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

Primary Purpose

Crohn's Disease, Inflammatory Bowel Diseases

Status

Recruiting

Phase

Phase 2

Locations

Canada

Study Type

Interventional

Intervention

Itraconazole 400 mg/day and terbinafine 500 mg/day administered orally.

Itraconazole's matching placebo 400 mg/day and terbinafine's matching placebo 500 mg/day administered orally.

About this trial

This is an interventional treatment trial for Crohn's Disease focused on measuring Endoscopy, Radiology, Itraconazole, Terbinafine, Chronic Inflammatory Disorder, Malassezia Restricta

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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;
Elevated FC levels at baseline (≥ 250 mcg/gm);
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).

Sites / Locations

CIUSSS de l'Est-de-l'Île-de-Montréal, Hôpital Maisonneuve-RosemontRecruiting
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)Recruiting
McGill University Health CenterRecruiting
Centre intégré universitaire de santé et de services sociaux de l'Estrie - CHUSRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Itraconazole and Terbinafine

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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

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

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

Full Information

NCT ID

NCT05049525

First Posted

August 25, 2021

Last Updated

February 14, 2023

Sponsor

Montreal Heart Institute

1. Study Identification

Unique Protocol Identification Number

NCT05049525

Brief Title

Evaluation of the Response of Itraconazole and Terbinafine Therapy in Subjects With Crohn's Disease

Acronym

CD-IT

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

February 2023

Overall Recruitment Status

Recruiting

Study Start Date

February 22, 2022 (Actual)

Primary Completion Date

March 2024 (Anticipated)

Study Completion Date

March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Montreal Heart Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Crohn's Disease, Inflammatory Bowel Diseases

Keywords

Endoscopy, Radiology, Itraconazole, Terbinafine, Chronic Inflammatory Disorder, Malassezia Restricta

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

68 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Itraconazole and Terbinafine

Arm Type

Active Comparator

Arm Description

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Itraconazole 400 mg/day and terbinafine 500 mg/day administered orally.

Intervention Description

Itraconazole capsules of 100 mg, antifungal agent. Terbinafine tablets 250 mg (as terbinafine hydrochloride), antifungal agent.

Intervention Type

Drug

Intervention Name(s)

Itraconazole's matching placebo 400 mg/day and terbinafine's matching placebo 500 mg/day administered orally.

Intervention Description

Matching placebo of itraconazole capsules of 100 mg, antifungal agent. Matching placebo of terbinafine tablets 250 mg, antifungal agent.

Primary Outcome Measure Information:

Title

To evaluate the response of itraconazole and terbinafine therapy compared to placebo in subjects with CD, assessed by the Modified Harvey Bradshaw Index (HBI).

Description

Clinical response defined as a decrease from baseline to end of treatment in HBI ≥ 3 points

Time Frame

20 Weeks

Secondary Outcome Measure Information:

Title

To evaluate the response of the itraconazole and terbinafine therapy compared to placebo in subjects with CD on clinical remission assessed by the HBI.

Description

Time Frame

20 Weeks

Title

Description

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

Time Frame

20 Weeks

Title

To evaluate the response of the itraconazole and terbinafine therapy compared to placebo in subjects with CD on fecal and serologic markers.

Description

Change from baseline to end of treatment in FC levels Change from baseline to end of treatment in CRP levels

Time Frame

20 Weeks

Title

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).

Description

Change from baseline to end of treatment in ASCA levels Change from baseline to 8 weeks post end of treatment in ASCA levels

Time Frame

20 weeks

Other Pre-specified Outcome Measures:

Title

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.

Description

To determine the link between genetics and the response to therapy and inflammation. The microbiote genes will also be evaluated.

Time Frame

28 Weeks

Title

To evaluate steroid use between active and placebo groups at study completion.

Description

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.

Time Frame

28 Weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

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).

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Jean-Claude Tardif, MD

Phone

514-376-3330

Ext

3612

jean-claude.tardif@icm-mhi.org

First Name & Middle Initial & Last Name or Official Title & Degree

Marianne Rufiange

Phone

514-461-1300

Ext

2036

marianne.rufiange@mhicc.org

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Jean-Claude Tardif, MD

Organizational Affiliation

Montreal Heart Institute (MHI)

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Edmond-Jean Bernard, MD

Organizational Affiliation

Centre hospitalier de l'Université de Montréal (CHUM)

Official's Role

Principal Investigator

Facility Information:

Facility Name

CIUSSS de l'Est-de-l'Île-de-Montréal, Hôpital Maisonneuve-Rosemont

City

Montréal

State/Province

Quebec

ZIP/Postal Code

H1T2M4

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Louis-Charles Rioux, MD

Facility Name

Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM)

City

Montréal

State/Province

Quebec

ZIP/Postal Code

H2X0A9

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Edmond-Jean Bernard, MD

Facility Name

McGill University Health Center

City

Montréal

State/Province

Quebec

ZIP/Postal Code

H3G1A4

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Talat Bessissow, MD

Facility Name

Centre intégré universitaire de santé et de services sociaux de l'Estrie - CHUS

City

Sherbrooke

State/Province

Quebec

ZIP/Postal Code

J1G 2E8

Country

Canada

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Joannie Ruel, MD

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Evaluation of the Response of Itraconazole and Terbinafine Therapy in Subjects With Crohn's Disease

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