Clinical trial NCT03432260
Conditions: Alcoholic Hepatitis
Keywords: Alcoholic Hepatitis acute alcoholic liver disease progressive inflammatory liver injury IV infusion
Sponsor: Durect
Start date: 2018-04-18; Completion date: 2019-09-09
Enrollment: 19 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a research trial testing DUR-928 (an experimental medication). The purpose of this trial is to assess the dose related safety, Pharmacokinetics, and Pharmacodynamics of DUR 928 in patients with moderate and severe alcoholic hepatitis (AH).

Detailed description:

Arms: arm 1: Lowest dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg arm 2: Middle dose of 3 dose escalation arms: 30mg, 90 mg and 150 mg arm 3: Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg arm 4: Lowest dose of dose escalation arms: 30mg, 90 mg and 150 mg arm 5: Middle dose of dose escalation arms: 30mg, 90 mg and 150 mg arm 6: Highest dose of dose escalation arms: 30mg, 90 mg and 150 mg
Interventions: intervention 1: DUR-928 30 mg intervention 2: DUR-928 90 mg intervention 3: DUR-928 150 mg
Intervention descriptions: intervention 1: Lowest dose of 3 dose escalation arms. intervention 2: Middle dose of 3 dose escalation arms. intervention 3: Highest dose of 3 dose escalation arms.

Protocol documents:
Prot_SAP_001.pdf: 
DURECT Corporation 
Protocol # C928-010, Amendment 1 
Protocol Date: 19 September 2018 
CONFIDENTIAL 
Page 1 of 60 
Clinical Protocol 
Protocol No. 
C928-010 
Title: 
An Open- Label, Dose Escalation Study to Assess the Safety, Pharmacokinetics 
and Pharmacodynamic Signals of DUR-928 in Patients with Alcoholic 
Hepatitis. 
Phase 
2a  
IND: 
134468 
Version: 
Original: 06 December 2017 
Amendment 1: 19 September 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the recipient that no previously unpublished information contained herein will be 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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Protocol # C928-010, Amendment 1 
 
 
Protocol Date: 19 September 2018 
CONFIDENTIAL 
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SPONSOR CONTACTS 
 
DURECT Corporation 
10260 Bubb Road 
Cupertino, CA  95014 
USA 
 
Project Leader 
 
 
 
 
Clinical Pharmacology 
 
 
 
 
 
 
Team Leader 
 
 
 
 
CONTRACT RESEARCH 
ORGANIZATION 
Medical Monitor  
 
 
 
 
 
Biostatistician 
 
 
 
   
 
LABORATORIES 
 
 
 
 
 
 
 
 
 
 
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1.0 
TABLE OF CONTENTS 
CLINICAL PROTOCOL ............................................................................................................. 1 
INVESTIGATOR AGREEMENT PAGE .................................................................................. 2 
1.0 
TABLE OF CONTENTS .................................................................................................. 4 
List of Appendices .............................................................................................................. 7 
List of Tables....................................................................................................................... 7 
List of Figures ..................................................................................................................... 7 
2.0 
TRIAL SYNOPSIS ........................................................................................................... 8 
3.0 
LIST OF ABBREVIATIONS ........................................................................................ 16 
4.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.0 
CURRENT TRIAL ......................................................................................................... 24 
5.1 
Trial Objectives and Primary Endpoints ............................................................... 24 
5.2 
Trial Rationale and Design.................................................................................... 24 
5.3 
Population ............................................................................................................. 25 
5.3.1 
Inclusion Criteria .................................................................................. 25 
5.3.2 
Exclusion Criteria ................................................................................. 26 
5.3.3 
Number of Patients ............................................................................... 27 
5.3.4 
Dosage and Regimen ............................................................................ 27 
6.0 
TRIAL CONDUCT ......................................................................................................... 28 
6.1 
Investigative Sites ................................................................................................. 28 
6.2 
Sponsor Obligations of Trial Conduct .................................................................. 28 
6.3 
Duration................................................................................................................. 28 
6.4 
Discontinuation of Trial ........................................................................................ 28 
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7.0 
TRIAL PROCEDURES ................................................................................................. 28 
7.1 
Trial Test Drug ...................................................................................................... 28 
7.1.1 
Dosing schedule and Proposed Dose ................................................... 28 
7.1.2 
Packaging and Labeling of Test Drug .................................................. 29 
7.1.3 
Storage of Test Drug ............................................................................ 29 
7.1.4 
Preparation of Test Drug ...................................................................... 29 
7.1.5 
Drug Accountability ............................................................................. 30 
7.2 
Trial Visits and Study Procedures ......................................................................... 30 
7.2.1 
Screening (Day -3 –Day 0) ................................................................... 30 
7.2.2 
Day 1 .................................................................................................... 31 
7.2.3 
Day 2 .................................................................................................... 32 
7.2.4 
Day 3 .................................................................................................... 32 
7.2.5 
Day 4, if performed (pre-dose unless otherwise noted) ....................... 33 
7.2.6 
Day 5 and Day 6 (if performed) ........................................................... 33 
7.2.7 
Day 7 (+/- 1 day) .................................................................................. 34 
7.2.8 
Day 28 (+/- 1 day) Trial Completion / Early Termination ................... 34 
7.3 
Concomitant Medication(s) ................................................................................... 35 
7.3.1 
Prohibited Concomitant Medications ................................................... 35 
8.0 
ASSESSMENT OF EFFICACY .................................................................................... 35 
8.1 
Efficacy Assessments ............................................................................................ 35 
8.2 
Method and Timing of Assessments ..................................................................... 35 
9.0 
ASSESSMENT OF SAFETY ......................................................................................... 36 
9.1 
Safety Assessments ............................................................................................... 36 
9.2 
Method and Timing of Assessments ..................................................................... 36 
9.2.1 
Adverse Event Recording ..................................................................... 36 
9.2.2 
12-Lead ECGs ...................................................................................... 37 
9.2.3 
Laboratory Tests ................................................................................... 37 
9.2.4 
Vital Signs ............................................................................................ 38 
9.2.5 
Physical Examination ........................................................................... 38 
9.2.6 
Biomarkers ........................................................................................... 38 
9.3 
Adverse Events...................................................................................................... 40 
9.3.1 
Definitions ............................................................................................ 40 
9.3.2 
Adverse Event Reporting ..................................................................... 42 


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Protocol # C928-010, Amendment 1 
 
 
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9.3.3 
Reporting of Serious Adverse Events .................................................. 43 
9.3.4 
Adverse Event Follow-up ..................................................................... 44 
9.4 
Pregnancy .............................................................................................................. 45 
10.0 
PHARMACOKINETICS ............................................................................................... 45 
11.0 
STATISTICAL METHODS AND DATA ANALYSIS ............................................... 46 
11.1 
Trial Design Considerations .................................................................................. 46 
11.2 
Sample Size Determination ................................................................................... 46 
11.3 
Patient Randomization .......................................................................................... 46 
11.4 
Definition of Analysis Population ......................................................................... 46 
11.5 
General Statistical Analysis Considerations ......................................................... 47 
11.6 
Demographic and Baseline Characteristics ........................................................... 47 
11.7 
Changes and Deviations to the Protocol and Statistical Analysis Plan ................. 47 
12.0 
ACCESS TO SOURCE DATA/DOCUMENTATION ................................................ 47 
12.1 
Confidentiality ...................................................................................................... 48 
12.2 
Data Identification ................................................................................................. 48 
13.0 
QUALITY CONTROL AND QUALITY ASSURANCE ............................................ 48 
13.1 
Monitoring ............................................................................................................ 48 
13.2 
Protocol Deviations ............................................................................................... 48 
13.3 
Case Report Forms ................................................................................................ 49 
13.4 
Coding ................................................................................................................... 49 
13.5 
Data Safety Monitoring Committee ...................................................................... 49 
13.6 
Adjudication Committee ....................................................................................... 49 
14.0 
ETHICAL CONSIDERATIONS ................................................................................... 50 
14.1 
Institutional Review Board / Ethics Committee.................................................... 50 
14.2 
Regulatory Compliance ......................................................................................... 50 
14.3 
Regulatory Status .................................................................................................. 50 
14.4 
Patient Information and Informed Consent ........................................................... 51 
14.4.1 
Patient Withdrawal ............................................................................... 51 
15.0 
DATA HANDLING AND RECORD RETENTION ................................................... 52 
15.1 
Data Ownership ..................................................................................................... 52 
15.2 
Retention of Trial Records .................................................................................... 52 
 
 
 
 
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18.0 
REFERENCES ................................................................................................................ 54 
19.0 
APPENDICES ................................................................................................................. 55 
List of Appendices 
 
 
 
 
 
List of Tables 
 
 
List of Figures 
 
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Protocol # C928-010, Amendment 01 
 
 
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Table 1: Schedule of Events  
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3.0 
LIST OF ABBREVIATIONS 
AE  
Adverse event 
AH   
Alcoholic Hepatitis 
ALD  
Alcoholic Liver Disease 
ALT  
Alanine aminotransferase 
AST  
Aspartate aminotransferase 
AUC  
Area under the curve 
BMI  
Body mass index 
BP  
Blood pressure 
BUN  
Blood urea nitrogen 
CFR  
Code of Federal Regulations 
CK-18 
Cytokeratin-18 
CL  
Clearance 
Cmax  
Maximum serum concentration 
Cr 
 
Creatinine 
CRF  
Case Report Form  
CRP  
C-reactive protein 
CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events 
Cys-C 
Cystatin-C 
DLT  
Dose-Limiting Toxicity 
ECG  
Electrocardiogram 
 
FFA  
Free fatty acids 
GGT  
Gamma-glutamyl transpeptidase 
GI 
 
Gastrointestinal 
GST  
Glutathione S-transferase 
HIV  
Human immunodeficiency virus 
hERG 
Human ether-a-go-go related gene 
HFD  
High Fat Diet 
HR  
Heart rate 
Ht 
 
Height 
HV  
Healthy volunteer 
IL 
 
Interleukin 
IM  
Intramuscular 
IND  
Investigational New Drug 
INR  
International normalized ratio 
IP 
 
Investigational product 
ITT   
Intention to Treat 
IV 
 
Intravenous 
LDL  
Low-density lipoprotein 
LPS  
Lipopolysaccharide 


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Protocol # C928-010, Amendment 01 
 
 
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MDF 
Maddrey discriminant function 
MELD 
Model for End Stage Liver Disease 
MTD 
Maximum Tolerated Dose 
NAFLD 
Nonalcoholic Fatty Liver Disease 
NASH 
Nonalcoholic Steatohepatitis 
PEth  
Phosphatidylethanols  
PI 
 
Principal Investigator 
PMN 
Polymorphonuclear leukocyte 
PK  
Pharmacokinetic 
PO  
Oral 
PPARγ 
Peroxisome proliferator activated receptor-gamma 
PSC  
Primary sclerosing cholangitis 
PT 
 
Prothrombin time 
RR  
Respiratory rate 
SAA  
Serum Amyloid A  
SAC  
Safety Assessment Committee 
SAD  
Single ascending dose 
SAE  
Serious adverse event 
SBP  
Spontaneous bacterial peritonitis 
SC  
Subcutaneous 
sCr  
Serum creatinine 
SST   
Serum Separating Tube 
SOFA 
Sequential Organ Failure Assessment 
TGF  
Tubuloglomerular feedback 
TIMP-2 
Tissue inhibitor of metalloproteinase-2 
T1/2 
 
Half-life 
Tmax  
Time to maximum serum concentration 
UDS  
Urine drug screen 
USAE 
Unexpected serious adverse event 
ULN  
Upper limit of normal 
Vd 
 
Volume of distribution 
Wt  
Weight


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5.0 
CURRENT TRIAL 
5.1 
Trial Objectives and Primary Endpoints 
1. Assess the safety and tolerability of DUR-928 in patients with AH as determined by 
the absence of SUSARs. 
2. Determine the PK of DUR-928 in patients with AH.  
3. Assess the pharmacodynamic signals of DUR-928 in patients with AH as determined 
by:  
a. Biochemical: Improvement in liver biochemistry, MELD score, and the 
components  of the MELD score individually (INR/sCr and bilirubin) at Day 7 
and Day 28 and Lille score at Day 7 
b. Biomarkers: improvement of biomarkers 
 
 
 
5.2 
Trial Rationale and Design 
The study will be conducted in 2 Parts using a staggered parallel design.  Part A will include 
patients with MELD scores of 11-20, and Part B will include patients with MELD of scores 
21-30.  
Within each Part, the study will be conducted using a starting dose level of 30 mg with 
sequential dose escalation following review of safety and PK results of the prior dose level 
by the sponsor, the principal investigators and the medical monitor.  The planned subsequent 
doses of DUR-928 after the starting dose are 90 mg and 150 mg.  
Patients with a MELD score of 21-30 (Part B) receiving the 30 mg dose level will only be 
enrolled once safety review of the 30 mg dose of DUR-928 in patients with MELD score 
11-20 (Part A) has been completed.  The subsequent dose escalation in each Part will not 
proceed until the sponsor, the principal investigators, and the medical monitor complete the 
review of safety and evaluate PK results of the 30 mg dose level and determine it is safe to 
do so. 
 
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If no SUSAR is observed and PK results are satisfactory, dose escalation to the next dose 
cohort will proceed. All patients will be followed up to Day 28.  
Figure 1: Trial Schema 
5.3 
Population 
Patients with AH will be enrolled at clinical sites in the US. The target number of 
participants to complete the study is 24-36. During the trial, patients should receive standard 
of care as determined by their PI. 
5.3.1 Inclusion Criteria  
To participate in this study, patients must meet all of the following criteria:  
1. 
Able to provide written informed consent (either from patient or patient’s legally 
acceptable representative)  
2. 
Male or female patients 21 years of age or older with BMI ≥ 20 to ≤ 40 kg/m2 
3. 
Patients with alcoholic hepatitis defined as:  
a. History of heavy alcohol abuse: > 40 g/day in females or > 60 g/day in males for a 
minimum period of 6 months, AND 
b. Consumed alcohol within 12 weeks of entry into the study, AND  
c. Serum bilirubin > 3 mg/dL AND AST > ALT,  
but less than 300 U/L AND  
d. MELD score between 11-30, inclusive 
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4. 
Any active malignancies other than curatively treated skin cancer 
 
 or any other malignancy diagnosed within the last five years 
5. 
Active tuberculosis on chest x-ray at study entry  
6. 
Significant systemic or major illness other than liver disease, 
 
 
  
7. 
Patients requiring the use of vasopressors or inotropic support.
 
8. 
Liver biopsy, if carried out, showing findings not compatible with AH 
9. 
Any patient that has received any investigational drug or device within 30 days of 
dosing or who is scheduled to receive another investigational drug or device at any time 
during the study 
10. 
 
 
11. If female, known pregnancy, or has a positive serum pregnancy test, or is 
lactating/breastfeeding  
12. Serum creatinine > 2.5 mg/dL  
13. Patients who have had organ transplantation 
 
 
14. Stage 3 or greater encephalopathy by West Haven criteria 
5.3.3 Number of Patients 
Each dose cohort will have at least 4 and no more than 6 patients. There will be 3 dose 
cohorts in each part of the study. The total number of participants to complete the study is at 
least 24 and no more than 36. 
5.3.4 Dosage and Regimen 
DUR-928 will be administered on Day 1 and Day 4 (if performed) in 
 
 by slow intravenous infusion over approximately 2 hrs 
 until 
entire dose is given. If a patient meets the hospital discharge criteria prior to the 2nd dose, the 
patient will receive only one dose of DUR-928 instead of 2 doses.  
See Section 5.2 for details on dose escalation. 
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6.0 
TRIAL CONDUCT 
6.1 
Investigative Sites 
This will be a multicenter study with approximately 10 clinical sites 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 laboratory services for PK and 
biomarkers will be transferred to one or more contract research organizations (CROs).   
6.3 
Duration 
Patient participation is approximately 33 days. 
6.4 
Discontinuation of Trial 
DURECT Corporation reserves the right to terminate the trial at any time. 
7.0 
TRIAL PROCEDURES 
The study procedures are listed below 
.  
7.1 
Trial Test Drug  
7.1.1 Dosing schedule and Proposed Dose  
DUR-928 will be administered after the patient is confirmed with the clinical diagnosis of 
AH. A total of no more than two doses of DUR-928 will be given, with 72 hrs between each 
dose. 
A second dose of the assigned study treatment (test drug) will be repeated 3 days after 
Dose 1 to patients who are still hospitalized. If a patient meets the discharge criteria prior to 
Day 4, the patient will receive only one dose of DUR-928. 
A Cohort Management System will be used to assign patients based on their MELD score to 
the appropriate Part and Cohort and associated dose.   
Patients of Part A (MELD 11-20) will follow the dose escalation procedure based on cohort; 
each patient will receive an intravenous infusion dose of:  
• Cohort 1A: 30 mg of DUR-928in 
 
administered over approximately 2 hrs via IV infusion. 
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• Cohort 2A: 90 mg of DUR-928 in 
 
administered over approximately 2 hrs via IV infusion. 
• Cohort 3A: 150 mg of DUR-928  in 
 
administered over approximately 2 hrs via IV infusion 
Dose escalation to the next cohort will be determined after review of safety, tolerability and 
pharmacokinetic data of the previous cohort. 
Dose escalation for Part B will follow the same requirements as for Part A. The dose levels 
for Part B are planned to be the same as Part A.   
Patients of Part B (MELD 21-30) will follow the dose escalation procedure based on cohort; 
each patient will receive an intravenous infusion dose of:  
• Cohort 1B: 30 mg of DUR-928 in 
 
administered over approximately 2 hrs via IV infusion. 
• Cohort 2B: 90 mg of DUR-928 in 
 
administered over approximately 2 hrs via IV infusion. 
• Cohort 3B: 150 mg of DUR-928  in 
 
administered over approximately 2 hrs via IV infusion 
More details on preparation and administration of study drug will be provided in the 
Investigation Product Manual for this study. 
7.1.2 Packaging and Labeling of Test Drug 
The sponsor will supply the sterile ready to use DUR-928 Injection,
 
.  Each vial 
is labeled with product name, lot number, and quantity. 
7.1.3 Storage of Test Drug 
 
7.1.4 Preparation of Test Drug 
The DUR-928 Injection will be diluted into a 
 
intravenous solution infusion bag.  The DUR-928 solution will be administered to the patient 
by IV infusion over approximately 2 hrs.  The diluted DUR-928 in 
 
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7.1.5 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 administered to 
patients, 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 cohort, and quantity of the drug dispensed to each patient.  
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.  If the clinical study 
unit is unable to dispose of the investigational product, unused drug will be returned to 
DURECT.   
7.2 
Trial Visits and Study Procedures 
. 
7.2.1 Screening 
 
The screening visit will be performed 
 of the day of dosing. After obtaining 
informed consent, patients will be assigned a patient number and screening procedures will 
be performed. For the patient number, patients will be numbered consecutively within each 
site in order of their consent into the trial. Only their assigned patient number and date of 
birth will identify patients to the Sponsor in order to maintain anonymity.  
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• 
Safety labs (clinical chemistry, hematology, urinalysis, coagulation) 
• 
12-lead ECG  
• 
Physical Exam (including weight) 
• 
Concomitant medications 
• 
Adverse events  
• 
Assessment of the patient’s alcohol consumption status 
• 
Assessment of MELD Score  
• 
Biomarker sample collection 
  
• 
UDS and PEth test  
7.3 
Concomitant Medication(s) 
Any required treatment deemed necessary for treatment of the patient will be under the 
treating physician’s discretion and given as medically required. All concomitant medications 
will be recorded on the appropriate eCRF. 
7.3.1 Prohibited Concomitant Medications 
 
 
Other investigational agents are the only other prohibited medication within this trial. 
8.0 
ASSESSMENT OF EFFICACY 
8.1 
Efficacy Assessments  
Change in MELD score and the components of the MELD score individually (INR/sCr and 
bilirubin), Lille score, biochemistry
, and biomarkers. 
8.2 
Method and Timing of Assessments 
MELD score will be calculated on screening, Day 1 (pre-dose), Day 7 and Day 28. 
Lille score will be calculated on Day 7  
Biochemistry and all safety lab parameters will be collected at 
 
 
 
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9.0 
ASSESSMENT OF SAFETY   
9.1 
Safety Assessments 
Safety will be determined based on clinical and laboratory monitoring.  
Clinical: At each study follow-up visit, patients will have a physical examination with 
specific attention to pulmonary abnormalities, worsening in liver function as noted by 
increasing jaundice, ascites, or hepatic encephalopathy and presence of infection.  
Laboratory: Biochemical parameters that are monitored include CRP, liver biochemistry, 
creatinine, and electrolytes.  
Stopping Criteria: 
 
  The study will also be halted for 
adjudication review if more than 2 patients have an adverse event grade 3 or above on the 
CTCAE scale that is determined to be possibly or probably attributable to study drug as per 
the Adjudication Committee.  
 
 
The Adjudication Committee will also be contacted ad hoc when there is question of 
symptom causality for SUSAR’s. 
The following parameters will be recorded for the safety evaluation: 
• 
Adverse events 
• 
Standard 12-lead ECG  
• 
Safety Laboratory Tests (clinical chemistry, hematology, coagulation, and urinalysis)  
• 
Vital Signs and Physical Examination  
9.2 
Method and Timing of Assessments 
Safety will be evaluated using adverse events, vital signs, clinical laboratory tests and 
electrocardiograms. Refer to Table 1 for the frequency of assessments. 
9.2.1 Adverse Event Recording  
Adverse events will be recorded from the time the patient signs the informed consent form 
through trial completion final visit/early termination (see Section 7.2.8).  
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9.2.1.1 Spontaneously Reported Adverse Events 
Spontaneously reported AEs; either volunteered by the patient, prompted by non-directed 
questioning or reported by an investigator will be documented on the eCRF. 
9.2.2 12-Lead ECGs  
Standard resting 12-lead ECGs will be obtained after patient is resting in the supine position 
for 10 minutes at Screening, post-dose completion (end of infusion) on Day 1 and Day 4 
daily at Day 2-6 while patient hospitalized, at Day 7 and Day 28.  Additional ECGs may be 
obtained if clinically indicated. 
Overall interpretation and machine read intervals (HR, PR, QRS, QT, and QTc) will be 
recorded on the ECG eCRF.  Clinically significant ECG findings that emerge after treatment 
will be recorded on the AE eCRF. 
9.2.3 Laboratory Tests 
All routine laboratory analyses will be conducted by a local laboratory and have been listed 
below.  Laboratory tests will be obtained as indicated on the Schedule of Events table.  When 
completing the safety laboratory tests there may be instances where the windows for two 
time points overlap due to time of study drug dosing, only one lab sample should be collected 
if time points overlap (see Sections 7.2.2 and 7.2.6).  
Female patients of childbearing potential will have a serum pregnancy test at Screening and 
Day 28.  
Chemistry: 
 
 
 
 
Hematology: 
 
 
 
Urinalysis: 
 
  
Coagulation: 
 
Urine Drug Screen: 
 
  
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Phosphatidylethanols test (PEth): 
 
 
Other: 
 
 
 
