Comparison of efficacy of masitinib versus placebo in the treatment of Crohn's disease

• Register: EUCTR
• Last refreshed on: 10 December 2019
• Main ID: EUCTR2012-004222-25-SK
• Date of registration: 09/01/2014
• Prospective Registration: Yes
• Primary sponsor: AB Science
• Public title: Comparison of efficacy of masitinib versus placebo in the treatment of Crohn's disease
• Scientific title: A 12-week with possible extension, prospective, multicenter, randomised, double-blind, controlled, 2-parallel groups, phase 2b/3 study to compare efficacy and safety of masitinib to placebo, in the treatment of moderate Crohn’s disease in patients intolerant or with unsatisfactory response to immunosuppressive drugs and/or TNF-inhibitors - AB1010 in treatement of patients with moderate Crohn's disease
• Date of first enrolment: 28/04/2014
• Target sample size: 450
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-004222-25
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: yes; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 4
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Belgium, Czech Republic, France, Greece, India, Morocco, Slovakia, Spain, Tunisia

Contacts

• Name: vissac-sabatiet
• Affiliation: AB Science

• Name: vissac-sabatiet
• Affiliation: AB Science

Key inclusion & exclusion criteria

Inclusion criteria:
Patient with at least a 6-month history of Crohn’s disease (CD) from diagnosis.
2. Patient with CD based on clinical history and radiologic or endoscopic findings within the previous 24 months. Patients with active disease following surgical resection must have radiological or endoscopic confirmation of CD post-surgery.
3. Patient with a CDAI (Crohn’s disease activity index) score at baseline between 220 and 450 ([220;450]).
4. Patient intolerant or with unsatisfactory response to [Azathioprine or 6-mercaptopurine or methotrexate] and/or TNF-inhibitors.
Patient with unsatisfactory response is defined as patient with active Crohn’s disease (CDAI>=220) after at least 3 months under stable dose of treatment.
Patient intolerant is defined as patient who have had to discontinue treatment at any time for tolerability or safety reason
5. Patient with active Crohn’s disease confirmed by at least one of the following criteria:
? level of C-reactive protein > 5 mg/L within 2 weeks prior to study treatment initiation
? faecal calprotectin level > 250 µg within 2 weeks prior to study treatment initiation
? ulcers demonstrated at colonoscopy within 12 weeks prior to study treatment initiation
? small intestine or colonic inflammation defined as postcontrast parietal relative contrast enhancement after gadolinium injection and/or the presence of deep ulcerations on MRI or CT within 6 weeks prior to study treatment initiation
6. Patient with adequate organ function:
? Absolute neutrophils count (ANC) = 2 x 109/L
? Haemoglobin = 10 g/dL
? Platelets (PTL) = 100 x 109/L
? AST/ALT = 3 x ULN
? Bilirubin = 1.5x ULN
? Creatinine clearance >60 mL/min
? Albuminemia > 1 x LLN
? Proteinuria < 30 mg/dL (1+) on the dipstick; in case of proteinuria = 1+ on the dipstick, 24 hours proteinuria < 1.5g/24 hours
7. Male or female patient aged 18 to 75 years, weight > 50 kg, BMI between 18 and 35 kg/m²
8. Female patient of childbearing potential (entering the study after a menstrual period and who have a negative pregnancy test), who agrees to use two highly effective methods (one for the patient and one for the partner) of medically acceptable forms of contraception during the study and for 3 months after the last treatment intake. Acceptable forms of contraception include:
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? A documented placement of an intrauterine device (IUD) or intrauterine system (IUS) and the use of a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository)
? Documented tubal ligation (female sterilization). In addition, a barrier method (condom or occlusive cap [diaphragm or cervical/vault caps] used with spermicidal foam/gel/film/cream/suppository) should also be used
? Double barrier method: Condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
? Any other contraceptive method wi
Exclusion criteria:
1. Patient with less than 3 months exposure to Azathioprine or 6-mercaptopurine or methotrexate.
2. Patient treated with biological agents (natalizumab, ...) other than anti-TNF alpha.
3. Patient with known active or draining fistula.
4. Patient currently receiving nasogastric/nasoenteric tube feeding, an elemental/polymeric diet or total parenteral nutrition e.g. liquid diet and oral supplements, must remain stable during the treatment phase (baseline to week 4).
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5. Patient likely to require emergency surgery for persistent intestinal obstruction, bowel perforation, uncontrolled bleeding or abdominal abscess infection, in the investigator’s opinion and patients who have undergone bowel surgery within the 3 months prior to study treatment initiation.
6. Patient with previous proctocolectomy or with symptomatic stricture or with abscess
7. Patient with a clinically relevant short bowel syndrome, in the opinion of the investigator.
8. Patient whose symptoms are believed to be largely due to the presence of fixed fibrotic strictures in the opinion of the investigator.
9. Patient with a history of malignant neoplastic diseases of the bowel including diseases occurring more than 5 years before the inclusion in the study.
10. Patient with active infection (HBV, HCV, HIV, EBV, CMV)
11. Patient presenting with cardiac disorders defined by at least one of the following conditions:
? Patient with recent cardiac history (within 6 months) of:
- Acute coronary syndrome
- Acute heart failure (class III or IV of the NYHA classification)
- Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death)
? Patient with cardiac failure class III or IV of the NYHA classification
? Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)
? Syncope without known aetiology within 3 months
? Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic hypertension
12. Patient with life expectancy < 6 months
13. Patient with history of primary malignancy < 5 years; except treated basal cell skin cancer or cervical carcinoma in situ
14. Patient with a severe and/or uncontrolled medical condition according to judgment of the investigator
15. Pregnant or lactating female patient
16. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent.
17. Patient with Body Mass Index (BMI) strictly above 35.
PREVIOUS TREATMENTS (WASH OUT)
1. NSAID must be stopped within 2 weeks prior to study treatment initiation
2. In

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Crohn's disease
MedDRA version: 20.0 Level: PT Classification code 10011401 Term: Crohn's disease System Organ Class: 10017947 - Gastrointestinal disorders

Therapeutic area: Diseases [C] - Digestive System Diseases [C06]

Intervention(s)

Product Name: Masitinib
Product Code: AB1010
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: masitinib mesylate
CAS Number: 790-299-79-5
Current Sponsor code: AB1010
Other descriptive name: not applicable
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Product Name: Masitinib
Product Code: AB1010
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: masitinib mesylate
CAS Number: 790-299-79-5
Current Sponsor code: AB1010
Other descriptive name: not applicable
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: Clinical remission, defined as CDAI < 150 and absence of surgery at W4, W8 and W12
? Clinical response defined as a decrease in CDAI = 70 at W4, W8 and W12
? Enhanced clinical response, defined as a decrease in CDAI = 100 at W4 and W8
? Cumulative clinical response
? Cumulative enhanced clinical response
? Cumulative clinical remission
? C-reactive protein change at W4, W8 and W12
? Faecal calprotectin level at W4, W8 and W12
? Corticosteroids consumption at W4, W8, W9, W10, W11 and W12
? Quality of Life
o Absolute and relative change from baseline in IBDQ (Inflammatory Bowel Disease Questionnaire) scores at W4, W8 and W12
o Absolute and relative change from baseline in FACIT-Fatigue (Functional Assessment of Chronic IllnesTherapy-Fatigue) score at W4, W8 and W12
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o Absolute and relative change from baseline in W12 IBD disability index

Primary end point(s): Primary criterion is assessed by the percentage of patients with enhanced clinical response, defined as a decrease in CDAI = 100 between baseline and W12.

Main Objective: Enhanced clinical response, defined as a decrease in CDAI (Crohn’s Disease Activity Index) = 100 at W12

Timepoint(s) of evaluation of this end point: W12

Secondary Outcome(s)

Secondary end point(s): Efficacy
- Percentage of patients with Clinical remission is defined as CDAI < 150 maintained for at least 2 weeks and absence of surgery.
- Percentage of patients with Clinical response is defined as a decrease in CDAI = 70 from baseline.
- Cumulative clinical response is defined as the sum of the time periods where patients are in clinical response in the 12-week study.
- Cumulative enhanced clinical response is defined as the sum of the time periods where patients are in enhanced clinical response in the 12-week study.
- Cumulative clinical remission is defined as the sum of the time periods where patients are in clinical remission in the 12-week study.
- C-reactive protein (CRP) absolute and relative change from baseline is assessed at every time point. CRP level is raised in inflammatory bowel disease as Crohn’s disease.
- Faecal calprotectin level absolute and relative change from baseline is assessed at every time point.
Faecal calprotectin is biochemical test for inflammatory bowel disease (IBD). It may replace the need for invasive colonoscopy. Levels are increased in patients with IBD and might be a predictive marker of relapse in Crohn's disease.
- Corticosteroids consumption is described by the posology administered in “equivalent prednisone” at every time point and the percentage of patient without oral corticosteroids at every time point.
Quality of Life
- IBDQ (Inflammatory Bowel Disease Questionnaire) is a self-report 32-item questionnaire with questions in four subscales: bowel symptoms (10 items), systemic symptoms (5 items), emotional status (12 items) and social functioning (5 items). Each item is a 7-point Likert type (1 to 7 points for each question). Global IBDQ score has values from 32 to 224, the higher the score, the better the quality of life. Sub-scores are also calculated for each sub-scale by summing points from each item from the subscale. IBDQ global score and the four associated sub-scores are described with absolute and relative change from baseline.
- FACIT-Fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue or FACIT-F) is a 13-item specific scale used to measure fatigue. Each item is a 4-point Likert type (0 to 4 points for each question).
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Global score is calculated by summing points from each item and hasvalues from 0 to 52 (52 = no fatigue). Variation of FACIT-F score >= 4 are considered as clinically significant. FACIT-F score is described with absolute and relative change from baseline.
- The World Health Organisation (WHO)’s integrative model of human functioning and disability in the International Classification of Functioning, Disability and Health (ICF) makes disability assessment possible. The ICF is a hierarchical coding system with 4 levels of details that includes>1,400 categories. The IBD disability index (Inflammatory Bowel Disease disability index) is constructed using a selection of 19 ICF Core Set categories: 7 on Body Functions, 2 on Body Structures, 5 on Activities and Participation, and 5 on Environmental Factors. IBD disability index is decribed with absolute and relative change from baseline.
Safety
Safety of the study treatment will be assessed on occurrence of adverse events (AEs), intake of concomitant treatments, per-treatment changes in physical examination, vital signs (blood pressure, pulse rate and body temperature), ECG, chest X-Ray, clinical laboratory tests (biochemistry, haematology) and urinary analysis.
Ancillary study
Ileo-colonoscopies will be performed in selected sites only at W0 and W12. CDEIS et and SES-CD scores will be calculated. These scores are described with absolute and relative change from baseline. Endoscopic response defined as a CDEIS decrease >5, endoscopic remission as a CDEIS <6, and complete endoscopic remission as a CDEIS <3.
Pharmacogenomic assessment: relationship between genomic data, efficacy variables (Enhanced clinical response) and safety.

Timepoint(s) of evaluation of this end point: W4, W8, W12

Secondary ID(s)

AB11003

2012-004222-25-BE

Source(s) of Monetary Support

AB Science

Ethics review

Status: Approved
Approval date:
Contact: