Clinical trial NCT04966585: 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
Overall status: TERMINATED
Phase: PHASE4
Conditions: Crohn Disease
CARD9 S12N Risk Allele
Keywords: Crohn's
Malassezia
CARD9 S12N
Antifungal
Lead sponsor: Cedars-Sinai Medical Center
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2021-07-19
Enrollment: 10
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Subjects will be randomly assigned to receive posaconazole or placebo in 1:1 fashion.
Primary purpose: TREATMENT

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 caspase recruitment domain family member 9 (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.


Eligibility criteria: Inclusion Criteria:

* Male or female patients aged 18 years and older, 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 S12N 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) Hydroxymethylglutaryl-CoA (HMG-CoA) reductase 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.

Primary outcomes:
measure: Endoscopic Response
timeFrame: Week 12
Secondary outcomes:
measure: Induction of Clinical Remission
timeFrame: Week 12
measure: Incidence of adverse events
timeFrame: Week 12
measure: Change in amount of concomitant medications
timeFrame: Week 12
measure: Proportion of subjects in endoscopic remission
timeFrame: Week 12
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center (CSMC)
state: California
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Cedars-Sinai Medical Center
name: Gil Y Melmed, MD
role: PRINCIPAL_INVESTIGATOR
References: