E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HIV-1 infected antiretroviral therapy experienced adult subjects |
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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 | 10008922 |
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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 select a once daily dose of GSK2248761 for further evaluation in Phase 3 based on a comparison of the Week 16 antiviral activity and tolerability of two oral doses of GSK2248761 in treatment-experienced HIV-1 infected subjects who have documented NNRTI-resistant virus. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of GSK2248761 on virologic and immunologic markers of HIV infection through week 48; To evaluate the safety and tolerability of GSK2248761 through week 48; To characterize GSK2248761 PK and identify potential covariates that influence the PK, also to evaluate the effect of GSK2248761 on darunavir and ritonavir exposures To confirm the optimal GSK2248761 dose at Week 24 based on antiviral activity in conjunction with immunologic, safety and PK measures; To explore exposure-response relationships of GSK2248761 and predict clinical PK and PD outcome to assist with dose selection for Phase 3 trials; To assess the development of viral resistance in subjects experiencing protocol-defined virologic failure; To evaluate the effect of subject characteristics on exposure-response parameters of GSK2248761; To evaluate the antiviral activity, safety, tolerability and development of viral resistance of the selected dose of GSK2248761 relative to ETV over 48 weeks. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) HIV-1 infected adults ≥18 years of age. A female is eligible to enter and participate in the study if she falls into one of the following categories: a. Non-childbearing potential; or, b. Child-bearing potential, with a negative pregnancy test at screen and Day 1 and agrees to one of the methods of contraception listed below. Premenarchal females who develop child-bearing potential while on study will also be expected to follow one of the methods of contraception listed below: - Complete abstinence from intercourse from 2 weeks prior to administration of IP, throughout the study, and for at least 2 weeks after discontinuation of all study medications. Should a subject of child-bearing potential decide to become sexually active during the course of the study, she must be counseled and be willing to use one of the other contraception methods listed below: - Double barrier method (male condom/spermicide, male condom/diaphragm, diaphragm/spermicide). - Any intrauterine device (IUD) with published data showing that the expected failure rate is <1% per year (not all IUDs meet this criterion). - Any other method with published data showing that the lowest expected failure rate for that method is <1% per year. Note: Since no data is currently available on interactions between hormonal contraceptives and GSK2248761, hormonal contraceptives are excluded medications in this study unless supportive drug interaction data becomes available. Note:Non-child-bearing potential is defined as pre-menopausal with a documented tubal ligation, hysterectomy or bilateral oophorectomy; or post-menopausal defined as 24 months of spontaneous amenorrhea. Any contraception method must be used consistently and in accordance with the approved product label. All study subjects should be counseled on the practice of safer sexual practices including the use of effective barrier methods (e.g. male condom/spermicide). 2) HIV-1 infection with a screening plasma HIV-1 RNA ≥400copies/mL; 3) Previously received or current treatment with antiretroviral therapy (HAART) for HIV-1 infection (patient may be off ART at time of screening); 4) HIV-1 harboring NNRTI resistance by screening genotype (defined as the presence of ≥1 NNRTI resistance-associated mutations. |
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E.4 | Principal exclusion criteria |
Exclusionary Medical Conditions: 1. Any pre-existing physical or mental condition (including substance abuse disorder) which, in the opinion of the Investigator, may interfere with the subject’s ability to comply with the dosing schedule and/or protocol evaluations or which may compromise the safety of the subject; 2. Any condition which, in the opinion of the Investigator, may interfere with the absorption, distribution, metabolism or excretion of the drug or render the subject unable to take oral medication; 3. Women who are currently breastfeeding; 4. Any evidence of an active Centers for Disease and Prevention Control (CDC) Category C disease, except cutaneous Kaposi’s sarcoma not requiring systemic therapy; 5. History of ongoing or clinically relevant hepatitis within the previous 6 months, including chronic hepatitis B virus (HBV) infection (HBsAg positive). Asymptomatic individuals with chronic hepatitis C virus (HCV) infection will not be excluded, however Investigators must carefully assess if therapy specific for HCV infection is required; subjects who are anticipated to require such therapy during the randomized portion of the study must be excluded; 6. History of liver cirrhosis with or without hepatitis viral co-infection; 7. Ongoing or clinically relevant pancreatitis; 8. History of the following cardiac diseases: myocardial infarction, congestive heart failure, documented hypertrophic cardiomyopathy, sustained ventricular tachycardia; 9. Personal or known family history of prolonged QT syndrome; 10. History or presence of allergy or intolerance to the study drugs or their components, or a history of drug or other allergy that, in the opinion of the Principal Investigator, contraindicates their participation. In addition, if heparin is used during PK sampling, subjects with a history of sensitivity to heparin or heparin-induced thrombocytopenia should not be enrolled |
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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of subjects with HIV-1 RNA <50copies/mL at Week 16. Dose selection will be based primarily on antiviral activity and tolerability in conjunction with immunologic, safety, virologic resistance and PK measures. Data from the Week 24 analysis will be used to confirm dose selection. |
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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 | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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.8.2.3.1 | Comparator description |
- same IMP used at different dosage |
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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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
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 |
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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
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La durata dello studio e` di 48 settimane. Tuttavia,il farmaco GSK2248761 sara` fornito ai pazienti fino alla commercializzazione o all`interruzione dello sviluppo dello stesso. I dati ricavati da questi soggetti forniranno informazioni descrittive. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |