ABTECT-2 - ABX464 Treatment Evaluation for ulcerative Colitis Therapy - 2

JRCT ID: jRCT2031230081

Registered date:20/05/2023

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Ulcerative colitis
• Date of first enrollment: 08/05/2023
• Target sample size: 90
• Countries of recruitment: Argentina,Japan,Belgium,Japan,Bosnia,Japan,Brazil,Japan,Bulgaria,Japan,Canada,Japan,Croatia,Japan,Czech Republic,Japan,France,Japan,Germany,Japan,Greece,Japan,Hungary,Japan,India,Japan,Ireland,Japan,Israel,Japan,Italy,Japan,Lithuania,Japan,Mexico,Japan,New Zealand,Japan,Poland,Japan,Romania,Japan,Serbia,Japan,Slovenia,Japan,Spain,Japan,Taiwan,Japan,United Kingdom,Japan,United States,Japan
• Study type: Interventional

Intervention(s)

This is a multicenter, randomized, placebo controlled study to evaluate the efficacy and safety of ABX464 given at 25 or 50 mg QD in inducing clinical remission in subjects with moderately to severely active UC who have inadequate response, no response, a loss of response, or an intolerance to either conventional therapies [corticosteroids, immunosuppressant (i.e. azathioprine, 6-mercaptopurine*, methotrexate*)] and/or advanced therapies [biologics (TNF inhibitors, anti-integrins, anti-IL-23), and/or S1P receptor modulators*, and/or JAK inhibitors] (* not approved in Japan).
As shown below, this study consists of a screening period of up to 28 days, an 8-week induction period followed by 28-day follow up period. Subjects who complete the 8-week induction will be given the opportunity to take part in the maintenance study (i.e. ABX464-107) either:
-In the randomized double-blind placebo-controlled study part [part 1; placebo, 25 mg, 50 mg] for clinical responders at week 8.
-In the randomized open label arms study part [part 2; 25 mg or 50 mg] for non-clinical responders at week 8.
Approximately 612 subjects, aged at least 16 years, will be randomized in this study.
On Day 1, eligible subjects will be randomized and allocated into three treatment arms according to ratio 1:1:2 as follows:
-Placebo: 153 subjects
-ABX464 - Daily dose 25 mg QD: 153 subjects
-ABX464 - Daily dose 50 mg QD: 306 subjects

Randomization will be stratified according to the following factors:
-Subjects with inadequate response to advanced therapies [AT-IR subjects] (no response, loss of response or intolerance to biologics, S1P receptor modulators, JAK inhibitors) (Yes/No)
-Subjects with concomitant corticosteroids at baseline (Yes/No)
-Japanese subjects or non- Japanese subjects
Approximately 60% of the enrolled population should be subjects with inadequate response to Advanced Therapies (biologics, S1P receptor modulators, JAK inhibitors). In addition, percentage of subjects who have failed to JAK inhibitors should be limited to 15% of subjects with inadequate response to Advanced Therapies.
Subjects with previous exposure to Advanced Therapies without a documented inadequate response will be considered as non-AT-IR subjects.
Following Day 1 (randomization day), subjects will come at the investigational site at Day 28 (Week 4) and Day 56 (Week 8) according to the study schedule of assessments.
At Day 56, subjects will be given the choice to either take part in the maintenance study (ABX464 107) or to end their participation in the present induction study by completing the study. For the latter option, subjects will return for an end of study visit 28 days after the last study drug intake. However, subjects who are eligible for the maintenance study should be encouraged to enter the maintenance study.
Subjects will be evaluated for safety and efficacy throughout the induction study.
During the screening period, a full colonoscopy will be performed for all subjects. At week 8, a flexible sigmoidoscopy is only required. At screening and week 8, during both endoscopic procedures, biopsies at the most severely affected area will be performed. Endoscopies will be centrally read. Sigmoidoscopy might be substituted by a full colonoscopy if requested by national medical practices or in case of proximal disease involvement. Biopsies will be centrally analyzed.
e-Diaries will be used to collect stool frequency, rectal bleedings, nocturnal bowel movements, bowel urgency and fatigue NRS on a daily basis, as well as the study drug intake time.
PK samples will be collected in all subjects. Subjects will be allocated into two different groups via IWRS. At each time point collection (D1, D28, D56) samples will be taken as follows:
-for group 1: pre-dose, 0.5, 1.5, 3 h (and 6 h and/or 10 h if possible) post-dose
-for group 2: pre-dose, 1, 2, 4 h (and 8 h and/or 12 h if possible) post-dose
A time window of +- 10 minutes is allowed for each time point collection for both groups.
In addition, a cardiac safety sub-study consisting in a cardiac ultrasound performed at baseline and Week 8 (and potentially over the maintenance study if the subject takes part) will be performed in selected sites with appropriate equipment and resources. Echocardiograms will be centrally read and reviewed by an Independent Cardiovascular Safety Committee in case of relevant findings. 70 subjects or more per treatment arm (coming from both induction studies) should be part of the sub-study cardiac assessment. In addition, cardiac biomarkers will be tested through induction study in all participants.

Outcome(s)

Primary Outcome

The primary objective is to compare the efficacy of ABX464 versus placebo on clinical remission.
oProportion of subjects who achieve clinical remission per Modified Mayo Score at week 8.

Key inclusion & exclusion criteria

• Age minimum: >= 16age old
• Age maximum: Not applicable
• Gender: Both

Include criteria

1.Men or women at least 16 years old. To be eligible, adolescent subjects must weight >= 40 kg and meet the definition of Tanner Stage 5 at the screening visit.
2.Subjects must understand, sign and date the written voluntary informed consent form at the visit prior to any protocol-specific procedures. For under-aged subjects, national requirements regarding consent should also be met.
3.Documented diagnosis of UC confirmed by endoscopy and histology. Should histology results not be available at screening, results from biopsies taken at screening may be used.
4.Active disease defined by modified Mayo score (MMS) >= 5 with rectal bleeding subscore (RBS) >= 1 and endoscopy subscore (MES) of 2 or 3 (confirmed by central reader).
5.Subjects with documented inadequate response (defined as lack of response or loss of response or intolerance) to at least one of the following treatments: corticosteroids, immunosuppressant, biologic therapies, S1P receptor modulators* and/or JAK inhibitors and/or new drugs approved during the study (note: failure to only 5-ASA is not accepted).
a.Inadequate response to corticosteroids (CS) is defined as either a CS resistance (i.e., signs and symptoms of persistently active disease despite current or prior course of oral prednisone/prednisolone >= 40 mg/day for at least 2 weeks (For Japan: >= 30 mg/day for at least 2 weeks for moderate UC or >= 40 mg/day for at least 1 week for severe UC), or to budesonide >= 9 mg/day for at least 2 weeks, or to beclomethasone** >= 5 mg/day for at least 2 weeks) or a CS dependence (i.e., failure to taper to <=10 mg/day of prednisone/prednisolone, < 9 mg/day of budesonide or < 5 mg/day of beclomethasone** or relapse occurring within 3 months after stopping CS).
Intolerance to CS includes (but not limited to) Cushing's syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, infection.
b.Inadequate response to immunosuppressants is defined as signs and symptoms of persistently active disease despite azathioprine treatment at 1.5 to 2.5 mg/kg/day (For Japan: 1 to 2 mg/kg/day or 50 to 100 mg/day) for at least 8 weeks, 6-mercaptopurine** 0.5 to 1.5 mg/kg/day (For Japan: 30 to 50 mg/day) for at least 8 weeks, or methotrexate** 12.5 mg to 15 mg/week for at least 8 weeks, cyclosporine** 2 to 4 mg/kg/day for at least 2 weeks or physician's discretion, or tacrolimus at documented trough level of 5 to 10 ng/mL for at least 2 weeks or physician's discretion.
Intolerance to immunosuppressant includes (but not limited to) nausea/vomiting, abdominal pain, pancreatitis, liver enzyme abnormalities, lymphopenia, infection.
c.Inadequate response to biologics is defined as:
-Primary non responders to full induction course as in the USPI/SmPC of the following:
-infliximab or biosimilars (>= 5 mg/kg intravenously at 0, 2, and 6 weeks),
-adalimumab or biosimilars (160 mg subcutaneous dose followed by 80 mg SC, followed by 40 mg SC dose at least 2 weeks apart),
-golimumab (200 mg SC dose followed by 100 mg SC dose at least 2 weeks apart),
-vedolizumab (300 mg IV at 0, 2, and 6 weeks),
-ustekinumab (one single IV using weight-based dosing - 260 mg for subjects with body <= 55 kg; 390 mg for subjects with body weight > 55 kg and <= 85 kg; 520 mg for subjects with body weight > 85 kg),
-Loss of response is defined as recurrence of symptoms during maintenance course following primary response after full induction course (discontinuation despite clinical benefit does not qualify)
Intolerance includes (but not limited to) infusion-related reaction, serious opportunistic infection, malignancies.
d.Inadequate response to JAK inhibitors is defined as signs and symptoms of persistently active disease despite at least one full induction course according to USPI/SmPC of tofacitinib (i.e., at least 8 weeks), or to at least one full induction course according to SmPC of filgotinib (i.e., at least 10 weeks), or to at least one full induction course according to USPI of upadacitinib (i.e., 8 weeks), or recurrence of symptoms during maintenance course.
Intolerance to JAK inhibitor treatment that includes (but not limited to) increase of serious infection, malignancies, deep venous thrombosis (DVT), or major adverse cardiac event (MACE).
e.Inadequate response to S1P receptor modulators is defined as signs and symptoms of persistently active disease despite at least one full induction course according to USPI/SmPC of ozanimod* (i.e., at least 12 weeks) or recurrence of symptoms during maintenance course.
Intolerance to ozanimod* that includes (but not limited to) serious infections, liver enzyme, cardiac abnormalities, lymphopenia.
f.Inadequate response or intolerance to any new drug approved for moderate to severe active UC during the course of the study defined according to USPI/SmPC.
* Not approved in Japan
** Not approved in Japan in UC indication but 6-mercaptopurine and cyclosporin are used in clinical practices according to guidelines.
6.Women of childbearing potential (WOCBP) subjects and male subjects with WOCBP partners must agree to use highly effective contraception methods as stated in Section 4.4. (Contraception) of this protocol.
7.Subjects able and willing to comply with study visits and procedures as per protocol.

Exclude criteria

1.Subjects with UC limited to an isolated proctitis (<= 15cm from anal verge).
2.Subjects with primary sclerosing cholangitis or autoimmune hepatitis.
3.Subjects who have failed on 5-ASA therapy only.
4.Subjects with CD or presence or history of fistula, indeterminate colitis, infectious/ischemic colitis or microscopic colitis (lymphocytic and collagenous colitis).
5.History or current evidence of toxic megacolon, fulminant colitis, bowel perforation.
6.History of colon cancer, past or current evidence of low grade or high-grade colonic dysplasia and/or adenomatous polyps that have not been completely removed.
7.Recent or planned bowel surgery or history of proctocolectomy or partial colectomy or current stoma.
8.Subjects on antidiarrheals including those working on motility (e.g., loperamide, diphenoxylate* with atropine, etc.) (* not approved in Japan).
9.Subjects on probiotics (e.g., CulturelleR [Lactobacillus GG, i-Health, Inc.], Saccharomyces boulardii).
10.Subjects who do not meet the washout period requirements prior to the screening endoscopy as described in the prohibited medication section (section 4.3.2) of the study protocol.
11.Subjects with the following hematological and biochemical laboratory parameters obtained during the screening period:
-Hemoglobin <= 8.0 g dL-1
-Absolute neutrophil count < 750 mm-3
-Platelets < 100,000 mm-3
-Creatinine clearance < 60 mL.min-1 (Cockroft-Gault formula)
-Total serum bilirubin > 1.5 x ULN
-Alkaline phosphatase, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) > 2 x ULN
12.Subjects with the following conditions (infection):
-Subjects with chronic or recurrent grade 3 or grade 4 infection within the last 2 months prior to screening or a history of opportunistic infection while not on immunosuppressive therapy.
-Herpes zoster reactivation within the last 2 months prior to screening.
-Subjects with active infection at screening or any major episode of infection that required hospitalization or treatment with intravenous antibiotics within 1 month of screening or during screening. Fungal infection of nail beds is allowed.
-Positive assay or stool culture for pathogens (ova and parasite examination, bacteria), positive serum B-D-glucan test (only for Japan), or positive test for Clostridium difficile toxin at screening. If C. difficile is positive, subject may be treated and retested >= 2 weeks after completing treatment.
-Subjects with HIV infection.
-Subjects having acute or chronic hepatitis B infection at screening (positive for hepatitis B surface antigen [HBsAg], or negative for HBsAg but positive for anti-hepatitis B core antibody [HBcAb] and/or anti-hepatitis B surface antibody [HBsAb] in conjunction with detectable HBV-DNA). Subjects who were enrolled with positive HBcAb and/or HBsAb in conjunction with undetectable HBV-DNA should be monitored for HBV-DNA every 4 weeks.
-Subjects having acute or chronic hepatitis C infection at screening as defined by positive for hepatitis C antibody (subjects successfully treated and without recurrence >= 1 year with no detectable HCV-RNA [assessed centrally] are eligible). Subjects who were enrolled with positive HCV antibody in conjunction with undetectable HCV-RNA should be monitored for HCV-RNA every 4 weeks.
-Active tuberculosis (TB) or untreated latent TB are ruled out. For subjects with positive or intermediate QuantiFERON test see section 5.3.8.1 of the current study protocol.
13.Subjects with an uncontrolled ischemic heart disease and/or a history of congestive heart failure with New York Heart Association (NYHA) class 3 or 4 symptoms.
14.Subjects with a family or personal history of congenital or acquired long QT syndrome, or subjects with a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval [Fridericia or Bazett correction] >450 milliseconds for male and > 460 milliseconds for female).
15.Subjects with a history of torsade de pointe (TdP).
16.Acute or chronic of clinically relevant pulmonary, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable central nervous system pathology such as seizure disorder, or any other clinically significant medical problems as determined by physical examination and/or laboratory screening tests and/or medical history (note: treated autoimmune hypothyroidy and autoimmune diabetes are allowed).
17.History or active malignancy (subjects with a 5-year disease free survival are eligible).
18.Serious illness requiring hospitalization within 4 weeks prior to screening (except UC flare).
19.Subjects previously treated with ABX464.
20.WOCBP subject and WOCBP partner of male subject who are pregnant at screening, intend or are planning to become pregnant during the study duration, and breast-feeding women.
21.Illicit drug or alcohol abuse or dependence.
22.Subjects who received live vaccine within 3 months prior to screening and/or who's planning to receive such a vaccine during the study duration.
23.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.
24.Any condition, which in the opinion of the investigator, could compromise the subject's safety or adherence to the study protocol.

Related Information

• Primary Sponsor: Shono Masushi
• Secondary ID(s): NCT05507216