Clinical trial NCT00310843: Case-Control Viramune (Nevirapine) Toxicogenomics Study
Official title: A Case-Control Toxicogenomics Study to Identify Unique Genetic Polymorphisms in Patients Who Have Experienced Symptomatic Hepatotoxicity or Severe Cutaneous Toxicity Within the First 8 Weeks of Nevirapine Therapy
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: HIV Infections
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2006-04-05
Enrollment: 889
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients Who Have Experienced Symptomatic Hepatotoxicity or Severe Cutaneous Toxicity Within the First 8 Weeks of Nevirapine Therapy

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.


Eligibility criteria: 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

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

Primary outcomes:
measure: 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 outcomes:
measure: 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.
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: 1100.1452.01006 Boehringer Ingelheim Investigational Site
state: Alabama
city: Denver
country: United States
facility: 1100.1452.01013 Boehringer Ingelheim Investigational Site
state: Colorado
city: Baltimore
country: United States
facility: 1100.1452.99999 Boehringer Ingelheim Investigational Site
state: Connecticut
city: New Haven
country: United States
facility: 1100.1452.01011 Boehringer Ingelheim Investigational Site
state: Connecticut
city: Baltimore
country: United States
facility: 1100.1452.01003 Boehringer Ingelheim Investigational Site
state: Maryland
city: Boston
country: United States
facility: 1100.1452.01002 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: Springfield
country: United States
facility: 1100.1452.01014 Boehringer Ingelheim Investigational Site
state: Massachusetts
city: St. Louis
country: United States
facility: 1100.1452.01015 Boehringer Ingelheim Investigational Site
state: Missouri
city: New York
country: United States
facility: 1100.1452.01016 Boehringer Ingelheim Investigational Site
state: New York
city: Chapel hill
country: United States
facility: 1100.1452.01012 Boehringer Ingelheim Investigational Site
state: North Carolina
city: Nashville
country: United States
facility: 1100.1452.01001 Boehringer Ingelheim Investigational Site
state: Tennessee
city: Fort Worth
country: United States
facility: 1100.1452.01004 Boehringer Ingelheim Investigational Site
state: Texas
city: Capital Federal
country: Argentina
facility: 1100.1452.54001 Fundación Huésped
city: Capital Federal
country: Argentina
facility: 1100.1452.54002 Funcei
city: Capital Federal
country: Argentina
facility: 1100.1452.54003 Boehringer Ingelheim Investigational Site
city: Rosario
country: Argentina
facility: 1100.1452.54004 Boehringer Ingelheim Investigational Site
city: Darlinghurst
country: Australia
facility: 1100.1452.61004 Boehringer Ingelheim Investigational Site
state: New South Wales
city: DarlingHurst
country: Australia
facility: 1100.1452.61005 Boehringer Ingelheim Investigational Site
state: New South Wales
city: Darlinghurst
country: Australia
facility: 1100.1452.61006 Boehringer Ingelheim Investigational Site
state: New South Wales
city: Miami
country: Australia
facility: 1100.1452.61003 Boehringer Ingelheim Investigational Site
state: Queensland
city: Carlton
country: Australia
facility: 1100.1452.61002 Boehringer Ingelheim Investigational Site
state: Victoria
city: Melbourne
country: Australia
facility: 1100.1452.61008 Boehringer Ingelheim Investigational Site
state: Victoria
city: South Yarra
country: Australia
facility: 1100.1452.61001 Boehringer Ingelheim Investigational Site
state: Victoria
city: Vancouver
country: Canada
facility: 1100.1452.01501 St. Paul's Hospital
state: British Columbia
city: Vancouver
country: Canada
facility: 1100.1452.01504 Boehringer Ingelheim Investigational Site
state: British Columbia
city: Toronto
country: Canada
facility: 1100.1452.01502 Toronto General Hospital
state: Ontario
city: Bordeaux
country: France
facility: 1100.1452.3304A Hôpital Saint André
city: Lyon cedex 2
country: France
facility: 1100.1452.3306A Hôpital Hôtel Dieu
city: Lyon Cedex 3
country: France
facility: 1100.1452.3311A Hôpital Edouard Herriot
city: Lyon cedex 3
country: France
facility: 1100.1452.3311C Hôpital Edouard Herriot
city: Lyon cedex 3
country: France
facility: 1100.1452.3311D Hôpital Edouard Herriot
city: Lyon
country: France
facility: 1100.1452.3306B Hop Hôtel Dieu
city: Lyon
country: France
facility: 1100.1452.3311B Pavillon P
city: Nantes cedex 1
country: France
facility: 1100.1452.3305A Hôpital hôtel Dieu
city: Nantes cedex 1
country: France
facility: 1100.1452.3305B Hôpital hôtel Dieu
city: Nantes cedex 1
country: France
facility: 1100.1452.3305C Hôpital hôtel Dieu
city: Nantes cedex 1
country: France
facility: 1100.1452.3305E Hôpital hôtel Dieu
city: Nantes cedex 1
country: France
facility: 1100.1452.3305H Hôpital hôtel Dieu
city: Nantes
country: France
facility: 1100.1452.3305D Hôpital Hôtel Dieu
city: Nantes
country: France
facility: 1100.1452.3305F Hôpital Hôtel Dieu
city: Nantes
country: France
facility: 1100.1452.3305G Hôpital Hôtel Dieu
city: Nantes
country: France
facility: 1100.1452.3305I Hôpital Hôtel Dieu
city: Paris cedex 12
country: France
facility: 1100.1452.3313A Hôpital Saint Antoine
city: Paris cedex 20
country: France
facility: 1100.1452.3302A Hôpital Tenon
city: Paris
country: France
facility: 1100.1452.3301A Hôpital Saint Louis
city: Paris
country: France
facility: 1100.1452.3303A Hôpital de la Pité Salpêtrière
city: Paris
country: France
facility: 1100.1452.3310A Hôpital Bichat Claude Bernard
city: Paris
country: France
facility: 1100.1452.3310B Hôpital Bichat Claude Bernard
city: Paris
country: France
facility: 1100.1452.3313B Hôpital Saint Antoine
city: Paris
country: France
facility: 1100.1452.3313C Hôpital Saint Antoine
city: Paris
country: France
facility: 1100.1452.3314A Hôpital Européen Georges Pompidou
city: Toulouse cedex 9
country: France
facility: 1100.1452.3308A Hôpital Purpan
city: Toulouse
country: France
facility: 1100.1452.3308B Hôpital Purpan
city: Tourcoing cedex
country: France
facility: 1100.1452.3307A Hôpital Guy Chateliez
city: Tourcoing cedex
country: France
facility: 1100.1452.3307B Hôpital Guy Chateliez
city: Tourcoing cedex
country: France
facility: 1100.1452.3307C Hôpital Guy Chateliez
city: Tourcoing cedex
country: France
facility: 1100.1452.3307D Hôpital Guy Chateliez
city: Tourcoing cedex
country: France
facility: 1100.1452.3307E Hôpital Guy Chateliez
city: Vandoeuvre les Nancy
country: France
facility: 1100.1452.3312A Hôpital Brabois
city: Berlin
country: Germany
facility: 1100.1452.4901 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1100.1452.4902 Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1100.1452.9907 Boehringer Ingelheim Investigational Site
city: Bochum
country: Germany
facility: 1100.1452.4903 Boehringer Ingelheim Investigational Site
city: Bonn
country: Germany
facility: 1100.1452.4918 Boehringer Ingelheim Investigational Site
city: Düsseldorf
country: Germany
facility: 1100.1452.4912 Boehringer Ingelheim Investigational Site
city: Essen
country: Germany
facility: 1100.1452.4904 Boehringer Ingelheim Investigational Site
city: Frankfurt am Main
country: Germany
facility: 1100.1452.4933 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 1100.1452.4916 Boehringer Ingelheim Investigational Site
city: Hamburg
country: Germany
facility: 1100.1452.4931 Boehringer Ingelheim Investigational Site
city: München
country: Germany
facility: 1100.1452.4910 Boehringer Ingelheim Investigational Site
city: Ulm
country: Germany
facility: 1100.1452.4900 Universitätsklinikum Ulm
city: Würzburg
country: Germany
facility: 1100.1452.4932 Boehringer Ingelheim Investigational Site
city: Amsterdam
country: Netherlands
facility: 1100.1452.31001 Academisch Medisch Centrum
city: Amsterdam
country: Netherlands
facility: 1100.1452.31002 Onze Lieve Vrouwen Gasthuis
city: Badalona
country: Spain
facility: 1100.1452.34005 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1100.1452.34001 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1100.1452.34002 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1100.1452.34004 Boehringer Ingelheim Investigational Site
city: L'Hospitalet de Llobregat
country: Spain
facility: 1100.1452.34003 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1100.1452.34006 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1100.1452.34007 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1100.1452.34010 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1100.1452.34011 Boehringer Ingelheim Investigational Site
city: Sevilla
country: Spain
facility: 1100.1452.34009 Boehringer Ingelheim Investigational Site
city: Kaohsiung
country: Taiwan
facility: 1100.1452.88602 Kaohsiung Veterans General Hospital
city: Kaohsiung
country: Taiwan
facility: 1100.1452.88603 E-Da Hospital
city: Kaohsiung
country: Taiwan
facility: 1100.1452.88605 Chung-Ho Memorial Hospital, Kaohsiung Medical University
city: Taichung
country: Taiwan
facility: 1100.1452.88606 China Medical University Hospital
city: Taipei
country: Taiwan
facility: 1100.1452.88601 National Taiwan University Hospital
city: Taipei
country: Taiwan
facility: 1100.1452.88604 Taipei City Hospital
city: Bangkok
country: Thailand
facility: 1100.1452.66001 Boehringer Ingelheim Investigational Site
city: Bangkok
country: Thailand
facility: 1100.1452.66002 Boehringer Ingelheim Investigational Site
city: Khon Kaen
country: Thailand
facility: 1100.1452.66003 Boehringer Ingelheim Investigational Site
city: Birmingham
country: United Kingdom
facility: 1100.1452.44006 Boehringer Ingelheim Investigational Site
city: Brighton
country: United Kingdom
facility: 1100.1452.44004 Boehringer Ingelheim Investigational Site
city: Coventry
country: United Kingdom
facility: 1100.1452.44001 Boehringer Ingelheim Investigational Site
city: London
country: United Kingdom
facility: 1100.1452.44002 Boehringer Ingelheim Investigational Site
city: London
country: United Kingdom
facility: 1100.1452.44005 Boehringer Ingelheim Investigational Site
city: London
country: United Kingdom
facility: 1100.1452.44008 Boehringer Ingelheim Investigational Site
city: London
country: United Kingdom
facility: 1100.1452.44009 Boehringer Ingelheim Investigational Site
city: Manchester
country: United Kingdom
facility: 1100.1452.44003 Boehringer Ingelheim Investigational Site
city: Plaistow, London
country: United Kingdom
facility: 1100.1452.44007 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References: