E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Treatment of heavily pretreated patients |
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MedDRA Classification |
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 test the superiority of the increased FPV dose (FPV/RTV 1400mg/100mg BID; Group B) and the dual boosted PI combination FPV/LPV/RTV (700mg/533mg/133mg BID) based therapy (Group C) over the standard FPV/RTV (700mg/100mg BID) based therapy (Group A) as measured by the average area under the curve minus baseline [AAUCMB] in plasma HIV-1 RNA at 24 weeks when each are administered in combination with an optimised background therapy, in a multiple PI-experienced population experiencing virological failure.
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E.2.2 | Secondary objectives of the trial |
To compare the antiviral response of the increased FPV dose (Group B) and FPV/LPV/RTV based therapy (Group C) versus the standard FPV/RTV based therapy (Group A) over 24 weeks of therapy; To compare the safety and tolerability of Group B and Group C versus Group A over 24 weeks of therapy; To compare the occurrence of events related to metabolic abnormalities of Group B and Group C versus Group A over 24 weeks of therapy; To compare the immunologic response of Group B and Group C versus Group A over 24 weeks of therapy; To characterise steady-state plasma APV trough concentrations and, where applicable, LPV trough concentrations; To evaluate the impact of absolute values in GIQ on virological outcome at Week 24; To assess viral resistance patterns at baseline and those which emerge in subjects with virological failure, and to correlate these patterns with treatment outcome. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Adult male and female PI-experienced HIV-infected subjects ≥18 years. 2. Three antiretroviral class (N(t)RTI, NNRTI and PI) therapy experienced subjects 3. ≥2 prior PI-based regimen with a documented history of virological failure (a confirmed plasma HIV-1 RNA concentration of 400 copies/mL) 4. Documented evidence of a viral genotype with at least one primary protease mutation other than the D30N. 5. HIV-1 RNA assay ≥1000 copies/mL at screening 6. No antiretroviral therapy (ART) modifications between Screening and Day 1. 7. A female subjects is eligible to enter and participate in the study if she is of: a Non-childbearing potential (ie, physiologically incapable of becoming pregnant, including any female who is pre-menarchal or post-menopausal); b Childbearing potential, has a negative serum beta human chorionic gonadotropin (beta-HCG, pregnancy) test at screen and negative urine pregnancy test at Day 1 and who agrees to use one of the following methods of contraception (any contraception method must be used consistently and correctly, i.e., in accordance with both the approved product label and the instructions of a physician): Complete abstinence from intercourse from 2 weeks prior to administration of the investigational products or permitted substitution medications, throughout the study, and for at least 2 weeks after discontinuation of all investigational products or permitted substitution medications; 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; Sterilization (female subject or male partner of female subject). Hormonal contraception is not acceptable for inclusion into this study. All subjects participating in this study should be counselled on the practice of safe sex. 8. The subject is able to understand and comply with protocol requirements and instructions and is likely to complete the study as planned. 9. Subject or subject’s legal representative is willing and able to understand and provide written informed consent prior to participation in this study |
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E.4 | Principal exclusion criteria |
1. Subjects with virus harboring the I50V mutation, the V32I with I47V mutations or six or more of the following PRO mutations in the screening genotype (APV/RTV resistance algorithm): L10F/I/V, K20M/R, E35D, R41K, I54V, L63P, V82A/F/T/S or I84V 2. Subjects with virus harboring eight or more of the following PRO mutations in the screening genotype (LPV/RTV mutation score [Kempf et al., 2001]): L10F/I/R/V, K20M/R, L24I, M46I/L, F53L, I54L/T/V, L63P, A71I/L/T/V, V82A/F/T, I84V, or L90M 3. Known non-adherence as key cause for detectable viral load 4. Planned use of NNRTIs as part of the study salvage regimen 5. Planned use of atazanavir or hydroxyurea as part of the study salvage regimen 6. Evidence of current active hepatitis or any clinically relevant hepatitis within 28 days prior to entry. 7. History of clinically relevant pancreatitis or any clinically relevant hepatitis within the last 6 months. 8. If, in the opinion of the examining physician, an unstable hepatic, cardiovascular, renal, pulmonary, endocrine, metabolic, neurological, haematological, or gastrointestinal condition is present or any other medical condition which the investigator considers sufficiently serious to interfere with the conduct, completion, or results of this trial or constitutes an unacceptable risk to the subject. 9. Subject has any acute laboratory abnormality at screening, which, in the opinion of the investigator, would preclude the subject’s participation in the study of an investigational compound. 10. Any grade 4 laboratory abnormality would exclude a subject from study participation 11. Subject has an active or acute CDC Clinical Category C event at screening. Treatment for the acute event must have been completed at least 30 days prior to screening. 12. Subject is enrolled in one or more investigational drug protocols, which may impact HIV RNA suppression 13. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN) within 28 days prior to Day 1. 14. Total bilirubin >2.5 times ULN within 28 days prior to Day 1. 15. Subject has an estimated creatinine clearance <60 mL/min via the Cockcroft-Gault method. NOTE: Creatinine clearance should be estimated using the following formula: - For serum creatinine concentration in mg/dL: - ((140-age)(weight in kg)/ serum creatine x 72 ) x (0.85 for women only) - For serum creatinine concentration in µmol/L: - ((140-age)(weight in kg) / serum creatine x 0.8) x (0.85 for women only) 16. Subjects who require treatment with any of the following medications within 28 days of commencement of investigational product, or an anticipated need during the study: Amiodarone, astemizole, bepridil, cisapride, dihydroergotamine, ergonovine, ergotamine, flecainide, halofantrine, lidocaine, lovastatin, methylergonovine, midazolam, pimozide, propafenone, quinidine, simvastatin, terfenadine, triazolam (these drugs have been excluded due to potential drug interactions with either FPV, LPV and/or RTV leading to safety problems) Carbamazepine, dexamethasone, phenobarbital, phenytoin, primidone, rifampin, St Johns Wort (Hypericum perforatum), troglitazone (these drugs have been excluded because they have the potential to decrease plasma protease inhibitor concentrations). Investigators should consult the most current prescribing information for each Investigational product for medications that are "Contraindicated" as well as Section 8.2 "Prohibited Medications" 17. Subject requires treatment with radiation therapy or cytotoxic chemotherapeutic agents within 28 days prior to screening, or has an anticipated need for these agents within the study period. 18. Subject requires treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, vaccines, or interferons) within 28 days prior to Screen, or subject has received an HIV-1 immunotherapeutic vaccine within 90 days prior to Screen. 19. Subject has a history of inflammatory bowel disease or malignancy, intestinal ischemia, malabsorption, or other gastrointestinal dysfunction, which may interfere with drug absorption or render the subject unable to take oral medication. 20. Subject has a pre-existing mental, physical, or substance abuse disorder which, in the opinion of the investigator, may interfere with the subject’s ability to comply with the dosing schedule and protocol evaluations and assessments. 21. Subject is, in the opinion of the investigator, unable to complete the 24-week dosing period and protocol evaluations and assessments 22. Subject is either pregnant or breastfeeding. 23. Female subjects who are lactating. 24. Subject has a history of allergy to any of the investigational products or any excipients therein. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the average area under the curve minus baseline (AAUCMB) in log10 plasma HIV-1 RNA at Week 24. |
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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 | Information not present in EudraCT |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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 | |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 11 |