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Renal Effect of Stribild or Other Tenofovir DF-containing Regimens Compared to Ritonavir-boosted Atazanavir Plus Abacavir/Lamivudine in Antiretroviral Treatment-naive HIV-1 Infected Adults

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ClinicalTrials.gov Identifier: NCT02246998
Recruitment Status : Completed
First Posted : September 23, 2014
Results First Posted : January 3, 2018
Last Update Posted : January 3, 2018
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences

Brief Summary:
The primary objective of this study is to assess glomerular function before and during administration of stribild (STB; elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF)) or a regimen containing TDF without cobicistat (COBI) as ritonavir (RTV)-boosted atazanavir (ATV/r) plus truvada (TVD; FTC/TDF) or atripla (ATR; efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF)) compared to a regimen containing neither TDF nor COBI as ATV/r plus abacavir/lamivudine (ABC/3TC) via determination of actual glomerular filtration rate (aGFR) using iohexol (a probe GFR marker) plasma clearance and estimated (calculated) glomerular filtration rate (eGFR).

Condition or disease Intervention/treatment Phase
HIV-1 Infection Drug: STB Drug: TVD Drug: ATR Drug: RTV Drug: ATV Drug: ABC/3TC Drug: Iohexol Phase 4

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized, Open Label, Phase 4 Study Evaluating the Renal Effect of Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF or Other Tenofovir DF-containing Regimens (Ritonavir-boosted Atazanavir Plus Emtricitabine/Tenofovir DF or Efavirenz/Emtricitabine/Tenofovir DF) Compared to Ritonavir-boosted Atazanavir Plus Abacavir/Lamivudine in Antiretroviral Treatment-naïve HIV-1 Infected Adults With eGFR ≥70 mL/Min
Actual Study Start Date : December 15, 2014
Actual Primary Completion Date : January 20, 2016
Actual Study Completion Date : February 17, 2016

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: STB+iohexol
Participants will receive STB+iohexol for 24 weeks.
Drug: STB
150/150/200/300 mg fixed dose combination (FDC) tablet administered orally once daily with food
Other Name: Stribild®

Drug: Iohexol
1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24
Other Name: Omnipaque™

Experimental: RTV+ATV+TVD+iohexol
Participants will receive RTV+ATV+TVD+iohexol for 24 weeks.
Drug: TVD
200/300 mg FDC tablet administered orally once daily with food
Other Name: Truvada®

Drug: RTV
100 mg tablet administered orally once daily with food
Other Name: Norvir®

Drug: ATV
300 mg capsule administered orally once daily with food
Other Name: Reyataz®

Drug: Iohexol
1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24
Other Name: Omnipaque™

Experimental: ATR+iohexol
Participants will receive ATR+iohexol for 24 weeks.
Drug: ATR
600/200/300 mg FDC tablet administered orally once daily on an empty stomach at bedtime
Other Name: Atripla®

Drug: Iohexol
1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24
Other Name: Omnipaque™

Experimental: RTV+ATV+ABC/3TC+iohexol
Participants will receive RTV+ATV+ABC/3TC+iohexol for 24 weeks.
Drug: RTV
100 mg tablet administered orally once daily with food
Other Name: Norvir®

Drug: ATV
300 mg capsule administered orally once daily with food
Other Name: Reyataz®

Drug: ABC/3TC
600/300 mg FDC tablet administered orally once daily with food
Other Name: Kivexa®

Drug: Iohexol
1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24
Other Name: Omnipaque™




Primary Outcome Measures :
  1. Actual Glomerular Filtration Rate (aGFR) Using Iohexol Plasma Clearance (CLiohexol) at Week 24 [ Time Frame: Week 24 ]
  2. Estimated GFR (eGFR) Calculated by Cockcroft-Gault Formula at Week 24 [ Time Frame: Week 24 ]
    GFR is a measure of the rate at which blood is filtered by the kidney. Cockcroft-Gault is an equation (calculation) used to estimate GFR based on serum creatinine, weight, and gender. eGFR = (140 - age) * (mass in kg) * (0.85 if female) divided by 72 * serum creatinine in mg/dL

  3. Estimated GFR Calculated by Modification of Diet in Renal Disease (MDRD) Formula at Week 24 [ Time Frame: Week 24 ]
    MDRD is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and gender. eGFR (mL/min/1.73 m^2) = 186 * (Scr)^-1.154 * (Age)^(-0.203) * (0.742 if female) * (1.212 if black). Scr = serum creatinine in mg/dL


Secondary Outcome Measures :
  1. Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Urine Glucose (by Dipstick) [ Time Frame: Up to 24 weeks plus 30 days ]
  2. Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Serum Glucose (Fasting) [ Time Frame: Up to 24 weeks plus 30 days ]
  3. Percentage Change From Baseline in Urine Albumin to Creatinine Ratio (mg/g) at Week 24 [ Time Frame: Baseline; Week 24 ]
  4. Percentage Change From Baseline in Urine Protein to Creatinine Ratio (mg/g) at Week 24 [ Time Frame: Baseline; Week 24 ]
  5. Percentage Change From Baseline in Urine β2-microglobulin to Creatinine Ratio (µg/g) at Week 24 [ Time Frame: Baseline; Week 24 ]
  6. Percentage Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio (µg/g) at Week 24 [ Time Frame: Baseline; Week 24 ]
  7. Pharmacokinetic (PK) Parameter: Cmax for COBI [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    Cmax is defined as the maximum observed concentration of drug in plasma.

  8. PK Parameter: Tmax for COBI [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    Tmax is defined as the time of Cmax.

  9. PK Parameter: Clast for COBI [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    Clast is defined as the last observable concentration of drug.

  10. PK Parameter: Tlast for COBI [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    • Tlast is defined as the time of Clast.
    • Plasma samples for PK analysis were collected out to 10 hours postdose, and the predose concentration was used as a surrogate for the 24 hour concentration for PK parameter generation.

  11. PK Parameter: Ctau for COBI [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    Ctau is defined as the observed drug concentration at the end of the dosing interval.

  12. PK Parameter: λz for COBI [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    λz is defined as the terminal elimination rate constant.

  13. PK Parameter: AUCtau for COBI [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).

  14. PK Parameter: t1/2 for COBI [ Time Frame: Predose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    t1/2 is defined as the estimate of the terminal elimination half-life of the drug.

  15. PK Parameter: Cmax for RTV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  16. PK Parameter: Tmax for RTV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  17. PK Parameter: Clast for RTV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  18. PK Parameter: Tlast for RTV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    Plasma samples for PK analysis were collected out to 10 hours postdose, and the predose concentration was used as a surrogate for the 24 hour concentration for PK parameter generation.

  19. PK Parameter: Ctau for RTV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  20. PK Parameter: AUCtau for RTV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  21. PK Parameter: λz for RTV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  22. PK Parameter: t1/2 for RTV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  23. PK Parameter: Cmax for TFV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  24. PK Parameter: Tmax for TFV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  25. PK Parameter: Clast for TFV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  26. PK Parameter: Tlast for TFV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
    Plasma samples for PK analysis were collected out to 10 hours postdose, and the predose concentration was used as a surrogate for the 24 hour concentration for PK parameter generation.

  27. PK Parameter: Ctau for TFV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  28. PK Parameter: λz for TFV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  29. PK Parameter: AUCtau for TFV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  30. PK Parameter: t1/2 for TFV [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24 ]
  31. PK Parameter: AUCinf for Iohexol [ Time Frame: Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" on Day 1 and Weeks 4, 8, 16, and 24 ]
    AUC inf is defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time).

  32. Percentage of Participants With HIV-1 RNA < 50 Copies/mL Week 24 as Determined by Snapshot Algorithm [ Time Frame: Week 24 ]
  33. Change From Baseline in Cluster of Differentiation 4 Positive (CD4+) Cell Count at Week 24 [ Time Frame: Baseline; Week 24 ]
  34. Percentage of Participants Experiencing Adverse Events (AEs) [ Time Frame: Up to the last dose date plus 30 days (Up to 24 weeks plus 30 days) ]
    Incidences of adverse events and laboratory abnormalities will be summarized.

