| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Human Innunodeficiency Virus (HIV-1) Infections |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10020192 |
| E.1.2 | Term | HIV-1 |
|
| 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 assess non-inferiority of a regimen containing ritonavirboosted elvitegravir versus raltegravir, each administered with a background regimen in HIV-1 infected, antiretroviral treatment-experienced adult subjects as determined by the proportion of subjects achieving and maintaining confirmed HIV-1 RNA < 50 copies/mL through Week 48 |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate the efficacy, safety and tolerability of the two treatment regimens through 48 weeks of treatment |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| A pharmacokinetic substudy will be performed at the Week 2 study visit in a subset of subjects (target N up to 45) at selected study sites. |
|
| E.3 | Principal inclusion criteria |
Exemptions for inclusion and exclusion criteria will not be granted.
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:
• Plasma HIV-1 RNA levels ≥ 1,000 copies/mL at screening.
• Subjects must have documented resistance, as defined by current IAS-USA definitions (refer to Appendix 5 of the protocol), or at least six months experience prior to screening with two or more different classes of antiretroviral agents. Thus, subjects may have resistance to one class and at least six months experience prior to screening with a second class of antiretroviral agents, or resistance to two classes of antiretroviral agents, or at least six months experience with the two classes of antiretroviral agents. Subjects may also have resistance or at least six months experience prior to screening with three or more classes of antiretroviral agents.
• Stable antiretroviral regimen for at least 30 days prior to screening; however, subjects may discontinue the antiretroviral regimen after screening and remain off therapy until baseline at the discretion of the investigator.
• Subjects must be eligible to receive one of the fully-active ritonavir-boosted-PIs, based on the results of screening phenotype analysis provided by Monogram Biosciences, and an allowed second agent (see Table 3-1). Fully-active PIs are defined as those with fold changes below the lower clinical or biological cutoff for each drug.
• Normal ECG (or if abnormal, determined by the investigator to be not clinically
significant).
• Adequate renal function:
Estimated glomerular filtration rate ≥ 60 mL/min according to the Cockcroft-Gault
formula:
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)
• 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 Syndrome or hyperbilirubinemia due to indinavir or atazanavir therapy may
have total bilirubin up to 5 × ULN).
• Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm3; platelets
≥ 50,000/mm3; hemoglobin ≥ 8.5 g/dL).
• Serum amylase < 1.5 × ULN (subjects with serum amylase ≥ 1.5 × ULN will remain
eligible if serum lipase is ≤ 1.5 × ULN).
• Negative serum pregnancy test (females of childbearing potential only).
• Males and females of childbearing potential (i.e., a non-menopausal female or a female with menopausal ≤ 2 years, who has not had a hysterectomy, bilateral oophorectomy or medically documented ovarian failure; this definition includes a young woman who has not yet started menstruating) 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 drugs.
- 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 are postmenopausal for less than two years are required to have FSH > 40 mIU/mL. If the FSH is ≤ 40 mIU/mL, the subject must agree to use highly effective method of birth control (as described above) to participate in the study.
- Male subjects who are sexually active must be willing to use effective barrier
contraception (e.g., condom with spermicide) during heterosexual intercourse from screening through completion of the study and continue for at least 30 days from date of last dose of study drug.
• Age ≥ 18 years.
• Life expectancy ≥ 1 year.
• The ability to understand and sign a written informed consent form, which must be
obtained prior to initiation of study procedures.
• Subjects participating in Study GS-US-183-0144 who have either met all screening criteria or have enrolled are eligible to participate and continue with their regular visit schedule; subjects must consent to participate in Study GS-US-183-0145.
|
|
| 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 (Refer to Appendix 6 of the protocol)
• Prior treatment with any HIV-1 integrase inhibitor
• Subjects experiencing ascites
• Subjects experiencing encephalopathy
• Females who are breastfeeding
• Positive serum pregnancy test at any time during the study (female of childbearing
potential)
• Subjects receiving ongoing therapy with any medication listed in section 4.3. of the protocol that is not to be taken with a component of the BR, including drugs not to be used with ritonavir (refer to prescribing information). Administration of any of the medications detailed in section 4.3. of the protocol must be discontinued at least 30 days prior to the Baseline/Day 1 visit and for the duration of the study.
• Current alcohol or substance use judged by the investigator to potentially interfere with subject study compliance.
• A history of or ongoing malignancy other than cutaneous Kaposi’s sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Subjects with biopsy-confirmed cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Baseline and are not 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.
• Participation in any other clinical trial (except for the Etravirine or Maraviroc expanded access programs), 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.
• Known hypersensitivity to the study drugs, the metabolites or formulation excipients.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of subjects achieving and maintaining
confirmed HIV-1 RNA < 50 copies/mL through Week 48. |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| E.8.2.3 | Other | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 | Information not present in EudraCT |
| 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 |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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, subjects will continue to take their blinded study drug and attend visits every 8 weeks until treatment assignments have been unblinded, at which point they will be given the option to participate in an open-label rollover study. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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