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

• ClinicalTrials.gov Identifier: NCT01797445
• Recruitment Status: Completed
• First Posted: February 22, 2013
• Results First Posted: January 8, 2016
• Last Update Posted: March 2, 2020
• Sponsor: Gilead Sciences
• Information provided by (Responsible Party): Gilead Sciences

Tracking Information

• First Submitted Date: February 20, 2013
• First Posted Date: February 22, 2013
• Results First Submitted Date: December 4, 2015
• Results First Posted Date: January 8, 2016
• Last Update Posted Date: March 2, 2020
• Actual Study Start Date: March 12, 2013
• Actual Primary Completion Date: September 19, 2014 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 4, 2015)

Percentage of Participants Achieving 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.

Original Primary Outcome Measures (submitted: February 20, 2013)

The proportion of subjects who have HIV-1 RNA < 50 copies/mL [ Time Frame: 48 Weeks ]

The primary efficacy endpoint is determined by the achievement of HIV-1 RNA < 50 copies/mL at Week 48

Current Secondary Outcome Measures (submitted: October 1, 2019)

• Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 [ Time Frame: Week 96 ]
  The percentage of participants achieving HIV-1 RNA < 50 copies/mL at Week 96 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.
• Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Weeks 48 and 96 [ Time Frame: Weeks 48 and 96 ]
  The percentage of participants achieving HIV-1 RNA < 20 copies/mL at Weeks 48 and 96 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.
• 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 ]
• 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 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.
• 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 ]
• Percentage of Participants With Treatment-emergent Proteinuria Through Week 48 [ Time Frame: Baseline to Week 48 ]
  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 With Treatment-emergent Proteinuria Through Week 96 [ Time Frame: Baseline to Week 96 ]
  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 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.

Original Secondary Outcome Measures (submitted: February 20, 2013)

• To determine the safety by the percent change from baseline in hip bone mineral density [ Time Frame: 48 Weeks ]
  To determine the safety of the two treatment regimens as determined by the percent change from baseline in hip bone mineral density at Week 48
• To determine the safety determined by the change from baseline in serum creatinine at Week 48 [ Time Frame: 48 Weeks ]
  To determine the safety of the two treatment regimens as determined by the change from baseline in serum creatinine at Week 48

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study to Evaluate the Safety and Efficacy of E/C/F/TAF Versus E/C/F/TDF in HIV-1 Positive, Antiretroviral Treatment-Naive Adults
• Official Title: 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
• Brief Summary: 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) in HIV-1 positive, antiretroviral treatment-naive adults.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• HIV
• HIV Infections

Intervention

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

Study Arms

• Experimental: E/C/F/TAF (Double-Blind)

  E/C/F/TAF plus E/C/F/TDF placebo for 144 weeks

  After 144 weeks, participants will continue to take their blinded study drug until treatment assignments have been unblinded.

  Interventions:

  • Drug: E/C/F/TAF
  • Drug: E/C/F/TDF Placebo
• Active Comparator: E/C/F/TDF (Double-Blind)

  E/C/F/TDF plus E/C/F/TAF placebo for 144 weeks

  After 144 weeks, participants will continue to take their blinded study drug until treatment assignments have been unblinded.

  Interventions:

  • Drug: E/C/F/TDF
  • Drug: E/C/F/TAF Placebo
• Experimental: Open-Label E/C/F/TAF
  After the unblinding visit, in countries where E/C/F/TAF is not commercially available, participants (except in UK) who complete 144 weeks of study will be given the option to receive open-label E/C/F/TAF and attend study visits every 12 weeks until it becomes commercially available, or until Gilead terminates the study in that country.
  Intervention: Drug: E/C/F/TAF

Publications *

• 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.
• Margot N, Cox S, Das M, McCallister S, Miller MD, Callebaut C. Rare emergence of drug resistance in HIV-1 treatment-naïve patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide for 144 weeks. J Clin Virol. 2018 Jun;103:37-42. doi: 10.1016/j.jcv.2018.03.012. Epub 2018 Apr 2.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 16, 2015): 872
• Original Estimated Enrollment (submitted: February 20, 2013): 840
• Actual Study Completion Date: October 3, 2018
• Actual Primary Completion Date: September 19, 2014 (Final data collection date for primary outcome measure)

Eligibility Criteria

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 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
• Age ≥ 18 years

Key Exclusion Criteria:

• A new 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
• Receiving ongoing therapy with drugs not to be used with elvitegravir, cobicistat, emtricitabine, tenofovir DF, and TAF or participants with any known allergies to the excipients of E/C/F/TDF or E/C/F/TAF

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Canada, Dominican Republic, France, Italy, Mexico, Netherlands, Portugal, Puerto Rico, Sweden, United Kingdom, United States
• Removed Location Countries: Australia, Austria, Belgium, Brazil, Germany, Spain, Switzerland, Thailand

Administrative Information

• NCT Number: NCT01797445
• Other Study ID Numbers: GS-US-292-0111; 2013-000102-37 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Qualified external researchers may request IPD for this study after study completion. For more information, please visit our website at www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Time Frame: 18 months after study completion
• Access Criteria: A secured external environment with username, password, and RSA code.
• URL: https://www.gilead.com/science-and-medicine/research/clinical-trials-transparency-and-data-sharing-policy

• Responsible Party: Gilead Sciences
• Study Sponsor: Gilead Sciences
• Collaborators: Not Provided

Investigators

• Study Director: Gilead Study Director; Gilead Sciences

• PRS Account: Gilead Sciences
• Verification Date: October 2019