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

• ClinicalTrials.gov Identifier: NCT02269917
• Recruitment Status: Completed
• First Posted: October 21, 2014
• Results First Posted: November 9, 2018
• Last Update Posted: December 9, 2021
• Sponsor: Janssen R&D Ireland
• Information provided by (Responsible Party): Janssen R&D Ireland

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Human Immunodeficiency Virus Type 1	Drug: D/C/F/TAF; Drug: Boosted Protease Inhibitor (bPI); Drug: FTC/TDF	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 1149 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: March 2015
• Actual Primary Completion Date: February 2017
• Actual Study Completion Date: October 2020

Arms and Interventions

Arm	Intervention/treatment
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).	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.
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).	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).

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. Percentage of Participants With Non-Virologic Rebound at Week 48 by Kaplan-Meier Estimates [ Time Frame: Baseline up to Week 48 ]
   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). Here Kaplan-Meier estimates percentage of participants with non-virologic rebound at week 48.
4. Percentage of Participants Experiencing Grade 3 and 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Premature Discontinuation Due to AEs Through Week 48 [ 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.
5. 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.
6. 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).
7. 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.
8. 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).
9. 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.
10. 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.
11. 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.
12. 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).
13. 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.
14. 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.
15. 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).
16. 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).
17. 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 >=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.
18. 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.
19. 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.
20. 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.
21. 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.
22. 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.
23. 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.
24. Percentage of Participants With Virologic Rebound (HIV-1 RNA >=20 Copies/mL) Cumulative Through Week 96 [ Time Frame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm) ]
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA level >=20 copies/mL up to and including Week 96, last available on-treatment (single) HIV-1 RNA >=20 copies/mL at premature discontinuation (irrespective of reason), and last available on-treatment HIV-1 RNA >=20 copies/mL at the study cutoff of Week 96 (that is, any last viral load [re]test having occurred no later than 6 weeks after Week 96). Percentage of participants with virologic rebound were reported.
25. Percentage of Participants With Virologic Rebound (HIV-1 RNA >=50 Copies/mL) Cumulative Through Week 96 [ Time Frame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm) ]
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA level >=50 copies/mL up to and including Week 96, last available on-treatment (single) HIV-1 RNA >=50 copies/mL at premature discontinuation (irrespective of reason), and last available on-treatment HIV-1 RNA >=50copies/mL at the study cutoff of Week 96 (that is, any last viral load [re]test having occurred no later than 6 weeks after Week 96). Percentage of participants with virologic rebound were reported.
26. Percentage of Participants With Virologic Rebound (HIV-1 RNA >=200 Copies/mL) Cumulative Through Week 96 [ Time Frame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm) ]
    Virologic rebound was defined as: confirmed plasma HIV-1 RNA level >=200 copies/mL up to and including Week 96, last available on-treatment (single) HIV-1 RNA >=200 copies/mL at premature discontinuation (irrespective of reason), and last available on-treatment HIV-1 RNA >=200 copies/mL at the study cutoff of Week 96 (that is, any last viral load [re]test having occurred no later than 6 weeks after Week 96). Percentage of participants with virologic rebound were reported.
27. Percentage of Participants With Non-Virologic Rebound at Week 96 by Kaplan-Meier Estimates [ Time Frame: Baseline to Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm) ]
    Here Kaplan-Meier estimates percentage of participants with non-virologic rebound at Week 96.
28. Percentage of Participants With Virologic Response Based on HIV-1 RNA <20, <50, and <200 Copies/mL Threshold at Week 96 as Defined by the FDA Snapshot Approach [ Time Frame: Week 96 (Comprising up to Week 96 for D/C/F/TAF and 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52 up to Week 96]) ]
