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Pilot Study of Posaconazole in Crohn's Disease

Primary Purpose

Crohn Disease, CARD9 S12N Risk Allele

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Posaconazole Delayed Release Oral Tablet
Matching Placebo Tablet
Sponsored by
Cedars-Sinai Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Crohn Disease focused on measuring Crohn's, Malassezia, CARD9 S12N, Antifungal

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female patients aged 18 to 60 years, inclusive based on the date of the screening visit.
  • A diagnosis of CD with minimum disease duration of 6 months with involvement of the ileum and/or colon documented on colonoscopy
  • Have an endoscopically-confirmed active Crohn's disease with active disease defined by SES-CD > 6 (>4 if ileal only), AND active symptoms of Crohn's disease (CDAI score >220)
  • Homozygous for CARD9 SN12 risk allele, without the protective exon 11 polymorphism
  • Subjects receiving oral aminosalicylates (at a stable dose for 2 weeks prior to baseline), immunomodulators (at a stable dose for 4 weeks prior to baseline), anti-TNF, anti IL12/23, or anti-integrin therapy (at stable maintenance doses for > 8 weeks) may continue their use during the study.
  • Subjects receiving oral corticosteroids may continue their use during the study provided the dose (prednisone up to 20 mg/day, budesonide up to 9 mg/day) has been stable for two weeks prior to screening.
  • Have had age-appropriate and disease-duration-appropriate colon cancer screening1 without unresected dysplasia.
  • Women of childbearing age, excluding those with prior bilateral tubal ligation or at least one-year post-menopause, must not be pregnant, lactating, or planning to become pregnant. They must agree to use effective contraception throughout the study period.
  • Subjects must be able to provide informed consent and understand, agree with, and be able to adhere to daily diary entries, all scheduled visits, tests, procedures, and protocol in English.

Exclusion Criteria:

  • Known hypersensitivity or allergy to posaconazole or other azole antifungal agents
  • Concomitant medications primarily metabolized by CY3PA4 including: a) HMG-CoA inhibitors primarily metabolized by CY3PA4 (increases risk of rhabdomyolysis), b) Sirolimus, c) Ergot alkaloids, d) vincristine
  • Proarrhythmic conditions
  • Moderate or severe renal impairment (Cr Clearance <50)
  • Current diagnosis of ulcerative colitis, indeterminate colitis, ischemic colitis, infectious colitis, or microscopic colitis.
  • Fulminant colitis, toxic megacolon, peritonitis, ileostomy or colostomy.
  • Stool sample positive for pathogens including ova and parasites, Salmonella, Shigella, and C. difficile at screening.
  • History of any clinically significant neurological, renal, hepatic, gastrointestinal, pulmonary, metabolic, cardiovascular, psychiatric, endocrine, hematological disorder or disease or any other medical condition that, in the Investigators opinion, would prevent the subject from participation in the study.
  • Treatment with antibiotics, antifungal agents, probiotics, or prebiotics within two weeks of screening.
  • Alcohol or drug abuse (in the opinion of the Investigator) that would interfere with compliance.
  • Any other investigational therapy or treatment within four weeks of screening.

Sites / Locations

  • Cedars-Sinai Medical Center (CSMC)Recruiting
  • Mayo ClinicRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Posaconazole

Placebo

Arm Description

Subjects administered posaconazole (Noxifil®, Merck) 300mg twice daily for 1 day followed by 300mg daily for 12 weeks

Subjects administered three matching placebo tablets twice daily for 1 day followed by three tablets daily for 12 weeks

Outcomes

Primary Outcome Measures

Endoscopic Response
Defined as ≥ 50% reduction from baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD). The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The total SES-CD is calculated as the sum of the 4 variables for the 5 bowel segments: rectum, left colon, transverse colon, right colon, and ileum. Scores range from 0 to 60, with higher scores indicating more severe disease.

Secondary Outcome Measures

Induction of Clinical Remission
Defined as Patient-Reported Outcome (PRO2) abdominal pain score ≤1 AND stool frequency ≤3, and Crohn's Disease Activity Index (CDAI) (<150). PRO2 is the weighted average of the 2 variables of frequency of liquid or very soft stool and abdominal pain, based on 7-day participant diary data. The PRO2 score has a minimum score of 0 and has no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity.
Incidence of adverse events
Change in amount of concomitant medications
Proportion of subjects in endoscopic remission
Defined as a Simple Endoscopic Score for Crohn's Disease (SES-CD) score of ≤3. The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The total SES-CD is calculated as the sum of the 4 variables for the 5 bowel segments: rectum, left colon, transverse colon, right colon, and ileum. Scores range from 0 to 56, with higher scores indicating more severe disease.

Full Information

First Posted
July 8, 2021
Last Updated
May 23, 2023
Sponsor
Cedars-Sinai Medical Center
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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1. Study Identification

Unique Protocol Identification Number
NCT04966585
Brief Title
Pilot Study of Posaconazole in Crohn's Disease
Official Title
A Multicenter Randomized, Double-Blinded, Placebo-Controlled Study of Posaconazole in Genetically-Defined Patients With Active Crohn's Disease
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 17, 2022 (Actual)
Primary Completion Date
December 31, 2023 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Cedars-Sinai Medical Center
Collaborators
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This trial is designed to evaluate the effects of oral antifungal treatment with posaconazole on active Crohn's disease (CD) activity and the burden of Malassezia spp. in CD patients with the CARD9 S12N risk allele. Further, this project will investigate the hypothesis that the microbial changes induced by antifungal treatment are associated with dampened downstream immune responses in those with a genetic predisposition to developing strong immune responses to Malassezia.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Crohn Disease, CARD9 S12N Risk Allele
Keywords
Crohn's, Malassezia, CARD9 S12N, Antifungal

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Model Description
Subjects will be randomly assigned to receive posaconazole or placebo in 1:1 fashion.
Masking
ParticipantCare ProviderOutcomes Assessor
Masking Description
Both subject and clinical staff will be masked to treatment group assigned.
Allocation
Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Posaconazole
Arm Type
Experimental
Arm Description
Subjects administered posaconazole (Noxifil®, Merck) 300mg twice daily for 1 day followed by 300mg daily for 12 weeks
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Subjects administered three matching placebo tablets twice daily for 1 day followed by three tablets daily for 12 weeks
Intervention Type
Drug
Intervention Name(s)
Posaconazole Delayed Release Oral Tablet
Other Intervention Name(s)
Noxifil
Intervention Description
Three 100mg delayed-release tablets twice a day on the first day, then three 100mg delayed-release tablets once a day, starting on the second day. Duration of therapy will be 12 weeks.
Intervention Type
Drug
Intervention Name(s)
Matching Placebo Tablet
Intervention Description
Three matching placebo tablets twice a day on the first day, then three tablets once a day, starting on the second day. Duration of therapy will be 12 weeks.
Primary Outcome Measure Information:
Title
Endoscopic Response
Description
Defined as ≥ 50% reduction from baseline in Simple Endoscopic Score for Crohn's Disease (SES-CD). The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The total SES-CD is calculated as the sum of the 4 variables for the 5 bowel segments: rectum, left colon, transverse colon, right colon, and ileum. Scores range from 0 to 60, with higher scores indicating more severe disease.
Time Frame
Week 12
Secondary Outcome Measure Information:
Title
Induction of Clinical Remission
Description
Defined as Patient-Reported Outcome (PRO2) abdominal pain score ≤1 AND stool frequency ≤3, and Crohn's Disease Activity Index (CDAI) (<150). PRO2 is the weighted average of the 2 variables of frequency of liquid or very soft stool and abdominal pain, based on 7-day participant diary data. The PRO2 score has a minimum score of 0 and has no upper bound, with a higher score indicating more frequent stools and more severe abdominal pain. The CDAI is a weighted, composite index of 8 disease variables (stool frequency, severity of abdominal pain, degree of general well-being, presence or absence of extra-intestinal manifestations or fistula, use or non-use of antidiarrheal agents, presence or absence of an abdominal mass, hematocrit, and body weight). Scores range from approximately 0 to 600, with a higher score indicating more-severe disease activity.
Time Frame
Week 12
Title
Incidence of adverse events
Time Frame
Week 12
Title
Change in amount of concomitant medications
Time Frame
Week 12
Title
Proportion of subjects in endoscopic remission
Description
Defined as a Simple Endoscopic Score for Crohn's Disease (SES-CD) score of ≤3. The SES-CD evaluates 4 endoscopic variables: ulcer size, ulcerated surface, affected surface, and presence of narrowings. The total SES-CD is calculated as the sum of the 4 variables for the 5 bowel segments: rectum, left colon, transverse colon, right colon, and ileum. Scores range from 0 to 56, with higher scores indicating more severe disease.
Time Frame
Week 12

