Clinical trial NCT05588843: Dose-finding Study of SAR443122 in Adult Participants With Ulcerative Colitis
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Colitis Ulcerative
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2022-10-20
Enrollment: 182
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a randomized, double-blind, placebo controlled, dose-ranging Phase 2 study. The primary objective is to evaluate the efficacy and safety of SAR443122 compared to placebo in participants with moderate to severe UC. Dose selection for further clinical development will be based on the multiple efficacy, safety and PK parameters.

The study consists of 4 parallel arms (3 dose groups of SAR443122 vs placebo) to assess the efficacy and safety of SAR443122 in participants with moderate to severe UC. All participants will receive a total of 52 weeks (a 12-week induction treatment phase and a 40-week maintenance phase) of study treatment, except if treatment should be discontinued per investigator's assessment.

At the end of the first 12 weeks of induction treatment, all participants in clinical response or remission will be offered study treatment up to 40 weeks and will continue with the same blinded treatment that was assigned. Participants who do not achieve clinical response or remission at the end of the initial 12 weeks induction treatment will roll over in an open-label treatment arm and will be treated with SAR443122 at the highest tested dose.

In addition, participants from the maintenance treatment that lose clinical efficacy at any time up to V10/Week 40 (Week 28 of maintenance) will be offered to roll over in the open-label treatment arm with SAR443122 at the highest dose.

Detailed description: Total study duration per participant will be up to 58 weeks, including a screening period of up to 4 weeks, a treatment period up to 52 weeks and a post-treatment follow-up period of 2 weeks.

Eligibility criteria: 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 or 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.

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 half--lives, (whichever is longer) prior to screening.
* Presence of significant laboratory findings at the Screening Visit.

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Primary outcomes:
measure: Proportion of participants who achieve clinical remission at Week 12 by modified Mayo Score (mMS)
timeFrame: At Week 12
Secondary outcomes:
measure: Proportion of participants who achieve endoscopic improvement at Week 12
timeFrame: At Week 12
measure: Proportion of participants who achieve clinical response at Week 12 by mMS
timeFrame: At Week 12
measure: Proportion of participants who achieve clinical remission at Week 12 by full Mayo Score (MS)
timeFrame: At Week 12
measure: Proportion of participants who achieve clinical response at Week 12 by MS.
timeFrame: At Week 12
measure: Change from baseline on patient-reported outcome 2 (PRO2) total score (Mayo stool frequency and rectal bleeding subscores) over time
timeFrame: From baseline to Week 12
measure: Proportion of participants who achieve histological improvement at Week 12
timeFrame: At Week 12
measure: Proportion of participants who achieve Histologic-endoscopic mucosal improvement (HEMI) at Week 12 defined by achievement of modified Mayo endoscopic improvement and histological improvement
timeFrame: At Week 12
measure: Change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) total score at Week 12
timeFrame: At Week 12
measure: Change from baseline in bowel signs and symptoms assessed by Ulcerative Colitis Patient Reported Outcome Signs and Symptoms (UC-PRO/SS) at Week 12
timeFrame: At Week 12
measure: Change from baseline in abdominal signs and symptoms assessed by UC-PRO/SS at Week 12
timeFrame: At Week 12
measure: Pharmacokinetic parameters: maximum concentration [Cmax]
timeFrame: Until Week 52
measure: Pharmacokinetic parameters: time to Cmax [tmax]
timeFrame: Until Week 52
measure: Pharmacokinetic parameters: area under the curve over the dosing interval [AUC0-tau]
timeFrame: Until Week 52
measure: Pharmacokinetic parameters: elimination half-life [t1/2z]
timeFrame: Until Week 52
measure: Participants with any Treatment Emergent Adverse Events (TEAEs) during induction and maintenance treatment period
timeFrame: Until Week 52
measure: Participants with any TEAEs during open-label treatment period
timeFrame: Up to Week 52
Other outcomes:
Locations:
city: Lancaster
country: United States
facility: Om Research LLC- Site Number : 8400014
state: California
city: Atlanta
country: United States
facility: Agile Clinical Research Trials- Site Number : 8400024
state: Georgia
city: Liberty
country: United States
facility: BVL Research- Site Number : 8400015
state: Missouri
city: Las Vegas
country: United States
facility: Vector Clinical Trials- Site Number : 8400004
state: Nevada
city: East Orange
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facility: Sanmora Bespoke Clinical Research Solutions- Site Number : 8400016
state: New Jersey
city: Brooklyn
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facility: NY Scientific- Site Number : 8400013
state: New York
city: New York
country: United States
facility: Pioneer Clinical Research - New York- Site Number : 8400017
state: New York
city: Germantown
country: United States
facility: Gastro One - Germantown- Site Number : 8400002
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist Research Institute- Site Number : 8400023
state: Texas
city: Houston
country: United States
facility: 1960 Family Practice- Site Number : 8400019
state: Texas
city: Mansfield
country: United States
facility: GI Alliance - Mansfield- Site Number : 8400010
state: Texas
city: Sugar Land
country: United States
facility: Integrity Research - Sugar Land- Site Number : 8400026
state: Texas
city: Richmond
country: United States
facility: Richmond VA Medical Center- Site Number : 8400022
state: Virginia
city: Rosario
country: Argentina
facility: Investigational Site Number : 0320003
state: Santa Fe
city: San Miguel de Tucumán
country: Argentina
facility: Investigational Site Number : 0320001
state: Tucumán
city: Buenos Aires
country: Argentina
facility: Investigational Site Number : 0320006
city: Buenos Aires
country: Argentina
facility: Investigational Site Number : 0320002
city: Córdoba
country: Argentina
facility: Investigational Site Number : 0320004
city: Córdoba
country: Argentina
facility: Investigational Site Number : 0320005
city: Talcahuano
country: Chile
facility: Investigational Site Number : 1520004
state: Biobío
city: Santiago
country: Chile
facility: Investigational Site Number : 1520001
state: Reg Metropolitana De Santiago
city: Santiago
country: Chile
facility: Investigational Site Number : 1520005
state: Reg Metropolitana De Santiago
city: Santiago
country: Chile
facility: Investigational Site Number : 1520006
state: Reg Metropolitana De Santiago
city: Guangzhou
country: China
facility: Investigational Site Number : 1560001
city: Hangzhou
country: China
facility: Investigational Site Number : 1560004
city: Hefei
country: China
facility: Investigational Site Number : 1560003
city: Nanchang
country: China
facility: Investigational Site Number : 1560006
city: Nanjing
country: China
facility: Investigational Site Number : 1560007
city: Shanghai
country: China
facility: Investigational Site Number : 1560005
city: Shenyang
country: China
facility: Investigational Site Number : 1560002
city: Hradec Králové
country: Czechia
facility: Investigational Site Number : 2030001
city: Klatovy
country: Czechia
facility: Investigational Site Number : 2030002
city: Prague
country: Czechia
facility: Investigational Site Number : 2030003
city: České Budějovice
country: Czechia
facility: Investigational Site Number : 2030007
city: Marseille
country: France
facility: Investigational Site Number : 2500007
city: Nantes
country: France
facility: Investigational Site Number : 2500008
city: Neuilly-sur-seine
country: France
facility: Investigational Site Number : 2500006
city: Vandœuvre-lès-nancy
country: France
facility: Investigational Site Number : 2500001
city: Batumi
country: Georgia
facility: Investigational Site Number : 2680003
city: Tbilisi
country: Georgia
facility: Investigational Site Number : 2680002
city: Tbilisi
country: Georgia
facility: Investigational Site Number : 2680004
city: Fulda
country: Germany
facility: Investigational Site Number : 2760003
city: Kiel
country: Germany
facility: Investigational Site Number : 2760001
city: Ludwigshafen
country: Germany
facility: Investigational Site Number : 2760008
city: ULM
country: Germany
facility: Investigational Site Number : 2760006
city: Budapest
country: Hungary
facility: Investigational Site Number : 3480005
city: Budapest
country: Hungary
facility: Investigational Site Number : 3480002
city: Békéscsaba
country: Hungary
facility: Investigational Site Number : 3480001
city: Gyöngyös
country: Hungary
facility: Investigational Site Number : 3480006
city: Gurugram
country: India
facility: Investigational Site Number : 3560003
city: Jaipur
country: India
facility: Investigational Site Number : 3560009
city: Kochi
country: India
facility: Investigational Site Number : 3560005
city: Ludhiana
country: India
facility: Investigational Site Number : 3560004
city: Pune
country: India
facility: Investigational Site Number : 3560007
city: Rajkot
country: India
facility: Investigational Site Number : 3560008
city: Surat
country: India
facility: Investigational Site Number : 3560010
city: Surat
country: India
facility: Investigational Site Number : 3560011
city: Thiruvananthapuram
country: India
facility: Investigational Site Number : 3560006
city: Vivekanand MARG
country: India
facility: Investigational Site Number : 3560001
city: Milan
country: Italy
facility: Investigational Site Number : 3800007
state: Milano
city: Milan
country: Italy
facility: Investigational Site Number : 3800003
state: Milano
city: Rozzano
country: Italy
facility: Investigational Site Number : 3800005
state: Milano
city: Rome
country: Italy
facility: Investigational Site Number : 3800002
state: Roma
city: Catanzaro
country: Italy
facility: Investigational Site Number : 3800004
city: Palermo
country: Italy
facility: Investigational Site Number : 3800006
city: Pavia
country: Italy
facility: Investigational Site Number : 3800001
city: Nagaoka
country: Japan
facility: Investigational Site Number : 3920011
state: Niigata
city: Hamamatsu
country: Japan
facility: Investigational Site Number : 3920005
state: Shizuoka
city: Fukushima
country: Japan
facility: Investigational Site Number : 3920002
city: Oita
country: Japan
facility: Investigational Site Number : 3920001
city: Osaka
country: Japan
facility: Investigational Site Number : 3920003
city: Saitama
country: Japan
facility: Investigational Site Number : 3920006
city: Tokyo
country: Japan
facility: Investigational Site Number : 3920007
city: Chihuahua
country: Mexico
facility: Investigational Site Number : 4840001
city: Chihuahua
country: Mexico
facility: Investigational Site Number : 4840003
city: Durango
country: Mexico
facility: Investigational Site Number : 4840002
city: Amsterdam
country: Netherlands
facility: Investigational Site Number : 5280001
city: Nijmegen
country: Netherlands
facility: Investigational Site Number : 5280002
city: Tilburg
country: Netherlands
facility: Investigational Site Number : 5280004
city: Wroclaw
country: Poland
facility: Investigational Site Number : 6160004
state: Dolnoslaskie
city: Leczna
country: Poland
facility: Investigational Site Number : 6160010
state: Lubelskie
city: Krakow
country: Poland
facility: Investigational Site Number : 6160006
state: Malopolskie
city: Warsaw
country: Poland
facility: Investigational Site Number : 6160002
state: Mazowieckie
city: Katowice
country: Poland
facility: Investigational Site Number : 6160009
state: Slaskie
city: Katowice
country: Poland
facility: Investigational Site Number : 6160016
city: Krakow
country: Poland
facility: Investigational Site Number : 6160015
city: Tychy
country: Poland
facility: Investigational Site Number : 6160011
city: Wloclawek
country: Poland
facility: Investigational Site Number : 6160018
city: Banská Bystrica
country: Slovakia
facility: Investigational Site Number : 7030003
city: Košice
country: Slovakia
facility: Investigational Site Number : 7030002
city: Nitra
country: Slovakia
facility: Investigational Site Number : 7030001
city: Gijón
country: Spain
facility: Investigational Site Number : 7240007
state: Asturias
city: Barcelona
country: Spain
facility: Investigational Site Number : 7240006
state: Barcelona [Barcelona]
city: Cambridge
country: United Kingdom
facility: Investigational Site Number : 8260002
state: Cambridgeshire
city: London
country: United Kingdom
facility: Investigational Site Number : 8260006
state: London, City Of
city: Warrington
country: United Kingdom
facility: Investigational Site Number : 8260003
Study officials:
References: