Effect of ITF2357 on Mucosal Healing in Patients With Moderate-to-severe Active Crohn's Disease

Objectives:

The primary objective of the study was to determine the ability of ITF2357, administered orally at the dose of 50 mg b.i.d. for 8 consecutive weeks, to induce complete healing of mucosal ulcerations of ileum and/or colon, assessed by endoscopy, in patients with endoscopic and clinical evidence of active moderate-to-severe Crohn's disease not controlled by conventional therapies.

The secondary objectives of the study were:

* to evaluate the effect of ITF2357 on endoscopic disease activity assessed using both the Crohn's Disease Endoscopic Index of Severity (CDEIS) and the Simple Endoscopic Score of Crohn's Disease (SES-CD);
* to evaluate the effect of ITF2357 on clinical disease activity, assessed using the Crohn's Disease Activity Index (CDAI);
* to assess the safety and tolerability of ITF2357; to assess the pharmacokinetic profile of ITF2357.

The study was conducted according to a randomized, double-blind placebo-controlled, parallel group design in up to 25 clinical sites in Europe.

Eligible patients were randomly assigned to two parallel treatment groups (1:1 randomization ratio) receiving either ITF2357, as hard gelatine capsule for oral administration, at the dose of 50 mg b.i.d. (total daily dose of 100 mg), or matching placebo capsules.

Treatment was administered on an outpatient basis for 8 consecutive weeks, followed by a 4-week follow-up.

During screening, in the 8-week treatment period and in the 4-week follow-up period, patients attended scheduled visits, with physical and laboratory assessments, in order to monitor disease evolution and safety and tolerability of ITF2357.

The study was planned to be conducted in up to 80 patients of both genders, with established diagnosis of CD, who presented with ulcerations greater than aphthous ulcers in at least one of the five bowel segments investigated endoscopically, from the ileum to the rectum, with endoscopic and clinical evidence of moderate-to-severe active disease, not controlled by on-going treatment with conventional therapies such as 5-aminosalicylates, steroids or immunosuppressants.

The present study has been designed in order to assessed wether short-term (8 weeks) treatment with oral ITF2357 can induce disease improvement in a substantial proportion of patients.

Its aim to evaluate whether a short term treatment with ITF2357 for 8 weeks, at the selected dose of 50 mg b.i.d., is able to induce healing of mucosal lesions, evaluated endoscopically, in patients with endoscopic and clinical evidence of moderate-to-severe active Crohn's disease, not controlled by ongoing treatment with conventional therapies such as 5-aminosalicylates, steroids or immunosuppressants, was not addressed and the study was prematurely interrupted according to IDSMC (Independent Data and Safety Monitoring Committee) decision, based on the results of the interim analysis, which did not demonstrate any benefit of ITF2357 over placebo in the primary variable rate of patients achieving complete healing at week 8.

There was also no evidence of benefits in patients treated with ITF2357 compared to placebo in the secondary efficacy endpoints (full remission rate, remission rate, CDEIS endoscopic response, changes from baseline of CDEIS score and SES-CD score, changes from baseline of CDAI score, CDAI remission rate, and CDAI response rate).

Eligibility Criteria:
Inclusion Criteria:

* Age: \> 18 years
* Diagnosis of CD, re-established by endoscopy and/or X-ray and/or surgery in the last 36 months
* CD in active phase since at least 2 weeks before screening
* CDAI between 220 and 450
* CDEIS \> 8
* Ulcerations greater than aphthous ulcers in at least 1 of the bowel segments from ileum to rectum
* If any on-going treatment with corticosteroids (prednisone, prednisolone or budesonide), it must be at a dose equivalent to or less than 30 mg/day prednisone, or 9 mg of budesonide, and in use for at least one month and at a stable dose for at least two weeks before patient enrolment
* If any on-going treatment with immunosuppressant (azathioprine, 6-mercaptopurine, methotrexate), it must be in use for at least 3 months before patient enrolment
* If any on-going treatment with 5-aminosalicylates, it must be in place for at least 4 weeks before patient enrolment, at a dose \> 2 g
* Females of childbearing potential with negative pregnancy tests
* Signed written informed consent to participate in this trial.

Exclusion Criteria:

* Treatment in the 2 months with anti-TNF-alfa antibodies and in the previous 3 months with cytokines inhibitors or experimental drugs
* Primary failure to previous treatment with anti-TNF-alfa antibodies-
* Current bowel obstruction or any condition that may predispose to its development (e.g. clinically significant unresolved intestinal stricture, adhesions or any other condition that would place the patient at risk for developing overt bowel obstruction) or intestinal perforation or significant GI hemorrhage
* Expected surgery for the duration of the study
* Any ostomy or extensive bowel resection
* Positive serological anti-HCV and anti-HIV testing and positive testing for active HBV replication, e.g. HBV-DNA or HBsAg or HBeAg (to be performed at screening)
* Other on-going clinical relevant viral infections (e.g. herpes zoster, Epstein-Barr, CMV), systemic fungal infections or history of recurrent serious bacterial infections
* Signs and symptoms of severe, progressive or uncontrolled renal, hepatic, haematologic, endocrine, pulmonary, cardiac, neurologic or cerebral disease
* Any previous evidence, irrespective of its severity, of coronary disease, cardiac rhythm abnormalities or congestive heart failure
* QTc interval \> 450 msec at pre-treatment evaluation
* Serum magnesium and potassium below the LLN at pre-treatment evaluation
* Platelet counts below 200 x 10\^9/L at pre-treatment evaluation
* Any previous evidence, irrespective of its severity, of renal function impairment
* Unavoidable concomitant treatment with any drug known for potential risk of causing Torsades de Pointes
* Presence of a transplanted organ
* History of cancer with less than 5 years documentation of a disease-free state
* History of tuberculosis
* Severe lactose intolerance
* Pregnant or nursing women
* Female of childbearing potential without using a safe contraceptive measure
* Participation in a clinical trial within 30 days prior to initiation of study treatment.