E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Human Immunodeficiency Virus (HIV-1) Infections |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020192 |
E.1.2 | Term | HIV-1 |
E.1.2 | System Organ Class | 100000004862 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the effect of COBI-containing regimens on renal parameters at Week 24 |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of COBI-containing regimens
- To evaluate the long term effect of COBI-containing regimens on renal parameters
- To measure the proportion of subjects achieving virologic response at Weeks 24, 48 and 96 (HIV-1 RNA < 50 copies/mL, snapshot analysis) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Cohort 1 (Treatment Naïve)
Subjects who are treatment naïve must meet the following inclusion criteria:
- Plasma HIV-1 RNA levels ≥ 1,000 copies/mL at screening
- Screening genotype report provided by Gilead Sciences must show sensitivity to FTC and TDF
- No prior use of any approved or investigational antiretroviral drug for any length of time
Cohort 2 (Pharmacoenhancer Switch)
Subjects who are treatment experienced must meet the following inclusion criteria:
- Subjects must be receiving ATV 300 mg/RTV 100 mg plus 2 NRTIs OR DRV 800 mg/RTV 100 mg plus 2 NRTIs for at least 6 months prior to screening
- Plasma HIV-1 RNA concentrations (at least 2 measurements) at undetectable levels (according to the local assay being used) in the 6 months preceding the screening visit and have HIV-1 RNA < 50 copies/mL at screening
- Subjects experiencing intolerance to RTV (as determined by the Investigator)
All subjects must meet all of the following inclusion criteria to be eligible for participation in
this study:
- The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures
- Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)
- Mild to Moderate renal function:
Estimated GFR 50-89 mL/min according to the Cockcroft-Gault formula {2202}:
Male: (140 – age in years) × (wt in kg) = CLcr (mL/min)
72 × (serum creatinine in mg/dL)
Female: (140 – age in years) × (wt in kg) × 0.85 = CLcr (mL/min)
72 × (serum creatinine in mg/dL)
- Stable renal function: serum creatinine measurements to be taken at least once (within three months of screening). Measurements must be within 20% of the screening value
- Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN)
- Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin (subjects with documented Gilbert's Syndromes or hyperbilirubinemia due to atazanavir therapy may have total bilirubin up to 5 x ULN)
- Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm3; platelets ≥ 50,000/mm3; hemoglobin ≥ 8.5 g/dL)
- Serum amylase ≤ 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if serum lipase is ≤ 5 × ULN)
- Females of childbearing potential (as defined in Section 7.8) must agree to utilize highly effective contraception methods (two separate forms of contraception, one of which must be an effective barrier method, or be non-heterosexually active, practice sexual abstinence or have a vasectomized partner) from screening throughout the duration of study treatment and for 30 days following the last dose of study drug.
— Female subjects 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
— Female subjects 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
- Male subjects must agree to utilize a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of investigational medicinal product. A highly effective method of contraception is defined as two separate forms of contraception, one of which must be an effective barrier method, or male subjects must be non-heterosexually active, practice sexual abstinence, or be vasectomized.
- Age ≥ 18 years |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following exclusion criteria are not to be enrolled in (or may be
discontinued from) this study:
- A new AIDS-defining condition (excluding CD4 cell count and percentage criteria) diagnosed within the 30 days prior to screening (refer to Appendix 6)
- Subjects receiving drug treatment for Hepatitis C, or subjects who are anticipated to receive treatment for Hepatitis C during the course of the study
- Subjects experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, etc.)
- Females who are breastfeeding
- Positive serum pregnancy test (female of childbearing potential)
- Have an implanted defibrillator or pacemaker
- Current alcohol or substance use judged by the Investigator to potentially interfere with subject 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. Subjects with cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Baseline 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 Baseline
- Subjects receiving ongoing therapy with any of the medications in the table presented in section 4.3 of the protocol, including drugs not to be used with EVG, COBI, FTC, TDF, ATV, DRV (refer to the individual agents Prescribing Information); or subjects with any known allergies to the excipients of EVG/COBI/FTC/TDF STR, COBI tablets, atazanavir capsules or darunavir tablets or contraindicated for the 2 NRTIs as part of the Cohort 2 regimen.
- Participation in any other clinical trial without prior approval from the sponsor is prohibited while participating in this trial
- Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with the dosing requirements |
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E.5 End points |
E.5.1 | Primary end point(s) |
Estimated GFR
- Creatinine clearence
- Cystatin C clearence
True GFR
- Iohexol clearence
Other urinary and serum markers of renal tubular disfunction |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Virologic response
- HIV-1 RNA < 50 copies/mL |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
Dominican Republic |
Mexico |
Puerto Rico |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LPLS. If EVG/COBI/FTC/TDF or COBI is commercially not available in the country where the study is being conducted, subjects will have the option to participate in extension phase of the study to continue receiving their study regimen and attend visits every 12 weeks until all subjects have discontinued from the study or EVG/COBI/FTC/TDF STR or COBI becomes commercially available in the applicable country. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |