E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The patient population for this study will be comprised of patients with HIV-1 infection who have taken or are currently taking nevirapine and who have (cases) or have not (controls) experienced symptom. There will be two matched controls for each case.
This study is a non-interventional, retrospective case-controlled (1:2) study with prospective genomic blood sampling. |
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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 |
Attempt to identify genetic polymorphisms in interrogated candidate genes which may be associated with symptomatic hepatotoxicity or severe cutaneous toxicity observed in case patients within the first 8 weeks of nevirapine therapy.
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E.2.2 | Secondary objectives of the trial |
Descriptive demographics will be utilized to compare cases with matched controls in an attempt to link genetic polymorphisms associated with symptomatic hepatotoxicity or severe cutaneous toxicity (cases) to gender, race or other patient characteristics. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion for Case 1. Male or female patients ≥18 years of age with HIV-1 infection who experienced one or more of the following adverse reactions within the first 8 weeks of starting nevirapine therapy: Grade 3 or 4 LFT elevation (ALT or AST > 5X ULN) and symptoms consistent with clinical hepatitis (see Appendix 10.1) *Acute liver failure secondary to nevirapine therapy Functional group III or IV rash (see Appendix 10.2) *Acute liver failure is defined as serious liver injury usually requiring hospitalization that may lead to death or liver transplantation. (MODIFIED: TP AMENDMENT #1) Inclusion for Control 2.Male or female patients ≥18 years of age with HIV-1 infection who have been exposed to nevirapine therapy and who do not meet any of the case inclusion criteria
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E.4 | Principal exclusion criteria |
Exclusion for Cases 1. Patients with any hepatotoxicity or rash event which in the investigator’s judgement is not related to nevirapine use (ex. hepatotoxicity due to alcohol or other medicinal use or rash due to other medicinal use). 2. Patients who began abacavir or TMP-SMX (trimethoprim/sulfamethoxazole) therapy 2 weeks or less prior to or up to 8 weeks after initiating nevirapine therapy. 3. Patients with AST or ALT elevations >5 times the ULN (≥Grade 3) just prior to the initiation of nevirapine therapy. (ADDED: TP AMENDMENT #1).
Exclusion for Controls 4. Patients who discontinued nevirapine before completing 18 weeks of dosing with 200 mg/day for 2 weeks followed by 400 mg/day thereafter. 5. Patients who developed functional group I, IIa or IIb rash within 18 weeks of starting nevirapine therapy, or any dermatologic condition that could plausibly be attributed to nevirapine. 6. Patients with ALT or AST elevations >2.5 X ULN (>Grade 1) within 18 weeks of starting nevirapine therapy. (MODIFIED: TP AMENDMENT #1) 7. Any hepatobiliary adverse event that could possibly be attributed to nevirapine. (ADDED: TP AMENDMENT #1) 8. Patients who develop any systemic reaction attributable to nevirapine use during the first 18 weeks of nevirapine treatment such as flu-like symptoms, arthralgia, myalgia, or conjunctivitis.
Exclusion for Case and Controls 9. Patients who have participated in the 2NN-Long-term Follow-up study (1100.1454). 10. Patients with CD4 count ≤150 cells/mm3 prior to the initiation of nevirapine therapy (last available result measured ≤6 months prior to the initiation of nevirapine therapy). (ADDED: TP AMENDMENT #3, NUMBERING CORRECTED TP AMENDMENT #4) 11. Evidence of acute co-infection with viral hepatitis. 12. Patients taking prednisone, prednisolone, or immuno-modulatory medication within the first 8 weeks of nevirapine therapy. 13. Patients who are unwilling to provide blood samples for DNA testing. 14. Patients who do not sign informed consent and/or authorization to release protected health information per local requirements. 15. Patients without available liver function test (LFT) results ≤6 months prior to initiating nevirapine therapy. (ADDED: TP AMENDMENT #3, NUMBERING CORRECTED TP AMENDMENT #4) |
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E.5 End points |
E.5.1 | Primary end point(s) |
The endpoints to be analyzed are the relationship between nevirapine-related adverse events and genetic polymorphisms at the following loci: • Drug metabolizing enzymes (e.g., cytochrome P450 isoforms) • Drug transporters (e.g., MDR1 and OATP-C) • Human Major Histocompatibility Complex (MHC) region genes. |
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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 | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
case-controlled (1:2) study |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
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 | 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 | 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 | 2 |
E.8.9.1 | In the Member State concerned months | 1 |
E.8.9.1 | In the Member State concerned days | |
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 | 1 |