Overview
This study has 3 treatment phases, a 12-Week Induction Phase, a 40-Week Maintenance Phase, and a 48-Week Extension Phase.
The objective is to evaluate the efficacy and safety of obefazimod compared to placebo as induction and maintenance therapy in subjects with moderately to severely active CD after inadequate response (no response, loss of response, or intolerance) to conventional therapies and/or advanced therapies.
The primary objective for the 48-Week Extension Phase is to evaluate the safety and tolerability of obefazimod compared with placebo in subjects who are enrolled in the Extension Phase.
Principal investigator
Eligibility criteria
Inclusion Criteria:
1. Male or female (at birth) 18 to 75 years old and able to understand, sign, and date the written voluntary informed consent at the visit prior to any protocol-specified procedures
2. Able and willing to comply with study visits and procedures as per protocol.
3. Confirmed and documented diagnosis of CD based on endoscopy and histology reports.
4. Moderately to severely active CD as defined by 220 ≤ CDAI ≤ 450 and SES-CD ≥ 6 for ileo-colonic or colonic disease or SES-CD ≥ 4 for isolated ileal disease (per central reading).
5. Documented inadequate response (defined as lack of response or loss of response or intolerance) to at least one of the following treatments: corticosteroids (CS), immunosuppressants (IS), biologic or biosimilar therapies, or janus kinase (JAK) (note: failure to only 5-aminosalicylic acid \[5-ASA\] is not accepted)
6. Women of childbearing potential (WOCBP) and male subjects with WOCBP partner must agree to comply with contraception requirements as stated in section 4.5 (contraception) of this protocol.
7. Subject should be affiliated to a health insurance policy whenever required by a participating country or state.
8. Subject is able and willing to comply with usual public recommendations for sun protection.
Exclusion Criteria: Subjects who meet any of the following exclusion criteria will be excluded from the study: 1. WOCBP subject who is pregnant or breast-feeding at screening, or intends to become pregnant during the study; or male subject with WOCBP partner who intends to be pregnant during the study. 2. Current diagnosis of ulcerative colitis (UC) or indeterminate colitis 3. CD without ileal and/or colonic involvement 4. Untreated active external or perianal fistula or abscess. Stable fistula without abscess and with minimal or low drainage may be enrolled. Recent cutaneous and perianal abscesses are not exclusionary if drained and adequately treated at least 3 weeks before screening colonoscopy or 8 weeks before screening colonoscopy for intra-abdominal abscesses, if no additional surgery is anticipated. 5. Symptomatic bowel stricture and/or stenosis not passable in endoscopy 6. Related to CD surgery: 1. Current stoma or ileoanal pouch 2. More than 2 missing complete segments of the following 5 segments: terminal ileum, right colon, transverse colon, left colon, and sigmoid and rectum 3. Combined previous small bowel resections \> 100 cm 4. Surgical bowel resection within the past 3 months prior to baseline 5. Any other manifestation that might require surgery while enrolled in the study 7. Related to CD treatments: 1. Subject who is currently treated with prohibited concomitant therapies for CD as described in the study protocol 2. Subject who has previously received natalizumab (or any other α4β1 integrin agonist) 3. Subject who has failed more than three advanced therapies for the treatment of CD, or two different mechanisms of action for advanced therapies of CD 8. History of, or active, malignancy including nonmelanoma skin cancer (subjects with a 5-year disease-free survival are eligible) 9. History of colonic cancer or colonic low grade or high grade dysplasia adenomatous polyps, and/or at the screening endoscopy, evidence of low grade or high grade dysplasia adenomatous polyps (fully removed or not) 10. Subject with history of, or diagnosed with, the following during screening: primary sclerosing cholangitis, autoimmune hepatitis, or primary biliary cirrhosis 11. Serious illness requiring hospitalization (not related to CD) within 4 weeks prior to screening 12. Subject with the following infectious conditions: 1. Chronic or recurrent Grade 3 or Grade 4 infection within the last 2 months prior to screening or history of opportunistic infection while not on immunosuppressive therapy 2. Herpes zoster reactivation within the last 2 months prior to screening 3. Active infection at screening or any major episode of infection that required hospitalization or treatment with IV antibiotics within 1 month of screening or during screening (fungal infection of nail beds is allowed) 4. Positive assay or stool culture for pathogens (ova and parasite examination, bacteria) that required treatment per local medical practice or positive test for Clostridioides difficile (C. difficile) toxin at screening. 5. Subject with human immunodeficiency virus (HIV) infection 6. Acute or chronic hepatitis B infection at screening (positive for hepatitis B surface antigen \[HbsAg\] or negative for HbsAg and positive for anti-hepatitis B core antibody in conjunction with detectable hepatitis B virus \[HBV\] deoxyribonucleic acid \[DNA\], or detectable HBV DNA). 7. Acute or chronic hepatitis C virus (HCV) infection 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) 8. Active tuberculosis (TB) or untreated latent TB (For subjects with positive or intermediate QuantiFERON test) 13. Subject with uncontrolled ischemic heart disease and/or a history of congestive heart failure 14. Subject with a known family or personal history of congenital or acquired long QT syndrome, or subjects with a marked baseline prolongation of QT/ heart rate-corrected QT (QTc) interval 15. Subject with a history of torsade de pointe (TdP) 16. Acute or chronic clinically relevant pulmonary, hepatic, or renal functional abnormality, encephalopathy, neuropathy or unstable central nervous system pathology such as seizure disorder, or any other clinically significant medical problems. 17. Subjects who received live vaccine within 3 months prior to screening and/or subject who is planning to receive such a vaccine during the study duration 18. Acute or chronic pancreatitis 19. Subject with the following hematological and biochemical laboratory parameters obtained during the screening period: 1. Hemoglobin ≤ 8.0 g/dL1 2. Absolute neutrophil count \< 750/mm3 3. Platelets \< 100,000 /mm3 4. eGFR \< 60 mL/min/1.73 m2 5. Total serum bilirubin \> 1.5 x ULN (except if related to pre-existing and documented Gilbert syndrome) 6. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 2 x ULN 20. Subject who does not meet the washout period requirements prior to the screening endoscopy as described in the prohibited medication section of the study protocol 21. Use of any investigational or nonregistered product within 3 months or within 5 halflives preceding baseline, whichever is longer, and during the study. 22. Subjects previously treated with obefazimod or with a known hypersensitivity to the active substance or to any of the excipients 23. Illicit drug or alcohol abuse or dependence 24. Subject who is committed to an institution by virtue of an order issued either by the judicial or the administrative authorities 25. Any condition, which in the opinion of the investigator, could compromise the subject's safety or adherence to the study protocol
Exclusion Criteria: Subjects who meet any of the following exclusion criteria will be excluded from the study: 1. WOCBP subject who is pregnant or breast-feeding at screening, or intends to become pregnant during the study; or male subject with WOCBP partner who intends to be pregnant during the study. 2. Current diagnosis of ulcerative colitis (UC) or indeterminate colitis 3. CD without ileal and/or colonic involvement 4. Untreated active external or perianal fistula or abscess. Stable fistula without abscess and with minimal or low drainage may be enrolled. Recent cutaneous and perianal abscesses are not exclusionary if drained and adequately treated at least 3 weeks before screening colonoscopy or 8 weeks before screening colonoscopy for intra-abdominal abscesses, if no additional surgery is anticipated. 5. Symptomatic bowel stricture and/or stenosis not passable in endoscopy 6. Related to CD surgery: 1. Current stoma or ileoanal pouch 2. More than 2 missing complete segments of the following 5 segments: terminal ileum, right colon, transverse colon, left colon, and sigmoid and rectum 3. Combined previous small bowel resections \> 100 cm 4. Surgical bowel resection within the past 3 months prior to baseline 5. Any other manifestation that might require surgery while enrolled in the study 7. Related to CD treatments: 1. Subject who is currently treated with prohibited concomitant therapies for CD as described in the study protocol 2. Subject who has previously received natalizumab (or any other α4β1 integrin agonist) 3. Subject who has failed more than three advanced therapies for the treatment of CD, or two different mechanisms of action for advanced therapies of CD 8. History of, or active, malignancy including nonmelanoma skin cancer (subjects with a 5-year disease-free survival are eligible) 9. History of colonic cancer or colonic low grade or high grade dysplasia adenomatous polyps, and/or at the screening endoscopy, evidence of low grade or high grade dysplasia adenomatous polyps (fully removed or not) 10. Subject with history of, or diagnosed with, the following during screening: primary sclerosing cholangitis, autoimmune hepatitis, or primary biliary cirrhosis 11. Serious illness requiring hospitalization (not related to CD) within 4 weeks prior to screening 12. Subject with the following infectious conditions: 1. Chronic or recurrent Grade 3 or Grade 4 infection within the last 2 months prior to screening or history of opportunistic infection while not on immunosuppressive therapy 2. Herpes zoster reactivation within the last 2 months prior to screening 3. Active infection at screening or any major episode of infection that required hospitalization or treatment with IV antibiotics within 1 month of screening or during screening (fungal infection of nail beds is allowed) 4. Positive assay or stool culture for pathogens (ova and parasite examination, bacteria) that required treatment per local medical practice or positive test for Clostridioides difficile (C. difficile) toxin at screening. 5. Subject with human immunodeficiency virus (HIV) infection 6. Acute or chronic hepatitis B infection at screening (positive for hepatitis B surface antigen \[HbsAg\] or negative for HbsAg and positive for anti-hepatitis B core antibody in conjunction with detectable hepatitis B virus \[HBV\] deoxyribonucleic acid \[DNA\], or detectable HBV DNA). 7. Acute or chronic hepatitis C virus (HCV) infection 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) 8. Active tuberculosis (TB) or untreated latent TB (For subjects with positive or intermediate QuantiFERON test) 13. Subject with uncontrolled ischemic heart disease and/or a history of congestive heart failure 14. Subject with a known family or personal history of congenital or acquired long QT syndrome, or subjects with a marked baseline prolongation of QT/ heart rate-corrected QT (QTc) interval 15. Subject with a history of torsade de pointe (TdP) 16. Acute or chronic clinically relevant pulmonary, hepatic, or renal functional abnormality, encephalopathy, neuropathy or unstable central nervous system pathology such as seizure disorder, or any other clinically significant medical problems. 17. Subjects who received live vaccine within 3 months prior to screening and/or subject who is planning to receive such a vaccine during the study duration 18. Acute or chronic pancreatitis 19. Subject with the following hematological and biochemical laboratory parameters obtained during the screening period: 1. Hemoglobin ≤ 8.0 g/dL1 2. Absolute neutrophil count \< 750/mm3 3. Platelets \< 100,000 /mm3 4. eGFR \< 60 mL/min/1.73 m2 5. Total serum bilirubin \> 1.5 x ULN (except if related to pre-existing and documented Gilbert syndrome) 6. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 2 x ULN 20. Subject who does not meet the washout period requirements prior to the screening endoscopy as described in the prohibited medication section of the study protocol 21. Use of any investigational or nonregistered product within 3 months or within 5 halflives preceding baseline, whichever is longer, and during the study. 22. Subjects previously treated with obefazimod or with a known hypersensitivity to the active substance or to any of the excipients 23. Illicit drug or alcohol abuse or dependence 24. Subject who is committed to an institution by virtue of an order issued either by the judicial or the administrative authorities 25. Any condition, which in the opinion of the investigator, could compromise the subject's safety or adherence to the study protocol
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