Safety Evaluation of ABX464 in Patients With Moderate to Severe Active Crohn's Disease

Study Overview
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Brief Summary
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This Phase IIa study is a 16-week, double-blind, placebo-controlled, randomized study aiming at evaluating the safety and the efficacy of ABX464 given once a day (o.d) at 50 mg in subjects with moderate to severe active Crohn's Disease who have inadequate response, loss of response, or intolerance to prior amino-salicylates, immunosuppressant treatment, biologics, and/or corticosteroid treatment, and followed by a 4 weeks period of follow-up after the last study drug intake.

Detailed Description
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This Phase 2a study is a 16-week, double-blind, placebo-controlled, randomized study aiming at evaluating the safety and the efficacy of ABX464 given once a day (o.d) at 50 mg in subjects with moderate to severe active Crohn's Disease who have inadequate response, loss of response, or intolerance to prior amino-salicylates, immunosuppressant treatment, biologics, and/or corticosteroid treatment, and followed by a 4 weeks period of follow-up after the last study drug intake. Eligible patients will be randomized according to a 2/1 ratio in two different groups of treatment : ABX464 50mg OR placebo. After the treatment phase at week 16, all randomized patients willing to continue with the study treatment will have the possibility to enter a separate open-label study. In that case, patients will stop their participation after week 16, otherwise they will go through the 4 weeks follow-up period and the end of study visit will take place on week 20.

Official Title
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A Phase 2a, Randomized, Parallel-group, Double-blind, Placebo-controlled, Multicenter Study to Evaluate the Safety of ABX464 Compared With Placebo in Patients With Moderate to Severe Active Crohn's Disease Who Have Inadequate Response, Loss of Response, or Intolerance to Prior Amino-salicylates, Immunosuppressant Treatment, Biologics, and/or Corticosteroid Treatment

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: ABX464
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women age 18-75 years; Patients must have a documented diagnosis (endoscopic with histology) of CD for ≥ 3 months before screening; Patients must have active moderate to severe ileal, ileocolic, or colonic CD at baseline as defined by 220 ≤ CDAI > 450, Patients must have a SES-CD score > 6 (≥4 if isolated ileal disease) at screening, assessed by ileocolonoscopy and confirmed by a central reading. Patients must be willing and able to undergo endoscopy during screening after all other inclusion criteria have been met and at the end of Week 16. Patients must have had either a documented inadequate response, no response, a loss of response, or an intolerance (defined as the occurrence of at least one Adverse Reaction leading to treatment discontinuation) to either amino-salicylates, immunosuppressant treatment (i.e., azathioprine, 6-mercaptopurine, methotrexate, biologics (i.e. tumor necrosis factor inhibitors, vedolizumab, ustekinumab), and/or corticosteroid treatment. Patients should be able and willing to comply with study visits and procedures as per protocol; Patients should understand, sign and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures being performed; Patients should be affiliated to a social security regimen (for French sites only); Females and males receiving the study treatment and their partners must agree to use a highly effective contraceptive method during the study and for 3 months after end of study or early termination. Exclusion Criteria: Patients with indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis or clinical/histologic findings suggestive of ulcerative colitis; Patients with colonic dysplasia or neoplasia or adenomatous colonic polyp; Patients with presence of fistulae; Patients with current symptomatic diverticulitis or diverticulosis; Patients with obstructive colonic stricture/stenosis, past medical history of colonic resection, a history of bowel surgery within 6 months before screening, or who are likely to require surgery for CD during the treatment period; Patients with past medical history of clinically significant short bowel syndrome; Patients requiring parenteral nutrition; Patients with past medical history of bowel surgery resulting in an existing or current stoma; Patients with active infections at screening such as infected abdominal abscess, Clostridium difficile (stool antigen and toxin required), cytomegalovirus, tuberculous colitis and recent infectious hospitalization; Acute, chronic or history of clinically relevant pulmonary, cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable central nervous system pathology such as seizure disorder, angina or cardiac arrhythmias, or any other clinically significant medical problems as determined by physical examination and/or laboratory screening tests and/or medical history; Acute, chronic or history of immunodeficiency or autoimmune disease; History of malignancy excluding patients considered cure (5 years disease free survivors); Active malignancy that may require chemotherapy or radiation therapy; Serious illness requiring systemic treatment and/or hospitalization within 3 Weeks prior to baseline; Pregnant or breast-feeding woman; Illicit drug or alcohol abuse or dependence; Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, whichever is longer; Any condition, which in the opinion of the investigator, could compromise the patient's safety or adherence to the study protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Double-blind, placebo-controlled, randomized study
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABX464<br>50 mg | Drug: ABX464<br>* ABX464 is a new anti-inflammatory drug. In the treatment arm, patients will receive 50 mg of ABX464 orally once daily during 112 days.<br>|
| Placebo Comparator: Placebo<br>50 mg matching placebo | Drug: Placebo<br>* In the placebo group, patients will receive 50mg ABX464-matching-placebo orally once daily during 112 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events of ABX464 | Number and rates of treatment-emergent adverse events in the ABX464 treated patients versus placebo | Through study completion, an average of 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with a clinical response | Proportion of patients achieving at least a decrease of ≥100-point in Crohn's Disease Activity Index from baseline by treatment group. | from baseline, at week 8 and week 16 | 
| Proportion of patients with a clinical remission | Proportion of patients with clinical remission defined as a Crohn's Disease Activity Index below 150. | from baseline, at week 8 and week 16 | 
| Time to clinical response | Time to achieve a decrease of ≥100-point in Crohn's Disease Activity Index from baseline by treatment group. | from baseline, at week 8 and week 16 | 
| Time to clinical remission | Time to achieve a Crohn's Disease Activity Index below 150 from baseline, by treatment group. | from baseline, at week 8 and week 16 | 
| Evaluation of the effect of ABX464 50mg on Clinical Response and Remission assessed by 2-item Patient Reporting Outcome versus placebo; | Proportion of patients with Symptomatic Remission using the 2-item Patient Reporting Outcome by treatment group. (Symptomatic Remission is defined as: Stool frequency: (Weekly average over 7 days prior to visit) mean daily score ≤3; and abdominal pain: (Weekly average over 7 days prior to visit) mean daily score ≤1);) | from baseline, at week 8 and week 16 | 
| Proportion of patients with endoscopic response | Proportion of patients achieving at least a decrease of at least 50% in the Simple Endoscopic Score for Crohn's Disease | from screening, at week 16 | 
| Proportion of patients with endoscopic remission | Proportion of patients with endoscopic remission define as Simple Endoscopic Score for Crohn's Disease <=3 | from screening, at week 16 | 
| Evaluation of the effect of ABX464 on the histopathology of the Crohn's disease | Change from screening in the histopathology pattern of colon biopsies | from screening, at week 16 | 
| Proportion of patients with both clinical response and endoscopic response | Proportion of patients with both a decrease of ≥100-point in Crohn's Disease Activity Index from baseline AND an endoscopic response defined as a decrease of at least 50% in the Simple Endoscopic Score for Crohn's Disease by treatment group | from screening/baseline, at week 8 and week 16 | 
| Evaluation of the effect of ABX464 50mg on C-reactive protein levels and fecal calprotectin at week 8 and week 16 versus placebo; | Relative change to baseline in C-reactive protein levels and fecal calprotectin by treatment group | from baseline, at week 8 and week 16 | 
| Evaluation of the effect of ABX464 50mg on patients' quality of life measured by Inflammatory Bowel Disease Questionnaire | Scores and changes in the Inflammatory Bowel Disease Questionnaire. This questionnaire has been validated and consists in 32 items to describe 4 different types of symptoms/manifestations related to: digestive symptoms, systemic symptoms, emotional disorders, social function. Patients evaluate their quality of life with a 7-point Likert type answering system. The global score (from 32 to 224) is obtained by the sum of each individual item score. | from baseline, at week 8 and week 16 | 
| Evaluation of treatment-emergent serious adverse events | Incidence of treatment-emergent serious adverse events; | Through study completion, an average of 16 weeks | 
| Evaluation of adverse events leading to investigational product discontinuation | Incidence of adverse events leading to investigational product discontinuation | Through study completion, an average of 16 weeks | 
| Change from baseline of the micro RNA-124 expression in whole blood and in tissue in the ABX464 treatment group vs placebo; | Assessment of micro-RNA-124 expression in whole blood (PAXgene®) and in tissue (RNA later) in both group | baseline, week 16 | 
| Assessment of ABX464 pharmacokinetics and its main active metabolite N-Glu-ABX464 after oral administration of a 50 mg dose of ABX464 | Peak Plasma Concentration (Cmax) of ABX464 and its main metabolite N-Glu ABX464 at pre-dose and post-dose. | baseline, week 4, week 12, week 16, end of study visit (week 20) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inflammatory Bowel Disorders, ABX464