PATHFINDER: Evaluating the Optimal First-Line Treatment Strategy for Moderate-to-Severely Active Ileal-dominant Crohn's Disease (PATHFINDER)

PATHFINDER: A Pragmatic, Active-comparator, Parallel-group, Randomized Trial to Evaluate the Optimal First-line Treatment Strategy for Moderate-to-Severely Active Ileal-dominant Crohn's Disease

There are currently three classes of biologic treatments approved in Canada for the management of moderate-to-severe Crohn's disease: anti-tumor necrosis factor [TNF] alpha, anti-integrin, and anti-interleukin [IL]-23 targeted agents. The purpose of this trial is to determine which of these three classes of biologics results in the highest percentage of patients with small bowel (ileal) Crohn's disease entering into endoscopic remission without needing corticosteroids at 1 year. Endoscopic remission means that the ulcers in the small bowel from Crohn's disease have healed. All treatments in this trial are approved by Health Canada. No experimental drugs will be included.

Study Overview

• Status: Recruiting
• Conditions: Crohn Disease
• Intervention / Treatment: Biological: TNFa Antagonist - Infliximab; Biological: TNFa Antagonist - Adalimumab; Biological: Anti-IL12/23 or anti-IL23 - Ustekinumab; Biological: Anti-IL12/23 or anti-IL23 - Risankizumab; Biological: Anti-integrin - Vedolizumab IV; Biological: Anti-integrin - Vedolizumab IV and SC

Detailed Description

This is a pragmatic, real-world trial of patients with moderate-to-severe, ileal-dominant Crohn's disease. At week 0, participants who meet the eligibility criteria will be randomized in a 1:1:1 ratio to a TNF antagonist; anti-integrin; or anti-IL23 targeted treatment. All interventions will be offered according to standard of care.

The dosing will be as follows:

TNFα antagonist

• Infliximab 5 mg/kg intravenously [IV] at weeks 0, 2, 6, then 5 mg/kg every 8 weeks; OR
• Adalimumab subcutaneously [SC] 160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks

Anti-integrin

• Vedolizumab 300 mg IV at weeks 0, 2, and 6, then every 8 weeks; OR
• Vedolizumab 300 mg IV at weeks 0 and 2, then 108 mg SC every 2 weeks

Anti-IL23 targeted agents

• Ustekinumab ~6 mg/kg IV x1, then 90 mg SC every 8 weeks; OR
• Risankizumab 600 mg IV at weeks 0, 4, and 8, then 360 mg SC every 8 weeks

All treatments will be administered as part of the participant's routine care. All participants will be monitored per standard of care. Participants on corticosteroids at baseline will begin a steroid taper within 6 weeks of starting their biologic. At months 4, 8 and 12 participants will be evaluated for the Harvey Bradshaw Index (HBI), EuroQOL 5-domain questionnaire (EQ-5D), and be tested for C-reactive protein and fecal calprotectin concentrations. At month 12 patients will undergo a video-recorded ileocolonoscopy to determine if they have achieved endoscopic remission.

• Study Type: Interventional
• Enrollment (Estimated): 297
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Harsha Ashton; Phone Number: 226-919-6959; Email: harsha.ashton@alimentiv.com
• Study Contact Backup: Name: Christopher Ma, MD MPH; Phone Number: 4035925013; Email: christopher.ma@ucalgary.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Recruiting
      • University of Calgary
      • Contact: Heather Baylis; Email: hbaylis@ucalgary.ca
      • Principal Investigator: Christopher Ma, MD MPH
      • Sub-Investigator: Remo Panaccione, MD
      • Contact: Ashley Clarke, MSc; Phone Number: 4032109141; Email: anclarke@ucalgary.ca
    • Edmonton, Alberta, Canada
      • Recruiting
      • University of Alberta IBD Clinic
      • Principal Investigator: Frank Hoentjen, MD
  • British Columbia
    • Vancouver, British Columbia, Canada
      • Not yet recruiting
      • GI Research Institute (G.I.R.I)
      • Principal Investigator: Yvette Leung, MD
    • Vancouver, British Columbia, Canada
      • Not yet recruiting
      • West Coast Gastroenterology
      • Principal Investigator: Sunny Singh, MD
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Active, not recruiting
      • Nova Scotia Health Victoria
  • Ontario
    • Brampton, Ontario, Canada
      • Not yet recruiting
      • GNRR Digestive Clinics and Research Center Inc.
      • Principal Investigator: Girsh Bajaj, MD
    • Brantford, Ontario, Canada
      • Not yet recruiting
      • Rajbir Rai Medical Corporation
      • Principal Investigator: Rajbir Rai, MD
    • Hamilton, Ontario, Canada
      • Recruiting
      • McMaster University
      • Principal Investigator: Neeraj Narula, MD
    • London, Ontario, Canada
      • Active, not recruiting
      • London Health Sciences Centre
    • Mississauga, Ontario, Canada
      • Not yet recruiting
      • West GTA Research Inc.
    • Oakville, Ontario, Canada
      • Not yet recruiting
      • ABP Research Services Corp.
      • Principal Investigator: Naveen Arya, MD
    • Oshawa, Ontario, Canada
      • Not yet recruiting
      • Taunton Surgical Center
      • Principal Investigator: Daniel Green, MD
    • Ottawa, Ontario, Canada
      • Recruiting
      • The Ottawa Hospital Research Institute
      • Principal Investigator: Sanjay Murthy, MD
    • Thunder Bay, Ontario, Canada
      • Active, not recruiting
      • Thunder Bay Regional Health Research Institute
    • Toronto, Ontario, Canada
      • Recruiting
      • Mount Sinai Hospital
      • Principal Investigator: Laura Targownik, MD
    • Toronto, Ontario, Canada
      • Active, not recruiting
      • TIDHI Clinic
  • Quebec
    • Montreal, Quebec, Canada
      • Recruiting
      • Centre Hospitalier de l'Universite de Montreal (CHUM)
      • Principal Investigator: Robert Battat, MD
    • Montreal, Quebec, Canada
      • Recruiting
      • Hôpital du Sacré-Cœur-de-Montréal
      • Principal Investigator: Jean-Frédéric LeBlanc, MD
    • Montreal, Quebec, Canada
      • Recruiting
      • Research Institute of the McGill University Health Centre (MUHC)
      • Principal Investigator: Talat Bessisow, MD
    • Sherbrooke, Quebec, Canada
      • Not yet recruiting
      • Université de Sherbrooke
      • Principal Investigator: Maxime Delisle, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or nonpregnant, nonlactating females, 18 years of age or older. Females of childbearing potential must have a negative serum or urine pregnancy test prior to randomization
2. Established CD diagnosis by conventional criteria
3. Baseline colonoscopy within 3 months of the first day of the screening period, with photo or video documentation of at least one large ileal ulcer >5 mm and ileal segment SES-CD ≥4 (eligibility will be determined by local endoscopist, with subsequent confirmation by a CR at a later time, post enrolment)
4. HBI ≥5
5. Biologic-treatment naïve for CD-related therapies
6. Would otherwise have been eligible to start a biologic for moderate-to-severely active CD as part of their routine clinical care and for whom there is equipoise around which biologic class to start
7. Willing and able to participate fully in all aspects of this clinical trial, including adherence to study protocol and treatment algorithm
8. Written informed consent must be obtained and documented

Exclusion Criteria:

1. Condition(s) for which the biologics included in this study is contraindicated
2. CD-related complications such as symptomatic, endoscopically impassable strictures or abscesses that require imminent surgery (at investigator's discretion)
3. Participants with current or history of colonic dysplasia or neoplasia, toxic megacolon, or fulminant colitis
4. Recent bowel resection <3 months before screening
5. Active enteric infection (positive stool culture), including but not limited to bacterial (including C. difficile), viral, or parasitic enteric infections
6. Known active hepatitis B, hepatitis C, or human immunodeficiency virus infection
7. Active COVID-19 infection during the screening period
8. Tested positive as part of SOC for tuberculosis (TB) at screening by QuantiFERON® TB Gold Test, tuberculin skin test, or history of untreated latent or active TB
9. History of malignancy within 5 years of screening, except fully treated carcinoma in-situ of the cervix, fully treated and resolved nonmetastatic squamous or basal cell carcinoma of the skin
10. Active chronic or acute infections requiring treatment with systemic antibiotics, antivirals, antifungals, antiparasitics, or antiprotozoals during the screening period
11. Serious underlying disease other than CD that, in the opinion of the investigator, may interfere with the participant's ability to participate fully in the study
12. Not willing to withhold protocol-prohibited medications during the trial, or planned or anticipated use of any prohibited medications during screening
13. Received previously or currently receiving a TNF antagonist, anti-integrin, monoclonal antibody targeting IL-12/23 or IL-23, Janus kinase (JAK) inhibitors, or sphingosine 1 phosphate (S1P) receptor modulators (irrespective of indication)
14. History of alcohol or drug abuse that, in the opinion of the investigator, may interfere with the participant's ability to comply with the study procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: TNFα antagonist; Participants will receive either: Infliximab 5 mg/kg intravenously [IV] at weeks 0, 2, 6, then 5 mg/kg every 8 weeks; OR; Adalimumab subcutaneously [SC] 160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks	Biological: TNFa Antagonist - Infliximab; • Infliximab 5 mg/kg intravenously [IV] at weeks 0, 2, 6, then 5 mg/kg every 8 weeks; Biological: TNFa Antagonist - Adalimumab; • Adalimumab subcutaneously [SC] 160 mg at week 0, 80 mg at week 2, then 40 mg every 2 weeks
Active Comparator: Anti-IL12/23 or anti-IL23; Participants will receive either: Ustekinumab ~6 mg/kg IV x1, then 90 mg SC every 8 weeks; OR; Risankizumab 600 mg IV at weeks 0, 4, and 8, then 360 mg SC every 8 weeks	Biological: Anti-IL12/23 or anti-IL23 - Ustekinumab; • Ustekinumab ~6 mg/kg IV x1, then 90 mg SC every 8 weeks; Biological: Anti-IL12/23 or anti-IL23 - Risankizumab; • Risankizumab 600 mg IV at weeks 0, 4, and 8, then 360 mg SC every 8 weeks
Active Comparator: Anti-integrin; Participants will receive either: Vedolizumab 300 mg IV at weeks 0, 2, and 6, then every 8 weeks; OR; Vedolizumab 300 mg IV at weeks 0 and 2, then 108 mg SC every 2 weeks	Biological: Anti-integrin - Vedolizumab IV; • Vedolizumab 300 mg IV at weeks 0, 2, and 6, then every 8 weeks; Biological: Anti-integrin - Vedolizumab IV and SC; • Vedolizumab 300 mg IV at weeks 0 and 2, then 108 mg SC every 2 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Corticosteroid-free endoscopic remission	SES-CD ≤4, ileal segment SES-CD ≤2, and no ulcers in any segment >5 mm, off corticosteroids for ≥ 16 weeks	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD-related complications	Composite of disease flare, obstruction, new fistula/abscess, CD-related hospitalization, CD-related surgery	1 year
Biomarker remission	C-reactive protein (CRP) <5 mg/L and fecal calprotectin <250 µg/g, assessed in participants with elevated biomarkers at baseline	Months 4, 8, and 12
Corticosteroid-free clinical remission	Harvey Bradshaw Index [HBI] ≤4 without exposure to systemic corticosteroids for ≥16 weeks prior to assessment	Months 4, 8, and 12
Treatment persistence	Duration of time from first biologic dose to discontinuation, the proportion of participants requiring a class switch, and the proportion of participants requiring dose optimization of biologic treatment or addition of rescue immunomodulators	1 year
Health-related quality of life after first-line biologic treatment	Quality of life at 1-year measured using EuroQol 5D (range 0 [worst imaginable health state] to 100 [best imaginable health state])	1 year
Safety of first-line biologic treatment	Unexpected AEs, severe AEs, drug and procedure-related AEs, any serious AEs (SAEs), any AEs leading to biologic discontinuation	1 year
Time to first Crohn's disease-related complication.	Composite of disease flare, obstruction, new fistula/abscess, CD-related hospitalization, CD-related surgery	From date of randomization until the date of first documented Crohn's disease-related complication or date of death from any cause, whichever came first, assessed up to 12 months

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Alimentiv Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2023
• Primary Completion (Estimated): July 30, 2027
• Study Completion (Estimated): December 31, 2028

Study Registration Dates

• First Submitted: June 13, 2023
• First Submitted That Met QC Criteria: June 22, 2023
• First Posted (Actual): July 3, 2023

Study Record Updates

• Last Update Posted (Actual): June 11, 2025
• Last Update Submitted That Met QC Criteria: June 6, 2025
• Last Verified: June 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Intestinal Diseases; Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Inflammatory Bowel Diseases; Crohn Disease; Tumor Necrosis Factor Inhibitors; Antineoplastic Agents; Immunologic Factors; Physiological Effects of Drugs; Anti-Inflammatory Agents; Gastrointestinal Agents; Antirheumatic Agents; Dermatologic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Adjuvants, Immunologic; Adalimumab; Infliximab; Ustekinumab; Vedolizumab; Interleukin-12; Interleukin-23
• Other Study ID Numbers: REB22-1641/RCT-01741

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified patient information may be shared at the discretion the the trial steering committee and upon written request.
• IPD Sharing Time Frame: Data will be available after completion of the trial and publication of results. Data will be retained for 15 years.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No