Evaluation of the Response of Itraconazole and Terbinafine Therapy in Subjects With Crohn's Disease (CD-IT)

Evaluation of the Response of Itraconazole and Terbinafine Therapy in Subjects With Crohn's Disease Not Responding Adequately to Current Therapy

This study will evaluate the response of itraconazole and terbinafine therapy compared to placebo in patients with mild to moderate Crohn's disease (CD).

Study Overview

• Status: Recruiting
• Conditions: Inflammatory Bowel Diseases; Crohn's Disease
• Intervention / Treatment: Drug: Itraconazole 400 mg/day and terbinafine 500 mg/day administered orally.; Drug: Itraconazole's matching placebo 400 mg/day and terbinafine's matching placebo 500 mg/day administered orally.

Detailed Description

This multicenter, randomized, double-blind, placebocontrolled, phase II, proof of concept study will randomize 68 subjects at 2 to 5 clinical sites in Canada. Following signature of informed consent, subjects who meet entry criteria will be randomized in a 1:1 ratio to receive either itraconazole and terbinafine, or matching placebos. During the first 4 weeks subjects will receive itraconazole 200 mg twice daily or matching placebo, followed by itraconazole 200 mg twice daily and terbinafine 250 mg twice daily or matching placebos for the remaining 16 weeks. The 2 drugs will be administered orally.

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jean-Claude Tardif, MD; Phone Number: 3612 514-376-3330; Email: jean-claude.tardif@icm-mhi.org
• Study Contact Backup: Name: Marianne Rufiange; Phone Number: 2036 514-461-1300; Email: marianne.rufiange@mhicc.org

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H1T2M4
      • Recruiting
      • CIUSSS de l'Est-de-l'Île-de-Montréal, Hôpital Maisonneuve-Rosemont
      • Contact: Louis-Charles Rioux, MD
    • Montréal, Quebec, Canada, H2X0A9
      • Recruiting
      • Centre de Recherche du Centre Hospitalier de l'Universite de Montreal (CRCHUM)
      • Contact: Edmond-Jean Bernard, MD
    • Montréal, Quebec, Canada, H3G1A4
      • Recruiting
      • McGill University Health center
      • Contact: Talat Bessissow, MD
    • Sherbrooke, Quebec, Canada, J1G 2E8
      • Recruiting
      • Centre intégré universitaire de santé et de services sociaux de l'Estrie - CHUS
      • Contact: Joannie Ruel, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subjects with endoscopy/radiology confirmation of active disease within 6 months prior to enrolment;
• Mild to moderate active CD defined by the HBI score of ≥ 5 to ≤ 16 at baseline;
• Female of childbearing potential must have a negative urine pregnancy test at screening and at randomization baseline Visit 2. Women are considered not of childbearing potential if they either:
• Have had a hysterectomy or tubal ligation prior to baseline visit or;
• Are postmenopausal defined as no menses for 12 months or a FSH level (if available) in the menopausal range.
• Women of childbearing potential must agree to use an effective double method of birth control throughout the study: barrier method (e.g. male or female condoms, spermicides, sponges, foams, jellies, and diaphragm) in combination with other methods of contraception including implantable contraceptives, injectable contraceptives, oral contraceptives, transdermal contraceptives, intrauterine devices, abstinence, or a sterile sexual partner.
• Subjects with the capacity to provide informed consent.

Exclusion Criteria:

• Subject with a current diagnosis of ulcerative colitis (UC);
• Contraindication to the use of itraconazole including congestive heart failure, ventricular dysfunction, ventricular arrhythmia, or negative inotropic state;
• Subjects with elevated or abnormal liver enzymes (ALT/AST>3 ULN) or patients with pre-existing chronic or active liver disease at screening;
• Female subject who is pregnant, planning to become pregnant during the study, or breastfeeding;
• Subject with renal impairment (creatinine clearance ≤ 50 mL/min using Cockcroft-Gault equation);
• Subject with a known hypersensitivity to itraconazole, terbinafine, or any of their excipients;
• Subjects on medications which interact with itraconazole: methadone, pimozide, quinidine or other CYP3A4 inhibitors;
• Positive C. difficile toxin test at screening;
• Use of steroid greater than 20 mg/day;
• Change of steroid dosage in the 2 weeks prior to enrolment;

• Change in CD therapy:

  • The Anti-TNFs, anti-integrins, anti-IL12/23 in the 4 months prior to enrolment;
  • Thiopurines or methotrexate (MTX), in the 2 months prior to enrolment;
• Participation in other clinical trial within 30 days of signing the Information and Consent Form (ICF).

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Itraconazole and Terbinafine; During the first 4 weeks itraconazole will be administered alone at 200 mg twice daily, followed by itraconazole 200 mg twice daily and terbinafine 250 mg twice daily for the remaining 16 weeks. Both drugs will be administered orally.	Drug: Itraconazole 400 mg/day and terbinafine 500 mg/day administered orally.; Itraconazole capsules of 100 mg, antifungal agent. Terbinafine tablets 250 mg (as terbinafine hydrochloride), antifungal agent.
Placebo Comparator: Placebo; During the first 4 weeks a placebo will be administered alone at 200 mg twice daily, followed by placebo 200 mg twice daily and another placebo 250 mg twice daily for the remaining 16 weeks. Both placebos will be administered orally.	Drug: Itraconazole's matching placebo 400 mg/day and terbinafine's matching placebo 500 mg/day administered orally.; Matching placebo of itraconazole capsules of 100 mg, antifungal agent. Matching placebo of terbinafine tablets 250 mg, antifungal agent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the response of itraconazole and terbinafine therapy compared to placebo in subjects with CD, assessed by the Modified Harvey Bradshaw Index (HBI).	Clinical response defined as a decrease from baseline to end of treatment in HBI ≥ 3 points	20 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To evaluate the response of the itraconazole and terbinafine therapy compared to placebo in subjects with CD on clinical remission assessed by the HBI.	Persistence of clinical response defined as a decrease from baseline to 8 weeks post end of treatment in HBI ≥ 3 points; Clinical remission defined as an HBI at end of treatment ≤ 4 points; Persistence of clinical remission defined as an HBI at 8 weeks post end of treatment ≤ 4 points; Change from baseline to end of treatment in HBI	20 Weeks
To evaluate the response of the itraconazole and terbinafine therapy compared to placebo in subjects with CD on endoscopic response assessed by the Simplified Endoscopic Score for Crohn's disease (SES-CD).	Endoscopic response defined a decrease from baseline to end of treatment in SES-CD ≥ 50% of the baseline SES-CD; Change from baseline to end of treatment in SES-CD	20 Weeks
To evaluate the response of the itraconazole and terbinafine therapy compared to placebo in subjects with CD on fecal and serologic markers.	Change from baseline to end of treatment in FC levels; Change from baseline to end of treatment in CRP levels	20 Weeks
To evaluate the effect of study treatment on the primary endpoint in the subgroup of patients with positive ASCA (as measured on frozen plasma samples at end of the study).	Change from baseline to end of treatment in ASCA levels; Change from baseline to 8 weeks post end of treatment in ASCA levels	20 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory analyses using genetic data (pharmacogenomic and metagenomics) as well as microbiotic testing will be described at a later time point and in a separate document.	To determine the link between genetics and the response to therapy and inflammation. The microbiote genes will also be evaluated.	28 Weeks
To evaluate steroid use between active and placebo groups at study completion.	Steroid Use in Subjects with Crohn's Disease will be reported as the proportion of subjects who's steroid use was decreased. increased, changed or stopped.	28 Weeks

Collaborators and Investigators

• Sponsor: Montreal Heart Institute
• Investigators: Principal Investigator: Jean-Claude Tardif, MD, Montreal Heart Institute (MHI); Principal Investigator: Edmond-Jean Bernard, MD, Centre Hospitalier de l'Université de Montréal (CHUM)

Study record dates

Study Major Dates

• Study Start (Actual): February 22, 2022
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): December 1, 2024

Study Registration Dates

• First Submitted: August 25, 2021
• First Submitted That Met QC Criteria: September 16, 2021
• First Posted (Actual): September 20, 2021

Study Record Updates

• Last Update Posted (Actual): February 26, 2024
• Last Update Submitted That Met QC Criteria: February 23, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Endoscopy; Radiology; Itraconazole; Terbinafine; Chronic Inflammatory Disorder; Malassezia Restricta
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Hormones, Hormone Substitutes, and Hormone Antagonists; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; 14-alpha Demethylase Inhibitors; Itraconazole; Hydroxyitraconazole; Terbinafine
• Other Study ID Numbers: MHICC-2019-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

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