| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to Severe Ulcerative Colitis |
| Mérsékelten súlyos és súlyos colitis ulcerosa |
|
| E.1.1.1 | 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). |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066678 |
| E.1.2 | Term | Acute ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | 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. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the global effect of ABX464 on MMS at Week (W) 8 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 mucosal healing, 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 RHI, 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 PK of the ABX464 and its main active metabolite ABX464- N-Glu |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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 inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment. Inadequate response, no response, loss of response is defined as:
oActive 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
oActive disease despite corticosteroids treatment (prednisolone up to 0.75 mg/kg/day) over a period of 4 Weeks, and/or
oActive disease or relapse in spite of adequate treatment with tumor necrosis factor inhibitors or vedolizumab, and/or
oActive 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 (≤9mg/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 must be on stable doses for at least 2 Weeks
prior to the screening visit;
▪Patients on antidiarrheals must be on stable doses for at least 2 Weeks prior to the screening visit;
▪Patients who have received tumor necrosis factor 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:
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 > 90 mL min-1 by the Cockcroft-Gault equation within 60 days prior to baseline;
o Total serum bilirubin < 1.5 x ULN;
o 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 ICF 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 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. Male should use condoms
and not donate sperm as long as contraception is required. |
|
| E.4 | 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 active infections at screening such as infected abdominal
abscess, Clostridium difficile (stool antigen and toxin required), CMV
[(positive immunoglobulin M (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;
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▪ 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Reduction from baseline in Modified Mayo Score at Week 8. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
▪ Number and rate of patients in clinical remission at Week 8, per each
intervention/treatment group. 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).
▪ 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.
▪Number and rate of patients with mucosal healing. Mucosal healing is
defined as both endoscopic remission and histological remission (Geboes
score < 2.0).
▪ Number and rate of patients with endoscopic improvement.
▪ 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 medicinal
product discontinuation per intervention/treatment group.
▪ The number of clinically-significant laboratory abnormalities per
intervention/treatment group. |
|
| E.5.2.1 | 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 W8 and at W16 (if available) per intervention/treatment group
5. at W8 and at W6
6.at W8 and at W16
7.at every study visit by ABX464 dose group and versus placebo
8. at W16 (if available) by ABX464 dose group and versus placebo
9. at W8 and W16 by intervention/treatment group
10. in rectal/sigmoidal biopsies at W8 and W16 and in total blood at
every timepoints by intervention/treatment group
11. at W8 and W16
12. at W8 and W16 (if available)
13. at every timepoints
14. through the study
15. through the study
16.through the study
17.through the study
18.through the study |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 140 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belarus |
| Belgium |
| Canada |
| Czechia |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Serbia |
| Slovakia |
| Slovenia |
| Spain |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
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 |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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