Clinical trial NCT03394781
Conditions: Primary Sclerosing Cholangitis
Sponsor: Durect
Start date: 2018-01-22; Completion date: 2019-01-31
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a research trial testing DUR-928 (an experimental medication). The purpose of the trial is to assess whether treatment with DUR-928 has any effect on the treatment of Primary Sclerosing Cholangitis (PSC). This trial will also assess safety (side effects).

Detailed description:

Arms: arm 1: 10 mg oral suspension arm 2: 50 mg oral suspension
Interventions: intervention 1: DUR-928
Intervention descriptions: intervention 1: oral suspension daily for 28 days

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
OFFICIAL TITLE: 
A RANDOMIZED, OPEN-LABEL, PHASE 2 STUDY TO 
EVALUATE SAFETY AND EFFICACY OF DUR-928 IN 
SUBJECTS WITH PRIMARY SCLEROSING CHOLANGITIS (PSC) 
NCT Number: 
NCT03394781 
Document Date: 
September 13, 2018 
 


DURECT Corporation 
 
 Protocol # C928-008  
 
 
Protocol Amendment Date: 13 SEP 2018 
CONFIDENTIAL 
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Clinical Protocol 
Protocol No. 
C928-008   
Title: 
A Randomized, Open-label, Phase 2 Study to Evaluate Safety and Efficacy of 
DUR-928 in Subjects with Primary Sclerosing Cholangitis (PSC)  
Phase 
2    
IND: 
133885 
Version: 
Original:  23 AUG 2017  
Amendment 01:  27 SEP 2017 
Amendment 02:  30 MAY 2018 
Amendment 03: 13 SEP 2018 
Sponsor: 
DURECT Corporation  
10260 Bubb Road 
Cupertino, CA  95014, USA 
TEL: 
 
FAX: 
 
GCP Statement: The trial will be conducted in accordance with the principles of Good Clinical 
Practice (GCP) set forth in the International Conference on Harmonization 
(ICH) Good Clinical Practice, the US Code of Federal Regulations (CFR Title 
21), the Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
and any local requirements. 
 
 
CONFIDENTIAL 
This document contains proprietary and confidential information of DURECT Corporation 
(hereafter, DURECT) Acceptance of this document constitutes agreement by the recipient 
that no previously unpublished information contained herein will be published or disclosed 
without the prior written approval of DURECT with the exception that this document may 
be disclosed to trial personnel under your supervision who need to know the contents for 
conducting the trial and appropriate Institutional Review Boards (IRBs)/Ethics 
Committees (EC) under the condition that the personnel have agreed to keep this 
information confidential. The foregoing shall not apply to disclosure required by 
governmental regulations or laws; however, DURECT shall be promptly notified of any 
such disclosure. 
 
 
 
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1.0 
TABLE OF CONTENTS 
CLINICAL PROTOCOL ..............................................................................................................1 
INVESTIGATOR AGREEMENT PAGE ...................................................................................2 
1.0 
TABLE OF CONTENTS ..................................................................................................4 
2.0 
TRIAL SYNOPSIS ............................................................................................................9 
3.0 
LIST OF ABBREVIATIONS .........................................................................................18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.0 
CURRENT TRIAL ..........................................................................................................25 
5.1 
Trial Objective .......................................................................................................25 
5.2 
Trial Rationale .......................................................................................................25 
5.3 
Population ..............................................................................................................25 
5.3.1 
Inclusion Criteria ...................................................................................26 
5.3.2 
Exclusion Criteria..................................................................................27 
5.3.3 
Trial Design ...........................................................................................29 
5.3.4 
Dosage and Regimen.............................................................................29 
6.0 
TRIAL CONDUCT ..........................................................................................................30 
6.1 
Investigative Sites ..................................................................................................30 
6.2 
Sponsor Obligations of Trial Conduct ...................................................................30 
6.3 
Duration .................................................................................................................30 
6.4 
Discontinuation of Trial .........................................................................................30 
7.0 
TRIAL PROCEDURES ..................................................................................................30 
7.1 
Patient Randomization ...........................................................................................30 
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7.2 
Trial Test Drug .......................................................................................................31 
7.2.1 
Administration of Test Drug .................................................................31 
7.2.2 
Packaging and Labeling of Test Drug ...................................................31 
7.2.3 
Storage of Test Drug .............................................................................31 
7.2.4 
Preparation of Test Drug .......................................................................31 
7.2.5 
Drug Accountability ..............................................................................31 
7.3 
Trial Visits and Study Procedures..........................................................................32 
7.3.1 
Visit 1: Screening (Day -42 to Day 0) ..................................................32 
7.3.2 
Visit 2: Day 1 and Randomization ........................................................33 
7.3.3 
Treatment Period visits: Day 8 (±1day), Day 15 (±1day), 
Day 22 (±1day) and Day 28 (±2days) ...................................................33 
7.3.4 
Day 42 (±3days): Follow-up Visit ........................................................34 
7.3.5 
Day 56 (±3days): Trial Completion / Early Termination ......................35 
7.4 
Study Stopping Criteria..........................................................................................35 
7.5 
Concomitant Medication(s) ...................................................................................35 
7.5.1 
Prohibited Concomitant Medications ....................................................35 
8.0 
ASSESSMENT OF EFFICACY .....................................................................................36 
8.1 
Efficacy Assessments.............................................................................................36 
9.0 
ASSESSMENT OF SAFETY ..........................................................................................36 
9.1 
Safety Assessments ................................................................................................36 
9.1.1 
Discontinuation of Study Drug .............................................................36 
9.2 
Interim Safety Profile .............................................................................................37 
9.3 
Adverse Event Recording ......................................................................................38 
9.3.1 
Spontaneously Reported Adverse Events .............................................38 
9.4 
12-Lead ECGs ........................................................................................................38 
9.5 
Laboratory Tests ....................................................................................................38 
9.5.1 
Safety Laboratory Tests ........................................................................39 
9.6 
Biomarkers .............................................................................................................39 
9.7 
Vital Signs ..............................................................................................................40 
9.8 
Physical Examination.............................................................................................40 
9.9 
Partial Mayo score .................................................................................................41 


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9.10 
Blood and Urine Sampling.....................................................................................41 
9.11 
VAS Itch Score and 5-D Pruritus Itch Scale ..........................................................42 
9.12 
Transient Elastography (TE) or FibroScan® .........................................................42 
9.13 
Adverse Events ......................................................................................................42 
9.13.1 
Definitions .............................................................................................42 
9.13.2 
Classifications .......................................................................................44 
9.13.3 
Adverse Event Reporting ......................................................................45 
9.13.4 
Reporting of Serious Adverse Events ...................................................46 
9.13.5 
Adverse Event Follow-up .....................................................................47 
9.14 
Pregnancy ...............................................................................................................47 
10.0 
PHARMACOKINETICS ................................................................................................48 
11.0 
STATISTICAL METHODS AND DATA ANALYSIS ................................................48 
11.1 
Sample Size Determination....................................................................................48 
11.2 
Patient Randomization ...........................................................................................49 
11.3 
Definition of Analysis Populations ........................................................................49 
11.4 
General Statistical Analysis Considerations ..........................................................49 
11.5 
Methodology for Dropouts and/or Missing Data ...................................................49 
11.6 
Demographic and Baseline Characteristics ...........................................................50 
11.7 
Statistical Analyses of Efficacy Endpoints ............................................................50 
11.7.1 
Primary Efficacy Endpoint ....................................................................50 
11.7.2 
Secondary Efficacy Endpoints ..............................................................50 
11.7.3 
Exploratory Efficacy Endpoints ............................................................51 
11.7.4 
Adjustment for Multiple Hypotheses Testing .......................................51 
11.7.5 
Subgroup Analysis ................................................................................51 
11.7.6 
Analyses Strategy for Pooling Trial Centers .........................................51 
11.8 
Interim Analyses and Data Monitoring..................................................................51 
11.9 
Statistical Analysis of Safety Endpoints ................................................................51 
11.9.1 
Safety Variables and Descriptive Summaries .......................................51 
11.10 Changes and Deviations to the Protocol and Statistical Analysis Plan .................52 
12.0 
ACCESS TO SOURCE DATA/DOCUMENTATION .................................................52 
12.1 
Confidentiality .......................................................................................................52 


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12.2 
Data Identification .................................................................................................53 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE .............................................53 
13.1 
Monitoring .............................................................................................................53 
13.2 
Protocol Deviations ................................................................................................53 
13.3 
Case Report Forms .................................................................................................54 
13.4 
Coding ....................................................................................................................54 
13.5 
Data Safety Monitoring Committee .......................................................................54 
13.6 
Safety Assessment Committee ...............................................................................54 
14.0 
ETHICAL CONSIDERATIONS ....................................................................................54 
14.1 
Institutional Review Board / Ethics Committee ....................................................55 
14.2 
Regulatory Compliance .........................................................................................55 
14.3 
Regulatory Status ...................................................................................................55 
14.4 
Patient Information and Informed Consent............................................................55 
14.4.1 
Patient Withdrawal ................................................................................55 
15.0 
DATA HANDLING AND RECORD RETENTION ....................................................56 
15.1 
Data Ownership .....................................................................................................56 
15.2 
Retention of Trial Records .....................................................................................56 
 
 
 
 
 
 
 
 
 
 
18.0 
REFERENCES .................................................................................................................59 
19.0 
APPENDICES ..................................................................................................................60 
 
 
 
 
 
 
 
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List of Tables 
 
List of Figures 
 
 
 
 
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Safety Assessments: 
• Adverse Events (AEs) will be recorded from signing the 
informed consent form through the end of study or early 
termination visit 
• Vital Signs, Physical Examinations and 12-lead ECG 
findings 
• Safety Laboratory Tests (chemistry, hematology, and 
urinalysis)  
Trial Design: 
The proposed study is a randomized, open-label, 2 dose (10 mg 
and 50 mg, both once daily) study to evaluate the safety and 
efficacy of DUR-928  administered orally for 28 days, both at 
the end of dosing and throughout the follow-up period (28 days 
post-dose). 
Trial Rationale: 
PSC is an unmet medical need and an idiopathic condition 
characterized by the presence of beading and stricture formation 
of the intra and/or extrahepatic bile ducts that cannot be ascribed 
to another cause, thus differentiating PSC from secondary 
sclerosing cholangitis. Therefore, PSC is a diagnosis that can be 
established in the absence of toxic, infectious, or inflammatory 
processes, which may lead to the characteristic bile duct injury 
pattern (Lindor et al, 2015). 70-80% of patients with PSC have 
associated chronic inflammatory bowel disease (IBD). 
Currently there is no medical treatment for PSC patient. Liver 
transplantation is the only management intervention which exists 
currently for selected patients with end-stage disease.  
PSC patients invariably have persistently elevated serum ALP 
levels, this parameter is routinely measured and monitored in the 
clinic. Normalization of ALP has been found to be a reliable 
biomarker associated with better prognosis, and thus been 
suggested as a valuable and readily available treatment endpoint 
(Stanich et al, 2011). 
 
 
 
 
 
 
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Trial Population: 
Forty adult male and female subjects, diagnosed with PSC, with 
or without IBD aged between 18 and 80 years (inclusive), will 
be enrolled into the study, to result in at least thirty-six evaluable 
subjects. 
Inclusion Criteria: 
1. Subjects must be able and willing to provide written 
informed consent to participate in the study 
2. Males and females subjects aged between 18 and 80 years, 
inclusive, at the time of signing informed consent 
3. Verified diagnosis of PSC 
 prior to 
Day 1, with or without IBD, based on either a magnetic 
resonance cholangiogram (MRC) or endoscopic retrograde 
cholangiogram (ERC) demonstrating bile duct 
abnormalities consistent with sclerosing cholangitis. In 
addition, these subjects will be required to enter the study 
with a Mayo risk score (Kim et al, 2000) of 0-3, inclusive. 
For subjects with IBD, documented evidence of IBD either 
by prior endoscopy or in previous medical records should 
be ≥ 6 months prior to Day 1  
4. Serum ALP ≥1.5 times ULN 
 
  
5. In subjects receiving treatment with ursodeoxycholic acid 
(UDCA), therapy must be stable for at least 3 months prior 
to Day 1 (no dose adjustment), and at a dose not greater 
than 20 mg/kg/day so that in subjects who are taking 
UDCA, the investigational drug can be given as a 
co-medication 
6. Subjects of childbearing potential must agree to use a 
medically acceptable method of contraceptive to prevent 
pregnancy in the subject and/or the partner for the duration 
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of their participation in the trial, and up to 2 months after 
the last study drug dosing. 
 
 
 
 
 
 
 
 
 
 
Exclusion Criteria: 
1. Presence of documented secondary sclerosing cholangitis 
 
 
 
on prior 
clinical investigations 
2. Small duct PSC 
3. Bacterial cholangitis 
 
 
4. Presence of percutaneous drain or endoscopic bile duct stent 
 
5. History of, or suspicion of cholangiocarcinoma by 
MRC/ERC and other cross-sectional imaging or clinical 
judgment, at screening 
6. Prior liver transplantation, or currently listed for liver 
transplantation on the basis of recurrent cholangitis and with 
a match-run MELD-Na+ score > 10 
7. Presence of other concomitant liver diseases 
 
 
 
 
 
 
 
8. Cirrhosis and/or hepatic impairment and/or hepatic 
decompensation
 
 
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9. Subjects with evidence of cirrhosis, as determined by local 
transient elastography (TE, e.g., FibroScan®) values of 
≥ 14.4 kPa (Corpechot et al, 2014),
 
 
 
 
10. Moderate–to-Severe active IBD or flare in colitis activity 
 
11. Active Crohn’s disease not currently in remission, as 
assessed by the investigator and the CRO’s medical monitor 
12. Use of oral prednisolone 
 and/or hospitalization 
for IBD 
 
13. AST, ALT, and Total Bilirubin concentrations above the 
allowed cut-offs, 
 
 
 
 
 
 
 
  
 
 
14. International normalized ratio (INR) ≥ 1.2  
15. 
 
16. 
 
17. 
 
18. 
 
 
19. Any active malignant disease (within 3 years), other than 
non-melanomatous skin cancer 
20. Human immunodeficiency virus (HIV) infection 
21. Existing or intended pregnancy, and/or breast feeding 
22. Has received any study medication in the context of another 
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clinical trial within the 30 days prior to screening 
23. 
 
 
24. Any other clinically significant disorders or prior therapy 
that, in the opinion of the investigator, would make the 
subject unsuitable for the study or unable to comply with 
the dosing and protocol requirements 
 
 
 
 
 
Pharmacokinetics:  At selected center(s), blood samples will be collected for drug 
concentration measurements in approximately 5 subjects from each 
dose group.  These samples will be collected on Day 1 and Day 28 of 
dosing.  
 
 
 
Plasma concentration data of DUR-928 from each available patient 
will be used to calculate relevant pharmacokinetic parameters 
determined using standard non-compartmental method with linear/log-
trapezoidal rule utilizing an appropriate pharmacokinetic data analysis 
program. 
Pharmacokinetic parameters for DUR-928 will be summarized using 
descriptive statistics. 
 
 
 
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Table 1: Schedule of Events  
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Footnotes for Schedule of Events Table:  
 
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3.0 
LIST OF ABBREVIATIONS  
AE  
Adverse event 
AH  
Alcoholic Hepatitis 
AKI   
Acute Kidney Injury 
ALP  
Alkaline Phosphatase 
ALT  
Alanine aminotransferase 
AST  
Aspartate aminotransferase 
AR  
Adverse Reaction 
AUC  
Area under the curve 
BMI  
Body mass index 
BP  
Blood pressure 
BUN  
Blood urea nitrogen 
CFR  
Code of federal regulations 
CK  
Cytokeratin  
CM  
Concomitant Medication  
Cmax  
Maximum serum concentration 
CPK  
Creatine Kinase or Creatine Phosphokinase 
Cr 
 
Creatinine 
CRP  
C-reactive protein 
ECG  
Electrocardiogram 
ERC  
Endoscopic Retrograde Cholangiogram 
DILI  
Drug-Induced Liver Injury 
FPFV 
First Patient First Visit 
GCP  
Good Clinical Practice 
GGT  
Gamma-glutamyl transpeptidase 
HDPE 
High-Density Polyethylene 
HFD  
High Fat Diet 
HIPPA 
Health Insurance Portability and Accountability Act 
HIV  
Human immunodeficiency virus 
HR  
Heart rate 
Ht 
 
Height 
IBD  
Inflammatory bowel disease 
ICF  
Informed Consent Form 
ICH  
International conference on harmonization 
ICU  
Intensive care unit 
IEC  
Independent Ethics Committee 
I/R  
Ischemia/reperfusion 
IL 
 
Interleukin 
IM  
Intramuscular 
IND  
Investigational New Drug 


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INR  
International normalized ratio 
IP 
 
Investigational product 
IRB  
Institutional Review Board 
ITT  
Intent to treat  
IV 
 
Intravenous 
LDL  
Low-density lipoprotein 
LPS  
Lipopolysaccharides 
MRC 
Magnetic Resonance Cholangiogram 
NDA 
New Drug Application 
NAFLD 
Nonalcoholic fatty liver disease 
NASH 
Nonalcoholic steatohepatitis  
PI 
 
Principal Investigator 
PK  
Pharmacokinetic 
PO  
Oral 
PSC  
Primary Sclerosing Cholangitis 
 
RR  
Respiratory rate 
SAP  
Statistical Analysis Plan 
SAS  
Statistical Analysis System 
sBA  
Serum Bile Acids 
SC  
Subcutaneous 
sCr  
Serum creatinine 
SD  
Standard deviation 
SUSAR 
Suspected unexpected Serious Adverse Reaction 
TE  
Transient Elastography 
TEAE 
Treatment emergent adverse event 
Tmax  
Time to maximum serum concentration 
UDCA 
Ursodeoxycholic acid 
ULN  
Upper limit of normal 
USAE 
Unexpected Serious Adverse Event 
WHO 
World Health Organization 
Wt  
Weight 
 
 


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5.3.1 
Inclusion Criteria  
1. Subjects must be able and willing to provide written informed consent to participate in 
the study 
2. Males and females subjects aged between 18 and 80 years, inclusive, at the time of 
signing informed consent 
3. Verified diagnosis of PSC 
 prior to Day 1, with or without IBD, 
based on either a consistent magnetic resonance cholangiogram (MRC) or endoscopic 
retrograde cholangiogram (ERC) demonstrating bile ducts abnormalities consistent with 
sclerosing cholangitis. In addition, these subjects will be required to enter the study with 
a Mayo risk score (Kim et al, 2000) of 0-3, inclusive. For subjects with IBD, 
documented evidence of IBD either by prior endoscopy or in previous medical records 
should be ≥ 6 months prior to Day1.   
4. Serum (ALP) ≥ 1.5 times ULN 
  
5. In subjects receiving treatment with ursodeoxycholic acid (UDCA), therapy must be 
stable for at least 3 months prior to Day 1 (no dose adjustment) and at a dose not greater 
than 20 mg/kg/day so that for subjects who are taking UDCA, the investigational drug 
can be given as a co-medication 
6. Subjects of childbearing potential must agree to use a medically acceptable method of 
contraceptive to prevent pregnancy in the subject and/or the partner for the duration of 
their participation in the trial up to 2 months after the last study drug dosing.  
 
 
 
 
 
 
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5.3.2 
Exclusion Criteria 
1. Presence of documented secondary sclerosing cholangitis
 
 
 on prior clinical 
investigations 
2. Small duct PSC 
3. Bacterial cholangitis 
  
4. Presence of percutaneous drain or endoscopic bile duct stent 
 
 
5. History of, or suspicion of cholangiocarcinoma  by MRC/ERC and other cross sectional 
imaging , or clinical judgment at screening 
6. Prior liver transplantation, or currently listed for liver transplantation on the basis of 
recurrent cholangitis and with a match-run MELD-Na+ score > 10 
7. Presence of other concomitant liver diseases 
 
 
 
 
  
8. Cirrhosis and/or hepatic impairment and/or hepatic decompensation 
 
  
9. Subjects with fibrosis evidence of cirrhosis, as determined by local transient 
elastography (TE, e.g., FibroScan®) values of ≥14.4 kPa (Corpechot et al, 2014)
 
 
10. Moderate to Severe active IBD or flare in colitis activity 
 
 
11. Active Crohn’s disease not currently in remission, as assessed by the investigator and 
the CRO’s medical monitor 
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12. Use of oral prednisolone 
 and/or hospitalization for IBD 
 
 
13. AST, ALT, and Total Bilirubin concentrations above the allowed cut-offs
  
 
 
 
 
 
 
 
 
 
14. International normalized ratio (INR) ≥ 1.2  
15. 
 
16. 
 
17. 
 
18. 
 
19. Any active malignant disease (within 3 years), other than non-melanomatous skin cancer 
20. Human immunodeficiency virus (HIV) infection 
21. Existing or intended pregnancy, and/or breast feeding 
22. Has received any study medication in the context of another clinical trial within the past 
the 30 days prior to screening 
23. 
 
24. Any other clinically significant disorders or prior therapy that, in the opinion of the 
investigator, would make the subject unsuitable for the study or unable to comply with 
the dosing and protocol requirements 
 
 
 
 
  
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• DUR 928 10 mg PO daily for 28 days  
• DUR 928 50 mg PO daily for 28 days 
6.0 
TRIAL CONDUCT 
6.1 
Investigative Sites 
This will be a multicenter study with approximately 12 clinical sites (hospitals) in the US.  
6.2 
Sponsor Obligations of Trial Conduct 
Sponsor responsibilities such as data management (including electronic data capture), site 
management, site monitoring, medical monitoring, and central safety laboratory services will 
be transferred to one or more contract research organizations (CROs).   
6.3 
Duration 
The first patient, first [screening] visit (FPFV) has been planned for October 2017. Patient 
participation will last for up to 100 days. 
6.4 
Discontinuation of Trial 
DURECT Corporation reserves the right to terminate the trial at any time.  
See Section 7.4 regarding study stopping criteria. 
7.0 
TRIAL PROCEDURES 
The study procedures are listed below 
  
7.1 
Patient Randomization 
Oral DUR-928 will be administered daily for 28 days.  Subjects will be randomly assigned 
with equal allocation to one of two treatment groups. 
• DUR 928 10 mg PO daily for 28 days 
• DUR 928 50 mg PO daily for 28 days 
 
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7.2 
Trial Test Drug  
7.2.1 
Administration of Test Drug 
The test drug will be self-administered by study subjects daily from Day 1 through Day 28 
(with up to 2 extra doses if patient returns to site at Day 30) according to the instructions 
provided by the study staff.  The first dose will be administered in the clinic where the staff 
will instruct the subjects on how to take their study drug.  See Appendix 1. 
7.2.2 
Packaging and Labeling of Test Drug 
The Sponsor will supply the investigational product (DUR-928) in 
 
labeled with the product name, lot number, and quantity. 
7.2.3 
Storage of Test Drug 
 
 
 
7.2.4 
Preparation of Test Drug 
 
 
7.2.5 
Drug Accountability 
All materials supplied are for use only in this clinical study and should not be used for any 
other purpose. 
The Investigator is responsible for investigational product accountability, reconciliation, and 
record maintenance at the investigational site.  In accordance with all applicable regulatory 
requirements, the Investigator or designated site staff must maintain investigational product 
accountability records throughout the course of the study.  This person will document the 
amount of investigational product received from DURECT, the amount dispensed to subjects, 
and the amount of investigational product remaining. 
A Drug Dispensing Log must be kept current and will contain the following information: 
• 
Study identification of the patient to whom the drug was dispensed; 
• 
Date(s), study treatment group, and quantity of the drug dispensed to each patient.  
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The inventory must be available for inspection by the study monitor during the study.  Drug 
supplies will either be returned by the Investigator or designee to DURECT or, if requested in 
writing by the Sponsor, unused drug supplies may be destroyed by the clinical study unit 
according to local standard operating procedures (SOPs).  Records shall be maintained by the 
Investigator of any such alternate disposal of the test drug.  These records must show the 
identification and quantity of each unit disposed of, the method of destruction (taking into 
account the requirements of local law), and the person who disposed of the test substance.  
Documentation of the disposition of all IP will be provided to DURECT.  In the event that the 
clinical study unit is unable to dispose of the investigational product, unused drug will be 
returned to DURECT.   
7.3 
Trial Visits and Study Procedures 
Refer to Table 1 for Schedule of Events by Visit. 
7.3.1 
Visit 1: Screening (Day -42 to Day 0) 
All screening procedures will be performed after obtaining informed consent.  After obtaining 
informed consent, subjects will be assigned a patient screening number and screening 
procedures will be performed.  For the patient screening number, subjects will be numbered 
consecutively within each site in order of their consent into the trial.  Only their assigned 
patient screening number and date of birth will identify subjects to the Sponsor in order to 
maintain anonymity.  
Screening procedures include completion of: 
• 
Demographic information  
• 
Medical and surgical history 
• 
Complete Physical examination (including height and weight)  
• 
Vital signs (BP, HR, RR and T)  
• 
Review of inclusion / exclusion criteria 
• 
Safety laboratory tests (fasted:  chemistry, hematology, urinalysis) 
• 
sBA test, HIV-1, HIV-2, Hepatitis B, Hepatitis C and IgG4 (if absence of evidence of 
IgG4-related sclerosing cholangitis) testing 
• 
Urine pregnancy test (females of childbearing potential)  
• 
12-lead ECG  
• 
Record prior and concomitant medications (taken within 30 days of screening) 
• 
Biomarker sample collection (see Section 9.6) 
• 
VAS-itch score and 5-D pruritus itch scale diaries given to subjects for completion 
• 
Transient Elastography/FibroScan® (only required if not performed within 3 months 
of screening) 
• 
MRC or ERC (only required if not performed within 12 months of Day 1 ) 
• 
Collection of partial Mayo score for IBD flare assessment 




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Subjects will return to clinic weekly for the following study procedures: 
Day 8, 15 and 22 
: 
• 
Vital signs (BP, HR, RR and T) 
• 
Safety laboratory tests (fasted: chemistry, hematology, urinalysis ) 
• 
Biomarker sample collection 
• 
Limited Physical exam (excluding height)  
• 
 sBA test (only on Day 15) 
• 
Collection of unused drug and accountability check 
• 
Concomitant medications 
• 
Adverse events  
• 
Dispensing of new drug supply (7 days + 2 extra back up doses) 
 
 
• 
Transient Elastography/FibroScan® (only on Day 8 and Day 15) 
• 
12-Lead ECG 
• 
Collection of partial Mayo score for IBD flare assessment 
Day 28 
  
• 
Vital signs (BP, HR, RR and T) 
• 
Safety laboratory tests (fasted: chemistry, hematology, urinalysis ) 
• 
Biomarker sample collection 
• 
sBA test 
• 
PK samples (at selected sites) 
• 
Collection of unused drug and accountability check 
• 
Concomitant medications 
• 
Adverse events  
• 
Complete Physical exam (excluding height)  
• 
12-Lead ECG 
• 
Transient Elastography/FibroScan® 
• 
Collection of partial Mayo score for IBD flare assessment 
• 
Urine Pregnancy Test for Females 
• 
VAS-itch score and 5-D pruritus itch scale diaries given to subjects 
7.3.4 
Day 42 
: Follow-up Visit 
The following procedures will be performed 
• 
Vital signs (BP, HR, RR and T) 
• 
Limited Physical exam (excluding height) 
• 
Safety labs (fasted- chemistry, hematology, urinalysis ) 
• 
Biomarker sample collection 
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• 
sBA test 
• 
12-lead ECG 
• 
Transient Elastography/FibroScan®  
• 
Collection of partial Mayo score for IBD flare assessment 
• 
VAS-itch score and 5-D pruritus itch scale diaries collected by study staff 
• 
Unused drug return and accountability check 
• 
Concomitant medications 
• 
Adverse events  
7.3.5 
Day 56 
: Trial Completion / Early Termination 
• 
Complete Physical examination (excluding height) 
• 
Vital signs (BP, HR, RR and T)  
• 
Safety laboratory tests (fasted: chemistry, hematology, urinalysis) 
• 
Biomarker sample collection 
• 
sBA test 
• 
12-lead ECG 
• 
Collection of partial Mayo score for IBD flare assessment 
• 
Urine pregnancy test (females of childbearing potential) 
• 
Unused drug return and accountability check  
• 
Concomitant medications 
• 
Adverse events  
7.4 
 Study Stopping Criteria 
In the event a subject experiences grade 5 CTCAE toxicity, the study will be paused and 
safety reports will be submitted to FDA for review and agreement prior to dosing any further 
subject. 
If more than 2 subjects develop a CTCAE grade 3 or higher in the same category, the study 
will be paused and safety data will be evaluated to determine the next step. 
Based on the above evaluations, the study may proceed or may be stopped in accordance with 
the SAC Charter (see Section 13.6, Safety Assessment Committee).  
7.5 
Concomitant Medication(s) 
All medications taken since 30 days prior to screening will be recorded on the appropriate 
source document and concomitant medication (CM) CRFs.  Any required treatment deemed 
necessary for treatment of the patient will be under the treating physician’s discretion, given 
as medically required, and documented on the CRFs 
7.5.1 
Prohibited Concomitant Medications 
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 prednisolone 
 or other investigational drugs are 
prohibited during the course of the study. 
8.0 
ASSESSMENT OF EFFICACY 
8.1 
Efficacy Assessments  
The primary efficacy endpoint is: 
% change of serum ALP from baseline through the end of study treatment and throughout the 
follow-up period. 
The secondary efficacy endpoints are:  
• 
% of subjects with ≥ 20% reduction of serum ALP from baseline 
• 
% of subjects with ≥ 30% reduction of serum ALP from baseline 
• 
% of subjects with ≥ 40% reduction of serum ALP from baseline 
• 
% change of liver enzymes, including ALT, AST, GGT, bilirubin, from baseline 
through the end of study treatment and throughout the follow-up period. 
• 
% change of selected biomarkers from baseline through the end of study treatment and 
throughout the follow-up period. 
• 
% change of serum bile acids (sBA) from baseline through the end of study treatment 
and throughout the follow-up period. 
  
 
 
 
 
 
 
9.0 
ASSESSMENT OF SAFETY   
9.1 
Safety Assessments 
• AEs: Spontaneously reported AEs; either volunteered by the patient, prompted by 
non-directed questioning or reported by an investigator will be documented on the 
eCRF. 
• Standard 12-lead ECG  
• Safety Laboratory Tests (Serum chemistry, hematology, urinalysis)  
• Vital Signs and Physical Examination  
9.1.1 
Discontinuation of Study Drug 
Study drug will be discontinued for any subject who experiences: 
• a diagnosed IBD flare up based on clinical judgment or the partial Mayo score 
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• cholangitis 
• biliary strictures  
• drug-induced liver injury (DILI, see below) 
Drug-induced liver injury (DILI) 
Cholestatic markers (ALP/GGT) need to be monitored closely for emergent complications of 
PSC and/or disease progression.  To protect patient safety, sites will be instructed to closely 
monitor for DILI of all subjects as defined by the following criteria: 
• Normal total bilirubin throughout the trial and only transaminase elevations are 
observed: 
-  ALT or AST increase ≥ 5X baseline levels AND the patient doesn’t have 
liver-related symptoms or immunological reaction, e.g. anorexia, nausea, 
vomiting, right upper quadrant pain, rash and pruritus (but not confined to 
these clinical features only)  
- ALT or AST increase ≥ 3X baseline levels AND are associated with liver-
related symptoms or immunological reaction, e.g, anorexia, nausea, 
vomiting, right upper quadrant pain, rash and pruritus (but not confined to 
these clinical features only) 
 
• Increase in total bilirubin ≥ 2X baseline AND exceeds 2X ULN with or without 
liver-related symptoms or immunological reaction, e.g. anorexia, nausea, 
vomiting, right upper quadrant pain, rash and pruritus (but not confined to these 
clinical features only) 
 
• ALP or GGT that increase to 3X baseline without OR 2X baseline with liver-
related symptoms or immunological reaction, e.g. anorexia, nausea, vomiting, right 
upper quadrant pain, rash and pruritus (but not confined to these clinical features 
only) 
 
• INR increased by at least 50% above baseline level to abnormal value.  
 
For the subjects described above, the study drug will be discontinued, the liver profile tests 
(ALT, AST, bilirubin and PT/INR) will be repeated within 2-3 days along with a physical 
examination. The AE will be followed per adverse event reporting instructions and a report 
form will be completed accordingly. All cases will be reviewed by the DURECT Safety 
Assessment Committee (SAC), see Section 13.6.   
9.2 
Interim Safety Profile 
There is no interim safety analysis planned for this study.  




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9.5.1 
Safety Laboratory Tests 
Chemistry:  Sodium, potassium, chloride, bicarbonate, serum bile acids (total and 
sub-speciation), serum creatinine, urea, glucose, albumin, calcium, uric acid, alanine 
aminotransferase, alkaline phosphatase, aspartate transaminase, creatine kinase (CPK), 
bilirubin (total and conjugated), cholesterol (total, LDL and HDL), triglycerides and 
gamma-glutamyl transpeptidase (GGT). 
Hematology:  White cell count with differential (neutrophils, lymphocytes, monocytes, 
eosinophils, basophils), red blood cell count, hemoglobin, hematocrit, platelet count, mean 
platelet volume, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular 
haemoglobin concentration, red cell distribution width.   
Coagulation: PT (INR) 
Urinalysis:  Macroanalysis by dipstick for glucose, bilirubin, ketones, blood, pH, protein, and 
urobilinogen.   
Other:  Hepatitis B surface antigen, Hepatitis C antibody *HIV 1/HIV 2 and IgG4. 
Laboratory values that are out of range for the central lab will be identified and may be 
repeated at the Investigator's discretion.  The Investigator will classify laboratory values 
outside the normal range as either clinically significant or not clinically significant.  Clinically 
significant laboratory values outside the normal range (i.e. any clinical abnormality or change 
that suggests a disease and/or organ toxicity and is of a severity that requires active 
management) that emerge after signature of the Informed Consent Form will be considered 
and recorded as an AE.  Clinically significant out of range laboratory values that emerge after 
treatment will be followed and treated (if appropriate) by the Investigator until resolution or 
lost to follow-up.   
9.6 
Biomarkers  
A 
 sample will be collected at screening visit 
 and at pre-dose at 
Day 1, Day 8, Day 15, Day 22, Day 28, Day 42 and Day 56 (or early termination visit) for 
assessment of selected exploratory biomarkers.  
 
 
 
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Where time-points of different sample or test types coincide then the following sequence 
applies: 
• 
Vital Signs  
• 
ECG 
• 
Biomarkers (serum) 
• 
 PK (plasma- at selected sites) 
• 
Safety lab tests 
Details on sample collection, processing, storage and shipment will be provided in the 
study specific Study Reference Manual. 
9.7 
Vital Signs 
Systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature will be 
measured.  Blood pressure and heart rate will be measured after the patient has been resting 
(supine or sitting) for 5 minutes.  Measurements will be taken at the times specified in the 
Schedule of Events table and will be recorded on the appropriate source document and eCRF. 
9.8 
Physical Examination 
A Complete Physical Examination will be conducted at Screening, ,Day 1, Day 28, and at the 
Trial Completion Visit (Study Day 56) or Early Termination Visit.  Day 1 Complete Physical 
Exam will establish a baseline for comparison with findings at subsequent study visits. 
The Complete Physical Exam includes the following assessments: 
• 
Weight 
• 
Height (at screening only) 
• 
General Appearance: head, eyes, ears, nose, mouth, throat, neck (including thyroid) 
• 
Cardiovascular System 
• 
Respiratory System 
• 
Gastrointestinal and Liver System, including rectal examination where indicated 
• 
Skin 
• 
Musculoskeletal System 
• 
Lymph Nodes 
• 
Neurological System 




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9.11 
VAS Itch Score and 5-D Pruritus Itch Scale 
The VAS (Visual Analogue Scale) Itch Score evaluates the subject’s severity of itching 
(Appendix 3). The 5-D Pruritus Itch Scale is developed as a brief but multi-dimensional 
questionnaire designed to be useful as an outcome measure in clinical trials (Appendix 4).  
 
 
 
 
 
At Day 1 and Day 42 visits, patients will bring in and hand over their itch diaries to the study 
staff. 
9.12 
Transient Elastography (TE) or FibroScan® 
Transient elastography (TE) e.g. FibroScan® will be conducted at the screening visit for 
subjects 
 
  If result shows a value ≥14.4 kPa, the subject won’t be 
enrolled in the study.  
 
9.13 
Adverse Events  
9.13.1 
Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.  An AE can therefore be any 
unfavorable and unintended sign or symptom, including clinically significant laboratory 
values and test results, concomitant illness, accident, or worsening of an existing medical 
condition. 
The following should not be recorded as an AE if noted at screening: 
• 
A pre-planned procedure for an illness included in the patient’s medical history, unless 
the condition for which the procedure was planned has worsened since baseline.  
Please observe that complications to pre-planned procedures should be recorded as 
AEs. 
• 
A pre-existing condition found as a result of screening procedures. 
Any worsening in severity or frequency of a baseline concomitant illness or any new illness 
diagnosed in the trial period must be regarded as an AE. 
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Serious Adverse Event 
A serious adverse event (SAE) is any adverse event that, at any dose: 
• 
Results in death  
• 
Is life-threatening.  Life-threatening refers to an event in which the patient is at risk of 
death at the time of the event.  It does not include an event that, had it occurred in a 
more severe form, might have caused death. 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization – 
Inpatient hospitalization includes an overnight admission. 
• 
Results in persistent or significant disability/incapacity.  Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions. 
• 
Results in the birth of a child with a congenital anomaly/birth defect. 
• 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE (when based upon appropriate medical 
judgment). These events may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed above. 
Adverse Reaction  
An adverse reaction (AR) is any untoward and unintended response to a test drug that has 
been considered to have a causal relationship with the treatment. 
Suspected Unexpected Serious Adverse Reaction 
A suspected unexpected serious adverse reaction (SUSAR) is an adverse reaction that is 
serious and where the nature or severity of which is not consistent with information in the 
current Investigator’s Brochure. 
Abnormal Laboratory Value as an AE  
An abnormal clinical laboratory value (i.e. any clinical laboratory abnormality or change that 
suggests a disease and/or organ toxicity and is of a severity that requires active management 
[i.e. change of test drug dose, discontinuation of test drug, medical treatment, more frequent 
follow-up or diagnostic investigation]), will be regarded as an AE. If clinical sequelae have 
been associated with a laboratory abnormality the diagnosis or medical condition should be 
reported (e.g. renal failure, hematuria) to replace the laboratory abnormality (e.g. elevated 
creatinine, urine RBC increased). 


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9.13.2 
Classifications 
Severity  
The Investigator will evaluate the intensity of each adverse event using the following 
definitions: 
• Mild:  An event that is easily tolerated by the subject, causing minimal discomfort 
and not interfering with everyday activities (CTCAE Grade 1). 
• Moderate:  An event that is sufficiently discomforting to interfere with normal 
everyday activities (CTCAE Grade 2). 
• Severe:  An event that prevents normal everyday activities (CTCAE Grade 3-5). 
Adverse events should be assessed according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) Version 4.0. 
In the event of the occurrence of a severe adverse event, the Investigator will be instructed to 
immediately inform the sponsor for follow-up steps. 
An AE that is assessed as severe should not be confused with an SAE.  Severity is a category 
utilized for rating the intensity of an event; and both AEs and SAEs can be assessed as severe.  
An event is described as ‘serious’ when it meets one of the pre-defined outcomes as described 
in Section 9.13.1. 
Causality  
A blinded Investigator is obligated to assess the relationship between test drug and the 
occurrence of each AE/SAE.  The Investigator will use clinical judgment to determine if there 
is a reasonable possibility that the pharmacological action of the test drug was responsible for 
the AE/SAE being reported.  Alternative causes such as natural history of the underlying 
diseases, concomitant therapy, other risk factors, and the temporal relationship of the event to 
the test drug will be considered and investigated.  The Investigator will also consult the 
Clinical Investigator’s Brochure and/or Product Information, for marketed products, in the 
determination of his/her assessment. 
After careful medical consideration, the Investigator will evaluate the relationship of each 
adverse event to test drug applying the following definitions: 
Probably Related – Good reasons and sufficient documentation to assume a causal 
relationship 
Possibly related – A causal relationship is conceivable  
Unlikely related – The event is most likely related to etiology other than the test drug   
Not Related – Good reasons and sufficient documentation to exclude a causal relationship. 


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There may be situations when an SAE has occurred and the Investigator has minimal 
information to include in the initial report.  However, it is very important that the Investigator 
always make an assessment of causality for every event prior to transmission of the SAE 
Report Form to the Sponsor (or designee). 
9.13.3 
Adverse Event Reporting 
All events that meet the definition of an AE that occur in the period from when the patient has 
signed the informed consent form (ICF) through trial completion (final visit), or early 
termination, must be recorded on the adverse event eCRF.  All SAEs will be recorded on the 
appropriate eCRF and on the Serious Adverse Event Report Form from the time written 
informed consent has been obtained through trial completion (final visit), or early termination. 
At each contact between the investigative site and the patient (visit or phone), after the patient 
has had an opportunity to spontaneously mention any problems, the Investigator should 
inquire about the occurrence of AEs.  The following are examples of open-ended questions 
that may be used to obtain this information:  
“How are you feeling?” 
“Have you had any medical problems since your last visit/assessment?”  
“Have you taken any new medicines, other than those given to you in this study, since your 
last visit/assessment?”  
All AEs and SAEs will be documented in source records (at each assessment time or when 
otherwise volunteered by the patient and recorded on the appropriate eCRF.  Information to 
be collected includes the nature, date and time of onset, severity, duration, relationship to test 
drug, and outcome of the event.  Even if the Investigator assesses the AE as not reasonably 
attributable to the test drug, its occurrence must be recorded in the source documents and 
reported on the eCRF along with the assessment of association. 
The Investigator will treat the patient as medically required, and this may extend beyond the 
duration of the trial.  The Investigator will record treatment and medications required to treat 
AEs on the appropriate eCRF(s).  All SAEs, and any possibly/probably related severe AEs 
will be followed until resolution (no further changes in the event are expected, i.e., the point 
at which a subject experiencing such an AE is appropriately treated and stabilized even 
though they may continue to experience lingering sequelae that may never resolve.   
DURECT will evaluate all AEs with respect to seriousness, causality and expectedness in 
accordance with Directive 2001/20/EC (3) and FDA Guidelines.  The expectedness of an AE 
will be determined according to the current version of the Investigators Brochure. 


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9.13.3.1 
 Clinical Laboratory Assessments and Other Abnormal 
Assessments as Adverse Events and Serious Adverse Events  
Abnormal clinical laboratory findings (e.g., clinical chemistry, hematology, and urinalysis) or 
other abnormal assessments (e.g., ECGs, vital signs) that are judged by the Investigator as 
clinically significant will be recorded as AEs or SAEs if they meet the definition described 
above.  Abnormal assessments that are detected during the study or are present at baseline and 
significantly worsen following the start of the study will be reported as AEs or SAEs.   
9.13.4 
Reporting of Serious Adverse Events 
Regardless of causality, the investigator must complete and submit an SAE form to 
 within 24 hours of 
knowledge of the event for all serious adverse events.    
  
  
  
 
The Investigator must indicate the SAE’s relationship to test drug and sign the SAE form.  
When additional relevant information (final diagnosis, outcome, results of specific 
investigations, etc.) becomes available, the investigator must record that follow-up 
information in the eCRF.  Follow-up information should be recorded according to the process 
used for reporting the initial event as described above.  The investigator will follow all 
reportable events (i.e., SAEs) until resolution. Resolution means no further changes in the 
event would be expected, i.e., the point at which a subject experiencing such an AE is 
appropriately treated and stabilized even though they may continue to experience lingering 
non-serious sequelae that may never resolve.    
 will follow all SAEs until resolution (no further changes in the event are 
expected, i.e., the point at which a subject experiencing such an AE is appropriately treated 
and stabilized even though they may continue to experience lingering sequelae that may never 
resolve).  
 will report all SAEs to DURECT within 1 business day of 
receipt.    
All serious adverse events will also be reported on the AE CRF and concomitant medications 
administered in association with the serious AE will be documented on the CM CRF. 
If a serious adverse event occurs and comes to the attention of the Investigator after trial 
completion/termination within 30 days of test drug dosing or within 30 days of the last trial 
visit (whichever occurs later), it must be reported immediately to 
 in the 
same manner as the serious adverse events occurring during the trial. Investigators are not 
obligated to actively seek AEs from former study participants. 
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The Investigator must report SAEs to the IRB/IEC (per the IRB/IEC guidelines/SOPs), 
including all SAEs that have occurred at the investigative site and all trial related SAEs that 
have resulted in an expedited safety report to a regulatory agency.  Concurrently, the 
Investigator must send DURECT documentation of such IRB/IEC notification or if reporting 
is not required immediately per IRB/IEC guidelines, then a copy of the local SOP stating the 
reporting guidelines should be supplied by the site to DURECT and the CRO.   
DURECT complies with applicable regulatory requirement(s) related to the reporting of 
SUSARs to the competent authorities and the IRBs/IECs.  In addition, DURECT will prepare 
annual safety reports covering all SUSARs that have occurred in clinical studies with the 
concerned test drug during the reporting period. 
If a clinically relevant SAE related to PSC progression occurs, a blood sample (approximately 
8 mL) will be collected as soon as possible for measurement of plasma DUR-928 
concentration.  The collection date and time should be documented.  Refer to the sample 
processing, shipping and handling instructions provided within the laboratory manual. 
9.13.5 
Adverse Event Follow-up 
During and after participation by a patient in a clinical trial, the Investigator will ensure that 
adequate medical care has been provided to the patient for any AEs including clinically 
significant laboratory values related to the trial.  The Investigator will inform the patient when 
medical care will be needed for intercurrent illness(es) of which the Investigator becomes 
aware.  
All SAEs and possibly/probably related, severe AEs must be followed by the Investigator 
until resolution (no further changes in the event are expected, i.e., the point at which a subject 
experiencing such an AE has been appropriately treated and stabilized even though they may 
continue to experience lingering sequelae that may never resolve), until the subject is lost to 
follow-up, or died and until all queries related to the AEs have been resolved.  If a subject 
dies during participation in the study or during a recognized follow-up period, the Sponsor (or 
designee) must be notified immediately and then provided with a copy of any post-mortem 
findings, including histopathology. 
9.14 
Pregnancy 
A urine pregnancy test (for female with childbearing potential) will be collected at screening 
visit, Day 1, Day 28 and Day 56 (end of study/early termination visit). 
Female subjects will be advised to notify the Investigator immediately if they become 
pregnant during the course of the trial.   
The Investigator must complete the appropriate pregnancy reporting forms and send them to 
DURECT (or DURECT’s designee) within 14 calendar days of obtaining information of the 
pregnancy.  The Investigator will follow the pregnancy through its course and complete the 


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appropriate documentation and forward immediately to DURECT (or DURECT’s designee).  
The infant must be followed at least until one month of age. Consent of a parent must be 
obtained before registration of infant data. 
Abortion, stillbirth and any malformation/disease must be reported as an SAE.  A pregnancy 
outcome other than abortion, stillbirth and any malformation/disease as well as follow-up of 
the infant must be reported by the Investigator within 14 calendar days of obtaining the 
information using the appropriate pregnancy reporting forms. 
10.0 
PHARMACOKINETICS 
At selected center(s), blood samples will be collected for drug concentration measurements in 
approximately 5 subjects from each dose group).  These samples will be collected on Day 1 
and Day 28 of dosing. 
 
 
 
 
 
For details on sample collection please refer to Appendix 2, for sample collection, processing 
and shipping details. 
If a clinically relevant SAE related to PSC disease progression occurs, a blood sample 
(approximately 8 mL) will be collected as soon as possible for measurement of plasma 
DUR-928 concentration.  The collection date and time should be documented, in addition to 
the date and time of last 2 doses taken.  Refer to the sample processing, shipping and handling 
instructions provided within the laboratory manual. 
11.0 
STATISTICAL METHODS AND DATA ANALYSIS 
11.1 
Sample Size Determination 
A sample size estimation was performed for the primary efficacy endpoint ‘Percentage 
change from baseline to week 4 in the serum alkaline phosphatase (ALP) level. 
Forty subjects will be randomized in total.  Considering an early withdrawal rate of 10%, a 
sample size of 36 subjects (18 subjects per dose group) provides a statistical power of 80% to 
detect a 15% decrease (with a standard deviation of 35%) compared to baseline in serum ALP 
after 4 weeks of treatment using a one-group t-test.  
 
  
 
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Details of statistical measures and data analysis will be further specified in the Statistical 
Analysis Plan for this study. 
11.2 
Patient Randomization  
Subjects will be randomized into DUR-928 10 mg and 50 mg treatment groups at a 1:1 ratio, 
without stratification.  
11.3 
Definition of Analysis Populations 
Intent-to-Treat (ITT) Population: The ITT population will include all randomized subjects 
independent of their exposure to test drug. 
Safety Population: The Safety population will include all subjects who received any amount 
of test drug.  The Safety population will be used for all safety analyses. 
Modified Intent-to-Treat (mITT) Population: The mITT population will include all 
randomized subjects who receive any test drug. 
All efficacy endpoints will be analyzed using the mITT population.  The disposition data will 
be summarized using ITT population.  
11.4 
General Statistical Analysis Considerations  
Study data will be summarized by treatment group and overall using descriptive statistics.  
Categorical variables will be reported with frequencies and percentages.  Continuous 
variables will be reported with number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum. 95% confidence intervals will also be provided when appropriate.  
All summaries, statistical analyses, and individual patient data listings will be completed 
using Version 9.3 or later of the SAS Statistical Analysis System (SAS Institute, Inc. Cary, 
NC). 
The primary efficacy endpoint of detecting a signal with regards to the decrease of the percentage 
change from baseline in ALP will be tested in the ‘pooled group’ of both dose levels. The 
comparison between the dose levels will be performed by exploratory testing. Secondary and 
other endpoints will be analyzed and explored in a descriptive manner. 
11.5 
Methodology for Dropouts and/or Missing Data 
Missing data will not be imputed except missing date of concomitant medication.  Missing 
dates of concomitant medication may be imputed according to rules to be specified in the 
SAP. Subjects who discontinued the study early will be summarized by reasons and treatment 
group.  


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11.6 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics will be summarized using descriptive statistics 
specified in section 11.5.  Baseline is defined as the last non-missing value before the first 
dose of study drug. 
11.7 
Statistical Analyses of Efficacy Endpoints 
11.7.1 
Primary Efficacy Endpoint 
• % change from baseline of serum ALP to the end of the study treatment 
• % change from baseline of serum ALP at all post-baseline visits and throughout the 
follow-up period 
11.7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• % of subjects with ≥ 20% reduction of serum ALP from baseline to the end of the 
study treatment 
• % of subjects with ≥ 30% reduction of serum ALP from baseline to the end of the 
study treatment 
• % of subjects with ≥ 40% reduction of serum ALP from baseline to the end of the 
study treatment 
• Mean and % change from baseline of bilirubin (total and direct) to the end of the 
study treatment 
• % change from baseline of ALT to the end of the study treatment 
• % change from baseline of AST to the end of the study treatment 
• % change from baseline of GGT to the end of the study treatment 
• % of subjects with ≥ 20% reduction of serum ALP from baseline at all post-baseline visits 
and throughout the follow-up period 
• % of subjects with ≥ 30% reduction of serum ALP from baseline at all post-baseline visits 
and throughout the follow-up period 
• % of subjects with ≥ 40% reduction of serum ALP from baseline at all post-baseline visits 
and throughout the follow-up period 
• % change from baseline of bilirubin (total and direct) at all post-baseline visits and 
throughout the follow-up period 
• % change from baseline of ALT at all post-baseline visits and throughout the 
follow-up period 


DURECT Corporation 
 
Protocol # C928-008  
 
 
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• % change from baseline of AST at all post-baseline visits and throughout the 
follow-up period 
• % change from baseline of GGT at all post-baseline visits and throughout the 
follow-up period 
• % change of selected biomarkers (to be specified in the Statistical Analysis Plan (SAP) 
from baseline and throughout the follow-up period 
• % change of serum bile acids (sBA) from baseline and throughout the follow-up period 
 
 
 
 
 
 
 
 
 
11.7.4 
Adjustment for Multiple Hypotheses Testing 
Only the primary efficacy criterion will be tested confirmatorily, thus no adjustment for multiple 
testing is required.  
11.7.5 
Subgroup Analysis  
No subgroup analysis is planned for this study.  
11.7.6 
Analyses Strategy for Pooling Trial Centers 
All trial centers will be pooled for statistical summary.  
11.8 
Interim Analyses and Data Monitoring 
No interim analyses have been planned for this study.  
11.9 
Statistical Analysis of Safety Endpoints 
11.9.1 
Safety Variables and Descriptive Summaries 
Safety variables include incidence of AEs, results of ECG recordings, laboratory test results 
(chemistry, hematology, urinalysis and other tests specified in section 9.1.4), and physical 
examination findings.  
Safety variables will be summarized descriptively based on the safety analysis population.  
No formal statistical testing will be performed for the safety analyses. 
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Protocol # C928-008  
 
 
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Adverse Events (AEs) will be recorded from signing the informed consent through the end of 
study or early termination.  All AEs will be coded using the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA).  A treatment-emergent AE (TEAE) is 
defined as any AE that emerges on or after first dosing of study drug or worsens relative to 
the pretreatment state. Various TEAEs will be summarized by MedDRA system organ class, 
prefer term and treatment. 
Summary statistics of clinical laboratory test values at all applicable study visit and change 
from baseline to each post-baseline study visit will be calculated by treatment.   
Vital sign results at each time point and change from baseline to each post-baseline study visit 
will be summarized by treatment.  
ECG results at each study visit and change of these parameters from baseline to each post-
baseline study visit will be summarized by treatment.   
PE results will be displayed in by-patient listings. 
11.10 Changes and Deviations to the Protocol and Statistical Analysis Plan 
Any deviations from the planned analyses methods and the rationale for such deviations will 
be carefully documented in the SAP and as a protocol amendment, if applicable.  The 
amended SAP will be submitted to the FDA.  If amended, the protocol will be submitted to 
the IRB and to the FDA.   
12.0 
ACCESS TO SOURCE DATA/DOCUMENTATION     
The investigative site will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspections by providing direct access to source data/documentation (e.g. medical 
records, original laboratory records and original informed consent forms).  The Investigator 
should immediately notify DURECT of any Health Authority inspection.  Essential 
documents must be maintained at the investigative site throughout the trial. 
12.1 
Confidentiality  
 
  
 
 
 
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12.2 
Data Identification 
Safety laboratory results from the central safety laboratory will be considered source data.  All 
other data will be recorded on a source document prior to being entered into the eCRF. 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE   
13.1 
Monitoring  
DURECT or DURECT’s designee will monitor the trial for regulatory and protocol adherence 
at all stages of trial conduct from inception to completion in accordance with ICH-GCP.  This 
monitoring will be in the form of site visits and other communication and will include review 
of original source documents and eCRFs.  DURECT’s monitor or designee will notify the 
Investigator prior to conducting any site visit.  These visits will include monitoring to assess 
facilities, required certifications, IRB/IEC records, equipment, patient recruiting ads, 
record-keeping, protocol adherence, data verification and transmission, adverse event 
reporting, and other factors. Final quality assurance visits by the Sponsor should be expected, 
and possibly by the FDA. 
The completed eCRFs will be reviewed against source documents by the monitor at each 
monitoring visit.  If any data, signatures, or forms are missing or discrepant, the Investigator 
will be informed and appropriate written corrections will be made in a timely manner.   
13.2 
Protocol Deviations 
All departures from the protocol will be referred to as protocol deviations and not protocol 
violations (ICH E3R1 Guidance, June 2012). 
Definitions 
• 
A protocol violation is “a serious non-compliance that may lead to exclusion of a 
subject from analyses and/or discontinuation from the trial.” 
• 
A protocol deviation is “related to study inclusion or exclusion criteria, conduct of the 
trial, subject management or subject assessment.” 
An important protocol deviation is “a subset of protocol deviations that might significantly 
affect the completeness, accuracy, and/or reliability of the study data or that might 
significantly affect a subject's rights, safety, or well-being” 
The Investigator should not deviate from the protocol.  Except for changes intended to 
eliminate any immediate hazard to subjects, the trial should be conducted as described in the 
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Protocol # C928-008  
 
 
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approved protocol.  In medical emergencies, the Investigator will use medical judgment and 
will remove the trial participant from immediate hazard followed by notification to DURECT 
and the IRB/IEC regarding the type of emergency and the course of action taken.  All protocol 
deviations will be documented by the investigative site or monitor on the designated log.   
13.3 
Case Report Forms  
Electronic case report forms will be used for this trial. Data entry will occur at the 
investigative site and will be performed by trained and qualified site personnel. The 
Investigator will ensure all the eCRFs are completed after each patient visit in a timely 
manner. Specific instructions are provided in the eCRF completion guidelines. 
13.4 
Coding  
MedDRA will be used to code adverse events.  WHO-Drug will be used to code concomitant 
medications. 
13.5 
Data Safety Monitoring Committee  
A Data Safety Monitoring Committee has not been planned for this open-label trial.  Periodic 
reviews of safety data will be performed by the Sponsor's medical monitor. 
13.6 
Safety Assessment Committee  
In accordance with the Guidance for Industry, Safety Assessment for IND Safety Reporting, 
DURECT implemented a Safety Assessment Committee (SAC) to closely monitor all safety 
parameters
 
 
 
 
14.0 
ETHICAL CONSIDERATIONS 
This trial will be conducted according to US and international standards of Good Clinical 
Practice (FDA regulations 21 CFR 312 for IND studies and ICH guidance E6) for all studies. 
All subjects for this trial will be provided a consent form describing this trial and providing 
sufficient information for subjects to make an informed decision about their participation in 
this trial.  This consent form will be submitted with the protocol for review and approval by 
the IRB.  The formal consent of a subject, using the IRB-approved consent form, will be 
obtained before that subject is submitted to any trial procedure.  This consent form must be 
signed by the subject or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent. Each subject will be given a copy of the signed consent 
form. 
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Protocol # C928-008  
 
 
Protocol Amendment Date: 13 SEP 2018 
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14.1 
Institutional Review Board / Ethics Committee   
The protocol, consent form, advertisements and any other information for subjects will be 
reviewed and approved by DURECT Corporation (or DURECT’s designee) and by the 
Institutional Review Board (IRB/Independent Ethics Committee (IEC) of the participating 
investigative site prior to the start of the trial at that site in accordance with the International 
Conference on Harmonization (ICH) and institutional IRB/IEC policies.  All protocol 
amendments and changes to the consent form occurring during the trial must also be IRB/IEC 
approved. 
14.2 
Regulatory Compliance  
The trial will be conducted in accordance with the principles of Good Clinical Practice (GCP) 
set forth in the International Conference on Harmonization (ICH) Good Clinical Practice, the 
US Code of Federal Regulations (CFR Title 21), the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA) and any local requirements. 
14.3 
Regulatory Status 
DUR-928 is under development and has not been approved for commercial use. 
14.4 
Patient Information and Informed Consent 
Prior to participation in the trial, the Investigator or designee will obtain written consent from 
each patient using the IRB/IEC-approved informed consent form that explains the nature, 
purpose, possible risks and benefits of the trial, and the duration of an individual’s 
participation.  The basic elements of the informed consent as specified by the FDA (21 CFR 
§50.25), and HIPAA will be followed.   
Before consenting, the patient must be left with ample time to consider and to pose questions. 
The Investigator and/or the designated investigative site personnel who conduct the informed 
consent discussion must also sign and date the consent form.  Each patient will be given a 
copy of the signed consent form.  The original, signed consent forms will be maintained at the 
investigative site.   
14.4.1 
Patient Withdrawal 
Subjects will be informed during the informed consent process (in writing and verbally) that 
they are free to withdraw from the trial at any time.  The Investigator may exercise his 
medical judgment to terminate a patient’s participation in the trial due to clinically relevant 
changes in any clinical or laboratory parameter.  DURECT Corporation also reserves the right 
to terminate the trial at any time.  All trial procedures normally performed at completion of 
the trial must be done at the time of the patient’s early termination, before the scheduled final 
clinic visit, or on the scheduled final clinic visit as described in Section 7.3.5 and Section 
9.1.1 unless the patient withdraws consent.  If a patient withdraws consent they will be 


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Protocol # C928-008  
 
 
Protocol Amendment Date: 13 SEP 2018 
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encouraged to complete an early termination visit and AE follow-up.  Subjects with ongoing 
SAEs and any possibly/probably related severe AEs will be followed until resolution. 
Resolution means no further changes in the event are expected, i.e., the point at which a 
subject experiencing such an AE is appropriately treated and stabilized even though they may 
continue to experience lingering sequelae that may never resolve.  Subjects with ongoing 
adverse events (other than SAEs, and any possibly/probably related severe AEs) will be 
followed until resolved or until 30 days after the patient’s last trial visit, whichever comes 
first.  
Subjects who withdraw prior to assignment of test drug will be considered as screen failures 
and will not be considered randomized (See Section11.2).   
15.0 
DATA HANDLING AND RECORD RETENTION   
15.1 
Data Ownership 
The eCRFs, associated documents and reports from the trial are the property of DURECT.  
DURECT has the right to use the results for registration purposes, internal presentation and 
promotion. 
15.2 
Retention of Trial Records 
The Investigator will retain all trial documents (e.g., approved protocol, copies of completed 
eCRFs and electronic diaries, original informed consent forms, relevant source documents) in 
a secure place protected from fire and theft until:  
At least 2 years after the last approval of an NDA by the US FDA; 
At least 2 years after the last approval of a marketing application in an ICH region; 
There are no pending or contemplated marketing applications in an ICH region; or 
At least 2 years have elapsed since the formal discontinuation of the clinical development of 
the test drug 
These documents should be retained for a longer period if required by the local/regional 
regulations or by an agreement with DURECT.  It is the responsibility of the Sponsor to 
inform the Investigator/Institution when these documents no longer need to be archived. 
The medical files of trial subjects must be retained in accordance with national legislation and 
in accordance with the maximum period of time permitted by the hospital, institution or 
private practice. 
DURECT will maintain the documentation pertaining to the trial as long as the test drug is on 
the market. 


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Protocol # C928-008  
 
 
Protocol Amendment Date: 13 SEP 2018 
CONFIDENTIAL 
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Trial records must be made available by the Investigator for inspection upon reasonable 
request by authorized representatives of DURECT, the Food and Drug Administration (FDA), 
or the corresponding regulatory Health Authorities of the relevant countries. 
DURECT will provide the Investigator with information concerning the current status of the 
test drug as it relates to the Investigator’s responsibility for the retention of trial records.  The 
Investigator should contact DURECT prior to disposing of any such records. DURECT will 
arrange for continued storage of all records, if necessary. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Protocol # C928-008  
 
 
Protocol Amendment Date: 13 SEP 2018 
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18.0 
REFERENCES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
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