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Trial registered on ANZCTR


Registration number
ACTRN12615001355561
Ethics application status
Approved
Date submitted
2/12/2015
Date registered
14/12/2015
Date last updated
16/12/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
A Single Oral Dose Study of DUR-928 in Nonalcoholic Steatohepatitis (NASH) Patients and Healthy Volunteers
Scientific title
Dose Ranging, Single Dose Safety and Pharmacokinetic Study of DUR-928 in Subjects with Nonalcoholic Steatohepatitis (NASH) and Control Healthy Subjects
Secondary ID [1] 288042 0
Nil Known.
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Nonalcoholic Steatohepatitis (NASH) 296908 0
Condition category
Condition code
Metabolic and Endocrine 297142 297142 0 0
Other metabolic disorders
Oral and Gastrointestinal 297143 297143 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
DUR-928 powder for constitution.
Each dose of DUR-928 is given in 60 mL of ORA-Blend (registered trademark) SF taste masking suspending vehicle. The dose will be taken orally.
Each subject will receive a single dose of DUR-928 according to the Cohort they are participating in.
The study will look at the effect of DUR-928 when given as a single dose at 2 different dose levels. All doses will be administered and supervised by study staff. The doses of the intervention are described below per cohort:
Cohort 1: 50 mg DUR-928
Cohort 2: 200 mg DUR-928
Participants will be confined to the study unit for a total of 2 nights and 3 days, inclusive of 24 hours post dose monitoring. Study participants may take part in more than one cohort, as long as a 4 week washout period is observed. All study participants will be confined to the study unit for the treatment period. Study staff will administer all doses.

Intervention code [1] 293366 0
Treatment: Drugs
Comparator / control treatment
Healthy volunteers are allocated to the same dose cohorts as the NASH patients, and serve as the control group at each dose level.
Control group
Active

Outcomes
Primary outcome [1] 296771 0
To evaluate the safety of DUR-928 in subjects with NASH following single ascending dose at three dose level compared to healthy subjects control.
Timepoint [1] 296771 0
Routine vital sign measurements (temperature [T], blood pressure [BP], pulse and respiratory rate [RR]) will be measured at screening, check-in (Day -1), pre-dose, and 1, 2, 4, 6, 12, 24 and 48 hours post-dose and at trial completion. Physical examination will be performed at screening, check-in (Day -1), and at trial completion. The physical exam done on Day -1 will be abbreviated (including general appearance and evaluation of head, eyes, ears, nose, throat and neurological system). Safety Laboratory tests (Chemistry, Hematology, and Urinalysis) will be drawn at screening, check-in (Day -1), 24 and 48 hours post-dose, and on Day 7 (trial completion). Twelve-lead ECGs will be obtained from subjects at screening, check-in (Day -1), and at approximately 2, 4, 12 and 48 hours post-dose. Additional ECGs may be obtained if clinically indicated. Timepoint: AE collection starts from the time the subject checks in (Day -1) and continues through trial completion/early termination (Day 7).
Primary outcome [2] 296839 0
To evaluate the pharmacokinetics of DUR-928 in subjects with NASH following single ascending dose at three dose level compared to healthy subjects control. The pharmacokinetics of DUR-928 are evalutated using blood and urine samples.
Timepoint [2] 296839 0
Pharmacokinetic samples are collected at the following timepoints: pre-dose, and at 0.5, 1, 2, 4, 8, 12, 16, 24 and 48 hours post-dose.
Secondary outcome [1] 319298 0
To evaluate the effects of DUR-928 selected biomarkers following a single dose.
Timepoint [1] 319298 0
The following biomarkers will be assessed using blood samples:
*High-sensitivity C-reactive protein (hs-CRP)
*HOMA- IR (insulin sensitivity)
*CK-18 fragments (cCK18, fCK18)
*Subset of cytokines (IL-1beta, IL6, IL12, IL-18 and TNFa)
*Lipid Panel (TG, HDL, LDL), Hepatic Enzyme Levels (AST, ALT), Total Bilirubin
Biomarker blood samples are collected at the following timepoints: Day -1, pre-dose , and at 1, 2, 4, 8, 12, 24 and 48 hours post-dose.

