 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
timeFrame: At Week 48 and 96
measure: Change From Baseline in log10 HIV-1 RNA Levels at Week 48
timeFrame: Baseline and Week 48
measure: Change From Baseline in Cluster of Differentiation-4 (CD4+) Cell Count at Week 48
timeFrame: Baseline and Week 48
measure: Change From Baseline in Serum Creatinine at Week 48
timeFrame: Baseline and Week 48
measure: 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
timeFrame: Baseline and Week 48
measure: Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine by (Cockcroft-Gault Formula) at Week 48
timeFrame: Baseline and Week 48
measure: Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula at Week 48
timeFrame: Baseline and Week 48
measure: 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
timeFrame: Up to Weeks 48
measure: Change From Baseline in Urine Protein to Creatinine Ratio (UPCR) at Week 48
timeFrame: Baseline and Week 48
measure: Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) at Week 48
timeFrame: Baseline and Week 48
measure: Change From Baseline in Urine Retinol Binding Protein To Creatinine Ratio (URBPCR) at Week 48
timeFrame: Baseline and Week 48
measure: Change From Baseline in Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Week 48
timeFrame: Baseline and Week 48
measure: Percent Change From Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Week 48
timeFrame: Baseline and Week 48
measure: Area Under the Plasma Concentration-Time Curve From Time of Administration to 24 Hours Post-dose (AUC0-24h) of Darunavir
timeFrame: 0 to 24 hours post dose
measure: Predose (Trough) Plasma Concentration (C0h) of Darunavir
timeFrame: 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)
measure: Area Under the Plasma Concentration Time Curve Across the Dosing Interval (AUCtau) of Tenofovir Alafenamide
timeFrame: 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)
measure: Plasma Concentrations 2 Hours After Dosing (C0-2h) of Tenofovir Alafenamide
timeFrame: 0 to 2 hours post dose
measure: Percent Change From Baseline in Hip and Spine Bone Mineral Density (BMD)
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in BMD T-score of Hip and Spine
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Alkaline Phosphatase (ALP) Levels at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Levels of Serum Procollagen 1 N-Terminal Propeptide (P1NP) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Levels of Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Levels of Parathyroid Hormone (PTH) at Weeks 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Change From Baseline in Levels of 25-Hydroxyvitamin D (25-OH Vitamin D), at Week 24 and 48
timeFrame: Baseline, Weeks 24 and 48
measure: Percentage of Participants With HIV-1 RNA <50 Copies Per mL at Week 96 Defined by FDA Snapshot Approach
timeFrame: At Week 96
measure: Change From Reference in log10 HIV-1 RNA Levels at Week 96
timeFrame: 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
measure: Change From Reference in CD4+ Cell Count at Week 96
timeFrame: 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
measure: Percentage of Participants With >95% Treatment Adherence Assessed by Drug Accountability
timeFrame: Baseline to Switch and switch to EOE to Open-Label D/C/F/TAF (Up to 3 years)
measure: 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
timeFrame: Up to Week 96
measure: Change From Reference in Serum Creatinine
timeFrame: 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
measure: Change From Reference in eGFRcr by CKD-EPI Formula
timeFrame: 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
measure: Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine by Cockcroft-Gault Formula
timeFrame: 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
measure: Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula
timeFrame: 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
measure: Change From Reference in UPCR
timeFrame: 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
measure: Change From Reference in UACR
timeFrame: 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
measure: Change From Reference in URBPCR
timeFrame: 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
measure: Change From Reference in UB2MGCR
timeFrame: 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
measure: Percent Change From Reference in Urine FEPO4
timeFrame: 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
measure: Percent Change From Reference in Hip and Spine BMD
timeFrame: 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
measure: Change From Reference in BMD T-score of Hip and Spine at Week 96
timeFrame: 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
measure: Change From Reference in ALP Levels
timeFrame: 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
measure: Change From Reference in Levels of Serum P1NP
timeFrame: 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
measure: Change From Reference in Levels of Serum CTX
timeFrame: 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
measure: Change From Reference in Levels of PTH
timeFrame: 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
measure: Change From Reference in Levels of 25-OH Vitamin D
timeFrame: 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
measure: Percentage of Participants With HIV RNA <50, <20, and <200 Copies/mL Post-week 96 to End of Extension
timeFrame: Week 96 to end of extension (up to 3 years)
measure: Percentage of Participants With Protocol-defined Virologic Failure (PDVF)
timeFrame: From Baseline up to Week 96
measure: Percentage of Participants With PDVF Post-week 96 to End of Extension
timeFrame: Week 96 to end of extension (up to 3 years)
measure: Percentage of Participants With Non-PDVF by Kaplan-Meier Estimates
timeFrame: From Week 96 to end of extension (up to 2 years and 6 months)
measure: Percentage of Participants With Time to Treatment Failure by Kaplan-Meier Estimates
timeFrame: From Week 96 to end of extension (up to 3 years)
measure: CD4+ Cell Count Post-Week From 96 to End of Extension
timeFrame: Week 96 to end of extension (up to 3 years)
measure: Number of Participants With ARV Resistance
timeFrame: Baseline to end of extension (up to 4 years)
measure: Percentage of Participants With Grade 3 and 4 AEs, SAEs, and Premature Discontinuations Due to Adverse Events Post-Week 96 to End of Extension
timeFrame: From Week 96 to end of extension (up to 3 years)
Other outcomes:
Locations:
city: Birmingham
country: United States
state: Alabama
city: Phoenix
country: United States
state: Arizona
city: Bakersfield
country: United States
state: California
city: Long Beach
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: North Hollywood
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Washington
country: United States
state: District of Columbia
city: Fort Pierce
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: West Palm Beach
country: United States
state: Florida
city: Savannah
country: United States
state: Georgia
city: Boston
country: United States
state: Massachusetts
city: Springfield
country: United States
state: Massachusetts
city: Berkley
country: United States
state: Michigan
city: Minneapolis
country: United States
state: Minnesota
city: Saint Louis
country: United States
state: Missouri
city: Hillsborough
country: United States
state: New Jersey
city: Newark
country: United States
state: New Jersey
city: Somers Point
country: United States
state: New Jersey
city: Santa Fe
country: United States
state: New Mexico
city: Manhasset
country: United States
state: New York
city: Chapel Hill
country: United States
state: North Carolina
city: Winston-Salem
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Fort Worth
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: Seattle
country: United States
state: Washington
city: Antwerpen
country: Belgium
city: Brussels
country: Belgium
city: Brussel
country: Belgium
city: Gent
country: Belgium
city: Toronto
country: Canada
state: Ontario
city: Montreal
country: Canada
state: Quebec
city: Clamart
country: France
city: Le Kremlin Bicetre
country: France
city: Lyon
country: France
city: Marseille
country: France
city: Montpellier
country: France
city: Nantes
country: France
city: Paris
country: France
city: Strasbourg
country: France
city: Tourcoing
country: France
city: Berlin
country: Germany
city: Bonn
country: Germany
city: Essen
country: Germany
city: Frankfurt
country: Germany
city: Freiburg im Breisgau
country: Germany
city: Hamburg
country: Germany
city: Hannover
country: Germany
city: Köln
country: Germany
city: München
country: Germany
city: Bydgoszcz
country: Poland
city: Chorzow
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Szczecin
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: San Juan
country: Puerto Rico
city: Ekaterinburg
country: Russian Federation
city: Krasnodar
country: Russian Federation
city: Orel
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: Saratov
country: Russian Federation
city: Smolensk
country: Russian Federation
city: Tolyatti
country: Russian Federation
city: Voronezh
country: Russian Federation
city: Alicante
country: Spain
city: Badalona
country: Spain
city: Barcelona
country: Spain
city: Cordoba
country: Spain
city: Elche
country: Spain
city: Madrid
country: Spain
city: Santiago de Compostela
country: Spain
city: Sevilla
country: Spain
city: Valencia
country: Spain
city: Brighton
country: United Kingdom
city: Bristol
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Janssen Sciences Ireland UC
name: Janssen Sciences Ireland UC Clinical Trial
role: STUDY_DIRECTOR
References:
citation: Ackaert O, McDougall D, Perez-Ruixo C, Perez-Ruixo JJ, Jezorwski J, Crauwels HM. Population Pharmacokinetic Analysis of Darunavir and Tenofovir Alafenamide in HIV-1-Infected Patients on the Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Single-Tablet Regimen (AMBER and EMERALD Studies). AAPS J. 2021 Jun 7;23(4):82. doi: 10.1208/s12248-021-00607-8.
citation: Orkin C, Eron JJ, Rockstroh J, Podzamczer D, Esser S, Vandekerckhove L, Van Landuyt E, Lathouwers E, Hufkens V, Jezorwski J, Opsomer M; AMBER study group. Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2020 Apr 1;34(5):707-718. doi: 10.1097/QAD.0000000000002463.
citation: Lathouwers E, Wong EY, Brown K, Baugh B, Ghys A, Jezorwski J, Mohsine EG, Van Landuyt E, Opsomer M, De Meyer S; AMBER and EMERALD Study Groups. Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials. AIDS Res Hum Retroviruses. 2020 Jan;36(1):48-57. doi: 10.1089/AID.2019.0111. Epub 2019 Oct 21.
citation: Rashbaum B, Spinner CD, McDonald C, Mussini C, Jezorwski J, Luo D, Van Landuyt E, Brown K, Wong EY. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive patients with HIV-1: subgroup analyses of the phase 3 AMBER study. HIV Res Clin Pract. 2019 Feb;20(1):24-33. doi: 10.1080/15284336.2019.1608714. Epub 2019 May 29.
citation: Eron JJ, Orkin C, Gallant J, Molina JM, Negredo E, Antinori A, Mills A, Reynes J, Van Landuyt E, Lathouwers E, Hufkens V, Jezorwski J, Vanveggel S, Opsomer M; AMBER study group. A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients. AIDS. 2018 Jul 17;32(11):1431-1442. doi: 10.1097/QAD.0000000000001817.