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

HIV-1 Infection Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02246998
• Other study ID #: GS-US-236-0140
• Secondary ID: 2014-002095-93
• Status: Completed
• Phase: Phase 4
• First received: September 19, 2014
• Last updated: December 1, 2017
• Start date: December 15, 2014
• Est. completion date: February 17, 2016

Study information

• Verified date: December 2017
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 72
• Est. completion date: February 17, 2016
• Est. primary completion date: January 20, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• HIV-1 Infection

Intervention

Drug:
• STB
150/150/200/300 mg fixed dose combination (FDC) tablet administered orally once daily with food
• TVD
200/300 mg FDC tablet administered orally once daily with food
• ATR
600/200/300 mg FDC tablet administered orally once daily on an empty stomach at bedtime
• RTV
100 mg tablet administered orally once daily with food
• ATV
300 mg capsule administered orally once daily with food
• ABC/3TC
600/300 mg FDC tablet administered orally once daily with food
• Iohexol
1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

Belgium,  France,  Ireland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Actual Glomerular Filtration Rate (aGFR) Using Iohexol Plasma Clearance (CLiohexol) at Week 24		Week 24
Primary	Estimated GFR (eGFR) Calculated by Cockcroft-Gault Formula at 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	Week 24
Primary	Estimated GFR Calculated by Modification of Diet in Renal Disease (MDRD) Formula at 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	Week 24
Secondary	Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Urine Glucose (by Dipstick)		Up to 24 weeks plus 30 days
Secondary	Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Serum Glucose (Fasting)		Up to 24 weeks plus 30 days
Secondary	Percentage Change From Baseline in Urine Albumin to Creatinine Ratio (mg/g) at Week 24		Baseline; Week 24
Secondary	Percentage Change From Baseline in Urine Protein to Creatinine Ratio (mg/g) at Week 24		Baseline; Week 24
Secondary	Percentage Change From Baseline in Urine ß2-microglobulin to Creatinine Ratio (µg/g) at Week 24		Baseline; Week 24
Secondary	Percentage Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio (µg/g) at Week 24		Baseline; Week 24
Secondary	Pharmacokinetic (PK) Parameter: Cmax for COBI	Cmax is defined as the maximum observed concentration of drug in plasma.	Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Tmax for COBI	Tmax is defined as the time of Cmax.	Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Clast for COBI	Clast is defined as the last observable concentration of drug.	Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Tlast for COBI	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.	Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Ctau for COBI	Ctau is defined as the observed drug concentration at the end of the dosing interval.	Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: ?z for COBI	?z is defined as the terminal elimination rate constant.	Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: AUCtau for COBI	AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).	Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: t1/2 for COBI	t1/2 is defined as the estimate of the terminal elimination half-life of the drug.	Predose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Cmax for RTV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Tmax for RTV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Clast for RTV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Tlast for RTV	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.	Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Ctau for RTV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: AUCtau for RTV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: ?z for RTV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: t1/2 for RTV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Cmax for TFV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Tmax for TFV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Clast for TFV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Tlast for TFV	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.	Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: Ctau for TFV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: ?z for TFV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: AUCtau for TFV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: t1/2 for TFV		Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24
Secondary	PK Parameter: AUCinf for Iohexol	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).	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
Secondary	Percentage of Participants With HIV-1 RNA < 50 Copies/mL Week 24 as Determined by Snapshot Algorithm		Week 24
Secondary	Change From Baseline in Cluster of Differentiation 4 Positive (CD4+) Cell Count at Week 24		Baseline; Week 24
Secondary	Percentage of Participants Experiencing Adverse Events (AEs)	Incidences of adverse events and laboratory abnormalities will be summarized.	Up to the last dose date plus 30 days (Up to 24 weeks plus 30 days)
Secondary	Percentage of Participants Experiencing Treatment Emergent (TE) Grade 3 or 4 Laboratory Abnormalities	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.	Up to the last dose date plus 30 days (Up to 24 weeks plus 30 days)