Investigate the safety and efficacy of study drug ABX464 compared with placebo in patients with moderate to severe ulcerative colitis who have failed to other treatments.

• Register: EUCTR
• Last refreshed on: 10 August 2021
• Main ID: EUCTR2018-003558-26-FR
• Date of registration: 08/02/2019
• Prospective Registration: Yes
• Primary sponsor: ABIVAX
• Public title: Investigate the safety and efficacy of study drug ABX464 compared with placebo in patients with moderate to severe ulcerative colitis who have failed to other treatments.
• Scientific title: 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-a] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment.
• Date of first enrolment: 10/12/2019
• Target sample size: 232
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-003558-26
• 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): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belarus, Belgium, Canada, Czech Republic, France, Germany, Hungary, Ireland, Italy, Netherlands, Poland, Serbia, Slovakia, Slovenia, Spain, Ukraine, United Kingdom

Contacts

• Name: Clinical Operations
• Affiliation: Abivax

• Name: Clinical Operations
• Affiliation: Abivax

Key inclusion & exclusion criteria

Inclusion criteria:
A patient will be eligible to participate in this study if ALL the following criteria are met:
? Men or women age 18-75 years;
? Diagnosis of moderate to severe active UC confirmed by endoscopy and histology at least 12Weeks prior to screening visit.Moderate to severe active UC defined by 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 to either immunosuppressant treatment,tumor necrosis factor [TNF] inhibitors,vedolizumab,JAK inhibitors and/or corticosteroid treatment.Inadequate response,no response,loss of response is defined as:
o Active disease or relapse in spite of thiopurines or methotrexate given at an appropriate dose for at least 3months (i.e. azathioprine 2–2.5 mg/kg/day or mercaptopurine 1–1.5 mg/kg/day in the absence of leukopenia),and/or
o Active disease despite corticosteroids treatment (prednisolone up to 0.75 mg/kg/day) over a period of 4weeks,and/or
o Active disease or relapse in spite of adequate treatment with tumor necrosis factor [TNF] inhibitors or vedolizumab,and/or
o Active disease or relapse in spite of adequate treatment with JAK inhibitors over a period of at least 6Weeks.
? 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 (=9mg/day) for at least 2Weeks prior to the screening visit;
?Topical corticosteroids and topical 5-aminosalicylic acid preparations must have been withdrawn at least 2Weeks prior to the screening visit;
?Patients who are on oral 5-aminosalicylic acid must have been on a stable dose for at least 4Weeks 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 4Weeks prior to screening visit.Patients taking methotrexate also are advised to take folic acid 1mg/day (or equivalent) supplementation if there is no contraindication;
?Patients on probiotics must be on stable doses for at least 2Weeks prior to the screening visit;
?Patients on antidiarrheals must be on stable doses for at least 2Weeks 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 4Weeks 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 3Weeks 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 within 28 days prior to baseline:
oHemoglobin >9.0 g dL-1;
oAbsolute neutrophil count =750 mm-3;
oPlatelets =100,000 mm-3;
oTotal serum creatinine =1.3 x ULN (upper limit of normal);
oCre
Exclusion criteria:
Patients who meet any of the following exclusion criteria will be excluded from the study:
? 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 known active infections at screening such as infected abdominal abscess, Clostridium difficile (stool antigen and toxin required), CMV, TB colitis 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;
? Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, whichever is longer, or patient who exceeds the maximal amount of indemnification allowed by the French law (i.e.: 4500€) ;
? Any condition, which in the opinion of the investigator, could compromise the patient's safety or adherence to the study protocol.


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

Health Condition(s) or Problem(s) studied

Moderate to Severe Ulcerative Colitis
MedDRA version: 20.1 Level: LLT Classification code 10066678 Term: Acute ulcerative colitis System Organ Class: 100000004856

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

Intervention(s)

Product Code: ABX464
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ABX464
Current Sponsor code: ABX464
Other descriptive name: ABX464
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Code: ABX464
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: ABX464
Current Sponsor code: ABX464
Other descriptive name: ABX464
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: ? To evaluate the global effect of ABX464 on MMS at W8 and W16 and on partial Modified Mayo Score (MMS) at every study visit vs placebo.
To evaluate the effect of the different dose groups of ABX464 vs placebo:
? on MMS at W16 and on partial MMS at every study visit.
? on clinical remission at W8 and at W16
? on clinical response at W8 and at W16
? on endoscopic improvement/remission by segment at W8 and W16
? on stool and rectal bleeding frequency at every study visit
? on fecal calprotectin and CRP levels at W8 and W16
? on miR-124 expression in tissue at W8 and W16 and in total blood at every timepoint
? on the rectal/sigmoidal infiltrates using the Robarts Histopathology Index,the Geboes and Nancy Histology Scoring Scales at W8 and W16
? on Quality of Life measured by the IBDQ at W8 and W16
? on IL-6,TNFa,IL-1b, IL-10 plasma concentrations at every timepoint
? its safety profile
? To assess the pharmacokinetics of the ABX464 and its main active metabolite ABX464-N-Glu

Main Objective: The primary objective of the study is to determine an optimal ABX464 dose to be used in moderate to severe active ulcerative colitis patients who have failed or are intolerant to immunomodulators, Anti-TNFa, vedolizumab, JAK inhibitors and/or corticosteroids by comparing the mean change from baseline in the MMS at week 8 between each ABX464 group and placebo.

Primary end point(s): Reduction from baseline in Modified Mayo Score at Week 8.

Timepoint(s) of evaluation of this end point: At Week 8

Secondary Outcome(s)

Secondary end point(s): ? Number and rate of patients in clinical remission at the end of Week 8, per each intervention/treatment group. Clinical remission, based on the Mayo Scoring system, is defined as a rectal bleeding sub-score = 0 and an Endoscopy sub-score =1 (excluding friability) and at least one-point decrease in stool frequency sub score from baseline to achieve a stool frequency sub-score =1
? Combined number and rate of patients in clinical remission at Week 8 and at Week 16, per each intervention/treatment group.
? Number and rate of patients with clinical response at Week 8 and Week 16 per intervention/treatment group. 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.
? Number and rate of patients with endoscopic improvement, by segment, and number and rate of patients with endoscopic remission, by segment, at Week 8 and at Week 16 (if available) per intervention/treatment group. Endoscopic improvement is defined as a Mayo endoscopic sub score of =1 (excluding friability) and endoscopic remission defined as sub score of 0.
? Reduction relative to baseline in stool and rectal bleeding frequency at every study visit by ABX464 dose group and versus placebo.
? Reduction relative to baseline in partial Modified Mayo Score at every study visit and Modified Mayo Score at Week 16 (if available) by ABX464 dose group and versus placebo.
? Reduction relative to baseline in fecal calprotectin and CRP levels at Week 8 and Week 16 by intervention/treatment group.
? Change relative to baseline in miRNA-124 expression in rectal/sigmoidal biopsies at Week 8 and Week 16 and in total blood at every timepoints by intervention/treatment group.
? The scores and changes from baseline in IBDQ at Week 8 and Week 16 per intervention treatment group.
? Reduction relative to baseline of infiltrate/histopathology (rectal/sigmoidal biopsies) using the Robarts Histopathology Index (RHI), the Geboes and Nancy Histology Scoring Scales at Week 8 and Week 16 (if available) per intervention/treatment group.
? Change relative to baseline in IL-6, TNFa, IL-1b, IL-10 plasma concentrations at every timepoints by intervention/treatment group.
? Serum concentration of ABX464 and N-Glu ABX464 according to dose group.
? Number and rate of all adverse events, causally-related adverse events, all SAE and causally-related SAEs classified by severity per intervention/treatment group.
? Incidence of treatment-emergent serious adverse event per intervention/treatment group.
? Incidence of adverse events leading to investigational product discontinuation per intervention/treatment group.
? The number of clinically-significant laboratory abnormalities per intervention/treatment group.

Timepoint(s) of evaluation of this end point: 1. at the end of Week 8, per each intervention/treatment group
2. at Week 8 and at Week 16, per each intervention/treatment group
3. at Week 8 and at Week 16, per each intervention/treatment group
4. at Week 8 and at Week 16 (if available) per intervention/treatment group
5. at every study visit by ABX464 dose group and versus placebo
6. at Week 16 (if available) by ABX464 dose group and versus placebo
7. at Week 8 and Week 16 by intervention/treatment group
8. in rectal/sigmoidal biopsies at Week 8 and Week 16 and in total blood at every timepoints by intervention/treatment group
9. at Week 8 and Week 16
10. at Week 8 and Week 16 (if available)
11. at every timepoints
12. through the study
13. through the study
14.through the study
15.through the study
16.through the study

Secondary ID(s)

ABX464-103

Source(s) of Monetary Support

ABIVAX

Ethics review

Status: Approved
Approval date: 10/12/2019
Contact: