Study to Evaluate the Safety and Efficacy of E/C/F/TAF (Genvoya®) Versus E/C/F/TDF (Stribild®) in HIV-1 Positive, Antiretroviral Treatment-Naive Adults

Overview

The primary objective of this study is to evaluate the efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) versus elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) FDC in HIV-1 positive, antiretroviral treatment-naive adults.

Full Title of Study: “A Phase 3, Randomized, Double-Blind Study to Evaluate the Safety and Efficacy of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Versus Elvitegravir/Cobicistat/Emtricitabine/ Tenofovir Disoproxil Fumarate in HIV-1 Positive, Antiretroviral Treatment-Naïve Adults”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: August 26, 2014

Interventions

  • Drug: E/C/F/TAF
    • 150/150/200/10 mg FDC tablet administered orally once daily
  • Drug: E/C/F/TDF
    • 150/150/200/300 mg FDC tablet administered orally once daily
  • Drug: E/C/F/TDF Placebo
    • Tablet administered orally once daily
  • Drug: E/C/F/TAF Placebo
    • Tablet administered orally once daily

Arms, Groups and Cohorts

  • Experimental: E/C/F/TAF (Double-Blind Phase)
    • E/C/F/TAF plus E/C/F/TDF placebo for 144 weeks
  • Active Comparator: E/C/F/TDF (Double-Blind Phase)
    • E/C/F/TDF plus E/C/F/TAF placebo for 144 weeks
  • Experimental: Open-Label Extension Phase
    • After study unblinding, participants who complete 144 weeks of the study had the option to receive open-label E/C/F/TAF until commercially available, or until Gilead Sciences terminated the study in that country.

Clinical Trial Outcome Measures

Primary Measures

  • Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48
    • Time Frame: Week 48
    • The percentage of participants achieving HIV-1 RNA < 50 copies/mL at Week 48 was analyzed using the snapshot algorithm, which defines a patient’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.

Secondary Measures

  • Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Weeks 96 and 144
    • Time Frame: Weeks 96 and 144
    • The percentage of participants achieving HIV-1 RNA < 50 copies/mL at Weeks 96 and 144 were analyzed using the snapshot algorithm, which defines a patient’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.
  • Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Weeks 48, 96, and 144
    • Time Frame: Weeks 48, 96. and 144
    • The percentage of participants achieving HIV-1 RNA < 20 copies/mL at Weeks 48, 96, and 144 were analyzed using the snapshot algorithm, which defines a patient’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.
  • Change From Baseline in CD4+ Cell Count at Week 48
    • Time Frame: Baseline; Week 48
  • Change From Baseline in CD4+ Cell Count at Week 96
    • Time Frame: Baseline; Week 96
  • Change From Baseline in CD4+ Cell Count at Week 144
    • Time Frame: Baseline; Week 144
  • Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48
    • Time Frame: Baseline; Week 48
    • Hip BMD was assessed by dual energy x-ray absorptiometry (DXA) scan.
  • Percent Change From Baseline in Hip BMD at Week 96
    • Time Frame: Baseline; Week 96
    • Hip BMD was assessed by DXA scan.
  • Percent Change From Baseline in Hip BMD at Week 144
    • Time Frame: Baseline; Week 144
    • Hip BMD was assessed by DXA scan.
  • Percent Change From Baseline in Spine BMD at Week 48
    • Time Frame: Baseline; Week 48
    • Spine BMD was assessed by DXA scan.
  • Percent Change From Baseline in Spine BMD at Week 96
    • Time Frame: Baseline; Week 96
    • Spine BMD was assessed by DXA scan.
  • Percent Change From Baseline in Spine BMD at Week 144
    • Time Frame: Baseline; Week 144
    • Spine BMD was assessed by DXA scan.
  • Change From Baseline in Serum Creatinine at Week 48
    • Time Frame: Baseline; Week 48
  • Change From Baseline in Serum Creatinine at Week 96
    • Time Frame: Baseline; Week 96
  • Change From Baseline in Serum Creatinine at Week 144
    • Time Frame: Baseline; Week 144
  • Percentage of Participants Experiencing Treatment-emergent Proteinuria Through Week 48
    • Time Frame: Up to 48 weeks
    • Grades 1 (mild), 2 (moderate), and 3 (severe) were the highest treatment-emergent postbaseline grades for urine protein using the dipstick method. The worst postbaseline value is presented for each participant.
  • Percentage of Participants Experiencing Treatment-emergent Proteinuria Through Week 96
    • Time Frame: Up to 96 weeks
    • Grades 1 (mild), 2 (moderate), and 3 (severe) were the highest treatment-emergent postbaseline grades for urine protein using the dipstick method. The worst postbaseline value is presented for each participant.
  • Percentage of Participants Experiencing Treatment-emergent Proteinuria Through Week 144
    • Time Frame: Up to 144 weeks
    • Grades 1 (mild), 2 (moderate), and 3 (severe) were the highest treatment-emergent postbaseline grades for urine protein using the dipstick method. The worst postbaseline value is presented for each participant.
  • Percent Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio at Week 48
    • Time Frame: Baseline; Week 48
    • Urine RBP is a renal biomarker which is used to detect drug-induced kidney injury.
  • Percent Change From Baseline in Urine RBP to Creatinine Ratio at Week 96
    • Time Frame: Baseline; Week 96
    • Urine RBP is a renal biomarker which is used to detect drug-induced kidney injury.
  • Percent Change From Baseline in Urine RBP to Creatinine Ratio at Week 144
    • Time Frame: Baseline; Week 144
    • Urine RBP is a renal biomarker which is used to detect drug-induced kidney injury.
  • Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 48
    • Time Frame: Baseline; Week 48
    • Urine Beta-2-microglobulin is a renal biomarker which is used to detect drug-induced kidney injury.
  • Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 96
    • Time Frame: Baseline; Week 96
    • Urine Beta-2-microglobulin is a renal biomarker which is used to detect drug-induced kidney injury.
  • Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 144
    • Time Frame: Baseline; Week 144
    • Urine Beta-2-microglobulin is a renal biomarker which is used to detect drug-induced kidney injury.

Participating in This Clinical Trial

Key Inclusion Criteria:

  • Ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
  • Plasma HIV-1 RNA levels ≥ 1,000 copies/mL at screening
  • No prior use of any approved or investigational antiretroviral drug for any length of time, except the use for pre-exposure prophylaxis (PREP) or post-exposure prophylaxis (PEP), up to 6 months prior to screening
  • Screening genotype report must show sensitivity to elvitegravir, emtricitabine, tenofovir disoproxil fumarate (tenofovir DF)
  • Normal electrocardiogram (ECG)
  • Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min according to the Cockcroft-Gault formula for creatinine clearance
  • Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
  • Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin
  • Adequate hematologic function
  • Serum amylase ≤ 5 × ULN
  • Males and females of childbearing potential must agree to utilize highly effective contraception methods or be non-heterosexually active or practice sexual abstinence from screening throughout the duration of study treatment and for 30 days following the last dose of study drug
  • Females who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing
  • Females who have stopped menstruating for ≥ 12 months but do not have documentation of ovarian hormonal failure must have a serum follicle stimulating hormone (FSH) level at screening within the post-menopausal range based on the Central Laboratory reference range

Key Exclusion Criteria:

  • A new acquired immunodeficiency syndrome (AIDS) defining condition diagnosed within the 30 days prior to screening
  • Hepatitis B surface antigen (HBsAg) positive
  • Hepatitis C antibody positive
  • Individuals experiencing decompensated cirrhosis
  • Females who are breastfeeding
  • Positive serum pregnancy test
  • Have an implanted defibrillator or pacemaker
  • Current alcohol or substance use judged by the Investigator to potentially interfere with study compliance
  • History of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, noninvasive cutaneous squamous carcinoma
  • Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline
  • Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the individual unsuitable for the study or unable to comply with dosing requirements
  • Participation in any other clinical trial (including observational trials) without prior approval
  • Individuals receiving ongoing therapy with drugs not to be used with elvitegravir, cobicistat, emtricitabine, tenofovir DF, and TAF or individuals with any known allergies to the excipients of E/C/F/TDF or E/C/F/TAF single-tablet regimen tablets

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Gilead Sciences
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Gilead Study Director, Study Director, Gilead Sciences

Citations Reporting on Results

Sax PE, Wohl D, Yin MT, Post F, DeJesus E, Saag M, Pozniak A, Thompson M, Podzamczer D, Molina JM, Oka S, Koenig E, Trottier B, Andrade-Villanueva J, Crofoot G, Custodio JM, Plummer A, Zhong L, Cao H, Martin H, Callebaut C, Cheng AK, Fordyce MW, McCallister S; GS-US-292-0104/0111 Study Team. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials. Lancet. 2015 Jun 27;385(9987):2606-15. doi: 10.1016/S0140-6736(15)60616-X. Epub 2015 Apr 15. Erratum in: Lancet. 2016 Apr 30;387(10030):1816.

Arribas JR, Thompson M, Sax PE, Haas B, McDonald C, Wohl DA, DeJesus E, Clarke AE, Guo S, Wang H, Callebaut C, Plummer A, Cheng A, Das M, McCallister S. Brief Report: Randomized, Double-Blind Comparison of Tenofovir Alafenamide (TAF) vs Tenofovir Disoproxil Fumarate (TDF), Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine (E/C/F) for Initial HIV-1 Treatment: Week 144 Results. J Acquir Immune Defic Syndr. 2017 Jun 1;75(2):211-218. doi: 10.1097/QAI.0000000000001350.

Margot N, Cox S, Das M, McCallister S, Miller MD, Callebaut C. Infrequent development of drug resistance in HIV-1-infected treatment-naive subjects after 96 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide or elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate. Antivir Ther. 2017;22(5):443-446. doi: 10.3851/IMP3125. Epub 2017 Jan 11.

Margot NA, Kitrinos KM, Fordyce M, McCallister S, Miller MD, Callebaut C. Rare emergence of drug resistance in HIV-1 treatment-naïve patients after 48 weeks of treatment with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide. HIV Clin Trials. 2016 Mar;17(2):78-87. doi: 10.1080/15284336.2016.1142731.

Funderburg NT, McComsey GA, Kulkarni M, Bannerman T, Mantini J, Thornton B, Liu HC, Zhang Y, Song Q, Fang L, Dinoso J, Cheng A, McCallister S, Fordyce MW, Das M. Equivalent Decline in Inflammation Markers with Tenofovir Disoproxil Fumarate vs. Tenofovir Alafenamide. EBioMedicine. 2016 Nov;13:321-327. doi: 10.1016/j.ebiom.2016.10.009. Epub 2016 Oct 11.

Wohl D, Oka S, Clumeck N, Clarke A, Brinson C, Stephens J, Tashima K, Arribas JR, Rashbaum B, Cheret A, Brunetta J, Mussini C, Tebas P, Sax PE, Cheng A, Zhong L, Callebaut C, Das M, Fordyce M; GS-US-2,92-01040111 and Study Team. Brief Report: A Randomized, Double-Blind Comparison of Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate, Each Coformulated With Elvitegravir, Cobicistat, and Emtricitabine for Initial HIV-1 Treatment: Week 96 Results. J Acquir Immune Defic Syndr. 2016 May 1;72(1):58-64. doi: 10.1097/QAI.0000000000000940.

Custodio JM, Garner W, Callebaut C, Fordyce M, Plummer A, Zhong L, et al. The Pharmacokinetics of Tenofovir and Tenofovir Diphosphate Following Administration of Tenofovir Alafenamide vs Tenofovir Disoproxil Fumarate [Oral Abstract #6]. The 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy. Washington DC, USA, May 26-28, 2015.

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