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

Trial ID: 2022-500290-14-01
Protocol: DRI16804
Sponsor: Sanofi-Aventis Recherche & Developpement

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Diseases & Conditions

Colitis ulcerative

Objectives

The primary objective of this study is to assess the **efficacy** of different doses of SAR443122 in participants with moderate to severe **ulcerative colitis** (UC) during the induction treatment period. This is clinically relevant as it aims to determine the optimal dosing strategy for achieving therapeutic benefits in managing UC, a chronic inflammatory bowel disease that significantly impacts patients' quality of life.

Secondary objectives include evaluating the effect of SAR443122 on various clinical and histological parameters in participants with UC during the induction treatment period. These objectives are:

Assess the effect on endoscopic improvement.
Evaluate clinical remission and clinical response.
Determine histologic improvement.
Assess histologic-endoscopic mucosal improvement (HEMI).
Evaluate disease-specific quality of life.
Assess patient-reported signs and symptoms of UC.
Evaluate the pharmacokinetics of SAR443122.
Assess the safety and tolerability of SAR443122 over 52 weeks in participants with moderate to severe UC.

These secondary objectives are crucial for understanding the comprehensive impact of SAR443122 on disease progression, patient well-being, and treatment safety, thereby informing clinical decision-making and therapeutic strategies for UC management.

Participants

The clinical trial involves a total of **196 participants** diagnosed with **ulcerative colitis**. The study population includes both male and female subjects, with an age range that encompasses adults and adolescents. Participants were selected based on clinical evidence of active ulcerative colitis for at least three months prior to screening, confirmed by endoscopy. The trial includes individuals who have not adequately responded to, have lost response to, or are intolerant of at least one approved treatment such as amino-salicylates, corticosteroids, immunosuppressants, or biologics. Participants are required to maintain stable doses of any ongoing treatments, such as corticosteroids or oral 5-aminosalicylates, for specified periods before and during the screening. The trial also considers lifestyle factors, requiring consistent contraceptive use in accordance with local regulations, and excludes pregnant or breastfeeding women. The study population includes a vulnerable group, ensuring comprehensive representation in assessing the efficacy of different doses of SAR443122 during the induction treatment period for moderate to severe ulcerative colitis.

Plans and Procedures

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of SAR443122 in adult patients with moderate to severe **ulcerative colitis**. The trial aims to assess the efficacy of different doses of SAR443122 during the induction treatment period. The study will involve the administration of SAR443122 in the form of hard capsules, with a maximum daily dose of 600 mg and a total treatment period of up to 52 weeks. Participants will be randomly assigned to receive either the active drug or a matched placebo, administered orally.

The trial will commence with a screening visit to confirm eligibility, which includes clinical evidence of active ulcerative colitis for at least three months prior to screening, as confirmed by endoscopy. Participants must meet specific inclusion criteria, such as having a minimum disease extent of 15 centimeters from the anal verge and being inadequate or non-responders to certain approved treatments. The primary endpoint is the proportion of participants achieving clinical remission at Week 12, assessed by the modified Mayo Score. Secondary endpoints include endoscopic improvement, clinical response, and changes in patient-reported outcomes.

Study visits will be scheduled at regular intervals throughout the trial, including follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will occur at the conclusion of the treatment period, where final assessments will be conducted. The expected duration of participant involvement is approximately 52 weeks, with conditions for early termination including withdrawal of consent, adverse events, or non-compliance with the study protocol. The trial is estimated to conclude by April 2026, with recruitment having started in April 2023.

Treatment

The clinical trial involves the administration of **Eclitasertib**, an experimental medication developed by Sanofi Aventis Recherche et Développement (SAR). **Eclitasertib** is provided in the form of a hard capsule and is administered orally. The trial includes two dosing regimens of **Eclitasertib**. The first regimen involves a maximum daily dose of 150 mg, with a total maximum dose of 54.60 grams over a treatment period of up to 52 weeks. The second regimen allows for a higher maximum daily dose of 600 mg, with a total maximum dose of 218.40 grams over the same treatment period. The active substance is of chemical origin, and the trial aims to assess the efficacy and safety of these doses in adult patients with moderate to severe ulcerative colitis.

In addition to the experimental medication, a matched placebo is used as a comparator in this randomized, double-blind, placebo-controlled study. The placebo is designed to mimic the appearance of the **Eclitasertib** capsules but does not contain any active pharmaceutical ingredients. The use of a placebo allows for the evaluation of the true efficacy of **Eclitasertib** by providing a control group for comparison. The placebo is administered in the same manner as the experimental drug, ensuring consistency in the trial's methodology.

Efficacy

The efficacy of SAR443122 in the treatment of moderate to severe **ulcerative colitis** will be assessed through a randomized, double-blind, placebo-controlled, dose-finding study. The primary endpoint for evaluating efficacy is the proportion of participants achieving clinical remission at Week 12, as determined by the modified Mayo Score (mMS). The mMS is a composite instrument that includes patient-reported stool frequency and rectal bleeding, endoscopy-derived measures, and omits the physician-reported assessment (PGA). An endoscopy score of 1 with no friability is also required for clinical remission.

Secondary endpoints include the proportion of participants achieving endoscopic improvement, clinical response by mMS and full Mayo Score (MS), and histological improvement at Week 12. Additional assessments involve changes from baseline in patient-reported outcomes such as the Inflammatory Bowel Disease Questionnaire (IBDQ) total score and the Ulcerative Colitis Patient Reported Outcome Signs and Symptoms (UC-PRO/SS) at Week 12. Pharmacokinetic parameters, including maximum concentration (Cmax), time to Cmax (tmax), area under the curve over the dosing interval (AUC0-tau), and elimination half-life (t1/2z), will also be evaluated. The occurrence of Treatment Emergent Adverse Events (TEAEs) during the induction, maintenance, and open-label treatment periods will be monitored.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participants who have clinical evidence of active Ulcerative Colitis [UC] for ≥3 months before screening as confirmed by endoscopy during the screening period.
Participants must have a minimum disease extent of 15 centimeters from the anal verge.
-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, biologics other than natalizumab (Tysabri®) or small molecules.
Participants on corticosteroids must be on a stable dose ≥2 weeks prior to screening and during screening period.
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.
Participants on oral 5-aminosalicylates, mesalamine or sulfasalazine must be on a stable dose for ≥4 weeks prior to screening and during screening period.
Participants on advanced therapies must have 1) last administration at least 5 half-lives prior to randomization, or 2) undetectable level of the biologic in their blood prior to randomization.
Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Women participants should not be pregnant or breastfeeding.

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Exclusion Criteria

Participants with Crohn’s Disease (CD).
Participants with diagnosis of indeterminate colitis or microscopic colitis.
Participants with stool sample positive for culture for aerobic pathogens or C difficile.
Participants with prior colectomy or anticipated colectomy during their participation in the study.
Participants with presence of ileal pouch or ostomy.
Participants with fulminant disease or toxic megacolon.
Participants with colonic dysplasia except for adenoma.
Participants with intestinal failure or short bowel syndrome requiring Total Parenteral Nutrition (TPN).
Participants with history of recurrent or recent serious infection that has not resolved within 4 weeks prior to randomization.
Participants presenting with active malignancies or recurrence of malignancy within the 5 years before screening.
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.
Participants presenting with fever (≥38°C) or persistent chronic or active recurring infection within 4 weeks prior to the Screening Visit requiring treatment with antibiotics, antivirals, or any history of frequent recurrent infections deemed unacceptable per investigator’s judgment.
Participants who were administered any live (attenuated) vaccine within 3 months prior to the randomization Visit.
Participants with a history of recurrent herpes zoster.
Participants with uncontrolled diabetes, defined as HbA1c ≥9.0% at the Screening Visit.
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.
Participants presenting with opportunistic infections within six months prior to screening or while receiving anti-TNF treatment in the last 6 months.
Participants undergoing hemodialysis or peritoneal dialysis.
Participants with a known history of Human Immunodeficiency Virus (HIV) infection or positive HIV serology at screening.
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 were treated for HCV and clear the virus documented by HCV RNA by PCR below the limit of quantification can be eligible.
Positive COVID-19 test, suspected COVID-19 infection or known exposure to COVID-19 during the screening period.
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.
Participants presenting alcohol or drug dependency within the 2 years prior to the Screening Visit.
Participants with unexplained, uncontrolled, or untreated thyroid disease or unexplained abnormal serum prolactin levels at screening.
Participants under cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide or tacrolimus treatment within 4 weeks prior to screening.
Participants with previous exposure to natalizumab (Tysabri®)
Participants with previous exposure to RIPK1 inhibitor.
Participants under antidiarrheals within 2 weeks prior to screening and during screening period.
Participants under prednisone >25 mg/day (or equivalent).
Participants under budesonide >9 mg/day.
Participants who received intravenous corticosteroids or cytapheresis therapy within 2 weeks prior to screening or during screening.
Participants who were rectally administered topical 5-aminosalicylate or corticosteroids within 4 weeks prior to screening.
Participants who received therapeutic enema or suppository, other than required for colonoscopy or flexible sigmoidoscopy within 4 weeks prior to screening or during screening.
Participants who received antibiotics for UC or gastrointestinal infection within 4 weeks prior to screening.
Participants who have taken other investigational medications within 2 months or 5 halflives, (whichever is longer) prior to screening.
Presence of significant laboratory findings at the Screening Visit.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	30 Apr 2023	4
Czechia	Not Recruiting	30 Apr 2023	15
France	Not Recruiting	30 Apr 2023	10
Germany	Not Recruiting	30 Apr 2023	15
Hungary	Not Recruiting	30 Apr 2023	17
Italy	Not Recruiting	30 Apr 2023	13
The Netherlands	Not Recruiting	30 Apr 2023	—
Poland	Not Recruiting	30 Apr 2023	13
Romania	Not Recruiting	30 Apr 2023	10
Slovakia	Not Recruiting	30 Apr 2023	7