 
Note:  If HIV antibody screening returns a positive result, test will be confirmed by Western 
Blot. 
9.2.4 Vital Signs 
Systolic/diastolic blood pressure, heart rate, respiratory rate, and temperature will be 
measured at: 
a.
Screening
b. Day 1 and Day 4 pre-dose and post-dose completion (end of infusion), Day 2, Day 7,
and Day 28 (or Early Termination)
c.
If patient is in hospital on Day 3, Day 5, Day 6
Vital signs will be measured prior any blood collection.  Blood pressure and heart rate will be 
measured after the patient has been resting (supine or sitting) for at least 3 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. 
9.2.5 Physical Examination 
A physical examination will be conducted at the Screening Visit, Day 1, Day 2, daily on Day 
3-6 (if in hospital), Day 7 and Day 28 (or Early Termination). It will include general
appearance, evaluation of head, eyes, ears, nose, throat, neurological exam, weight and
specific attention to pulmonary abnormalities, worsening in liver function as noted by
increasing jaundice, ascites, or hepatic encephalopathy and presence of infection.
Any changes from baseline outside the normal range that emerge after treatment will be 
recorded on the AE eCRF.   
9.2.6 Biomarkers 
 
 
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9.3 
Adverse Events 
9.3.1 Definitions 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation patient 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 prior to dosing.
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. 
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 
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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. 
Note: Hospitalizations that occurred prior to the signing of informed consent, and where the 
underlying condition of AH for which the hospitalization was planned has not worsened will 
not be considered SAEs.  
Unexpected Serious Adverse Event 
An unexpected serious adverse event (USAE) is any serious adverse event that is 
independent of the underlying liver disease causality and is not consistent with information in 
the current Investigator’s Brochure, the protocol, and the consent document. 
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 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).   
9.3.1.1 Classifications 
Severity  
The Investigator will evaluate the severity of each adverse event using the following 
definitions: 
Mild – An event that is easily tolerated by the patient, causing minimal discomfort and not 
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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 medical monitor. 
An AE that has been 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 should be described as ‘serious’ when it meets one of the pre-defined 
outcomes as described in Section 9.3.1. 
Causality 
The 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. 
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). 
9.3.2 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 


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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 patient experiencing such an AE is appropriately treated and stabilized even 
though they may continue to experience lingering sequelae that may never resolve.   
DURECT’s designee 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. 
9.3.3 Reporting of Serious Adverse Events 
Regardless of causality, the investigator must complete and submit an SAE form to 
 within 24 hrs of 
knowledge of the event for all serious adverse events.    
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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 patient 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 patient 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. 
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. 
9.3.4 Adverse Event Follow-up 
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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 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 patient 
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 patient is lost to 
follow-up, or died and until all queries related to the AEs have been resolved.  If a patient 
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 autopsy and histopathology. 
9.4 
Pregnancy 
Serum pregnancy tests will be done at screening visit and Day 28 for females of 
child-bearing potential 
Female patients 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 
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 
Plasma concentration data of DUR-928 from each 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. 


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Pharmacokinetic parameters, such as Cmax, Tmax, T1/2, AUC0-last, AUCinf, CL, and Vd, for 
DUR-928 will be calculated and summarized by dose group and Part A or B using 
descriptive statistics. 
 
 
  
 
 
 
  
 
 
 
 
  
 
11.0 
  STATISTICAL METHODS AND DATA ANALYSIS 
11.1 
Trial Design Considerations 
An open label dose finding study, stratified by disease severity is an appropriate design to 
assess the safety and tolerability of DUR-928 in this patient population. 
11.2 
Sample Size Determination 
No formal sample size estimates were performed. The number of patients planned for this 
study is consistent with trials of this design and objectives. 
11.3 
Patient Randomization 
N/A. This is an open label study. 
11.4 
Definition of Analysis Population 
The primary analysis set for all safety analyses will be the Intent-to-Treat (ITT) set, which is 
defined as all enrolled patients who received at least one dose of study drug (DUR-928). 
The PK evaluable data set is defined as including those patients who have met criteria for 
analysis defined in the SAP. 
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Additional details about the analysis plan, including how missing data will be handled, will 
be specified in the Statistical Analysis Plan. 
11.5 
General Statistical Analysis Considerations 
The primary objective of this study is to assess dose-related safety and tolerability of 
DUR-928, with secondary objectives of assessing PK and dose-related evidence of potential 
efficacy of DUR-928. Study results for dose-related safety, efficacy, and PK profiles will 
utilize descriptive statistics.  
Due to the small number of patients expected to be enrolled at each center, all summaries and 
analyses will be performed using data pooled across centers. Unless otherwise specified, 
continuous variables will be summarized by treatment cohort (DUR-928 dose levels) using 
the ITT analysis set with the number of non-missing observations, mean, standard deviation, 
median, 25th and 75th percentile, min, and max displayed. Categorical variables will be 
summarized by DUR-928 dose level using the ITT analysis set as counts and percentages. 
Missing data will not be estimated or carried forward in any of the analyses. 
A thorough description of the statistical methods as well as presentation of study results will 
be developed and finalized prior to locking the database. Deviations from the statistical 
analysis plan (SAP) will be documented in the clinical trial report. 
Except where other software maybe deemed more appropriate, all analyses will be performed 
using SAS Version 9.4 statistical software (SAS Institute, Cary, NC). 
11.6 
Demographic and Baseline Characteristics 
Continuous variables will be summarized using descriptive statistics such as mean, median, 
standard deviation, and ranges.  Categorical variables will be summarized using frequencies 
and percentages. 95% confidence intervals will also be provided when appropriate. 
11.7 
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 Statistical Analysis Plan (SAP) and as a protocol amendment, 
if applicable.   
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. 


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12.1 
Confidentiality  
 
 
 
 
 
 
 
12.2 
Data Identification 
All 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. 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). 
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Definitions: 
A protocol deviation is “any change, divergence, or departure from the study design or 
procedures defined in the protocol.” 
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 patient's rights, safety, or well-being” 
The Investigator should not deviate from the protocol.  Except for changes intended to 
eliminate any immediate hazard to patients, the trial should be conducted as described in the 
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 trial.  
13.6 
Adjudication Committee 
The Adjudication Committee will be contacted on an as needed basis by the medical monitor 
to distinguish relatedness to the study drug from worsening of the underlying AH disease for 
any unexpected SAE and to provide advice regarding dose escalation. 
 
 
 
 
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The Adjudication Committee will also be contacted ad hoc when there is question of 
symptom causality for SUSAR’s. 
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 patients for this trial will be provided a consent form describing this trial and providing 
sufficient information for patients 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 patient, using the IRB-approved consent form, will be 
obtained before that patient is submitted to any trial procedure.  This consent form must be 
signed by the patient or legally acceptable surrogate, and the investigator-designated research 
professional obtaining the consent. Each patient will be given a copy of the signed consent 
form. 
14.1 
Institutional Review Board / Ethics Committee 
The protocol, consent form, advertisements and any other information for patients 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 an investigational product. 
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14.4 
Patient Information and Informed Consent 
Prior to participation in the trial, the Investigator or designee will obtain written consent from 
each patient, or legally acceptable representative, 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 
Patients 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 7.2.7 unless the patient withdraws consent.  If a patient withdraws 
consent they will be encouraged to complete an early termination visit and AE follow-up.  
Patients 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 patient experiencing such an AE is appropriately treated and stabilized even 
though they may continue to experience lingering sequelae that may never resolve.  Patients 
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. 
Patients who withdraw prior to assignment of test drug will be considered as screen failures. 
If a patient discontinues prior to completion of the 24 hour PK sample they will be replaced, 
since PK is one of the criteria for dose escalation assessment.   
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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 patients 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. 
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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18.0 
REFERENCES 
 
 
 
 
 
  
 
 
  
 
  
 
 
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19.0 
Appendices  
 


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