|E.1 Medical condition or disease under investigation
|Medical condition(s) being investigated
|Moderate to Severe Ulcerative Colitis
|Medical condition in easily understood language
|In Ulcerative Colitis the lining of the colon becomes inflamed and develops tiny open sores that produce pus and mucous.This causes abdominal discomfort and frequent emptying of the colon (diarrhoea).
|Diseases [C] - Digestive System Diseases [C06]
|E.1.2 Medical condition or disease under investigation
|Acute ulcerative colitis
|System Organ Class
|Condition being studied is a rare disease
|E.2 Objective of the trial
|Main objective of the trial
|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-TNFα, 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.
|Secondary objectives of the trial
|▪ 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,TNFα,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
|Trial contains a sub-study
|Principal 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);
oCreatinine clearance >50 mL min-1 by the Cockcroft-Gault equation within 60 days prior to baseline;
oTotal serum bilirubin <1.5 x ULN;
oAlkaline 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 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.In each case of delayed menstrual period (over 1 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.Male should use condoms and should'nt donate sperm as long as contraception is required
|Principal 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.
|E.5 End points
|Primary end point(s)
|Reduction from baseline in Modified Mayo Score at Week 8.
|Timepoint(s) of evaluation of this end point
|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, TNFα, 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
|E.6 and E.7 Scope of the trial
|Scope of the trial
|Trial type and phase
|Human pharmacology (Phase I)
|First administration to humans
|Other trial type description
|Therapeutic exploratory (Phase II)
|Therapeutic confirmatory (Phase III)
|Therapeutic use (Phase IV)
|E.8 Design of the trial
| Comparator of controlled trial
|Other medicinal product(s)
|Number of treatment arms in the trial
The trial involves single site in the Member State concerned
| The trial involves multiple sites in the Member State concerned
|Number of sites anticipated in Member State concerned
|The trial involves multiple Member States
|Number of sites anticipated in the EEA
|E.8.6 Trial involving sites outside the EEA
|Trial being conducted both within and outside the EEA
|Trial being conducted completely outside of the EEA
|If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
|Trial has a data monitoring committee
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|E.8.9 Initial estimate of the duration of the trial
|In the Member State concerned years
|In the Member State concerned months
|In the Member State concerned days
|In all countries concerned by the trial years
|In all countries concerned by the trial months