Eligibility
Key inclusion criteria
All participants:
* Be in good health as determined by medical history, physical examination, 12 lead ECG and clinical laboratory evaluations at screening;
* Male subjects must agree to use a medically acceptable method of contraception/birth control throughout the study duration and for 90 days after the study is completed;
* Female subjects must be of non-childbearing potential;
* Willing and be able to be admitted to the clinical study unit for 2 nights and 3 days;
* Able to abstain from alcohol and tobacco use during the trial.

NASH Subjects (in addition to “All Participants”)
* A diagnosis of NASH on the basis of liver biopsy performed within the last 6 months or radiological evidence of steatosis and a clinical diagnosis of NASH based on fulfilling the remaining inclusion/exclusion criteria.
* For subjects with cirrhosis there must be a prior histological evidence of cirrhosis or clinical and/or radiological evidence of cirrhosis in conjunction with a FibroScan greater than or equal to 12.5 kPa and Child Pugh A 5-6.
* For non cirrhosis subjects there must be prior histological evidence for the absence of cirrhosis within the past 12 months or the absence of clinical and/or radiological evidence for cirrhosis in conjunction with a FibroScan less than 9.5 kPa.
For cirrhotic/non-cirrhotic indeterminate subjects will include subjects who have:
(a) Fibroscan greater than or equal to 12.5 but no radiological evidence of cirrhosis
(b) Fibroscan less than 12.5 but greater than or equal 9.5
(c) Clinical / radiological features of cirrhosis but Fibroscan less than 9.5


Healthy Volunteers (in addition to “All Participants”)
* Subjects must have normal hepatic function.
* Demographically comparable to NASH subjects as follows:
^ Mean BMI (kg/m2) within +/- 25%
^ Mean age within +/- 10 years
^ Similar gender ratio
Minimum age
18 Years
Maximum age
70 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
All participants:
* Disease or surgery of the gastrointestinal tract that may interfere with drug absorption or may otherwise influence the pharmacokinetics of the investigational medicinal product
* Participation in an investigational drug study within 30 days prior to dosing.
* History of drug or alcohol abuse.
* Disease or surgery of the gastrointestinal tract that may interfere with drug absorption or may otherwise influence the pharmacokinetics of the investigational medicinal product (e.g., inflammatory bowel disease, restrictions of the small or large intestine, etc.)
* History of febrile illness within 5 days prior to dosing.
* Positive tests for HIV, hepatitis B, drugs of abuse or alcohol breath-test.
* Clinically significant abnormalities
* Women of child-bearing potential, pregnant or nursing (lactating) women

NASH Subjects (in addition to “All Participants”)
* Subject has evidence of other forms of chronic liver disease
* Hepatic Cirrhosis with a Child-Pugh classification of B or C (score > 6)
* Alcohol use greater than or equal to 30 g/day
* Type I diabetes
* History of bariatric surgery
* Concurrent Anti-NASH therapy(s) with washout less than or equal to 30 days
* Viral hepatitis (i.e., serologies for Hepatitis B and C should be negative) However, subjects who are Hepatitis C Virus (HCV)-antibody positive but hepatitis C virus-ribonucleic acid (HCV-RNA) negative who have been successfully treated with antiviral agents and have a sustained virological response (SVR) following HCV therapy or documentation of HCV-RNA negative for a minimum of 6 months prior to inclusion and who meet all other eligibility criteria may be considered for enrollment.
Healthy Volunteers (in addition to “All Participants”)
* Evidence of clinically significant uncontrolled hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, renal, psychiatric, neurologic, or allergic disease (including drug allergies, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing)
* Presence of impaired renal function as indicated by abnormal creatinine (creatinine clearance < 80 ml/min) values and/or serum creatinine greater than or equal to 1.8 mg/dL
* History of regular alcohol consumption exceeding 28 drinks/week within 6 months of screening
* Positive tests for hepatitis C.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The proposed multiple cohort study will be conducted in 2 successive cohorts evaluating 2 single-dose levels of oral DUR-928.
For each cohort 10 subjects with Nonalcoholic Steatohepatitis (NASH) will be enrolled. Of those 10 NASH subjects to be enrolled there will be an approximately equal distribution of cirrhotic and non-cirrhotic subjects.
Following enrollment of the NASH subjects in a cohort, six additional healthy subjects with normal liver function will be enrolled and receive a single dose of DUR-928. The healthy subjects will be matched to the NASH group for a given cohort by average age (+/- 10 years), average BMI (+/- 25%) and gender ratio.
Allocation is not concealed
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
NA
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
2 cohorts (10 NASH Subjects and 6 Healthy Volunteers per cohort) will be given a single oral dose of DUR-928. Cohort 2 continues only after the safety assessment of Cohort 1. 32 subjects in total will be enrolled (20 NASH Subjects and 12 Healthy Volunteers).
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Safety – Safety will be evaluated by assessment of clinical laboratory tests, physical examinations including vital signs, and ECGs, and by the documentation of all spontaneously reported adverse events. Treatment-emergent AEs will be listed and summarized by dose level and cirrhotic status. Treatment-emergent changes from baseline in clinical laboratory tests, ECG, and vital signs will be derived by dose level.
Pharmacokinetics – Plasma concentration data of DUR-928 and its metabolite at each dose level will be used to calculate relevant pharmacokinetic parameters. Pharmacokinetic parameters will summarized by dose level, using descriptive statistics. At each dose level, the pharmacokinetics of DUR-928 will be compared between the NASH subjects and the healthy subjects control to support the safety review for escalation to the next dose level.
Biomarkers - The biomarker data at baseline and at each post-dose time point will be plotted and listed for each subject for evaluation of any change from baseline or over time. Baseline for each biomarker will be derived from the average.
This is an exploratory study. No power or sample size calculations have been performed.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 12340 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 292491 0
Commercial sector/Industry
Name [1] 292491 0
DURECT Corporation
Address [1] 292491 0
10260 Bubb Road
Cupertino, CA 95014, USA
Country [1] 292491 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
INC Research
Address
159 Port Rd,
Hindmarsh,
South Australia, 5007
Country
Australia
Secondary sponsor category [1] 291203 0
None
Name [1] 291203 0
NA
Address [1] 291203 0
NA
Country [1] 291203 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293959 0
Alfred Health
Ethics committee address [1] 293959 0
55 Commercial Rd
Melbourne VIC, 3004
Ethics committee country [1] 293959 0
Australia
Date submitted for ethics approval [1] 293959 0
04/11/2015
Approval date [1] 293959 0
09/12/2015
Ethics approval number [1] 293959 0
547/15

Summary
Brief summary
This research project is being conducted to look at how safe and well tolerated a new drug called DUR-928 is when given as an oral dose to subjects with Nonalcoholic Steatohepatitis (NASH), when compared to healthy volunteers. The study will look at the study drug’s effect when given as a single dose at 2 different dose levels. The pharmacokinetics of DUR-928 will also be studied; this is done by measuring the amount of DUR-928 in the blood at different times throughout the dosing periods, allowing us to evaluate how DUR-928 is handled by the body (for example how quickly it gets into the blood stream). The pharmacodynamics will also be studied; this is done by measuring the amount of selected biomarkers in the blood at different times throughout the dosing periods, allowing us to evaluate the effect of DUR-928 on the body.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 61890 0
Dr William Kemp
Address 61890 0
Alfred Health
Gastroenterology Dept
55 Commercial Road
Melbourne, Victoria, Australia 3004
Country 61890 0
Australia
Phone 61890 0
+ 61 3 9076 3375
Fax 61890 0
+ 61 3 9076 2194
Email 61890 0
W.Kemp@alfred.org.au
Contact person for public queries
Name 61891 0
Ms Biljana Georgievska
Address 61891 0
Nucleus Network Limited
Level 5, Burnet Tower, AMREP Precinct,
89 Commercial Road, Melbourne
Victoria 3004
Country 61891 0
Australia
Phone 61891 0
+61 3 9076 9017
Fax 61891 0
+61 3 9076 8911
Email 61891 0
b.georgievska@nucleusnetwork.com.au
Contact person for scientific queries
Name 61892 0
Ms Jemma Lawson
Address 61892 0
INC Research
159 Port Road,
Hindmarsh, SA 5007
Country 61892 0
Australia
Phone 61892 0
+61 8 7202 1510
Fax 61892 0
+61 8 7202 1599
Email 61892 0
jemma.lawson@incresearch.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary