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Trial registered on ANZCTR


Registration number
ACTRN12616001557426
Ethics application status
Approved
Date submitted
21/09/2016
Date registered
11/11/2016
Date last updated
11/11/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1, Single-Center, Open-label Study to Evaluate the Safety and Pharmacokinetics of Two Tablet Formulations of PRN1008
Scientific title
A Phase 1, Single-Center, Open-label Study to Evaluate the Safety and Pharmacokinetics of Two Tablet Formulations of PRN1008 in healthy adult volunteers.
Secondary ID [1] 290189 0
NIL
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pemphigus Vulgaris 300333 0
Rheumatoid Arthritis 300334 0
Condition category
Condition code
Skin 300198 300198 0 0
Dermatological conditions
Inflammatory and Immune System 300338 300338 0 0
Rheumatoid arthritis

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a single center, open-label, 4-period crossover study (meaning subjects will receive all treatments) to investigate:
1) The single dose pharmacokinetics of PRN1008 when administered as new tablet formulation compared to the current tablet formulation under fasted conditions (no food for at least 8 hours prior to dosing, water permissible until 1 hour pre-dose).
2) The effect of a moderate fat meal on the single dose pharmacokinetics of PRN1008 when administered as a new tablet formulation.

Participants will be screened for participation within 28 days before dosing. Participants will be admitted to the study unit the day before dosing in Period 1 (Day -1).

Following an overnight fast of at least 8 hours, participants will receive a single oral 200 mg dose of the new tablet (Treatment 1) formulation under fasting conditions and will remain in the clinic until the final PK and PD samples are collected on the morning of Day 2. Participants will be contacted 7 days (+/- 2 days) following dosing in Period 1 to collect safety and adverse event information.

Following a washout of up to 28 days to facilitate Period 1 data review of the safety and tolerability, and pharmacokinetic and pharmacodynamic parameters of the new tablet formulation by the Sponsor in consultation with the Principal Investigator, the dose to be used in Periods 2-4 will be confirmed and participants will be re-admitted to the study unit the day before dosing in Period 2 (Day -1). The dose of PRN1008 new tablet formulation selected for Periods 2-4 will not exceed 800 mg and will be chosen to approximate the expected exposure (AUC0-8) of a single 400 mg IR tablet dose.

Treatments for Periods 2 to 4 are listed below. Doses will be administered at least 48 hours apart.

* Treatment 2 (Test Formulation Fasted):
A single oral dose [TBD] not to exceed 800 mg of PRN1008 administered following an overnight fast of at least 8 hours as new tablet formulation (100mg tablet) under fasted conditions
* Treatment 3 (Test Formulation Fed):
A single oral dose [TBD] not to exceed 800 mg of PRN1008 administered as a new tablet formulation (100 mg tablet) under fed conditions following a moderate fat meal
* Treatment4 (Reference Formulation Fasted):
A single oral 400 mg dose of PRN1008 administered as the current tablet formulation (300 mg tablet and/ or 100 mg tablet(s)) under fasted conditions following an overnight fast of at least 8 hours

All doses are administered and monitored by study staff to ensure compliance.

There are 6 possible sequences in which the listed treatments will be administered:
- 1, 2, 3, 4
- 1, 2, 4, 3
- 1, 4, 2, 3
- 1, 4, 3, 2
- 1, 3, 4, 2
- 1, 3, 2, 4

Following discharge from the study unit after Period 4, subjects will return for a Follow-Up visit and assessments on Day 7 +/- 2 days after the final study drug administration.
Intervention code [1] 295944 0
Treatment: Drugs
Comparator / control treatment
The single dose pharmacokinetics of PRN1008 when administered as a new clinical tablet formulation compared to the current clinical tablet formulation under fasted conditions.
* The effect of a meal on the single dose pharmacokinetics of PRN1008 when administered as a tablet formulation.
Control group
Active

Outcomes
Primary outcome [1] 299683 0
Relative oral bioavailability (AUC, Cmax) of PRN1008 assessed by plasma assay when administered as a new tablet formulation (test formulation), compared to an existing clinical tablet formulation (reference formulation), both under fasted conditions.
Timepoint [1] 299683 0
Time 0 (pre-dose), and post-dose at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours after PRN1008 dosing
Primary outcome [2] 299684 0
Assessment of the impact of food (AUC, Cmax) on PRN1008 PK assess by plasma assay when administered as a new tablet formulation under fed or fasted conditions
Timepoint [2] 299684 0
Time 0 (predose) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 10, 12 and 24 hours after PRN1008 dosing
Secondary outcome [1] 327844 0
Safety and tolerability, including the assessment of physical examinations, ECGs, vital signs, clinical laboratory results and adverse events
Timepoint [1] 327844 0
Physical Examination: will be performed at Screening and Day -1 prior to Periods 1 & 2, and at 7 days following last dose of study drug or at early discontinuation.

ECGs will be obtained within a +/- 10 minute period per time point.
- Single ECGs will be collected at Screening and Day -1, Period 1 and 2, at the Follow Up visit, or upon the participant’s early discontinuation or withdrawal from the study.
- Triplicate ECGs will be collected in each Period prior to PRN1008 dosing and at four (4) hours after dosing. Triplicate ECGs will be taken within approximately 1 minute intervals.

Vital Signs: will be taken at Screening, Day -1 prior to Periods 1 & 2, and during periods 1-4 within 30 mins before dosing (pre-dose) and at 4 hours post dose in all study periods and at the Follow Up visits.

Clinical Laboratory Tests:
Laboratory safety tests will be collected in Period 1 at Day -1/ Admission and prior to Discharge on Day 2. In Periods 2-4, laboratory safety tests will collected on Day -1/ Admission (Eligibility/ Re-eligibility lab tests) for Period 2, and on Day 2/ Discharge of Period 4, or at early discontinuation, as applicable.

Adverse Events: Will be recorded from Screening and throughout the study including all visits through the Follow up visit 7 days after the last dose of study drug.
Secondary outcome [2] 327845 0
Assessment of PD effects of PRN1008 (BTK occupancy assay)
Timepoint [2] 327845 0
Blood samples for PRN1008 PD (BTK occupancy in PBMCs): Pre-dose (< 15 mins prior to dosing) and at 4, 8, 12, & 24 hours post-dose.

Eligibility
Key inclusion criteria
- Healthy adult male or non-pregnant, non-lactating females, 18 to 65 years of age (inclusive) at the time of screening
- Body mass index (BMI) greater than or equal to 18 (kg/m2) (inclusive), and less than or equal to 35 (kg/m2) (inclusive), and a minimum body weight of 45 kg
- Able to participate and comply with all study procedures and restrictions, and willing to provide written informed consent to participate in the study
- A female subject of childbearing potential with a negative pregnancy test agrees to abstinence or use of condoms plus one other acceptable form of contraception; i.e. intrauterine device, hormonal contraception, or a female diaphragm, until 4 weeks after dosing with study drug – OR – has only same-sex partners, when this is her preferred and usual lifestyle
- Male subjects with female partners of childbearing potential must agree to use condoms for the duration of the study and until 12 weeks after dosing with the study drug
- Negative urine drug/alcohol testing at screening and check-in (Day -1). Screening urine drug/alcohol testing may be repeated once if deemed appropriate by the site Investigator
- Willing to abstain from consuming grapefruit- or Seville orange-containing products from 14 days prior to first dose of study medication through follow-up
Minimum age
18 Years
Maximum age
65 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
- Use of any prescription or over-the-counter (OTC) medication, including herbal products and supplements, within the 14 days or 5 half-lives prior to Day 1 (whichever is longer). Use of less than or equal to 2g paracetamol per day is allowed prior to and during the study.
- Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HbsAg), or hepatitis C antibodies (HCV)
- Use of more than two tobacco/nicotine-containing products per month within 6 months prior to the first study drug administration
- History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration.
- Regular alcohol consumption of greater than 14 units per week (1 unit = 1/2 pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
- History of any significant (as determined by the Investigator) drug-related allergic reactions such as, anaphylaxis, Stevens-Johnson syndrome, urticarial or multiple drug allergies
- Blood donation or significant blood loss within 30 days prior to screening
- Plasma donation within 14 days prior to the first study drug administration
- Participation in another clinical trial of a drug or device whereby the last investigational drug/device administration is within 30 days prior to the first study drug administration or 5 half-lives, whichever is longer
- surgery within the past three months prior to the first study drug administration determined by the PI to be clinically relevant
- Personal or family history of prolonged QT syndrome or family history of sudden death
- QTcF greater than 450 msec (males) or greater than 470 msec (females) or less than 300 msec at screening,or prior to dosing, unless deemed clinically insignificant by the Investigator
- Screening ECG with QRS and/or T-wave judged to be unfavorable for a consistently accurate QT measurement as judged by the Investigator
- Evidence of atrial fibrillation, atrial flutter, complete bundle branch or heart block, Wolff-Parkinson-White Syndrome, or cardiac pacemaker at screening or prior to dosing
- Semi-supine resting systolic blood pressure (SBP) greater than 150 or less than 90 mm Hg, or diastolic blood pressure greater than 95 or less than 50 mm Hg
- Resting HR less than 45 bpm or greater than 90 bpm at screening or prior to dosing.
- Hypersensitivity or history of idiosyncratic reaction to any components or excipients of the investigational formulation
- Active infection
- Participant is febrile, temperature greater than 37.5 degrees C assessed at screening or prior to dosing
- Any acute illness within 30 days prior to Day 1 unless deemed clinically insignificant by the Investigator and discussed with the Sponsor.
- History of seizure within the past 5 years, whether epileptic, paroxysmal, or of unknown origin
- Failure to satisfy the Investigator of fitness to participate for any other reason
- History or presence of any other medical condition that makes the participant unsuitable for the study in the opinion of the Investigator.

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)
Participants cannot commence enrolment procedures until all entry criteria have been fulfilled. Where clinical significance of an abnormal screening test result (lab or any other test) is considered uncertain, the test may be repeated.
Participants will be recruited from the study site's internal database. Eligible subjects will be randomized to a treatment sequence, using a randomized block approach. Whilst the treatment allocation is not concealed, participants will be randomly assigned to one of six possible treatment sequences.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be numbered sequentially in the following format:

Brnn (where B is the study number, R is the replacement number should the participant be a replacement, nn being the sequential number into the study starting with 01).

Subjects will be randomised to a treatment via a simple randomisation table created by computer software (i.e computerised sequence generation) which will be provided to the site by the biostatistician.

The investigator or designee will enter data of each enrolled participant
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis
Plasma concentrations and the computed PK parameters will be listed for PRN1008 by treatment period. Individual and mean concentration versus time data will be plotted on linear and semi-logarithmic scales. Summary statistics of PK parameters (primary and secondary) will be presented for each treatment period including means, geometric means, standard deviations, coefficient of variation (CV), medians and ranges, as appropriate.
Geometric mean ratios and 90% confidence limits of AUC and Cmax by formulation will be computed for PRN1008 to assess the relative bioavailability of the tablet formulations (test vs. reference), and to assess the impact of food on the new formulation tablet. Analysis of variance (ANOVA) will be applied to the log-transformed primary PK parameters. Additional summaries or analyses may be applied to the data as appropriate.
BTK occupancy values will be listed for each subject by treatment. Individual and mean occupancy versus time data will be plotted on linear scales. Summary statistics of occupancy results by time point will be presented for each treatment period including means, geometric means, standard deviations, coefficient of variation (CV), medians and ranges, as appropriate.

No sample size calculations were performed. The sample size for this study was determined by practical considerations, and is typical for a study of this type. Based on past experience withPRN1008, 12 subjects are sufficient to characterize the PK of a single dose administration considering observed PK variability. To account for potential drop-outs, a total of 14 will be enrolled.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
12/09/2016
Date of last participant enrolment
Anticipated
Actual
7/10/2016
Date of last data collection
Anticipated
Actual
28/10/2016
Sample size
Target
14
Accrual to date
Final
16
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 6705 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 14342 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 294550 0
Commercial sector/Industry
Name [1] 294550 0
Principia Biopharma Australia Pty Ltd
Country [1] 294550 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] 293420 0
Commercial sector/Industry
Name [1] 293420 0
Clinical Network Services Pty Ltd
Address [1] 293420 0
Level 4
88 Jephson Street
Toowong
QLD, 4066
Country [1] 293420 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 295988 0
Bellberry Limited
Ethics committee address [1] 295988 0
129 Glen Osmond Road
Eastwood
SA 5063
Ethics committee country [1] 295988 0
Date submitted for ethics approval [1] 295988 0
20/07/2016
Approval date [1] 295988 0
22/08/2016
Ethics approval number [1] 295988 0
2016-07-593

Summary
Brief summary
This will be a single-center, open-label, 4-period study to investigate the relative bioavailability of a single dose of PRN1008 when administered as a new tablet formulation compared to the current tablet formulation under fasted and fed conditions. Period 1 is intended to investigate the pharmacokinetics of the 100mg new formulation tablet at a 200mg dose, and to determine an appropriate dose for the new tablet formulation to be used in Periods 2 to 4, the relative bioavailability crossover portion of the study.
Participants will be screened for this study within 28 days before dosing. Total length of participation in the study for participants is 76 days from screening through study completion.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 69158 0
Dr Andrew Redfern
Address 69158 0
Linear Clinical Research
Level 1, B Block, QEII Medical Cntr, Hospital Avenue
Nedlands WA 6009
Country 69158 0
Australia
Phone 69158 0
+61 (0)8 63825100
Fax 69158 0
Email 69158 0
[email protected]
Contact person for public queries
Name 69159 0
Simon Scott
Address 69159 0
Linear Clinical Research Ltd
1st Floor B Block
Hospital Avenue
Nedlands
WA 6009
Country 69159 0
Australia
Phone 69159 0
+61 (0)8 63825100
Fax 69159 0
Email 69159 0
[email protected]
Contact person for scientific queries
Name 69160 0
Andrew Redfern
Address 69160 0
Linear Clinical Research Ltd
1st Floor B Block
Hospital Avenue
Nedlands
WA 6009
Country 69160 0
Australia
Phone 69160 0
+61 (0)8 63825100
Fax 69160 0
Email 69160 0
[email protected]

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No Supporting Document Provided



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