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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

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ClinicalTrials.gov Identifier: NCT02431247
Recruitment Status : Active, not recruiting
First Posted : April 30, 2015
Results First Posted : September 14, 2018
Last Update Posted : September 14, 2018
Sponsor:
Information provided by (Responsible Party):
Janssen Sciences Ireland UC

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.

Condition or disease Intervention/treatment Phase
Immunodeficiency Virus Type 1, Human Drug: Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide FDC Drug: DRV/COBI FDC Drug: FTC/TDF FDC Drug: D/C/F/TAF FDC - Matching Placebo Drug: FTC/TDF FDC Matching Placebo Drug: DRV/COBI FDC Matching Placebo Phase 3

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 Type : Interventional  (Clinical Trial)
Actual Enrollment : 725 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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
Actual Study Start Date : July 6, 2015
Actual Primary Completion Date : March 2, 2017
Estimated Study Completion Date : April 5, 2020


Arm Intervention/treatment
Experimental: 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.
Drug: Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide FDC
A tablet containing DRV 800 mg, COBI 150 mg, FTC 200 mg and TAF) 10 mg will be administered once daily.

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

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

Active Comparator: 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.
Drug: DRV/COBI FDC
A tablet containing DRV 800 mg and COBI 150 mg will be administered once daily.

Drug: FTC/TDF FDC
A tablet containing FTC 200 mg and TDF 300 mg will be administered once daily.

Drug: D/C/F/TAF FDC - Matching Placebo
Matching placebo of D/C/F/TAF FDC will be administered once daily.




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. Percentage of Participants With HIV-1 RNA Less Than 20 and 200 Copies Per mL at Week 48 Defined by FDA Snapshot Approach [ Time Frame: At Week 48 ]
    Percentage of participants with HIV-1 RNA < 20/200 copies per mL 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 >= 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.

  2. Percentage of Participants With HIV-1 RNA < 20, 50, and 200 Copies Per mL at Week 48 Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm [ Time Frame: At Week 48 ]
    Percentage of participants with HIV-1 RNA less than 20, 50, and 200 copies per mL at Week 48 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.

  3. Change From Baseline in log10 HIV-1 RNA Levels at Week 48 [ Time Frame: Baseline and Week 48 ]
    Change from baseline in log10 HIV-1 RNA levels were reported.

  4. Change From Baseline in Cluster of Differentiation-4 (CD4+) Cell Count at Week 48 [ Time Frame: Baseline and 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.

  5. Number of Participants With Antiretroviral (ARV) Resistance Through Week 48 [ Time Frame: Up to Week 48 ]
    Number of participants with DRV, FTC, TDF/TAF resistance were reported.

  6. Change From Baseline in Serum Creatinine at Week 48 [ Time Frame: Baseline and Week 48 ]
    Change from baseline in serum creatinine at Week 48 was reported. Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine.

  7. 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 [ Time Frame: Baseline and Week 48 ]
    Change from baseline in eGFRcr 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 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 x (Scr/0.7)^-0.329 x 0.993^age (Scr =< 0.7 mg/dL) and eGFRcr mL/min/1.73m^2 = 144 x (Scr/0.7)^-1.209 x 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 x (Scr/0.9)^-1.209 x 0.993^age (Scr >0.9 mg/dL) for male participants.

  8. Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine by (Cockcroft-Gault Formula) at Week 48 [ Time Frame: Baseline and 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.

  9. Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst) by CKD-EPI Formula at Week 48 [ Time Frame: Baseline and 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 CKD-EPI equation: eGFRcyst mL/min/1.73m^2 = 133 x (Scyst/0,8)^-0.499 x 0.996^age [x 0.932 if female] (Scyst =<0.8 mg/L) and eGFRcr mL/min/1.73m^2 = 133 x (Scyst/0,8)^-1.328 x 0.996^age [x 0.932 if male] (Scyst >0.8 mg/L).

  10. Percentage of Participants With Grade 3 and 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Premature Discontinuations Due to Adverse Events [ Time Frame: Up to 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.

  11. Change From Baseline in Urine Protein to Creatinine Ratio (UPCR) at Week 48 [ Time Frame: Baseline and Week 48 ]
    Change from baseline in UPCR at Week 48 were reported.

  12. Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) at Week 48 [ Time Frame: Baseline and Week 48 ]
    Change from baseline in UACR at Week 48 were reported.

  13. Change From Baseline in Urine Retinol Binding Protein To Creatinine Ratio (URBPCR) at Week 48 [ Time Frame: Baseline and Week 48 ]
    Change from baseline in URBPCR at Week 48 were reported.

  14. Change From Baseline in Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Week 48 [ Time Frame: Baseline and Week 48 ]
    Change from baseline in UB2MGCR at Week 48 were reported.

  15. Percent Change From Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Week 48 [ Time Frame: Baseline and Week 48 ]
    Percent change from baseline in FEPO4 at Week 48 were reported.

  16. Area Under the Plasma Concentration-Time Curve From Time of Administration to 24 Hours Post-dose (AUC0-24h) of Darunavir [ 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) ]
    The AUC (0-24) is the area under the plasma concentration-time curve from time zero to 24 hours post dose.

  17. Predose (Trough) Plasma Concentration (C0h) of Darunavir [ 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) ]
    C0h is defined as the predose (trough) plasma concentration or concentration just prior to study drug administration.

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

  19. Plasma Concentrations 2 Hours After Dosing (C0-2h) of Tenofovir Alafenamide [ 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) ]
    C0-2h is defined as as the plasma concentrations 2 hours after dosing.

  20. Percent Change From Baseline in Hip and Spine Bone Mineral Density (BMD) [ Time Frame: Baseline, Weeks 24 and 48 ]
    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.

  21. Change From Baseline in BMD T-score of Hip and Spine [ Time Frame: Baseline, Weeks 24 and 48 ]
    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.

  22. Change From Baseline in Alkaline Phosphatase (ALP) Levels at Week 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in ALP at Week 24 and 48 were reported.

  23. Change From Baseline in Levels of Serum Procollagen 1 N-Terminal Propeptide (P1NP) at Week 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in serum P1NP at Week 24 and 48 were reported.

  24. Change From Baseline in Levels of Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) at Week 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in serum CTX at Week 24 and 48 were reported.

  25. Change From Baseline in Levels of Parathyroid Hormone (PTH) at Week 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in PTH at Week 24 and 48 were reported.

  26. Change From Baseline in Levels of 25-Hydroxyvitamin D (25-OH Vitamin D), at Week 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in 25-OH Vitamin D at Week 24 and 48 were reported.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02431247


  Show 81 Study Locations
Sponsors and Collaborators
Janssen Sciences Ireland UC
Investigators
Study Director: Janssen Sciences Ireland UC Clinical Trial Janssen Sciences Ireland UC
  Study Documents (Full-Text)

Documents provided by Janssen Sciences Ireland UC:
Study Protocol  [PDF] April 18, 2017
Statistical Analysis Plan  [PDF] April 25, 2017


Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Janssen Sciences Ireland UC
ClinicalTrials.gov Identifier: NCT02431247     History of Changes
Other Study ID Numbers: CR107277
TMC114FD2HTX3001 ( Other Identifier: Janssen Sciences Ireland UC )
2015-000754-38 ( EudraCT Number )
First Posted: April 30, 2015    Key Record Dates
Results First Posted: September 14, 2018
Last Update Posted: September 14, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Janssen Sciences Ireland UC:
Immunodeficiency Virus Type 1, Human
Darunavir
Cobicistat
Tenofovir Alafenamide
Emtricitabine
Tenofovir Disoproxil Fumarate

Additional relevant MeSH terms:
Immunologic Deficiency Syndromes
Immune System Diseases
Tenofovir
Emtricitabine
Darunavir
Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Cobicistat
Antiviral Agents
Anti-Infective Agents
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Retroviral Agents
Anti-HIV Agents
HIV Protease Inhibitors
Protease Inhibitors
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors