Case-Control Viramune (Nevirapine) Toxicogenomics Study

Completed

• Conditions: HIV Infections
• Interventions: Drug: Nevirapine

• Registration Number: NCT00310843
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

Attempt to identify genetic polymorphisms in interrogated pathways which may be associated with symptomatic hepatotoxicity or severe cutaneous toxicity observed in case patients within the first 8 weeks of nevirapine therapy.

Detailed Description

Not available

Study Timeline

• Study Start: 2006-02
• Study First Submitted: 2006-03-28
• Study First Submitted QC: 2006-04-02
• Study First Posted: 2006-04-05
• Primary Completion: 2008-09
• Status Verified: 2013-07
• Last Update Submitted: 2013-07-31
• Last Update Posted: 2013-08-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 889

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 any symptom consistent with clinical hepatitis (see Appendix 10.1)
   • Acute liver failure secondary to nevirapine therapy*
   • Functional group III or IV rash
   • *Acute liver failure is defined as serious liver injury usually requiring hospitalization that may lead to death or liver transplantation.

   Inclusion for Control

2. Male or female patients >=18 years of age with HIV-1 infection who have been exposed to nevirapine therapy for at least 18 weeks and who do not meet any of the case inclusion criteria

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Exclusion Criteria

Exclusion for Cases

1. Patients with any hepatotoxicity or rash event which in the investigators 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.

   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.

7. Any hepatobiliary adverse event that could possibly be attributed to nevirapine.

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 Cases 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).

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 did not sign informed consent and or authorization to release protected health information per local requirements.

15. Patients without available liv

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Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
All study population	Nevirapine	-

Primary Outcome Measures

Name	Time	Method
Endpoints: relationship between nevirapine-related AEs and genetic polymorphisms loci: Drug metabolizing enzymes (e.g., cytochrome P450 isoforms) Drug transporters (e.g., MDR1 and OATP-C) Human Major Histocompatibility Complex region genes

Secondary Outcome Measures

Name	Time	Method
Descriptive demographics comparing 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.

Trial Locations

Locations (102)

1100.1452.01003 Boehringer Ingelheim Investigational Site; 🇺🇸 Baltimore, Maryland, United States

1100.1452.99999 Boehringer Ingelheim Investigational Site; 🇺🇸 Baltimore, Connecticut, United States

1100.1452.54002 Funcei; 🇦🇷 Capital Federal, Argentina

1100.1452.54003 Boehringer Ingelheim Investigational Site; 🇦🇷 Capital Federal, Argentina

1100.1452.61004 Boehringer Ingelheim Investigational Site; 🇦🇺 Darlinghurst, New South Wales, Australia

1100.1452.01004 Boehringer Ingelheim Investigational Site; 🇺🇸 Fort Worth, Texas, United States

1100.1452.3311C Hôpital Edouard Herriot; 🇫🇷 Lyon cedex 3, France

1100.1452.01501 St. Paul's Hospital; 🇨🇦 Vancouver, British Columbia, Canada

1100.1452.54001 Fundación Huésped; 🇦🇷 Capital Federal, Argentina

1100.1452.61003 Boehringer Ingelheim Investigational Site; 🇦🇺 Miami, Queensland, Australia

1100.1452.61001 Boehringer Ingelheim Investigational Site; 🇦🇺 South Yarra, Victoria, Australia

1100.1452.3306B Hop Hôtel Dieu; 🇫🇷 Lyon, France

1100.1452.3305A Hôpital hôtel Dieu; 🇫🇷 Nantes cedex 1, France

1100.1452.3311B Pavillon P; 🇫🇷 Lyon, France

1100.1452.3305C Hôpital hôtel Dieu; 🇫🇷 Nantes cedex 1, France

1100.1452.3305E Hôpital hôtel Dieu; 🇫🇷 Nantes cedex 1, France

1100.1452.3307E Hôpital Guy Chateliez; 🇫🇷 Tourcoing cedex, France

1100.1452.4916 Boehringer Ingelheim Investigational Site; 🇩🇪 Hamburg, Germany

1100.1452.4931 Boehringer Ingelheim Investigational Site; 🇩🇪 Hamburg, Germany

1100.1452.4900 Universitätsklinikum Ulm; 🇩🇪 Ulm, Germany

1100.1452.34005 Boehringer Ingelheim Investigational Site; 🇪🇸 Badalona, Spain

1100.1452.44002 Boehringer Ingelheim Investigational Site; 🇬🇧 London, United Kingdom

1100.1452.44005 Boehringer Ingelheim Investigational Site; 🇬🇧 London, United Kingdom

1100.1452.01006 Boehringer Ingelheim Investigational Site; 🇺🇸 Birmingham, Alabama, United States

1100.1452.01013 Boehringer Ingelheim Investigational Site; 🇺🇸 Denver, Colorado, United States

1100.1452.3305I Hôpital Hôtel Dieu; 🇫🇷 Nantes, France

1100.1452.3311D Hôpital Edouard Herriot; 🇫🇷 Lyon cedex 3, France

1100.1452.01015 Boehringer Ingelheim Investigational Site; 🇺🇸 St. Louis, Missouri, United States

1100.1452.01002 Boehringer Ingelheim Investigational Site; 🇺🇸 Boston, Massachusetts, United States

1100.1452.01016 Boehringer Ingelheim Investigational Site; 🇺🇸 New York, New York, United States

1100.1452.01001 Boehringer Ingelheim Investigational Site; 🇺🇸 Nashville, Tennessee, United States

1100.1452.54004 Boehringer Ingelheim Investigational Site; 🇦🇷 Rosario, Argentina

1100.1452.61005 Boehringer Ingelheim Investigational Site; 🇦🇺 DarlingHurst, New South Wales, Australia

1100.1452.61006 Boehringer Ingelheim Investigational Site; 🇦🇺 Darlinghurst, New South Wales, Australia

1100.1452.61002 Boehringer Ingelheim Investigational Site; 🇦🇺 Carlton, Victoria, Australia

1100.1452.3306A Hôpital Hôtel Dieu; 🇫🇷 Lyon cedex 2, France

1100.1452.61008 Boehringer Ingelheim Investigational Site; 🇦🇺 Melbourne, Victoria, Australia

1100.1452.3311A Hôpital Edouard Herriot; 🇫🇷 Lyon Cedex 3, France

1100.1452.01502 Toronto General Hospital; 🇨🇦 Toronto, Ontario, Canada

1100.1452.01504 Boehringer Ingelheim Investigational Site; 🇨🇦 Vancouver, British Columbia, Canada

1100.1452.3304A Hôpital Saint André; 🇫🇷 Bordeaux, France

1100.1452.3305B Hôpital hôtel Dieu; 🇫🇷 Nantes cedex 1, France

1100.1452.3305H Hôpital hôtel Dieu; 🇫🇷 Nantes cedex 1, France

1100.1452.3305F Hôpital Hôtel Dieu; 🇫🇷 Nantes, France

1100.1452.3305D Hôpital Hôtel Dieu; 🇫🇷 Nantes, France

1100.1452.3305G Hôpital Hôtel Dieu; 🇫🇷 Nantes, France

1100.1452.3313B Hôpital Saint Antoine; 🇫🇷 Paris, France

1100.1452.3301A Hôpital Saint Louis; 🇫🇷 Paris, France

1100.1452.3302A Hôpital Tenon; 🇫🇷 Paris cedex 20, France

1100.1452.3313A Hôpital Saint Antoine; 🇫🇷 Paris cedex 12, France

1100.1452.3303A Hôpital de la Pité Salpêtrière; 🇫🇷 Paris, France

1100.1452.3310A Hôpital Bichat Claude Bernard; 🇫🇷 Paris, France

1100.1452.3310B Hôpital Bichat Claude Bernard; 🇫🇷 Paris, France

1100.1452.3313C Hôpital Saint Antoine; 🇫🇷 Paris, France

1100.1452.3314A Hôpital Européen Georges Pompidou; 🇫🇷 Paris, France

1100.1452.3308A Hôpital Purpan; 🇫🇷 Toulouse cedex 9, France

1100.1452.3308B Hôpital Purpan; 🇫🇷 Toulouse, France

1100.1452.3307A Hôpital Guy Chateliez; 🇫🇷 Tourcoing cedex, France

1100.1452.3307B Hôpital Guy Chateliez; 🇫🇷 Tourcoing cedex, France

1100.1452.3307C Hôpital Guy Chateliez; 🇫🇷 Tourcoing cedex, France

1100.1452.3307D Hôpital Guy Chateliez; 🇫🇷 Tourcoing cedex, France

1100.1452.3312A Hôpital Brabois; 🇫🇷 Vandoeuvre les Nancy, France

1100.1452.4902 Boehringer Ingelheim Investigational Site; 🇩🇪 Berlin, Germany

1100.1452.4901 Boehringer Ingelheim Investigational Site; 🇩🇪 Berlin, Germany

1100.1452.9907 Boehringer Ingelheim Investigational Site; 🇩🇪 Berlin, Germany

1100.1452.4903 Boehringer Ingelheim Investigational Site; 🇩🇪 Bochum, Germany

1100.1452.4904 Boehringer Ingelheim Investigational Site; 🇩🇪 Essen, Germany

1100.1452.4918 Boehringer Ingelheim Investigational Site; 🇩🇪 Bonn, Germany

1100.1452.4912 Boehringer Ingelheim Investigational Site; 🇩🇪 Düsseldorf, Germany

1100.1452.4933 Boehringer Ingelheim Investigational Site; 🇩🇪 Frankfurt am Main, Germany

1100.1452.4932 Boehringer Ingelheim Investigational Site; 🇩🇪 Würzburg, Germany

1100.1452.4910 Boehringer Ingelheim Investigational Site; 🇩🇪 München, Germany

1100.1452.31002 Onze Lieve Vrouwen Gasthuis; 🇳🇱 Amsterdam, Netherlands

1100.1452.31001 Academisch Medisch Centrum; 🇳🇱 Amsterdam, Netherlands

1100.1452.34001 Boehringer Ingelheim Investigational Site; 🇪🇸 Barcelona, Spain

1100.1452.34002 Boehringer Ingelheim Investigational Site; 🇪🇸 Barcelona, Spain

1100.1452.34003 Boehringer Ingelheim Investigational Site; 🇪🇸 L'Hospitalet de Llobregat, Spain

1100.1452.34011 Boehringer Ingelheim Investigational Site; 🇪🇸 Madrid, Spain

1100.1452.34004 Boehringer Ingelheim Investigational Site; 🇪🇸 Barcelona, Spain

1100.1452.34006 Boehringer Ingelheim Investigational Site; 🇪🇸 Madrid, Spain

1100.1452.34010 Boehringer Ingelheim Investigational Site; 🇪🇸 Madrid, Spain

1100.1452.88602 Kaohsiung Veterans General Hospital; 🇨🇳 Kaohsiung, Taiwan

1100.1452.88605 Chung-Ho Memorial Hospital, Kaohsiung Medical University; 🇨🇳 Kaohsiung, Taiwan

1100.1452.34009 Boehringer Ingelheim Investigational Site; 🇪🇸 Sevilla, Spain

1100.1452.88603 E-Da Hospital; 🇨🇳 Kaohsiung, Taiwan

1100.1452.88601 National Taiwan University Hospital; 🇨🇳 Taipei, Taiwan

1100.1452.88604 Taipei City Hospital; 🇨🇳 Taipei, Taiwan

1100.1452.66001 Boehringer Ingelheim Investigational Site; 🇹🇭 Bangkok, Thailand

1100.1452.66002 Boehringer Ingelheim Investigational Site; 🇹🇭 Bangkok, Thailand

1100.1452.66003 Boehringer Ingelheim Investigational Site; 🇹🇭 Khon Kaen, Thailand

1100.1452.44006 Boehringer Ingelheim Investigational Site; 🇬🇧 Birmingham, United Kingdom

1100.1452.44009 Boehringer Ingelheim Investigational Site; 🇬🇧 London, United Kingdom

1100.1452.44004 Boehringer Ingelheim Investigational Site; 🇬🇧 Brighton, United Kingdom

1100.1452.44008 Boehringer Ingelheim Investigational Site; 🇬🇧 London, United Kingdom

1100.1452.44003 Boehringer Ingelheim Investigational Site; 🇬🇧 Manchester, United Kingdom

1100.1452.44001 Boehringer Ingelheim Investigational Site; 🇬🇧 Coventry, United Kingdom

1100.1452.44007 Boehringer Ingelheim Investigational Site; 🇬🇧 Plaistow, London, United Kingdom

1100.1452.34007 Boehringer Ingelheim Investigational Site; 🇪🇸 Madrid, Spain

1100.1452.01014 Boehringer Ingelheim Investigational Site; 🇺🇸 Springfield, Massachusetts, United States

1100.1452.01011 Boehringer Ingelheim Investigational Site; 🇺🇸 New Haven, Connecticut, United States

1100.1452.01012 Boehringer Ingelheim Investigational Site; 🇺🇸 Chapel hill, North Carolina, United States

1100.1452.88606 China Medical University Hospital; 🇨🇳 Taichung, Taiwan