Clinical trial NCT00190255: Pharmacogenetics of Gastrointestinal Bleeding
Official title: Pharmacogenetics of Gastrointestinal Bleeding Under Nonsteroidal Anti-inflammatory Drugs : the Role of Cytochrome P450 2C9
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Gastrointestinal Hemorrhage
Stomach Ulcer
Non-steroidal Anti-inflammatory Drug Sensitivity
Keywords: gastrointestinal haemorrhage
stomach ulcer
anti-inflammatory agents, non-steroidal
CYP2C9 protein, human
genotype
pharmacogenetics
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2005-09-19
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Inclusion Criteria:

* Upper gastrointestinal bleeding revealed by hematemesis, melena or lowering of at least 2g/dl of haemoglobin
* Endoscopic report of gastrointestinal ulcer or haemorrhagic lesion
* Immediate antecedents of NSAID therapy

Exclusion Criteria:

* Cirrhosis (Child B or C)
* Coma
* Concomitant therapy with substrates or inhibitors of CYP2C9 : ketoconazole, itraconazole, ritonavir, phenobarbital, rifampicin, depakine, phenytoin, St John's worts
* Patients treated by a NSAID metabolized by CYP2C9 and a NSAID not metabolized by CYP2C9

Brief summary: Gastrointestinal bleeding is a severe adverse effect occurring in subjects secondary to the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The enzyme CYP2C9 is responsible for the elimination of several NSAIDs. This protein is inactive in 12% of the subjects because of genetic mutations. We hypothesized that individuals carrying such mutations should be at higher risk of gastrointestinal bleeding since they display decreased NSAIDs elimination.

Detailed description: Gastrointestinal bleeding is a severe adverse effect occurring in subjects secondary to the use of nonsteroidal anti-inflammatory drugs (NSAIDs). The enzyme CYP2C9 is responsible for the elimination of most NSAIDs. Several polymorphisms have been observed in CYP2C9. Of these, the CYP2C9\*3 allele, found in 12% of caucasian subjects, leads to reduced function of the enzyme.

We hypothesized that individuals carrying this mutation should be at higher risk of gastrointestinal bleeding since they display decreased elimination of some NSAIDs.

The purpose of this study is to determine whether the frequency for CYP2C9\*3 variant allele is increased in subjects using NSAIDs metabolized by CYP2C9 in comparison with subjects under NSAIDs not metabolized by this enzyme.

The study groups consist of 200 patients suffering from gastrointestinal bleeding after NSAIDs use, divided in 100 patients using NSAIDs metabolized by CYP2C9 and 100 patients using other NSAIDs.

Eligibility criteria: Inclusion Criteria:

* Upper gastrointestinal bleeding revealed by hematemesis, melena or lowering of at least 2g/dl of haemoglobin
* Endoscopic report of gastrointestinal ulcer or haemorrhagic lesion
* Immediate antecedents of NSAID therapy

Exclusion Criteria:

* Cirrhosis (Child B or C)
* Coma
* Concomitant therapy with substrates or inhibitors of CYP2C9 : ketoconazole, itraconazole, ritonavir, phenobarbital, rifampicin, depakine, phenytoin, St John's worts
* Patients treated by a NSAID metabolized by CYP2C9 and a NSAID not metabolized by CYP2C9

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Paris
country: France
facility: Service d'hépato-gastroentérologie, Hôpital Saint Antoine
city: Paris
country: France
facility: Service d'hépato-gastroentérologie, Hôpital Pitié Salpétrière
city: Paris
country: France
facility: : Service d'hépato-gastroentérologie, Hôpital Henri Mondor
city: Villejuif
country: France
facility: Service d'hépato-gastroentérologie, Hôpital Paul BROUSSE
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Nicolas CARBONNELL, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Assistance Publique - Hôpitaux de Paris
name: Laurent BECQUEMONT, MD
role: STUDY_DIRECTOR
References:
citation: Martin JH, Begg EJ, Kennedy MA, Roberts R, Barclay ML. Is cytochrome P450 2C9 genotype associated with NSAID gastric ulceration? Br J Clin Pharmacol. 2001 Jun;51(6):627-30. doi: 10.1046/j.0306-5251.2001.01398.x.
citation: Martinez C, Blanco G, Ladero JM, Garcia-Martin E, Taxonera C, Gamito FG, Diaz-Rubio M, Agundez JA. Genetic predisposition to acute gastrointestinal bleeding after NSAIDs use. Br J Pharmacol. 2004 Jan;141(2):205-8. doi: 10.1038/sj.bjp.0705623. Epub 2004 Jan 5.