The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12616000389404
Ethics application status
Approved
Date submitted
16/03/2016
Date registered
24/03/2016
Date last updated
15/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A single injection dose study of DUR-928 in patients with impaired kidney function and healthy volunteers
Scientific title
A Study to Evaluate the Pharmacokinetics (PK) and Safety of DUR-928 in Subjects with Impaired Kidney Function and Matched Control Subjects with Normal Kidney Function
Secondary ID [1] 288731 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Impaired Kidney Function – stage 3 and 4 297974 0
Condition category
Condition code
Renal and Urogenital 298131 298131 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
DUR-928 powder for constitution of intramuscular injection.
Each dose of DUR-928 is given as a single intramuscular injection into the gluteal muscle (buttock).
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 3 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: 30mg DUR-928 (as an injection of 1mL)
Cohort 2: 120mg DUR-928 (as an injection of 4mL)
The solution used for constitution consists of 250 mg/mL hydroxypropyl betadex, NF (hydroxypropyl beta cyclodextrin), 0.276 mg/mL of sodium phosphate monobasic monohydrate, USP, and 1.136 mg/mL sodium phosphate dibasic anhydrous, USP, in sterile water for injection, USP. The final concentration of DUR-928 is 30 mg/mL.
All doses will be administered and supervised by study staff. For each cohort, participants will be confined to the study unit for a total of 3 nights and 3 days, and have to attend the unit for additional 3 out-patient visits (including the screening visit). Study participants may take part in more than one cohort, as long as a washout period of at least 4 weeks is observed.
Intervention code [1] 294170 0
Treatment: Drugs
Comparator / control treatment
Two ascending active doses will be tested as a single dose; comparison will be done between the two dose levels as well as between patients with kidney disease and healthy controls receiving the same intervention.
Healthy volunteers are allocated to the same dose cohorts as the kidney failure patients, and serve as the control group at each dose level.
Control group
Active

Outcomes
Primary outcome [1] 297638 0
To evaluate the safety of DUR-928 in subjects with impaired kidney function and matched control subjects with normal kidney function
Timepoint [1] 297638 0
Routine vital sign measurements (temperature, blood pressure, pulse and respiratory rate will be measured at screening, at check-in (day -1), pre-dose and 1, 2, 4, 6, 12, 24, 36 and 48 hours post-dose and at trial completion (between day 7 and day 10 post-dose).
Physical examination will be preformed at screening, check-in (day -1) and at trial completion. The physical examination on day -1 will be abbreviated (including general appearance and evaluation of head, eyes, nose, throat and neurological system).
Safety laboratory tests (Chemistry, Hematology and Urinalysis) will be done at screening, check-in (day -1), at approximately 24 and 48 hours post-dose and at trial completion.
Twelve-lead ECGs will be obtained from subjects at screening, check-in (day -1), pre-dose and at approximately 2, 4, 6, 12 and 48 hours post-dose.
Adverse Event collection will start from the time the subject checks-in (day -1) and continues through the trial completion (between day 7 and day 10)/early termination.
Primary outcome [2] 297639 0
To evaluate single ascending dose pharmacokinetics of DUR-928 in subjects with impaired kidney function and matched control subjects with normal kidney function.
The following parameters will be assessed: Pharmacokinetic parameters in blood of DUR-928 and its metabolite 25-hydroxycholesterol: Cmax, Tmax, Clast, Tlast, l, t1/2, AUC0-last, AUCinf, %AUCexp, Vz/F
Timepoint [2] 297639 0
Pharmacokinetic samples (blood) are collected at the following time-points: pre-dose, and at 0.5, 1, 2, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
Secondary outcome [1] 321662 0
To evaluate the effects of single ascending doses of DUR-928 on selected biomarkers in subjects with impaired kidney function and matched control subjects with normal kidney function.
Timepoint [1] 321662 0
The following biomarkers will be assessed using blood and urine samples: serum NT pro-BNP; BUN; urine Cys-C; eGFR (derived from CKD-EPI combined sCr-Cys-C equation 2012); urine GST-alpha and GST-pi; serum IL-1beta, IL-6, IL-12, IL-18 and TNF-alpha; serum KIM-1; serum NGAL; and sCr.
Biomarkers will be collected pre-dose, and at 4, 12, 24, 48 and 72 hours post-dose.

Eligibility
Key inclusion criteria
All participants:
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 3 nights and 3 days
Able to abstain from alcohol and tobacco use during the study
Patient with impaired kidney function:
Impaired kidney function at screening, defined as Stage 3 kidney disease (eGFR between 30 and 59 ml/min/1.73m2) and stage 4 kidney disease (eGFR between 15 and 29 ml/min/1.73m2)
Existing diagnosis of chronic kidney disease
Matching healthy control subjects:
Healthy as determined by medical history, physical examination, laboratory tests, ECG and vital signs in consideration of the individual’s age
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
All participants:
Females of child-bearing potential; pregnant or breastfeeding
Significant blood loss, donated blood or received medication in another clinical trial 30 days prior to study participation
Be immunocompromised (including history/seropositive of HIV)
Be receiving any pharmacological treatment which might alter the absorption or metabolism of drugs
Have a history of febrile illness 5 days prior to dosing
Positive drug of abuse or alcohol breath test
History of malignancy within 5 years before screening (except squamous and basal cell carcinomas of the skin and carcinomas of the cervix in situ, or a malignancy that in the opinion of the study physician and the medical monitor as cured with minimal risk of recurrence
History of maintenance dialysis or kidney transplant
History or presence of clinically concerning arrhythmias or prolongation of screening QT or QTc intervals
Patient with impaired kidney disease:
History of clinically significant comorbidity that increases the risk of adverse events
Have any surgical or medical condition (other than impaired kidney disease) which might significantly alter the absorption or metabolism of drugs or which may jeopardies the subject during participation
Presence of impaired liver function
Clinical evidence of active liver disease, liver cirrhosis or severe ascites requiring intervention
Symptoms or history of hepatic encephalopathy within 4 weeks of study entry
Evidence of progressive kidney disease or unstable kidney function in the view of the investigator
Matching healthy control subjects:
Evidence of clinically significant uncontrolled hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, psychiatric, neurologic, or allergic disease (excluding well treated, asymptomatic seasonal allergies)
Have any surgical or medical condition which might significantly alter the absorption or metabolism of drugs or which may jeopardies the subject during participation
Presence of impaired liver function
Clinical evidence of kidney disease or kidney injury

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)
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 (6 kidney disease patients and 3 healthy control subjects per cohort) will be given a single intramuscular dose of DUR-928. Cohort 2 only continues after the safety and PK assessment of cohort 1. 18 subjects in total will be enrolled (12 kidney disease patients and 6 healthy controls).
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis
Safety:
For laboratory test, vital signs and ECGS, baseline data will be assessed at Day-1. Summary statistics will be prepared for measured values and changes from baseline values by dose cohort. Summaries of treatment-emergent clinically significant abnormalities in ECGs, vital signs, and clinical laboratory values will be provided. Individual data for 12-lead ECGs, vital signs measurements, and physical examination findings will be listed by subject.
Pharmacokinetics:
Plasma concentrations of DUR-928 and 25-HC from each subject will be used to calculate relevant pharmacokinetic parameters using standard non-compartmental methods with linear/log-trapezoidal rule. Calculations will be performed using an appropriate pharmacokinetic data analysis program. Pharmacokinetic parameters for DUR-928 will be summarized by subject using descriptive statistics.
Biomarkers:
The biomarker data at baseline (pre-dose) and at each post-dose time point will be plotted and listed for each subject for evaluation of any change from baseline over time. The summary of absolute change in each biomarker will be presented by dose level and kidney function status.
Due to the exploratory nature of this study, no inferential analysis will be performed. Therefore, power or sample size calculations have not 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 hospital [1] 5417 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 12907 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 293085 0
Commercial sector/Industry
Name [1] 293085 0
DURECT Corporation
Address [1] 293085 0
10260 Bubb Road
Cupertino, CA 95014 USA
Country [1] 293085 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
George Clinical Pty Ltd
Address
50 Bridge Street
Sydney NSW 2000
Country
Australia
Secondary sponsor category [1] 291870 0
None
Name [1] 291870 0
None
Address [1] 291870 0
None
Country [1] 291870 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294593 0
Alfred Health
Ethics committee address [1] 294593 0
55 Commercial Rd
Melbourne VIC 3004
Ethics committee country [1] 294593 0
Australia
Date submitted for ethics approval [1] 294593 0
03/02/2016
Approval date [1] 294593 0
04/03/2016
Ethics approval number [1] 294593 0
65/16

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 intramuscular injection to subjects with chronic kidney disease when compared with healthy control subjects. The study will look at the study drugs effect when given as a single-dose injection 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 and/or urine at different times throughout the dosing periods, allowing us to evaluate the effect of DUR-928 on the body.
Trial website
NA
Trial related presentations / publications
NA
Public notes
NA

Contacts
Principal investigator
Name 64290 0
Dr Jason Lickliter
Address 64290 0
Nucleus Network Limited
Level 5, Burnet Tower, AMREP Precinct
89 Commercial Road
Melbourne VIC 3004
Country 64290 0
Australia
Phone 64290 0
+61 3 9076 8960
Fax 64290 0
+61 3 9076 8911
Email 64290 0
j.lickliter@nucleusnetwork.com.au
Contact person for public queries
Name 64291 0
Ms Biljana Georgievska
Address 64291 0
Nucleus network Limited
Level 5, Burnet Tower, AMREP Precinct
89 Commercial Road
Melbourne VIC 3004
Country 64291 0
Australia
Phone 64291 0
+61 3 9076 9017
Fax 64291 0
+61 3 9076 8911
Email 64291 0
b.georgievska@nucleusnetwork.com.au
Contact person for scientific queries
Name 64292 0
Dr Manthinda Hettiarachchi
Address 64292 0
George Clinical Pty Ltd
Level 3, 50 Bridge Street
Sydney NSW 2000
Country 64292 0
Australia
Phone 64292 0
+61 2 8052 4405
Fax 64292 0
+61 2 8238 2400
Email 64292 0
mhettiarachchi@georgeclinical.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