A Prospective Randomised Study of Treatment Selection Based on Epigenetic Markers Versus Standard of Care Treatment Selection in Adults With CROHN's Disease

Overview

This is a multicentre, prospective, randomised, controlled, open-label study to assess the efficacy, safety, and cost-effectiveness of epigenome-guided treatment selection compared to usual standard-of-care (SOC) treatment selection in patients initiating biologic therapy for the treatment of their active Crohn's Disease (CD).

Detailed description

This trial will include 378 participants with active CD, defined as an HBI \> 6 and the presence of endoscopic ulceration. Approximately 50% of the enrolled population will be bio-naïve and 50% exposed to no more than 1 prior biologic.

Eligible participants will be randomised 1:1 to either epigenome-guided treatment selection or usual SOC treatment selection. Randomization will be stratified by prior biologic use (yes/no) and corticosteroid use (yes/no) at baseline.

Blood samples for the assessment will be collected for all participants during screening. Peripheral blood will be tested via a machine-learning-powered epigenetic biomarker assay. EpiPredict is a software designed for CSV file input, data transfer, storage, and display, and will be serving as a EpiPredict clinical decision support system. It recommends treatment selections for 2 biologics (Vedolizumab (VDZ) and Vedolizumab (UST)) for CD utilizing genetic data.

The intervention (EpiPredict software) will indicate the probability of response to both VDZ and UST (though sites will only be provided with the treatment with the highest outcome) for the treatment of CD using a hybrid capture-based methylation assay (approved for research use only) and the EpiPredict software.

All participants in the study will be administered their biologic therapy in accordance with the product label and local SOC recommendations. Dose adjustments will be allowed in both groups at the treating investigator's discretion.

During the 26-week treatment period, the study assessments will follow the SOC regimen of the assigned biologic treatment. For participants receiving VDZ, study assessments are to occur at Weeks 6, 14, and 26; for participants receiving UST, study assessments are to occur at Weeks 8, 16, and 26.

Long-term follow up assessments are to occur every 6 months (Months 12, 18, and 24) after Week 26. Data for long-term follow up assessments will be collected from the participant's medical records captured at routine SOC visits and online questionnaires.

Interventions

• Device Epigenome-Guided Treatment Arm
  Participants will receive UST or VDZ biologic therapy as indicated by an epigenome read-out of peripheral blood using a hybrid capture-based methylation assay. The assay and EpiPredict software will indicate the probability of response to VDZ and UST. The biologic with the predicted highest likelihood of success will be communicated to the investigator and the biologic initiated using standard dosing regimens.
• Other Investigator-Guided Treatment Arm
  Assigned to UST or VDZ per conventional SOC and without the use or knowledge of epigenome results.

Primary outcome measures

• To compare the efficacy of epigenome-guided treatment selection to usual SOC treatment selection for inducing clinical remission and endoscopic response at Week 26 in participants with active CD. [Time frame: Baseline to Week 26]

Secondary outcome measures (3)

• To explore the optimal threshold of EpiPredict results in predicting treatment response using data from participants assigned to the epigenome-guided treatment selection group [Time frame: Baseline to Week 26]
• To compare the efficacy of epigenome-guided treatment selection to usual SOC treatment selection for improving clinical and endoscopic outcome measures at Week 26 in participants with active CD [Time frame: Baseline to Week 26]
• To evaluate the cost-effectiveness of epigenome-guided treatment selection compared to usual SOC treatment selection [Time frame: Baseline to 24 Months]

Eligibility criteria

Inclusion criteria

Participants must meet all of the following criteria for enrolment into the study:

• Aged 18 years or older at the time of informed consent.
• Documented diagnosis of ileal, ileocolonic, or colonic CD (may be confirmed at baseline study endoscopy).
• Active CD, as defined by HBI > 6 and SES-CD ≥ 6 for colitis/ileocolitis and ≥ 4 for ileitis only.
• Eligible to receive either VDZ and/or UST therapy for the treatment of CD per the approved drug label requirements and in the opinion of the treating physician.
• Must meet all eligibility criteria for biologic therapy initiation as per local SOC, including absence of chronic/opportunistic infections as demonstrated by local protocols for human immunodeficiency virus, tuberculosis, active cytomegalovirus, hepatitis B and C, and Clostridioides difficile infection. Local vaccination protocols apply as per SOC.
• Nonpregnant and nonlactating. Participants of childbearing potential must agree to follow local SOC guidelines for use of biologics in pregnancy/lactation, including appropriate contraception, during the study; must agree to avoid becoming pregnant from the time of informed consent up until Week 26.
• If receiving nonbiologic therapies for inflammatory bowel disease, including thiopurines and methotrexate, must have initiated at least 3 months prior to screening and must be on a stable dose for at least 2 weeks prior to screening.
• If receiving oral corticosteroids, the participant is eligible if they meet all the following criteria:

• The dose is up to a maximum of prednisone ≤ 40 mg/day or budesonide ≤ 9 mg/day or equivalent.
• The dose has been stable for ≥ 2 weeks prior to screening.
• The participant is willing to initiate a corticosteroid taper within 2 weeks after initiating biologic treatment.
• In the opinion of the investigator, the participant is able to understand and comply with protocol requirements including treatment as assigned per the protocol.
• Able to participate fully in all aspects of this clinical study. Full comprehension of consent language and informed consent must be obtained from the participant, or the participant's legally acceptable representative, and documented

Exclusion criteria

Participants who meet any of the following criteria are to be excluded from the study:

• Prior treatment with VDZ or UST.
• Prior treatment with more than 1 advanced therapy (eg, any biologic \[ie, anti- tumour necrosis factor (TNF), anti-interleukin, anti-integrin\]) or advanced oral small molecule \[ie, Janus kinase inhibitor\]) for CD.
• CD-related complications that in the opinion of the investigator would interfere with participation in the study, including but not limited to:

• Ileorectal anastomosis (rectum < 15 cm), or a proctocolectomy.
• Short bowel syndrome.
• All ostomies.
• Symptomatic strictures in the bowel or symptomatic strictures in the ileum or ileocecal valve that have a stenosis.
• Suspected or diagnosed active intra-abdominal or perianal abscess that have not been appropriately treated.
• History or current diagnosis of ulcerative colitis (unless this diagnosis was made erroneously), indeterminate colitis, idiopathic colitis (ie, colitis not consistent with CD), microscopic colitis, or colonic mucosal dysplasia (excluding dysplasia in resected adenomas).
• Increased risk of infectious complications (eg, recent pyogenic infection, any congenital or acquired immunodeficiency, or past organ, bone marrow, or stem cell transplantation).
• Any topical rectal therapy for treatment of CD within 2 weeks prior to the screening endoscopy.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) as chronic treatment, except for cyclooxygenase-2logic selective NSAIDS (celecoxib).
• Faecal microbiota transplant (includes human microbiota-based therapeutics) within 4 weeks prior to randomisation.
• Any major surgery (in the investigator's opinion) performed within 8 weeks prior to randomisation or planned during the study.
• History of excessive alcohol or drug abuse that, in the opinion of the investigator, may interfere with the participant's ability to comply with the study procedures.
• 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 or would compromise participant safety (such as history of malignancies, major neurological disorders, any unstable or uncontrolled medical disorder, or any known or suspected contraindication to any of the study biologics according to local prescribing information).

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

Open label

Primary purpose

Treatment

Study locations

Belgium · 15 centers

• GZA Antwerpen — Antwerp
• Imeldahospital — Bonheiden
• AZ Klina — Brasschaat
• H.U.B. - Hôpital Erasme — Brussels
• Universitair Ziekenhuis Antwerpen (UZA) — Edegem
• AZ Maria Middelares — Ghent
• AZ Sint Lucas — Ghent
• UZ Ghent — Ghent
• … and 7 more centers

United Kingdom · 10 centers

• Northern Care Alliance - Fairfield General Hospital — Bury
• Cambridge University Hospitals NHS Trust — Cambridge
• Hull University Teaching Hospital NHS Trust — Cottingham
• The Dudley Group NHS Foundation Trust — Dudley
• Cardiff & Vale UHB — Llandough
• Guy's and St. Thomas' NHS Foundation Trust — London
• King's College Hospital NHS Foundation Trust — London
• Oxford University Hospitals NHS Foundation Trust — Oxford
• … and 2 more centers

Netherlands · 7 centers

• Flevoziekenhuis Hospitaalweg 1 — Almere Stad
• Amsterdam UMC — Amsterdam
• OLVG Oost — Amsterdam
• Maastricht UMC — Maastricht
• Radboudumc — Nijmegen
• Elisabeth-TweeSteden Ziekenhuis (ETZ) — Tilburg
• Universitair Medisch Centrum Utrecht — Utrecht

Italy · 6 centers

• IRCCS "Saverio de Bellis", National Institute of Gastroenterology — Castellana Grotte
• Azienda Ospedaliero Universitaria Careggi Padiglione San Luca Nuovo — Florence
• IRCCS Ospedale San Raffaele — Milan
• Agostino Gemelli University Policlinic — Roma
• San Camillo-Forlanini Hospital — Rome
• UOC di Gastroenterologia ed Endoscopia Digestiva — San Giovanni Rotondo

Slovenia · 1 center

• UKC Ljubljana — Ljubljana

Identifiers

NCT: NCT07363044 · RCT-01727

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