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Trial registered on ANZCTR


Registration number
ACTRN12618000249257
Ethics application status
Approved
Date submitted
26/01/2018
Date registered
16/02/2018
Date last updated
30/04/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Study of Two PRN1008 Tablet Formulations and the impact of Midazolam and Famotidine on PRN1008 in Healthy Subjects
Scientific title
A Phase 1 Study of the Relative Bioavailability of Two PRN1008 Tablet Formulations, Effect of PRN1008 on Midazolam Pharmacokinetics, and Impact of Famotidine on PRN1008 Pharmacokinetics in Healthy Subjects
Secondary ID [1] 293885 0
Nil known
Universal Trial Number (UTN)
U1111-1208-5270
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Immune-related disorders, 306352 0
Condition category
Condition code
Inflammatory and Immune System 305506 305506 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This will be a single center, four-period, open-label, randomized, complete cross-over study in healthy adult participants. Participants will be screened for participation within 29 days before dosing. Participants will be admitted to the study unit on Day -2, the day before the first midazolam dosing (Day -1), and participants will receive PRN1008 on Days 1, 3, 5, and 7. Participants will remain in the study unit to observe safety and protocol compliance until the last PK sample draw on Day 8.

All participants will complete all four Periods of the study.

All participants will receive a single 2 mg oral dose of midazolam (1 mg/mL solution) on Day -1, followed by intensive blood sampling for 12 hours for midazolam pharmacokinetics (PK). Beginning Day 1, participants will be randomized to order of PRN1008 treatment (Treatment 1, 2, or 3) for the first three Study Periods.
All participants will receive Treatment 4 in Period 4.
Treatments are as listed below. Subjects will be dosed with PRN1008 once on Days 1, 3, and 5 and twice on Day 7. Doses will be administered approximately 48 hours apart for all PRN1008 Treatments.

Treatment 1
Following an overnight fast, participants will receive a single 400 mg oral dose of PRN1008
(Reference Formulation), and simultaneously receive a single 2 mg oral dose of midazolam.
Blood samples will be obtained over a period of 12 hours for determination of the PRN1008
and midazolam PK profiles.
Treatment 2
Following an overnight fast, participants will receive a single 400 mg oral dose of PRN1008
(Test Formulation #1), and simultaneously receive a single 2 mg oral dose of midazolam.
Blood samples will be obtained over a period of 12 hours for determination of the PRN1008
and midazolam PK profiles.
Treatment 3
Following an overnight fast, participants will receive a single 400 mg oral dose of PRN1008
(Test Formulation #2), and will receive a single 2 mg oral dose of midazolam 2 hours after
PRN1008. Blood samples will be obtained over a period of 14 hours for determination of the PRN1008 and midazolam PK profiles.
Treatment 4
Participants will receive 20 mg oral doses of famotidine in the evening of Days 5, 6, and 7.
Following an overnight fast on Day 7, participants will receive one 400 mg oral dose of
PRN1008 (Reference Formulation) administered in the morning and a second dose in the
evening (10-12 hours after the am dose), 2 hours prior to famotidine dosing, and after a four
hour period of fasting. Blood samples will be obtained over a period of 12 hours following
each PRN1008 dose for determination of PRN1008 PK.

Participants will be randomized to complete one of 6 possible treatment sequences:
• 1234
• 1324
• 2134
• 2314
• 3124
• 3214

Following discharge from the study unit on the morning of Day 8, subjects will return for a
follow-up assessment on Day 15 (+/- 2 days).
Intervention code [1] 300153 0
Treatment: Drugs
Comparator / control treatment
The active comparator is the current reference formulation of PRN1008 used in our ongoing Phase 2 trial (PRN1008-005), a 100 mg and 300 mg tablet. PRN1008 Reference Tablets contains either 100 mg or 300 mg of PRN1008 drug substance. In addition, both tablet contains Microcrystalline Cellulose (filler), Crospovidone (disintegrant), and Sodium Stearyl Fumarate (lubricant). The 100 mg tablets are round, and are orange film coated with Opadry II. The 300 mg tablets are oval, and are white film coated with Opadry II. The Reference formulation is given in Treatment 1.
Control group
Active

Outcomes
Primary outcome [1] 304574 0
Relative oral bioavailability of PRN1008 when administered via the Reference Formulation (Treatment 1) and two Test Formulations (Treatments 2 & 3) as assess by PK serum samples during the 24 hour period following administration of each Treatment. Primary PK parameters are Cmax, Tmax, AUC and plasma half-life when administered via the Reference Formulation and two Test Formulations.


Timepoint [1] 304574 0
Serum samples for PRN1008 PK will be collected pre-dose (prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after PRN1008 morning dosing on Days 1, 3, and
5, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after both morning and evening doses of PRN1008 on Day 7.

