Clinical trial NCT02367326: Identification of Scores Associated With a Favorable Clinical Response With Thiopurines in IBD Patients
Official title: Identification of Composite Clinical and Lab Scores Associated With a Favorable Clinical Response With Thiopurines in Patients With IBD (Inflammatory Bowel Disease): an International Clinical Trial
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Inflammatory Bowel Diseases
Keywords: score
inflammatory bowel disease
crohn's disease
ulcerative colitis
clinical response
thiopurines
Lead sponsor: Centre Hospitalier Universitaire de Saint Etienne
Sponsor class: OTHER
Collaborators: name: Apsen Farmaceutica S.A.
First posted: 2015-02-20
Enrollment: 400
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: patients with Crohn's Disease or Ulcerative Colitis and on thiopurines at stable doses for at least 3 months, monotherapy or combined with corticotherapy

Brief summary: Inflammatory bowel disease (IBD) groups together Crohn's Disease (CD) and ulcerative colitis (UC). Its prevalence is high representing approximately 0.4% of the population. The peak incidence for these diseases ranges between 2 and 30 years of age with a second peak for CD recently reported at 60. These diseases develop over time into complications requiring in 2/3 of cases surgical resection procedures in CD and colectomy in over 20% of cases. Cohort data has recently shown that the early use of azathioprine from the first year would decrease the need for surgery. Aside from biologics, azathioprine is the most widely used immunosuppressant in IBD management. Its metabolism is highly variable in the overall population since over 10% of patients are slow metabolizers and 15% fast metabolizers. This explains partly treatment failures and side effects with thiopurines. A lot of research has shown that metabolite measurement of azathioprine (6-TGN end methylated derivatives) could be used clinically even if these results remain controversial. In fact, their positive predicative value (PPV) in clinical response does not exceed 60%. This costly testing cannot be done everywhere, is not reimbursed by national health services, and may not be used in some countries. It is, however, key in order optimize these drugs at a time when only two anti-TNFs are possible in the event of failure on thiopurines. Older studies have shown that MCV and lymphonenia could be markers for thiopurine impregnation. Recently, an American study provided a mathematic formula enabling to achieve over 80% PPV for the clinical response on AZA but this calculation needs to be confirmed and it is, moreover, patented (costly).

Detailed description: We suggest developing a predictive score for clinical thiopurines in IBD based on routine lab data obtained when monitoring patients on thiopurines. This initial work will enable to identify clinical and/or lab factors in order to develop a score based on an international, multicenter, cross-section study. Two hundred patients with treatment failure on thiopurines will be included and at least as many in clinical remission on thiopurines. A subsequent longitudinal study, over all recruiting centers will enable to validate the score. Finally, a prospective study will assess the clinical impact of the optimization of this score in patients sustaining a treatment failure on thiopurines. This score - if confirmed - will subsequently be at no additional cost in the management of patients on thiopurines.

Eligibility criteria: Inclusion Criteria:

* Adult patients affiliated with or beneficiaries of a national health insurance scheme
* Male our female over 18 years of age and under 70 having given his/her informed consent to participate in this trial.
* Any patients with Crohn's Disease or Ulcerative Colitis meeting clinical, endoscopic and histological criteria.
* Patients on thiopurines at stable doses for at least 3 months, monotherapy or combined with corticotherapy using the following doses:

AZATHIOPRINE at the dose of 2 to 2.5 mg/kg/day, regular oral dosing for 3 months or PURINETHOL at the dose of 1 to 1.5 mg/kg/day, regular oral dosing for 3 months

Exclusion Criteria:

* Patients with intolerance to thiopurines resulting in reduction or discontinuation of thiopurines by the referring physician.
* Post operative Crohn's Disease patients for whom thiopurines were indicated preventively or in the event of endoscopic abnormalities.
* Extensive colic resection, (sub)total colectomy.
* History of \> 3 resections of the small intestine or diagnosis of a short bowel
* Crohn's Disease with a perianal lesion whether the latter is isolated or the focus of the disease
* Patient with a enterocutaneous, abdominal or pelvic fistula with abscess or fistula likely to require surgery during the study
* Ileostomy, colostomy or known intestinal stenosis
* Severe active infection
* Active neoplasia
* Known TPMPT homozygote mutation
* Patients on anti-TNF or Methotrexate in the last 3 months or during thiopurine therapy
* Patients on Allopurinol.
* Patient who expressed his/her refusal to participate in the study

Primary outcomes:
measure: number of patient with therapeutic failure on thiopurines
timeFrame: day 0 (inclusion)
Secondary outcomes:
measure: number of patient in clinical remission on thiopurines
timeFrame: day 0 (inclusion)
Other outcomes:
Locations:
city: Besançon
country: France
facility: CHU Jean Minjoz
city: Caen
country: France
facility: CHU Caen
city: Dijon
country: France
facility: CHU Dijon
city: Lilles
country: France
facility: CHRU Lilles
city: Montpellier
country: France
facility: CHU Montpellier
city: Nancy
country: France
facility: CHU Nancy
city: Nantes
country: France
facility: CHU Nantes - Hôtel-Dieu
city: Nice
country: France
facility: CHU Nice
city: Orléans
country: France
facility: CHR Orléans
city: Paris
country: France
facility: Hôpital Saint-Antoine
city: Pessac
country: France
facility: CHU Bordeaux
city: Pierre Bénite
country: France
facility: CH Lyon Sud
city: Reims
country: France
facility: CHU Reims
city: Rennes
country: France
facility: CHU Rennes
city: Saint-Etienne
country: France
facility: CHU Saint-Etienne
Study officials:
affiliation: CHU SAINT-ETIENNE
name: Xavier ROBLIN, MD
role: PRINCIPAL_INVESTIGATOR
References: