A Global Phase-III Clinical Trial to be conducted in adult population who are suffering from moderate to severe ulcerative colitis to evaluate the efficacy and safety of Test Drug (SAR443122) vs Placebo.

Phase 2

Recruiting

• Conditions: Ulcerative colitis, unspecified,

• Registration Number: CTRI/2023/06/053613
• Lead Sponsor: SanofiAventis Recherche Dveloppement

Brief Summary

This is amultinational, multi-center, randomized, double-blind, placebo controlled,Phase 2 study to assess the efficacy and safety of different doses of theRIPK1-inhibitor SAR443122 in patients with moderate to severe UC.

The treatment inthe study includes a first induction treatment phase of 12 weeks and asubsequent maintenance treatment phase of 40 weeks.

The targetpopulation of the study is patients with active UC confirmed by endoscopyduring the

screening periodand within no more than 10 days prior to randomization and demonstratingmoderate to severe disease at baseline as defined by a modified Mayo score mMSof 5-9 (without the Physician Global

Assessment [PGA]and with an endoscopy subscore ≥2 confirmed by central reader). The studyincludes 3 parts plus an open label arm

Inductiontreatment phase (Parts A and B),

• Maintenancetreatment phase (Part C),

• Open-labelarm.

Both Parts A andB consist of a 12-week randomized double-blind induction treatment period andwill evaluate efficacy, safety, pharmacokinetic (PK) and pharmacodynamic (PD)up to Week 12.

treatment that was assigned in Part A or B. Participants that are not inclinical response or remission at the end of induction in Part A or B, will beoffered to roll over into the open-label treatment

Detailed Description

Not available

Study Timeline

• Study Start: 2023-08-18
• Last Update Posted: 2025-05-19

Recruitment & Eligibility

• Status: Open to Recruitment
• Sex: All
• Target Recruitment: 182

Inclusion Criteria

• I 02. Participants who have clinical evidence of active Ulcerative Colitis [UC] for ≥3 months before screening as confirmed by endoscopy during the screening period and within no more than 10 days prior to randomization. I 03. Active moderate to severe UC at baseline as defined by a modified Mayo score of 5-9 (without the PGA, with a minimum score of RB ≥1 and SF ≥1, endoscopy subscore ≥2 confirmed by central reader, and a minimum sum of all subscores of 5). I 04. Participants must have a minimum disease extent of 15 centimeters from the anal verge. I 05. Participants are inadequate or non-responders, have shown loss of response, or are intolerant to at least 1 of following approved treatments: -amino-salicylate, -corticosteroids, -immunosuppressants or biologics (anti-TNF alpha, anti-integrin, anti-IL-12/IL-23, or anti- IL-23) other than natalizumab (Tysabri®) -small molecules (JAKi or S1P receptor modulator). I 06. Participants on corticosteroids must be on a stable dose ≥2 weeks (dose not exceeding 25 mg/day prednisone or equivalent) prior to screening and during screening period. I 07. Participants on methotrexate, azathioprine or 6- mercaptopurine must be on treatment for at least 8 weeks prior to screening; and on a stable dose ≥4 weeks prior to screening and during screening period. I 08. Participants on oral 5-aminosalicylates, mesalamine or sulfasalazine must be on a stable dose for ≥4 weeks prior to screening and during screening period. I 09. Participants on advanced therapies must have 1) last administration at least 5 half lives prior to start of randomization, or 2) undetectable level of the biologic in their blood prior to randomization 1.10 Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. a) Male participants Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 5 days after the last dose of IMP, corresponding to time needed to eliminate study intervention(s) (eg, 5 terminal half-lives).
• Refrain from donating sperm . PLUS, either:.
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent. OR.
• Must agree to use contraception/barrier as detailed below: A male condom and an additional highly effective contraceptive method when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant. b) Female participants A female participant is eligible to participate if she is not pregnant or breastfeeding, and one of the following conditions applies:.
• Is a woman of non-childbearing potential (WONCBP) as defined in Appendix 4 Contraceptive and barrier guidance ( OR.
• Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, as described in Appendix 4 Contraceptive and barrier guidance, during the study intervention period and for at least 5 days, corresponding to the time needed to eliminate any study intervention(s) (eg, 5 terminal half-lives) plus 30 days (a menstrual cycle) after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.
• A WOCBP must have a negative highly sensitive pregnancy test (urine and/or serum as required by local regulations) at Screening and Baseline visits before the first administration of study intervention Pregnancy testing). I.11 Capable of giving signed informed consent.