    Percentage of participants with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 96 using FDA snapshot approach. FDA Snapshot approach analysis was based on the last observed viral load data: virologic response was defined as having last available HIV-1 RNA <20/50/200 copies/mL (observed case).
29. Percentage of Participants With Virologic Response Based on HIV-1 RNA <20, <50, and <200 Copies/mL Threshold at Week 96 as Defined by the TLOVR Algorithm [ Time Frame: Week 96 (Comprising up to Week 96 for D/C/F/TAF and 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52 up to Week 96]) ]
    Percentage of participants with virologic response based on HIV-1 RNA <20, <50, and <200 copies/mL threshold were analyzed at Week 96 using TLOVR algorithm approach. TLOVR was defined as sustained HIV-1 RNA <20/50/200 copies/mL.
30. Percentage of Participants With Virologic Failure Based on HIV-1 RNA >=20, >=50, and >=200 Copies/mL Threshold at Week 96 as Defined by the FDA Snapshot Approach [ Time Frame: Week 96 (Comprising up to Week 96 for D/C/F/TAF and 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52 up to Week 96]) ]
    Percentage of participants with virologic failure based on HIV-1 RNA >=20, >=50, and >=200 copies/mL threshold were analyzed at Week 96 using FDA snapshot approach. FDA Snapshot approach analysis was based on the last observed viral load data: virologic failure was defined by the FDA snapshot approach as having last available HIV-1 RNA >=20/50/200 copies/mL at Week 96; virologic failure - leading to discontinuation; virologic failure - discontinued due to other reason and last available HIV-1 RNA >=20/50/200 copies/mL.
31. Change From Reference in CD4+ Cell Count at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF (Comprising 44 weeks of D/C/F/TAF exposure [that is, from the switch to D/C/F/TAF at Week 52]) ]
    Change from reference in CD4+ cell count was assessed at Week 96. The change from reference in CD4+ count at a given time point is defined as: CD4+ at a given time point minus reference CD4+. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
32. Number of Participants With Resistance to Study Drug Through Week 96 [ Time Frame: Through Week 96 (D/C/F/TAF arm), up to Week 48 (Control arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm) ]
    HIV-1 genotypes were analyzed from samples of participants with confirmed virologic rebound in case they had HIV-1 RNA values >=400 copies/mL at failure or at later time points, including participants who discontinued with last HIV-1 RNA >=400 copies/mL. Virologic rebound was defined as: confirmed plasma HIV-1 RNA level >=20 copies/mL up to and including Week 96, last available on-treatment (single) HIV-1 RNA >=20 copies/mL at premature discontinuation (irrespective of reason), and last available on-treatment HIV-1 RNA >=20 copies/mL at the study cutoff of Week 96 (that is, any last viral load [re]test having occurred no later than 6 weeks after Week 96). Number of participants who developed resistance to any of the study drug (DRV, FTC, and TFV/TAF) were reported.
33. Percentage of Participants With Treatment Adherence of >95 (Approach 1) Through Week 96 [ Time Frame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm) ]
    Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability cumulative through Week 96 (Approach 1).
34. Percentage of Participants With Treatment Adherence of >95% (Approach 2) Through Week 96 [ Time Frame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm) ]
    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 96, whichever came sooner (Approach 2).
35. Percentage of Participants Experiencing Grade 3 and Grade 4 AEs, SAEs, and Premature Discontinuation Due to AEs Through Week 96 [ Time Frame: Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm) ]
    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. SAE is any 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.
36. Change From Reference in Serum Creatinine Levels at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF ]
    Change from reference in serum creatinine levels at Week 96 was assessed. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
37. Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF ]
    Change from reference in eGFRcr (by Cockcroft-Gault formula) was assessed at Week 96. 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). For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
38. Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (by CKD-EPI) at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF ]
    Change from reference in eGFRcr (by CKD-EPI) was assessed at Week 96. 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*0.993^age; 2) Scr greater than (>)0.7 mg/dL: 144*(Scr/0.7)^-1.209*0.993^age. Male: 1) Scr <=0.9 mg/dL: 141*(Scr/0.9)^-0.411*0.993^age; 2) Scr >0.9 mg/dL: 141*(Scr/0.9)^-1.209*0.993^age. . For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
39. Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Cystatin C (by CKD-EPI) at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF ]
    Change from reference in eGFRcyst (by CKD-EPI) was assessed at Week 96. eGFRcyst according to the CKD-EPI formula - 1) Serum Cystatin C (Scyst) <=0.8 mg/L: 133*(Scyst/0.8)^-0.499*0.996^age (*0.932 if female); 2) Scyst >0.8 mg/L: 133*(Scyst/0.8)^-1.328*0.996^age (*0.932 if female). For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
40. Change From Reference in UACR at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF ]
    Change from reference in UACR was assessed at Week 96. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
41. Change From Reference in URBPCR at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF ]
    Change from reference in URBPCR was assessed at Week 96. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
42. Change From Reference in UPCR at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF ]
    Change from reference in UPCR was assessed at Week 96. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
43. Change From Reference in UB2MGCR at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF ]
    Change from reference in UB2MGCR was assessed at Week 96. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
44. Percent Change From Reference in FEPO4 at Week 96 [ Time Frame: From Reference 1 to Week 96 for D/C/F/TAF+ F/TDF Group and Reference 2 to Week 96 for Switch to D/C/F/TAF ]
    Percent change from reference in FEPO4 at Week 96 was reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
45. Percent Change From Reference in Levels of Serum P1NP at Week 96 [ 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 ]
    Percent change from reference in serum P1NP levels at Week 96 was reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
46. Percent Change From Reference in Levels of Serum CTX at Week 96 [ 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 ]
    Percent change from reference in serum CTX at Week 96 was reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
47. Percent Change From Reference in Levels of PTH at Week 96 [ 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 ]
    Percent change from reference in PTH at Week 96 was reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
48. Percent Change From Reference in Levels of 25-OH Vitamin D at Week 96 [ 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 ]
    Percent change from reference in 25-OH Vitamin D at Week 96 were reported. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
49. Percent Change From Reference in Hip and Spine BMD at Week 96 [ 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 ]
    The BMD is the amount of mineral in gram per square centimeter of bone, which was assessed by DXA 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. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
50. Change From Reference in BMD T-score of Hip and Spine at Week 96 [ 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 ]
    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. For the D/C/F/TAF group, reference is the comparative treatment phase baseline as in Week 48 analysis (Reference 1). For the Switch to D/C/F/TAF (late switch) group, the last value prior to the switch was used as reference (reference 2).
51. Percentage of Participants With Non-Virologic Rebound by Kaplan-Meier Estimates [ Time Frame: Week 96 to end of extension (at every 6 months, up to 42 months) ]
    Virologic rebound is defined as participants who show confirmed HIV-1 RNA >=50 copies/mL, or for which the last available (single) HIV-1 RNA value on treatment was >=50 copies/mL. Here, Kaplan-Meier estimates (%) of non-virologic rebound at every 6 months interval are presented.
52. Percentage of Participants With Non-Treatment Failure by Kaplan-Meier Estimates [ Time Frame: Week 96 to end of extension (up to 42 months) ]
    Percentage of participants with non-treatment failure by Kaplan-Meier Estimates were reported. Treatment failure was defined as having either protocol-defined virologic rebound or having discontinued for reasons other than alternate access to D/C/F/TAF (or other antiretroviral [ARV]).
53. Percentage of Participants With HIV RNA <50, <20, <200 Copies/mL Post Week 96 to End of Extension [ Time Frame: Week 96 to end of extension (up to 42 months) ]
    Percentage of participants with HIV RNA <50, <20, <200 copies/mL post Week 96 to end of extension were reported.
54. CD4+ Cell Count Post-Week 96 to End of Extension [ Time Frame: Week 96 to end of extension (up to 42 months) ]
    The immunologic change was determined by Cluster of CD4+ cell count. CD4+ cell count post-Week 96 to end of extension were assessed.
55. Percentage of Participants With Treatment Adherence of >95% From Week 96 to End of Extension [ Time Frame: Week 96 to end of extension (up to 42 months) ]
    Treatment adherence (defined as adherence of >95%) was assessed by the drug accountability and was calculated cumulative 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 from Week 96 to end of extension.
56. Percentage of Participants Experiencing Grade 3 and 4 AEs, Serious Adverse Events (SAEs), and Premature Discontinuation Due to AEs Post-Week 96 to End of Extension [ Time Frame: From Week 96 to end of extension (up to 42 months) ]
    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. SAE is any 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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Arizona

Phoenix, Arizona, United States

United States, California

Bakersfield, California, United States

Beverly Hills, California, United States

Long Beach, California, United States

Los Angeles, California, United States

San Diego, California, United States

San Francisco, California, United States

United States, District of Columbia

Washington, District of Columbia, United States

United States, Florida

Fort Lauderdale, Florida, United States

Fort Pierce, Florida, United States

Orlando, Florida, United States

West Palm Beach, Florida, United States

United States, Georgia

Atlanta, Georgia, United States

Savannah, Georgia, United States

United States, Illinois

Chicago, Illinois, United States

United States, Massachusetts

Boston, Massachusetts, United States

Springfield, Massachusetts, United States

United States, Michigan

Berkley, Michigan, United States

Detroit, Michigan, United States

United States, Minnesota

Minneapolis, Minnesota, United States

United States, Missouri

Kansas City, Missouri, United States

Saint Louis, Missouri, United States

United States, New Jersey

Hillsborough, New Jersey, United States

Newark, New Jersey, United States

Somers Point, New Jersey, United States

United States, New Mexico

Santa Fe, New Mexico, United States

United States, New York

New York, New York, United States

United States, North Carolina

Chapel Hill, North Carolina, United States

Winston-Salem, North Carolina, United States

United States, Ohio

Cincinnati, Ohio, United States

United States, Pennsylvania

Philadelphia, Pennsylvania, United States

United States, Rhode Island

Providence, Rhode Island, United States

United States, Texas

Austin, Texas, United States

Dallas, Texas, United States

Fort Worth, Texas, United States

Houston, Texas, United States

Longview, Texas, United States

United States, Washington

Seattle, Washington, United States

Belgium

Antwerpen, Belgium

Brussels, Belgium

Bruxelles, Belgium

Gent, Belgium

Leuven, Belgium

Liège, Belgium

Canada, Alberta

Edmonton, Alberta, Canada

Canada, British Columbia

Vancouver, British Columbia, Canada

Canada, Ontario

Toronto, Ontario, Canada

Canada, Quebec

Montreal, Quebec, Canada

France

Le Kremlin Bicetre, France

Lyon, France

Marseille, France

Montpellier, France

Nantes, France

Paris Cedex 10, France

Paris Cedex 12, France

Paris, France

Strasbourg Cedex, France

Tourcoing, France

Poland

Bydgoszcz, Poland

Chorzow, Poland

Lodz, Poland

Warszawa, Poland

Wroclaw, Poland

Puerto Rico

San Juan, Puerto Rico

Spain

Alicante, Spain

Badalona, Spain

Barcelona, Spain

Cordoba, Spain

Elche, Spain

Madrid, Spain

San Sebastian, Spain

Sevilla, Spain

Valencia, Spain

Sweden

Göteborg, Sweden

Malmö, Sweden

Stockholm, Sweden

Switzerland

Basel, Switzerland

Bern, Switzerland

Zurich N/a, Switzerland

United Kingdom

Brighton, United Kingdom

London, United Kingdom

Manchester, United Kingdom

Sponsors and Collaborators

Janssen R&D Ireland

Investigators

• Study Director: Janssen R&D Ireland Clinical Trial; Janssen R&D Ireland

  Study Documents (Full-Text)

Documents provided by Janssen R&D Ireland:

Study Protocol  [PDF] May 29, 2015

Statistical Analysis Plan  [PDF] March 28, 2018

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Huhn GD, Wilkin A, Mussini C, Spinner CD, Jezorwski J, El Ghazi M, Van Landuyt E, Lathouwers E, Brown K, Baugh B; AMBER and EMERALD study groups. Week 96 subgroup analyses of the phase 3, randomized AMBER and EMERALD trials evaluating the efficacy and safety of the once daily darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) single-tablet regimen in antiretroviral treatment (ART)-naive and -experienced, virologically-suppressed adults living with HIV-1. HIV Res Clin Pract. 2020 Dec;21(6):151-167. doi: 10.1080/25787489.2020.1844520. Epub 2021 Feb 2.

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.

Huhn GD, Eron JJ, Girard PM, Orkin C, Molina JM, DeJesus E, Petrovic R, Luo D, Van Landuyt E, Lathouwers E, Nettles RE, Brown K, Wong EY. Darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-experienced, virologically suppressed patients with HIV-1: subgroup analyses of the phase 3 EMERALD study. AIDS Res Ther. 2019 Aug 29;16(1):23. doi: 10.1186/s12981-019-0235-1.

Orkin C, Molina JM, Negredo E, Arribas JR, Gathe J, Eron JJ, Van Landuyt E, Lathouwers E, Hufkens V, Petrovic R, Vanveggel S, Opsomer M; EMERALD study group. Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial. Lancet HIV. 2018 Jan;5(1):e23-e34. doi: 10.1016/S2352-3018(17)30179-0. Epub 2017 Oct 6.

• Responsible Party: Janssen R&D Ireland
• ClinicalTrials.gov Identifier: NCT02269917
• Other Study ID Numbers: CR105736; TMC114IFD3013 ( Other Identifier: Janssen R&D Ireland ); 2014-003052-31 ( EudraCT Number )
• First Posted: October 21, 2014
• Results First Posted: November 9, 2018
• Last Update Posted: December 9, 2021
• Last Verified: November 2021

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

Keywords provided by Janssen R&D Ireland:

Human Immunodeficiency Virus Type 1; Emerald; Darunavir; Cobicistat; Emtricitabine; Tenofovir Alafenamide

Additional relevant MeSH terms:

Acquired Immunodeficiency Syndrome; HIV Infections; Immunologic Deficiency Syndromes; Immune System Diseases; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; HIV Protease Inhibitors; Protease Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Viral Protease Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Antiviral Agents; Anti-Infective Agents