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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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HIV-1 Infection

Intervention / Treatment
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* Drug: STB
* Drug: TVD
* Drug: ATR
* Drug: RTV
* Drug: ATV
* Drug: ABC/3TC
* Drug: Iohexol


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STB+iohexol<br>Participants will receive STB+iohexol for 24 weeks. | Drug: STB<br>* 150/150/200/300 mg fixed dose combination (FDC) tablet administered orally once daily with food<br>* Other names: Stribild®;Drug: Iohexol<br>* 1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24<br>* Other names: Omnipaque™;|
| Experimental: RTV+ATV+TVD+iohexol<br>Participants will receive RTV+ATV+TVD+iohexol for 24 weeks. | Drug: TVD<br>* 200/300 mg FDC tablet administered orally once daily with food<br>* Other names: Truvada®;Drug: RTV<br>* 100 mg tablet administered orally once daily with food<br>* Other names: Norvir®;Drug: ATV<br>* 300 mg capsule administered orally once daily with food<br>* Other names: Reyataz®;Drug: Iohexol<br>* 1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24<br>* Other names: Omnipaque™;|
| Experimental: ATR+iohexol<br>Participants will receive ATR+iohexol for 24 weeks. | Drug: ATR<br>* 600/200/300 mg FDC tablet administered orally once daily on an empty stomach at bedtime<br>* Other names: Atripla®;Drug: Iohexol<br>* 1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24<br>* Other names: Omnipaque™;|
| Experimental: RTV+ATV+ABC/3TC+iohexol<br>Participants will receive RTV+ATV+ABC/3TC+iohexol for 24 weeks. | Drug: RTV<br>* 100 mg tablet administered orally once daily with food<br>* Other names: Norvir®;Drug: ATV<br>* 300 mg capsule administered orally once daily with food<br>* Other names: Reyataz®;Drug: ABC/3TC<br>* 600/300 mg FDC tablet administered orally once daily with food<br>* Other names: Kivexa®;Drug: Iohexol<br>* 1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24<br>* Other names: Omnipaque™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Actual Glomerular Filtration Rate (aGFR) Using Iohexol Plasma Clearance (CLiohexol) at Week 24 |  | Week 24 | 
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Urine Glucose (by Dipstick) |  | Up to 24 weeks plus 30 days | 
| Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Serum Glucose (Fasting) |  | Up to 24 weeks plus 30 days | 
| Percentage Change From Baseline in Urine Albumin to Creatinine Ratio (mg/g) at Week 24 |  | Baseline; Week 24 | 
| Percentage Change From Baseline in Urine Protein to Creatinine Ratio (mg/g) at Week 24 |  | Baseline; Week 24 | 
| Percentage Change From Baseline in Urine β2-microglobulin to Creatinine Ratio (µg/g) at Week 24 |  | Baseline; Week 24 | 
| Percentage Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio (µg/g) at Week 24 |  | Baseline; Week 24 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| PK Parameter: λz for COBI | λz 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| PK Parameter: λz 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| PK Parameter: λz 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 | 
| 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 | 
| 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 | 
| 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 | 
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL Week 24 as Determined by Snapshot Algorithm |  | Week 24 | 
| Change From Baseline in Cluster of Differentiation 4 Positive (CD4+) Cell Count at Week 24 |  | Baseline; Week 24 | 
| 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) | 
| 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) |