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.
Scientific Title of Study
A randomized, double-blind, placebo controlled, dose finding study to assess the efficacy and safety of SAR443122 in adult patients with moderate to severe ulcerative colitis
Placebo for SAR443122 50 mg and 100 mg hard capsules.
The Part A serves as a proof of concept (POC) study with two parallel arms randomized in a ratio of 1:1 to either SAR443122 300 mg twice a day (BID) or matching placebo. The randomization will be stratified by previous use of any biologics for the treatment of UC (yes/no). Specifically,78 participants are
expected to be randomized in Part A.
In Part B, 104 participants will be randomized in a ratio of 1:4:2:1 to receive SAR443122 300 mg BID, 150 mg BID, 50 mg BID or matching placebo, respectively. The same stratification as in Part A will apply.
The randomization in Part B will be sequentially initiated after the completion of the randomization to Part A.
Intervention
SAR443122 – hard capsules
The Part A serves as a proof of concept (POC) study with two parallel arms randomized in a ratio of 1:1 to either SAR443122 300 mg twice a day (BID) or matching placebo. The randomization will be stratified by previous use of any biologics for the treatment of UC (yes/no). Specifically,78 participants are
expected to be randomized in Part A.
In Part B, 104 participants will be randomized in a ratio of 1:4:2:1 to receive SAR443122 300 mg BID, 150 mg BID, 50 mg BID or matching placebo, respectively. The same stratification as in Part A will apply.
The randomization in Part B will be sequentially initiated after the completion of the randomization to Part A.
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
ExclusionCriteria
Details
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
Method of Generating Random Sequence
Computer generated randomization
Method of Concealment
Centralized
Blinding/Masking
Participant and Investigator Blinded
Primary Outcome
Outcome
TimePoints
Part A+B (induction treatment):
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
Outcome
TimePoints
• Part A and B (induction treatment):
- Assess the effect of SAR443122 on endoscopic improvement in participants with UC.
Proportion of participants who achieve endoscopic improvement at Week 12
• 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.
- Proportion of participants who achieve clinical remission at Week 12 by full Mayo Score (MS).
- Proportion of participants who achieve clinical response at Week 12 by MS.
- Change from baseline on patient-reported outcome 2 (PRO2) total score (Mayo stool frequency and rectal
bleeding subscores) over time
• 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
mucosal improvement (HEMI) at Week 12 defined by achievement of modified Mayo endoscopic improvement and histological improvement
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
of ulcerative colitis
Change from baseline in bowel signs and symptoms
assessed by Ulcerative Colitis Patient Reported Outcome Signs and Symptoms (UC-PRO/SS) at Week
12.
Change from baseline in abdominal signs and symptoms assessed by UC-PRO/SS at Week 12.
Assess SAR443122 pharmacokinetics of participants with UC.
SAR443122 plasma concentrations over time.
- Pharmacokinetic parameters (maximum concentration
[Cmax], time to Cmax [tmax], area under the curve over the
dosing interval [AUC0-tau], and elimination half-life [t1/2z]).
Assess the safety and tolerability of
SAR443122 in participants with moderate to severe UC over 52 weeks
Number (percentage) of participants with any Treatment Emergent Adverse Events (TEAEs) during induction and maintenance treatment period.
- Number (percentage) of participants with any TEAEs during open-label treatment period.
Total Sample Size="182" Sample Size from India="40" Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials" Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials"
Individual Participant Data (IPD) Sharing Statement
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
Brief Summary
This is a
multinational, multi-center, randomized, double-blind, placebo controlled,
Phase 2 study to assess the efficacy and safety of different doses of the
RIPK1-inhibitor SAR443122 in patients with moderate to severe UC.
The treatment in
the study includes a first induction treatment phase of 12 weeks and a
subsequent maintenance treatment phase of 40 weeks.
The target
population of the study is patients with active UC confirmed by endoscopy
during the
screening period
and within no more than 10 days prior to randomization and demonstrating
moderate to severe disease at baseline as defined by a modified Mayo score mMS
of 5-9 (without the Physician Global
Assessment [PGA]
and with an endoscopy subscore ≥2 confirmed by central reader). The study
includes 3 parts plus an open label arm
Induction
treatment phase (Parts A and B),
• Maintenance
treatment phase (Part C),
• Open-label
arm.
Both Parts A and
B consist of a 12-week randomized double-blind induction treatment period and
will 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 in
clinical response or remission at the end of induction in Part A or B, will be
offered to roll over into the open-label treatment