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

• ClinicalTrials.gov Identifier: NCT00792740
• Recruitment Status: Terminated
• First Posted: November 18, 2008
• Results First Posted: July 19, 2023
• Last Update Posted: July 19, 2023
• Sponsor: Italfarmaco
• Information provided by (Responsible Party): Italfarmaco

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Crohn's Disease	Drug: ITF2357; Other: Placebo	Phase 1; Phase 2

Detailed Description:

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: October 22, 2007
• Actual Primary Completion Date: December 2008
• Actual Study Completion Date: March 11, 2009

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Oral matching placebo capsules, administered bid.	Other: Placebo; 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)
Experimental: ITF2357; Oral ITF2357 50 mg bid	Drug: ITF2357; 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.; Other Name: Givinostat

Outcome Measures

Primary Outcome Measures :

1. Number of Patients Achieving Complete Healing of Mucosal Ulcerations of Ileum and/or Colon [ Time Frame: At week 8 ]

   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.

Secondary Outcome Measures :

1. Number of Patients Achieving Full Endoscopic Remission ( Based on CDEIS Score) [ Time Frame: At Week 8 ]

   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.

2. Number of Patients Achieving Endoscopic Remission (Based on CDEIS Score) [ Time Frame: At week 8 ]

   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.

3. Number of Patients Achieving Endoscopic Response (Based on CDEIS Score) [ Time Frame: At week 8 ]

   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.

4. The Mean Changes of Crohn's Disease Endoscopic Index of Severity (CDEIS) From Baseline to Week 8 [ Time Frame: From Baseline to week 8 ]

   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.

5. The Mean Changes of Simple Endoscopic Score for Crohn Disease (SES-CD) From Baseline to Week 8 [ Time Frame: From Baseline to week 8 ]

   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%

   1. <10%
   2. 10-30%
   3. >30% Stenosis?

   0: No

   1. Single, can be passed
   2. Multiple, can be passed
   3. 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

6. The Mean Changes of CDAI Score From Baseline to Week 4-8-follow up [ Time Frame: Weeks 4 and 8, and follow-up at 1 month ]

   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

7. Number of Patients Achieving Remission (Based on CDAI Score) [ Time Frame: Weeks 4 and 8, and follow-up at 1 month ]

   "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

8. Number of Patients Achieving Response (Based on CDAI Score) [ Time Frame: Weeks 4 and 8, and follow-up at 1 month ]

   "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

9. Number of Patients With at Least One Related Adverse Event to Study Treatment [ Time Frame: At Pre-Treatment period (Week 0); At treatment period (Week 1, Week 2, Week 4, week 6, Week 8); At Follow-up period (1month) ]
   Treatment-related adverse events are adverse events (AE) which occurs during an interventional study and which are surely related to study treatment dosing.
10. Plasma Levels of ITF2357 Before Morning Dose of ITF2357 [ Time Frame: Pre-dose, week 2, week 4, week 6 ]
    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.
11. Plasma Levels of Metabolite ITF2374 Before Morning Dose of ITF2357. [ Time Frame: Pre-dose, week 2, week 4, week 6 ]
    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.
12. Plasma Levels of Metabolite ITF2375 Before Morning Dose of ITF2357. [ Time Frame: Pre dose, week 2, week 4, week 6. ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Belgium

AZ Sint Lucas Gastro-enterologie

Assebroek, Belgium, 8310

Imelda Hospital Gastro-enterology dept.

Bonheiden, Belgium, 2820

CHU Saint-Pierre Médecine Interne

Bruxelles, Belgium, 1000

UZ Gent Gastro-enterologie 1K12IE

Gent, Belgium, 9000

AZ Groeninge (St-Niklaas) Gastro-enterologie

Kortrijk, Belgium, 8500

University Hospital Gasthuisber

Leuven, Belgium, 3000

Italy

Divisione di Gatroenterologia Istituto Clinico Humanitas IRCCS in. Gastroenterology

Rozzano, Italy, 20089

Netherlands

Vrije Universiteit (VU) Medisch Centrum Afdeling M.D.L.ziekten

Amsterdam, Netherlands, 1007 MB

Academisch Medisch Centrum (AMC) Afdeling M.D.L. ziekten

Amsterdam, Netherlands, 1100 DD

Leids Universitair Medisch Centrum (LUMC) Afdeling M.D.L. ziekten

Leiden, Netherlands, 2300 RC

Sponsors and Collaborators

Italfarmaco

Investigators

• Study Chair: Paul Rutgeerts, MD; University Hospital Gasthuisberg, Leuven, Belgium

More Information

• Responsible Party: Italfarmaco
• ClinicalTrials.gov Identifier: NCT00792740
• Other Study ID Numbers: DSC/06/2357/23; 2007-000189-19 ( EudraCT Number )
• First Posted: November 18, 2008
• Results First Posted: July 19, 2023
• Last Update Posted: July 19, 2023
• Last Verified: January 2022

Additional relevant MeSH terms:

Crohn Disease; Inflammatory Bowel Diseases; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases; Givinostat hydrochloride; Histone Deacetylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action