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female patients aged 18 to 60 years, inclusive based on the date of the screening visit. A diagnosis of CD with minimum disease duration of 6 months with involvement of the ileum and/or colon documented on colonoscopy Have an endoscopically-confirmed active Crohn's disease with active disease defined by SES-CD > 6 (>4 if ileal only), AND active symptoms of Crohn's disease (CDAI score >220) Homozygous for CARD9 SN12 risk allele, without the protective exon 11 polymorphism Subjects receiving oral aminosalicylates (at a stable dose for 2 weeks prior to baseline), immunomodulators (at a stable dose for 4 weeks prior to baseline), anti-TNF, anti IL12/23, or anti-integrin therapy (at stable maintenance doses for > 8 weeks) may continue their use during the study. Subjects receiving oral corticosteroids may continue their use during the study provided the dose (prednisone up to 20 mg/day, budesonide up to 9 mg/day) has been stable for two weeks prior to screening. Have had age-appropriate and disease-duration-appropriate colon cancer screening1 without unresected dysplasia. Women of childbearing age, excluding those with prior bilateral tubal ligation or at least one-year post-menopause, must not be pregnant, lactating, or planning to become pregnant. They must agree to use effective contraception throughout the study period. Subjects must be able to provide informed consent and understand, agree with, and be able to adhere to daily diary entries, all scheduled visits, tests, procedures, and protocol in English. Exclusion Criteria: Known hypersensitivity or allergy to posaconazole or other azole antifungal agents Concomitant medications primarily metabolized by CY3PA4 including: a) HMG-CoA inhibitors primarily metabolized by CY3PA4 (increases risk of rhabdomyolysis), b) Sirolimus, c) Ergot alkaloids, d) vincristine Proarrhythmic conditions Moderate or severe renal impairment (Cr Clearance <50) Current diagnosis of ulcerative colitis, indeterminate colitis, ischemic colitis, infectious colitis, or microscopic colitis. Fulminant colitis, toxic megacolon, peritonitis, ileostomy or colostomy. Stool sample positive for pathogens including ova and parasites, Salmonella, Shigella, and C. difficile at screening. History of any clinically significant neurological, renal, hepatic, gastrointestinal, pulmonary, metabolic, cardiovascular, psychiatric, endocrine, hematological disorder or disease or any other medical condition that, in the Investigators opinion, would prevent the subject from participation in the study. Treatment with antibiotics, antifungal agents, probiotics, or prebiotics within two weeks of screening. Alcohol or drug abuse (in the opinion of the Investigator) that would interfere with compliance. Any other investigational therapy or treatment within four weeks of screening.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Melissa Hampton
Phone
310-423-0035
Email
melissa.hampton@cshs.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Gil Y Melmed, MD
Organizational Affiliation
Cedars-Sinai Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Cedars-Sinai Medical Center (CSMC)
City
Los Angeles
State/Province
California
ZIP/Postal Code
90048
Country
United States
Individual Site Status
Recruiting
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55901
Country
United States
Individual Site Status
Recruiting

12. IPD Sharing Statement

Plan to Share IPD
No

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Pilot Study of Posaconazole in Crohn's Disease

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