Dose-Ranging Phase 2b Study of ABX464 in Moderate to Severe Ulcerative Colitis

Study Overview
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Brief Summary
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Phase IIb study to evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in patients with moderate to severe Ulcerative Colitis.

Detailed Description
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This phase IIb study will evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in improving Modified Mayo Score (MMS) in patients with moderate to severe Ulcerative Colitis who have inadequate response, loss of response, or intolerance with at least one of the following agents: immunosuppressant treatment (i.e. azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor alpha [TNF-α] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment . Eligible patients will be randomized into 4 parallel intervention/treatment groups: 25mg q.d of ABX464, 50mg q.d of ABX464, 100mg q.d of ABX464, or matching placebo and will be treated for 16 weeks.

Official Title
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A Randomized, Double Blind, Placebo Controlled, Parallel Group, Multiple Dose, Induction Study to Evaluate the Safety, Tolerability and Optimal Dose of ABX464 Compared With Placebo in Patients With Moderate to Severe Ulcerative Colitis Who Have Inadequate Response, Loss of Response, or Intolerance With at Least One of the Following Agents: Immunosuppressant Treatment (i.e. Azathioprine, 6-mercaptopurine, Methotrexate), Tumor Necrosis Factor Alpha [TNF-α] Inhibitors, Vedolizumab, JAK Inhibitors and/or Corticosteroid Treatment

