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

Sponsor
University of Calgary (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05928039
Collaborator
Alimentiv Inc. (Other)
297
1
3
65
4.6

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
  • 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
Phase 4

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 Design

Study Type:
Interventional
Anticipated Enrollment :
297 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
This trial is a prospective, randomized, open-label, blinded-endpoint (PROBE) trial. The primary endpoint will be evaluated by a blinded, external central reviewer.This trial is a prospective, randomized, open-label, blinded-endpoint (PROBE) trial. The primary endpoint will be evaluated by a blinded, external central reviewer.
Masking:
Single (Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Anticipated Study Start Date :
Aug 1, 2023
Anticipated Primary Completion Date :
Jul 30, 2027
Anticipated Study Completion Date :
Dec 31, 2028

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

  1. Corticosteroid-free endoscopic remission [1 year]

    SES-CD ≤4, ileal segment SES-CD ≤2, and no ulcers in any segment >5 mm, off corticosteroids for ≥ 16 weeks

Secondary Outcome Measures

  1. CD-related complications [1 year]

    Composite of disease flare, obstruction, new fistula/abscess, CD-related hospitalization, CD-related surgery

  2. Time to first Crohn's disease-related complication. [Time to event]

    Composite of disease flare, obstruction, new fistula/abscess, CD-related hospitalization, CD-related surgery

  3. Biomarker remission [Months 4, 8, and 12]

    C-reactive protein (CRP) <5 mg/L and fecal calprotectin <250 µg/g, assessed in participants with elevated biomarkers at baseline

  4. Corticosteroid-free clinical remission [Months 4, 8, and 12]

    Harvey Bradshaw Index [HBI] ≤4 without exposure to systemic corticosteroids for ≥16 weeks prior to assessment

  5. Treatment persistence [1 year]

    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

  6. Health-related quality of life after first-line biologic treatment [1 year]

    Quality of life at 1-year measured using EuroQol 5D (range 0 [worst imaginable health state] to 100 [best imaginable health state])

  7. Safety of first-line biologic treatment [1 year]

    Unexpected AEs, severe AEs, drug and procedure-related AEs, any serious AEs (SAEs), any AEs leading to biologic discontinuation

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Calgary Calgary Alberta Canada

Sponsors and Collaborators

  • University of Calgary
  • Alimentiv Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
University of Calgary
ClinicalTrials.gov Identifier:
NCT05928039
Other Study ID Numbers:
  • REB22-1641/RCT-01741
First Posted:
Jul 3, 2023
Last Update Posted:
Jul 3, 2023
Last Verified:
Jun 1, 2023
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

No Results Posted as of Jul 3, 2023