Clinical trial NCT01797445: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV
HIV Infections
Keywords: HIV
Treatment Naive
HIV 1 Infected
Women
Female
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2013-02-22
Enrollment: 872
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


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.

Primary outcomes:
measure: Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Week 48
timeFrame: Week 48
Secondary outcomes:
measure: Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96
timeFrame: Week 96
measure: Percentage of Participants With HIV-1 RNA < 20 Copies/mL at Weeks 48 and 96
timeFrame: Weeks 48 and 96
measure: Change From Baseline in CD4+ Cell Count at Week 48
timeFrame: Baseline; Week 48
measure: Change From Baseline in CD4+ Cell Count at Week 96
timeFrame: Baseline; Week 96
measure: Percent Change From Baseline in Hip Bone Mineral Density (BMD) at Week 48
timeFrame: Baseline; Week 48
measure: Percent Change From Baseline in Hip BMD at Week 96
timeFrame: Baseline; Week 96
measure: Percent Change From Baseline in Spine BMD at Week 48
timeFrame: Baseline; Week 48
measure: Percent Change From Baseline in Spine BMD at Week 96
timeFrame: Baseline; Week 96
measure: Change From Baseline in Serum Creatinine at Week 48
timeFrame: Baseline; Week 48
measure: Change From Baseline in Serum Creatinine at Week 96
timeFrame: Baseline; Week 96
measure: Percentage of Participants With Treatment-emergent Proteinuria Through Week 48
timeFrame: Baseline to Week 48
measure: Percentage of Participants With Treatment-emergent Proteinuria Through Week 96
timeFrame: Baseline to Week 96
measure: Percent Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio at Week 48
timeFrame: Baseline; Week 48
measure: Percent Change From Baseline in Urine RBP to Creatinine Ratio at Week 96
timeFrame: Baseline; Week 96
measure: Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 48
timeFrame: Baseline; Week 48
measure: Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio at Week 96
timeFrame: Baseline; Week 96
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Phoenix
country: United States
facility: Spectrum Medical Group
state: Arizona
city: Los Angeles
country: United States
facility: Kaiser Permanente - Los Angeles Medical Center
state: California
city: Los Angeles
country: United States
facility: University of Southern California AIDS Clinical Trials Group
state: California
city: Los Angeles
country: United States
facility: Peter J. Ruane, Inc.
state: California
city: Los Angeles
country: United States
facility: Anthony Mills MD Inc
state: California
city: Oakland
country: United States
facility: Alameda County Medical Center
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Sacramento
country: United States
facility: University of California, Davis Medical Center
state: California
city: Sacramento
country: United States
facility: Kaiser Permanente Medical Group
state: California
city: San Diego
country: United States
facility: La Playa Medical Group and Clinical Research
state: California
city: San Francisco
country: United States
facility: Kaiser Permanente San Francisco
state: California
city: San Leandro
country: United States
facility: Kaiser Permanente
state: California
city: Torrance
country: United States
facility: Los Angeles Biomedical Research Institute at Harbor - UCLA Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Denver
country: United States
facility: APEX Research LLC
state: Colorado
city: Greenwich
country: United States
facility: Greenwich Hospital
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Dupont Circle Physicians Group
state: District of Columbia
city: Washington
country: United States
facility: Whitman-Walker Health
state: District of Columbia
city: Washington
country: United States
facility: Capital Medical Associates, PC
state: District of Columbia
city: Washington
country: United States
facility: Medical Faculty Associates
state: District of Columbia
city: Fort Lauderdale
country: United States
facility: Gary J. Richmond,M.D.,P.A.
state: Florida
city: Fort Pierce
country: United States
facility: Midway Immunology and Research Center
state: Florida
city: Miami Beach
country: United States
facility: AIDS Healthcare Foundation
state: Florida
city: Miami
country: United States
facility: AIDS Healthcare Foundation
state: Florida
city: Orlando
country: United States
facility: Orlando Immunology Center
state: Florida
city: Orlando
country: United States
facility: Idocf/Valuhealthmd
state: Florida
city: Sarasota
country: United States
facility: Infectious Diseases Associates of NW FL
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Tampa
country: United States
facility: Infectious Disease Research Institute Inc.
state: Florida
city: Tampa
country: United States
facility: St. Joseph's Comprehensive Research Institute
state: Florida
city: West Palm Beach
country: United States
facility: Triple O Research Institute PA
state: Florida
city: Atlanta
country: United States
facility: AIDS Research Consortium of Atlanta
state: Georgia
city: Atlanta
country: United States
facility: Atlanta ID Group, PC
state: Georgia
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Augusta
country: United States
facility: Georgia Regents University
state: Georgia
city: Decatur
country: United States
facility: Infectious Disease Specialist of Atlanta
state: Georgia
city: Macon
country: United States
facility: Mercer University
state: Georgia
city: Honolulu
country: United States
facility: University of Hawaii - Hawaii Center for AIDS
state: Hawaii
city: Chicago
country: United States
facility: Rush University Medical Center, Section of Infectious Diseases
state: Illinois
city: Chicago
country: United States
facility: The Ruth M. Rothstein CORE Center
state: Illinois
city: Boston
country: United States
facility: Community Research Initiative of New England
state: Massachusetts
city: West Springfield
country: United States
facility: The Research Institute
state: Massachusetts
city: Berkley
country: United States
facility: Be Well Medical Center
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Saint Louis
country: United States
facility: Central West Clinical Research
state: Missouri
city: Saint Louis
country: United States
facility: Southampton Healthcare, Inc.
state: Missouri
city: Hillsborough
country: United States
facility: ID Care
state: New Jersey
city: Santa Fe
country: United States
facility: Southwest CARE Center
state: New Mexico
city: Albany
country: United States
facility: Albany Medical College
state: New York
city: Albany
country: United States
facility: Upstate ID Assoc
state: New York
city: Bronx
country: United States
facility: Jacobi Medical Center
state: New York
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital - Division of Infectious Diseases
state: New York
city: New York
country: United States
facility: Chelsea Village Medical
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina AIDS Clinical Trials Unit
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center Myer's Park Clinic
state: North Carolina
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Greenville
country: United States
facility: East Carolina University The Brody School of Medicine
state: North Carolina
city: Huntersville
country: United States
facility: Rosedale Infectious Disseases
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Providence
country: United States
facility: The Miriam Hospital
state: Rhode Island
city: Austin
country: United States
facility: Central Texas Clinical Research
state: Texas
city: Bellaire
country: United States
facility: St. Hope Foundation, Inc.
state: Texas
city: Dallas
country: United States
facility: Trinity Health & Wellness Center / AIDS Arms, Inc.
state: Texas
city: Dallas
country: United States
facility: Southwest Infectious Disease Clinical Research, Inc.
state: Texas
city: Dallas
country: United States
facility: North Texas Infectious Diseases Consultants
state: Texas
city: Fort Worth
country: United States
facility: Tarrant County Infectious Disease Associates
state: Texas
city: Houston
country: United States
facility: Therapeutic Concepts, PA
state: Texas
city: Houston
country: United States
facility: Gordon E. Crofoot, MD, PA
state: Texas
city: Houston
country: United States
facility: Research Access Network
state: Texas
city: Longview
country: United States
facility: DCOL Center for Clinical Research
state: Texas
city: Annandale
country: United States
facility: Clinical Alliance for Research & Education - Infectious Diseases (CARE-ID)
state: Virginia
city: Seattle
country: United States
facility: Peter Shalit, MD
state: Washington
city: Montreal
country: Canada
facility: Research Institute of McGill University Health Care
state: Quebec
city: Montreal
country: Canada
facility: Clinique Medicale L'actuel
city: Toronto
country: Canada
facility: University Health Network/Toronto General Hospital
city: Toronto
country: Canada
facility: Maple Leaf Research
city: Vancouver
country: Canada
facility: Spectrum Health Care
city: Santo Domingo
country: Dominican Republic
facility: Instituto Dominicano de Estudios Virologicos--IDEV
city: Lyon
country: France
facility: Hopital de la Croix Rousse
city: Montpellier
country: France
facility: University Hospital of Montpellier (CHU-Gui de Chauliac)
city: Nice
country: France
facility: Archet 1 CHU de Nice, Department of Infectiology
city: Paris
country: France
facility: Saint Louis Hospital of Infectious Diseases
city: Paris
country: France
facility: Hopital Saint Antoine
city: Paris
country: France
facility: Hôpital Bichat Claude Bernard
city: Paris
country: France
facility: Hopital Tenon
city: Paris
country: France
facility: Hopital Pitie Salpetriere
city: Tourcoing
country: France
facility: CH Tourcoing
city: Bologna
country: Italy
facility: Universitaria di Bologna-Policlicnico S' Orsola Malpighi
city: Milan
country: Italy
facility: IRCCS Ospedale San Raffaele
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara
city: Mexico City
country: Mexico
facility: Insituto Nacional De Enfermedades Respiratorias "Ismael Cosio Villegas"
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwe Gasthuis
city: Coimbra
country: Portugal
facility: Serviço de Doenças Infecciosas, HUC-CHUC, EPE
city: Lisboa
country: Portugal
facility: Hospital Santo Antonio dos Capuchos
city: Lisbon
country: Portugal
facility: Hospital de Santa Maria - CHLN, EPE
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto - Hospital Joaquim Urbano
city: San Juan
country: Puerto Rico
facility: Hope Clinical Research
city: San Juan
country: Puerto Rico
facility: University of Puerto Rico ACTU
city: Stockholm
country: Sweden
facility: Venhalsan / Sodersjukhuset
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Huddinge
city: Birmingham
country: United Kingdom
facility: Whittall Street Clinic
city: Birmingham
country: United Kingdom
facility: Heart Of England NHS Foundation Trust
city: Brighton
country: United Kingdom
facility: Brighton and Sussex University Hospitals NHS Trust
city: Glasgow
country: United Kingdom
facility: Brownlee Centre, Gartnavel General Hospital
city: London
country: United Kingdom
facility: Barts Health NHS Trust
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: Kings College Hospital
city: London
country: United Kingdom
facility: Chelsea and Westminster
city: London
country: United Kingdom
facility: Mortimer Market Centre
city: Manchester
country: United Kingdom
facility: North Manchester General Hospital
Study officials:
affiliation: Gilead Sciences
name: Gilead Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Margot N, Cox S, Das M, McCallister S, Miller MD, Callebaut C. Rare emergence of drug resistance in HIV-1 treatment-naive 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.
citation: 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.
citation: 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.
citation: Margot NA, Kitrinos KM, Fordyce M, McCallister S, Miller MD, Callebaut C. Rare emergence of drug resistance in HIV-1 treatment-naive 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.
citation: 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.
citation: 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.
citation: 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.