Efficacy and Safety Evaluation of SAR442970 in Adults with Moderate to Severe Ulcerative Colitis: A Randomized, Double-Blind, Placebo-Controlled Study

Trial ID: 2024-515241-41-00
Protocol: ACT18134
Sponsor: Sanofi-Aventis Recherche & Developpement

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Diseases & Conditions

Colitis ulcerative

Objectives

The primary objective of this study is to evaluate the **efficacy** of different dose regimens of SAR442970 in inducing clinical remission in participants with moderate to severe **ulcerative colitis** (UC). This is clinically relevant as achieving clinical remission is a critical goal in the management of UC, aiming to improve patient outcomes and quality of life.

Secondary objectives include:

Assessing the effect of different dose regimens of SAR442970 on endoscopic improvement, endoscopic response, and endoscopic remission in participants with UC.
Evaluating the effect of different dose regimens on clinical remission and clinical response.
Investigating the effect on histological improvement based on OGS and RHI, as well as histologic endoscopic mucosal improvement (HEMI).
Assessing the impact of different dose frequencies on disease-specific quality of life (QOL).
Evaluating the pharmacokinetics (PK) of SAR442970 in participants with UC.
Assessing the safety and tolerability of SAR442970 in this patient population.

Participants

The clinical trial involves a total of **108 participants** diagnosed with **Ulcerative Colitis** (UC), aiming to assess the efficacy of different dose regimens of SAR442970 in inducing clinical remission in individuals with moderate to severe UC. The study population includes both male and female subjects, aged between **18 to 75 years**. Participants were selected based on specific criteria, including a confirmed diagnosis of active UC for more than three months and a history of inadequate response or intolerance to standard UC treatments. The trial includes individuals who have a minimum disease extent of 15 centimeters from the anal verge and have received prior treatment for UC. Participants are required to be on stable doses of certain medications, such as corticosteroids or immunosuppressants, for specified periods before and during the screening. The trial population is not limited by gender, and both male and female participants are included, with considerations for contraceptive use as per local regulations. The study also involves a vulnerable population, ensuring comprehensive monitoring and adherence to ethical standards.

Plans and Procedures

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of SAR442970 in adult participants with moderate to severe **ulcerative colitis**. The trial is structured in two phases: an initial dose-ranging study followed by a long-term extension. The primary objective is to assess the efficacy of different dose regimens of SAR442970 in inducing clinical remission. The trial is expected to last until November 2029, with participant recruitment starting in September 2025. The total duration of participant involvement is up to 52 weeks, with the possibility of early termination if specific conditions arise, such as adverse events or non-compliance with the study protocol.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, disease activity, and prior treatment history. Following randomization, participants will receive either SAR442970 or a placebo administered as a **solution for injection** via the **subcutaneous** route. The study includes regular follow-up visits to monitor safety, efficacy, and adherence to the treatment regimen. Key assessments will occur at Week 16 and Week 52, focusing on clinical remission and endoscopic improvement. The end-of-study visit will conclude the participant's involvement, ensuring all necessary data is collected and any remaining health concerns are addressed.

Participants are required to comply with specific contraceptive measures and must not have any contraindications to the study drug. The primary endpoint is the proportion of participants achieving clinical remission at Week 16, defined by a modified Mayo score (mMS) of 0 to 2. Secondary endpoints include endoscopic improvement and response, as well as histological assessments. The trial will also monitor the incidence of treatment-emergent adverse events (TEAEs) and the presence of anti-drug antibodies (ADAs) over time. Participants may be withdrawn from the study if they experience significant adverse effects, fail to adhere to the protocol, or choose to discontinue participation.

Treatment

The clinical trial involves the administration of **SAR442970**, an experimental medication formulated as a **solution for injection**. The active substance, SAR442970, is a protein of other origin, developed by Sanofi Aventis Recherche et Développement (SAR). The medication is administered subcutaneously with a maximum daily dose of 300 mg. The treatment period extends up to 52 weeks, allowing for dose-ranging to assess efficacy in inducing clinical remission in participants with moderate to severe **ulcerative colitis**. Participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.

In addition to the experimental treatment, a **placebo** is utilized as a comparator in this double-blind, placebo-controlled study. The placebo, branded as NANOBODY® Placebo, is administered in a manner consistent with the experimental treatment to maintain the study's blinding integrity. The placebo does not contain any active substance and serves to evaluate the efficacy and safety of SAR442970 by providing a baseline for comparison. The administration of the placebo follows the same subcutaneous route and frequency as the experimental medication, ensuring consistency across treatment groups.

Efficacy

The efficacy of SAR442970 in the treatment of moderate to severe **ulcerative colitis** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the proportion of participants achieving clinical remission at the end of Week 16, as determined by the modified Mayo Score (mMS). Clinical remission is defined as an mMS score of 0 to 2, including a stool frequency (SF) subscore of 0 or 1, a rectal bleeding (RB) subscore of 0, and a centrally read modified Mayo endoscopic subscore (mMES) of 0 or 1, where a score of 1 does not include friability.

Secondary endpoints include the proportion of participants achieving endoscopic improvement, response, and remission at both Week 16 and Week 52. Endoscopic improvement is defined as an mMES of 0 or 1, endoscopic response as a decrease in mMES of at least 1, and endoscopic remission as a centrally read mMES of 0. Additional secondary endpoints involve clinical response and remission at Weeks 16 and 52, assessed by both total Mayo Score (MS) and mMS, as well as changes from baseline in patient-reported outcomes (PRO2 total score), mMS, and partial Mayo Score (PMS) at Week 16 and over time.

Histological assessments will also be conducted, with endpoints including the proportion of participants achieving histological improvement and remission at Week 16 by the Geboes Score (OGS) and Robarts Histopathology Index (RHI), and at Week 52. The study will also evaluate the proportion of participants achieving histological and endoscopic mucosal improvement (HEMI) at Week 16, defined by achieving both modified Mayo endoscopic improvement and histological improvement.

Additional assessments include changes in the Inflammatory Bowel Disease Questionnaire (IBDQ) scores at Weeks 16 and 52, serum SAR442970 concentrations, incidence of anti-drug antibodies (ADAs) over time, and the number and percentage of participants experiencing treatment-emergent adverse events (TEAEs) during the induction, maintenance, and long-term extension (LTE) periods. The study will also monitor the proportion of participants achieving corticosteroid-free remission at Week 52, defined by meeting mMS remission criteria without receiving steroids at the assessment timepoint or within 90 days prior.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant must be 18 to 75 years of age inclusive, at the time of signing the informed consent.
Participants have had clinical evidence of active UC for >3 months before Screening as confirmed by endoscopy during the screening period.
Participants must have active moderate to severe UC at Baseline as defined by mMS of 5 to 9 (without the PGA, with a minimum RB subscore of >1 and SF subscore of >1, mMES >2 )
Participants must have a minimum disease extent of 15 centimeters from the anal verge.
Must have received prior treatment for UC (either “a” or “b” below or combination of both): a) History of inadequate response to, loss of response to or intolerance to standard treatment with any of the following compounds: amino-salicylates, corticosteroids (oral or intravenous), MTX, AZA, or 6MP, or history of corticosteroid dependence (defined as an inability to successfully taper corticosteroids without recurrence of UC) AND history of no prior exposure to approved ATs, such as a biologic agent used to treat UC (eg, anti-TNFs, anti-integrins, anti-IL-12/IL-23, or anti-IL-23) or advanced small molecules used to treat UC (JAKis or S1PR modulators). b) History of inadequate response to, loss of response to or intolerance to treatment with >1 approved AT such as a biologic agent used to treat UC (eg, anti-TNFs, anti-integrins, anti-IL-12/IL-23, or anti-IL-23) or advanced small molecules used to treat UC (JAKis or S1PR modulators).
Oral corticosteroids must be at a stable dose >2 weeks (dose not exceeding 25 mg/day prednisone or prednisone-equivalent dose of ≤20 mg/day, or ≤9 mg/day of budesonide have been at a stable dose for at least 3 weeks prior to baseline or stopped at least 3 weeks prior baseline.
Participants on MTX, AZA, or 6-MP must be on; and on a stable dose for at least 4 weeks prior to baseline; if stopped, medication must have been discontinued at least 4 weeks prior to baseline./
Participants on oral 5-aminosalicylates, mesalamine, or sulfasalazine must be on a stable dose for >2 weeks prior baseline stopped treatment at least 2 weeks prior to baseline./
Participants on biologics must have 1) last administration at least 8 weeks prior to enrollment OR 2) undetectable level of the biologic in their blood prior to enrollment.
Participants who have been diagnosed with UC for ≥8 years must be up to date on their colorectal cancer screening per local guidelines by the time of randomization.
All 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 Treatment Period and for at least 5 months after the last administration of study intervention: - Refrain from donating or cryopreserving 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; the participant should also be advised of the benefit for a female partner to use a highly effective method of contraception as described in Appendix 4 Contraceptive and barrier guidance (Section 10.4) as a condom may break or leak when having sexual intercourse with a WOCBP who is not currently pregnant. b) Female participants - A female participant is eligible to participate if she is incapable of becoming pregnant, not pregnant, or breastfeeding, and one of the following conditions applies: - Is a WONCBP as defined in Appendix 4 Contraceptive and barrier guidance (Section 10.4). 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 defined in Appendix 4 Contraceptive and barrier guidance (Section 10.4) during the study treatment period (to be effective before starting the intervention) and for at least 5 months after the last administration of study intervention. - A WOCBP must have a negative highly sensitive pregnancy test (serum as required by local regulations) within 28 (+7 if needed) days before the first administration of study intervention, see Section 8.3.6. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Capable of giving signed informed consent as described in Section 10.1 which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

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Exclusion Criteria

Participants with Crohn’s Disease.
Known history of or suspected significant current immunosuppression, including history of invasive opportunistic or helminthic infections despite infection resolution or otherwise recurrent infections of abnormal frequency or prolonged duration.
History of solid organ transplant.
History of splenectomy.
History of moderate to severe congestive heart failure (New York Health Association Class III or IV), or recent cerebrovascular accident, or any other condition which, in the opinion of the Investigator, would put the participant at risk by participation in the protocol.
History of demyelinating disease (including myelitis), family history of demyelinating disease, or neurologic symptoms suggestive of demyelinating disease.
Participants with a history of malignancy or lymphoproliferative disease other than adequately treated localized carcinoma in situ of the cervix or nonmetastatic squamous cell carcinoma, or nonmetastatic basal cell carcinoma of the skin.
Participants with a diagnosis of inflammatory conditions other than UC (including but not limited to systemic lupus erythematosus, systemic sclerosis, myositis, rheumatoid arthritis, primary biliary cirrhosis, multiple sclerosis, Behcet’s disease, sarcoidosis, etc.).
Participants with diagnosis of indeterminate colitis or microscopic colitis.
Participants with fecal sample positive for culture/ova 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, or positive on any active infection in the stool with these parasites.
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.
History of recurrent or recent serious infection (eg, pneumonia, septicemia) within 4 weeks of screening, or infection(s) requiring hospitalization or treatment with IV anti-infectives (antibiotics, antivirals, antifungals, antihelminthics) within 30 days prior to baseline, or infections(s) requiring oral anti-infectives (antibiotics, antivirals, antifungals, antihelminthics) within 14 days prior to baseline, except as required as part of an anti-TB regimen.
History of HIV infection or positive HIV serology at Screening.
History of Interstitial Lung Disease.
Participants with any of the following result at Screening: - Positive HBs Ag or, • Positive total anti-HBc AB, • Positive HCV antibody confirmed by positive HCV RNA (participants with HCVAb and negative HCV RNA may be included).
Elective surgery within 4 weeks prior to the Screening Visit or with planned surgery during the treatment period, or in the period up to 3 months following the last dose of IMP.
Positive COVID-19 molecular test, suspected of having COVID-19 infection, or known exposure to COVID-19 during the screening period.
Participants who are simultaneously on AZA, 6-MP, and corticosteroids <4 weeks prior to baseline (participants may be on any two of these therapies >4 weeks prior to baseline).
Participants on cyclosporine, mycophenolate mofetil, sirolimus (rapamycin), thalidomide, or tacrolimus treatment within 28 days prior to baseline..
Participants who have received any of the following agents according to the following timelines: • Anti-TNF therapy (eg, infliximab, adalimumab, certolizumab pegol): within 8 weeks of baseline.* • Anti-integrin therapy (eg, vedolizumab): within 8 weeks of baseline.* • Anti-IL12/23 therapy (eg, ustekinumab): within 8 weeks of baseline.* • Anti-IL-23 therapy (eg, risankizumab, mirikizumab): within 8 weeks of baseline.* • JAKi (eg, tofacitinib, filgotinib, upadacitinib) within 2 weeks of randomization; • S1Prm 2 weeks or less3 half-lives (whichever is longer) within 2 weeks of randomization. *Note: If there is proper documentation of an undetectable drug level measured by a commercially available assay for any of the approved biologics above, there is no mínimum washout prior to randomization
Participants with previous exposure to natalizumab (Tysabri®).
Participants on anti-diarrheals within 2 weeks prior to screening and during the screening period.
Participants on prednisone >20 mg/day (or equivalent) at baseline.
Participants on budesonide >9 mg/day at baseline.
Participants who received IV corticosteroids or cytapheresis therapy within 2 weeks prior to screening or during baseline.
Participants who were rectally administered topical 5-aminosalicylate or corticosteroids within 2 weeks prior to screening colonoscopy..
Participants who received therapeutic enema or suppository, within 2 weeks prior to or during screening.
Participants who received antibiotics for UC or gastrointestinal infection within 4 weeks prior to baseline.
Treatment with a live (attenuated) immunization within 12 weeks prior to baseline; treatment with a non-live immunization 2 weeks prior to baseline; completion of COVID-19 vaccine within 14 days prior to baseline.
Participants who have taken other investigational medications within 2 months or 5 half-lives (whichever is longer) prior to screening.
Exclusion related to TB infection: - Active TB infection a history of incompletely treated TB infection regardless of screening QuantiFERON TB gold test result. - Participants with QuantiFERON TB gold test positive or 2 indeterminate test results (no active disease) are excluded from the study unless the following conditions are met: - Participants with a history of prior documented completed chemoprophylaxis for latent TBI (eg, acceptable treatments would be 9 months of isoniazid 300 mg PO daily or equivalent proven regimen per local guidelines) or treatment of active TBI who has obtained consultation with a specialist to rule out active TBI or treat active TBI.- Participants with no prior history of chemoprophylaxis for latent TBI or treatment for active TBI but have obtained consultation with a specialist to initiate an appropriate regimen of chemoprophylaxis, based on local epidemiology and applicable guidelines and have demonstrated compliance and tolerated treatment for ≥1 month. -Known clinically significant abnormality consistent with prior/active TB infection based upon previously performed chest radiograph with at least posterior-anterior view (radiograph must be taken within 12 weeks prior to Screening Visit or during the screening period). Additional lateral view is recommended but not required. - Suspected extrapulmonary TB infection regardless of screening QuantiFERON TB Gold test result. - Participants at high risk of contracting TB, such as close contact with individuals with active or latent TB. - Participant who received Bacille Calmette-Guérin vaccination within 12 months prior to screening.
Any of the following laboratory abnormalities at the Screening Visit: - Hemoglobin <8 g/dL. - ANC <1500/mm3. - Platelet count <100 000/mm3. - Creatinine clearance <60 mL/min using Cockcroft-Gault equation. - ALT, AST, or ALP >2 × ULN. - Total bilirubin >2 × ULN or, ≥3 × ULN if diagnosed with Gilbert's syndrome verified by genetic testing. - Fasting triglyceride level ≥300 mg/dL.
Individuals accommodated in an institution because of regulatory or legal order; prisoners or participants who are legally institutionalized.
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.
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 (in conjunction with Section 1.61 of the ICH-GCP Ordinance E6).
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.
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.
Any country-related specific regulation that would prevent the participant from entering the study – see Section 10.7.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Czechia	Not Recruiting	20 Sept 2025	8
France	Not Recruiting	20 Sept 2025	6
Germany	Recruiting	20 Sept 2025	15
Hungary	Not Recruiting	20 Sept 2025	4
Poland	Not Recruiting	20 Sept 2025	20
Spain	Not Recruiting	20 Sept 2025	4