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Trial registered on ANZCTR


Registration number
ACTRN12615000936527
Ethics application status
Approved
Date submitted
7/08/2015
Date registered
8/09/2015
Date last updated
19/01/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
Relative Bioavailability and Effect of Food and Esomeprazole on the Pharmacokinetics of PRN1008 in Healthy Volunteers.
Scientific title
Relative Bioavailability and Effect of Food and Esomeprazole on the Pharmacokinetics of PRN1008 in Healthy Volunteers
Secondary ID [1] 287196 0
Nil
Universal Trial Number (UTN)
Nil
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rheumatoid Arthritis 295782 0
Inflammatory Bowel Disease 295783 0
Systemic Lupus Erythematosus 295784 0
Condition category
Condition code
Inflammatory and Immune System 296053 296053 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a single center, four-period, open-label, complete crossover (meaning subjects will receive all treatments) study to investigate:
* The single dose pharmacokinetics of PRN1008 when administered as a liquid formulation compared to a tablet formulation under fasted conditions (no food for at least 8 hours prior to dosing, water permissible until 1 hour pre-dose).
* The effect of a meal on the single dose pharmacokinetics of PRN1008 when administered as a tablet formulation.
* The effect of prior administration of a Proton Pump Inhibitor on the single dose pharmacokinetics of PRN1008 when administered as a 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 (Day -1), then dosed in the mornings of Days 1, 3, 5 and 10, and will remain in the clinic up to Day 11, after collection of the final PK sample.

All participants will complete all four Periods of the study
Participants will be randomized to order of treatment (1, 2 & 3) for the first three Periods. All participants will receive Treatment 4 as the final treatment. Therefore, the final Period will be identical for all participants.

Treatments are as listed below. Doses will be administered approximately 48 hours apart for the first three treatments:

Treatment 1
Immediately prior to and following a single oral 300 mg dose of PRN1008 liquid formulation, blood samples will be obtained over a period of 24 hours for determination of the PRN1008 PK profile. Participants will be in a fasted state (i.e an overnight fast -no food-of at least 8 hours, water permissible until 1 hr pre-dose).Food will be restricted until 4 hours after dosing.

Treatment 2
Immediately prior to and following a single oral 300 mg dose of PRN1008 tablet formulation, blood samples will be obtained over a period of 24 hours for determination of the PRN1008 PK profile. Participants will be in a fasted state (i.e an overnight fast -no food-of at least 8 hours, water permissible until 1 hr pre-dose).Food will be restricted until 4 hours after dosing.


Treatment 3
Immediately prior to and following a single oral 300 mg dose of PRN1008 tablet formulation, blood samples will be obtained over a period of 24 hours for determination of the PRN1008 PK profile. Participants will be in a fed state (following an overnight fast of at least 8 hours, and water restricted for 1 hour before food administration, participants will receive a standardized moderate fat meal (breakfast). The meal will be started 30 minutes prior to dosing and ingested within 30 minutes.Further food will be restricted until 4 hours after dosing.

Treatment 4
Following collection of the final PK sample from Period 3, participants will begin dosing esomeprazole 40 mg once daily (oral capsule) in the morning, on Days 6 – 10. On Day 10, immediately prior to and following a single oral 300 mg dose of PRN1008 tablet formulation, blood samples will be obtained over a period of 24 hours for determination of the PRN1008 PK profile. The Day 10 PRN1008 dose will be administered in a fasted state (i.e an overnight fast -no food-of at least 8 hours, water permissible until 1 hr pre-dose). Food will be restricted until 4 hours after dosing.

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

There are 6 possible sequences in which the listed treatments will be completed:
* 1234
* 1324
* 2134
* 2314
* 3124
* 3214

Following discharge from the study unit, subjects will return for a follow-up assessment one week (plus or minus 2 days) after final study drug administration.

The total duration for participants will be up to approximately 47 days.
Intervention code [1] 292478 0
Treatment: Drugs
Comparator / control treatment
* The single dose pharmacokinetics of PRN1008 when administered as a liquid formulation compared to a tablet formulation under fasted conditions.
* The effect of a meal on the single dose pharmacokinetics of PRN1008 when administered as a tablet formulation.
* The effect of prior administration of a
Proton Pump Inhibitor (esomeprazole) on the single dose pharmacokinetics of PRN1008 when administered as a tablet formulation.
Control group
Active

Outcomes
Primary outcome [1] 295719 0
Relative oral bioavailability (AUC, Cmax) of PRN1008 when administered as a tablet (test formulation) compared to a liquid (reference formulation) as determined by plasma assay.
Timepoint [1] 295719 0
Time 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours after PRN1008 dosing on Days 1, 3, 5 and 10.
Primary outcome [2] 295720 0
Single dose PK of PRN1008, including plasma Cmax, Tmax, AUC and plasma half-life.
Timepoint [2] 295720 0
Time 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours after PRN1008 dosing on Days 1, 3, 5 and 10.
Primary outcome [3] 295721 0
Impact of food on the PK of PRN1008 (AUC, Cmax) when administered as a tablet as determined by plasma assay.
Timepoint [3] 295721 0
Time 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours after PRN1008 dosing on Days 1, 3, 5 and 10.
Secondary outcome [1] 316306 0
Safety and tolerability, including the assessment of physical examinations, ECGs, vital signs, clinical laboratory results and adverse events.
Timepoint [1] 316306 0
Physical Examination:Will be done at Screening, Day-1 and Follow-Up.

ECGs: Triplicate ECGs will be collected on Days 1, 3, 5 and 10 prior to PRN1008 dosing and at two hours after dosing. Single ECGs will be done at other times (screening, Day-1 and Follow up).

Vital Signs: Will be taken at screening, Day -1, Days 1, 3, 5 and 10 (pre-dose, and 1.5, 2, and 3 hours post dose), Days 2, 4, 6 and 11 (24 hours post dose), Days 7, 8, 9 and at Follow up.

Clinical Laboratory Tests:
Will be taken at Screening, Day-1, Day 5, Day 10 and Follow up visits.

Adverse Events: Will be recorded from Screening including all visits until follow up. Known adverse reactions previously observed we gastrointestinal in nature and are being assed per the safety and tolerability assessments as well as subject reporting.
Secondary outcome [2] 316818 0
Additional Primary outcome:
Impact of prior administration of esomeprazole on the PK of PRN1008 (AUC, Cmax) as determined by plasma assay.
Timepoint [2] 316818 0
Additional Primary outcome timepoint:
Time 0 (pre-dose), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours after PRN1008 dosing on Days 1, 3, 5 and 10.

Eligibility
Key inclusion criteria
* Healthy adult male or non-pregnant non-lactating females, 18 to 75 years of age (inclusive) at the time of screening
* Body mass index (BMI) greater than or equal to 18 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 4 weeks after dosing with the study drug
*Negative urine drug and alcohol testing at screening and check-in (Day -1). Screening urine drug and alcohol testing may be repeated once if deemed appropriate by the site Investigator.
* Willing to or has abstain(ed) 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
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
* Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV)
* History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration.
* History of any significant (as determined by the Investigator) drug-related allergic reactions such as, anaphylaxis, Stevens-Johnson syndrome, urticaria 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 baseline visit, 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 baseline visit.
* Seated 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 baseline (Day -1) visit (the heart rate recorded from vital sign assessment will be utilised for this exclusion criteria).
* Hypersensitivity or history of idiosyncratic reaction to any components or excipients of the investigational formulation
* Regular alcohol consumption greater than 14 units per week (1 unit equals half a pint beer, 25 mL of 40 percent spirit or a 125 mL glass of wine).
* Active infection
* Participant is febrile, temperature greater 37.5 degrees centigrade (assessed at Screening and at Baseline (Day -1))
* 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, 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 sites's internal database. Eligible subjects will be allocated to a treatment by a treatment scheduled randomly generated by a biostatistician.
Whilst the treatment allocation is not concealed, participants will be randomly assigned to one of six possible treatment schedules.
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
NIL
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis
Safety and Tolerability:
Quantitative safety data will be summarised by descriptive statistics (simple counts, arithmetic mean, standard deviation, median, minimum, and maximum) by treatment group. Summaries will also be presented for the change from baseline, when appropriate.

Pharmacokinetics:
Plasma concentrations and the computed PK parameters will be listed for PRN1008. 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 percent confidence limits of AUC and Cmax by formulation will be computed. 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.

No formal sample size calculations were performed. The sample size of the study was determined by practical considerations, and is typical for a study of this type. Based on past experience with PRN1008, 12 subjects are sufficient to characterize the PK of a single dose administration considering observed PK variability.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
22/08/2015
Actual
22/08/2015
Date of last participant enrolment
Anticipated
16/09/2015
Actual
16/09/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
12
Accrual to date
Final
12
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 4123 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 10051 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 291757 0
Commercial sector/Industry
Name [1] 291757 0
Principia Biopharma Australia Pty Ltd
Country [1] 291757 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services Pty Ltd
Address
Level 4
88 Jephson Street
Toowong
QLD, 4066
Country
Australia
Secondary sponsor category [1] 290429 0
None
Name [1] 290429 0
NIL
Address [1] 290429 0
NIL
Country [1] 290429 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293279 0
Bellberry Limited
Ethics committee address [1] 293279 0
129 Glen Osmond Road
Eastwood
SA 5063
Ethics committee country [1] 293279 0
Australia
Date submitted for ethics approval [1] 293279 0
22/07/2015
Approval date [1] 293279 0
13/08/2015
Ethics approval number [1] 293279 0
N/A

Summary
Brief summary
This will be a single center, four-period, open-label, complete crossover study to investigating the single dose pharmacokinetics of PRN1008 when administered as a liquid formulation compared to a tablet formulation under fasted conditions, the effect of a meal on the single dose pharmacokinetics of PRN1008 when administered as a tablet formulation and also, the effect of prior administration of a Proton Pump Inhibitor on the single dose pharmacokinetics of PRN1008 when administered as a 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 (Day -1), then dosed in the mornings of Days 1, 3, 5 and 10, and will remain in the clinic up to Day 11, after collection of the final PK sample. Total participation will be approximately 47 days.
Trial website
NIL
Trial related presentations / publications
NIL
Public notes
NIL

Contacts
Principal investigator
Name 59242 0
Dr Janakan Krishnarajah
Address 59242 0
Linear Clinical Research Ltd
1st Floor B Block
Hospital Avenue
Nedlands
WA 6009
Country 59242 0
Australia
Phone 59242 0
+61 (0)8 63825100
Fax 59242 0
Email 59242 0
[email protected]
Contact person for public queries
Name 59243 0
Simon Scott
Address 59243 0
Linear Clinical Research Ltd
1st Floor B Block
Hospital Avenue
Nedlands
WA 6009
Country 59243 0
Australia
Phone 59243 0
+61 (0)8 63825100
Fax 59243 0
Email 59243 0
[email protected]
Contact person for scientific queries
Name 59244 0
Janakan Krishnarajah
Address 59244 0
Linear Clinical Research Ltd
1st Floor B Block
Hospital Avenue
Nedlands
WA 6009
Country 59244 0
Australia
Phone 59244 0
+61 (0)8 63825100
Fax 59244 0
Email 59244 0
[email protected]

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No Supporting Document Provided



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