Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614001303639
Ethics application status
Approved
Date submitted
3/12/2014
Date registered
15/12/2014
Date last updated
17/02/2015
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase I, Single-center, Open-label Fixed-sequence Study to Assess the Effects of PRN1008 on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Healthy Adults
Scientific title
A Phase I, Single-center, Open-label Fixed-sequence Study to Assess the Effects of PRN1008 on the Pharmacokinetics of Midazolam, a CYP3A4 Substrate, in Healthy Adults
Secondary ID [1] 285698 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Healthy Volunteers 293555 0
Rheumatoid Arthritis 293719 0
Condition category
Condition code
Inflammatory and Immune System 293840 293840 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a single centre, open-label, fixed-sequence study to investigate the effects of PRN1008 on the PK of midazolam, a CYP3A4 substrate, in healthy participants.

Participants will be screened for participation in this study within 28 days before dosing. Participants will be admitted to the study unit the day before dosing (Day -1) and will remain in the clinic up to Day 5, after collection of the final PK sample.
Participants enrolled will complete a two-period, fixed sequence study:

Period 1: Study Days 1 to 3.
Following a single oral 2 mg dose of midazolam on Day 1, blood samples will be obtained over a period of 24 hours to characterize the PK profile of midazolam and alpha-hydroxymidazolam.

Period 2: Study Days 4 to 5
On Day 4, participants will receive an oral 600 mg dose of PRN1008 one hour prior to receiving an oral 2 mg dose of midazolam. Blood samples for determination of PRN1008, midazolam and alpha-hydroxymidazolam PK will be obtained over a period of 25 hours.

For both periods, subjects will be monitored on dosing days under supervision of the researcher to ensure administration of the products has been completed in accordance to protocol.

Following discharge from the study unit, participants will return for a final follow-up assessment between day 11 to 14.
Intervention code [1] 290706 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] 293701 0
Maximum observed plasma concentration (Cmax) of midazolam and alpha- hydroxymidazolam.
Timepoint [1] 293701 0
Day 1 and Day 4 : Pre-dose (prior to midazolam dosing) and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours after midazolam dosing.
Primary outcome [2] 293798 0
Area under the plasma concentration-time curve (AUC) of midazolam and alpha- hydroxymidazolam.
Timepoint [2] 293798 0
Day 1 and Day 4 : Pre-dose (prior to midazolam dosing) and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours after midazolam dosing.
Secondary outcome [1] 311624 0
Time of maximum observed plasma concentration (Tmax), plasma half-life (t1/2), metabolite to parent (M/P) AUC ratio of midazolam and alpha-hydroxymidazolam
Timepoint [1] 311624 0
Day 4: Pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours after PRN1008 dosing.
Secondary outcome [2] 311625 0
Cmax, AUC, Tmax, t1/2, renal clearance (CLr) and amount excreted unchanged in the urine (Ae) of PRN1008.
Timepoint [2] 311625 0
Urine will be collected to determine the PK of PRN1008 at the following timepoints on Day 4 and Day 5:
Pre-dose (prior to PRN1008 dosing) within 60 minutes prior to dosing and at 0-4, 4-8, 8-12 and 12-24 hours after dosing.
Secondary outcome [3] 311626 0
Safety and tolerability, including the assessment of physical examinations, ECGs, vital signs, clinical laboratory results and adverse events.
Timepoint [3] 311626 0
Vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate) will be taken at screening, Day -1, Day 1 (pre-dose and 0.5, 1, 2 hours post dose), Day 4 (pre-dose and 1.5, 2, and 3 hours post-PRN1008 dose), Day 5 and at follow-up.
Body temperature will be measured at screening and on Day -1.
ECGs will be recorded at screening, Day -1,Day 4 (pre-dose and 3 hours post-PRN1008 dose), Day 5 and at follow-up.

Blood and urine samples for hematology (Coagulation panel at screening only), biochemistry and urinalysis will be collected at screening, and in the morning on Day -1, Day 3, Day 5 and at the follow-up visit.

Eligibility
Key inclusion criteria
1. Healthy adult male and/or females, 18 to 55 years of age (inclusive) at the time of screening.
2. Body mass index (BMI) equal to or greater than 18 and equal to or less than 30 kg/m2 (inclusive) and a minimum body weight of 45 kg.
3. Able to participate and comply with all study procedures and restrictions, and willing to provide written informed consent to participate in the study.
4. If male, agrees to be sexually abstinent or to use a condom or other adequate barrier method of contraception when engaging in sexual activity from study check-in through completion of the end-of study. Participants will be advised to use adequate contraception for 30 days following the last administration of the study drug, and to not donate sperm during this same period of time. In the event that the sexual partner is surgically sterile, use of adequate method of contraception is not necessary.
5. Female participants must be surgically sterile or post-menopausal (no spontaneous menstrual period for at least one year), confirmed by FSH greater than 40 mIU/mL. Sterilization procedure must have been completed at least 6 months prior to Day 1.
a. Essure sterilization (with a copy of the confirmation test) and be using an adequate barrier method (condom or diaphragm) throughout the study.
b. bilateral tubal ligation and be using an adequate barrier method (condom or diaphragm) throughout the study.
c. hysterectomy.
d. bilateral oophorectomy.
6. Negative drug/alcohol testing at screening and check-in (Day -1). Screening drug/alcohol testing may be repeated once if deemed appropriate by the site investigator.
7. Willing to abstain from consuming grapefruit or Seville orange containing products from 7 days prior to Day 1 through follow-up.
Minimum age
18 Years
Maximum age
55 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Pregnant or lactating women.
2. Women of child-bearing potential.
3. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C antibodies (HCV).
4. Any active acute or chronic disease judged to be clinically significant by the site investigator.
5. Use of more than 1-2 tobacco/nicotine-containing products per month within 6 months prior to Day 1.
6. Participant is febrile, temperature greater than 37.5 degrees Celsius.
7. History or presence of alcoholism or drug abuse within 2 years prior to Day 1.
8. History of any significant (as determined by the Investigator) drug-related allergic reactions such as,anaphylaxis, Stevens-Johnson syndrome, urticaria or multiple drug allergies.
9. Use of any over-the-counter (OTC) medication, including herbal products, within 7 days prior to Day 1. Use of any prescription medication within 14 days prior to Day 1 or 5 half-lives, whichever is longer.
10. Blood donation or significant blood loss within 60 days prior to screening.
11. Plasma donation within 14 days prior to Day 1.
12. Participation in another clinical trial of a drug or device whereby the last investigational drug/device administration is within 60 days prior to Day 1 or 5 half-lives, whichever is longer.
13. Surgery within the past three months prior to Day 1 determined by the site investigator to be clinically relevant.
14. Personal or family history of prolonged QT syndrome or family history of sudden death.
15. QTcF greater than 450 msec (males) or greater than 470 msec (females) or less than 300 msec at screening or baseline visit, or deemed clinically significant by the site investigator.
16. Screening ECG with QRS and/or T-wave judged to be unfavorable for a consistently accurate QT measurement as judged by the site investigator.
17. Evidence of atrial fibrillation, atrial flutter, complete bundle branch block, Wolff-Parkinson-White Syndrome or cardiac pacemaker at screening or baseline visit.
18. Seated resting systolic blood pressure (SBP) greater than 140 or less than 90 mm Hg, or diastolic blood pressure greater than 90 or less than 50 mm Hg.
19. Resting HR less than 45 bpm or greater than 90 bpm at screening or baseline visit.
20. Hypersensitivity or history of idiosyncratic reaction to any components or excipients of the investigational formulation.
21. Any contraindication to the use of midazolam including, but not limited to: hypersensitivity to benzodiazepines or formulation ingredients, myasthenia gravis, severe respiratory insufficiency and sleep apnea syndrome.
22. Regular alcohol consumption >14 units per week(1 unit half a pint of beer, 25 mL of 40 percent spirit or a 125 mL glass of wine).
23. Failure to satisfy the site investigator of fitness to participate for any other reason.
24. Active infection.
25. History of seizure, whether epileptic, paroxysmal or of unknown origin.
26. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological or psychiatric disease.
27. Any acute illness within 30 days prior to Day 1.

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)
Participants will be recruited from the study site's internal database.
Eligible subjects will be allocated to a treatment by the site in sequential order. All participants will receive the same treatment allocation (as it is an open label fixed-sequence study) therefore concealment procedures are not required.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be allocated a screening number (Snnn) at screening and then once enrolled, an "R" number based on the numbering system Rrnn (r being replacement number if needed, n being sequential numbering) in sequential order.
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
Based on historical healthy volunteer data for midazolam PK, an intrapatient coefficient of variation (CV) of 15% was utilized. Using a two one-sided tests procedure with alpha = 0.05, 10 participants are required to have greater than 80 percent power to detect equivalence assuming no true differences in mean PK parameters. Equivalence is defined as the 90 percent confidence limit of the ratio of AUC or Cmax within the equivalence interval of 80-125 percent. To account for dropouts, 12 participants will be enrolled.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
7/12/2014
Date of last participant enrolment
Anticipated
22/12/2014
Actual
7/12/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
12
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment postcode(s) [1] 8993 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 290318 0
Commercial sector/Industry
Name [1] 290318 0
Clinical Network Services (CNS) Pty Ltd.
Country [1] 290318 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Principia Biopharma Australia Pty Ltd
Address
Level 29, 525 Collins Street, Melbourne, VIC, 3000
Country
Australia
Secondary sponsor category [1] 289034 0
None
Name [1] 289034 0
Nil
Address [1] 289034 0
Nil
Country [1] 289034 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292025 0
Bellberry HREC
Ethics committee address [1] 292025 0
Ethics committee country [1] 292025 0
Australia
Date submitted for ethics approval [1] 292025 0
22/10/2014
Approval date [1] 292025 0
20/11/2014
Ethics approval number [1] 292025 0
2014-10-569

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

Contacts
Principal investigator
Name 52302 0
Dr Janakan Krishnarajah
Address 52302 0
Linear Clinical Research Level 1, B Block, QEII Medical Centre, Hospital Ave,
Nedlands WA 6009
Country 52302 0
Australia
Phone 52302 0
+61863825100
Fax 52302 0
Email 52302 0
[email protected]
Contact person for public queries
Name 52303 0
Dougal Thring
Address 52303 0
Linear Clinical Research Level 1, B Block, QEII Medical Centre, Hospital Ave,
Nedlands WA 6009
Country 52303 0
Australia
Phone 52303 0
+61863825100
Fax 52303 0
Email 52303 0
[email protected]
Contact person for scientific queries
Name 52304 0
Janakan Krishnarajah
Address 52304 0
Linear Clinical Research Level 1, B Block, QEII Medical Centre, Hospital Ave,
Nedlands WA 6009
Country 52304 0
Australia
Phone 52304 0
+61863825100
Fax 52304 0
Email 52304 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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