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.

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.
A previous study completed in CD patients provided preliminary evidence that
short-term (8 weeks) treatment with oral ITF2357 can induce disease improvement
in a substantial proportion of patients. The dose of 50 mg b.i.d. appeared to
be the most promising one, as it was able to induce a clinical benefit, with
more than 40 % of the patients achieving remission after 8-weeks.

Primary objective of the study is 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,
Secondary objectives are:
1. 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)
2. to evaluate the effect of ITF2357 on clinical disease activity, assessed
using the Crohn*s Disease Activity Index (CDAI)
3. to assess safety and tolerability of ITF2357
4. to assess pharmacokinetic properties of ITF2357

Multicentre, randomized (1:1), double-blind, placebo-controlled study;
sequential design with interim analysis after completion of 40 subjects.

Oral ITF2357 50 mg b.i.d. or matching placebo for 8 consecutive weeks.

Based on the known mechanism of action of ITF2357, the results of pre-clinical
studies in animals and on the previous clinical trial conducted in patients
with Crohn*s disease, it can be expected that ITF2357 offers a clinical benefit
associated with healing of intestinal mucosa to those patients affected by
Crohn*s disease who do not respond to standard therapies.
Up to now ITF 2357 has been administered to 243 subjects, including healthy
volunteers and patients The side effects most notified of ITF2357 are mild to
moderate platelets count reductions, non specific gastrointestinal symptoms
including nausea, vomiting and diarrhea, mild upper respiratory tract
infections, isolated cases of palpitation and tachycardia. In addition a slight
increase in creatinine levels, possibly suggesting an effect on renal function,
was observed in some Crohn*s patients receiving ITF2357.
The effects on platelets observed in Crohn*s disease and psoriasis patients
were more evident at the 100 mg twice daily, conversely, at doses such as 50 mg
given once or twice daily the decrease in platelet counts were well confined
within the range of normality.
More pronounced effects on blood cells and reduced gastro-intestinal
tolerability were seen on patients with hematological malignancies treated with
higher doses of ITF23547. Recently, some important alterations in the ECG,
which can possibly cause severe arrhythmias, were seen in two patients with
blood tumors treated with high doses of ITF2357. In addition one patient with a
severe and rare type of lymphoma had a fatal liver failure while in treatment
with ITF 2357 and ITF2357 could have contributed to the occurrence of this
event.