Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614000359639
Ethics application status
Approved
Date submitted
25/03/2014
Date registered
4/04/2014
Date last updated
3/02/2015
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1 Randomised, Double-Blind, Placebo-Controlled, Ascending Dose Study of the Safety, Tolerability and Pharmacokinetics of Orally Administered PRN1008
Scientific title
A Phase 1 Randomised, Double-Blind, Placebo-Controlled, Ascending Dose Study of the Safety, Tolerability and Pharmacokinetics of Orally Administered PRN1008 in healthy adult volunteers.
Secondary ID [1] 284259 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Healthy Volunteers 291378 0
Condition category
Condition code
Inflammatory and Immune System 291740 291740 0 0
Autoimmune diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This placebo-controlled, First-In-Human study is looking at the safety and tolerability of a single dose and multiple dose of study drug PRN1008 in healthy volunteers.

The study is designed into two parts:
Single Dose (Part A):
Each participant will be randomised to receive either a single dose (50mg, 150mg, 300mg, 600mg, 1200mg or 1800mg) of PRN1008 oral liquid or a single dose of matching placebo (6 active: 2 placebo, N=8 per cohort). 6 dosing cohorts may be evaluated. Dosing will be escalated upon review of safety and tolerability of each cohort.

Multiple Dose (Part B)
Each participant will be randomised to receive active or placebo drug either once daily (orally) or twice daily (orally) for ten days. Up to five cohorts of eligible participants will be studied. The planned doses of either PRN1008 oral liquid or matching placebo are 300mg once daily, 300mg twice daily, 600mg once daily or 900mg once daily (8 active: 2 placebo, N=10 per cohort) An optional cohort of either 600mg twice daily or 1200mg once daily may be studied depending on the evaluation of the PK, PD and safety data. 6 dosing cohorts may be evaluated. Dosing will be escalated upon review of safety and tolerability of each cohort

For both Part A and Part B, All doses will be administered in the clinic and directly observed by study personnel to ensure compliance. Participants in Part A will be admitted to the clinic on day -1 and remain domiciled until day 3. Participants in Part B will be admitted on Day -1 or -2 and domiciled until Day 12.
Intervention code [1] 288964 0
Treatment: Drugs
Comparator / control treatment
Liquid formulation matching placebo (vehicle only)
Control group
Placebo

Outcomes
Primary outcome [1] 291676 0
To assess the safety and tolerability of single and multiple doses of PRN1008 when administered to healthy adult participants. Specific assessments to evaluate treatment safety include the following: the frequency and type of adverse events, clinical laboratory testing, 12-lead ECGs and vital signs.
Timepoint [1] 291676 0
For SAD Part A Up to 8 (+/-1) days after dosing
For MAD Part B Up to 17 days (+/-2) days after dosing
Secondary outcome [1] 307269 0
To assess the pharmacokinetics (PK) of single once-daily and multiple (once or twice daily) oral doses of PRN1008 when administered to healthy adult participants. For Part A (single dose) blood samples and urine samples will be taken throughout the study for assessment of PK.

For Part B (multiple dose) blood samples only will be taken throughout the study for assessment of PK.
Timepoint [1] 307269 0
For the SAD Part A first three cohorts blood collection time points for PK will be 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 36 and 48 hours post dose.

For the SAD Part A remaining cohorts blood collection time points for PK will be 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12 and 24 hours post dose.

For the SAD Part A (one cohort only) Urine collections for measurement of PRN1008 (one cohort only, dose to be determined) will occur pre-dose, and at times 0-4, 4-8, 8-12, and 12-24 hours after dosing. All excreted urine will be collected during each time interval.

For MAD Part B, blood samples will be collected within 15 minutes prior to dosing and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours after dosing on Day 1, at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours after dosing on Day 10, and within 15 minutes prior to dosing on Days 3, 5, and 7.


Cohort B1 only will receive a single oral dose of PRN1008 liquid formulation on Day -1 with a standardized meal. PK blood samples will be collected within 15 minutes prior to dosing and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, and 24 hours after dosing. Note: the 24 hour sample is the same sample as the pre-dose sample on Day 1.

For MAD part B, PK Blood samples will be collected
Secondary outcome [2] 307270 0
To assess the impact of PRN1008 on occupancy of Bruton’s Tyrosine Kinase (BTK).
In Part A (SAD) two blood samples at the following three time points (six samples in total) post dose will be taken to assess the BTK occupancy on Peripheral Blood Mononuclear Cells.

In Part B (MAD) two blood samples at the following ten time points (twenty samples in total) post dose will be taken to assess the BTK occupancy on Peripheral Blood Mononuclear Cells.
Timepoint [2] 307270 0
For SAD (Part A): 4, 12 and 24 hours post dose

For MAD (Part B): 4, 12 and 24 hours, post dose then Day 2, Day 3, Day 7 and Day 10 (4hrs and 12hrs post dose) Day 11 and Day 12 (36hrs post dose of Day 11 dose).

