| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10068341 |
| E.1.2 | Term | HIV-1 infection |
| 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 non-inferiority of EVG/COBI/FTC/TDF relative to regimens consisting of a ritonavir-boosted protease inhibitor (PI/r) plus FTC/TDF in maintaining HIV 1 RNA < 50 copies/mL at Week 48 (Snapshot Analysis) in virologically suppressed, HIV 1 infected subjects. |
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of the two regimens through Week 96
- To evaluate the efficacy of the two regimens through 96 weeks of treatment |
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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:
1. The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures.
2. Be on a stable antiretroviral regimen consisting of a ritonavir boosted PI plus FTC/TDF continuously for ≥ 6 consecutive months preceding the screening visit.
3. Be on the first or second antiretroviral regimen with documented undetectable plasma HIV-1 RNA levels (according to the local assay being used) for ≥ 6 months preceding the screening visit (measured at least twice using the same assay) and never experienced two consecutive HIV-1RNA above detectable levels after first achieving a confirmed (two consecutive) HIV-1 RNA below detectable levels on the first or second regimen.
4. Be on the first or second antiretroviral drug regimen; if on the second regimen, must not have had HIV-1 RNA above detectable levels (according to the local assay being used) at the time of change in antiretroviral drugs nor ever experienced two consecutive HIV 1 RNA above detectable levels.(according to the local assay being used) after first achieving a confirmed HIV-1 RNA below detectable levels.
5. No previous use of any approved or experimental integrase strand transfer inhibitor (INSTI) for any length of time.
6. Documented historical genotype prior to starting initial antiretroviral therapy showing no known resistance to TDF or FTC, including, but not limited to the presence of reverse transcriptase resistance mutants K65R, M184V/I, or 3 or more thymidine analog-associated mutations that include M41L or L210W (TAMs are M41L, D67N, K70R, L210W, T215Y/F, K219Q/E/N/R).
7. HIV RNA < 50 copies/mL at the screening visit.
8. Normal ECG (or if abnormal, determined by the Investigator to be not clinically significant).
9. Hepatic transaminases (AST and ALT) ≤ 5 × upper limit of normal (ULN).
10. Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin (subjects with documented Gilbert's Syndrome or hyperbilirubinemia due to indinavir or atazanavir therapy may have total bilirubin up to 5 x ULN if they have normal direct bilirubin).
11. Adequate hematologic function (absolute neutrophil count ≥ 750/mm3; platelets ≥ 50,000/mm3; hemoglobin ≥ 8.5 g/dL).
12. Serum amylase ≤ 5 × ULN (subjects with serum amylase > 5 × ULN will remain eligible if serum lipase is ≤ 5 × ULN).
13. Estimated glomerular filtration rate ≥ 70 mL/min according to the Cockcroft-Gault formula at the screening visit.
14. Females of childbearing potential (as defined in Section 7.9) 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, and choose continuous heterosexual abstinence as a lifestyle choice) from screening throughout the duration of the study period and for 30 days following the last dose of study drug.
15. 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. It is recommended that an oral contraceptive contain 30 μg of ethinyl estradiol if administered with EVG/COBI/FTC/TDF.
16. 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, and choose continuous heterosexual abstinence as a lifestyle choice, or be vasectomized.
17. Age ≥ 18 years
18. 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.
1. A new AIDS-defining condition diagnosed within the 30 days prior to screening (except CD4 cell count and/or percentage criteria) (refer to the Study Protocol, Appendix 4).
2. Females who are breastfeeding.
3. Positive serum pregnancy test (female of childbearing potential).
4. Receiving drug treatment for Hepatitis C, or subjects who are anticipated to receive treatment for Hepatitis C during the course of the study.
5. Experiencing decompensated cirrhosis (e.g., ascites, encephalopathy, etc.).
6. Have an implanted defibrillator or pacemaker.
7. Current alcohol or substance abuse judged by the Investigator to potentially interfere with subject compliance.
8. 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.
9. Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Baseline, except for intramuscular penicillin for the treatment of syphilis.
10. 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).
11. Subjects receiving ongoing therapy with any of the medications in the table listed in the Study Protocol Section 4.3, including drugs not to be used with EVG, COBI, FTC, TDF (refer to the individual agents Prescribing Information or current investigator’s brochure); or subjects with any known allergies to the excipients of EVG/COBI/FTC/TDF tablets, or Truvada tablets.
12. Anticipated need to initiate drugs or herbal/natural supplements during the study that are
contraindicated or not recommended for use as indicated in the table below, including drugs not to be used with EVG/COBI/FTC/TDF (refer to individual agents' Prescribing Information).
13. Receiving other investigational drugs.
14. Participation in any other clinical trial without prior approval from the sponsor is prohibited while participating in this trial.
15. 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 who have HIV 1 RNA < 50 copies/mL as defined by the FDA snapshot analysis. |
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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) |
1. The proportion of subjects wth HIV-1 RNA < 50 copies/mL at Week 96 as defined by the FDA snapshot analysis
2. The change from baseline in CD4+ cell count at Weeks 48 and 96. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. The safety and tolerability of each treatment arm over 48 weeks, namely at baseline, 4, 8, 12, 24, 36 and 48 weeks.
2. The change from baseline in CD4 cell count in each treatment arm at 48 weeks.
|
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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 | 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 | Yes |
| 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) | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| 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 |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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