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Trial registered on ANZCTR


Registration number
ACTRN12615000903583
Ethics application status
Approved
Date submitted
6/08/2015
Date registered
28/08/2015
Date last updated
20/01/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Single and Multiple Daily Injection Study of DUR-928 in Healthy Volunteers.
Scientific title
A Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose Study to Assess the Safety, Tolerability and Pharmacokinetics of DUR 928 Administered Intramuscularly (IM) in Healthy Volunteers
Secondary ID [1] 287230 0
None
Universal Trial Number (UTN)
None
Trial acronym
None
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute Kidney Injury (AKI) 295830 0
Other Types of Acute Organ Injury 295977 0
Condition category
Condition code
Renal and Urogenital 296087 296087 0 0
Kidney disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
DUR-928 (powder for constitution): 30 mg/mL DUR-928 solution after constitution with sterile vehicle solution.
Placebo: sterile vehicle solution. The sterile vehicle solution contains hydroxypropyl betadex in phosphate buffered water.
In Part A, each subject will receive a single dose of either active DUR-928 or placebo according to the Cohort they are participating in and the intervention they are randomised to. The dose will be administered intramuscularly in the subject’s gluteal muscle (buttocks).The doses of the intervention are described below per cohort:
Cohort 1: 1.0 mL of 30 mg/mL (30 mg) DUR-928 or placebo
Cohort 2: 3.0 mL of 30 mg/mL (90 mg) DUR-928 or placebo
Cohort 3: 5.0 mL of 30 mg/mL (150 mg) DUR-928 or placebo
Cohort 4: 10.0 mL of 30 mg/mL (150 mg) DUR-928 or placebo

In Part B, each subject will receive 5 daily doses of either active DUR-928 or placebo according to the Cohort they are participating in and the intervention they are randomised to. The doses will be administered intramuscularly in the subject’s gluteal muscle (buttocks) once daily for 5 days, alternating sides for injection sites. Doses for Cohort 1 and 2 in Part B will be determined after review of safety and PK data from Part A of the study.
Cohort 1: 5.0 mL of 30 mg/mL DUR-928 or placebo
Cohort 2: x.x mL of 30 mg/mL DUR-928 or placebo

Study participants will take part in only one cohort, in either Part A or Part B. During Part A and Part B, all study participants will be confined to the study unit for the treatment period. Study staff will administer all doses.
Intervention code [1] 292516 0
Treatment: Drugs
Comparator / control treatment
Placebo: sterile vehicle solution. The sterile vehicle solution contains hydroxypropyl betadex in phosphate buffered water.

In Part A, each subject will receive a single dose of either active DUR-928 or placebo according to the Cohort they are participating in and the intervention they are randomised to. In Part B, each subject will receive 5 daily doses of either active DUR-928 or placebo according to the Cohort they are participating in and the intervention they are randomised to.
Control group
Placebo

Outcomes
Primary outcome [1] 295763 0
Primary Outcome 1:
To evaluate the safety and tolerability of single and multiple ascending dose regimen of DUR-928 administered intramuscularly (IM) in healthy volunteers.
Timepoint [1] 295763 0
Safety Timepoints, Part A:
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 8 times post-dose over a 48 hour period.
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 (study termination).
Injection sites will be evaluated and rated (mild, moderate, severe) for redness, tenderness, swelling, induration and other symptoms at injection site and measurements will be recorded for any redness noted at injections sites. Injection sites will be assessed at 1, 12 and 24 hours post-dose, and prior to discharge from unit.
Injection Site Pain Intensity Assessments: Subjects will be asked to rate the pain intensity at the injection sites using an 11-point Numeric Rating Scale (NPRS)(Turk DC, et al. 1993; Keller, et al. 2004). Injections site pain will be assessed pre-dose and 9 times post-dose over a 24 hour period.
Twelve-lead ECGs will be obtained from subjects at screening, check-in (Day -1), and 5 times post-dose over a 48 hour period. Additional ECGs may be obtained if clinically indicated.
AE collection starts from the time the subject checks in (Day -1) and continues through trial completion/early termination (Day 7).
Safety Timepoints, Part B:
Routine vital sign measurements (temperature [T], blood pressure [BP], pulse and respiratory rate [RR]) will be measured at screening, check-in (Day -1), and at Dose 1: pre-dose, 2, 4, and 12 hours post-dose, Dose 2: pre-dose, 2 and 4 hours post-dose, Dose 3: pre-dose, 2 and 4 hours post-dose, Dose 4: pre-dose, 2 and 4 hours post-dose, Dose 5: pre-dose, 2, 4, 12, 24 and 48 hours post-dose.
Physical examination will be performed at screening, check-in (Day -1), 48 hours post Dose 5, and at trial completion. The physical exam done on check-in (Day -1) and 48 hours post Dose 5 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), pre Dose 2, pre Dose 5, 24 hours and 48 hours post Dose 5, and at trial completion.
Injection sites will be evaluated and rated (mild, moderate, severe) for redness, tenderness, swelling, induration and other symptoms at injection site and measurements will be recorded for any redness noted at injections sites. injection site assessment will be done approximately 1, 12, and 24 hours after each dose for 5 days then all injection sites will be assessed prior to discharge from unit.
Injection Site Pain Intensity Assessments: Subjects will be asked to rate the pain intensity at the injection sites using an 11-point Numeric Rating Scale (NPRS)(Turk DC, et al. 1993; Keller, et al. 2004). Injections site pain will be assessed pre-dose and 9 times post each dose over a 24 hour period.
Twelve-lead ECGs will be obtained from subjects at screening, check-in (Day -1), and at 2 and 4 hours post Dose 1 and at 2, 4 and 48 hours post Dose 5. Additional ECGs may be obtained if clinically indicated.
AE collection starts from the time the subject checks in (Day -1) and continues through trial completion/early termination (Day 12).
Primary outcome [2] 295764 0
Primary Outcome 2:
To characterize the pharmacokinetics of DUR-928 in plasma following administration of single and multiple ascending IM doses in healthy volunteers.
The following PK parameters will be assessed - Cmax, Tmax, Clast, Tlast, Terminal elimination rate constant, AUC0-last, AUC0-t, AUCinf, %AUCexp, T1/2, Vz/F, CL/F.
Timepoint [2] 295764 0
Pharmacokinetic Timepoints: Part A, single dose - PK samples are collected at the following timepoints: pre-dose, and at 0.5, 1, 2, 3, 4, 6, 8, 12 , 24, 36 and 48 hours post -dose. Part B, mulitple dose - PK samples are collected at the following timepoints: Dose 1(pre-dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12 hours post-Dose 1), Dose 2 – 4 (pre-dose), Dose 5 (pre-dose, and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours post-Dose 5).
Secondary outcome [1] 316459 0
Secondary Outcome 1:
To determine any dose limiting adverse drug effects following single and multiple ascending IM dosing of DUR-928 in healthy volunteers.
There are no known systemic, dose-related adverse reactions to DUR-928 when given as an oral solution to healthy volunteers in doses up to 1000 mg.
Possible adverse reactions to the intramuscular injection of DUR-928 may include pain, tenderness, swelling or induration, or erythema - at the injection site. Pain will be assessed with a numerical rating scale (0 to 10, where 0 is no pain and 10 is the worst imaginable pain). Injection pain will be assessed at frequent intervals, from 5 minutes after injection until 48 hours after injection. Physical adverse reactions at the injection site will be assessed from 1 hour after injection to 48 hours after injection, and will be graded by severity (none, mild, moderate, or severe). Any other adverse events will be recorded on a standard case report form and will be followed until resolution.
Timepoint [1] 316459 0
Timepoint: Adverse events are collected for the duration of the study; from Day 1 (Dose 1) to the follow-up visit - Day 7 for Part A and Day 12 for Part B.

Eligibility
Key inclusion criteria
- 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 3 nights and 4 days if enrolled in Part A, or 7 nights and 8 days if enrolled in Part B;
- Able to abstain from alcohol and tobacco use during the trial.
Minimum age
19 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Significant blood loss or donated blood in the 30 days prior to study participation
- Participation in an investigational drug study within 30 days prior to dosing.
- History of drug or alcohol abuse.
- Use of any medications, including OTC and herbal or nutritional supplements during the week prior to drug dosing
- Positive tests for HIV, hepatitis B/C, drugs of abuse or alcohol breath-test.
- Clinically significant abnormalities

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Part A, single dose: 4 cohorts of 6 subjects will be dosed with a 2:1 randomisation ratio - 4 subjects receiving DUR-928 and 2 subjects receiving placebo. The dose will be provided to blinded subjects by study staff in a blinded fashion.
Part B, multiple dose: 2 cohorts of 10 subjects will be dosed with a 4:1 randomisation ratio - 8 subjects receiving DUR-928 and 2 subjects receiving placebo. The dose will be provided to blinded subjects by study staff in a blinded fashion.

A central randomization schedule will be generated by the INC Research Head of Biometrics – who will have no further involvement in the study. The central Randomization schedule will be provided only to the site pharmacy staff (unblinded) who will be exclusively responsible for preparing the doses. Subjects will be assigned a randomization number in sequential order, as their eligibility is confirmed, by blinded site staff (who have no access to the Randomization schedule).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table/schedule generated by computer software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Other
Other design features
Part A, single dose: 4 cohorts (6 subjects per cohort) will be given a single an intramuscular dose of DUR-928 or placebo. For each cohort, subjects will be randomized in 2:1 ratio - 4 subjects will receive active (DUR-928) and 2 subjects will receive placebo. Cohort 2 continues only after the safety assessment of Cohort 1. Similarly, Cohort 3 continues only after the safety assessment of Cohort 2, and Cohort 4 continues after safety review of Cohort 3. 24 subjects in total will be enrolled.
Following principle investigator and medical monitor review finding acceptable safety, tolerability and pharmacokinetic data of the first 3 cohorts in Part A of the study, Part B of the study will be initiated.
Part B, multiple dose: doses for Cohort 1 and 2 will be determined after review of safety and PK data from Part A of the study. Two cohorts (10 subjects per cohort) will be treated daily for 5 days with an intramuscular dose of DUR-928 or placebo. For each cohort, subjects will be randomized in 4:1 ratio - 8 subjects will receive active (DUR-928) and 2 subjects will receive placebo. The second cohort of 10 subjects continues only after the safety assessment of the first cohort. 20 subjects in total will be enrolled.
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. Safety will be summarised by dose level for Part A (single dose), and by dose level and dosing day for Part B (multiple dose).
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.
Due to the exploratory nature of this study, no power or sample size calculations have been performed.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
25/08/2015
Actual
25/08/2015
Date of last participant enrolment
Anticipated
10/12/2015
Actual
7/12/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
44
Accrual to date
Final
34
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 10072 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 291799 0
Commercial sector/Industry
Name [1] 291799 0
DURECT Corporation
Country [1] 291799 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] 290457 0
None
Name [1] 290457 0
Address [1] 290457 0
Country [1] 290457 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293315 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 293315 0
Ethics committee country [1] 293315 0
Australia
Date submitted for ethics approval [1] 293315 0
01/07/2015
Approval date [1] 293315 0
06/08/2015
Ethics approval number [1] 293315 0
EC00117

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes
Attachments [1] 657 657 0 0
/AnzctrAttachments/369076-APP 325-15 Certificate of Approval_Amend2 Nov15.pdf

Contacts
Principal investigator
Name 59362 0
Dr Jason Lickliter
Address 59362 0
Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct
89 Commercial Road
Melbourne, Victoria, Australia, 3004
Country 59362 0
Australia
Phone 59362 0
+ 61 3 9076 8960
Fax 59362 0
+ 61 3 9076 8911
Email 59362 0
[email protected]
Contact person for public queries
Name 59363 0
Jemma Lawson
Address 59363 0
INC Research
159 Port Road,
Hindmarsh, SA 5007, Australia
Country 59363 0
Australia
Phone 59363 0
+61 8 7202 1510
Fax 59363 0
+61 8 7202 1599
Email 59363 0
[email protected]
Contact person for scientific queries
Name 59364 0
Jemma Lawson
Address 59364 0
INC Research
159 Port Road,
Hindmarsh, SA 5007, Australia
Country 59364 0
Australia
Phone 59364 0
+61 8 7202 1510
Fax 59364 0
+61 8 7202 1599
Email 59364 0
[email protected]

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