Exclusion Criteria

• E 01. Participants with Crohn’s Disease (CD). E 02. Participants with diagnosis of indeterminate colitis or microscopic colitis. E 03. Participants with fecal sample positive for culture for aerobic pathogens at screening including: Aeromonas, Plesiomonas, Shigella, Salmonella, Yersinia, Campylobacter, and E. coli spp. or positive for Clostridium difficile B toxin in stools. E 04. Participants with prior colectomy or anticipated colectomy during their participation in the study. E 05. Participants with presence of ileal pouch or ostomy. E 06. Participants with fulminant disease or toxic megacolon. E 07. Participants with colonic dysplasia except for adenoma. E 08. Participants with intestinal failure or short bowel syndrome requiring Total Parenteral Nutrition (TPN). E 09. Participants with history of recurrent or recent serious infection (eg, pneumonia, septicemia as defined by the Investigator). E 10. Participants presenting with malignancies except history of basal cell carcinoma or in-situ cervical carcinoma. E.11. Participants with a history or presence of another significant illness that according to the Investigator’s judgment would adversely affect the subject’s ability to participate in this study such as (and not limited to) cardiovascular (including stage III or IV cardiac failure according to New York Heart Association (NYHA), renal, neurological, endocrine, gastrointestinal, hepatic disease, metabolic, pulmonary or lymphatic disease. E.12. Participants presenting with fever (more than equal to 38°C) or persistent chronic or active recurring infection within 4 weeks prior to the Screening Visit requiring treatment with antibiotics, antivirals, or antifungals, or any history of frequent recurrent infections deemed unacceptable per Investigators judgment. E 13. Participants who were administered any live (attenuated) vaccine within 3 months prior to the randomization Visit. E 14. Participants with a history of recurrent herpes zoster. E 15. Participants with uncontrolled diabetes, defined as HbA1c ≥9.0% at the Screening Visit. E 16. Participants with active tuberculosis (TB) or non-tuberculous mycobacterial infection, or a history of incompletely treated active or latent TB per local guidelines will be excluded from the study unless it is documented by a specialist that the participant has been adequately treated and can now start treatment with the RIPK1 kinase inhibitor Also, participants with a positive PPD test, Mantoux test or Quantiferon-TB Gold test at Screening indicating latent TB or another mycobacterial infection, will be excluded from the study. Positive PPD or Mantoux is acceptable if it can be explained by a documented BCG-vaccination. E 17. Participants presenting with opportunistic infections within six months prior to screening or while receiving anti-TNF treatment in the last 6 months. The participants presenting infection that have been treated and that result in no sequelae or consequences can be randomized in the study if they meet the other entry criteria. E 18. Participants undergoing hemodialysis or peritoneal dialysis. E 19. Participants with a known history of Human Immunodeficiency Virus (HIV) infection or positive HIV serology at screening. E 20. Participants with Positive Hepatitis B surface antigen (HBsAg) or positive Hepatitis B core antibody (HBcAb); and/or positive Hepatitis C antibody (HCV) at the Screening Visit. Participants that have cleared the virus as documented by a negative HCV RNA polymerase chain reaction (PCR) that is below the limit of quantification can be randomized in the study if they meet all other inclusion and exclusion criteria. E 21. Positive COVID-19 test, suspected COVID-19 infection or known exposure to COVID-19, at screening or during the screening period. E 22. History of COVID-19 infection within 4 weeks prior to Screening; history of mechanical ventilation or extracorporeal membrane oxygenation (ECMO) due to COVID-19 infection within 3 months prior to Screening or with residual significant complications from COVID-19 making it unsafe for the participant to enter this study. E 23. Participants presenting alcohol or drug dependency within the 2 years prior to the Screening Visit E 24. Participants with unexplained, uncontrolled, or untreated thyroid disease or unexplained abnormal serum prolactin levels at screening. E 25. Participants on cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide or tacrolimus treatment within 4 weeks prior to screening. E 26. Participants with measurable trough levels of other biologics (anti-TNF alpha, anti-IL-12/23, anti-IL-23 or anti-integrin) at 4 weeks or less prior to randomization. E 27. Participants with previous exposure to natalizumab (Tysabri®). E 28. Participants with previous exposure to a RIPK1 inhibitor. E 29. Participants on antidiarrheals within 2 weeks prior to screening and during the screening period. E 30. Participants on prednisone >25 mg/day (or equivalent). E 31. Participants on budesonide >9 mg/day. E 32. Participants who received intravenous corticosteroids or cytapheresis therapy within 2 weeks prior to screening or during screening. E 33. Participants who were rectally administered topical 5-aminosalicylate or corticosteroids within 4 weeks prior to screening. E 34. Participants who received therapeutic enema or suppository, other than required for colonoscopy or flexible sigmoidoscopy within 4 weeks prior to screening or during screening. E 35. Participants who received antibiotics for UC or gastrointestinal infection within 4 weeks prior to screening. Prior/concurrent clinical study experience E 36. Participants who have taken other investigational medications within 2 months or 5 half lives, (whichever is longer) prior to screening. Diagnostic assessments E 37. Presence of any of the following laboratory findings at the Screening Visit:.
• Hemoglobin <8.0 g/dL (ie, <80 g/L).
• Platelet count <100 000/μL.
• WBC <3500/μL.
• Neutrophils <2000/μL.
• AST or ALT >2 x ULN Total Bilirubin >2 x ULN; unless the participant has been diagnosed with Gilbert disease documented by genetic testing.
• Creatinine clearance <60 mL/min using Cockcroft-Gault equation E 38. Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized. E 39. Any country-related specific regulation that would prevent the participant from entering the study (country-specific requirements). E 40. Participant not suitable for participation, whatever the reason, as judged by the Investigator, including medical or clinical conditions, or participants potentially at risk of noncompliance to study procedures. E 41. Participants are employees of the clinical study site or other individuals directly involved in the conduct of the study, or immediate family members of such individuals E 42. Any specific situation during study implementation/course that may raise ethics considerations. E 43. Sensitivity to any of the study interventions, or components thereof, or drug or other allergy that, in the opinion of the Investigator, contraindicates participation in the study. E 44. Participants presenting with conditions/situations such as:.
• Short life expectancy,.
• Requirement for concomitant treatment that could bias primary evaluation,.
• Uncooperative behavior or any condition that could make the participant potentially non-compliant to the study procedures.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Part A+B (induction treatment):	Proportion of participants who achieve clinical remission at Week 12 by modified Mayo Score (mMS)
Assess efficacy of different doses of SAR443122 in participants with moderate to severe UC.	Proportion of participants who achieve clinical remission at Week 12 by modified Mayo Score (mMS)

Secondary Outcome Measures

Name	Time	Method
•Part A and B (induction treatment):	- Assess the effect of SAR443122 on endoscopic improvement in participants with UC.
•Assess the effect of SAR443122 on clinical remission and clinical response in participants with UC	Proportion of participants who achieve clinical response at Week 12 by mMS.
•Assess the effect of SAR443122 on the histologic improvement in participants with UC.	Proportion of participants who achieve histological improvement at Week 12.
•Assess the effect of SAR443122 on Histologic-endoscopic mucosal improvement (HEMI) in participants with UC.	Proportion of participants who achieve Histologicendoscopic
Assess the effect of SAR443122 on disease specific quality of life	Change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) total score at Week 12
Assess the effect of SAR443122 on	patient reported signs and symptoms
Assess SAR443122 pharmacokinetics of participants with UC.	SAR443122 plasma concentrations over time.
Assess the safety and tolerability of	SAR443122 in participants with moderate to severe UC over 52 weeks

Trial Locations

Locations (12)

All India Institute of Medical Sciences (AIIMS); 🇮🇳 Delhi, DELHI, India

Fortis Hospital; 🇮🇳 Ludhiana, PUNJAB, India

Fortis Memorial Research Institute; 🇮🇳 Gurgaon, HARYANA, India

Government Medical College; 🇮🇳 Thiruvananthapuram, KERALA, India

Grant Medical Foundation Ruby Hall Clinic; 🇮🇳 Pune, MAHARASHTRA, India

Gujarat Hospital – Gastro and Vascular Centre; 🇮🇳 Surat, GUJARAT, India

Lisie Hospital; 🇮🇳 Ernakulam, KERALA, India

S.R.Kalla Memorial Gastro & General Hospital; 🇮🇳 Jaipur, RAJASTHAN, India

Shree Giriraj Hospital; 🇮🇳 Rajkot, GUJARAT, India

SIDS Hospital and Research Centre; 🇮🇳 Surat, GUJARAT, India

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All India Institute of Medical Sciences (AIIMS)

🇮🇳Delhi, DELHI, India

Dr Vineet Ahuja

Principal investigator

vineet.aiims@gmail.com