Blood samples for midazolam PK will be collected Pre-dose (prior to dosing) and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after midazolam dosing on Days -1, 1, 3 and 5.
Primary outcome [2] 304694 0
Impact of PRN1008 formulations on midazolam PK, including the impact of dosing midazolam two hours after PRN1008.
Timepoint [2] 304694 0
Serum samples for midazolam PK will be collected pre-dose (prior to dosing) and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after midazolam dosing on Days -1, 1, 3 and 5.
Primary outcome [3] 304695 0
Impact of famotidine on the PK of PRN1008 (AUC, Cmax) when famotidine is administered the evening prior to PRN1008 and when famotidine is administered two hours after PRN1008
Timepoint [3] 304695 0
Serum samples for PRN1008/ famotidine PK will be collected pre-dose (prior to dosing) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, and 12 hours after PRN1008 morning and evening dosing on Day 7
Secondary outcome [1] 342437 0
Safety and tolerability of PRN1008 when co-administered with midazolam and famotidine as assessed by electrocardiograms (ECGs), vital signs, clinical laboratory results, and adverse events
Timepoint [1] 342437 0
Safety and tolerability will be assessed daily throughout the study from Day -2 and post-dose through Day 7 confinement, and at Day 15 follow-up visit via laboratory tests, daily adverse event, vital sign assessments and physical exams
Secondary outcome [2] 342644 0
To assess the pharmacodynamics of PRN1008 on BTK Occupancy in peripheral blood mononuclear cells (PBMCs).
Timepoint [2] 342644 0
Pharmacodynamics of PRN1008 will be assessed via whole blood samples collected pre-dose and post-dose following each PRN1008 dose and at 4, 8, and 12 hours post PRN1008 dosing on Days 1, 3, and 5 in Periods 1-3 only.

Eligibility
Key inclusion criteria
1. Healthy adult male or non-pregnant, non-lactating females, 18 to 75 years of age (inclusive) at the time of screening
2. Body mass index (BMI) greater than or equal 18 and less than or equal to 35 (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. 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
5. 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
6. Negative urine drug and alcohol breath testing at screening and check-in (Day -2). Screening drug/alcohol testing may be repeated once if deemed appropriate by the site Investigator
7. 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
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Use of any prescription or over-the-counter (OTC) medications, including herbal products and supplements, within the 14 days prior to Day -1 or 5 half-lives, whichever is longer. Use of hormonal contraception and less than or equal to 2g paracetamol per day is allowed prior to and during the study.
2. Positive testing for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C antibodies (HCV)
3. Use of more than two tobacco/nicotine-containing products per month within 6 months prior to the first study drug administration
4. History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration
5. Regular alcohol consumption >14 units per week (1 unit = ½ pint beer, 25 mL of 40% spirit, or a 125 mL glass of wine)
6. History of any significant (as determined by the Investigator) drug-related allergic reactions such as anaphylaxis, Stevens-Johnson syndrome, urticaria, or multiple drug allergies
7. Blood donation or significant blood loss within 30 days prior to screening
8. Plasma donation within 14 days prior to the first study drug administration
9. 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
10. Surgery within the past three months prior to the first study drug administration determined by the PI to be clinically relevant
11. Personal or family history of prolonged QT syndrome or family history of sudden death
12. QTcF > 450 msec (males) or > 470 msec (females) or < 300 msec at screening or baseline (Day -2), unless deemed clinically insignificant by the Investigator
13. Evidence of atrial fibrillation, atrial flutter, complete bundle branch or heart block, Wolff-Parkinson-White Syndrome, or cardiac pacemaker at screening or baseline visit
14. Seated or semi-supine resting systolic blood pressure (SBP) greater than 150 or less than 90 mm Hg, or diastolic blood pressure (DBP) greater than 95 or less than 50 mm Hg
15. Resting HR < 40 beats per minute (bpm) or > 90 bpm at screening or baseline (Day -2) (the heart rate recorded from vital sign assessment will be utilized for this exclusion criteria)
16. Hypersensitivity or history of idiosyncratic reaction to any components or excipients of the investigational formulation
17. Active infection
18. Participant is febrile, temperature > 37.5 °C (assessed at Screening and at Baseline [Day -2])
19. Any acute illness within 30 days prior to Day 1 unless deemed clinically insignificant by the Investigator and discussed with the Sponsor
20. Failure to satisfy the Investigator of fitness to participate for any other reason
21. 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)
numbered containers
central randomisation by phone/fax/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be recruited from the study site's internal database. Eligible subjects will be allocated to a treatment by the holder of the allocation schedule who is "off-site" or at central administration site. Treatment allocations will be concealed from the participant and investigator and will be held in sealed opaque envelopes for emergency code breaking events only.
Randomization will be via central provider or agreed local methodology such as randomization tables obtained via randomisation software.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s


Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Bio-availability
Statistical methods / analysis
The primary PK study parameters are AUC0-8, AUClast and Cmax of PRN1008 by formulation, and geometric mean rations (90% confidence interval [CI]) will be computed to determine the relative bioavailability of the two Test Formulation 400mg tablets compared to the Reference Formulation (1 x 100 mg + 1 x 300 mg tablets).
Plasma concentrations and the computed PK parameters will be listed for PRN1008 by formulation. Individual and mean-concentration-versus-time data will be plotted on linear and semi-logarithmic scales. Summary statistics of PK parameters 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. 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.
Participants will be randomized to 1 of 6 sequences of completing the 4 treatments (1, 2, 3, and 4), using a randomized block approach.
Two participants will be randomized to each of the following 6 sequences as follows (2 per sequence x 6 sequences = 12):
• 1234
• 1324
• 2134
• 2314
• 3124
• 3214

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC

Funding & Sponsors
Funding source category [1] 298508 0
Commercial sector/Industry
Name [1] 298508 0
Principia Biopharma Inc
Address [1] 298508 0
400 E. Jamie Court
Suite 302
S. San Francisco, California, USA 94080
Country [1] 298508 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Principia Biopharma Inc
Address
400 E. Jamie Court
Suite 302
S. San Francisco, California, USA 94080
Country
United States of America
Secondary sponsor category [1] 297652 0
None
Name [1] 297652 0
Address [1] 297652 0
Country [1] 297652 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299487 0
Bellberry HREC
Ethics committee address [1] 299487 0
229 Greenhill Road Dulwich, South Australia 5065
Ethics committee country [1] 299487 0
Australia
Date submitted for ethics approval [1] 299487 0
10/01/2018
Approval date [1] 299487 0
05/02/2018
Ethics approval number [1] 299487 0

Summary
Brief summary
PRN1008-011 is a single center, four-period, open-label, randomized, complete cross-over study in healthy adult participants.This study will evaluate the relative bioavailability of two novel formulations of PRN1008 (Test Formulations #1 and #2) compared to an existing tablet formulation (Reference Formulation), which has previously been administered in Phase 1 and Phase 2 studies. The information obtained in this study will evaluate the potential of the two novel formulations for use in future PRN1008 patient studies, and determine if any dosage adjustments are needed to obtain similar plasma exposures between the formulations.
PRN1008 is a novel, reversible covalent, investigational drug that inhibits Bruton’s agammaglobulinemia tyrosine kinase (BTK). PRN1008 acts as an adenosine triphosphate (ATP) competitive inhibitor that is both potent and selective for BTK. PRN1008 has a slow off-rate for binding to the target site, resulting in prolonged target occupancy relative to its low systemic exposure.
This study will also evaluate the PK of PRN1008 when co-administered with a customary dose of famotidine, an H2-receptor antagonist. Co-administration of PRN1008 in the morning after famotidine use, as well as in the evening 2 hours prior to famotidine will be studied. A prior study (PRN1008-006) found that PRN1008, when administered in combination with a proton-pump inhibitor (esomeprazole), demonstrated approximately a 50% reduction in plasma exposure, most likely due to the impact of esomeprazole on gastric pH. Based on these results, proton-pump inhibitors are currently excluded from PRN1008 clinical trials. The objective of this evaluation is to assess the potential impact of co-administering PRN1008 with H2-receptor antagonists, which are less potent reducers of gastric pH compared to proton-pump inhibitors. The results of these evaluations will inform the use of PRN1008 in future clinical studies.
Finally, this study will evaluate the potential for PRN1008 to alter the PK of midazolam when co-administered under various scenarios; this information will inform the use of PRN1008 in autoimmune diseases where drugs like midazolam and other CYP 3A substrates may be co-administered.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 80578 0
Dr Lara Hatchuel
Address 80578 0
Linear Clinical Research
QEII Medical Centre
First Floor, B Block Hospital Avenue
Nedlands WA 6009, Australia
Country 80578 0
Australia
Phone 80578 0
+61863825100
Fax 80578 0
Email 80578 0
lhatchuel@linear.org.au
Contact person for public queries
Name 80579 0
Mr Simon Scott
Address 80579 0
Linear Clinical Research
QEII Medical Centre
First Floor, B Block Hospital Avenue
Nedlands WA 6009, Australia
Country 80579 0
Australia
Phone 80579 0
+61 (0) 432 149 680
Fax 80579 0
Email 80579 0
sscott@linear.org.au
Contact person for scientific queries
Name 80580 0
Dr Lara Hatchuel
Address 80580 0
Linear Clinical Research
QEII Medical Centre
First Floor, B Block Hospital Avenue
Nedlands WA 6009, Australia
Country 80580 0
Australia
Phone 80580 0
+61863825100
Fax 80580 0
Email 80580 0
lhatchuel@linear.org.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary