Clinical trial NCT02978339
Conditions: Primary Sclerosing Cholangitis
Sponsor: John E. Eaton
Start date: 2017-06-09; Completion date: 2019-01-08
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine whether curcumin, a drug and naturally-occurring plant compound, is safe and effective in the treatment of primary sclerosing cholangitis (PSC).

Detailed description:

Arms: arm 1: Subjects will receive one 750 mg softgel by mouth twice a day for 12 weeks. Each each 750 mg CuraMed® softgel supplies 500 mg of highly bioavailable BCM-95 curcumin.
Interventions: intervention 1: Curcumin
Intervention descriptions: intervention 1: Subjects will receive one 750 mg softgel by mouth twice a day for 12 weeks. Each each 750 mg CuraMed® softgel supplies 500 mg of highly bioavailable BCM-95 curcumin.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
An Open-Label Pilot Study 
Evaluating the Safety and 
Efficacy of Curcumin in Patients 
with Primary Sclerosing 
Cholangitis 
 
NCT# NCT02978339 
 
Date 1/3/2018 


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An Open-Label Pilot Study Evaluating the Safety and Efficacy of 
Curcumin in Patients with Primary Sclerosing Cholangitis 
 
 
 
 
Regulatory Sponsor: 
John Eaton, M.D. 
Division of Gastroenterology and Hepatology, Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
Phone: (507)-284-3917 
Eaton.John@mayo.edu 
 
 
 
 
 
 
 
 
Study Product: 
 
 
 
 
 
CuraMed® BCM-95 curcumin softgel (EuroPharma, Inc.)   
 
 
Protocol Number: (IRBe) 
 
 
14-002660  
 
  Initial version:  8/16/13 Version (1) 
 
 
     9/10/13 Version (2) 
 
 
 
     10/2/14 Version (3) 
 
 
 
     7/29/15 Version (4) 
 
 
 
     9/07/16 Version (5) 
 
 
 
   12/07/17 Version (6) 
                       01/03/2018 Version (7) 
 
                            
 
 


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Table of Contents 
 
STUDY SUMMARY .................................................................................................................................................... 5 
1 
INTRODUCTION ............................................................................................................................................... 6 
1.1 
BACKGROUND .................................................................................................................................... 6 
1.2 
INVESTIGATIONAL AGENT .................................................................................................................... 6 
1.3 
PRECLINICAL DATA ............................................................................................................................. 7 
1.4 
CLINICAL DATA TO DATE..................................................................................................................... 7 
1.5 
DOSE RATIONALE AND RISK/BENEFITS .................................................................................................. 7 
2 
STUDY OBJECTIVES ........................................................................................................................................ 8 
3 
STUDY DESIGN ................................................................................................................................................. 8 
3.1 
GENERAL DESIGN ............................................................................................................................... 8 
3.2 
PRIMARY STUDY ENDPOINTS ................................................................................................................ 9 
3.3 
SECONDARY STUDY ENDPOINTS ........................................................................................................... 9 
3.4 
PRIMARY SAFETY ENDPOINTS .............................................................................................................. 9 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL .................................................................... 9 
4.1 
INCLUSION CRITERIA ........................................................................................................................... 9 
4.2 
EXCLUSION CRITERIA ........................................................................................................................ 10 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ....................................................................... 10 
4.4 
EARLY WITHDRAWAL OF SUBJECTS .................................................................................................... 11 
4.4.1 
When and How to Withdraw Subjects ........................................................................................ 11 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects .............................................................. 11 
5 
STUDY DRUG .................................................................................................................................................. 11 
5.1 
DESCRIPTION .................................................................................................................................... 11 
5.2 
TREATMENT REGIMEN ....................................................................................................................... 11 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ................................................................ 12 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ......................................................................... 12 
5.5 
SUBJECT COMPLIANCE MONITORING ................................................................................................... 12 
5.6 
PRIOR AND CONCOMITANT THERAPY .................................................................................................. 12 
5.7 
PACKAGING ...................................................................................................................................... 12 
5.8 
BLINDING OF STUDY .......................................................................................................................... 12 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ................................................................................. 12 
5.9.1 
Receipt of Drug Supplies .......................................................................................................... 12 
5.9.2 
Storage ................................................................................................................................... 13 
5.9.3 
Dispensing of Study Drug ......................................................................................................... 13 
6 
STUDY PROCEDURES………………………………………………………………………………………13    
    6.1 
VISIT 1………………………………………………………………………………..……………………14 
     6.2    VISIT 2                                                                         .................................................................................. 15 
    6.3    VISIT 2,4,5,…ETC………………………………………………………………………………………….15  
7 
STATISTICAL PLAN ....................................................................................................................................... 16 
7.1 
SAMPLE SIZE DETERMINATION ........................................................................................................... 16 
7.2 
STATISTICAL METHODS ..................................................................................................................... 16 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ............................................................................................. 16 
8 
SAFETY AND ADVERSE EVENTS ............................................................................................................... 17 
8.1 
ADVERSE EVENTS AND STUDY DISCONTINUATION ................................................................................. 17 


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8.1.1 
Investigator reporting ............................................................................................................... 17 
8.1.2 
Investigator reporting: Notifying the FDA .................................................................................. 18 
8.2 
STOPPING RULES ............................................................................................................................... 19 
8.3 
MEDICAL MONITORING ..................................................................................................................... 19 
9 
DATA HANDLING AND RECORD KEEPING .............................................................................................. 19 
9.1 
CONFIDENTIALITY ............................................................................................................................. 19 
9.2 
RECORDS RETENTION ........................................................................................................................ 19 
10 
STUDY MONITORING, AUDITING, AND INSPECTING............................................................................ 20 
10.1 STUDY MONITORING PLAN ................................................................................................................. 20 
10.2 AUDITING AND INSPECTING ................................................................................................................ 20 
11 
ETHICAL CONSIDERATIONS ....................................................................................................................... 20 
12 
STUDY FINANCES .......................................................................................................................................... 21 
12.1 
FUNDING SOURCE ......................................................................................................................... 21 
12.2 
CONFLICT OF INTEREST ................................................................................................................. 21 
13 REFERENCES ....................................................................................................................................................... 21 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
 
 
 
AE 
 
Adverse Event 
 
 
 
ALK  
Alkaline phosphatase 
 
 
 
AST 
 
Aspartate aminotransferase (also SGOT) 
 
 
 
CCA  
Cholangiocarcinoma 
 
 
 
CFR 
 
Code of Federal Regulations 
 
 
 
CRF 
 
Case Report Form 
 
 
 
DSMB  
Data and Safety Monitoring Board 
 
 
 
FDA  
Food and Drug Administration 
 
 
 
GCP 
 
Good Clinical Practice 
 
 
 
HIPAA 
Health Insurance Portability and Accountability Act 
 
 
 
IB 
 
Investigator’s Brochure 
 
 
 
IND 
 
Investigational New Drug Application 
 
 
 
IRB 
 
Institutional Review Board 
 
 
 
LT 
 
Liver transplantation 
 
 
 
PHI 
 
Protected Health Information 
 
 
 
PI 
 
Principal Investigator 
 
 
 
PSC 
 
Primary sclerosing cholangitis 
 
 
 
SAE 
 
Serious Adverse Event/Serious Adverse Experience 
 
 
 
SOP 
 
Standard Operating Procedure 
 
 
 
UDCA  
Ursodeoxycholic acid  
 


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Study Summary 
Title 
An Open-Label Pilot Study Evaluating the Safety and Efficacy of Oral 
Curcumin in Patients with Primary Sclerosing Cholangitis 
 
Running Title 
Curcumin in Patients with Primary Sclerosing Cholangitis 
Protocol Number 
14-002660 
Phase 
Phase I/II 
Methodology 
Open-label 
Overall Study 
Duration 
12-18 months 
Subject Participation 
Duration 
3 months 
Single or Multi-Site  
Single Site (Mayo Clinic in Rochester, MN) 
Objectives 
Determine the safety and efficacy of curcumin and whether it should be 
considered for further investigation in a randomized study with a larger 
number of patients. 
Number of Subjects 
15 
Diagnosis and Main 
Inclusion Criteria 
Patients with primary sclerosing cholangitis 
Study Product, Dose, 
Route, Regimen 
One 750 mg CuraMed® softgel (EuroPharma, Inc.) by mouth twice a 
day.  Each 750 mg CuraMed® softgel supplies 500 mg of highly 
bioavailable BCM-95 curcumin. 
Duration of 
Administration 
12 weeks 
Reference therapy 
NA/no pharmacotherapy 
Statistical 
Methodology 
Mann-Whitney U test for continuous variables, Chi-square/Fisher’s 
exact test for categorical variables. 
 
 
 


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1 Introduction 
 
This document is a protocol for a human research study.  This study will be carried out in 
accordance with the applicable United States government regulations and Mayo Clinic research 
policies and procedures.  
1.1 
Background 
 
Primary sclerosing cholangitis (PSC) is a chronic, fibro-inflammatory, cholestatic liver disease 
affecting approximately 25,000 adolescents and adults in the United States and a major 
indication for liver transplantation (LT).1-3  PSC leads to end-stage cirrhosis, represents a 
foremost risk factor for CCA, and carries a median LT-free survival of only 12 years.4-7  The 
etiopathogenesis of PSC is unknown, and despite trials of nearly 20 different 
immunosuppressants and other agents, safe and effective pharmacotherapy has yet to be 
established.2  Unlike in other cholestatic liver diseases (e.g. primary biliary cirrhosis), treatment 
with ursodeoxycholic acid (UDCA) has not been clearly shown to have a beneficial effect in 
PSC.  In addition, high doses of UDCA have been associated with significantly greater adverse 
outcomes.  Although operative treatment with liver transplantation (LT) is effective for PSC, it is 
available in limited specialty centers and only an option in select patients; even in suitable LT 
candidates, however, PSC and CCA can recur post-LT.8-10  Therefore, given the morbidity and 
mortality of PSC and the challenges associated with operative treatment, safe and effective 
pharmacotherapy is critically needed.  Furthermore, the negative results of previous clinical trials 
highlight the need to consider targeting alternative pathophysiologic pathways. 
 
Curcumin, the principal curcuminoid of the rhizome turmeric (Curcuma longa), is a naturally 
occurring compound with anti-inflammatory and anti-oxidant properties, among other potentially 
therapeutic effects.11-16  In a recent study of the mdr2 knockout murine model of PSC, it was 
shown that as little as 4 weeks of oral curcumin treatment resulted in a significant decrease in 
serum liver enzymes as well as histologic disease, including sclerosing cholangitis, ductular 
proliferation, and fibrosis, all of which are pathologic hallmarks of PSC.17, 18  Furthermore, 
curcumin has been shown to decrease cholangiocyte (i.e. biliary epithelial cell) reactivity as well 
as hepatic myofibroblast activation (i.e. pro-fibrogenic function), both of which are key 
phenomena in the pathogenesis of PSC.17, 18  Therefore, there is promising animal model and 
cultured human cell line evidence that curcumin may represent a safe, effective, and low-cost 
therapy for patients with PSC. 
1.2 
Investigational Agent 
 
Curcumin is an orange-red powder that is a mixture of 3 compounds— curcumin, 
demethoxycurcumin, and bisdemothyxcurcumin.   
 
Forty to eighty-five percent of an oral dose of curcumin passes through the gastrointestinal tract 
unchanged.  The bioavailability of curcumin is greatest in the colon.  Hexahydrocurcuminol is 
the major biotransformed metabolite of curcumin.  The major biliary metabolites are 
tetrahydrocurcumin and hexahydrocurcumin.   


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Curcumin has been shown in a growing number of in vitro and in vivo studies to demonstrate 
biological activity with a variety of potentially medicinal applications, e.g. anti-inflammatory, 
anti-oxidant, and chemopreventive (i.e. anti-cancer).11-16  In clinical studies, it is generally 
administered orally in capsule form, 2-3 times per day. 
 
1.3 
Preclinical Data 
 
Emerging insights into the etiopathogenesis of and potential therapeutic approaches for PSC 
have been facilitated by the growing use of relevant animal models, particularly the mdr2 
knockout mouse.19, 20  Indeed, recent experimental evidence from this model has demonstrated 
that as little as 4 weeks of treatment with the naturally-occurring compound curcumin results in a 
significant reduction of serum liver enzymes as well as histologic disease, including sclerosing 
cholangitis, ductular proliferation, and fibrosis (i.e. pathologic hallmarks of PSC).17  In addition 
to the promising mdr2 knockout mouse model data, curcumin has been shown in vitro to 
decrease insult-induced human cholangiocyte reactivity (a characteristic feature in PSC 
cholangiocytes),2, 17, 21 attenuate human myofibroblast activation (manifested classically in PSC 
as peri-ductal “onionskin” fibrosis),17, 22 and suppress proliferation and induce apoptosis of 
human CCA cells (which could serve a vital chemopreventive role in PSC patients).2, 23, 24  
Curcumin may also confer therapeutic benefits in PSC patients through other mechanisms, 
including its antimicrobial activity,16, 25 as microbiota have been implicated in the pathogenesis 
of PSC, and indeed 70% of patients with PSC have inflammatory bowel disease, a disorder 
associated with enteric microbial dysbiosis.2, 26-28 
1.4 
Clinical Data to Date 
 
Curcumin has demonstrated high tolerability, safety, and efficacy in multiple studies including 
randomized controlled trials involving healthy individuals as well as patients with a variety of 
hepatic and non-hepatic inflammatory, degenerative, malignant, neuropsychiatric, and other 
illnesses.11-15, 29-35  Collectively, these studies have demonstrated anti-inflammatory, 
hepatoprotective, anti-fibrotic, immunomodulatory, and anti-carcinogenic activities of curcumin.  
No significant toxicity has been reported following either acute or chronic administration of 
turmeric extracts at standard doses.  In a minority of patients, mild side-effects as nausea, 
diarrhea, headache, somnolence, and contact dermatitis (with topical use) have been reported.11-
15, 29, 30 
 
1.5 
Dose Rationale and Risk/Benefits 
In this pilot study, patients will receive 1500 mg of highly bioavailable BCM-95 curcumin®, 
which is supplied in one 750 mg CuraMed® softgel (EuroPharma, Inc.), to be taken orally twice 
a day for 12 weeks.  Each softgel contains 500 mg of pure, highly bioavailable curcuminoids.  
This dose and route is based on recent published clinical trials, wherein curcumin has been found 
to be well-tolerated, safe, and efficacious in inflammatory and other disorders.12, 31-33, 35   
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pursue the former given convenience and ease of adherence for patients and lack of inferiority 
data with this dosing regimen. 
 
As described above, serious adverse effects have not been reported with even high doses (e.g. 
10x higher than those used herein) of curcumin.14, 29   Mild adverse effects have been reported, 
however these have been uncommon and resolved with curcumin dose reduction or 
discontinuation.11-15, 29, 30, 36   These effects have included: yellow stool, diarrhea, headache, rash, 
increase in ALK or lactate dehydrogenase.) 
 
 
2 Study Objectives 
Primary Objective: to determine the change in serum Alkaline Phosphatase following 12 weeks 
of curcumin treatment as a biomarker of therapeutic efficacy.   
 
Secondary Objective: to determine: 1) change in serum AST, total bilirubin, albumin, C-reactive 
protein, and Mayo PSC risk score following 12 weeks of curcumin treatment compared to 
baseline values as markers of biochemical improvement; 2) change in self-reported health status, 
fatigue severity, and pruritus (as assessed by standardized questionnaires) following 12 weeks of 
treatment compared to baseline values as markers of symptomatic improvement, and 3) the 
adverse events occurring during 12 weeks of curcumin treatment in patients with PSC. 
 
3 Study Design 
3.1 
General Design 
 
We propose to conduct an open-label pilot study to preliminarily assess the efficacy and safety of 
oral curcumin in adult patients with PSC.  Fifteen patients with PSC will receive one 750 mg 
CuraMed® softgel (EuroPharma, Inc.) by mouth twice a day for 12 weeks.  Of note, each 750 
mg CuraMed® softgel supplies 500 mg of highly bioavailable BCM-95 curcumin.  A positive 
study, based on significant improvement in serum liver biochemistries, will establish the basis 
for further evaluation of curcumin in a larger, longer-term clinical trial.   
 
Table 1 in section 6 summarizes the patient evaluation and study procedures.  Briefly, prior to 
study entry, a complete history will be obtained and physical examination performed.  Serum 
Alkaline Phosphatase, AST, total bilirubin, albumin, C-reactive protein, complete blood count, 
and creatinine will be measured.  A blood pregnancy test will be performed on female patients of 
child bearing potential.  Standardized questionnaires regarding health status (SF-36 Health 
Survey and Chronic Liver Disease Questionnaires), fatigue (Fisk Fatigue Impact Scale) and 
pruritus (5-D Pruritus scale) will be completed by participants at baseline and at 12 weeks.  
Phone calls will be made to participants weekly during the study, at completion of the study (i.e. 
at 12 weeks of therapy) and/or early termination, and at two weeks after completion of the study 
to monitor for any adverse events or effects of the study drug.  Study staff will specifically 
inquire about local and systemic adverse effects including gastrointestinal upset, nausea, 
diarrhea, signs of anemia (e.g., weakness, fatigue), and rash; during weekly phone or in person 


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interviews.  Participants will be instructed to contact study nurse coordinators with the 
development of any possible symptoms related to therapy. 
 
3.2 
Primary Study Endpoints 
 
The primary study endpoint in this study will be treatment success, as determined by the 
proportion of PSC patients who experience clinically significant improvement in Alkaline 
Phosphatase, as defined by: 1) a ≥40% reduction in serum Alkaline Phosphatase (as compared to 
baseline value)37 or  2) a decrease in serum Alkaline Phosphatase to less than 1.5 times the upper 
limit of normal following 12 weeks of curcumin treatment.38   
 
Notably, serum Alkaline Phosphatase values have been repeatedly associated with disease 
response and prognosis,39-41 thus this readily measured biochemical test is an important endpoint 
and biomarker in studies of patients with PSC. 
 
3.3 
Secondary Study Endpoints 
 
Secondary efficacy endpoints will include change in: 1) serum AST, total bilirubin, albumin, C-
reactive protein, and Mayo PSC risk score42 following 12 weeks of curcumin treatment compared 
to baseline values as markers of biochemical improvement and 2) change in self-reported health 
status, fatigue severity, and pruritus (as assessed by standardized questionnaires) following 12 
weeks of treatment compared to baseline values as markers of symptomatic improvement. 
 
3.4 
Primary Safety Endpoints 
 
We will monitor for adverse events occurring during 12 weeks of curcumin treatment as part of 
this study.  In addition, occurrence of any of the following will be considered a treatment failure:  
• Deterioration of liver biochemistries (doubling of bilirubin and/or increase in AST, ALT, 
and alkaline phosphatase levels ≥ 3x upper limit of normal or baseline levels without 
mechanical obstruction) 
• Voluntary drug/study discontinuation for any reason (e.g. worsening of fatigue or pruritus 
or development of diarrhea, headache, nausea, or rash) 
• Death 
• Liver transplantation 
 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
Inclusion criteria will be as follows: 
• Diagnosis of PSC established by all of the following criteria:27, 43 
o ALK >1.5x upper limit of normal for at least 6 months prior to study enrollment 


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o Cholangiography demonstrating intrahepatic and/or extrahepatic biliary dilation, 
beading, and/or strictures consistent with PSC 
• Age 18-75 years 
• Male or female sex 
• Women of child-bearing potential willing to use birth control for the duration of the study  
• Informed consent provided by the patient for study participation 
 
4.2 
Exclusion Criteria 
 
Exclusion criteria will be as follows:27 
• Treatment with any investigational agents within three months prior to or during the study. 
• Known or suspected cholangiocarcinoma 
• Untreated dominant stricture within past 3 months 
• Suspected bacterial cholangitis within past 3 months 
•  Known decompensated cirrhosis. 
• Uncontrolled inflammatory bowel disease defined by ongoing symptoms requiring 
escalation of medical therapy within past 3 months 
• Treatment with  systemic corticosteroids, colchicine, methotrexate,  cyclosporine, 
chlorambucil, pentoxifylline, or tacrolimus,  within three months prior to or during the 
study. 
• Changes in Azulfidine, azathioprine, budesonide, or vitamin E therapies within three 
months prior to study enrollment. 
• Treatment with systemic antibiotics within one month prior or during study.  
• Concomitant treatment with NSAIDS,  and anticoagulant warfarin. 
• Changes in antiplatelet agents or antihyperlipidemics therapies within three months prior 
to study enrollment. 
• Anticipated need for liver transplant within one year as determined by Mayo PSC risk 
score (<80% one-year survival without transplant) 
• Active drug or alcohol use 
• Findings suggestive of liver disease of an alternative or concomitant etiology, such as 
autoimmune hepatitis, chronic alcoholic liver disease, chronic hepatitis B or C infection, 
hemochromatosis, Wilson’s disease, α1-antitrypsin deficiency, non-alcoholic 
steatohepatitis, primary biliary cirrhosis, or secondary sclerosing cholangitis (e.g. post-
LT biliary stricture) 
• Pregnancy or lactation 
• Extremes of age (younger than 18 or older than 75 years of age).   
• Any condition that, in the opinion of the investigator, would interfere with the patient’s 
ability to complete the study safely or successfully 
 
4.3 
Subject Recruitment, Enrollment and Screening 
 


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Patients with a diagnosis of PSC will be recruited by the study staff in the Division of 
Gastroenterology and Hepatology at Mayo Clinic ) and enrolled in the study if satisfying the 
above inclusion and exclusion criteria.  A total of 15 patients will be enrolled. 
 
4.4 
Early Withdrawal of Subjects 
 
Study participants may decide to withdraw from the study at any time; in such case, they will be 
asked to notify the study team so that they may be advised as to whether any additional tests may 
be needed to be performed for their safety.  Study investigators may withdraw participants from 
the study at any time if it is considered in a patient’s best interest or if a patient does not follow 
the study protocol.  Additional details are provided below. 
 
4.4.1 When and How to Withdraw Subjects 
 
Participants will be withdrawn from the study if they experience a CTCAE 4.0 criteria grade 3 or 
higher adverse event, are unable to adhere to the study protocol, inadvertently become pregnant 
during the study (in which case they will be referred to their primary physician for obstetric 
care), or experience treatment failure as described in section 3.4 above.   
 
Participants may voluntary withdraw from the study for any reason.  Patients who withdraw from 
the study (or decline participation) will not be penalized in any way.  Specifically, they do not 
have to be in this study to receive or continue to receive medical care from Mayo Clinic.   
 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
 
Patients who withdraw from (or complete) the study will be followed for a minimum of 2 weeks 
(to ensure safety) as part of the study in addition to longitudinal routine clinical care. 
 
5 Study Drug  
5.1 
Description 
 
The study drug will be administered in the form of a capsule (softgel). 
 
5.2 
Treatment Regimen 
 
Participants will receive one 750 mg CuraMed® BCM-95 curcumin softgel (EuroPharma, Inc.) 
by mouth twice a day for 12 weeks.   
 


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5.3 
Method for Assigning Subjects to Treatment Groups 
 
This will be an open-label pilot study with one treatment group. 
5.4 
Preparation and Administration of Study Drug 
 
The study drug will be prepared by EuroPharma, Inc.  The drug will be stored in the Mayo Clinic 
Pharmacy and dispensed in the Mayo Clinic Hepatology Clinic, Division of Gastroenterology of 
Hepatology, by the study coordinator (and/or co-investigators).   
5.5 
Subject Compliance Monitoring 
 
Adherence will be tracked by the study coordinator using telephone calls weekly.  The patient 
will be asked specifically about compliance with the study drug schedule.  If the patient is not 
deemed by the study investigators to be compliant based on phone call assessment, the patient 
will be withdrawn from the study but still followed (intention to treat).  A decision regarding 
non-compliance will be determined by the following: the patient has acknowledged being off the 
study drug for more than two weeks without reason or has been unable to be contacted by the 
study coordinator or study physician for greater than 6 consecutive weeks. 
 
5.6 
Prior and Concomitant Therapy 
 
Potential participants will be excluded if they receive or have received: 
• Treatment with any investigational agents within three months prior to or during the study. 
• Treatment with  UDCA, systemic corticosteroids, colchicine, methotrexate,  cyclosporine, 
chlorambucil,  pentoxifylline, or tacrolimus within three months prior to or during the 
study. 
 
5.7 
Packaging 
 
The study drug will be packaged with a label stating “Caution: New Drug--Limited by Federal 
(or United States) law to investigational use only", instructions for use, i.e. “Take one 750 mg 
CuraMed® curcumin softgel by mouth twice a day”, and the Mayo Clinic protocol number.  The 
amount of softgels will also be written on the label (12 week supply, i.e. 168 softgels).   
 
5.8 
Blinding of Study  
 
NA—open-label study. 
5.9 
Receiving, Storage, Dispensing and Return 
5.9.1 Receipt of Drug Supplies 
 


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The study drug will be shipped via UPS by EuroPharma, Inc., under the oversight of Cheryl 
Myers, Chief of Scientific Affairs and Education, Green Bay, WI), to the Mayo research 
pharmacy  at Mayo Clinic.   
 
Upon receipt of the  study drug, an inventory will be performed and a drug receipt log filled out 
accepting the shipment.  Any discrepancies from the shipping invoice or damaged or unusable 
study drug in a given shipment will be documented in the study files. The sponsor and 
investigators will be notified immediately of any discrepancies, damaged or unusable products 
that are received. 
5.9.2 Storage 
 
The study drug will be stored in a 4°C refrigerator in the dark in the institutional research 
pharmacy until it is dispensed.  This is a secure location with limited access to prevent 
unintended or unauthorized use.  No special handling precautions are otherwise necessary. 
5.9.3 Dispensing of Study Drug 
 
A 12 week supply of the study drug will be assigned and dispensed to each study participant. 
Drug reconciliation checks will be performed by the study team and documented in the medical 
record.    Subjects will be requested to mail in any unused study drug if unable to return for the 
12 week visit. 
Return or Destruction of Study Drug 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug 
dispensed, drug returns, and drug remaining.  This reconciliation will be documented in the study 
file.  Study drug destroyed on site per Mayo Pharmacy policy.  
 
6   Study Procedures 
 
Study procedures are summarized in section 3.1 as well as in Table 1. 
 
Screening Visit (-28 to Day 0)  
 
Screening assessments will be completed within 28 days of the baseline/Day 1 visit.  
The following procedures will be performed and documented: 
 
Obtain signed informed consent 
 
Determine inclusion eligibility 
 
Obtain medical history 
 
Perform complete physical examination 
 
Obtain body height and weight 
 
Obtain vital signs (resting blood pressure, pulse, respiratory rate and temperature) 
 
Obtain details of concomitant medications 
 
Obtain blood samples for 
 
 
Alkaline phosphatase 
 
 
AST 


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ALT 
 
 
Total bilirubin 
 
 
C-reactive protein 
 
 
Complete blood count (CBC) 
 
 
INR 
 
 
Sodium 
 
 
Creatinine 
 
 
Albumin 
 
 
Stored serum 
 
 
Serum pregnancy test for females of childbearing potential only 
 
Questionnaires 
 
 
Health status 
 
 
Pruritus 
 
 
Fatigue 
 
Subjects meeting all of the inclusion criteria and none of the exclusion criteria will return to the 
clinic for the Baseline/Day 1 visit. 
 
Treatment Assessments 
 
Baseline/Day 1 Visit 
 
Dispense study medication 
 
Instruct the subject on the packaging, storage and administration of the study drug 
 
If indicated, observe the subject take the first dose of the study drug 
 
Week 3 (+- 7 days) 
 
Obtain blood samples for  
Alkaline phosphatase 
 
 
AST 
 
 
Total bilirubin 
 
 
C-reactive protein 
 
 
Complete blood count (CBC) 
 
 
Creatinine 
 
 
Albumin 
 
Phone call or visit to assess for AEs, concomitant medications, and study drug 
compliance.  Note a local laboratory can be used for obtaining the blood samples if 
subject is unable to return to Mayo. 
 
Week 8 (+- 7 days) 
Phone call to assess for AEs, concomitant medications, and study drug compliance.  Note 
a local laboratory can be used for obtaining the blood samples if subject is unable to 
return to Mayo. 
 
Week 12 (+- 7 days) or Early Termination 


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Obtain blood samples for 
 
 
Alkaline phosphatase 
 
 
AST 
 
 
ALT 
 
 
Total bilirubin 
 
 
C-reactive protein 
Complete blood count (CBC) 
INR 
 
 
Creatinine 
 
 
Sodium 
 
 
Albumin 
 
 
Stored serum 
 
Questionnaires 
 
 
Health status 
 
 
Pruritus 
 
 
Fatigue 
Phone call to assess for AEs, concomitant medications, and study drug compliance.  Note 
a local laboratory can be used for obtaining the blood samples if subject is unable to 
return to Mayo.  Questionnaires can be mailed to subject if unable to return to Mayo or 
respond over the phone.  Remaining study medication can be returned by mail to study 
team. 
 
Post Treatment Assessment Week 14 (+- 7 days) (2 weeks after stopping study medication) 
 
Phone call to assess for AEs, concomitant medications 
 
Table 1. Patient evaluation and study procedures  
 
n=20 patients with PSC 
Entry 
3 weeks 
8 weeks 
12 weeks 
2 weeks after study 
completion (i.e. 14 weeks) 
Medical 
history 
and 
physical examination 
X 
 
 
 
 
Serum laboratory tests* 
 
 
 
 
 
  ALK 
X 
X 
 
X 
 
  AST 
X 
X 
 
X 
 
 ALT 
X 
 
 
X 
 
  Total bilirubin 
X 
X 
 
X 
 
  C-reactive protein 
X 
X 
 
X 
 
  Complete blood count 
X 
X 
 
X 
 
  INR 
X 
 
 
X 
 
  Creatinine 
X 
X 
 
X 
 
  Sodium 
X 
 
 
X 
 
  Albumin 
X 
X 
 
X 
 
  Stored serum ** 
X 
 
 
X 
 
  Pregnancy test *** 
X 
 
 
 
 
Questionnaires 
 
 
 
 
 


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  Health status 
X 
 
 
X 
 
  Pruritus 
X 
 
 
X 
 
  Fatigue 
X 
 
 
X 
 
Phone calls† 
 
X 
X 
X 
X 
* At study entry, approximately 2 teaspoons of blood will be collected for biochemical testing.   At 3 and 12 weeks, 
approximately 1 teaspoon will be collected for biochemical testing. 
**Serum collected at baseline and at the conclusion of the study will be stored for potential future assays to explore 
mechanisms of action in the pathogenesis of PSC if the study drug seems beneficial.   
***For female patients only. 
†Will be performed for safety and compliance monitoring as described above and documented accordingly. 
7 Statistical Plan 
7.1 
Sample Size Determination 
 
Approximately 5% of patients with PSC and chronically (>6 months) elevated ALK will 
spontaneously experience either a clinically significant reduction in serum ALK to less ≤1.5 
times the upper limit of normal38 or a reduction of > 40% of the baseline ALK value.37  In this 
open-label pilot study, our primary objective is to determine the proportion of patients who 
experience curcumin treatment success, as defined by either of these two ALK endpoints.  
Notably; these patients are hereinafter considered historical controls.39  Therefore, if treatment 
success is achieved in at least 30% of curcumin treated patients, i.e. a rate that is at least 25% 
more than the conservative estimate in historical controls, likely based on pre-clinical data, and 
clinically promising, this would encourage further study of curcumin in larger, randomized 
clinical trials in patients with PSC.   
 
 
By enrolling 15 patients with PSC in our study, an exact binomial test with a nominal two-sided 
significance level of α=0.05 will have approximately 90% power to detect a 25% difference in 
clinically significant ALK improvement between the null hypothesis of 5% (historical control) 
and the alternative hypothesis of 30%.  In addition, if 6 of 20 PSC patients (30%) experience 
treatment success, the 95% exact binomial confidence interval (CI) would be 11.9% to 54.3%, 
suggesting that the sample size has adequate precision to not include the null hypothesis (5%) in 
the CI. 
 
7.2 
Statistical Methods 
 
Univariate descriptive statistics and frequency distributions will be calculated, as appropriate, for 
all variables.  Baseline values for demographic, clinical, and outcome variables (primary and 
secondary) will be tabulated.  These analyses will help identify potential confounding variables 
to be used as covariates in advanced statistical (e.g. multivariate) analyses.  Bonferroni 
correction will be used to adjust p-values in the case of multiple comparisons. 
 
7.3 
Subject Population(s) for Analysis 
 


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The study participants whose data will be subjected to data analysis include: 
• All-treated population:  Any subject entered into the study that received at least one dose 
of study drug. 
• All-completed population:  Only subjects who completed all study related procedures and 
follow-up will be included  
8 Safety and Adverse Events 
8.1 
Adverse events and study discontinuation 
 
Patients will be discontinued from the study if they: 1) request withdrawal from the study, 2) 
develop worsening of underlying liver function defined as doubling of serum total bilirubin 
and/or increase in ALK or AST to ≥ 3x the upper limit of normal or baseline levels without 
mechanical biliary obstruction, 3) have side effects to study drug (e.g. diarrhea) that are not 
controlled by over the counter medication (e.g. loperamide), or 4) experience an adverse event 
based on CTCAE 4.0 criteria of grade 3 or higher that is not related to underlying disease. 
 
When an adverse event has been identified, the study team will take appropriated action 
necessary to protect the study participant and then complete the Study Adverse Event Worksheet 
and log.  The investigators will evaluate the event and determine the necessary follow-up and 
reporting required (see next section). 
 
8.1.1 Investigator reporting 
 
The investigators will personally supervise the study.  An adverse event is defined as any 
unfavorable and unintended diagnosis, symptom, or disease temporarily associated with use of 
the study medication, whether or not related to the medication.  Worsening of the pre-existing 
clinical condition will be considered an adverse event and, possibly, treatment failure.  
 
 
The investigators will use the following definitions to assess the relationship of the adverse 
event to the use of study drug: 
 
1. Probably related:  Adverse event has a strong temporal relationship to study drug or recurs on 
re-challenge and another etiology is unlikely or significantly less likely. 
2. Possibly related:  Adverse event has a strong temporal relationship to the study drug and an 
alternative etiology is equally or less likely compared to the potential relationship to study 
drug. 
3. Probably not related:  Adverse event has little or no temporal relationship to the study drug 
and/or a more likely alternative etiology exists. 
4. Not related:  Adverse event is due to an underlying or concurrent illness or effect of another 
drug and is not related to the study drug (e.g., has no temporal relationship to study drug or 
has a much more likely alternative etiology). 
 
 
Adverse events will be classified according to severity into: mild (transient and easily 
tolerated by the participant), moderate (causes the participant discomfort and interrupts the 


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participant’s usual activities), or severe (causes considerable interference with the participant’s 
usual activities and may be incapacitating or life-threatening).  A serious adverse event is defined 
as any untoward medical occurrence that results in death, is life-threatening, requires or prolongs 
hospitalization, causes persistent or significant disability/incapacity, or, in the opinion of the 
investigators, represents other significant hazards or potentially serious harm to research 
participants.  
 
 
The investigators will be responsible for communicating adverse events to the Mayo 
Institutional Review Board (IRB), the Data and Safety Monitoring Board, Co-investigators, and 
the Food and Drug Administration.  The following information will be recorded in the study 
database and provided as indicated: 
 
• Medical record number:  
• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (drug, procedure, or intervention):  
• If the adverse event was expected:  
• The severity of the adverse event: (use a table to define severity scale 1-5) 
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
• Date of Resolution:  
 
8.1.2 Investigator reporting: Notifying the FDA 
 
The investigators will report to the FDA all unexpected, serious suspected adverse reactions 
according to the required IND Safety Reporting timelines, formats and requirements. 
 
Unexpected fatal or life threatening suspected adverse reactions where there is evidence to 
suggest a causal relationship between the study drug/placebo and the adverse event, will be 
reported as a serious suspected adverse reaction.  This will be reported to the FDA on FDA Form 
3500A, no later than 7 calendar days after the investigator’s initial receipt of the information 
about the event. 
 
Other unexpected serious suspected adverse reactions where there is evidence to suggest a causal 
relationship between the study drug/placebo and the adverse event, will be reported as a serious 
suspected adverse reaction.  This will be reported to the FDA on FDA Form 3500A, no later than 
15 calendar days after the investigator’s initial receipt of the information about the event. 
 
Any clinically important increase in the rate of serious suspected adverse reactions over those 
listed in the protocol or product insert will be reported as a serious suspected adverse reaction.  
This will be reported to the FDA on FDA Form 3500A no later than 15 calendar days after the 
investigator’s initial receipt of the information about the event. 
 


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Findings from other studies in human or animals that suggest a significant risk in humans 
exposed to the drug will be reported.  This will be reported to the FDA on FDA Form 3500A, no 
later than 15 calendar days after the investigators initial receipt of the information about the 
event. 
 
8.2 
Stopping Rules  
 
The study will be stopped if two or more participants develop an adverse event based on 
Common Terminology Criteria for Adverse Events (CTCAE) 4.0 criteria of grade 3 or higher 
OR if one patient develops an adverse event based on CTCAE 4.0 criteria of grade 4 or higher 
that is not related to the participant’s underlying disease. 
 
8.3 
Medical Monitoring 
 
It is the responsibility of the principle investigators to oversee the safety of the study at their site.  
This safety monitoring will include careful assessment and appropriate reporting of adverse 
events as noted above, as well as the construction and implementation of a site data and safety-
monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  Medical 
monitoring will include a regular assessment of the number and type of serious adverse events. 
 
9 Data Handling and Record Keeping 
9.1 
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).  
Confidentiality of patient information will be protected by using a study number to identify 
participants.  Data collection forms will be kept in locked files designated for this study within 
an office, and computerized data will be password-secured. 
 
9.2 
Records Retention 
 
The investigators will maintain records and essential documents related to the conduct of the 
study.  These will include subject case histories and regulatory documents. 
 
The investigators will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing 
application is not submitted or approved for the drug, until 2 years after shipment and 
delivery of the drug for investigational use is discontinued and the FDA has been so 
notified or 
2. As outlined in the Mayo Clinic Research Policy Manual –“Access to and Retention of 
Research Data Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717 , 
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10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will 
also ensure that the monitor or other compliance or quality assurance reviewer is given access to 
all the study-related documents and study related facilities (e.g. pharmacy, diagnostic laboratory, 
etc.), and has adequate space to conduct the monitoring visit. 
 
This study will be monitored on a routine basis during the conduct of the trial.  The Mayo Clinic 
Office of Research Regulatory Support will be allowed to provide clinical monitoring for the 
trial as a service for the sponsor-investigator.  Clinical trial monitoring requires review of the 
study data generated throughout the duration of the study to ensure the validity and integrity of 
the data along with the protection of human research subjects.  This will assist sponsor-
investigators in complying with Food and Drug Administration regulations. 
 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the 
sponsor, and government regulatory agencies, 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.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional 
Review Board (IRB), in agreement with local legal prescriptions, for formal approval of the 
study.  The decision of the IRB concerning the conduct of the study will be made in writing to 
the sponsor-investigator before commencement of this study. 
 
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.  This consent form will be submitted with the protocol for review and approval by the IRB 
for the study.  The formal consent of a subject, using the Approved IRB consent form, must be 
obtained before that subject undergoes any study procedure.  The consent form must be signed 
by the subject or the subject’s legally authorized representative, and the individual obtaining the 
informed consent. 


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12 Study Finances 
12.1 Funding Source 
This study will be funded by Europharma.   
12.2 Conflict of Interest 
None.   
Any study team member who has a conflict of interest with this study (patent ownership, 
royalties, or financial gain greater than the minimum allowable by their institution, etc.) arise 
will 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-investigator prior to participation in this study. 
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