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

Janssen R&D Ireland0 sites1,149 target enrollmentMarch 2015

ConditionsHuman Immunodeficiency Virus Type 1

InterventionsD/C/F/TAF Boosted Protease Inhibitor (bPI)FTC/TDF

DrugsD/C/F/TAF Boosted Protease Inhibitor (bPI)FTC/TDF

Overview

Phase: Phase 3
Intervention: D/C/F/TAF
Conditions: Human Immunodeficiency Virus Type 1
Sponsor: Janssen R&D Ireland
Enrollment: 1149
Primary Endpoint: Percentage of Participants With Virologic Rebound (HIV-1 RNA >=50 Copies/mL) Cumulative Through Week 48
Status: Completed
Last Updated: 4 years ago

Overview Investigators Eligibility Criteria Arms & Interventions Outcomes Similar Trials

Overview

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.

Registry

clinicaltrials.gov

Start Date

March 2015

End Date

October 2020

Last Updated

4 years ago

Study Type

Interventional

Study Design

Parallel

Sex

All

Investigators

Sponsor

Janssen R&D Ireland

Responsible Party

Sponsor

Eligibility 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

Arms & Interventions

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: D/C/F/TAF

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).

Intervention: Boosted Protease Inhibitor (bPI)

Current Treatment Regimen

Intervention: FTC/TDF

Outcomes

Primary Outcomes

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 Outcomes

Number of Participants With Resistance to Study Drug(Up to Week 48)
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(Baseline, Weeks 24 and 48)
Change From Baseline in Urine Albumin to Creatinine Ratio (UACR) and Urine Protein to Creatinine Ratio (UPCR) at Weeks 24 and 48(Baseline, Weeks 24 and 48)
Percentage of Participants With Virologic Rebound (Plasma HIV-1 RNA >=20 Copies/mL) Cumulative Through 48 Weeks(Through 48 Weeks)
Percent Change From Baseline in Urine Fractional Excretion of Phosphate (FEPO4) at Weeks 24 and 48(Baseline, Weeks 24 and 48)
Percentage of Participants With Treatment Adherence of >95% (Approach 2) Through Week 48(Through Week 48)
Percentage of Participants With Virologic Rebound (HIV-1 RNA >=50 Copies/mL) Cumulative Through Week 96(Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm))
Percentage of Participants With Treatment Adherence of >95 (Approach 1) Through Week 96(Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm))
Percentage of Participants With Treatment Adherence of >95% (Approach 2) Through Week 96(Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm))
Percentage of Participants With Non-Virologic Rebound at Week 48 by Kaplan-Meier Estimates(Baseline up to Week 48)
Percentage of Participants Experiencing Grade 3 and 4 Adverse Events (AEs), Serious Adverse Events (SAEs), and Premature Discontinuation Due to AEs Through Week 48(Up to Week 48)
Change From Baseline in Serum Creatinine Levels at Weeks 24 and 48(Baseline and Weeks 24 and 48)
Change From Baseline in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Weeks 24 and 48(Baseline, Weeks 24 and 48)
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(Baseline, Weeks 24 and 48)
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(Baseline, Weeks 24 and 48)
Percent Change From Baseline in 25-hydroxy Vitamin D at Weeks 24 and 48(Baseline, Weeks 24 and 48)
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(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]))
Change From Reference in CD4+ Cell Count at Week 96(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 Baseline in Urine Retinol Binding Protein to Creatinine Ratio (URBPCR) and Urine Beta-2 Microglobulin to Creatinine Ratio (UB2MGCR) at Weeks 24 and 48(Baseline, 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(Week 48)
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(Week 48)
Predose (Trough) Plasma Concentration (C0h) of Darunavir(Predose at Weeks 2, 4, 8, 12, 24, 36, and 48)
Percent Change From Baseline in Spine and Hip Bone Mineral Density (BMD) at Weeks 24 and 48(Baseline, Weeks 24 and 48)
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(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]))
Change From Reference in UB2MGCR at Week 96(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 Levels of Serum P1NP at Week 96(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 Hip and Spine BMD at Week 96(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)
Percentage of Participants With Virologic Rebound (Plasma HIV-1 RNA >=200 Copies/mL) Cumulative Through 48 Weeks(Through 48 Weeks)
Change From Baseline in Cluster of Differentiation 4 Plus (CD4+) Cell Count at Weeks 24 and 48(Baseline, Weeks 24 and 48)
Percentage of Participants With Treatment Adherence of Greater Than (>)95 Percent (%) (Approach 1) Through Week 48(Through Week 48)
Percent Change From Baseline in Parathyroid Hormone (PTH) at Weeks 24 and 48(Baseline, Weeks 24 and 48)
Percentage of Participants With Non-Virologic Rebound at Week 96 by Kaplan-Meier Estimates(Baseline to Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm))
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(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]))
Change From Reference in Serum Creatinine Levels at Week 96(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 Levels of Serum CTX at Week 96(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)
Change From Baseline in Bone Mineral Density (BMD) T-Score at Weeks 24 and 48(Baseline, Weeks 24 and 48)
Percentage of Participants With Virologic Rebound (HIV-1 RNA >=20 Copies/mL) Cumulative Through Week 96(Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm))
Percentage of Participants With Virologic Rebound (HIV-1 RNA >=200 Copies/mL) Cumulative Through Week 96(Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm))
Change From Reference in URBPCR at Week 96(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(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)
CD4+ Cell Count Post-Week 96 to End of Extension(Week 96 to end of extension (up to 42 months))
Number of Participants With Resistance to Study Drug Through Week 96(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))
Percentage of Participants Experiencing Grade 3 and Grade 4 AEs, SAEs, and Premature Discontinuation Due to AEs Through Week 96(Through Week 96 (D/C/F/TAF arm) and from Week 52 to Week 96 (Switch to D/C/F/TAF arm))
Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (by CKD-EPI) at Week 96(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 at Week 96(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 Levels of 25-OH Vitamin D at Week 96(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)
Percentage of Participants With Non-Treatment Failure by Kaplan-Meier Estimates(Week 96 to end of extension (up to 42 months))
Change From Reference in Estimated Glomerular Filtration Rate Based on Serum Creatinine (eGFRcr, by Cockcroft-Gault Formula [eGFRcg]) at Week 96(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 Estimated Glomerular Filtration Rate Based on Serum Cystatin C (by CKD-EPI) at Week 96(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 at Week 96(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 Levels of PTH at Week 96(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)
Change From Reference in BMD T-score of Hip and Spine at Week 96(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)
Percentage of Participants With Non-Virologic Rebound by Kaplan-Meier Estimates(Week 96 to end of extension (at every 6 months, up to 42 months))
Percentage of Participants With Treatment Adherence of >95% From Week 96 to End of Extension(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(Week 96 to end of extension (up to 42 months))
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(From Week 96 to end of extension (up to 42 months))