A Multicenter Randomized, Double-Blinded, Placebo-Controlled Study of Posaconazole in Genetically-Defined Patients With Active Crohn's Disease
Phase: PHASE4
Conditions: Crohn Disease, CARD9 S12N Risk Allele
Sponsor: Cedars-Sinai Medical Center

A Multicenter Randomized, Double-Blinded, Placebo-Controlled Study of Posaconazole in 
Genetically-Defined Patients With Active Crohn's Disease   
NCT04966585 
February 23, 2023 
 

 
CONFIDENTIAL 
This material is the property of Cedars-Sinai Medical Center. 
CLINICAL RESEARCH PROTOCOL 
 
 
 
 
 
 
 
 
A MULTICENTER RANDOMIZED, DOUBLE-BLINDED, 
PLACEBO-CONTROLLED STUDY OF POSACONAZOLE IN 
GENETICALLY-DEFINED PATIENTS WITH ACTIVE CROHN’S 
DISEASE 
 
 
 
 
An Investigator-Initiated Study 
Funding Sponsor: 
NIDDK 
 
Study Product: 
Posaconazole (Noxifil®) 
Protocol Number: 
7.0   
 
 
 
 
 
 
 
 
 
Current version: 
February 4, 2021 
 
 
 
August 16, 2021 
 
 
 
 
October 15, 2021 
 
January 21, 2022 
 
October 31, 2022 
 
February 23, 2023 
 
 

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Summary of Changes – 23-Feb-2023 
 
 
 
 
 Pages 2 & 20 – Updated Inclusion #1 male and female patients age ≥ 18, 
there will no longer be a cutoff age.    
 
 

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Table of Contents 
 
PROTOCOL SYNOPSIS .............................................................................................................................. 1 
1.1 
BACKGROUND ................................................................................................................................ 8 
2 
INTRODUCTION ................................................................................................................................ 11 
2.1 
INDICATION .................................................................................................................................. 11 
2.2 
INVESTIGATIONAL AGENT .............................................................................................................. 11 
2.2.1 
Description ............................................................................................................................. 11 
2.2.2 
Pharmacokinetics of orally administered posaconazole ....................................................... 11 
2.2.3 
Use In Specific Populations ................................................................................................... 14 
2.3 
CLINICAL DATA TO DATE............................................................................................................... 15 
2.3.1 
Safety data from placebo-controlled trials of oral delayed-release tablets ........................... 15 
2.4 
DOSE RATIONALE ......................................................................................................................... 16 
3 
STUDY OBJECTIVES ....................................................................................................................... 16 
4 
STUDY DESIGN ................................................................................................................................. 17 
4.1 
GENERAL DESIGN ........................................................................................................................ 17 
4.2 
PRIMARY STUDY ENDPOINTS ........................................................................................................ 19 
4.3 
KEY SECONDARY STUDY ENDPOINTS ............................................................................................ 19 
4.4 
PRIMARY SAFETY ENDPOINTS ....................................................................................................... 19 
4.5 
QUALITY-OF-LIFE ENDPOINTS ....................................................................................................... 19 
4.6 
PHARMACOKINETICS ENDPOINTS .................................................................................................. 19 
4.7 
TRANSCRIPTOMICS ENDPOINTS .................................................................................................... 19 
5 
SUBJECT SELECTION AND WITHDRAWAL .................................................................................. 19 
5.1 
INCLUSION CRITERIA .................................................................................................................... 20 
5.2 
EXCLUSION CRITERIA ................................................................................................................... 20 
5.3 
SUBJECT RECRUITMENT AND SCREENING ..................................................................................... 21 
5.4 
LIFESTYLE GUIDELINES ................................................................................................................. 21 
5.5 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................... 21 
5.5.1 
When and How to Withdraw Subjects ................................................................................... 21 
5.5.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 22 
6 
STUDY DRUG .................................................................................................................................... 22 
6.1 
DESCRIPTION ............................................................................................................................... 22 
6.2 
TREATMENT REGIMEN .............................................................................................................. 2223 
6.3 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 23 
6.4 
SUBJECT COMPLIANCE MONITORING ............................................................................................. 23 
6.5 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 23 
6.6 
PACKAGING ............................................................................................................................. 2324 
6.7 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................... 24 
6.7.1 
Receipt of Drug Supplies ....................................................................................................... 24 
6.7.2 
Storage .................................................................................................................................. 24 
6.7.3 
Dispensing of Study Drug ...................................................................................................... 24 
6.7.4 
Return or Destruction of Study Drug ..................................................................................... 24 
7 
STUDY PROCEDURES ..................................................................................................................... 24 
7.1 
SCREENING (WEEK -4 TO WEEK 0) ............................................................................................... 24 
7.2 
BASELINE VISIT (WEEK 0) .............................................................................................................. 25 
7.3 
WEEKS 2, 4, 6, 8, AND 10 (±3 DAYS) ......................................................................................... 2526 
7.4 
WEEK 12 (±3 DAYS) OR EARLY TERMINATION ................................................................................. 26 
7.5 
WEEKS 16, 20, 24, 28, 32 (±3 DAYS) ............................................................................................ 26 
7.6 
WEEK 36 VISIT (OR FINAL FOLLOW UP VISIT AFTER EARLY TERMINATION) ......................................... 27 

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8 
ASSESSMENTS ................................................................................................................................ 27 
8.1 
EFFICACY MEASURES ................................................................................................................... 27 
8.1.1 
Bowel movement diary .......................................................................................................... 27 
8.1.2 
Crohn’s disease activity Index (CDAI), PRO2 and Simple Endoscopic Score for Crohn’s 
disease (SES-CD) .............................................................................................................................. 27 
8.1.3 
Health-related quality of life ................................................................................................... 27 
8.2 
LABORATORY MARKERS ............................................................................................................ 2728 
8.3 
PHARMACOKINETICS LABORATORY MARKERS ................................................................................. 28 
8.4 
IMAGING AND CARDIAC STUDIES .................................................................................................... 28 
8.5 
MICROBIOME ANALYSES ............................................................................................................... 28 
8.6 
TRANSCRIPTOMICS ANALYSES ...................................................................................................... 28 
9 
STATISTICAL PLAN ......................................................................................................................... 28 
9.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 28 
9.2 
STATISTICAL METHODS ................................................................................................................ 29 
9.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 29 
10 
SAFETY AND ADVERSE EVENTS ................................................................................................... 30 
10.1 
RECORDING OF ADVERSE EVENTS ................................................................................................ 30 
10.1.1 
Investigator reporting: notifying the Cedars Sinai IRB ...................................................... 30 
10.2 
MEDICAL MONITORING ................................................................................................................. 31 
11 
DATA HANDLING AND RECORD KEEPING ................................................................................... 31 
11.1 
CONFIDENTIALITY ......................................................................................................................... 31 
11.2 
SOURCE DOCUMENTS .................................................................................................................. 31 
11.3 
RECORDS RETENTION .................................................................................................................. 32 
11.4 
SAMPLE STORAGE ....................................................................................................................... 32 
12 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 32 
12.1 
STUDY MONITORING PLAN ............................................................................................................ 32 
12.2 
AUDITING AND INSPECTING ........................................................................................................... 32 
13 
ETHICAL CONSIDERATIONS .......................................................................................................... 32 
14 
STUDY FINANCES ............................................................................................................................ 33 
14.1 
CONFLICT OF INTEREST ................................................................................................................ 33 
15 
PUBLICATION PLAN ........................................................................................................................ 33 
16 
REFERENCES ................................................................................................................................... 33 
APPENDICES ............................................................................................................................................. 35 
 
 
 

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List of Abbreviations 
AE                                  Adverse Event 
CD 
 
 
Crohn’s Disease 
CXR 
 
 
Chest radiograph 
EKG 
 
 
Electrocardiogram 
EOS 
 
 
End of Study 
EOT 
 
 
End of Treatment 
FDA                                Food and Drug Administration 
GWAS  
 
Genome-wide association study 
hsCRP                            High-sensitivity C-reactive protein  
IBDQ                              Inflammatory bowel disease questionnaire 
IL                                    Interleukin 
IRB                                 Institutional Review Board 
ITT 
 
 
Intention-to-Treat 
PK 
 
 
Pharmacokinetic 
UC 
 
 
Ulcerative Colitis 
SES-CD  
 
Simple Endoscopic Score for Crohn’s Disease 
SF-36                             Short Form 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Pilot Study of Posaconazole in Active Crohn’s Disease 
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Protocol Synopsis 
 
 
Title 
Posaconazole foR gEnetiCally-defIned crohn’S dIsease Of the termiNal ileum 
(PRECISION): A two-center, placebo-controlled prospective  pilot study  
Short Title 
Pilot Study of posaconazole in Crohn’s disease 
Protocol Number 
TBD 
Sponsor 
Investigator-initiated 
Indication 
Posaconazole as treatment for active Crohn’s disease in people with active Crohn’s 
disease (CD) despite conventional therapy who are at risk for fungal infection based 
on genetically determined CARD9 S12N allele status 
Background 
The etiology of Crohn’s disease is thought to involve abnormal gut immune response 
to commensal flora in genetically-susceptible individuals. Several studies have 
implicated commensal fungi, including Malassezia spp with the development of CD.  
 Innate inflammatory responses to fungi are mediated in large part through a 
signaling pathway involving a protein called CARD9. Genome-wide association 
studies (GWAS) have linked a polymorphism in CARD9 (S12N) to the risk of CD, 
and we have found that the presence of Malassezia was positively linked to the 
presence of the CARD9 risk allele. We further found that the disease-associated risk 
allele of CARD9 specifically enhances human inflammatory responses to Malassezia 
and that Malassezia exacerbates colitis via CARD9 in mouse models of disease.  
This trial is designed to evaluate the effects of oral antifungal treatment with 
posaconazole on disease activity and the burden of Malassezia spp. in CD patients 
with the CARD9 S12N 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.  
Design 
Randomized, double-blinded, placebo-controlled trial  
Study Duration 
Four-week screening period followed by twelve-week double-blind induction period, 
followed by either 1) a 6-month follow-up period or 2) (for placebo non-responders 
only) a twelve-week open-label period followed by a twelve-week follow-up. 
Study Center(s) 
Two-centers: Cedars-Sinai Medical Center, Mayo Clinic (Rochester) 

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Objectives 
Primary Objective 
 To assess the effects of posaconazole on Crohn’s disease activity in patients 
with active Crohn’s disease  
 
Secondary Objectives 
 
 To assess the preliminary safety and tolerability of posaconazole for the 
induction of clinical remission and endoscopic response in patients with active 
Crohn’s disease with genetically-determined CARD9 S12N risk allele 
 
 To assess the preliminary influence on quality-of-life of posaconazole in patients 
with active Crohn’s disease with genetically-determined CARD9 S12N risk allele
 
 To assess the pharmacokinetics (PK) of posaconazole in patients with active 
Crohn’s disease with genetically-determined CARD9 S12N risk allele 
 
 To assess changes in the intestinal mycobiome after treatment with 
posaconazole in patients with active Crohn’s disease with genetically-
determined CARD9 S12N risk allele 
 
 To determine changes in gene expression (transcriptomics) in colonic mucosa 
after posaconazole in patients with active Crohn’s disease with genetically-
determined CARD9 S12N risk allele 
Number of 
Subjects 
24 
Diagnosis and 
Inclusion Criteria 
           
Subjects (n=24) will be individuals with active Crohn’s disease (SES-CD > 6 AND 
Crohn’s disease activity index score >220) despite use of conventional therapy. In this 
40-week trial, subjects will be administered posaconazole (Noxifil®, Merck) 300mg 
twice daily for 1 day followed by 300mg daily for 12 weeks, or matching placebo.  At 
12 weeks, subjects will undergo assessment for response, and treatment assignments 
will be unblinded. Based on active disease criteria at the end of induction and 
treatment assignment, subjects will either be observed off posaconazole over the next 
24 weeks, or (if they are deemed to be a ‘non-responder’ AND were assigned to 
placebo) will have the option to enroll into a twelve-week open label period, followed 
by a twelve week follow up period. In addition to the treatment intervention, subjects 
also will provide samples for parallel translational studies including blood for genetic 
analysis, stool samples for biomarker and microbial composition analysis, and 
biopsies for mucosal gene expression analysis.  
 
 Inclusion Criteria 
1. Male or female patients ≥  18  years of age.  
2. A diagnosis of CD with minimum disease duration of 6 months with 
involvement of the ileum and/or colon documented on colonoscopy 
3. 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) at Baseline Visit. 
 
 
 

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Inclusion Criteria 
(continued) and 
Exclusion 
Criteria 
Inclusion Criteria (continued) 
4. 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. 
5. 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. 
6. Lab findings of hypokalemia, hypomagnesemia, or hypocalcemia are eligible, 
provided electrolyte abnormalities are corrected and stable prior to study 
enrollment. 
7. Have had age-appropriate and disease-duration-appropriate colon cancer 
screening without unresected dysplasia.  
8. 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.  
9. 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 
The presence of any of the following will exclude a subject from enrollment:  
1. Known hypersensitivity or allergy to posaconazole or other azole antifungal 
agents 
2. Concomitant medications primarily metabolized by CYP3A4 including (but not 
limited to):  
a. HMG-CoA inhibitors primarily metabolized by CYP3A4 (increases risk 
of rhabdomyolysis) 
b. Sirolimus 
c. Ergot alkaloids 
d. Vincristine 
e. upadacitinib 
3. Proarrhythmic conditions, including baseline EKG demonstrating QTc > 
460msec 
4. Moderate or severe renal impairment (Cr Clearance <50) 
5. Elevated transaminases or bilirubin > 2.5x ULN. 
6. Current diagnosis of ulcerative colitis, indeterminate colitis, ischemic colitis, 
infectious colitis, or microscopic colitis. 
7. Fulminant colitis, toxic megacolon, peritonitis, ileostomy or colostomy. 
8. Stool sample positive for pathogens including ova and parasites, Salmonella, 
Shigella, and C. difficile at screening. 
9. 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. 
10. Treatment with antibiotics, antifungal agents, probiotics, or prebiotics within 
two weeks of screening. 
11. 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. 
 
 
 

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Study Product, 
Dose, Route, 
Regimen 
Posaconazole (Noxifil®) delayed-release over-encapsulated tablets:  
Loading dose: 300mg (three 100mg delayed-release over-encapsulated tablets) 
twice a day on the first day, then Maintenance dose: 300mg (three 100mg delayed-
release over-encapsulated tablets) once a day, starting on the second day. Duration 
of therapy will be 12 weeks.  
Duration of 
administration 
Twelve weeks double-blind, with possible twelve-week open label for placebo-treated 
non-responders at the end of 12 weeks 
Primary 
Endpoint 
 The primary endpoint is a 50% decrease in endoscopic disease activity 
(determined by Simple Endoscopic Score for Crohn’s Disease (SES-CD), 
centrally read) at Week 12
Key Secondary 
Endpoints 
 The proportion of subjects in clinical remission at Week 12, defined by the 
Crohn’s Disease Activity Index (<150) 
 The proportion of subjects in endoscopic remission at week 12, defined by SES-
CD < 3  
 The safety of posaconazole, determined by assessment of AEs and concomitant 
medications throughout the duration of the study.  
Safety 
Endpoints 
 Incidence and severity of adverse events 
 Change from baseline of laboratory values (chemistry, hematology, electrolytes, 
liver enzymes, renal function) 
 Incidence of electrocardiogram (EKG) abnormalities including QTc prolongation
Quality-of-life 
Endpoints 
 Inflammatory bowel disease questionnaire (IBDQ) 
 Short Form SF-36 (SF-36) 
Pharmacokinetic 
Endpoints 
 Serum posaconazole concentrations at baseline, and every 2 weeks during the 
12-week treatment period 
 Relationship between posaconazole serum concentration and clinical and 
antifungal effects 
Intestinal 
Microbiota 
Endpoints 
 Malassezia eradication, determined by a 95% decrease in Malassezia spp. in 
colonic mucosal washings at week 12, detected by qPCR.  
Transcriptomics 
Endpoints 
 Changes in stool and mucosal washing metabolites 
 Changes in microbiome / metabolome reflected in gene expression patterns in 
mucosal biopsies  

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Statistical 
Methodology 
The primary analysis population will be the intention-to-treat population. The primary 
efficacy endpoint and key secondary endpoints will also be analyzed with the per-
protocol population. The primary and key secondary endpoints will be evaluated using 
descriptive statistics, Exact Fisher’s and t-test to compare treated vs placebo-
controlled subjects. . In the case of missing clinical data, the missing data points will 
be treated by non-responder imputation. 
 
The primary endpoint is endoscopic response, defined as a 50% reduction SES-CD 
scores at week 12. Each patient will be scored on a binary response (improved/not 
improved).  We will assume the  placebo response rate of approximately 10% 2-4. We 
estimate that a study size of 24 patients is necessary, assuming a drop-off rate of 
~10% before the second colonoscopy, to yield final analysis of at least 11 subjects per 
arm. With a final sample size of 22 subjects, we will have76% power to detect a 
difference of 0.50 in the rate of response for treatment with posaconazole therapy vs 
placebo from the assumed underlying placebo response rate at the 0.05 significance 
level in a Fisher’s Exact Test. This assumes the treatment response rate will be 0.70h 
or greater.  
 
Secondary endpoints will include clinical remission (defined as Crohn’s disease 
activity index < 150), analysis of data regarding use of corticosteroids, mucosal 
healing, mucosal improvement, normalization of inflammatory biomarkers, and 
improvement in health-related quality of life. Repeated measures analysis will be used 
to examine changes over time from baseline. Categorical data will be analyzed with 
repeated measures logistic regression while continuous measures will used mixed 
modeling regression. Residuals will be inspected to confirm data meets assumptions 
necessary for parametric testing. Data will be considered significant at the two-sided 
p-value of <0.05. All analysis will be performed by the study biostatistician (C Bresee, 
MS) using SAS v9.4 software.   
 

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Table 1: Overview of Study Schedule 
 
 
Study 
Assessments 
Screening 
Baseline 
Treatment 
Follow-up 
Week -4 to 
day -1 
Week 
0/Day 0 
Week 
2±3 
days 
Week 
4±3 
days 
Week 
6±3 
days 
Week 
8 
±3 
days  
Week 
10 +/- 
3 days 
Week 12 (or 
early 
termination1) 
±3 days
Week 
16±3 
days 
Week 
20±3 
days 
Week 
24 ±3 
days 
Week 
28 ±3 
days 
Week 
32 ±3 
days 
Week 36 
±3 days 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History2 
X 
 
 
 
 
 
 
 
Eligibility 
Assessment3
X 
X 
 
 
 
 
 
 
Height + weight 
X 
 
 
 
 
 
 
 
Vital Signs  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
Complete 
Physical 
Examination
X 
X 
 
 
 
 
 
X 
X 
Targeted Physical 
Examination4 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X
X
 
Daily diary 
instructions 
X 
X 
 
 
 
 
 
 
Laboratory Studies 
 
 
 
Blood draw for 
genetics13 
X 
 
 
 
 
 
 
 
Serum pregnancy 
test5
X 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test5
 
X 
X 
X 
X 
X 
X 
X 
X12 
X12 
X12 
X12
X12
Pharmacokinetics 
laboratory studies 
 
 
X 
X 
X 
X 
X 
X 
High sensitivity 
CRP
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
Safety laboratory 
tests7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X 
Stool studies for 
pathogens8
X 
 
 
 
 
 
 
 
 
Stool calprotectin 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

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Stool collection 
for microbiome 
analysis
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood for 
Transcriptomics
X 
 
 
 
 
 
 
X 
X 
Imaging and Procedures 
 
 
 
EKG9 
X 
 
X 
 
 
 
 
X 
X12 
X12 
X12 
X12
X12
CXR9 
X 
 
 
 
 
 
 
 
Colonoscopy10  
X 
 
 
 
 
 
 
X 
X
Mucosal Washing 
X 
 
 
 
 
 
 
X 
X
Mucosal biopsies 
for RNA Later & 
Formalin 
X 
 
 
 
 
 
 
X 
X
Study therapy management 
 
 
 
Study therapy 
dispensed 
 
X 
X 
X 
X 
X 
X 
X11 
X11 
X11 
Study therapy 
accountability 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
Crohn's disease assessments 
 
 
 
Bowel movement 
diary 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
Crohn's Disease 
Activity Index  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
PRO2 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
SES-CD score 
X 
 
 
 
 
 
 
X 
X
Quality-of-Life assessments 
 
 
 
IBDQ 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
X
SF-36 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
X
 
 
1Subjects who discontinue early will undergo all tests and procedures according to the Week 12 visit at the time of discontinuation or as soon as possible thereafter 
2Medical history include date of symptom onset, date of diagnosis, and medication/surgical history. Medical history is detailed in Section 6. 

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3The first eligibility assessment will be performed after all other required study assessments for the screening visit except colonoscopy. The second eligibility assessment will be performed 
after review of concomitant medications, urine pregnancy test, and colonoscopy. 
4Targeted physical examination focuses on symptoms, as well as on eyes, throat, lymph nodes, cardiopulmonary systems, abdomen, musculoskeletal, extremities, and skin. 
5Only for females with childbearing potential excluding those with bilateral tubal ligation or at least one-year post-menopause. 
7Safety laboratory tests include serum chemistries, complete blood count with automatic differential, electrolyte panel (potassium, magnesium, calcium, sodium, chloride, phosphate), 
lipid  panel 
8Stool studies include stool ova and parasitology, culture, and C. difficile toxin assay Drawn only if not performed in the last 4 weeks 
9These tests will be read by non-study physicians. Chest Xray posterior/anterior and lateral if not performed in the last 12 months 
10Baseline colonoscopy will be performed between Week -4, Day 1 and Week 0, Day 1, after eligibility assessment. Bowel prep will be dispensed or prescribed at Week -4. 
11Dispensing for patients participating in Open-label 
12Only required for participants receiving Open-label drug 
13 gene testing will only be performed on patients whose CARD9 status is unknown.  

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1.1 Background 
 
Inflammatory bowel disease (IBD) is the result of a dysregulated inflammatory immune response 
in the mucosa of the gastrointestinal tract. Innate and adaptive immune cells drive disease by 
producing 
inflammatory 
mediators 
that 
sustain 
local 
inflammatory 
responses 
and 
promote expression of adhesion molecules that direct trafficking of further immune cells into the 
gut. The disease is associated with alterations in the permeability of the intestinal epithelia and in 
the intestinal microbiota (intestinal “dysbiosis”). IBD is usually classified as Crohn’s Disease (CD) 
or ulcerative colitis (UC) based on phenotypic features of disease location, “patchiness”, and 
depth of damage to the gastrointestinal (GI) tract. Patients can experience diarrhea, fever, fatigue, 
pain and cramping, blood in the stool, loss of appetite and weight loss. They may experience 
periods of active illness followed by periods of clinical remission, although cumulative bowel 
damage occurs leading to complications. These can include bowel obstruction and fistula 
formation, often requiring surgical resection of parts of the small or large bowel.   
 
IBD affects an estimated 1.6 million Americans (1 in 200 people in the U.S.) and more than 3.5 
million people worldwide. Furthermore, the incidence of IBD is increasing globally5. IBD can 
affect 
anyone, 
although 
it 
often 
runs 
in 
families 
suggesting 
a 
genetic 
predisposition. Caucasians are 
affected at 
a 
higher 
prevalence 
than 
other 
ethnic 
groups, especially among Jews of European descent (Ashkenazi Jews). However, the incidence 
of IBD among non-Caucasians including African Americans and Hispanics in the United States is 
increasing6. IBD is also an expensive condition due to the costs of medication, hospitalization, 
and surgery; the total annual financial burden of IBD in the United States has been figured to be 
between $14.6 and $31.6 billion7. There is no known “cure” for IBD.  
 
Precision care  
Rather than being a single disease, or two diseases (CD or UC), IBD is increasingly understood 
as a multifaceted disease that is initiated and exacerbated by influences such as genetic 
susceptibility, environmental factors such as diet and smoking, differing immune responses, and 
alterations in the intestinal microbiota. A major goal in IBD research and care is to improve 
outcomes 
by targeting disease 
treatment to 
an 
individual 
patient’s specific 
underlying 
disease mechanism(s). The heterogeneity of IBD has prompted searches for a marker or 
combination of markers to distinguish IBD from non-IBD, differentiate IBD subtypes (e.g. UC 
versus CD), anticipate disease outcomes, and predict response to therapies.   
 
Genetic diversity  
Genetic diversity is increasingly understood to play an important role in susceptibility to 
developing IBD and in severity of the disease. Large Genome-Wide Association Studies (GWAS) 
have 
implicated 
over 
200 
genetic 
polymorphisms in contributing 
to 
IBD. 
These 
associations reveal specific biological pathways to be involved in disease such as innate 
immunity 
(e.g. NOD2, CARD9), 
mucosal 
immunity 
(e.g. TNFSF15, IL23R), 
autophagy 
(e.g. ATG16L1, IRGM), and epithelial barrier function (e.g. COL7A1, GUCY2C). However, 
translating genetic observations into actionable decision making in clinical care has proven 
challenging. There are currently no genetic tests in use for informing treatment selection based 
on disease mechanism, although genetics can inform the safety of thiopurines based on 
thiopurine methyltransferase (TPMT) enzymatic activity. The search for biomarker identification 
to stratify patients by likelihood of response to therapy is an active and exciting area of research 
and development. This project focuses on understanding the role of CARD9 genotype to target 
potentially novel therapy.  

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Serological markers  
Serological markers have been used to categorize disease. Perinuclear anti-neutrophil 
cytoplasmic antibodies (pANCA) have been linked predominantly to UC, and anti-Saccharomyces 
cerevisiae antibodies (ASCA) have been associated with CD8, 9. These and other biomarkers can 
be useful for identifying phenotypic differences and might one day be helpful in making 
therapeutic choices. For example, clinical response to infliximab (an anti-tumor necrosis factor-α 
biologic 
therapy 
for 
both 
CD 
and 
UC) 
may 
have 
reduced 
efficacy 
in pANCA+ or pANCA+/ASCA- patients10, 
11. Thus, specific antibodies may help to inform 
therapeutic choices and may provide insights into underlying mechanisms of disease subtypes.  
 
The Microbiome  
Intestinal microbes are essential for health of the gut and development of the immune 
system. Many studies have reported changes in bacterial communities in the gut associated with 
IBD. Specifically, decreases in relative abundance of some genera of Bacteroidetes and 
Firmicutes have been reported as well as enrichment of Enterobacteriaceae12, 13.  Observations 
of disease-associated differences in intestinal microbial populations in IBD patients have 
prompted wide-spread interest in the idea that manipulating the gut microbiome may be 
beneficial. Still, it is not yet clear whether or when microbiota changes cause or are simply a result 
of disease. Approaches to manipulating the microbiome include fecal microbiota transplantation 
(FMT) and use of medications (i.e. antibiotics), probiotics, and prebiotics13.  
 
Reports from small randomized, controlled clinical trials employing FMT to treat IBD patients are 
mixed14-17. In patients with ulcerative colitis one trial showed no benefit, while three 
have suggested varying degrees of efficacy. However, the studies used different methods of FMT 
administration (nasoduodenal infusion, enema, colonoscopy), dose frequency (daily or weekly), 
and formulation of the FMT product (fresh or frozen, single donor or pooled donors). FMT thus 
remains an experimental treatment requiring further study. Data are similarly mixed for the use of 
antibiotics to treat IBD patients. While some metanalyses suggest that antibiotics might be helpful 
in some patients18, the data are inconsistent and it is not clear whether the risks of antibiotic use 
outweigh the putative (mostly short-term) benefits. Uses of pro- and pre-biotics to influence the 
makeup of the gut microbiome for benefit are popular among patients, but there are insufficient 
data supporting their efficacy for Crohn’s disease. In UC, several studies suggest that bacterial 
probiotics might provide modest benefit in preventing disease recurrence, although given the 
variety of probiotics and wide variations in patient profiles, the data are difficult to interpret12.   
 
Ultimately however, any clinical attempt to manipulate the microbiome for therapeutic benefit will 
be hindered by our inability to identify the specific patients who would benefit from therapies 
directly targeting the microbiome. While most studies have focused on evaluating the types of 
bacteria associated with disease, we have recently presented data suggesting a role for intestinal 
fungi and host immunity to fungi in intestinal inflammation in mice and humans19, 20. As discussed 
below, we have found that a specific yeast, Malassezia, is substantially more present in the 
intestinal mucosa of patients with Crohn’s disease and that this yeast exacerbates disease in 
mouse models of colitis. Innate immune responses to fungi are mediated in large part by the C-
type lectin family of receptors that includes Dectin-1, Dectin-2 and Mincle. These 
receptors, expressed by nearly all myeloid phagocytes, trigger inflammatory responses upon 
detecting fungi through a signaling pathway that uses a protein called CARD9 to activate NF-B. 
GWAS studies have linked a common polymorphism in CARD9 to the risk of CD. This non-
synonymous polymorphism results in a change in serine 12 to asparagine (CARD9S12N)21-23. As 
discussed below, we have observed that this polymorphism causes human phagocytes to 
respond more aggressively to Malassezia and that patients with this polymorphism have 

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more Malassezia in their gut mucosa. In this project, we will work toward the hypothesis 
that CARD9 genetics (and possibly fungal-specific serotyping) identify a subset of Crohn’s 
disease patients who would benefit from antifungal therapy targeting reduction of Malassezia in 
the colonic mucosa. 
 
Preliminary Data  
Based on the above-mentioned association between anti-Saccharomyces cerevisiae antibodies 
(ASCA) and increasing interest in the role of the microbiome in IBD, we analyzed over 160 
mucosal washing samples collected during colonoscopy of patients with Crohn’s disease and 
healthy controls at Cedars-Sinai Medical Center (CSMC) by high throughput sequencing of fungal 
rDNA “internal transcribed spacer 1” (ITS1) genes. We observed a strong association 
of Malassezia spp. (M. restricta & M. globosa) with CD. 
 
Malassezia spp. are members of the Basidiomycota phyla of fungi and, while all other members 
of the Ustilaginomycotina subdivision are plant pathogens, Malassezia are commensal skin 
microbes found on nearly all warm-blooded animals. Malassezia have among the smallest of 
eukaryotic genomes, having only around 4000 genes. They grow mainly as yeasts, although 
some species can develop hyphae. An important feature of Malassezia genomes is the loss 
of key enzymes required for lipid metabolism, including fatty acid synthase (FAS),  desaturase, 
and enoyl 
CoA 
isomerase (26). 
Therefore, 
they 
cannot 
produce 
fatty 
acids 
themselves and need lipids from the environment for growth. That Malassezia spp. might be 
important in intestinal inflammation is unexpected.  
 
Innate immune responses to fungi are mediated in large part by the C-type lectin family of 
receptors that includes Dectin-1, Dectin-2 and Mincle 24, 25. These receptors trigger inflammatory 
response upon detecting fungi through a signaling pathway that uses a protein called CARD9 to 
activate 
NF-B. 
GWAS 
studies 
have 
linked 
a nonsynonymous single 
nucleotide 
polymorphism (SNP) in exon 2 of CARD9 o the risk of CD21. This SNP leads to production of a 
CARD9S12N variant of the protein. The allele frequency of the “minor” N12 coding variant is around 
40% and present broadly in all ethnic groups examined. It is slightly less frequent in Africans and 
slightly more frequent in native South American populations. In Europeans, a rare second 
polymorphism at the end of exon 11 linked to the CARD9N12 variant results in production of a 
splice variant lacking exon 11 and production of a protein lacking function26. While the N12 variant 
confers increased risk of developing Crohn’s Disease, the truncation variant is protective22, 
23. The CARD9S12N polymorphism has also been linked to the risk of developing ulcerative 
colitis27, primary sclerosing cholangitis28, ankylosing spondylitis29, and immunoglobulin A (IgA) 
nephropathy30 – each of these has been associated with inflammatory bowel disease as 
‘extraintestinal manifestations’ in select patients. The high prevalence of the gene variant 
suggests that it may be protective against certain diseases, most likely specific fungal pathogens, 
but this has not yet been proven.   
 
We investigated whether this polymorphism was linked to the presence of specific fungi. Among 
patients with CD, the presence of Malassezia was positively linked to the presence of 
the CARD9 risk allele. To investigate whether the CARD9 risk allele altered how these patients 
respond to fungi, we collected blood from healthy volunteers. homozygous for the CARD9 risk 
allele or protective allele (via the “Material and Information Resources for Inflammatory and 
Digestive Diseases” (MIRIAD) biobank at CSMC, the largest repository of IBD specimens in the 
world). We stimulated monocyte-derived dendritic cells with Malassezia and other yeasts and 
found that the risk allele made the cells respond more vigorously. 
 

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To test whether Malassezia could influence intestinal inflammation, we used DSS and T cell 
transfer models of colitis in mice and found that Malassezia potently exacerbated 
disease_ENREF_1720. To evaluate whether oral antifungals can directly affect Malassezia levels 
in the gut, we treated mice with oral fluconazole and measured depletion of Malassezia from the 
stool. 
 
Together the data suggest that association of Malassezia with the intestinal mucosa may 
exacerbate disease in a subset of patients who can be identified by their genetics and/or 
serological markers.  
 
This trial is designed to test the hypothesis that oral antifungal treatment with posaconazole can 
reduce the burden of Malassezia spp.  in CD patients with the CARD9S12N 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.  
 
2 Introduction 
This document is a protocol for a human research study. This study is to be conducted according 
to US and international standards of Good Clinical Practice (FDA Title 21 part 312 and 
International Conference on Harmonization guidelines), applicable government regulations and 
Institutional research policies and procedures.  
 
2.1 Indication 
Posaconazole as treatment for active Crohn’s disease despite treatment with conventional 
therapy among people with the CARD 9 risk allele. 
2.2 Investigational Agent 
2.2.1 Description 
 
Posaconazole (Noxafil®, MERCK) is a broad-spectrum, second generation, triazole antifungal 
compound. Posaconazole inhibits 14-alpha demethylase, a common fungal enzyme necessary 
for conversion of lanosterol to ergosterol, a component of fungal cell walls.  Inhibition of ergosterol 
synthesis changes the fungal cell membrane composition and integrity, alters membrane 
permeability and leads to fungal cell lysis. Posaconazole is approved for treatment of 
mucocutaneous candidiasis, invasive aspergillosis, histoplasmosis, coccidiomycoses, fusariosis, 
cryptococcosis, periorbital cellulitis due to Rhizopus, and for prophylaxis against these infections 
in susceptible patients. Posaconazole is available in both parenteral and oral formulations, 
including delayed-release tablets and oral suspension.  
 
2.2.2 Pharmacokinetics of orally administered posaconazole 
 
Mechanism of Action: 
Posaconazole blocks the synthesis of ergosterol, a key component of the fungal cell membrane, 
through the inhibition of cytochrome P-450 dependent enzyme lanosterol 14α-demethylase 
responsible for the conversion of lanosterol to ergosterol in the fungal cell membrane. This 
results in an accumulation of methylated sterol precursors and a depletion of ergosterol within 

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the cell membrane thus weakening the structure and function of the fungal cell membrane. This 
may be responsible for the antifungal activity of posaconazole. The azole family of antifungal 
medications have been shown to inhibit the expression of TNF-alpha-induced cell adhesion 
molecules and angiogenesis, and have to improve colitis in rat models31, 32 33, and a case series 
of 6 patients with inflammatory bowel disease describes unexpected clinical improvement in 
Crohn’s disease after long-term (6 to 9 months) itraconazole treatment for fungal infections34. 
 
General Pharmacokinetic Characteristics (See Noxafil®, package insert) 
 
Noxafil® delayed-release tablets exhibit dose proportional pharmacokinetics after single and 
multiple dosing up to 300 mg. The mean pharmacokinetic parameters of posaconazole at 
steady state following administration of Noxafil delayed-release tablets 300 mg twice daily (BID) 
on Day 1, then 300 mg once daily (QD) thereafter in healthy volunteers and in neutropenic 
patients who are receiving cytotoxic chemotherapy for AML or MDS or HSCT recipients with 
GVHD are shown in Table: 
. 
 
N 
AUC0-24 
hr 
(ng·hr/mL)
Cav† 
(ng/mL)
Cmax 
(ng/mL)
Cmin 
(ng/mL)
Tmax 
‡ 
(hr)
t1/2 
(hr) 
CL/F 
(L/hr) 
Healthy 
Volunteers
12 
51618 
(25) 
2151 
(25) 
2764 
(21) 
1785 
(29) 
4 
(3-6) 
31 
(40) 
7.5 
(26) 
Patients 
50 
37900 
(42) 
1580 
(42) 
2090 
(38) 
1310 
(50) 
4 
(1.3-
8.3) 
 
9.39 
(45) 
CV = coefficient of variation expressed as a percentage (%CV); AUC0-T = Area under the plasma 
concentration-time curve from time zero to 24 hr; Cmax = maximum observed concentration; Cmin = 
minimum observed plasma concentration; Tmax = time of maximum observed concentration; t½ = terminal 
phase half-life; CL /F = Apparent total body clearance 
*300 mg BID on Day 1, then 300 mg QD thereafter 
† Cav = time-averaged concentrations (i.e., AUC0-24 hr/24hr) 
‡ Median (minimum-maximum) 
 
 
Absorption 
 
When given orally in healthy volunteers, posaconazole delayed-release tablets are absorbed 
with a median Tmax of 4 to 5 hours. Steady-state plasma concentrations are attained by Day 6 
at the 300 mg dose (QD after BID loading dose at Day 1). The absolute bioavailability of the oral 
delayed-release tablet is approximately 54% under fasted conditions. The Cmax and AUC of 
posaconazole following administration of posaconazole delayed-release tablets is increased 
16% and 51%, respectively, when given with a high fat meal compared to a fasted state (see 
Table 1). In order to enhance the oral absorption of posaconazole and optimize plasma 
concentrations, posaconazole delayed-release tablets should be administered with food. 
Concomitant administration of posaconazole delayed-release tablets with drugs affecting gastric 
pH (Mylanta®, ranitidine (Zantac®), esomeprazole (Nexium®)) or gastric motility 
(metoclopramide (Reglan®)) did not demonstrate any significant effects on posaconazole 
pharmacokinetic exposure (posaconazole, package insert). 
 
 
 

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Table: Statistical Comparison of Plasma Pharmacokinetics of Posaconazole Following 
Single Oral Dose Administration of 300 mg Posaconazole Delayed-Release Tablet to Healthy 
Subjects under Fasting and Fed Conditions 
 
Fasting Conditions 
Fed Conditions 
(High Fat Meal)*
Fed/Fasting 
Pharmacokinetic
Parameter
N 
Mean (%CV) 
N 
Mean (%CV) 
GMR (90% 
CI)
Cmax (ng/mL) 
14 
935 (34) 
16 
1060 (25) 
1.16 (0.96, 
1.41)
AUC0-72hr 
(hr∙ng/mL)
14 
26200 (28) 
16 
38400 (18) 
1.51 (1.33, 
1.72)
Tmax† (hr) 
14 
5.00 
(3.00, 8.00)
16 
6.00 
(5.00,24.00)
N/A 
GMR=Geometric least-squares mean ratio; CI=Confidence interval 
* 48.5 g fat 
† Median (Min, Max) reported for Tmax 
 
 
Distribution 
 
The mean volume of distribution of posaconazole after intravenous solution administration was 
261 L and ranged from 226-295 L between studies and dose levels. Posaconazole is highly 
bound to human plasma proteins (>98%), predominantly to albumin. 
 
Metabolism 
 
Posaconazole primarily circulates as the parent compound in plasma. Of the circulating 
metabolites, the majority are glucuronide conjugates formed via UDP glucuronidation (phase 2 
enzymes). Posaconazole does not have any major circulating oxidative (CYP450 mediated) 
metabolites. The excreted metabolites in urine and feces account for ~17% of the administered 
radiolabeled dose. Posaconazole is primarily metabolized via UDP glucuronidation (phase 2 
enzymes) and is a substrate for p-glycoprotein (P-gp) efflux. Therefore, inhibitors or inducers of 
these clearance pathways may affect posaconazole plasma concentrations.  
 
In vitro studies with human hepatic microsomes and clinical studies indicate that posaconazole 
is an inhibitor primarily of CYP3A4. A clinical study in healthy volunteers also indicates that 
posaconazole is a strong CYP3A4 inhibitor as evidenced by a >5-fold increase in midazolam 
AUC. Therefore, plasma concentrations of drugs predominantly metabolized by CYP3A4 may 
be increased by posaconazole. For this reason, the following drugs studied clinically, for which 
plasma concentrations were affected by posaconazole, will be prohibited during the current 
proposed trial (cyclosporine, tacrolimus, sirolimus, simvastatin, midazolam, rifabutin, phenytoin, 
ritonavir, atazanavir [see Exclusion Criteria]. 
 
Elimination 
Following administration of Noxafil oral suspension, posaconazole is predominantly eliminated 
in the feces (71% of the radiolabeled dose up to 120 hours) with the major component 
eliminated as parent drug (66% of the radiolabeled dose). Renal clearance is a minor 
elimination pathway, with 13% of the radiolabeled dose excreted in urine up to 120 hours 
(<0.2% of the radiolabeled dose is parent drug). Posaconazole delayed-release tablet is 
eliminated with a mean half-life (t½) ranging between 26 to 31 hours. 

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2.2.3 Use In Specific Populations 
 
Pregnancy and Lactation 
Based on findings from animal data, Noxafil® may cause fetal harm when administered to 
pregnant women. Available data for use of Noxafil in pregnant women are insufficient to 
establish a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal 
outcomes. Pregnant women will be excluded from the current study.  
 
There are no data on the presence of posaconazole in human milk, the effects on the breastfed 
infant, or the effects on milk production. Posaconazole is excreted in the milk of lactating rats. 
Lactating women will be excluded from the current study.  
 
Pediatrics 
The safety and effectiveness of Noxafil injection in pediatric patients below the age of 18 years 
of age has not been established. Subjects <18 years of age will be excluded from the current 
study.  
 
Geriatric Use 
Of the 230 patients treated with posaconazole delayed-release tablets, 38 (17%) were greater 
than 65 years of age. The pharmacokinetics of posaconazole delayed-release tablets are 
comparable in young and elderly subjects. No overall differences in safety were observed 
between the geriatric patients and younger patients; therefore, no dosage adjustment is 
recommended for geriatric patients. No overall differences in the pharmacokinetics and safety 
were observed between elderly and young subjects during clinical trials, 
 
Gender 
The pharmacokinetics of posaconazole are comparable in men and women. 
 
Weight 
Pharmacokinetic modeling suggests that patients weighing greater than 120 kg may have lower 
posaconazole plasma drug exposure. 
 
Renal Impairment 
Following single-dose administration of 400 mg of the oral suspension, there was no significant 
effect of mild (eGFR: 50-80 mL/min/1.73 m2, n=6) or moderate (eGFR: 20-49 mL/min/1.73 m2, 
n=6) renal impairment on posaconazole pharmacokinetics; therefore, no dose adjustment is 
required in patients with mild to moderate renal impairment. In subjects with severe renal 
impairment (eGFR: <20 mL/min/1.73 m2), the mean plasma exposure (AUC) was similar to that 
in patients with normal renal function (eGFR: >80 mL/min/1.73 m2); however, the range of the 
AUC estimates was highly variable (CV=96%) in these subjects with severe renal impairment as 
compared to that in the other renal impairment groups (CV<40%). Due to the variability in 
exposure, patients with severe renal impairment being treated for fungal infections should be 
monitored closely for breakthrough fungal infections, although this recommendation is not 
relevant to the present trial. Similar recommendations apply to posaconazole delayed-release 
tablets; however, a specific study has not been conducted with the delayed-release tablets. 
 
Hepatic Impairment 
After a single oral dose of posaconazole oral suspension 400 mg, the mean AUC was 43%, 
27%, and 21% higher in subjects with mild (Child-Pugh Class A, N=6), moderate (Child-Pugh 
Class B, N=6), or severe (Child-Pugh Class C, N=6) hepatic impairment, respectively, 
compared to subjects with normal hepatic function (N=18). Compared to subjects with normal 

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hepatic function, the mean Cmax was 1% higher, 40% higher, and 34% lower in subjects with 
mild, moderate, or severe hepatic impairment, respectively. The mean apparent oral clearance 
(CL/F) was reduced by 18%, 36%, and 28% in subjects with mild, moderate, or severe hepatic 
impairment, respectively, compared to subjects with normal hepatic function. The elimination 
half-life (t½) was 27 hours, 39 hours, 27 hours, and 43 hours in subjects with normal hepatic 
function and mild, moderate, or severe hepatic impairment, respectively. It is recommended that 
no dose adjustment of Noxafil is needed in patients with mild to severe hepatic impairment 
(Child-Pugh Class A, B, or C). Similar recommendations apply to posaconazole delayed-release 
tablets; however, a specific study has not been conducted with the delayed-release tablets. 
 
OVERDOSAGE 
There is no experience with overdosage of posaconazole injection and delayed-release tablets. 
During the clinical trials, some patients received posaconazole oral suspension up to 1600 
mg/day with no adverse reactions noted that were different from the lower doses. In addition, 
accidental overdose was noted in one patient who took 1200 mg BID posaconazole oral 
suspension for 3 days. No related adverse reactions were noted by the investigator. 
Posaconazole is not removed by hemodialysis. 
2.3 Clinical Data to Date 
2.3.1 Safety data from placebo-controlled trials of oral delayed-release tablets 
 
The safety of posaconazole delayed-release tablets has been assessed in 230 patients in 
clinical trials. Patients were enrolled in a non-comparative pharmacokinetic and safety trial of 
posaconazole delayed-release tablets when given as antifungal prophylaxis (Delayed-Release 
Tablet Study 1). Patients were immunocompromised with underlying conditions including 
hematological malignancy, neutropenia post-chemotherapy, GVHD, and post HSCT. This 
patient population was 62% male, had a mean age of 51 years (range 19-78 years, 17% of 
patients were ≥65 years of age), and were 93% white and 16% Hispanic. Posaconazole therapy 
was given for a median duration of 28 days. Twenty patients received 200 mg daily dose and 
210 patients received 300 mg daily dose (following twice daily dosing on Day 1 in each cohort). 
Table below presents treatment-emergent adverse reactions observed in patients treated with 
300 mg daily dose at an incidence of 10% in posaconazole delayed-release tablet study. The 
most frequently reported adverse reactions (>25%) with posaconazole delayed-release tablets 
300 mg once daily were diarrhea, pyrexia, and nausea. The most common adverse reaction 
leading to discontinuation of posaconazole delayed-release tablets 300 mg once daily was 
nausea (2%). 
 
Table: Posaconazole Delayed-Release Tablet Study 1: Number (%) of Subjects Treated with 
300 mg Daily Dose Reporting Treatment-Emergent Adverse Reactions: Frequency of at Least 10% 
 
Posaconazole delayed-release tablet (300 mg)  
(n=210) 
Subjects reporting any 
Adverse Reaction
201 
(99) 
Anemia 
22 
(10) 
Thrombocytopenia 
29 
(14) 
Abdominal Pain 
23 
(11) 
Constipation 
20 
(10) 
Diarrhea 
61 
(29) 
Nausea 
56 
(27) 
Vomiting 
28 
(13) 

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Asthenia 
20 
(10) 
Chills 
22 
(10) 
Mucosal inflammation 
29 
(14) 
Edema Peripheral 
33 
(16) 
Pyrexia 
59 
(28) 
Hypokalemia 
46 
(22) 
Hypomagnesemia 
20 
(10) 
Headache 
30 
(14) 
Rash 
34 
(16) 
Hypertension 
23 
(11) 
 
CONTRAINDICATIONS  
Hypersensitivity: Posaconazole is contraindicated in persons with known hypersensitivity to 
posaconazole or other azole antifungal agents.  
 
QT Prolongation with Concomitant Use with CYP3A4 Substrates: Posaconazole is 
contraindicated with CYP3A4 substrates that prolong the QT interval. Concomitant administration 
of posaconazole with substrates pimozide and quinidine may result in increased plasma 
concentrations of these drugs, leading to QTc prolongation and torsades de pointes.  
 
Coadministration with the HMG-CoA Reductase Inhibitors Primarily Metabolized Through 
CYP3A4: HMG-CoA reductase inhibitors (e.g., atorvastatin, lovastatin, and simvastatin) are 
contraindicated due to increased plasma concentration of these drugs can lead to 
rhabdomyolysis.  
 
Ergot Alkaloids: Posaconazole may increase the plasma concentrations of ergot alkaloids 
(ergotamine and dihydroergotamine) which may lead to ergotism.  
2.4 Dose Rationale 
 
Noxafil® delayed-release tablets are available as yellow, coated, oblong tablets, debossed with 
"100" on one side containing 100 mg of posaconazole. Noxifil® delayed-release tablets are 
approved for prophylaxis of invasive aspergillus and Candida infection at a dose of 300mg (3 
tablets) twice a day on the first day (loading dose) followed by 300mg (3 tablets) once a day, 
starting on the second day (maintenance dose). At this dose, steady state parameters are as 
noted in Table 1.  The current trial will evaluate the effects of this FDA-approved dose (for 
fungal prophylaxis) in patients with Crohn’s disease demonstrating genetic susceptibility to 
fungal infection. We propose a 3 month treatment duration which is expected to have inhibitory 
effects on the intestinal fungome (specifically Malassezia spp) as well as clinical effects on 
inflammation, as evidenced by a case series demonstrating clinical benefit for 5 patients with 
Crohn’s disease after itraconazole therapy was incidentally prescribed for fungal infections.34 
3 Study Objectives 
Primary Objective 
 To assess the effects of posaconazole endoscopic disease activity at week 12 in patients 
with active Crohn’s disease  
 
Secondary Objectives 
 To assess the preliminary efficacy of posaconazole for the induction of clinical remission in 
patients with active Crohn’s disease with genetically-determined CARD9 S12N risk allele 
 

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 To assess the preliminary safety and tolerability of posaconazole for the induction of clinical 
remission and endoscopic response in patients with active Crohn’s disease with genetically-
determined CARD9 S12N risk allele 
 
 To assess the preliminary influence on quality-of-life of posaconazole in patients with active 
Crohn’s disease with genetically-determined CARD9 S12N risk allele 
 
 To assess the pharmacokinetics (PK) of posaconazole in patients with active Crohn’s 
disease with genetically-determined CARD9 S12N risk allele 
 
 To assess changes in the intestinal microbiota after treatment with posaconazole in patients 
with active Crohn’s disease with genetically-determined CARD9 S12N risk allele 
 
 To determine changes in gene expression (transcriptomics) in colonic mucosa after 
posaconazole in patients with active Crohn’s disease with genetically-determined CARD9 
S12N risk allele 
4 Study Design 
4.1 General Design 
This study is designed as a two-center, placebo-controlled  induction trial in 24 subjects with active 
Crohn’s disease, who demonstrate at least one CARD9 S12N risk allele. Expected duration of 
participation is forty weeks. This will include screening period up to four-weeks and a twelve-
week, double-blind induction period.  
 
- 
Subjects who complete the 12-week induction period, meet criteria for active disease, 
AND upon unblinding at 12 weeks are determined to have received placebo during the 
12-week induction period will be eligible to receive open-label posaconazole for 12 weeks, 
followed by  a 12-week follow-up period. 
 
- 
Subjects who complete the 12-week induction period and do not meet criteria for active 
disease, OR upon unblinding at 12 weeks are determined to have received posaconazole 
during the 12-week induction period will have a follow-up period of twenty-four weeks.  
 
Clinical remission will be defined as the proportion of subjects with endoscopic improvement, 
defined by a decrease in 50% of the SES-CD endoscopic score. Subjects experiencing early 
withdrawal from study will be scheduled for a safety follow-up visit four weeks after the date of 
withdrawal. 
 
 
 

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Figure 1: Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SCREENING ASSESSMENT 
Week -4 to day -1 
1. Informed consent 
2. Blood genetic Testing 
3. Medical history and concomitant 
medication assessment 
4. Complete 
physical 
examination, 
height, vital signs, and weight 
5. Labs: Serum pregnancy test, safety 
laboratory 
tests, 
blood 
for 
transcriptomics, and stool studies 
(pathogens, microbiome) 
6. EKG 
7. CXR  
8. Eligibility assessment 
9. Colonoscopy with washing/ biopsies 
performed if patients meet all of the 
above criteria 
10. Daily diary instructions provided 
BASELINE VISIT 
Week 0 
 
1. Concomitant medication assessment 
2. Complete physical examination, vital 
signs, and weight 
3. Labs: 
Urine 
pregnancy 
test, 
stool 
calprotectin, high sensitivity CRP, safety 
laboratory tests 
4. CDAI and PRO2 scores calculated 
5. Eligibility assessment 
6. Bowel Diary assessed 
7. Adverse events recorded 
8. IBDQ and SF-36  completed 
9. Study therapy dispensed 
10. Microbiome assessment 
TREATMENT FOLLOW-UP VISITS 
Weeks 2, 4, 6, 8, and 10 
 
1. 
Concomitant medication 
assessment 
2. Targeted physical examination, vital 
signs, and weight 
3. Labs: 
Urine 
pregnancy 
test 
Pharmacokinetics 
studies, 
high 
sensitivity CRP, stool calprotectin, 
safety laboratory tests 
4. Study 
therapy 
dispensed 
and 
assessed with titration of dosing per 
protocol 
5. Daily  bowel diary assessed 
6. Adverse events recorded 
7. CDAI and PRO2 scores calculated 
8. IBDQ and SF-36 performed 
Week -4 
TIMELINE 
Week 12 
(EOT) 
TREATMENT FOLLOW-UP VISIT 
Week 12 or early termination 
 
1. Concomitant medication assessment 
2. Complete physical examination, vital 
signs, and weight 
3. Labs: 
Urine 
pregnancy 
test 
Pharmacokinetics 
studies, 
high 
sensitivity 
CRP, 
stool 
studies 
(calprotectin, microbiome), blood for 
transcriptomics, 
safety 
laboratory 
tests 
4. EKG performed 
5. Adverse events recorded 
6. Daily bowel diary assessed 
7. Mayo score and partial Mayo score 
calculated 
8. IBDQ and SF-36 performed 
9. Colonoscopy with washing/ biopsies 
10. If 
eligible, 
offer 
open 
label 
Week 36 (EOS) 
Week 0 
FINAL FOLLOW-UP VISIT 
Week 36 (end of study) 
 
1. Concomitant medication assessment 
2. Adverse events recorded 
3. Complete physical examination, vital 
signs, and weight 
4. Labs: Safety laboratory tests, stool 
studies (calprotectin, microbiome), 
blood for transcriptomics 
5. Daily bowel diary assessed 
6. PRO2 and CDAI assessed 
7. IBDQ and SF36 performed 
8. Colonoscopy with washings/biopsies 
FOLLOW-UP Period 
Weeks 16, 20, 24, 28, 32, 36 
 
1. Concomitant 
medication 
assessment 
2. Targeted physical examination, 
vital signs, and weight 
3. Labs: high sensitivity CRP, stool 
calprotectin, 
safety 
laboratory 
tests 
4. Daily  bowel diary assessed 
5. Adverse events recorded 
6. CDAI 
and 
PRO2 
scores 
calculated 
7. IBDQ and SF-36 performed 

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4.2 Primary Study Endpoints 
The primary endpoint is the proportion of subjects in endoscopic response at week 12, defined 
by SES-CD reduction of >50% from baseline.  
4.3 Key Secondary Study Endpoints 
 The proportion of subjects in clinical remission at Week 12, defined by PRO2 (abdominal 
pain score <1 AND stool frequency <3) and by the Crohn’s Disease Activity Index (<150) 
 Reduction of Malassezia spp in colonic mucosal washings at week 12 
 The safety of posaconazole, determined by assessment of AEs and concomitant 
medications throughout the duration of the study. The proportion of subjects in clinical 
remission at Week 8, defined by Mayo score≤2 with no subscore>1 
4.4 Primary Safety Endpoints 
 Incidence and severity of adverse events 
 Change from baseline of laboratory values (chemistry, hematology, electrolytes, liver 
enzymes, renal function) 
 Incidence of electrocardiogram (EKG) abnormalities including QTc prolongation 
4.5 Quality-of-life Endpoints 
 
Inflammatory bowel disease questionnaire (IBDQ) 
 
Short Form SF-36 (SF-36) 
4.6 Pharmacokinetics Endpoints  
 Serum posaconazole concentrations at weeks 2, 4, 6, 8, 10, and 12.Relationship between 
posaconazole serum concentration and clinical and antifungal effects  
4.7 Transcriptomics Endpoints 
 Changes in stool and mucosal washing metabolites 
 Changes in microbiome / metabolome reflected in gene expression patterns in mucosal 
biopsies 
 
5 Subject Selection and Withdrawal 
Subjects (n=24) will be individuals with active Crohn’s disease (SES-CD > 6 AND PRO2 score of 
abdominal pain >2 OR PRO2 daily stool frequency > 4) despite use of conventional therapy. 
Subjects will be randomly assigned to receive posaconazole or placebo in 1:1 fashion. In this 40-
week trial, subjects assigned to treatment will be administered posaconazole (Noxifil®, Merck) 
300mg daily for 12 weeks. and then observed off posaconazole over the next 24 weeks. In 
addition to the treatment intervention, subjects also will provide samples for parallel translational 
studies including blood for genetic analysis, stool samples for biomarker and microbial 
composition analysis, and biopsies for mucosal gene expression analysis. Patients meeting 
criteria for active disease at 12 weeks will be offered open-label posaconazole for 12 weeks and 
will continue all study-related visits and procedures until final safety visit at week 36.  
 
5.1 Randomization  
At the baseline visit, subjects will be randomized via REDCap to receive posaconazole or placebo.  

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5.2 Inclusion Criteria 
1. Male or female patients ≥ 18 years of age.   
2. A diagnosis of CD with minimum disease duration of 6 months with involvement of the 
ileum and/or colon documented on colonoscopy 
3. 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 >220) 
4. 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. 
5. 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. 
6. Lab findings of hypokalemia, hypomagnesemia, or hypocalcemia are eligible, provided 
electrolyte abnormalities are corrected and stable prior to study enrollment. 
7. Have had age-appropriate and disease-duration-appropriate colon cancer screening 
without unresected dysplasia.  
8. 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.  
a. Option 1: Any one of the following highly effective methods: hormonal 
contraception for example, birth control pills, injection, implant, transdermal patch, 
vaginal ring); intrauterine device (IUD); tubal ligation (tying your tubes); or a partner 
with a vasectomy    
b. Option 2: Any two of the following effective methods: male or female condom PLUS 
one of the following additional barrier methods (a)diaphragm with spermicide; (b) 
cervical cap with spermicide; or (c) contraceptive sponge with spermicide  
9. 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. 
5.3 Exclusion Criteria 
The presence of any of the following will exclude a subject from enrollment:  
1. Known hypersensitivity or allergy to posaconazole or other azole antifungal agents 
2. Concomitant medications primarily metabolized by CYP3A4 including (but not limited 
to):  
a. HMG-CoA inhibitors primarily metabolized by CYP3A4 (increases risk of 
rhabdomyolysis) 
b. Sirolimus 
c. Ergot alkaloids 
d. Vincristine 
e. upadacitinib 
3. Proarrhythmic conditions  
4. Moderate or severe renal impairment (Cr Clearance <50) 
5. Elevated transaminases or bilirubin > 2.5x ULN. 
6. Current diagnosis of ulcerative colitis, indeterminate colitis, ischemic colitis, infectious 
colitis, or microscopic colitis. 
7. Fulminant colitis, toxic megacolon, peritonitis, ileostomy or colostomy. 

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8. Stool sample positive for pathogens including ova and parasites, Salmonella, Shigella, 
and C. difficile at screening. 
9. 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.  
10. Treatment with antibiotics, antifungal agents, probiotics, or prebiotics within two weeks of 
screening. 
11. Alcohol or drug abuse (in the opinion of the Investigator) that would interfere with 
compliance. 
 
5.4 Subject Recruitment and Screening 
Potential study candidates will be identified from the Cedars-Sinai Inflammatory Bowel Disease 
Center genetic database (MIRIAD) and Mayo Clinic’s IBD Biobank; all MIRIAD and Biobank 
participants have previously provided written, informed consent to participate in genetic research 
and to be contacted for potential research opportunities.  Patients who have CARD9 risk allele 
will be notified of an opportunity to participate in this trial at the time of a routine clinical encounter, 
if deemed appropriate by their treating provider. They will be provided with information about the 
study, and if the study candidate is interested in study participation, they will be scheduled for the 
screening visit. 
 
Patients who wish to participate in this research, who have not previously had their CARD9 risk 
allele testing performed or who are not in MIRIAD or Mayo Clinic’s IBD Biobank, will have an 
opportunity to provide a blood sample for genetic testing of CARD9, once Informed Consent to 
participate has been provided.   
 
At the screening visit, patients will be asked to provide informed consent for the study. A complete 
medical history will be taken including list of current and recent medications. A complete physical 
examination, including height, weight, vital signs will be performed. Safety laboratory studies, 
pregnancy test, stool studies, and EKG will be performed at this visit (stool may be provided after 
the visit). Chest radiography will be performed. Then, patients meeting eligibility will be scheduled 
for baseline colonoscopy. Patients meeting eligibility criteria will be scheduled for the baseline 
visit. 
5.5 Lifestyle guidelines 
Patients will be instructed to continue their current dietary and exercise patterns during the trial, 
excluding non-prescription supplements or herbal preparations which might affect hepatic 
metabolism.  
5.6 Early withdrawal of Subjects 
5.6.1 When and How to Withdraw Subjects 
Subjects may be withdrawn from study for safety concerns, progression of Crohn’s disease 
(requiring new medication or escalation of dose of current therapies, hospitalization, or surgery), 
withdrawal of consent, failure to adhere to protocol requirements, patient request, or 
administrative reasons. Withdrawal may be warranted at the request of the patient, investigator, 
or study protocol. The reason for study withdrawal will be determined by the investigator. Patients 
will be required to return all remaining study therapy. 
 

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The data from subjects who withdraw consent will continue to be used in analysis before the date 
of withdrawal of consent, however no follow-up or inquiries will be conducted on these patients 
on or after this date. 
 
If a subject does not attend a scheduled visit, the subject will be called three times at the number 
provided by the subject. Subjects who do not answer will be sent a certified letter. The record of 
these contacts and any written communication will be included in the study documentation. 
Subjects who do not respond to these inquiries will be assigned as lost to follow-up (LTFU). 
5.6.2 Data Collection and Follow-up for Withdrawn Subjects 
Subjects with early withdrawal from study during the twelve-week intervention period, for any 
reason, will be scheduled for a safety follow-up visit four weeks from date of withdrawal. Subjects 
who withdraw from study after the intervention period will maintain the per-protocol final follow-up 
visit at week 36. The clinical outcome will be assessed at this follow-up visit. 
 
Subjects with abnormal laboratory findings, or other adverse events requiring early study 
withdrawal, will be followed until the abnormality has resolved to baseline or steady state. The 
investigators will determine if the adverse event was related to study therapy. The clinical course 
will be documented. 
 
5.7 Open Label Posaconazole:  
 
At 12 weeks, subjects will undergo colonoscopy and clinical assessment for response, after which 
they will be unblinded. Subjects who meet criteria for active disease AND who are determined to 
have received placebo will be eligible to receive 12 weeks of open-label posaconazole. Eligibility 
Criteria for open label posaconazole:  
1. Endoscopically-confirmed active Crohn’s disease with active disease defined by SES-
CD > 6 (>4 if ileal only) based on local reading, AND  
2. Active symptoms of Crohn’s disease (CDAI >220), AND 
3. Received placebo during the 12-week induction period 
 
Subjects who meet the above criteria and opt to receive open label posaconazole will be 
monitored for safety / adverse events at follow-up visits. Changes in corticosteroid dosing will be 
permitted after 12 weeks, regardless of whether subjects are receiving posaconazole or not. All 
subjects will undergo colonoscopy at 36 weeks.  
 
6 Study Drug  
6.1 Description 
Noxafil delayed-release tablets are available as yellow, coated, oblong tablets, debossed with 
"100" on one side containing 100 mg of posaconazole.   
6.2 Treatment Regimen 
Posaconazole (Noxifil®) delayed-release tablets: Loading dose: 300mg (three 100mg delayed-
release over-encapsulated tablets) twice a day on the first day, then Maintenance dose: 300mg 
(three 100mg delayed-release over-encapsulated tablets) once a day, starting on the second day. 
Duration of therapy will be 12 weeks.  

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6.3 Preparation and Administration of Study Drug 
To maintain study blind, placebo capsules will be manufactured using blue gelatin capsules, size 
00, and filled with Cellulose Microcrystalline.  Posaconazole tablets will be over-encapsulated, 
using the same blue gelatin capsules, size 00, and back-filled with Cellulose Microcrystalline. 
 
Posaconazole will be self-administered by the subjects, with the first dose observed at the time 
of the baseline visit. Subjects will be advised to swallow the capsules whole, and to not divide, 
crush or chew. The capsules should be taken with food to enhance the oral absorption of 
posaconazole and optimize plasma concentrations.  
6.4 Subject Compliance Monitoring 
Subjects need to keep the capsule containers and bring them to follow up visit. Compliance will 
be evaluated by the counts of unused tablets. If a deviation from protocol is identified, the 
investigators will inquire as to the reason for study deviation during the corresponding patient 
encounter. Non-compliance related to study medication regimen and (i.e., less than 80% or more 
than 120% of recommended dosing) and not due to adverse events will be evaluated by the 
Investigator who will encourage subject to follow the medication regimen prescribed.  Patients 
who remain significantly non-compliant with the drug regimen and not due to adverse events for 
two consecutive visits will be withdrawn from study or earlier at the discretion of the PI. The subject 
will then complete the final follow-up visit per protocol.  
6.5 Prior and Concomitant Therapy 
The following concomitant therapies are allowed as long as a stable dose was administered per 
eligibility criteria: 
 
Biologic agents (infliximab, adalimumab, certolizumab, ustekinumab, vedolizumab) 
 
Immunomodulators (azathioprine/6-mercaptopurine) 
 
Oral 5-aminosalicylates or sulfasalazine 
 
Oral corticosteroid preparations (maximum budesonide 9 mg/day, or prednisone 20 mg/day or 
equivalent) will be allowed as long as the dose has been stable dose for two weeks prior to 
screening. The dosage may not be reduced during the 12-week study period without premature 
discontinuation from the trial. Any dosage increases beyond that prescribed at the start of the trial 
will result in early withdrawal from study due to progression of Crohn’s disease. 
 
Concomitant prescribed therapies, non-prescription supplements, and herbal preparations 
which affect hepatic metabolism, antibiotics, probiotics, and antidiarrheals will not be allowed 
during the study. Drugs predominantly metabolized by CYP3A4 may be increased by 
posaconazole. Examples of drugs prohibited during the current proposed trial include, but are 
not limited to: cyclosporine, tacrolimus, sirolimus, simvastatin and other HMG-CoA inhibitors, 
midazolam, rifabutin, phenytoin, ritonavir, atazanavir, and upadacitinib. 
 
 
Data regarding the composition, dosage, dosing schedule, route of administration, and 
initiation/end dates of therapy will be recorded for each concomitant therapy. 
6.6 Packaging 
Noxafil delayed-release tablets are available as yellow, coated, oblong, debossed with "100" on 
one side containing 100 mg of posaconazole. Bottles with child-resistant closures of 60 delayed-

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release tablets (NDC 0085-4324-02). Upon arrival at site, tablets will be over-encapsulated with 
blue gelatin capsules. 
6.7 Receiving, Storage, Dispensing and Return 
Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F) [see USP Controlled 
Room Temperature]. 
6.7.1 Receipt of Drug Supplies 
Upon receipt of the of the study treatment supplies, an inventory will be performed, and a drug 
receipt log filled out and signed by the person accepting the shipment.  Designated study staff will 
verify that the shipment contains all the items noted in the shipment inventory.  Any damaged or 
unusable study drug in a given shipment will be documented in the study files.  
6.7.2 Storage 
Store at 20-25°C (68-77°F), excursions permitted to 15-30°C (59-86°F) 
6.7.3 Dispensing of Study Drug 
Patients will be dispensed a 2-week supply of study drug (or placebo) at each of the following 
study visits: baseline (week 0), and weeks 2, 4, 6, 8, and 10. Study drug reconciliation will be 
performed to document drug assigned, drug consumed, and drug remaining. This reconciliation 
will be logged on the drug reconciliation form and signed and dated by the study team. 
 
Patients who are eligible to receive open label posaconazole will be dispensed a 4-week supply 
of study drug at weeks 12, 16, and 20.  
6.7.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, 
and drug remaining. This reconciliation will be logged on the drug reconciliation form, signed and 
dated.  Any discrepancies noted will be investigated, resolved, and documented prior to return or 
destruction of unused study drug.  Drug will be destroyed per research pharmacy discretion.  
 
6.8 Placebo  
Placebo capsules will be developed for this study and will duplicate the size, color and shape of the over-
encapsulated Noxifil®.  
 
7 Study Procedures 
7.1 Screening (Week -4 to Week 0) 
After informed consent is given, eligibility will be evaluated over a period of four weeks. The study 
investigators will discuss with the patient the purpose, obligations, and risks of the study. 
 
The following tasks will be conducted or scheduled at the initial Week -4 visit: 
 
Complete medical history: date of diagnosis; extent of disease; date and reason for CD-
related hospitalizations; past medical history (including prior invasive fungal infection, 
arrythmia, chronic kidney disease stage III or greater, uncontrolled diabetes mellitus, 
cirrhosis, and major psychiatric disorder); alcohol and drug history; and extra-intestinal 
manifestations. 

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 
Medication history: list of current medications including date of initiation, length of current 
dosing regimen, current dose, current frequency, current route of administration; list of 
prior medications, including clinical response to medication and reason for medication 
withdrawal; all non-prescription medications, non-prescription supplements, and herbal 
preparations used within last twelve weeks. 
 
Complete physical examination, height, vital signs, and weight. 
 
Laboratory studies: serum β-hCG in women of childbearing potential, safety laboratory 
tests (serum chemistries, complete blood count with automatic differential, lipid panel, 
hemoglobin A1c, urinalysis), and stool studies (stool ova and parasitology, culture, and C. 
difficile toxin assay,  
 
12-lead EKG. 
 
Chest radiography posteroanterior and lateral (if patient meets all of the above eligibility 
requirements) if not performed within last 12 months. 
 
Bowel movement diary instructions. 
 
Eligibility assessment based on collected data. 
 
Colonoscopy to be scheduled within one week of baseline visit, with SES-CD score 
o  Mucosal biopsies will be collected from the Ileum, Right colon, and Left Colon.  2 
biopsies from most inflamed area  of each region will be taken.  One tissue will be 
placed in a solution of RNALater, and the other tissue will be placed in Formalin.   
o and Washings for fungome analyses 
 
Stool collection for microbiome analysis, stored at -70C, and batch shipped every 6-
Months.  
 
Blood for transcriptomics. 
 
Blood for genetics (if CARD9 status is not known) 
7.2 Baseline visit (week 0) 
The following tasks will be conducted at this visit: 
 
Assessment of concomitant medications. 
 
Complete physical examination, vital signs, and weight. 
 
Laboratory studies: urine pregnancy test in women of childbearing potential, hsCRP, 
serum chemistries, complete blood count with automatic differential, lipid panel, and stool 
calprotectin. 
 
Calculation of CDAI and PRO2 scores  
 
Eligibility assessment based on collected data. 
 
Study therapy dispensed and instructions on use given. 
 
Adverse event monitoring. 
 
Review of bowel movement diary. 
 
IBDQ and SF-36 assessments. 
 
Randomization of subjects to treatment arm via REDCap by research pharmacist. (Both 
subject and clinical staff will be masked to treatment group assigned.) 
7.3 Weeks 2, 4, 6, 8, and 10 (±3 days) 
These visits may be conducted within three days of the specific time-point marking the number of 
weeks since baseline visit. The following tasks will be conducted at these visits: 
 
Assessment of concomitant medications. 
 
Targeted physical examination (eyes, throat, lymph nodes, cardiopulmonary systems, 
abdomen, musculoskeletal, extremities, and skin), vital signs, and weight. 

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 
Laboratory studies: urine pregnancy test in women of childbearing potential, serum 
posaconazole concentration, hsCRP, serum chemistries, lipid panel, complete blood 
count with automatic differential, and  stool calprotectin. 
 
Study therapy usage reviewed, and further study drug dispensed  
 
Adverse event monitoring. 
 
Review of bowel movement diary. 
 
Calculation of CDAI and PRO2 scores  
 
IBDQ and SF-36 assessments. 
 Stool collection for microbiome analysis 
7.4 Week 12 (±3 days) or early termination 
This visit may be conducted within three days of the specific time-point marking the number of 
weeks since baseline visit. The following tasks will be conducted at these visits: 
 
Assessment of concomitant medications. 
 
Complete physical examination, vital signs, and weight. 
 
Laboratory studies: urine pregnancy test in women of childbearing potential, serum 
posaconazole concentration, hsCRP, serum chemistries, complete blood count with 
automatic differential, lipid panel, and stool calprotectin, microbiome, blood for 
transcriptomics. 
 
12-lead EKG. 
 
Study therapy usage reviewed. 
 
Adverse event monitoring. 
 
Review of bowel movement diary. 
 
Calculation of CDAI and PRO2 scores  
 
IBDQ and SF-36 assessments. 
 
Colonoscopy with biopsies (RNALater & Formalin) and washings scheduled ±7 days of 
this visit for calculation of SES-CD.  Biopsies and washings should be obtained from same 
area of each region as screening samples.  
 
Following the above evaluations, subjects will be unblinded and determined to have 
received either posaconazole or placebo during the 12-week induction period.  
 
Patients meeting criteria for active disease AND who are determined to have received 
placebo will be eligible to receive open label posaconazole; these subjects will be 
dispensed 4 weeks posaconazole at this visit.  
7.5 Weeks 16, 20, 24, 28, 32 (±3 days)  
This visit may be conducted within three days of the specific time-point marking the number of 
weeks since baseline visit. The following tasks will be conducted at these visits: 
 
Assessment of concomitant medications. 
 
Targeted physical examination, vital signs, and weight. 
 
Laboratory studies: serum chemistries, complete blood count with automatic differential, 
lipid panel, and  stool calprotectin and microbiome (not collected at W28 & 32),  blood for 
transcriptomics 
 
Review of bowel movement diary. 
 
Calculation of CDAI and PRO2 scores  
 
IBDQ and SF36 assessments 
 
Adverse event monitoring. 

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 
Weeks 16, 20, and 24: Female subjects receiving open label posaconazole will undergo 
urine pregnancy test, and all subjects receiving open label posaconazole will undergo 
EKG.  
7.6 Week 36 visit (or final follow up visit after early termination) 
The following tasks will be conducted at this visit: 
 
Assessment of concomitant medications. 
 
Complete physical examination, vital signs, and weight. 
 
Laboratory studies: urine pregnancy test in women of childbearing potential, hsCRP, 
serum chemistries, complete blood count with automatic differential, lipid panel, and stool 
calprotectin. 
 
Calculation of CDAI and PRO2 scores  
 
Eligibility assessment based on collected data. 
 
Adverse event monitoring. 
 
Review of bowel movement diary. 
 
IBDQ and SF-36 assessments. 
 
Colonoscopy with biopsies (RNALater & Formalin) and washings scheduled ±7 days of 
this visit for calculation of SES-CD.  Biopsies & washings should be obtained from same 
area of each region as screening samples. 
 
8 Assessments 
8.1 Efficacy measures 
8.1.1 Bowel movement diary 
Subjects will be provided with a daily diary to record bowel movement frequency and abdominal 
pain. Subjects will record the usual number of stools per day when not having a flare. Within their 
daily bowel movement history, subjects will record the number of bowel movements per day, and 
presence of blood in stool. 
8.1.2 Crohn’s disease activity Index (CDAI), PRO2 and Simple Endoscopic Score for 
Crohn’s disease (SES-CD) 
These scoring systems assess Crohn’s disease activity. The CDAI score ranges from 0 to 600, and has 
traditionally been used to assess clinical disease activity for Crohn’s disease clinical trials. Clinical remission 
will be defined by a CDAI score of <150 points AND a patient-reported outcome 2-item (PRO2) score of 
abdominal pain score <1 AND stool frequency <3. (See Appendix for calculations of both CDAI and PRO2).  
The SES-CD will determine endoscopic activity for eligibility as well as for determining mucosal 
improvement (See Appendix for SES-CD calculation).  
8.1.3 Health-related quality of life 
 
The following quality-of-life measures are recorded by subjects at the corresponding visits (pending 
permissions): 
 
Inflammatory bowel disease questionnaire (IBDQ) 
 
Short Form SF-36 (SF-36) 
8.2 Laboratory markers 
 
Serum chemistry (sodium, potassium, chloride, magnesium, phosphorous, bicarbonate, blood urea 
nitrogen, creatinine, glucose, total protein, albumin, alanine aminotransferase, aspartate 

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aminotransferase, total bilirubin, direct bilirubin, alkaline phosphatase, gamma-glutamine 
transferase,) 
 
Complete blood count with automated differential (hemoglobin, hematocrit, white blood cell count, 
platelet count) 
 
Urinalysis (pH, color, blood, specific gravity, glucose, protein, leukocyte esterase, nitrite) with 
microscopy if presence of blood, leukocyte esterase, nitrite, or if there is a clinical indication 
 
Serum β-hCG 
 
Urine β-hCG 
 
High-sensitivity C-reactive protein (hsCRP) 
 
Lipids 
 
Stool tests for C difficile, enteric pathogens, calprotectin 
8.3 Pharmacokinetics laboratory markers 
 
Serum posaconazole will be assessed at weeks 2, 4, 6, 8, 10, and 12. The exact time of day and 
date of collection will be recorded.  
8.4 Imaging and cardiac studies 
 
Chest xray (posteroanterior and lateral): findings must not be consistent with infiltrate, pulmonary 
malignancy, heart failure, or respiratory disease. 
 
12-lead EKG: findings must not be consistent with ischemia or prior infarction, left ventricular 
hypertrophy, delayed conduction, prolonged QT (>450ms in male or >460ms in female), or serious 
arrhythmias. 
8.5 Microbiome analyses 
Stool for microbiome analysis will be collected at screening visit and weeks 0, 2, 4, 6, 8, 10, 12, 
16, 20, 24, 36 or early termination. Microbial community structure will be analyzed from stored 
fecal samples collected in each patient group. Samples will be kept at -80 C until DNA extraction. 
The V4 region of the 16S rRNA gene will be PCR amplified in triplicate, and the resulting 
amplicons cleaned, quantified and sequenced on the Illumina MiSeq platform using custom 
barcoded primers.  Raw sequences will be processed using the QIIME software package 
(Quantitative Insights Into Microbial Ecology; http://qiime.org/). Only full-length, high-quality reads 
will be used for analysis. OTUs are picked at 97% similarity against the Greengenes database. 
Subsequent analysis of 16S rRNA data will include weighted and un-weighted UniFrac distance 
matrix, and calculations of α and β diversity.  
8.6 Transcriptomics analyses 
Serum metabolites and colonic mucosa will be obtained at Screen, week 12, and week 24 Blood 
and colonic mucosa (screening, week 12, week 36) will be collected for analyzing serum 
metabolites and RNAseq to determine treatment-related changes in gene expression 
(transcriptomics). 
 
9 Statistical Plan 
9.1 Sample Size Determination 
 
The primary endpoint is endoscopic response, defined as a 50% reduction SES-CD scores at 
week 12. We will assume a placebo response rate of 10% 2-4, and a treatment response rate of 
70%. Therefore, with a study size of 24 patients (11 in each group, plus 2 potential dropouts 
before the second colonoscopy) there will be 76% power in a Fisher’s Exact test with  a target 

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alpha of 0.05. The significance level actually achieved with binomial enumeration is 0.002. (Power 
estimates computed with PASS2020 software).   
 
9.2 Statistical Methods 
Secondary endpoints will include clinical remission (defined as Crohn’s disease activity 
index < 150), analysis of data regarding use of corticosteroids, mucosal healing, mucosal 
improvement, normalization of inflammatory biomarkers, and improvement in health-
related quality of life. Repeated measures analysis will be used to examine changes over 
time from baseline. Categorical data will be analyzed with repeated measures logistic 
regression while continuous measures will used mixed modeling regression. Residuals 
will be inspected to confirm data meets assumptions necessary for parametric testing. 
Data will be considered significant at the two-sided p-value of <0.05. All analysis will be 
performed by the study biostatistician (C Bresee, MS) using SAS v9.4 software.   
 
 
Primary Study Endpoints: The proportion of subjects with endoscopic response defined 
by a 50% reduction in SES-CD score at 12 weeks 
 
Key Secondary Study Endpoints: The proportion of subjects in clinical remission at 
Week 12  
 
Primary Safety Endpoints: Incidence and severity of adverse events, change from 
baseline of laboratory values (chemistry, hematology), incidence of electrocardiogram 
(EKG) abnormalities 
 
Quality-of-life Endpoints: Change from baseline in Inflammatory bowel disease 
questionnaire (IBDQ) and Short Form SF-36 (SF-36). 
 
Pharmacokinetic Endpoints: Changes in dosing regimen during study, relationship 
between nicotine concentrations and clinical effects. 
 
Intestinal Microbiota Endpoints: 
Subsequent analysis of 16S rRNA data will include 
weighted and un-weighted UniFrac distance matrix, and calculations of α and β diversity. 
 
Transcriptomics Endpoints: Our group has developed a standard transcriptome analysis 
pipeline, which uses the TopHat software package for performing gapped alignments 
against the reference genome, DESeq for detecting differential gene expression, and 
Cufflinks for detecting differential isoform expression.   
TopHat improves upon earlier RNA-Seq alignment tools as it allows paired-end 
sequencing, longer reads, and particularly gapped alignments of read fragments that 
reduce the uncertainty in assigning reads to alternative splice variants.  DESeq uses a 
negative binomial distribution model for read counts to identify differential gene 
expression.  Cufflinks uses a normal distribution model for the transcript length and linear 
model for the likelihood function to identify differentially expressed transcripts.   
 
Sample size: 12 patients will be recruited for this open-label pilot study.  Given the pilot 
nature of this study, a sample size justification is not provided.   
 
9.3 Subject Population(s) for Analysis 
 Intention-to-treat (ITT) population:  All subjects in the study who received at least one dose 
of study drug 
 Per-protocol population:  All subjects in the study who received the protocol-required study 
drug  

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10 Safety and Adverse Events 
10.1 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  Information on all adverse events 
should be recorded immediately in the source document. All clearly related signs, symptoms, and 
abnormal diagnostic procedures results should be recorded in the source document, though 
should be grouped under one diagnosis. 
 
All adverse events occurring during the study period will be recorded.  The clinical course of each 
event should be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause.  Serious adverse events that are still ongoing at 
the end of the study period must be followed up to determine the final outcome.  Any serious 
adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
10.1.1 Investigator reporting: notifying the Cedars Sinai IRB 
The Cedars Sinai IRB requires expedited reporting of those events related to study participation 
that are unforeseen and indicate that participants or others are at increased risk of harm.  The 
Cedars Sinai IRB requires researchers to submit reports of the following problems within 10 
working days from the time the investigator becomes aware of the event: 
 Any adverse event (regardless of whether the event is serious or non-serious, on-site or 
off-site) that occurs any time during or after the research study, which in the opinion of the 
principal investigator is: 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved informed consent 
document and other relevant sources of information, such as product labeling and package 
inserts.) 
AND 
Related to the research procedures (An event is “related to the research procedures” if in 
the opinion of the principal investigator or sponsor, the event was more likely than not to 
be caused by the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
Cedars Sinai IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others 
Including Reportable Adverse Events” or as a written report of the event (including a description 
of the event with information regarding its fulfillment of the above criteria, follow-up/resolution and 
need for revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
 
Other Reportable events: 
For clinical drug trials, the following events are also reportable to the Cedars Sinai IRB: 
 Any adverse experience that, even without detailed analysis, represents a serious 
unexpected adverse event that is rare in the absence of drug exposure (such as 
agranulocytosis, hepatic necrosis, Stevens-Johnson syndrome). 

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 Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol. 
 Breach of confidentiality 
 Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research participant. 
 Incarceration of a participant when the research was not previously approved under 
Subpart C and the investigator believes it is in the best interest of the subject to remain on 
the study. 
 Complaint of a participant when the complaint indicates unexpected risks, or the complaint 
cannot be resolved by the research team. 
 Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more participants at increased 
risk or affects the rights or welfare of subjects. 
10.2 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above.  
11 Data Handling and Record Keeping 
11.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those 
regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
11.2 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities 
in a clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are 
contained in source documents.  Examples of these original documents, and data records include: 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, 
copies or transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, subject files, and records kept at 
the pharmacy, at the laboratories, and at medico-technical departments involved in the clinical 
trial. 

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11.3 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after 
the last approval of a marketing application in their country and until there are no pending or 
contemplated marketing applications in their country or at least 2 years have elapsed since the 
formal discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period if required by an agreement with the sponsor.  In such an 
instance, it is the responsibility of the sponsor to inform the investigator/institution as to when 
these documents no longer need to be retained.  
11.4 Sample Storage 
For this study, subjects are being asked to let the Investigator use their blood and stool samples 
collected during the study for future research. Their samples will be labeled with a code. Their 
identity will be protected, and their name will not be attached to the samples. The samples will be 
prepared and stored in a freezer for up to 20 years. After 20 years, the samples will be 
destroyed. The stored samples may be used for gaining information about illness and to help 
answer study questions about the drug. 
 
12 Study Monitoring, Auditing, and Inspecting 
12.1 Study Monitoring Plan 
This pilot, investigator-initiated study will be routinely monitored as outlined in monitoring plan 
provided by UCLA CTSI Office of Regulatory Affairs’ (ORA) Quality Assurance Team (Appendix 
6) . 
12.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, 
government regulatory bodies, and institutional compliance and quality assurance groups of all 
study related documents (e.g., source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g., pharmacy, diagnostic laboratory, etc.). 
13 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to the Cedars-Sinai Institutional Review 
Board (IRB) for formal approval of the study conduct.  The decision of the IRB concerning the 
conduct of the study will be made in writing to the investigator. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. The formal consent of a subject, using the IRB-approved consent form, must be obtained 
before that subject undergoes any study procedures.  The consent form must be signed by the 
subject, and the investigator-designated research professional obtaining the consent.  

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14 Study Finances 
14.1 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the conflict 
reviewed by a properly constituted Conflict of Interest Committee with a Committee-sanctioned 
conflict management plan that has been reviewed and approved by the study sponsor prior to 
participation in this study.  All Cedars Sinai investigators will follow the institutional conflict of 
interest policy. 
15 Publication Plan 
It is the intention of the investigators to publish the results of this study after study completion. 
16 References 
 
1. 
Levin B, Lieberman DA, McFarland B, et al. Screening and surveillance for the early detection of 
colorectal cancer and adenomatous polyps, 2008: a joint guideline from the American Cancer 
Society, the US Multi-Society Task Force on Colorectal Cancer, and the American College of 
Radiology. Gastroenterology 2008;134:1570-95. 
2. 
Vermeire S, Schreiber S, Petryka R, et al. Clinical remission in patients with moderate-to-severe 
Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, 
randomised, placebo-controlled trial. Lancet 2017;389:266-275. 
3. 
Feagan BG, Sandborn WJ, D'Haens G, et al. Induction therapy with the selective interleukin-23 
inhibitor risankizumab in patients with moderate-to-severe Crohn's disease: a randomised, 
double-blind, placebo-controlled phase 2 study. Lancet 2017;389:1699-1709. 
4. 
Rutgeerts P, Gasink C, Chan D, et al. Efficacy of Ustekinumab for Inducing Endoscopic Healing 
in Patients With Crohn's Disease. Gastroenterology 2018;155:1045-1058. 
5. 
Kaplan GG. The global burden of IBD: from 2015 to 2025. Nat Rev Gastroenterol Hepatol 
2015;12:720-7. 
6. 
Afzali A, Cross RK. Racial and Ethnic Minorities with Inflammatory Bowel Disease in the United 
States: A Systematic Review of Disease Characteristics and Differences. Inflamm Bowel Dis 
2016;22:2023-40. 
7. 
Mehta F. Report: economic implications of inflammatory bowel disease and its management. Am 
J Manag Care 2016;22:s51-60. 
8. 
Spencer EA, Davis SM, Mack DR, et al. Serologic Reactivity Reflects Clinical Expression of 
Ulcerative Colitis in Children. Inflamm Bowel Dis 2018. 
9. 
Dubinsky MC. What is the role of serological markers in the diagnosis of IBD? Inflamm Bowel Dis 
2008;14 Suppl 2:S185-6. 
10. 
Ferrante M, Vermeire S, Katsanos KH, et al. Predictors of early response to infliximab in patients 
with ulcerative colitis. Inflamm Bowel Dis 2007;13:123-8. 
11. 
Taylor KD, Plevy SE, Yang H, et al. ANCA pattern and LTA haplotype relationship to clinical 
responses to anti-TNF antibody treatment in Crohn's disease. Gastroenterology 2001;120:1347-
55. 
12. 
Knox NC, Forbes JD, Van Domselaar G, et al. The Gut Microbiome as a Target for IBD 
Treatment: Are We There Yet? Curr Treat Options Gastroenterol 2019;17:115-126. 
13. 
Levy AN, Allegretti JR. Insights into the role of fecal microbiota transplantation for the treatment of 
inflammatory bowel disease. Therap Adv Gastroenterol 2019;12:1756284819836893. 
14. 
Moayyedi P, Surette MG, Kim PT, et al. Fecal Microbiota Transplantation Induces Remission in 
Patients With Active Ulcerative Colitis in a Randomized Controlled Trial. Gastroenterology 
2015;149:102-109 e6. 

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15. 
Paramsothy S, Kamm MA, Kaakoush NO, et al. Multidonor intensive faecal microbiota 
transplantation for active ulcerative colitis: a randomised placebo-controlled trial. Lancet 
2017;389:1218-1228. 
16. 
Rossen NG, Fuentes S, van der Spek MJ, et al. Findings From a Randomized Controlled Trial of 
Fecal Transplantation for Patients With Ulcerative Colitis. Gastroenterology 2015;149:110-118 
e4. 
17. 
Costello SP, Hughes PA, Waters O, et al. Effect of Fecal Microbiota Transplantation on 8-Week 
Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial. JAMA 2019;321:156-
164. 
18. 
Khan KJ, Ullman TA, Ford AC, et al. Antibiotic therapy in inflammatory bowel disease: a 
systematic review and meta-analysis. Am J Gastroenterol 2011;106:661-73. 
19. 
Iliev ID, Funari VA, Taylor KD, et al. Interactions between commensal fungi and the C-type lectin 
receptor Dectin-1 influence colitis. Science 2012;336:1314-7. 
20. 
Limon JJ, Tang J, Li D, et al. Malassezia Is Associated with Crohn's Disease and Exacerbates 
Colitis in Mouse Models. Cell Host Microbe 2019;25:377-388 e6. 
21. 
Beaudoin M, Goyette P, Boucher G, et al. Deep resequencing of GWAS loci identifies rare 
variants in CARD9, IL23R and RNF186 that are associated with ulcerative colitis. PLoS Genet 
2013;9:e1003723. 
22. 
Rivas MA, Beaudoin M, Gardet A, et al. Deep resequencing of GWAS loci identifies independent 
rare variants associated with inflammatory bowel disease. Nat Genet 2011;43:1066-73. 
23. 
Zhernakova A, Festen EM, Franke L, et al. Genetic analysis of innate immunity in Crohn's 
disease and ulcerative colitis identifies two susceptibility loci harboring CARD9 and IL18RAP. Am 
J Hum Genet 2008;82:1202-10. 
24. 
Limon JJ, Skalski JH, Underhill DM. Commensal Fungi in Health and Disease. Cell Host Microbe 
2017;22:156-165. 
25. 
Wheeler ML, Limon JJ, Underhill DM. Immunity to Commensal Fungi: Detente and Disease. Annu 
Rev Pathol 2017;12:359-385. 
26. 
Cao Z, Conway KL, Heath RJ, et al. Ubiquitin Ligase TRIM62 Regulates CARD9-Mediated Anti-
fungal Immunity and Intestinal Inflammation. Immunity 2015;43:715-26. 
27. 
McGovern DP, Gardet A, Torkvist L, et al. Genome-wide association identifies multiple ulcerative 
colitis susceptibility loci. Nat Genet 2010;42:332-7. 
28. 
Janse M, Lamberts LE, Franke L, et al. Three ulcerative colitis susceptibility loci are associated 
with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9. Hepatology 
2011;53:1977-85. 
29. 
Pointon JJ, Harvey D, Karaderi T, et al. Elucidating the chromosome 9 association with AS; 
CARD9 is a candidate gene. Genes Immun 2010;11:490-6. 
30. 
Kiryluk K, Li Y, Scolari F, et al. Discovery of new risk loci for IgA nephropathy implicates genes 
involved in immunity against intestinal pathogens. Nat Genet 2014;46:1187-96. 
31. 
Thapa D, Lee JS, Park MA, et al. Inhibitory effects of clotrimazole on TNF-alpha-induced 
adhesion molecule expression and angiogenesis. Arch Pharm Res 2009;32:593-603. 
32. 
Thapa D, Lee JS, Park SY, et al. Clotrimazole ameliorates intestinal inflammation and abnormal 
angiogenesis by inhibiting interleukin-8 expression through a nuclear factor-kappaB-dependent 
manner. J Pharmacol Exp Ther 2008;327:353-64. 
33. 
Takahashi H, Abe M, Sugawara T, et al. Clotrimazole, an imidazole antimycotic, is a potent 
inhibitor of angiogenesis. Jpn J Cancer Res 1998;89:445-51. 
34. 
Samuel S, Loftus EV, Jr., Sandborn WJ. The effects of itraconazole on inflammatory bowel 
disease activity in patients treated for histoplasmosis. Aliment Pharmacol Ther 2010;32:1207-9. 
35. 
Biancone L, Petruzziello C, Orlando A, et al. Cancer in Crohn's Disease Patients Treated with 
Infliximab: A Long-term Multicenter Matched Pair Study. Inflammatory Bowel Diseases 
2011;17:758-766. 
 
 
 

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Appendices 
 CDAI 
 PRO2 
 SES-CD 
 CTCAE Grading Scale for severity of adverse events 
 IBDQ form 
 SF36 form 
 DSMB Monitoring Plan 
 
 

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Appendix 1. Crohn’s Disease Activity Index (CDAI) and Patient Reported 
Outcomes – 2 items (PRO2) 
The Crohn’s Disease Activity Index (CDAI) will be calculated as follows: 
 
 
Number 
Variable 
Description 
Multiplier 
1 
Liquid or very soft stool 
Daily stool count summed 
over 7 days 
2 
2 
Abdominal Pain 
Sum of 7 days of daily 
ratings as 0 = none, 1 = 
mild, 2 = moderate, 3 = 
severe 
5 
 
General Wellbeing 
Sum of 7 days of daily 
ratings as 0 = generally 
well, 1 = slightly below 
par, 2 = poor, 3 = very 
poor, 4 = terrible 
7 
 
Complications 
Number of listed 
complications: Arthritis or 
arthralgia, Erythema 
nodosum, pyoderma 
gangrenosum or apthous 
stomatitis, Iritis or uveitis, 
Anal fissures or fistulae or 
abscess, Other fistula 
Fever over 37.8 C [100 F] 
during past week 
20 each 
 
Use of antidiarrheal 
medications 
Use of diphenoxylate or 
loperamide or other 
opiate for diarrhea 
0 = No, 1 = Yes 
30 
 
Abdominal Mass 
0 = none, 2 = 
questionable, 5 = definite 
10 
 
Hematocrit 
Males: 47 – Hct [%] 
Females: 42 – Hct [%] 
*Result must be greater 
than or equal to 0. 
If negative result enter 0 
6x difference 
 
Weight  
Percentage deviation 
from standard weight 
(1 – weight / standard 
weight) × 100 
*Limit of -10 
1 
CDAI Score  
 
 
TOTAL 
 
 
 

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Appendix 2. Patient Reported Outcomes – 2 items (PRO2) 
The patient reported outcomes of liquid or very soft stool and abdominal pain (PRO2) score will 
be assessed as follows: 
 
Number 
Variable 
Description 
1 
Liquid or very soft stool 
Mean of the daily (liquid or very 
soft) stool count for 7 days 
2 
Abdominal Pain 
Mean of 7 days of daily ratings as 
0=none, 1=mild, 2=moderate, 
3=severe 
35 
Each PRO2 score will be rounded to the nearest integer for determination of eligibility and calculation of 
endpoints. 
 
 
 

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Appendix 3: SES-CD (Simple endoscopic score for Crohn’s 
disease)  
 
Variables 
Score 
0 
1 
2 
3 
Size of ulcers 
(cm) 
None 
Aphthous 
ulcers (0.1 – 
0.5) 
Large ulcers 
(0.5 – 2.0) 
Very large 
ulcers (>2.0) 
Ulcerated 
surface (%) 
None 
<10 
10-30 
>30 
Affected 
surface (%) 
Unaffected 
segment 
<50 
50-75 
>75 
Presence of 
narrowings 
None 
Single, can be 
passed 
Multiple, can 
be passed 
Cannot be 
passed 
* Total SES-CD: sum of the values of the 4 variables for the 5 bowel segments. Values are given to each variable and 
for every examined bowel segment (eg, rectum, left colon, transverse colon, right colon, and ileum) 
 
 
 
 

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Appendix 4. CTCAE Grading Scale for Severity of Adverse Events 
Please refer to the Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03, 
which can be found at: 
 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
 
For AEs associated with laboratory abnormalities, the event should be graded on the basis of 
the clinical severity in the context of the underlying conditions; this may or may not be in 
agreement with the grading of the laboratory abnormality. 
 
 

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Appendix 5: IBDQ and SF-36 
 
This questionnaire is designed to find out how you have been feeling during the last two weeks. Please 
circle only one number for each question.  
 
1. How frequent have your bowel movements been during the last 2 weeks?  
a) Bowel movements as or more frequent than they have ever been  
b) Extremely frequent  
c) Very frequent  
d) Moderate increase in frequency of bowel movements  
e) Some increase in frequency of bowel movements  
f) Slight increase in frequency of bowel movements  
g) Normal, no increase in frequency of bowel movements  
 
2. How often has the feeling of fatigue or being tired and worn out been a problem for you during the last 2 
weeks?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
3. How often during the last 2 weeks have you felt frustrated, impatient, or restless?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
4. How often during the last 2 weeks have you been unable to attend school or work because of your bowel 
problem?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
5. How much time during the last 2 weeks have your bowel movements been loose?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
6. How much energy have you had during the last 2 weeks?  
a) No energy at all  

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b) Very little energy  
c) A little energy  
d) Some energy  
e) A moderate amount of energy  
f) A lot of energy  
g) Full of energy  
 
7. How often during the last 2 weeks did you feel worried about the possibility of needing surgery because 
of your bowel problem?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
8. How often during the last 2 weeks have you had to delay or cancel a social engagement because of your 
bowel problems?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
9. How often in the past 2 weeks have you been troubled by cramps in your abdomen?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
10. How often in the past 2 weeks have you felt generally unwell?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
11. How often during the last 2 weeks have you been troubled because of fear of not finding a bathroom?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
12. How much difficulty have you had, as a result of your bowel problems, doing leisure or sports activities 
you would liked to have done during the last 2 weeks?  
a) A great deal of difficulty; activities made impossible  

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b) A lot of difficulty  
c) A fair bit of difficulty  
d) Some difficulty  
e) A little difficulty  
f) Hardly any difficulty  
g) No difficulty; no limit sports or leisure activities  
 
13. How often during the last 2 weeks have you been troubled by pain in the abdomen?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
14. How often during the past 2 weeks have you had problems getting a good night's sleep, or been troubled 
by waking up during the night?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
15. How often during the past 2 weeks have you felt depressed or discouraged?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
16. How often during the past 2 weeks have you had to avoid attending events where there was no 
bathroom at hand?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
17. Overall, in the past 2 weeks, how much problem have you had with passing large amounts of gas?  
a) A major problem  
b) A big problem  
c) A significant problem  
d) Some trouble  
e) A little trouble  
f) Hardly any trouble  
g) No trouble  
 
18. Overall, in the last 2 weeks, how much of a problem have you had maintaining or getting to the weight 
you would like to be at?  

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a) A major problem  
b) A big problem  
c) A significant problem  
d) Some trouble  
e) A little trouble  
f) Hardly any trouble  
g) No trouble  
 
19. Many patients with bowel problems often have worries and anxieties related to their illness. These 
include worries about getting cancer, worries about never feeling better, and worries about having a relapse. 
In general, how often during the last 2 weeks have you felt worried or anxious?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
 20. How much of the time during the last 2 weeks have you been troubled by a feeling of abdominal 
bloating?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
21. How often during the last 2 weeks have you felt relaxed and free of tension?  
a) None of the time  
b) A little of the time  
c) Some of the time  
d) A good bit of the time  
e) Most of the time  
f) Almost all of the time  
g) All of the time  
 
22. How much time during the last 2 weeks have you had a problem with rectal bleeding with your bowel 
movements?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
23. How much time during the last 2 weeks have you felt embarrassed as the result of soiling, or because 
of an unpleasant odor caused by your bowel movement?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  

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g) None of the time  
 
24. How much of the time during the past 2 weeks have you been troubled by a feeling of having to go to 
the bathroom even though your bowels are empty?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
25. How much of the time during the last 2 weeks have you felt tearful of upset?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
26. How much of the time during the last 2 weeks have you been troubled by accidental soiling of your 
underpants?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
27. How much of the time in the 2 weeks have you felt angry as a result of your bowel problems?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
28. To what extent has your bowel problem limited sexual activity during the last 2 weeks?  
a) No sex as a result of Crohn’s disease  
b) Major limitation as a result of Crohn's disease  
c) Moderate limitation as a result of Crohn's disease  
d) Some limitation as a result of Crohn's disease  
e) A little limitation as a result of Crohn's disease  
f) Hardly any limitation as a result of Crohn's disease  
g) No limitation as a result of Crohn's disease  
 
29. How much of the time during the last 2 weeks have you been troubled by feeling sick to your stomach?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  

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 30. How much of the time during the past 2 weeks have you felt irritable?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
31. How often during the last 2 weeks have you felt a lack of understanding from others?  
a) All of the time  
b) Most of the time  
c) A good bit of the time  
d) Some of the time  
e) A little of the time  
f) Hardly any of the time  
g) None of the time  
 
32. How satisfied, happy, or pleased have you been with your personal life during the past 2 weeks?  
a) Very dissatisfied, unhappy most of the time  
b) Generally dissatisfied, unhappy  
c) Somewhat dissatisfied, unhappy  
d) Generally satisfied, pleased  
e) Satisfied most of the time, happy  
f) Very satisfied most of the time, happy  
g) Extremely satisfied, could not have been more happy or pleased  
 
 
 

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Appendix 6: Routine Study Monitoring Plan provided by UCLA 
CTSI Office of Regulatory Affairs’ (ORA) Quality Assurance 
Team. 
 
The CTSI DSMB meets monthly to review all SAE reports for trials overseen by the CTSI 
DSMB.  All SAE reports, which have been filed since the previous meeting, are presented to the 
Board for review.  SAEs shall be reported to the CTSI DSMB in a timely manner [ten days, two 
days for a death] regardless of relationship and expectedness.  The CTSI DSMB SAE reporting 
algorithms are outlined in Appendix B.  The CTSI ORA will review all submissions and the ORA 
staff will enter the information into the OnCore database.  Reports are generated for full CTSI 
DSMB review.    For trials where the CTSI DSMB has primary DSMB review responsibility, the 
DSMB requires that the PI generate cumulative adverse event reports for quarterly, biannual or 
annual review, as determined by the DSMB.  
 
The DSMB reviews each SAE report and determines whether or not protocol modifications are 
warranted to ensure subject safety.  In this review, prior occurrences of similar toxicity with the 
therapy under study are taken into consideration, as well as the severity of the event and the 
likelihood that it was related to a study drug.  The DSMB may recommend no changes to the 
study if the event is expected or related to other causes such as the subject’s underlying 
condition.  The DSMB may request an un-conflicted expert’s advice with national experience to 
support their deliberations and decisions.    
 
The CTSI DSMB reviews all dose-limiting toxicities (DLTs) for all dose-escalation studies.  
Protocol suspensions and re-opening of accrual to the next cohort based on DLT evaluation fall 
under the purview of the DSMB.    For phase II and III studies, early stopping rules and interim 
analyses are reviewed for appropriateness as well.  For Phase III studies, both toxicity and 
efficacy monitoring is required.   
 
The CTSI DSMB has the authority to immediately halt a study (i.e., discontinuation of any 
further treatment of enrolled subjects and discontinuation of enrollment of new subjects) should 
there be any serious unexpected toxicity that warrants further investigation.  The Principal 
Investigator is responsible for reporting to the appropriate agencies, including the FDA, if they 
are suspended from conducting research.  The CTSI ORA staff will work with the Investigator to 
ensure that the proper reporting procedures are followed. 
 
Requests for single subject exceptions/waivers from the approved study protocol, including out 
of window procedures and eligibility deviations, must be reviewed and approved by the DSMB.  
A physician member of the Board will review each exception/waiver request.  Approvals and 
disapprovals of the request are sent to the Principal Investigator via email and copied to the 
UCLA IRB.  Requests for single subject exceptions/waivers are made by the Principal 
Investigator via email utilizing the “Single Subject Exception Request Form.” This form is located 
in Appendix D. 
 
CTSI DSMB correspondences are addressed to the Principal Investigator and copied to the 
UCLA IRB.   Minutes of the DSMB meetings are maintained in a computer file. 
 
Confidentiality:  Each member of the CTSI DSMB is responsible for maintaining strict 
confidentiality of the study data.  Members will not share any study data or information about the 
study with any individual external to the DSMB.  Communication of deliberations or 

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recommendations of the DSMB, either written or oral, should not be made outside of the Board.  
Outcome results are strictly confidential and must not be divulged to any non-member of the 
DSMB except in those cases where DSMB is required to inform the UCLA IRB of its 
determinations.  Disclosure of outcome results to the IRB must only occur with written approval 
of the DSMB.  The DSMB reviews unblinded data.  All unblinded data will be maintained in a 
confidential manner and not shared with anyone outside of the DSMB.  A member who believes 
he or she may have a potential intellectual or financial conflict of interest during the course of 
review of the data must inform the chairperson of the DSMB. In such case, the meeting minutes 
will record the disclosure of the potential conflict of interest and that the individual recuse himself 
from the discussions and abstains from voting on the DSMB decision. 
 
Level of Risk of a Study  
 
The CTSI DSMB will determine the degree of risk of the study and will ensure that there are 
procedures in place to ensure the safety of the subjects that are enrolled in the trial.  The 
intensity level of study oversight is determined by the risk category.  Some of the factors that are 
considered when assigning the Level of Risk category include: 
 
 
A biostatistical design and appropriate procedures for proper data management so that 
the information collected can be properly validated. 
 
Appropriate Serious Adverse Event reporting procedures must be in place. 
 
The study duration must be appropriate and must be based on a realistic rate of 
enrollment. 
 
Data collection and data management must be adequate to verify and ensure subject 
eligibility.  
 
Assignment of risk 
 
Assigning risk ensures that the data and safety monitoring is based on the level of risk (low, 
medium, or high) to ensure that the data and safety monitoring activities are appropriate.  Below 
are some of the criteria used to make a decision regarding the assignment of risk: 
 
 
Expected duration of the study based upon the estimated rate of enrollment. 
 
Type of study population (e.g., children, geriatric). 
 
The procedures used in the trial are commensurate with the degree of risk. 
 
Adequate data management systems in place and appropriate case report forms. 
 
Proper serious adverse event reporting procedures in place. 
 
Proper biostatistical design and data analysis procedures in place. 
 
Level 2 
 
 
 
 

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Levels of Risk 
 
Level 1 
Example of type of trial: Investigator held IND of high complexity or of high toxicity potential.  
Examples are dendritic cell products from GMP suite, or an experimental agent still in phase I/II 
development.  Typically, these clinical trials involve the first use of the drugs in humans, so only 
the investigator is knowledgeable about the test article. 
 
The Compliance Officer meets with PI/Staff prior to study initiation and reviews 
regulatory requirements and operating system. Compliance Officer provides real time 
monitoring to determine eligibility prior to enrollment onto the protocol. 
 
Real time QA monitoring of the subjects and data collection occurs for all subjects 
entered onto the trial.  
 
Comprehensive QA auditing within first year or first 10 subjects enrolled, whichever 
comes first.  Subsequent audit frequency will be annually.  
 
Frequency of DSMB Summary Report is typically on a quarterly basis. 
 
Level 2 
Example of type of trial: Institutional study for which IND is exempt by FDA or has an IND, but the 
drug is approved by the FDA for a different indication and is in Phase II or III.  Examples are 
studies using commercially available agents for an unapproved indication based on standard 
regimen.  
 
Compliance Officer meets with PI/Staff prior to study initiation; review regulatory 
requirements and operating system.  Compliance Officer provides real time monitoring to 
determine eligibility prior to enrollment onto the protocol. 
 
Real time QA monitoring of the subjects and data collection occurs for all subjects 
entered onto the trial.  
 
Comprehensive QA auditing within first year or first 10 subjects enrolled, whichever 
comes first.  Subsequent audit frequency will be annually.  
 
Frequency of DSMB Summary Report is typically on a biannual basis or approximately 
every six months. 
 
Level 3 
Example of type of trial:  Institutional trials with low risk and not monitored by external systems 
(e.g., dietary intervention trials).   
 
Compliance Officer meets with PI/Staff prior to study initiation; review regulatory 
requirements and operating system. 
 
QA comprehensive audits are conducted every 18 months. 
 
Frequency of DSMB Summary Report is typically on an annual basis or approximately 
every 12 months. 
 
MONITORING/AUDITING ACTIVITIES:  
The Compliance Officer of the CTSI Office of Regulatory Affairs (ORA) will monitor and audit the 
clinical records for all human subjects enrolled onto trials overseen by the CTSI DSMB.  The 
CTSI ORA Compliance Officer will perform real time review of informed consent processes and 

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the meeting of all inclusion and exclusion criteria and screening results at study entry.  Active 
monitoring will offer the study teams with prospective information that can be used to enhance 
the quality of research being performed contemporaneously.  Auditing is a review of historic 
performance of the research effort and is performed on case report forms, regulatory files and 
source documents to measure the quality of the research effort in a retrospective manner.  
 
Detailed Reporting Mechanism for Adverse Events 
An adverse event is any undesirable experience associated with the use of a medical 
product in a subject (any unfavorable and unintended sign, symptom or disease 
temporally associated with the use of a medical treatment or procedure regardless of 
whether it is considered related to the medical treatment or procedure).  Any clinical 
adverse event must be recorded on the case report form during the course of the study. 
The investigator must evaluate and document the adverse event for severity, and grade 
it. 
 
CTCAE version 5 should be used in the grading and selection of SAE terminology. 
 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_5x7.pdf 
 
 
If the event is Serious, it should be reported immediately (in writing within 10 days of awareness, 
48 hours for death) by the Principal Investigator to the IND sponsor, CTSI DSMB (only if the trial 
is overseen by the CTSI DSMB) and to any appropriate agency (according to the agency’s 
requirements); UCLA IRB; the NIH and the UCLA IBC for gene medicine trial; and directly to the 
FDA if it is an institutional IND trial.  For institutional trials, the CTSI ORA Compliance Officer will 
assist the investigator to ensure that all serious adverse events are properly documented and 
reported in accordance to federal and institutional requirements. 
 
All serious adverse events that occur in a research study overseen by the CTSI DSMB must be 
submitted to the CTSI DSMB, regardless of relationship, expectedness, or severity.  Those 
adverse events that are not considered serious should be reported to the CTSI DSMB in the next 
DSMB Summary Report submission.