| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Antiretroviral - Naive HIV-1 Infected Adults and Antiretroviral Experienced HIV-1 Infected Adults
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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 |
| E.1.2 | Term | Chronic infection with HIV |
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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 investigate whether Telzir can be safely used in patients with HIV/HCV co-infection, and those with hepatic impairment, and to evaluate whether these patients benefit from dose adjustments?
To evaluate the hepatic safety/tolerability of FPV/rtv (Telzir)- containing HAART, at 48 weeks as measured by the incidence of grade 3-4 LFT elevations
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| E.2.2 | Secondary objectives of the trial |
To describe the effect of FPV/rtv on clinical progression of hepatic disease.
To evaluate the role of non-invasive markers (APRI, Forns index, SHASTA) and Fibroscan in the evaluation and monitoring of patients with HIV/HCV co-infection.
To investigate the role of therapeutic drug monitoring (TDM) in the evaluation and management of these patients.
To assess the role of TDM in monitoring/treatment adjustment in patients with liver fibrosis/cirrhosis receiving FPV/rtv.
To describe the overall safety of FPV/rtv in patients with mild or moderate hepatic impairment.
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| 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 |
Intensive pharmacokinetic substudy:
Objectives: To establish population models for therapeutic drug monitoring in a substudy of patients on telzir.
In a subgroup of patients (recruit 13 per group of normal, mild and moderate hepatic impairment to ensure 10 completing) more intensive pharmacokinetics will be studied at week 2. Blood samples will be taken at 0, 1, 4 and 12 hours and plasma concentrations of APV and RTV determined (not real time; batch tested). The data obtained will be used to populate pharmacokinetic models and used in conjunction with previously obtained data from the APV10017 study and the sparse data obtained from the TDM component of this study to make dosing recommendations. |
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| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Subject is ≥18 years of age.
2. Subject can be both antiretroviral-naïve and experienced.
3. Subject is willing and able to understand and provide written informed consent prior to participation in this study.
4. Documented HCV co-infection (PCR positive)
5. Documented HIV infection by HIV antibody
6. A female is eligible to enter and participate in the study if she is of:
7. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal); or,
8. Child-bearing potential, has a negative pregnancy test (serum β-HCG) at screen and agrees to an acceptable barrier and/or hormonal method 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): Sterilization (female subject or male partner of female subject).
ALL SUBJECTS PARTICIPATING IN THE STUDY SHOULD BE COUNSELLED ON THE PRACTICE OF SAFER SEX
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Subject is in the initial acute phase of a CDC Clinical Category C infection at Baseline. Subjects may be enrolled provided they are receiving treatment for such infections and are clinically improving at the Baseline visit.
2. Subject is enrolled in one or more investigational drug protocols, which may impact HIV RNA suppression.
3. Subject is, in the opinion of the Investigator, unable to complete the study dosing period and protocol evaluations and assessments.
4. Patients with severe hepatic impairment (CTP score >9)
5. Patients with HBV co-infection
6. Subject has evidence of genotypic (as defined by the current ANRS AC-11 algorithm) resistance to Telzir at screening or prior documented evidence of genotypic and/or phenotypic (above threshold for reduced susceptibility) resistance to amprenavir/ritonavir,.
7. Patients with alcohol and drug use problems that in the view of investigator will compromise participation in the study will be excluded.
8. Exclude patients receiving HCV treatment in first 48 weeks of study
9. Subject is either pregnant or breastfeeding.
10. Subject suffers from any serious medical condition (such as pancreatitis, diabetes, congestive heart failure, cardiomyopathy or other cardiac dysfunction), which in the opinion of the Investigator, would compromise the safety of the subject.
11. Subject has a pre-existing mental, physical, or substance abuse disorder that, in the opinion of the Investigator, may interfere with the subject’s ability to comply with the dosing schedule and protocol evaluations and assessments.
12. Subject has a history of inflammatory bowel disease or intestinal malignancy, intestinal ischemia, malabsorption, or other gastrointestinal dysfunction, which, in the opinion of the Investigator, may interfere with drug absorption or render the subject unable to take oral medication.
13. 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. If subjects are found to have an acute Grade 4 laboratory abnormality at screening, this test may be repeated once within the 45-day screening window. Any verified Grade 4 laboratory abnormality would exclude a subject from study participation.
14. Subject has an estimated creatinine clearance < 50 mL/min via the Cockcroft-Gault method [Cockcroft, 1976]. This test may be repeated once within the 45-day screening window.
NOTE: Creatinine clearance should be estimated using the following formula:
For serum creatinine concentration in mg/dL:
( ) ( ) (0.85 for women only)
serum creatinine x 72
140 - age weight in kg ×
For serum creatinine concentration in μmol/L:
(140 - age) (weight in kg ) (serum .8 × 0.85 for women only) creatinine
15. Alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN).
16. Subject is receiving, or has received within 90 days prior to screen, any drug that has been classified as ‘contraindicated’ from use with fpv/r.
17. Subject has received 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 has received treatment with an HIV-1 immunotherapeutic vaccine or any agents with documented activity against HIV-1 in vitro within 28 days prior to screening, or an anticipated need during the study.
19. 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 fosamprenavir, and/or ritonavir 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). Systemic interleukins or interferons.
20. Subject has a history of allergy to any of the treatment products or any excipients therein.
NOTWITHSTANDING THESE MINIMUM INCLUSION AND EXCLUSION CRITERIA, INVESTIGATORS ARE URGED TO FOLLOW COUNTRY SPECIFIC GUIDELINES WHERE THEY EXIST WHEN MAKING DECISIONS ABOUT SUBJECTS WHO ARE ELIGABLE FOR STUDY PARTICIPATION
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Incidence of grade 3-4 increases in ALT or AST over 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 | 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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| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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