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

Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effect of ITF2357 on Mucosal Healing in Patients With Moderate-to-severe Active Crohn's Disease

As no safety warnings were detected, Interim analysis from the first 40 patients recommends to stop the trial for futility

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).

ITF2357 was administered as hard gelatin capsules for oral administration at the dose strength of 50 mg. Capsules were administered as follow: one capsule in the morning and one in the evening.

Placebo was supplied as matching capsules for oral administration with the same outer appearance of the study drug and with the same dosing scheme (one capsule in the morning and one in the evening)

The outcome is assessed by endoscopy, in patients with endoscopic and clinical evidence of active moderate-to-severe Crohn's disease not controlled by conventional therapies. The outcome measure defines the rate of patients achieving complete healing in ITT population, i.e disappearance of mucosal ulceration, obtained with ITF2357 treatment.

CDEIS (Crohn's Disease Endoscopic Index of Severity) is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon; A patient was defined 'fully endoscopic remissed' whether the CDEIS score at week 8 was equal or lower than three points CDEIS score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon. The score can be calculated even in case of incomplete investigations, as the results of the individual segments are divided by the number of segments investigated. Score Scale: < 3 remission; 3 - 8 mild endoscopic activity; 9 - 12 moderate endoscopic activity; > 12 severe endoscopic activity. The higher the score, the worse is patient's situation.

CDEIS (Crohn's Disease Endoscopic Index of Severity) is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon; A patient was defined 'endoscopic remissed' whether the CDEIS score at week 8 was equal or lower than six points. CDEIS score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon ). The score can be calculated even in case of incomplete investigations, as the results of the individual segments are divided by the number of segments investigated. The higher the score, the worse is patient's situation. Score Scale: < 3 remission; 3 - 8 mild endoscopic activity; 9 - 12 moderate endoscopic activity; > 12 severe endoscopic activity. A patient was defined 'endoscopic remissed' whether the CDEIS score at week 8 was equal or lower than six points.

CDEIS (Crohn's Disease Endoscopic Index of Severity) is an index for determining the severity of Crohn's disease with endoscopic localization to ileum and colon; A patient was considered in 'endoscopic response' whether the change in CDEIS score at week 8 versus baseline was equal or greater than 4.5 points. CDEIS score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon ). The score can be calculated even in case of incomplete investigations, as the results of the individual segments are divided by the number of segments investigated. The higher the score, the worse is patient's situation Score Scale: < 3 remission; 3 - 8 mild endoscopic activity; 9 - 12 moderate endoscopic activity; > 12 severe endoscopic activity. A patient was considered in 'endoscopic response' whether the change in CDEIS score at week 8 versus baseline was equal or greater than 4.5 points.

CDEIS is an index to determ the endoscopic severity of Crohn's disease. Its score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). These 4 parameters are: Deep ulcerations (12 if present, 0 if absent = total 1); Superficial ulcerations (6 if present, 0 if absent = total 2); Surface involved by disease (mm/10 on VAS = = total 3); Surface involved by ulcerations (mm/10 on VAS = total 4). Sum of Totals 1+2+3+4 =Total A Number of segments visualized in part or entirely (from 1 to 5)= n Total A/n =Total B if ulcerated stenosis in any segment, add 3 =Total C If non-ulcerated stenosis in any segment, add 3= Total D Total B+C+D=CDEIS grand score (min=0; max=NA) Decoding score < 3 remission; 3 - 8 mild endoscopic activity; 9 - 12 moderate endoscopic activity; > 12 severe endoscopic activity. The higher the score, the worse is patient's status.

SES-CD is another index to determ the endoscopic severity of Crohn's disease. Its score considers 4 parameters, each one evaluated in 5 pre-defined segments of the colon (ileum, ascending colon, transverse colon, descending colon and sigmoid loop, and rectum). These 4 parameters are: ulcers? 0: no; 1: aphthous (0.1-0.5 cm); 2: large (0.5-2 cm); 3: very large (>2 cm); Surface involved by inflammation 0: 0% 1: <50% 2: 50-75% 3: >75% Surface involved by ulcerations 0: 0% <10% 10-30% >30% Stenosis? 0: No Single, can be passed Multiple, can be passed Cannot be passed The scores for each individual segment are added together as a sum score (min=0; max=60) The higher the score, the worse the outcome. Decoding score 0 - 2 remission 3 - 6 mild endoscopic activity 7 - 15 moderate endoscopic activity > 15 severe endoscopic activity

CDAI (Crohn's Disease Activity Index): frequently used to assess disease severity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 7 days, and other measurements such as the patient's weight and haematocrit. The higher the score, the worse is patient's situation A patient is defined 'remissed' whether the CDAI score is lower than 150 points. A patient is defined 'responder' whether the change in CDAI score versus baseline is greater to 100 points

"Remission" is defined as the disappearance of signs and symptoms of the disease. CDAI (Crohn's Disease Activity Index): frequently used to assess disease severity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 7 days, and other measurements such as the patient's weight and haematocrit. The higher the score, the worse is patient's situation A patient is defined 'remissed' whether the CDAI score is lower than 150 points. A patient is defined 'responder' whether the change in CDAI score versus baseline is greater to 100 points

"Response" is defined as the reaction to a stimulus or to a treatment, especially in a favorable way. CDAI (Crohn's Disease Activity Index): frequently used to assess disease severity. It gives a score ranging from 0 to over 600, based on a diary of symptoms kept by the patient for 7 days, and other measurements such as the patient's weight and haematocrit. The higher the score, the worse is patient's situation. A patient is defined 'remissed' whether the CDAI score is lower than 150 points. A patient is defined 'responder' whether the change in CDAI score versus baseline is greater to 100 points

Treatment-related adverse events are adverse events (AE) which occurs during an interventional study and which are surely related to study treatment dosing.

At Pre-Treatment period (Week 0); At treatment period (Week 1, Week 2, Week 4, week 6, Week 8); At Follow-up period (1month)

Individual plasma levels of ITF2357 (before morning dose) after repeated oral administration of ITF2357 (50mg b.i.d.) in patients with Crohn's disease were assessed.

Individual plasma levels of metabolite ITF2374 (before morning dose) after repeated oral administration of ITF2357 (50mg b.i.d.) in patients with Crohn's disease were assessed.

Individual plasma levels of Metabolite ITF2375 (before morning dose) after repeated oral administration of ITF2357 (50mg b.i.d.) in patients with Crohn's disease were assessed.

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.