  35. Percentage of Participants Experiencing Treatment Emergent (TE) Grade 3 or 4 Laboratory Abnormalities [ Time Frame: Up to the last dose date plus 30 days (Up to 24 weeks plus 30 days) ]
    Graded laboratory abnormalities were defined as values that increased at least one toxicity grade from predose at any postdose up to the last dose date of study drug plus 30 days. The most severe graded abnormality from all tests was counted for each participant.



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Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Key Inclusion Criteria:

  • Treatment naïve
  • Plasma HIV-1 RNA levels ≥ 5,000 copies/mL at Screening
  • CD4 cell count > 200 cells/µL
  • Screening genotype report provided by the site must show sensitivity to FTC, TDF, EFV, ABC, 3TC, ATV and absence of study drug resistance mutations that include K65R, K70E and M184V in RT
  • Estimated GFR ≥ 70 mL/min
  • Hepatic transaminases (aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) ≤ 5 × upper limit of normal (ULN)
  • Total bilirubin ≤ 1.5 mg/dL (≤ 26 umol/L), or normal direct bilirubin
  • Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm^3; platelets ≥ 50,000/mm^3; hemoglobin ≥ 8.5 g/dL)
  • Serum amylase ≤ 5 × ULN (individuals with serum amylase > 5 × ULN will remain eligible if serum lipase is ≤ 5 × ULN)
  • Normal electrocardiogram (ECG) or not clinically significant if abnormal ECG
  • Not pregnant or non-lactating females of non-childbearing potential. Or females with childbearing potential who 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 90 days if taking EFV/FTC/TDF or for 30 days for all other study drugs following the last study drug dose
  • Males who agree to utilize a highly effective method of contraception during heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence from first dose throughout the study period and for 90 days if taking EFV/FTC/TDF or for 30 days for all other study drugs following the last study drug dose. Males who agree to refrain from sperm donation from first dose until at least 90 days if taking EFV/FTC/TDF or for 30 days for all other study drugs following the last study drug dose
  • Body mass index (BMI) of 19 ≤ BMI ≤ 30 kg/m^2 and body weight ≥ 40 kg
  • Life expectancy ≥ 1 year

Key Exclusion Criteria:

  • HLA-B*5701 allele positive
  • A new AIDS-defining condition diagnosed within the 30 days prior to screening
  • Hepatitis B surface antigen (HBsAg) positive
  • Hepatitis C virus (HCV) antibody positive and HCV RNA detectable
  • Individuals experiencing decompensated cirrhosis
  • Females who are breastfeeding
  • Positive serum pregnancy test
  • Have an implanted defibrillator or pacemaker
  • Current alcohol or substance that could potentially interfere with study compliance
  • A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Individuals with cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Day 1 Visit and must not be anticipated to require systemic therapy during the study
  • Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 Visit

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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02246998


Locations
Belgium
Brussels, Belgium
Ghent, Belgium
France
Lyon, France
Paris, France
Rennes, France
Tourcoing, France
Ireland
Dublin, Ireland
Spain
Barcelona, Spain
Madrid, Spain
Seville, Spain
United Kingdom
Birmingham, United Kingdom
Bournemouth, United Kingdom
Brighton, United Kingdom
Bristol, United Kingdom
Coventry, United Kingdom
Liverpool, United Kingdom
London, United Kingdom
Manchester, United Kingdom
Newcastle, United Kingdom
Sheffield, United Kingdom
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Gilead Study Director Gilead Sciences

Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT02246998     History of Changes
Other Study ID Numbers: GS-US-236-0140
2014-002095-93 ( EudraCT Number )
First Posted: September 23, 2014    Key Record Dates
Results First Posted: January 3, 2018
Last Update Posted: January 3, 2018
Last Verified: December 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Additional relevant MeSH terms:
Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Ritonavir
Atazanavir Sulfate
Tenofovir
Lamivudine
Emtricitabine
Abacavir
Efavirenz, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
HIV Protease Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-HIV Agents
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Cytochrome P-450 CYP3A Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Reverse Transcriptase Inhibitors
Nucleic Acid Synthesis Inhibitors