Eligibility
Key inclusion criteria
1. Healthy adult males and/or females, 18 to 55 years of age (inclusive) at the time of screening
2. Body mass index (BMI) greater than or equal to 18.0 and less than or equal to 30.5 (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 until 30 days post dosing completion of the follow-up visit. Participants will be advised to use adequate contraception for 30 days following the last administration of the study drug, and not to donate sperm during this same period of time.
5. Female participants must be surgically sterile or post-menopausal (no spontaneous menstrual period for at least one year, confirmed by FSH > 40 mIU/mL.
Sterilization procedure must have been completed at least 6 months prior to the first study drug administration. The following are acceptable:
a. Essure (Registered Trademark) 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 urine drug/alcohol breath testing at screening and check-in (Day -1).
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, and male partners of women who are pregnant or lactating
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 Investigator
5. Use of more than 1-2 tobacco/nicotine-containing products per month within 6 months prior to the first study drug administration
6. Participant is febrile, temperature greater than 37.5 degrees Celsius.
7. History or presence of alcoholism or drug abuse within the 2 years prior to the first study drug administration
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 vitamins or nutritional supplements within the 7 days prior to Day 1. Use of any prescription medication within the 14 days prior to the first study drug administration or five 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 the first study drug administration
12. Participation in another clinical trial of a drug or device whereby the last investigational drug/device administration is within 60 days prior to the first study drug administration or five half-lives, whichever is longer
13. Surgery within the past three months prior to the first study drug administration determined by the 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 insignificant by the PI
16. Screening ECG with QRS and/or T-wave judged to be unfavorable for a consistently accurate QT measurement as judged by the 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 (DBP) greater than 90 or less than 50 mm Hg
19. Resting Heart rate 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 or placebo formulation
21. Regular alcohol consumption greater than 14 units per week (1 unit = one half pint beer, 25 mL of 40% spirit or a 125 mL glass of wine)
22. Failure to satisfy the Investigator of fitness to participate for any other reason
23. Active infection
24. History of seizure, whether epileptic, paroxysmal, or of unknown origin
25. History or presence of clinically significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological, or psychiatric disease
26. Any acute illness within 30 days prior to Day 1

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 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.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
4/05/2014
Actual
4/05/2014
Date of last participant enrolment
Anticipated
Actual
18/11/2014
Date of last data collection
Anticipated
Actual
Sample size
Target
108
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA

Funding & Sponsors
Funding source category [1] 288886 0
Commercial sector/Industry
Name [1] 288886 0
Principia Biopharma Australia Pty Ltd
Country [1] 288886 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Clinical Network Services (CNS) Pty Ltd.
Address
Level 4, 88 Jephson Street, Toowong, QLD, 4066
Country
Australia
Secondary sponsor category [1] 287609 0
None
Name [1] 287609 0
n/a
Address [1] 287609 0
n/a
Country [1] 287609 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290714 0
Bellberry HREC
Ethics committee address [1] 290714 0
Ethics committee country [1] 290714 0
Australia
Date submitted for ethics approval [1] 290714 0
19/03/2014
Approval date [1] 290714 0
15/04/2014
Ethics approval number [1] 290714 0

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

Contacts
Principal investigator
Name 46914 0
Dr Janakan Krishnarajah
Address 46914 0
Linear Clinical Research Level 1, B Block, QEII Medical Centre, Hospital Ave, Nedlands WA 6009
Country 46914 0
Australia
Phone 46914 0
+61863825100
Fax 46914 0
Email 46914 0
[email protected]
Contact person for public queries
Name 46915 0
Dougal Thring
Address 46915 0
Linear Clinical Research Level 1, B Block, QEII Medical Centre, Hospital Ave, Nedlands WA 6009
Country 46915 0
Australia
Phone 46915 0
+61863825100
Fax 46915 0
Email 46915 0
[email protected]
Contact person for scientific queries
Name 46916 0
Janakan Krishnarajah
Address 46916 0
Linear Clinical Research Level 1, B Block, QEII Medical Centre, Hospital Ave, Nedlands WA 6009
Country 46916 0
Australia
Phone 46916 0
+61863825100
Fax 46916 0
Email 46916 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

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseA phase I trial of PRN1008, a novel reversible covalent inhibitor of Bruton's tyrosine kinase, in healthy volunteers.2017https://dx.doi.org/10.1111/bcp.13351
Dimensions AICurrent Clinical Trials in Pemphigus and Pemphigoid2019https://doi.org/10.3389/fimmu.2019.00978
EmbaseTranslational autoimmunity in pemphigus and the role of novel Bruton tyrosine kinase inhibitors.2022https://dx.doi.org/10.1016/j.jtauto.2022.100156
N.B. These documents automatically identified may not have been verified by the study sponsor.