Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12617000579392
Ethics application status
Approved
Date submitted
13/04/2017
Date registered
24/04/2017
Date last updated
14/07/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A drug interaction study of DUR-928 and Midozolam
Scientific title
Drug Interaction Study to Evaluate the Effect of DUR-928 on the Pharmacokinetics of a Single Oral Dose of Midazolam in healthy participants.
Secondary ID [1] 291697 0
Nil Known.
Universal Trial Number (UTN)
Nil
Trial acronym
C928-018
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Liver Disease 302867 0
Condition category
Condition code
Metabolic and Endocrine 302345 302345 0 0
Metabolic disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The proposed study is an open label, single sequence, dosing study in 18 healthy male and female subjects, to obtain 15 evaluable subjects.
Subjects will be screened to determine eligibility within 14 days prior to dosing. Subjects will be admitted to the clinical unit on Day -1 for baseline assessments. On Day 1, subjects will receive an oral solution of midazolam 3mg. On Days 3, 4 and 5, subjects will receive an oral suspension of DUR-928 50 mg daily. On Day 6, subjects will receive an oral solution of midazolam 3mg as well as an oral suspension of DUR-928 50mg. On Day 8 subjects will receive DUR-928 (150 mg) as intravenous infusion over 2 hours immediately followed by an oral solution of midazolam 3 mg.
All study treatments will be administered after an overnight fast of at least 10 hours. Subjects will continue to fast for 4 hours after the study drug administration. During fasting no fluids will be allowed except water; however water will not be allowed from 1 hour before dosing to 1 hour after dosing (except for 240 mL of water required to swallow DUR-928 or midazolam). Subjects will be confined in the study unit from Day -1 through Day 9 procedures and return to the clinic on Day 14 for trial completion procedures.
DUR-928 oral dose: 50 mg of DUR-928 drug substance powder in a 60 cc wide mouth, amber glass bottle with a child-resistant screw cap. At the time of administration, 60 mL of a commercially available flavored, sugar-free, vehicle (ORA-Blend SF) is added to the bottle of DUR-928 powder to suspend the drug substance, and the entire bottle content is orally dosed, followed by two rinses with water.
Study staff will administer all doses.
Intervention code [1] 297782 0
Treatment: Drugs
Comparator / control treatment
Midazolam (drug interaction). This is a drug interaction study between study drug and CYP3A4 substrate.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 301767 0
To evaluate the effect of DUR-928 when administered as an oral dose or as IV infusion on the pharmacokinetics of midazolam.
Timepoint [1] 301767 0
The following PK parameters will be assessed - Cmax, Tmax, Terminal elimination rate constant, AUC0-last, AUCinf, %AUCexp, T1/2, Vz, CL.
Blood samples will be collected for analysis of plasma concentrations of midazolam, 1-OH midazolam up to 26 hours after study drug administration. The samples will be collected as follows: Day 1: pre-dose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post dose. Day 6: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose. Day 8 : pre-dose 0.5, 1, 1.5, 2, 2.25, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 14 and 26 hours post-dose.
Secondary outcome [1] 333800 0
To evaluate the effect of oral midazolam on the pharmacokinetics of an oral dose of DUR-928 in plasma.
Timepoint [1] 333800 0
The following PK parameters will be assessed - Cmax, Tmax, Terminal elimination rate constant, AUC0-last, AUCinf, %AUCexp, T1/2, Vz, CL.
Blood samples will be collected for analysis of plasma concentrations of DUR-928 and 25 hydroxycholesterol (25-HC) up to 26 hours after study drug administration. Day 3, Day 5 and Day 6: pre-dose, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 and 24 hours post-dose.
Secondary outcome [2] 333801 0
To evaluate the safety of DUR-928 and midazolam in healthy subjects.
Timepoint [2] 333801 0
Common adverse reactions observed with oral doses of midazolam include: slowed or impaired breathing, decreased blood pressure, fast or slow heart rate, drowsiness, lightheadedness, nausea and vomiting, and impaired motor skills. Subjects will be monitored closely by frequent assessments of vital signs and adverse events.
Routine vital sign measurements (blood pressure [BP], heart rate [HR] and respiratory rate [RR]) will be measured at screening, Day -1, pre-dose, and 0.25 (RR only), 0.5, 0.75 (RR only),1, 1.25 (RR only), 2, 3, 4, 6, 12, and 24 hours post-dose of each study treatment, and at trial completion (Day 14).
Continuous pulse oximetry will be obtained with an alarmed monitor maintained for 4 hours from start of Midazolam dosing on Days 1, 6 and 8. Readings will be recorded at pre-dose (immediately prior to administration of midazolam), 15 and 30 min, 1, 2 and 4 hours after dosing.
Physical examination will be performed at screening, Day -1, and at trial completion (Day 14). The physical exam done on Day -1 will be abbreviated.
Safety Laboratory tests (Chemistry, Hematology, Gamma-glutamyl transpeptidase (GGT), and Urinalysis) will be drawn at screening, Day 1, pre-dose and 24 hours post-dose of each study treatment, and at trial completion (Day 14).
All adverse events will be collected from Day -1 and continues through to trial completion (Day 14).
Twelve-lead ECGs will be obtained from subjects at screening, Day -1, pre-dose, and at approximately 1 and 24 hours post-dose on Days 1,3,4,5,6, and pre-dose and 2, 3 and 26 hours post-dose at Day 8. Additional ECGs may be obtained if clinically indicated.

Eligibility
Key inclusion criteria
Be in good health as determined by medical history, physical examination, 12 lead ECG and clinical laboratory evaluations at screening.
Weight at least 50kg and BMI between 18.0 kg/m2 and 30.0 kg/m2, inclusive.
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 9 nights and 9 days.
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 within 2 weeks prior to study drug dosing, and for the study duration.
Use of grapefruit or grapefruit juice, apple or orange juice, vegetables from mustard green family (e.g. kale, watercress, collard greens, brussels sprouts, mustard) and charbroiled (grilled) meats within 1 week prior to study drug dosing, and for the study duration.
Positive tests for HIV, hepatitis B/C, drugs of abuse or alcohol breath-test.
Clinically significant abnormalities.
Tobacco users who have used tobacco within the last 30 days prior to screening

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)
This is an open label, single sequence, dosing study in 18 healthy male and female subjects. Subjects will complete a Screening Phase, Treatment, and an End of Study Visit. The Screening phase will be conducted on an outpatient basis within 14 days prior to the start of dosing. Subjects will be confined in-house for 9 nights during study Treatment from Day -1 through 26 hours post-dose of Day 8. They will be discharged from the clinic and will return, for the End of Study Visit, at Day 14.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Fixed sequence drug interaction Study
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Comparison of AUC and Cmax of between treatments will be done using an analysis of variance (ANOVA) on the ratios of the least squares means (LSM) using linear mixed effects modeling to yield point estimates (geometric means) with 90% confidence intervals (CI).
18 subjects will be enrolled to achieve 15 evaluable subjects. A sample size of 15 subjects will provide greater than 80% power for the 90% confidence interval of the geometric mean ratio to fall within the specified no-effect boundary of 0.8 and 1.25.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
17/05/2017
Actual
2/06/2017
Date of last participant enrolment
Anticipated
8/06/2017
Actual
9/06/2017
Date of last data collection
Anticipated
22/06/2017
Actual
22/06/2017
Sample size
Target
18
Accrual to date
Final
17
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment postcode(s) [1] 15782 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 296195 0
Commercial sector/Industry
Name [1] 296195 0
DURECT Corporation
Country [1] 296195 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] 295106 0
None
Name [1] 295106 0
Address [1] 295106 0
Country [1] 295106 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297436 0
Alfred Health
Ethics committee address [1] 297436 0
Ethics committee country [1] 297436 0
Australia
Date submitted for ethics approval [1] 297436 0
29/03/2017
Approval date [1] 297436 0
10/05/2017
Ethics approval number [1] 297436 0
Project No: 137/17

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 74034 0
Dr Jason Lickliter
Address 74034 0
Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct
89 Commercial Road
Melbourne, Victoria, Australia, 3004
Country 74034 0
Australia
Phone 74034 0
+ 61 3 9076 8960
Fax 74034 0
+ 61 3 9076 8911
Email 74034 0
[email protected]
Contact person for public queries
Name 74035 0
Elaine Wong
Address 74035 0
Nucleus Network
5th Floor, Burnet Tower, AMREP Precinct
89 Commercial Road
Melbourne, Victoria, Australia, 3004
Country 74035 0
Australia
Phone 74035 0
+ 61 402 329 162
Fax 74035 0
+ 61 3 9076 8911
Email 74035 0
[email protected]
Contact person for scientific queries
Name 74036 0
Jemma Lawson
Address 74036 0
INC Research
159 Port Road,
Hindmarsh, SA 5007, Australia
Country 74036 0
Australia
Phone 74036 0
+61 8 7202 1500
Fax 74036 0
+61 8 7202 1599
Email 74036 0
[email protected]

No information has been provided regarding IPD availability


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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