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: ABX464 25mg
* Drug: ABX464 50mg
* Drug: ABX464 100mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women age 18 - 75 years; Diagnosis of moderate to severe active UC (including ulcerative proctitis if proximal extension of disease occurs beyond 10 cm) confirmed by endoscopy and histology at least 12 Weeks prior to screening visit. Moderate to severe active UC defined by Modified Mayo Score (MMS) of 5 to 9 inclusive (on a scale of 0-9). Moderate to severe active UC should be confirmed at screening visit with a centrally read endoscopy sub-score of at least 2 (on a scale of 0-3); Patients having 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 immunosuppressant treatment (i.e., azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor [TNF] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment. Inadequate response, no response, loss of response is defined as: i. Active disease or relapse in spite of thiopurines or methotrexate given at an appropriate dose for at least 3 months (i.e. azathioprine 2-2.5 mg/kg/day or mercaptopurine 1-1.5 mg/kg/day in the absence of leukopenia), and/or ii. Active disease despite corticosteroids treatment (prednisolone up to 0.75 mg/kg/day) over a period of 4 Weeks, and/or iii. Active disease or relapse in spite of adequate treatment (as defined in the SmPC) with tumor necrosis factor [TNF] inhibitors or vedolizumab, and/or iv. Active disease or relapse in spite of adequate treatment with JAK inhibitors over a period of at least 6 Weeks. Patients receiving oral corticosteroids must have been on a stable dose of prednisone or prednisone equivalent (≤20 mg/day) or on beclomethasone diproprionate (≤5mg/day) or on budesonide MMX (≤9 mg/day) for at least 2 Weeks prior to the screening visit; Topical corticosteroids and topical 5-aminosalicylic acid preparations must have been withdrawn at least 2 Weeks prior to the screening visit; Patients who are on oral 5-aminosalicylic acid must have been on a stable dose for at least 4 Weeks prior to the screening visit; Patients who are receiving immunosuppressants in the form of azathioprine, 6-mercaptopurine, or methotrexate needed to be on a stable dose for at least 4 Weeks prior to screening visit. Patients taking methotrexate also are advised to take folic acid 1 mg/day (or equivalent) supplementation if there is no contraindication; Patients on probiotics (e.g., Culturelle® [Lactobacillus GG, i-Health, Inc.], Saccharomyces boulardii) must be on stable doses for at least 2 Weeks prior to the screening visit; Patients on antidiarrheals (e.g., loperamide, diphenoxylate with atropine) must be on stable doses for at least 2 Weeks prior to the screening visit; Patients who have received tumor necrosis factor [TNF] inhibitors, vedolizumab or other biologics must have discontinued therapy at least 8 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance; Patients previously treated with cyclosporine, tacrolimus or JAK inhibitors must have discontinued therapy at least 4 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance; Patients previously treated with tube feeding, defined formula diets, or parenteral alimentation/nutrition must have discontinued treatment 3 Weeks before the screening visit and must be able to take, orally, appropriate amount of food (calories) and liquids to maintain body weight; Patients with surveillance colonoscopy defined as per ECCO guidelines; Patients with the following hematological and biochemical laboratory parameters obtained at screening: i. Hemoglobin > 9.0 g dL-1; ii. Absolute neutrophil count ≥ 750 mm-3; iii. Platelets ≥ 100,000 mm-3; iv. Total serum creatinine ≤ 1.3 x ULN (upper limit of normal); v. Creatinine clearance > 90 mL min-1 by the Cockcroft-Gault equation within 60 days prior to baseline; vi. Total serum bilirubin < 1.5 x ULN; vii. Alkaline phosphatase, AST (SGOT) and ALT (SGPT) < 2 x ULN; Patients are 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 are performed; Patients should be affiliated to a social security regimen (for French sites only); Females and males receiving the study treatment (potentially in combination with immunosuppressant) and their partners must agree to use a highly effective contraceptive method during the study and for 6 months after end of study or early termination. Contraception should be in place at least 2 Weeks prior to study participation. Women must be surgically sterile or if of childbearing potential must use a highly effective contraceptive method. Women of childbearing potential (WOCBP) will enter the study after confirmed menstrual period and a negative pregnancy test. Highly effective methods of contraception include true abstinence, intrauterine device (IUD) or hormonal contraception aiming at inhibition of ovulation, intrauterine hormone releasing system, bilateral tubal ligation, vasectomized partner. True abstinence is defined when this is in line with the preferred and usual lifestyle of the patient. In each case of delayed menstrual period (over one month between menstruations) confirmation of absence of pregnancy is required. This recommendation also applies to WOCBP with an infrequent or irregular menstrual cycle. Female and male patients must not be planning pregnancy during the trial and for 6 months post completion of their participation in the trial. In addition, male participants should use condoms and not donate sperm as long as contraception is required. Exclusion Criteria: Patients with Crohn's Disease (CD) or presence or history of fistula, indeterminate colitis (IC), infectious/ischemic colitis or microscopic colitis (lymphocytic and collagenous colitis); History of toxic megacolon, abdominal abscess, symptomatic colonic stricture or stoma; history or imminent colectomy, colonic malignancy; History or current evidence of colonic dysplasia or adenomatous colonic polyps. Patient with severe gastrointestinal complications; e.g., short bowel syndromes, recent or planned bowel surgery, Ileostomy and/or colostomy, recent bowel perforation; History of more than one episode of herpes zoster or a history (single episode) of disseminated zoster; Patients with active infections at screening such as infected abdominal abscess, Clostridium difficile (stool antigen and toxin required), CMV (positive IgM), TB and recent infectious hospitalization; Patients previously treated with ABX464; Acute, chronic or history of clinically relevant pulmonary, cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable CNS pathology such as seizure disorder, angina or cardiac arrhythmias, active malignancy 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 cured (5 years disease free survivors); Serious illness requiring systemic treatment and/or hospitalization within 3 Weeks prior to baseline; Pregnant or breast-feeding women; Illicit drug or alcohol abuse or dependence; Patients who received live vaccine 30 days or fewer before first dose of study treatment and/or who's planning to receive such a vaccine during the study duration; Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, whichever is longer and during the study; 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: Randomized, double blind, placebo controlled, parallel groups
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABX464<br>ABX464 will be administrated orally (Capsules) and daily for 16 weeks | Drug: ABX464 25mg<br>* ABX464 25mg (One capsule of ABX464 25 mg + One capsule of placebo) once daily for 16 weeks<br>Drug: ABX464 50mg<br>* ABX464 50mg (One capsule of ABX464 50 mg + One capsule of placebo) once daily for 16 weeks<br>Drug: ABX464 100mg<br>* ABX464 100mg (two capsules of ABX464 50 mg) once daily for 16 weeks<br>|
| Placebo Comparator: Matching Placebo<br>Matching placebo will be adminstrated orally (Capsules) and daily for 16 weeks | Drug: Placebo<br>* Two capsules of placebo once daily for 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Mayo Score | Reduction from baseline in Modified Mayo Score | Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical remission | Clinical remission, based on the Mayo Scoring system, is defined as stool frequency subscore = 0 or 1 and rectal bleeding subscore = 0 and endoscopy subscore = 0 or 1 (modified to exclude friability). | Week 8 and Week 16 | 
| Clinical response | Clinical Response is defined as a reduction in Mayo Score of at least 2 points and greater than or equal to 30 percent from baseline with an accompanying decrease in rectal bleeding sub-score of greater than or equal to 1 point or absolute rectal bleeding sub-score of less than or equal to 1 point. | Week 8 and Week 16 | 
| Endoscopic Improvement | Endoscopic improvement is defined as a Mayo endoscopic sub score of ≤1 (excluding friability) | Week 8 and Week 16 | 
| Mucosal healing | Mucosal healing is defined as both endoscopic remission and histological remission (Geboes score < 2.0). | Week 8 and Week 16 | 
| Stool and rectal bleeding frequency | Assessment of Reduction relative to baseline in stool and rectal bleeding frequency | Every visit | 
| Partial Modified Mayo Score | Change from baseline | Every visit | 
| Modified Mayo Score | Change from baseline | Week 16 | 
| Fecal calprotectin | Reduction from baseline in fecal calproctectin | Week 8 and Week 16 | 
| C Reactive Protein | Reduction from baseline in CRP | Week 8 and Week 16 | 
| miR-124 expression | Increase in miR-124 expression in Total Blood and rectal tissue | Week 8 and Week 16 | 
| IBDQ | Scores and changes from baseline i | Week 8 and Week 16 | 
| Inflammatory Infiltrate | Inflammatory Infiltrate assessment in rectal/colon biopsies | Week 8 and Week 16 | 
| IL-6, TNFα, IL-1b, IL-10 plasma concentrations | Change relative to baseline | Every visit | 
| ABX464 and ABX464-N-Glu | Serum concentration | Every visit (Except D57) | 
| Endoscopy Remission | Mayo endoscopic sub score of 0 | Week 8 and Week 16 | 
| Number and rate of all adverse events, causally-related adverse events, SAE and causally-related SAEs classified by severity |  | Every visit | 
| Incidence of treatment-emergent serious adverse event |  | Every visit | 
| Incidence of adverse events leading to investigational medicinal product discontinuation |  | Every visit | 
| Number of clinically-significant laboratory abnormalities |  | Every visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ABX464, Refractory patients, Phase 2b, Dose Ranging