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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

Primary Purpose

Immunodeficiency Virus Type 1, Human

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide FDC

DRV/COBI FDC

FTC/TDF FDC

D/C/F/TAF FDC - Matching Placebo

FTC/TDF FDC Matching Placebo

DRV/COBI FDC Matching Placebo

About this trial

This is an interventional treatment trial for Immunodeficiency Virus Type 1, Human focused on measuring Immunodeficiency Virus Type 1, Human, Darunavir, Cobicistat, Tenofovir Alafenamide, Emtricitabine, Tenofovir Disoproxil Fumarate

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide

DRV/COBI fixed dose combination (FDC) and FTC/TDF FDC

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

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 Outcome Measures

Percentage of Participants With HIV-1 RNA <20 and 200 Copies Per mL at Weeks 48 and 96 Defined by FDA Snapshot Approach

Percentage of participants with HIV-1 RNA < 20/200 copies per mL using FDA snapshot approach were reported. The snapshot approach classified participants into 3 outcome categories: 1) virologic success (HIV RNA < 20/50/200 copies per mL at Week 48 and 96), 2) virologic failure (HIV RNA >= 20/50/200 copies per mL at Week 48 and 96), 3) no viral load data in the Week 48 and 96 visit window (discontinued due to adverse event/death/other reason). The missing HIV-1 RNA is considered as non-response.

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

Percentage of participants with HIV-1 RNA less than (<) 20, 50, and 200 copies per mL at Weeks 48 and 96 based on TLOVR algorithm were assessed. TLOVR requires sustained HIV-1 RNA < 50 copies per mL; confirmed HIV-1 RNA >= 50 copies per mL is considered as non-response (rebound); participant is considered non-responder after permanent discontinuation.

Change From Baseline in log10 HIV-1 RNA Levels at Week 48

Change from baseline in log10 HIV-1 RNA levels were reported.

Change From Baseline in Cluster of Differentiation-4 (CD4+) Cell Count at Week 48

The immunologic change was determined by changes in Cluster of CD4+ cell count. Change from baseline in CD4+ cell count at Week 48 were assessed.

Change From Baseline in Serum Creatinine at Week 48

Change from baseline in serum creatinine at Week 48 was reported.

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

Change from baseline in eGFRcr was calculated using the CKD-EPI equation as per which Stage 1 (normal or high GFR [>=90 mL/min]); Stage 2 (Mild CKD [60 to 90 mL/min]); Stage 3 (Moderate CKD [30 to 59mL/min]); Stage 4 (Severe CKD [15 to 29 mL/min]); Stage 5 (End Stage CKD [<15 mL/min]). The eGFRcr was assessed by calculating serum creatinine (Scr) using the equation: eGFRcr milliliter per minute per 1.72 meter square (mL/min/1.73m^2) = 144*(Scr/0.7)^-0.329*0.993^age (Scr =< 0.7 mg/dL) and eGFRcr mL/min/1.73m^2 = 144*(Scr/0.7)^-1.209*0.993^age (Scr >0.7 mg/dL) for female participants and eGFRcr mL/min/1.73m^2 = 141*(Scr/0.9)^-0.411*0.993^age (Scr =<0.9 mg/dL) and eGFRcr mL/min/1.73m^2 = 141*(Scr/0.9)^-1.209*0.993^age (Scr >0.9 mg/dL) for male participants.

Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine by (Cockcroft-Gault Formula) at Week 48

Change from baseline in eGFRcr by cockcroft-gault formula at Week 48. The eGFRcr was assessed by calculated creatinine clearance (CrCl) using the Cockcroft-Gault formula, and was assessed using CrCl [mL/min] = (140 - A) * W / (72 * C) * R. Where A is age at sample date [years], W is body weight at specific visit (kilogram [kg]), C is the serum concentration of creatinine [mg/dL], R = 1 if the participant is male and = 0.85 if female.

Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula at Week 48

Change from baseline in eGFRcyst was calculated using the CKD-EPI equation as per which Stage 1 (normal or high GFR) >= 90 indicates normal kidney function; Stage 2 (Mild CKD): 60 to 89 mL/min indicates mildly reduced kidney function; Stage 3 (Moderate CKD): 30 to 59 mL/min indicates moderately reduced kidney function; Stage 4 (Severe CKD): 15 to 29 mL/min indicates severely reduced kidney function; Stage 5 (End Stage of CKD): <15 mL/min indicate very severe or end stage kidney failure. The eGFRcyst was assessed by calculated serum cystatin C (Scyst) using the equation: eGFRcyst mL/min/1.73m^2 = 133 * (Scyst/0,8)^-0.499 * 0.996^age [* 0.932 if female] (Scyst =<0.8 mg/L) and eGFRcr mL/min/1.73m^2 = 133 * (Scyst/0,8)^-1.328 * 0.996^age [* 0.932 if male] (Scyst >0.8 mg/L).

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

AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Events with Grade 3 or higher (3=Severe; 4=life-threatening; 5=fatal) are events that significantly interrupt usual daily activity, require systemic drug therapy/other treatment and are, in many situations, considered unacceptable or intolerable events. SAE is any adverse event (AE) that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize participant and/or may require medical or surgical intervention to prevent one of the outcomes listed above.

Change From Baseline in Urine Protein to Creatinine Ratio (UPCR) at Week 48

Change from baseline in UPCR at Week 48 was reported.

Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) at Week 48

Change from baseline in UACR at Week 48 was reported.

Change From Baseline in Urine Retinol Binding Protein To Creatinine Ratio (URBPCR) at Week 48

Change from baseline in URBPCR at Week 48 were reported.

Change From Baseline in Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Week 48

Change from baseline in UB2MGCR at Week 48 were reported.

Percent Change From Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Week 48

Percent change from baseline in FEPO4 at Week 48 was reported.

Area Under the Plasma Concentration-Time Curve From Time of Administration to 24 Hours Post-dose (AUC0-24h) of Darunavir

AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours post-dose.

Predose (Trough) Plasma Concentration (C0h) of Darunavir

C0h is defined as the predose (trough) plasma concentration or concentration just prior to study drug administration.

Area Under the Plasma Concentration Time Curve Across the Dosing Interval (AUCtau) of Tenofovir Alafenamide

The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption.

Plasma Concentrations 2 Hours After Dosing (C0-2h) of Tenofovir Alafenamide

C0-2h is defined as the plasma concentrations 2 hours after dosing.

Percent Change From Baseline in Hip and Spine Bone Mineral Density (BMD)

The BMD is the amount of mineral in gram per square centimeter of bone, which was assessed by dual energy x-ray absorptiometry (DEXA) scan. Positive values are "best values" and negative values are "worst values" of change. Percent change from baseline in hip and spine BMD was assessed.

Change From Baseline in BMD T-score of Hip and Spine

BMD status was assessed using BMD T-scores; normal bone status was defined by a BMD T-score >= -1, osteopenia by a T-score >= -2.5 to <-1.0, and osteoporosis by a T-score <-2.5.

Change From Baseline in Alkaline Phosphatase (ALP) Levels at Weeks 24 and 48

Change from baseline in ALP at Weeks 24 and 48 was reported.

Change From Baseline in Levels of Serum Procollagen 1 N-Terminal Propeptide (P1NP) at Weeks 24 and 48

Change from baseline in serum P1NP at Weeks 24 and 48 were reported.

Change From Baseline in Levels of Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) at Weeks 24 and 48

Change from baseline in serum CTX at Weeks 24 and 48 were reported.

Change From Baseline in Levels of Parathyroid Hormone (PTH) at Weeks 24 and 48

Change from baseline in PTH at Weeks 24 and 48 were reported.

Change From Baseline in Levels of 25-Hydroxyvitamin D (25-OH Vitamin D), at Week 24 and 48

Change from baseline in 25-OH Vitamin D levels at Week 24 and 48 were reported.

Percentage of Participants With HIV-1 RNA <50 Copies Per mL at Week 96 Defined by FDA Snapshot Approach

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 96), 2) virologic failure (HIV RNA greater than or equal to [>=] 20/50/200 copies per mL at Week 96), 3) no viral load data in the Week 96 visit window (discontinued due to adverse event/death/other reason). The missing HIV-1 RNA is considered as non-response.

Change From Reference in log10 HIV-1 RNA Levels at Week 96

Change from reference in log10 HIV-1 RNA levels were reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for Test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in CD4+ Cell Count at Week 96

The immunologic change was determined by changes in cluster of differentiation (CD4+) cell count. Change from reference in CD4+ cell count at Week 96 was assessed. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Percentage of Participants With >95% Treatment Adherence Assessed by Drug Accountability

Treatment adherence assessed by drug accountability (based on pill count) from start of treatment/switch to last study drug intake by determination of the cumulative treatment adherence in participants who returned all dispensed bottles prior to or at the last visit in the study. Adherent participants were defined as having an adherence >95% as assessed by drug accountability.

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

Change From Reference in Serum Creatinine

Change from reference in serum creatinine was reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in eGFRcr by CKD-EPI Formula

Change from reference in eGFRcr was calculated using the CKD-EPI equation as per Stage 1 (normal or high GFR) to Stage 5 (End Stage of CKD). The eGFRcr was assessed by calculating serum creatinine (Scr) using the CKD-EPI equation: eGFRcr milliliter per minute per 1.72 meter square (mL/min/1.73m^2) = 144 * (Scr/0.7)^-0.329 * 0.993^age (Scr =< 0.7 mg/dL) and eGFRcr mL/min/1.73m^2 = 144 * (Scr/0.7)^-1.209 * 0.993^age (Scr >0.7 mg/dL) for female participants and eGFRcr mL/min/1.73m^2 = 141 x (Scr/0.9)^-0.411 x 0.993^age (Scr =<0.9 mg/dL) and eGFRcr mL/min/1.73m^2 = 141 * (Scr/0.9)^-1.209 x 0.993^age (Scr >0.9 mg/dL) for male participants. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine by Cockcroft-Gault Formula

Change from reference in eGFRcr by cockcroft-gault formula was reported. The eGFRcr was assessed by calculated creatinine clearance (CrCl) using the Cockcroft-Gault formula, and was assessed using CrCl [mL/min] = (140 - A) * W / (72 * C) * R. Where A is age at sample date [years], W is body weight at specific visit (kilogram [kg]), C is the serum concentration of creatinine [mg/dL], R = 1 if the participant is male and = 0.85 if female. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula

Change from reference in eGFRcyst was calculated using the CKD-EPI equation as per Stage 1 (normal or high GFR) to Stage 5 (End Stage of CKD): <15 mL/min indicate very severe or end stage kidney failure. The eGFRcyst was assessed by calculated serum cystatin C (Scyst) using the CKD-EPI equation: eGFRcyst mL/min/1.73m^2 = 133 * (Scyst/0,8)^-0.499 * 0.996^age [x 0.932 if female] (Scyst =<0.8 mg/L) and eGFRcr mL/min/1.73m^2 = 133 * (Scyst/0,8)^-1.328 * 0.996^age [* 0.932 if male] (Scyst >0.8 mg/L). Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in UPCR

Change from reference in UPCR was reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in UACR

Change from reference in UACR at Week 96 was reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in URBPCR

Change from reference in URBPCR at Week 96 were reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in UB2MGCR

Change from reference in UB2MGCR was reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Percent Change From Reference in Urine FEPO4

Percent change from reference in FEPO4 at Week 96 were reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Percent Change From Reference in Hip and Spine BMD

The BMD is the amount of mineral in gram per square centimeter of bone, which was assessed by DEXA scan. Positive values are "best values" and negative values are "worst values" of change. Percent change from reference in hip and spine BMD was assessed. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in BMD T-score of Hip and Spine at Week 96

BMD status was assessed using BMD T-scores; normal bone status was defined by a BMD T-score >= -1, osteopenia by a T-score >= -2.5 to <-1.0, and osteoporosis by a T-score <-2.5. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in ALP Levels

Change from reference in ALP levels at Week 96 was reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in Levels of Serum P1NP

Change from reference in serum P1NP levels were reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in Levels of Serum CTX

Change from reference in serum CTX levels were reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in Levels of PTH

Change from reference in PTH levels were reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Change From Reference in Levels of 25-OH Vitamin D

Change from reference in 25-OH Vitamin D were reported. Here, reference 1 is the comparative phase baseline value in Week 48 analysis for test group and reference 2 is the last value prior to the switch for Control group.

Percentage of Participants With HIV RNA <50, <20, and <200 Copies/mL Post-week 96 to End of Extension

Percentage of participants with HIV RNA <50, <20, and <200 copies/mL post Week 96 to end of extension were reported.

Percentage of Participants With Protocol-defined Virologic Failure (PDVF)

Percentage of participants with PDVF were reported. Protocol-defined virologic failure was defined as having virologic non-response (HIV-1 RNA <1 log10 reduction from baseline and >=50 copies/mL at the Week 8 visit, confirmed at the next visit), virologic rebound (confirmed HIV-1 RNA >=50 copies/mL after confirmed consecutive HIV-1 RNA <50 copies/mL or confirmed >1 log10 increase in HIV-1 RNA from nadir), or viremic at final time point (final available on treatment HIV-1 RNA >=400 copies/mL).

Percentage of Participants With PDVF Post-week 96 to End of Extension

Percentage of Participants With Non-PDVF by Kaplan-Meier Estimates

Percentage of participants with non-PDVF by Kaplan-Meier Estimates were reported. PDVF was defined as having virologic non-response (HIV-1 RNA <1 log10 reduction from baseline and >=50 copies/mL at the Week 8 visit, confirmed at the next visit), virologic rebound (confirmed HIV-1 RNA >=50 copies/mL after confirmed consecutive HIV-1 RNA <50 copies/mL or confirmed >1 log10 increase in HIV-1 RNA from nadir), or viremic at final time point (final available on treatment HIV-1 RNA >=400 copies/mL).

Percentage of Participants With Time to Treatment Failure by Kaplan-Meier Estimates

Percentage of participants with time to treatment failure by Kaplan-Meier Estimates were reported. Treatment failure was defined as having either protocol-defined virologic failure or having discontinued for reasons other than alternate access to D/C/F/TAF (or other ARVs).

CD4+ Cell Count Post-Week From 96 to End of Extension

The immunologic change was determined by Cluster of CD4+ cell count. CD4+ cell count post-Week 96 to end of extension were assessed.

Number of Participants With ARV Resistance

Number of participants with DRV, FTC, TDF/TAF resistance were reported.

Percentage of Participants With Grade 3 and 4 AEs, SAEs, and Premature Discontinuations Due to Adverse Events Post-Week 96 to End of Extension

Full Information

NCT ID

NCT02431247

First Posted

April 27, 2015

Last Updated

September 27, 2022

Sponsor

Janssen Sciences Ireland UC

1. Study Identification

Unique Protocol Identification Number

NCT02431247

Brief Title

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

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Completed

Study Start Date

July 6, 2015 (Actual)

Primary Completion Date

March 2, 2017 (Actual)

Study Completion Date

September 30, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Janssen Sciences Ireland UC

4. Oversight

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Immunodeficiency Virus Type 1, Human

Keywords

Immunodeficiency Virus Type 1, Human, Darunavir, Cobicistat, Tenofovir Alafenamide, Emtricitabine, Tenofovir Disoproxil Fumarate

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

725 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide

Arm Type

Experimental

Arm Description

Arm Title

DRV/COBI fixed dose combination (FDC) and FTC/TDF FDC

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide FDC

Intervention Description

A tablet containing DRV 800 mg, COBI 150 mg, FTC 200 mg and TAF) 10 mg will be administered once daily.

Intervention Type

Drug

Intervention Name(s)

DRV/COBI FDC

Intervention Description

A tablet containing DRV 800 mg and COBI 150 mg will be administered once daily.

Intervention Type

Drug

Intervention Name(s)

FTC/TDF FDC

Intervention Description

A tablet containing FTC 200 mg and TDF 300 mg will be administered once daily.

Intervention Type

Drug

Intervention Name(s)

D/C/F/TAF FDC - Matching Placebo

Intervention Description

Matching placebo of D/C/F/TAF FDC will be administered once daily.

Intervention Type

Drug

Intervention Name(s)

FTC/TDF FDC Matching Placebo

Intervention Description

Matching placebo of FTC/TDF FDC will be administered once daily.

Intervention Type

Drug

Intervention Name(s)

DRV/COBI FDC Matching Placebo

Intervention Description

Matching placebo of DRV/COBI FDC will be administered once daily.

Primary Outcome Measure Information:

Title

Description

Time Frame

At Week 48

Secondary Outcome Measure Information:

Title

Percentage of Participants With HIV-1 RNA <20 and 200 Copies Per mL at Weeks 48 and 96 Defined by FDA Snapshot Approach

Description

Time Frame

At Weeks 48 and 96

Title

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

Description

Time Frame

At Week 48 and 96

Title

Change From Baseline in log10 HIV-1 RNA Levels at Week 48

Description

Change from baseline in log10 HIV-1 RNA levels were reported.

Time Frame

Baseline and Week 48

Title

Change From Baseline in Cluster of Differentiation-4 (CD4+) Cell Count at Week 48

Description

The immunologic change was determined by changes in Cluster of CD4+ cell count. Change from baseline in CD4+ cell count at Week 48 were assessed.

Time Frame

Baseline and Week 48

Title

Change From Baseline in Serum Creatinine at Week 48

Description

Change from baseline in serum creatinine at Week 48 was reported.

Time Frame

Baseline and Week 48

Title

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

Description

Time Frame

Baseline and Week 48

Title

Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine by (Cockcroft-Gault Formula) at Week 48

Description

Time Frame

Baseline and Week 48

Title

Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula at Week 48

Description

Time Frame

Baseline and Week 48

Title

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

Description

Time Frame

Up to Weeks 48

Title

Change From Baseline in Urine Protein to Creatinine Ratio (UPCR) at Week 48

Description

Change from baseline in UPCR at Week 48 was reported.

Time Frame

Baseline and Week 48

Title

Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) at Week 48

Description

Change from baseline in UACR at Week 48 was reported.

Time Frame

Baseline and Week 48

Title

Change From Baseline in Urine Retinol Binding Protein To Creatinine Ratio (URBPCR) at Week 48

Description

Change from baseline in URBPCR at Week 48 were reported.

Time Frame

Baseline and Week 48

Title

Change From Baseline in Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Week 48

Description

Change from baseline in UB2MGCR at Week 48 were reported.

Time Frame

Baseline and Week 48

Title

Percent Change From Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Week 48

Description

Percent change from baseline in FEPO4 at Week 48 was reported.

Time Frame

Baseline and Week 48

Title

Area Under the Plasma Concentration-Time Curve From Time of Administration to 24 Hours Post-dose (AUC0-24h) of Darunavir

Description

AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours post-dose.

Time Frame

0 to 24 hours post dose

Title

Predose (Trough) Plasma Concentration (C0h) of Darunavir

Description

C0h is defined as the predose (trough) plasma concentration or concentration just prior to study drug administration.

Time Frame

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)

Title

Area Under the Plasma Concentration Time Curve Across the Dosing Interval (AUCtau) of Tenofovir Alafenamide

Description

The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption.

Time Frame

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)

Title

Plasma Concentrations 2 Hours After Dosing (C0-2h) of Tenofovir Alafenamide

Description

C0-2h is defined as the plasma concentrations 2 hours after dosing.

Time Frame

0 to 2 hours post dose

Title

Percent Change From Baseline in Hip and Spine Bone Mineral Density (BMD)

Description

Time Frame

Baseline, Weeks 24 and 48

Title

Change From Baseline in BMD T-score of Hip and Spine

Description

BMD status was assessed using BMD T-scores; normal bone status was defined by a BMD T-score >= -1, osteopenia by a T-score >= -2.5 to <-1.0, and osteoporosis by a T-score <-2.5.

Time Frame

Baseline, Weeks 24 and 48

Title

Change From Baseline in Alkaline Phosphatase (ALP) Levels at Weeks 24 and 48

Description

Change from baseline in ALP at Weeks 24 and 48 was reported.

Time Frame

Baseline, Weeks 24 and 48

Title

Change From Baseline in Levels of Serum Procollagen 1 N-Terminal Propeptide (P1NP) at Weeks 24 and 48

Description

Change from baseline in serum P1NP at Weeks 24 and 48 were reported.

Time Frame

Baseline, Weeks 24 and 48

Title

Change From Baseline in Levels of Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) at Weeks 24 and 48

Description

Change from baseline in serum CTX at Weeks 24 and 48 were reported.

Time Frame

Baseline, Weeks 24 and 48

Title

Change From Baseline in Levels of Parathyroid Hormone (PTH) at Weeks 24 and 48

Description

Change from baseline in PTH at Weeks 24 and 48 were reported.

Time Frame

Baseline, Weeks 24 and 48

Title

Change From Baseline in Levels of 25-Hydroxyvitamin D (25-OH Vitamin D), at Week 24 and 48

Description

Change from baseline in 25-OH Vitamin D levels at Week 24 and 48 were reported.

Time Frame

Baseline, Weeks 24 and 48

Title

Percentage of Participants With HIV-1 RNA <50 Copies Per mL at Week 96 Defined by FDA Snapshot Approach

Description

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 96), 2) virologic failure (HIV RNA greater than or equal to [>=] 20/50/200 copies per mL at Week 96), 3) no viral load data in the Week 96 visit window (discontinued due to adverse event/death/other reason). The missing HIV-1 RNA is considered as non-response.

Time Frame

At Week 96

Title

Change From Reference in log10 HIV-1 RNA Levels at Week 96

Description

Time Frame

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

Title

Change From Reference in CD4+ Cell Count at Week 96

Description

Time Frame

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

Title

Percentage of Participants With >95% Treatment Adherence Assessed by Drug Accountability

Description

Time Frame

Baseline to Switch and switch to EOE to Open-Label D/C/F/TAF (Up to 3 years)

Title

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

Description

Time Frame

Up to Week 96

Title

Change From Reference in Serum Creatinine

Description

Time Frame

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

Title

Change From Reference in eGFRcr by CKD-EPI Formula

Description

Time Frame

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

Title

Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine by Cockcroft-Gault Formula

Description

Time Frame

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

Title

Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula

Description

Time Frame

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

Title

Change From Reference in UPCR

Description

Time Frame

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

Title

Change From Reference in UACR

Description

Time Frame

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

Title

Change From Reference in URBPCR

Description

Time Frame

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

Title

Change From Reference in UB2MGCR

Description

Time Frame

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

Title

Percent Change From Reference in Urine FEPO4

Description

Time Frame

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

Title

Percent Change From Reference in Hip and Spine BMD

Description

Time Frame

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

Title

Change From Reference in BMD T-score of Hip and Spine at Week 96

Description

Time Frame

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

Title

Change From Reference in ALP Levels

Description

Time Frame

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

Title

Change From Reference in Levels of Serum P1NP

Description

Time Frame

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

Title

Change From Reference in Levels of Serum CTX

Description

Time Frame

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

Title

Change From Reference in Levels of PTH

Description

Time Frame

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

Title

Change From Reference in Levels of 25-OH Vitamin D

Description

Time Frame

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

Title

Percentage of Participants With HIV RNA <50, <20, and <200 Copies/mL Post-week 96 to End of Extension

Description

Percentage of participants with HIV RNA <50, <20, and <200 copies/mL post Week 96 to end of extension were reported.

Time Frame

Week 96 to end of extension (up to 3 years)

Title

Percentage of Participants With Protocol-defined Virologic Failure (PDVF)

Description

Time Frame

From Baseline up to Week 96

Title

Percentage of Participants With PDVF Post-week 96 to End of Extension

Description

Time Frame

Week 96 to end of extension (up to 3 years)

Title

Percentage of Participants With Non-PDVF by Kaplan-Meier Estimates

Description

Time Frame

From Week 96 to end of extension (up to 2 years and 6 months)

Title

Percentage of Participants With Time to Treatment Failure by Kaplan-Meier Estimates

Description

Time Frame

From Week 96 to end of extension (up to 3 years)

Title

CD4+ Cell Count Post-Week From 96 to End of Extension

Description

The immunologic change was determined by Cluster of CD4+ cell count. CD4+ cell count post-Week 96 to end of extension were assessed.

Time Frame

Week 96 to end of extension (up to 3 years)

Title

Number of Participants With ARV Resistance

Description

Number of participants with DRV, FTC, TDF/TAF resistance were reported.

Time Frame

Baseline to end of extension (up to 4 years)

Title

Percentage of Participants With Grade 3 and 4 AEs, SAEs, and Premature Discontinuations Due to Adverse Events Post-Week 96 to End of Extension

Description

Time Frame

From Week 96 to end of extension (up to 3 years)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Janssen Sciences Ireland UC Clinical Trial

Organizational Affiliation

Janssen Sciences Ireland UC

Official's Role

Study Director

Facility Information:

City

Birmingham

State/Province

Alabama

Country

United States

City

Phoenix

State/Province

Arizona

Country

United States

City

Bakersfield

State/Province

California

Country

United States

City

Long Beach

State/Province

California

Country

United States

City

Los Angeles

State/Province

California

Country

United States

City

North Hollywood

State/Province

California

Country

United States

City

San Francisco

State/Province

California

Country

United States

City

Washington

State/Province

District of Columbia

Country

United States

City

Fort Pierce

State/Province

Florida

Country

United States

City

Miami

State/Province

Florida

Country

United States

City

Orlando

State/Province

Florida

Country

United States

City

West Palm Beach

State/Province

Florida

Country

United States

City

Savannah

State/Province

Georgia

Country

United States

City

Boston

State/Province

Massachusetts

Country

United States

City

Springfield

State/Province

Massachusetts

Country

United States

City

Berkley

State/Province

Michigan

Country

United States

City

Minneapolis

State/Province

Minnesota

Country

United States

City

Saint Louis

State/Province

Missouri

Country

United States

City

Hillsborough

State/Province

New Jersey

Country

United States

City

Newark

State/Province

New Jersey

Country

United States

City

Somers Point

State/Province

New Jersey

Country

United States

City

Santa Fe

State/Province

New Mexico

Country

United States

City

Manhasset

State/Province

New York

Country

United States

City

Chapel Hill

State/Province

North Carolina

Country

United States

City

Winston-Salem

State/Province

North Carolina

Country

United States

City

Cincinnati

State/Province

Ohio

Country

United States

City

Fort Worth

State/Province

Texas

Country

United States

City

Houston

State/Province

Texas

Country

United States

City

Seattle

State/Province

Washington

Country

United States

City

Antwerpen

Country

Belgium

City

Brussels

Country

Belgium

City

Brussel

Country

Belgium

City

Gent

Country

Belgium

City

Toronto

State/Province

Ontario

Country

Canada

City

Montreal

State/Province

Quebec

Country

Canada

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

12. IPD Sharing Statement

Citations:

PubMed Identifier

34100149

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.

Results Reference

derived

PubMed Identifier

31833849

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.

Results Reference

derived

PubMed Identifier

31516033

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.

Results Reference

derived

PubMed Identifier

31303147

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.

Results Reference

derived

PubMed Identifier

29683855

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.

Results Reference

derived

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