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

 Patients will be 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 will be
 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
 will attend scheduled visits, with physical and laboratory assessments, in order to monitor
 disease evolution and safety and tolerability of ITF2357.

 The study will be conducted in up to 80 patients of both genders, with established diagnosis
 of CD, who present 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-aminosalycylates, steroids or immunosuppressants.
ITF2357 is an orally active, synthetic inhibitor of histone deacetylase (HDAC) enzyme, which
 has been demonstrated to selectively inhibit the in-vitro production of pro-inflammatory
 cytokines and to exhibit in-vivo anti-inflammatory effects, both in animals and in humans.

 Crohn's Disease (CD) is a chronic and debilitating inflammatory disease of the
 gastrointestinal tract of unknown aetiology. The disease, which affects slightly more females
 than males and has a peak incidence at about 30 years of age, leads to significant physical
 morbidity and a marked impairment in quality of life. Abdominal pain and diarrhoea are the
 most common symptoms, although patients with CD may also develop a number of other clinical
 features such as malnutrition, anemia, osteoporosis, disabling perianal fistulae, and
 extra-intestinal symptoms such as fatigue, low-grade fever, arthritis and abnormalities of
 liver function. CD may affect any part of the gastrointestinal tract and is characterised by
 a pattern of relapses and remissions that may require treatment, including surgical
 intervention. More than 70% of subjects will require surgery during the course of their
 disease.

 The present study has been designed in order to prove that the short-term (8 weeks) treatment
 with oral ITF2357 can induce disease improvement in a substantial proportion of patients. Its
 aim is 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-aminosalycylates, steroids or immunosuppressants.
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-aminosalicilates, 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

 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.