| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Immunodeficiency Virus (Type 1) Infection |
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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 | 14.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020192 |
| E.1.2 | Term | HIV-1 |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 non-inferiority of FTC/RPV/TDF relative to regimens consisting of a ritonavir-boosted protease inhibitor (PI/r) and two nucleoside reverse transcriptase inhibitors (NRTIs) in maintaining HIV-1 RNA <50 copies/mL at Week 24. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the change from baseline in fasting lipid parameters (total cholesterol, LDL and HDL cholesterol, and triglycerides) over 24 and 48 weeks.
To evaluate the safety and tolerability of each treatment arm over 24 and 48 weeks.
To evaluate the change from baseline in CD4 cell count in each treatment arm at 24 and 48 weeks.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
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.
•Currently receiving antiretroviral therapy with a ritonavir-boosted PI and two NRTIs continuously for ≥6 months preceding the screening visit
•Have plasma HIV-1 RNA concentrations (at least two measurements) at undetectable levels (according to the local assay being used) for ≥6 months prior to the screening visit and have HIV RNA <50 copies/mL at the screening visit
•Be on their first or second antiretroviral drug regimen; if on their second regimen, must not have had HIV-1 RNA >50 copies/mL at the time of the change in antiretroviral drugs, nor ever experienced two consecutive HIV RNA >50 copies/mL after first achieving HIV RNA < 50 copies/mL
•No previous use of any approved or experimental non-nucleoside reverse transcriptase inhibitor (NNRTI) drug for any length of time
•Have a genotype prior to starting initial antiretroviral therapy and have no known resistance to any of the study agents at any time in the past including, but not limited to the RT resistance mutations K65R, K101E/P, E138G/K/R/Q, Y181C/I/V, M184V/I, or H221Y.
•Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant)
•Hepatic transaminases (AST and ALT) ≤5 x upper limit of normal (ULN)
•Total bilirubin ≤1.5 mg/dL, or normal direct bilirubin
•Adequate hematologic function (absolute neutrophil count ≥1,000/mm3; platelets ≥50,000/mm3; hemoglobin ≥8.5 g/dL)
•Serum amylase ≤5 x ULN (subjects with serum amylase > 5 x ULN will remain eligible if serum lipase is ≤5 x ULN)
•Adequate renal function:
Estimated glomerular filtration rate ≥70 mL/min according to the Cockcroft Gault formula:
Male: ((140 – age in years) x (wt in kg))/ (72 x (serum creatinine in mg/dL)) = CLcr (mL/min)
Female: ((140 – age in years) x (wt in kg) x 0.85) / (72 x (serum creatinine in mg/dL) = CLcr (mL/min)
•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 the study period 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, or serum follicle stimulating hormone level is not within the post-menopausal range must agree to utilize highly effective contraceptive methods
•Male subjects must agree to utilize a highly effective method of contraception during heterosexual intercourse from the screening visit, throughout the duration of the study 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
• Life expectancy ≥1 year
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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 diagnosed within the 30 days prior to screening (except CD4 cell count and/or percentage criteria) (refer to Appendix 5)
• Females who are breastfeeding
• Positive serum pregnancy test (female of childbearing potential)
• Proven or suspected acute hepatitis in the 30 days prior to study entry.
• Current alcohol or substance abuse judged by the Investigator to potentially interfere with subject 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.
• Anticipated need to initiate drugs during the study that are contraindicated as indicated below, including drugs not to be used with FTC, TDF, RPV (refer to the Prescribing Information for FTC and TDF, and Investigator’s Brochure for RPV); or subjects with known allergies to the excipients of FTC/RPV/TDF FDR tablets or Truvada tablets. Also refer to the PI Prescribing Information for subjects enrolled in Treatment Arm 2.
• All investigational drugs
• Medications listed in the the following table and use of herbal/natural supplements are excluded or should be used with caution while subjects are participating in the study including those not to be taken with Viread®, Emtriva ®, Truvada®, and Rilpivirine. Refer to the current Prescribing Information for these medications for additional information.
Drug Class Agents Disallowed
Antiarrhythmics: Bepridil
Anticonvulsants: Phenobarbital, carbamazepine, oxarbazepine, and phenytoin
Antibiotics: Rifabutin, rifampin, rifapentine, telithromycin, troleandomycin
Glucocorticoids (systemic): Dexamethasone and other glucocorticoids
Ergot Derivatives: Ergotamine, Ergonovine, Dihydroergotamine, Methylergonovine
Ergometrine
Proton Pump Inhibitors: Omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole
Herbal/Natural Supplements: St. John’s Wort, Echinaccea
• Participation in any other clinical trial without prior approval from the sponsor is prohibited while participating in this trial.
• Have been treated with immunosuppressant therapies or chemotherapeutic agents within 3 months of study screening, or expected to receive these agents or systemic steroids during the study (e.g., corticosteroids, immunoglobulins, and other immune- or cytokine based therapies).
• Have a history of liver disease, including Gilbert’s Disease.
• 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) |
| The primary efficacy endpoint is the proportion of subjects with HIV-1 RNA < 50 copies/mL at Week 24 as defined by the FDA snapshot analysis. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
The secondary objectives of this study are:
• To evaluate the change from baseline in fasting lipid parameters (total cholesterol, LDL and HDL cholesterol, and triglycerides) over 24 and 48 weeks.
• To evaluate the safety and tolerability of each treatment arm over 24 and 48 weeks.
• To evaluate the change from baseline in CD4 cell count in each treatment arm at 24 and 48 weeks. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 46 |
| 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 |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Puerto Rico |
| Spain |
| United Kingdom |
| 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
|
After Week 48, all subjects will complete a 30-day follow-up visit or telephone call. Subjects can opt to continue on the FDC countries where the FDC is not commercially available at the end of Week 48 until it becomes commercially available, or until Gilead Sciences elects to terminate clinical development of the FDC in that country.
Subjects continuing on the FDC will not complete the 30-day follow-up telephone call or visit and will continue with study visits every 12 weeks. |
|
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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