Efficacy and Safety Study of ABX464 as Maintenance Therapy in Patients With Moderate to Severe Ulcerative Colitis

Study Overview
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Brief Summary
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A phase 2b study to evaluate the long-term efficacy and safety study of ABX464 50mg as maintenance therapy in patients with moderate to severe Ulcerative Colitis.

Detailed Description
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This study is an open-label study aiming at evaluating the long-term safety and the efficacy profile of ABX464 given once a day (o.d) at 50 mg in subjects who have been previously enrolled in the ABX464-103 clinical study (induction study) and who are willing to continue their treatment. All subjects will receive ABX464 given at 50mg o.d regardless of their previous treatment and dose received in the ABX464-103 study (i.e. ABX464 100mg, ABX464 50mg, ABX464 25mg or Placebo). The enrolment in this follow-up study will be based on the willingness of the subject to carry on his/her participation. Subjects will be treated with ABX464 for an overall period of 48 weeks. Subjects will be followed up on a monthly basis.

Official Title
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A Phase 2b, Open-label, Efficacy and Safety Study of ABX464 as Maintenance Therapy in Patients With Moderate to Severe Ulcerative Colitis

Conditions
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Ulcerative Colitis

Intervention / Treatment
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* Drug: ABX464


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have completed the 16-week induction treatment period (ABX464-103); 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 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 (180 days) after end of study or early termination. Contraception should be in place at least 2 weeks prior to screening. Women must be surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy) or in the postmenopausal state (no menses for 12 months without an alternative medical cause) 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 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 patients should use condom during the trial and for 6 months (180 days) post completion of their participation in the study. Male patients must not donate sperm as long as contraception is required. Criteria that should be met by patients at week 48 to be eligible for 48 additional weeks of study treatment. Patients should be in clinical response. Clinical response is defined as: a reduction in Modified Mayo Score ≥ 2 points and ≥ 30 % from baseline (induction) with an accompanying decrease in rectal bleeding sub-score ≥ 1 point or absolute rectal bleeding sub-score ≤ 1 point. Patients able and willing to continue the study treatment and who are compliant with study visits and procedures and who signed the update of the written voluntary informed consent. Exclusion Criteria: Patients who had major protocol deviation(s) in the induction study; Patients who permanently discontinued study the treatment in induction study (ABX464-103) because of an adverse event (AE) regardless of relatedness to investigational product; Patients who have developed any major illness/condition or evidence of an unstable clinical condition (except UC) that, in the investigator's judgment, will substantially increase the risk to the participant if he or she participates in the study; Patients with any other severe acute or chronic medical or psychiatric condition or laboratory or electrocardiogram (ECG) abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study; Patients who are participating or plan to participate in other investigational studies (other than induction study) during the study.

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
Intervention Model: Single Group Assignment
Interventional Model Description: open-label, follow-up study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ABX464 50mg<br>All subjects will receive ABX464 administered at 50 mg o.d for an overall period of 96 weeks. | Drug: ABX464<br>* ABX464 All subjects will receive ABX464 administered at 50 mg o.d for an overall period of 96 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with clinical remission at week 48 compared to baseline of induction study (ABX464-103) | 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 1-point decrease in stool frequency sub-score from baseline to achieve a stool frequency sub-score ≤1 | week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Modified Mayo Score and in partial Modified Mayo Score | Change in Modified Mayo Score at weeks 48 and 96 and in partial Modified Mayo Score at every study visit among all patients. Modified Mayo Score evaluates ulcerative colitis stage, based on four parameters: stool frequency, rectal bleeding, endoscopic evaluation and Physician's global assessment. Each parameter of the score ranges from zero (normal or inactive disease) to 3 (severe activity). Partial Mayo score uses the 3 non-invasive components of the full Mayo Score (stool frequency, rectal bleeding and Physician's global assessment) and excludes the score for the endoscopic findings. Therefore the maximum score is reduced from 12 to 9 points. | From baseline to week 96 | 
| Endoscopic changes at week 48 | Proportion of patients with endoscopic changes by segment at week 48 among all patients. Endoscopic improvement is defined as a Mayo endoscopic sub score of ≤1 (excluding friability). Endoscopic remission is defined as a Mayo endoscopic sub score of 0. | weeks 48 and 96 | 
| Sustained endoscopic changes at week 48 | Proportion of patients with sustained endoscopic changes at week 48 and 96. Sustained endoscopic changes is defined as the number of patients with endoscopic changes at week 48 among patients who had endoscopic changes during the Induction study (at week 8 or week 16 of study ABX464-103). | weeks 48 and 96 | 
| Glucocorticoid-free clinical remission | Proportion of patients with glucocorticoid-free clinical remission at week 48. Glucocorticoid-free clinical remission is defined as clinical remission in addition to not requiring any treatment with glucocorticoids for at least 8 weeks prior to week 48. | From baseline to week 48 | 
| Rectal bleeding | Change to baseline in stool and rectal bleeding frequency at every study visit. | from baseline to week 96 | 
| Fecal calprotectin and C-Reactive Proteine | Change to baseline in fecal calprotectin and C-Reactive Proteine levels at week 24, 48, 60, 72, 84 and 96. | baseline, week 24, week 48 | 
| Clinical response at week 48 | Proportion of patients with clinical response at week 48 and 96. Clinical response is defined as: a reduction in Mayo Score ≥ 3 points and ≥ 30 % from baseline with an accompanying decrease in rectal bleeding sub-score ≥ 1 point or absolute rectal bleeding sub-score ≤ 1 point. | baseline, weeks 48 and 96 | 
| miRNA-124 expression | Change relative to baseline in miRNA-124 expression in rectal/sigmoidal biopsies at week 48 and in total blood at week 24 and week 48. | baseline, week 24 and week 48 | 
| Inflammatory Bowel Disease Questionnaire | This questionnaire is a validated and reliable tool to measure health-related quality of life in adult patients with inflammatory bowel disease, ulcerative colitis, or Crohn's disease. It contains 32 questions, which are divided into four health domains: bowel symptoms (10 questions), systemic symptoms (5 questions), emotional function (12 questions), and social function (5 questions). For each question there are graded responses on a 7-point Likert scale, ranging from 1 (representing the worst aspect) to 7 (representing the best aspect). Thus, the total IBDQ score ranges from 32 to 224, with higher scores reflecting better well-being. For study purpose, scores and changes in the Inflammatory Bowel Disease Questionnaire domains will be collected and compared from baseline to week 24 and 48. | baseline, week 24, week 48 | 
| Histopathological evaluation of the effect of ABX464 50 mg on the rectal/sigmoidal infiltrate based on Gebeos score | Week 48 biopsies will be compared to biopsies taken during the induction study (ABX464-103) to assess the disease evolution at a tissue level, based on the Geboes Score. The scoring system is composed of 6 major grades that assess the structural changes (0), chronic inflammation (1), lamina propria neutrophils (2), neutrophils in the epithelium (3), crypt destruction (4) and erosion and ulcers (5). | week 48 | 
| Histopathological evaluation of the effect of ABX464 50 mg on the rectal/sigmoidal infiltrate based on Nancy index scoring system | Week 48 biopsies will be compared to biopsies taken during the induction study (ABX464-103) to assess the disease evolution at a tissue level, based on Nancy index scoring system. It is a 5-level classification from 0 (absence of significant histological disease) to 4 (severely active disease). Classification in each category depends on the presence or absence of ulceration, acute inflammatory cells infiltrate and chronic inflammatory cells infiltrate. | week 48 | 
| Histopathological evaluation of the effect of ABX464 50 mg on the rectal/sigmoidal infiltrate based on the Robarts Histological index | Week 48 biopsies will be compared to biopsies taken during the induction study (ABX464-103) to assess the disease evolution at a tissue level, based on the Robarts Histological Index. The score ranges from 0 (no disease activity) to 33 (severe disease activity) is based on evaluation of 4 parameters: chronic inflammatory infiltrate, lamina propria neutrophils and eosinophils, neutrophils in the epithelium and erosion and ulceration. | week 48 | 
| Incidence and description of Adverse Events | Number and rate of all adverse events, causally-related adverse events, all serious adverse events and causally-related serious adverse events classified by severity. Incidence of treatment-emergent serious adverse events, hospitalizations, total inpatient days. Incidence of adverse events leading to investigational product discontinuation. Number of clinically significant laboratory abnormalities. | From baseline to week 52 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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moderate to severe ulcerative colitis