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Study to Evaluate Efficacy and Safety of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Regimen Versus Boosted Protease Inhibitor (bPI) Along With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) Regimen in Virologically-Suppressed, HIV-1 Infected Participants

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ClinicalTrials.gov Identifier: NCT02269917
Recruitment Status : Completed
First Posted : October 21, 2014
Results First Posted : November 9, 2018
Last Update Posted : December 17, 2020
Sponsor:
Information provided by (Responsible Party):
Janssen R&D Ireland

Tracking Information
First Submitted Date  ICMJE October 17, 2014
First Posted Date  ICMJE October 21, 2014
Results First Submitted Date  ICMJE August 14, 2018
Results First Posted Date  ICMJE November 9, 2018
Last Update Posted Date December 17, 2020
Actual Study Start Date  ICMJE April 2015
Actual Primary Completion Date February 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 8, 2018)
Percentage of Participants With Virologic Rebound (HIV-1 RNA >=50 Copies/mL) Cumulative Through Week 48 [ Time Frame: Through Week 48 ]
Virologic rebound was defined as: confirmed plasma human immunodeficiency virus - 1 (HIV-1) Ribonucleic Acid (RNA) level greater than or equal to (>=)50 copies per milliliter (copies/mL) up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=50 copies/mL at premature discontinuation (irrespective of reason). Percentage of participants with virologic rebound were reported.
Original Primary Outcome Measures  ICMJE
 (submitted: October 17, 2014)
Number of Participants With Plasma Human Immunodeficiency Virus - 1 (HIV-1) Ribonucleic Acid (RNA) Level <50 Copies/mL at Week 24 per FDA Snapshot Approach [ Time Frame: Week 24 ]
Food and Drug Administration (FDA) Snapshot analysis is based on the last observed viral load (VL) data within the Week 24 window: virologic response is defined as HIV-1 RNA less than (<) 50 copies per milliliter (copies/mL) (observed cases); missing HIV-1 RNA is considered as non-response.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 8, 2018)
  • Percentage of Participants With Virologic Rebound (Plasma HIV-1 RNA >=20 Copies/mL) Cumulative Through 48 Weeks [ Time Frame: Through 48 Weeks ]
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA >=20 copies/mL up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=20 copies/mL at premature discontinuation (irrespective of reason). Percentage of participants with virologic rebound were reported.
  • Percentage of Participants With Virologic Rebound (Plasma HIV-1 RNA >=200 Copies/mL) Cumulative Through 48 Weeks [ Time Frame: Through 48 Weeks ]
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA >=200 copies/mL up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=200 copies/mL at premature discontinuation (irrespective of reason). Percentage of participants with virologic rebound were reported.
  • Time to Virologic Rebound [ Time Frame: Baseline up to Week 48 ]
    Time to virologic rebound was calculated from baseline until the first rebound time point (that is, time point before confirmation of rebound). Virologic rebound was defined as: confirmed plasma HIV-1 RNA >=50 copies/mL up to, and including the upper bound of the Week 48 window (ie, 54 weeks) and last available on-treatment (single) HIV-1 RNA >=50 copies/mL at premature discontinuation (irrespective of reason).
  • Percentage of Participants Experiencing Grade 3 and 4 Adverse Events (AEs) [ Time Frame: Up to Week 48 ]
    An AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Grade 3 (Severe) events were symptoms causing inability to perform usual social & functional activities. Grade 4 (Life-threatening) events were symptoms causing inability to perform basic self-care functions or medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death.
  • Change From Baseline in Serum Creatinine Levels at Weeks 24 and 48 [ Time Frame: Baseline and Weeks 24 and 48 ]
    Change from baseline in serum creatinine levels at Weeks 24 and 48 was assessed.
  • Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in eGFRcr (by Cockcroft-Gault formula) was assessed at Weeks 24 and 48. eGFRcr according to the Cockcroft Gault formula- Male: (140 - age in years)*(weight in kilogram [kg])/72*(serum creatinine in milligram per deciliter [mg/dL])=eGFRcr (milliliter per minute [mL/min]); Female: (140 - age in years)*(weight in kg)/72*(serum creatinine in mg/dL)*0.85=eGFRcr (mL/min).
  • Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in eGFRcr (by CKD-EPI) was assessed at Weeks 24 and 48. eGFRcr per CKD-EPI formula - Female: 1) Serum creatinine (Scr) less than or equal to (<=)0.7 mg/dL: 144*(Scr/0.7)^-0.329*0.993age; 2) Scr greater than (>)0.7 mg/dL: 144*(Scr/0.7)^-1.209*0.993age. Male: 1) Scr <=0.9 mg/dL: 141*(Scr/0.9)^-0.411*0.993age; 2) Scr >0.9 mg/dL: 141*(Scr/0.9)^-1.209*0.993age.
  • Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (eGFRcyst, by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in eGFRcyst (by CKD-EPI) was assessed at Weeks 24 and 48. eGFRcyst according to the CKD-EPI formula - 1) Serum Cystatin C (Scyst) <=0.8 mg/L: 133*(Scyst/0.8)^-0.499*0.996age (*0.932 if female); 2) Scyst >0.8 mg/L: 133*(Scyst/0.8)^-1.328*0.996age (*0.932 if female).
  • Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) and Urine Protein to Creatinine Ratio (UPCR) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in UACR and UPCR was assessed at Weeks 24 and 48. Lower levels of albumin or protein in the urine indicates better proximal tubular function.
  • Change From Baseline in Urine Retinol Binding Protein to Creatinine Ratio (URBPCR) and Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in URBPCR and UB2MGCR was assessed at Weeks 24 and 48. Retinol binding protein is a marker of proximal tubular function.
  • Percent Change From Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Percent change from baseline in urine FEPO4 was assessed at Weeks 24 and 48.
  • Percentage of Participants With Virologic Response Based on HIV-1 RNA Less Than (<)20, <50, and <200 Copies/mL Threshold at Week 48 as Defined by the Food and Drug Administration (FDA) Snapshot Approach [ Time Frame: Week 48 ]
    Percentage of participants with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 48 using FDA snapshot approach. FDA Snapshot approach analysis was based on the last observed viral load data: virologic response was defined as HIV-1 RNA <20/50/200 copies/mL (observed case).
  • Percentage of Participants With Virologic Response Based on HIV-1 RNA <20, <50, and <200 Copies/mL Threshold at Week 48 as Defined by the Time to Loss of Virologic Response (TLOVR) Algorithm [ Time Frame: Week 48 ]
    Percentage of participants with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 48 using TLOVR algorithm approach. TLOVR was defined as sustained HIV-1 RNA <20/50/200 copies/mL.
  • Change From Baseline in Cluster of Differentiation 4 Plus (CD4+) Cell Count at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in CD4+ cell count was assessed at Weeks 24 and 48.
  • Percentage of Participants With Treatment Adherence of Greater Than (>)95 Percent (%) (Approach 1) Through Week 48 [ Time Frame: Through Week 48 ]
    Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability cumulative through Week 48 (Approach 1).
  • Percentage of Participants With Treatment Adherence of >95% (Approach 2) Through Week 48 [ Time Frame: Through Week 48 ]
    Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability cumulative treatment adherence up to time point where not more than one bottle was missing, or if available, through Week 48, whichever came sooner (Approach 2).
  • Number of Participants With Resistance to Study Drug [ Time Frame: Up to Week 48 ]
    HIV-1 genotypes were analyzed from samples of participants with confirmed virologic rebound (virologic rebound was defined as: confirmed HIV-1 RNA >=50 copies/mL up to, and including the upper bound of the Week 48 window) and with HIV-1 RNA value greater than or equal to (>=)400 copies/mL or who discontinued with last HIV-1 RNA >=400 copies/mL. Number of participants who developed resistance to any of the study drug was determined.
  • Predose (Trough) Plasma Concentration (C0h) of Darunavir [ Time Frame: Predose at Weeks 2, 4, 8, 12, 24, 36, and 48 ]
    Predose (trough) plasma concentration (C0h) of darunavir was determined. Pharmacokinetic (PK) data was only analyzed for participants in the D/C/F/TAF group as per planned analysis.
  • Percent Change From Baseline in Serum Procollagen 1 N-Terminal Propeptide (P1NP) and Serum Collagen Type 1 Beta Carboxy Telopeptide (CTX) Levels at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Percent change from baseline in bone biomarkers: P1NP and CTX was assessed at Weeks 24 and 48.
  • Percent Change From Baseline in Parathyroid Hormone (PTH) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Percent change from baseline in bone biomarker: PTH was assessed at Weeks 24 and 48.
  • Percent Change From Baseline in 25-hydroxy Vitamin D at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Percent change from baseline in bone biomarker: 25-hydroxy vitamin D was assessed at Weeks 24 and 48.
  • Percent Change From Baseline in Spine and Hip Bone Mineral Density (BMD) at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Percent change from baseline in spine and hip BMD was assessed at Weeks 24 and 48.
  • Change From Baseline in Bone Mineral Density (BMD) T-Score at Weeks 24 and 48 [ Time Frame: Baseline, Weeks 24 and 48 ]
    Change from baseline in spine, hip, and femoral neck BMD T-Score was assessed at Week 24 and 48. T-score values >= -1.0 were considered normal, T-score values < -1.0 to -2.5 indicate osteopenia and T-score values < -2.5 indicate osteoporosis.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 17, 2014)
  • Number of Participants With Plasma HIV-1 RNA Level <50 Copies/mL at Week 48 and 96 per FDA Snapshot Approach [ Time Frame: Week 48, 96 ]
    FDA Snapshot analysis is based on the last observed viral load data within the Week 48 and 96 window: virologic response is defined as HIV-1 RNA <50 copies/mL (observed cases); missing HIV-1 RNA is considered as non-response.
  • Number of Participants With Plasma HIV-1 RNA Level <50 Copies/mL at Weeks 24, 48, and 96 per TLOVR algorithm [ Time Frame: Week 24, 48, and 96 ]
    Time to loss of virologic response algorithm (TLOVR) requires sustained HIV-1 RNA <50 copies/mL; confirmed HIV-1 RNA greater than or equal to (>=) 50 copies/mL is considered non-response (rebound); participant is considered non-responder after permanent discontinuation.
  • Change From Baseline in Cluster of Differentiation (CD) 4+ Cell Counts at Week 24, 48, and 96 [ Time Frame: Baseline, Week 24, 48, and 96 ]
    Participant's immunological status will be assessed by CD4+ cell count at Weeks 24, 48, and 96.
  • Number of Participants With Serious Adverse Events (SAEs), Adverse Events (AEs) of Grade 3 and 4, and Premature Discontinuations due to AEs [ Time Frame: Baseline up to Week 48 ]
    An AE is any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Grade 3 (Severe) events are symptoms causing inability to perform usual social & functional activities. Grade 4 (Life-threatening) events are Symptoms causing inability to perform basic self-care functions or Medical or operative intervention indicated to prevent permanent impairment, persistent disability, or death.
  • Change From Baseline in Serum Creatinine, Estimated Glomerular Filtration Rate for Creatinine Clearance (eGFRcr), and eGFR for Cystatin-C Clearance (eGFRcyst) at Week 24 and 48 [ Time Frame: Baseline, Week 24, 48 ]
    The change from baseline in serum creatinine, eGFRcr (by Cockcroft-Gault and by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] methods) and eGFRcyst (by CKD-EPI method) at Week 24 and 48 will be assessed.
  • Change From Baseline in Renal Biomarkers at Week 24 and 48 [ Time Frame: Baseline, Week 24, 48 ]
    The change from baseline in renal biomarkers (including retinol binding protein and beta-2-microglobulin), at Week 24 and 48 will be assessed.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate Efficacy and Safety of Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) Regimen Versus Boosted Protease Inhibitor (bPI) Along With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) Regimen in Virologically-Suppressed, HIV-1 Infected Participants
Official Title  ICMJE A Phase 3, Randomized, Active-controlled, Open-label Study to Evaluate the Efficacy, Safety and Tolerability of Switching to a Darunavir/ Cobicistat/ Emtricitabine/ Tenofovir Alafenamide (D/C/F/TAF) Once-daily Single-tablet Regimen Versus Continuing the Current Regimen Consisting of a Boosted Protease Inhibitor (bPI) Combined With Emtricitabine/Tenofovir Disoproxil Fumarate (FTC/TDF) in Virologically-suppressed, Human Immunodeficiency Virus Type 1 (HIV-1) Infected Subjects
Brief Summary The purpose of this study is to demonstrate non-inferiority in efficacy while switching to a once-daily single-tablet regimen containing darunavir (DRV)/ cobicistat (COBI)/ emtricitabine (FTC)/ tenofovir alafenamide (TAF) (D/C/F/TAF tablet) relative to continuing the current regimen consisting of a boosted protease inhibitor (bPI) combined with tenofovir disoproxil fumarate (FTC/TDF) in virologically-suppressed (human immunodeficiency virus type 1 ribonucleic acid [HIV-1 RNA] concentrations less than [<] 50 copies per milliliter [copies/mL]) HIV-1 infected participants.
Detailed Description This is a randomized (study medication assigned to participants by chance), active-controlled (study in which the experimental treatment or procedure is compared to a standard treatment or procedure), open-label (participants and researchers are aware about the treatment, participants are receiving), multicenter (when more than 1 hospital or medical school team work on a medical research study), study in virologically-suppressed, HIV-1 infected adult participants. The study will include a Screening Period of approximately 30 days (up to maximum 6 weeks), a controlled Treatment Period of 48 weeks, an Extension Phase of 48 weeks. All eligible participants will be randomly assigned to receive either current treatment regimen - a bPI (limited to DRV with low-dose ritonavir [rtv] or COBI, atazanavir [ATV] with rtv or COBI, or lopinavir [LPV] with rtv) combined with FTC/TDF, or experimental treatment regimen - D/C/F/TAF once-daily single-tablet for 48 weeks. After completion of week 48, participants assigned to the experimental treatment will continue with D/C/F/TAF in the extension phase up to week 96 . Participants who continued their current regimen will receive the experimental treatment (if all criteria are fulfilled) at week 52 up to week 96. As from Week 96, all participants will be given the option to continue D/C/F/TAF treatment, if they wish and if they continue to benefit from it until D/C/F/TAF becomes commercially available and is reimbursed, or can be accessed through another source in the country where he/she is living,or until the sponsor terminates clinical development. A bone investigation substudy will be performed at selected study sites, to assess bone biomarkers and energy x-ray absorptiometry (DXA) scans, in approximately 300 participants (200 in the D/C/F/TAF treatment arm versus 100 in the control arm) who provide informed consent for the substudy.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Human Immunodeficiency Virus Type 1
Intervention  ICMJE
  • Drug: D/C/F/TAF
    Once-daily single-tablet regimen containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg.
  • Drug: Boosted Protease Inhibitor (bPI)
    Boosted protease inhibitor (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) as per current treatment regimen.
  • Drug: FTC/TDF
    Emtricitabine/tenofovir disoproxil fumarate (FTC/TDF).
Study Arms  ICMJE
  • Experimental: Experimental Treatment Regimen
    Participants will receive a single fixed dose combination (FDC) tablet containing darunavir (DRV) 800 milligram (mg)/ cobicistat (COBI) 150 mg/ emtricitabine (FTC) 200 mg/ tenofovir alafenamide (TAF) 10 mg (D/C/F/TAF tablet), orally once daily, up to Week 48. After Week 48, all participants will continue to receive the D/C/F/TAF tablet in a 48 week extension phase (up to Week 96).
    Intervention: Drug: D/C/F/TAF
  • Active Comparator: Current Treatment Regimen
    Participants will receive a boosted protease inhibitor (bPI) (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) up to Week 52. After Week 52, all participants will receive the D/C/F/TAF tablet in a 44 week extension phase (up to Week 96).
    Interventions:
    • Drug: Boosted Protease Inhibitor (bPI)
    • Drug: FTC/TDF
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 8, 2018)
1149
Original Estimated Enrollment  ICMJE
 (submitted: October 17, 2014)
660
Actual Study Completion Date  ICMJE October 2020
Actual Primary Completion Date February 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Currently being treated with a stable antiretroviral (ARV) regimen consisting of a boosted protease inhibitor (limited to darunavir [DRV] or atazanavir with low-dose ritonavir [rtv] or cobicistat [COBI], or lopinavir with rtv) combined with emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) only, for at least 6 consecutive months preceding the Screening visit
  • On-treatment plasma human immunodeficiency virus type 1 ribonucleic acid (HIV-1 RNA) concentrations less than (<) 50 copies per milliliter (copies/mL) or HIV-1 RNA undetectable by a local HIV-1 RNA test between 12 and 2 months prior to the Screening visit and have HIV-1 RNA <50 copies/mL at the Screening visit
  • A single virologic elevation of greater than or equal to (>=) 50 copies/mL after previously reaching viral suppression between 12 and 2 months prior to Screening is acceptable, provided a subsequent test prior to Screening was <50 copies/mL
  • Absence of history of failure on DRV treatment and absence of DRV resistance-associated mutations (RAMs), if documented historical genotypes are available
  • Normal electrocardiogram (ECG) at Screening (or if abnormal, determined by the Investigator to be not clinically significant)

Exclusion Criteria:

  • A new acquired immunodeficiency syndrome (AIDS) - defining condition diagnosed within the 30 days prior to Screening
  • Proven or suspected acute hepatitis within 30 days prior to study entry
  • Hepatitis C antibody positive; however, participants previously cured of hepatitis C virus (HCV) infection, with documented sustained virologic response, that is, undetectable HCV RNA 24 weeks after the last dose of HCV treatment, are allowed to participate
  • Hepatitis B surface antigen (HBsAg) positive
  • Participants with cirrhosis as diagnosed based on local practices
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Canada,   France,   Poland,   Puerto Rico,   Spain,   Sweden,   Switzerland,   United Kingdom,   United States
Removed Location Countries Germany,   Romania,   Russian Federation
 
Administrative Information
NCT Number  ICMJE NCT02269917
Other Study ID Numbers  ICMJE CR105736
TMC114IFD3013 ( Other Identifier: Janssen R&D Ireland )
2014-003052-31 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Janssen R&D Ireland
Study Sponsor  ICMJE Janssen R&D Ireland
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Janssen R&D Ireland Clinical Trial Janssen R&D Ireland
PRS Account Janssen R&D Ireland
Verification Date December 2020

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