NOV-ERA - A Clinical Trial to Assess the Efficacy and Safety of Ontunisertib Compared to Placebo in Patients With Fibrostenosing Crohn's Disease

Official title

A Phase 2b, Randomized, Placebo-controlled, Double-blind, Dose-ranging Trial to Assess the Efficacy and Safety of Ontunisertib in Patients With Fibrostenosing Crohn's Disease

Overview

Many patients with Crohn's disease (CD) develop fibrotic narrowing (strictures) in their bowel, causing obstructive symptoms such as abdominal pain, cramping, or vomiting after meals. Because of these symptoms, patients often require bowel resection surgery. The objective of this clinical trial is to evaluate the efficacy, safety, and dose-response relationship of ontunisertib in participants with CD and symptomatic strictures, and contribute to the validation of novel endpoints to assess potential treatment benefit in patients with fibrostenosing Crohn's disease (FSCD). The participants will be in the trial for a duration of up to 60 weeks, consisting of a 6-week screening period (with 2 screening visits), a 52-week treatment period, and a 2-week follow-up period. The visit frequency in the treatment period will be every 6 to 8 weeks.

Detailed description

This is a randomized, double-blind, placebo-controlled, dose-ranging, multicenter Phase 2b trial to assess the efficacy and safety of ontunisertib in participants diagnosed with FSCD. The trial population will include adults 18 years of age and older with symptomatic FSCD based on clinical, endoscopic, and radiological criteria.

This trial consists of 3 periods (a screening period, a placebo-controlled, double-blind treatment period, and safety follow-up). After signing informed consent, eligibility will be assessed during a 6-week screening period. The presence of qualifying intestinal strictures will be assessed by ileocolonoscopy and magnetic resonance enterography (MRE). The presence of obstructive symptoms will also be evaluated.

Eligible participants will be randomized 1:1:1:1 to receive AGMB-129 (Ontunisertib) high dose, medium dose, low dose or placebo for 52 weeks.

During Screening and Weeks 24 and 52 visits, participants will undergo ileocolonoscopy with biopsy collection for exploring pharmacodynamics. Participants will have blood sample collection at Weeks 6, 12, 18, 24, 30, 36, 44 and 52 to assess safety, pharmacokinetics, and pharmacodynamics.

Throughout the study, participants will undergo routine safety assessments at study visits, which will include physical examination, vital signs, clinical laboratory assessment, electrocardiogram (ECG), and recording of AEs.

Interventions

• Drug Ontunisertib
  Oral capsule
• Drug Ontunisertib
  Oral capsule
• Drug Ontunisertib
  Oral capsule
• Drug Placebo
  Matching oral capsule

Primary outcome measures

• Proportion of participants achieving endoscopic passability of the ileal index stricture [Time frame: At week 24]

Secondary outcome measures (12)

• Proportion of participants achieving endoscopic passability of the ileal index stricture [Time frame: At week 52]
• Change in reliable MRE imaging features (stricture length, bowel wall thickness, prestenotic dilatation diameter) of the index stricture [Time frame: At week 52 compared to baseline (week 1)]
• Change in total SES-CD (range, 0-56 points) (Reference: https://www.giejournal.org/article/S0016-5107(04)01878-4/abstract) [Time frame: At week 52 compared to baseline]
• Proportion of participants with an endoscopic response (≥50% decrease in total SES-CD) and remission (SES-CD ≤4 with no item >1) [Time frame: At week 52 compared to baseline]
• Change in S-PRO severity score [Time frame: At week 52 compared to baseline]
• Time to an FSCD- related event [Time frame: From baseline to week 52]
• Number of participants with adverse events (AEs) [Time frame: From baseline to week 52]
• Number of participants with abnormal clinical laboratory tests [Time frame: From baseline to week 52]
• Number of participants with abnormal ECG parameters [Time frame: From baseline to week 52]
• Number of participants with abnormal vital signs [Time frame: From baseline to week 52]
• Number of participants with abnormal physical examinations [Time frame: From baseline to week 52]
• Plasma level concentration of ontunisertib and metabolites [Time frame: From baseline to week 52]

Eligibility criteria

Inclusion criteria

• Diagnosis of ileal or ileocolonic CD based on clinical and endoscopic or radiological evidence established at least 12 weeks prior to signing the ICF.
• Presence of at least 1 endoscopically non-passable ileal stricture.
• Present stricture(s) can be naïve or anastomotic, and will be confirmed by centrally read MRE.
• Presence of (sub)obstructive symptoms AND/OR dietary restrictions like limiting the amount or type of food, and/or food processing methods.
• Participants should be on stable anti-inflammatory background therapy for CD and agree to maintain stable background therapy for the duration of the trial.
• Participants should have a body mass index ≥18 kg/m2 and <35 kg/m2.
• Not expected in the investigator's opinion to require hospitalization, endoscopic balloon dilation, surgical resection, or optimized anti-inflammatory therapy during the first 4 weeks of the trial.

Exclusion criteria

• History or current diagnosis of ulcerative colitis, indeterminate colitis, ischemic colitis, nonsteroidal anti-inflammatory drug-induced colitis, idiopathic colitis (i.e., colitis not consistent with CD), radiation colitis, microscopic colitis, colonic mucosal dysplasia, untreated bile acid malabsorption, or infectious colitis.
• CD-related complications:

• Short bowel syndrome (<200 cm small bowel remaining).
• Ileostomy (diverting or end), colostomy, small bowel stoma, or ileoanal pouch.
• Internal fistulae and sinus tracts deriving from the area of stenosis. Participants with perianal fistulae could be included if not septic.
• Anal and perianal stricture.
• Suspected or diagnosed active intra-abdominal or perianal abscess that has not been appropriately treated and abscess in relation to the stricture.
• Toxic megacolon.
• Blind-ending sinus could be included.
• Endoscopic balloon dilation or surgical treatment of the index small bowel stricture within the last 6 months prior to screening.
• Current or history of valvulopathy, or moderate or severe heart valve function defect, including moderate or severe valve stenosis or regurgitation OR left ventricular ejection fraction <50% as assessed locally through echocardiography.
• Any other severe acute or chronic medical condition, psychiatric disorder, laboratory abnormality, or systemic or opportunistic infection that may increase the risk associated with trial participation or trial treatment administration, or may interfere with the interpretation of trial results, as determined by the investigator.
• Clinically significant abnormal vital signs, physical examination, or abnormalities at 12-lead ECG at screening or baseline.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT07683325 · AGMB129-01-CL-201

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