Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12618001851257
Ethics application status
Approved
Date submitted
7/11/2018
Date registered
14/11/2018
Date last updated
17/07/2019
Date data sharing statement initially provided
14/11/2018
Date results information initially provided
17/07/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A randomized, double-blind, placebo-controlled study of single and multiple ascending doses of PN-10943A in normal healthy volunteers
Scientific title
A randomized, double-blind, placebo-controlled study to assess the safety and tolerability of PN-1094A after single and multiple ascending doses of PN-10943A in normal healthy volunteers
Secondary ID [1] 296219 0
None
Universal Trial Number (UTN)
Trial acronym
PN-10943A-01
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Ulcerative Colitis 309978 0
Condition category
Condition code
Oral and Gastrointestinal 308750 308750 0 0
Inflammatory bowel disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Intervention: PN-10943A
Route of Administration: Oral liquid formulation
Part 1: Single Ascending Dose
Four cohorts will receive a single dose of PN-10943A 100mg, 300mg, 1000mg, 1400mg or placebo. Cohorts will run sequentially. Subjects will be dosed under fasting condition.
The same participants in Cohort 2 (300 mg PN-10943A or placebo) will return to the clinic after a period of at least 7 days to receive a second dose of PN-10943A immediately after ingestion of a standard high fat meal. The study schedule for the fed participants will be the same as the fasted participants.

Part 2: Multiple Ascending Dose
Five cohorts will be enrolled sequentially.
Cohort 5: 100 mg PN-10943A or placebo once daily for 14 days; Cohort 6: 300 mg PN-10943A or placebo once daily for 14 days; Cohort 6a: 300 mg PN-10943A once daily on 3 days (Days 1, 8 and 14); Cohort 7: 300 mg PN-10943A or placebo once daily for 14 days with meal interval of 60 minutes; and Cohort 8: 1000 mg PN-10943A or placebo once daily for 14 days.
Part 3: Cross over
Participants in Cohort 9 will receive PN-10943A (900 mg PN-10943A once daily for 5 days and 450 mg PN-10943A twice daily for 5 days) in a randomised crossover design. All participants in Cohort 9 will receive PN-10943A, no placebo.

Each cohort will enrol new subjects.

All dosing will be observed by clinic staff to ensure compliance. A record will be maintained by the investigational site which will account for all dispensing and return of any used and unused investigational products. At the end of the study the investigational products will be reconciled.
Intervention code [1] 312627 0
Treatment: Drugs
Comparator / control treatment
50 mM sodium phosphate buffer solution at pH 7.4
Control group
Placebo

Outcomes
Primary outcome [1] 307733 0
Safety and tolerability assessments including vital signs
Timepoint [1] 307733 0
Vital signs (body temperature, blood pressure, heart rate, and respiratory rate) will be performed pre-dose in both Single ascending dose and Multiple ascending dose In Single Ascending Dose: Day 1, through to Day 7. The participants will remain in the clinical trial unit post-dose through to the completion of all scheduled post-dose procedures 48 hours after dosing. This will include daily in-patient monitoring and Vital signs measured at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 hours. Body temperature, blood pressure, heart rate, and respiratory rate will be measured at all time points. In Multiple Ascending Dose: Day 1, through to Day 21. The participants will remain in the clinical trial unit post-1st dose through to the completion of all scheduled procedures 48 hours after last dosing. This will include daily in-patient monitoring and assessments as follows: Vital signs will be measured at 0.25, 0.5, 1, 2, 4, 8 and 12 hours. Body temperature, blood pressure, heart rate, and respiratory rate will be measured at all time points. In cross over dose (cohort9), vital signs will be performed over Day 1 to Day 16. The participants will remain in the clinical trial unit post-1st dose through to the completion of all scheduled procedures 48 hours after last dosing. This will include daily in-patient monitoring and assessments as follows: Vital signs will be measured at Pre-dose, Day 1 (4, 8 and 12 hours), Days 2 – Day 6, Days 13-Days 17 and during the End of Study visit (7 days after last dose).
Primary outcome [2] 308090 0
Safety and tolerability assessments including clinical safety laboratory tests
Timepoint [2] 308090 0
In Single ascending dose, Multiple ascending dose, and cross over dosing, Fasting clinical laboratory testing (haematology, coagulation, serum chemistry and urinalysis) will be will be performed pre-dose: In Single Ascending Dose: Day 1, through to Day 7 The participants will remain in the clinical trial unit post-dose through to the completion of all scheduled post-dose procedures 48 hours after dosing. Clinical laboratory testing (haematology, coagulation, serum chemistry and urinalysis) performed at 8 and 24 hours. Fasting clinical laboratory testing will also be performed at 48 hours. In Multiple Ascending Dose: Day 1, through to Day 21. The participants will remain in the clinical trial unit post-1st dose through to the completion of all scheduled procedures 48 hours after last dosing. Clinical laboratory testing (haematology, coagulation, serum chemistry and urinalysis) will be performed at 8 hours and on Days 2, 8 and 11. Fasted clinical laboratory testing will be performed on Day 3. In cross over dosing (cohort 9): Days 1 through to Day 17. The participants will remain in the clinical trial unit post-1st dose through to the completion of all scheduled procedures 48 hours after last dosing. Clinical laboratory testing (haematology, coagulation, serum chemistry and urinalysis) will be performed on Day 2 to Day 5, Day 13 – Days 16 and at End of study visit (7 days after last dosing).
Primary outcome [3] 308091 0
Safety and tolerability assessments including electrocardiograms (ECGs)
Timepoint [3] 308091 0
In both Single ascending dose and Multiple ascending dose, ECG will be performed pre-dose. In Single Ascending Dose: Day 1, through to Day 7 The participants will remain in the clinical trial unit post-dose through to the completion of all scheduled post-dose procedures 48 hours after dosing. This will include 12-Lead ECG will be performed at 2, 8, 24 and 48 hours. In Multiple Ascending Dose: Day 1, through to Day 21. The participants will remain in the clinical trial unit post-1st dose through to the completion of all scheduled procedures 48 hours after last dosing. 12-Lead ECG will be performed at 2 and 8 hours and Days 2, 3, 8 and 11. In cross over(cohort 9), 12-lead ECG will be performed at pre-dose and end of study (7 days after last dosing).
Secondary outcome [1] 352692 0
PN-10943A pharmacokinetic and pharmacodynamic parameters with and without food.
Plasma pharmacokinetic parameters:
(Cmax, Tmax, AUC0-t, AUCtau - for MAD cohorts only, Kel, AUC0-inf, t1/2, CL/F, CL/Fss - for MAD cohorts only, Vz/F, Cssave - for MAD cohorts only, AI - for MAD cohorts only

Urine pharmacokinetic parameters
Rmax, TRmax, AUCR0-last
Timepoint [1] 352692 0
In Single Ascending Dose: Baseline PK and PD blood samples will be taken within 15 minutes prior to dosing. PK blood samples will be collected at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 hours post dose. PD blood samples will be taken 1, 4, 8, 12, 24 and 36 hours post dose. In Multiple Ascending Dose): Baseline PK and PD blood samples will be taken within 15 minutes prior to dosing on Day 1, Day 8 and Day 14. PK blood samples will be collected at 0.25, 0.5, 1,2,4,8,12,24,36 after first dose, 4 , 12 hours post dose on Day 8, and 0.25, 0.5, 1, 2, 4, 8 ,12, 24 & 36 hours after last dose. PK urine and faecal samples will be collected only from participants in Cohorts 6, 7 and 8. PD blood samples will be taken 4, 12, 24 hours post 1st dose, 4 and 12 hours post Day 8 dose, 4,12,24,36,24, 36 hours post last dose and at End of Study visit. For cohort 6a, Baseline PK samples will be collected 15 minutes prior to dosing on Day1, 8 and 14. PK and PD blood samples on Day 1, 8 and Day 14 at 0.25, 0.5, 1 2, 4, 8 and 12 hours will be taken . Additional PD samples will be collected 1 hour and 8 hours post dose on dosing days (Day 1, 8, and 14). For cohort 9 Baseline PK and PD blood samples will be taken within 15 minutes prior to dosing. PK blood samples will be collected Day 1 at 0.25, 0.5, 1, 2, 4, 8, 12, 13, 16, and 20 hours, Days 2-4 at 0, 4, and 12 hours, Day 5 at 0, 0.25, 0.5, 1, 2, 4, 8, 12, 13, 16, 20 hours, and 24 hours (Day 6). PD blood samples will be collected Day 1 at 1, 4, 8, 12, 13, 16, and 20 hours, Days 2-4 at 0 hour, Day 5 at 0, 1, 4, 8, 12, 13, 16, 20, and 24 hours (Day 6).
Secondary outcome [2] 353789 0
2.. Pharmacodynamic assessment of PN-10943A as assessed by:
a. Changes in a4ß7 integrin expression in blood T cells.
Timepoint [2] 353789 0
In Single Ascending Dose: Baseline PD blood samples will be taken within 15 minutes prior to dosing. PD blood samples will be taken 1, 4, 8, 12, 24 and 36 hours post dose. In Multiple Ascending Dose): Baseline PD blood samples will be taken within 15 minutes prior to dosing on Day 1, Day 8 and Day 14.PD blood samples will be taken 4, 12, 24 hours post 1st dose, 4 and 12 hours post Day 8 dose, 4,12,24,36,24, 36 hours post last dose and at End of Study visit. For cohort 6a, PD blood samples on Day 1, 8 and Day 14 at 0.25, 0.5, 1 2, 4, 8 and 12 hours will be taken . Additional PD samples will be collected 1 hour and 8 hours post dose on dosing days (Day 1, 8, and 14). For cohort 9 Baseline PD blood samples will be taken within 15 minutes prior to dosing. PD blood samples will be collected Day 1 at 1, 4, 8, 12, 13, 16, and 20 hours, Days 2-4 at 0 hour, Day 5 at 0, 1, 4, 8, 12, 13, 16, 20, and 24 hours (Day 6).
Secondary outcome [3] 353887 0
b. Assessment of PN-10943A receptor occupancy in peripheral blood.
Timepoint [3] 353887 0
In Single Ascending Dose: Baseline PD blood samples will be taken within 15 minutes prior to dosing. PD blood samples will be taken 1, 4, 8, 12, 24 and 36 hours post dose. In Multiple Ascending Dose): Baseline PD blood samples will be taken within 15 minutes prior to dosing on Day 1, Day 8 and Day 14.PD blood samples will be taken 4, 12, 24 hours post 1st dose, 4 and 12 hours post Day 8 dose, 4,12,24,36,24, 36 hours post last dose and at End of Study visit. For cohort 6a, PD blood samples on Day 1, 8 and Day 14 at 0.25, 0.5, 1 2, 4, 8 and 12 hours will be taken . Additional PD samples will be collected 1 hour and 8 hours post dose on dosing days (Day 1, 8, and 14). For cohort 9 Baseline PD blood samples will be taken within 15 minutes prior to dosing. PD blood samples will be collected Day 1 at 1, 4, 8, 12, 13, 16, and 20 hours, Days 2-4 at 0 hour, Day 5 at 0, 1, 4, 8, 12, 13, 16, 20, and 24 hours (Day 6).
Secondary outcome [4] 353888 0
c. Number of a4ß7 cells in the blood
Timepoint [4] 353888 0
In Single Ascending Dose: Baseline PD blood samples will be taken within 15 minutes prior to dosing. PD blood samples will be taken 1, 4, 8, 12, 24 and 36 hours post dose. In Multiple Ascending Dose): Baseline PD blood samples will be taken within 15 minutes prior to dosing on Day 1, Day 8 and Day 14.PD blood samples will be taken 4, 12, 24 hours post 1st dose, 4 and 12 hours post Day 8 dose, 4,12,24,36,24, 36 hours post last dose and at End of Study visit. For cohort 6a, PD blood samples on Day 1, 8 and Day 14 at 0.25, 0.5, 1 2, 4, 8 and 12 hours will be taken . Additional PD samples will be collected 1 hour and 8 hours post dose on dosing days (Day 1, 8, and 14). For cohort 9 Baseline PD blood samples will be taken within 15 minutes prior to dosing. PD blood samples will be collected Day 1 at 1, 4, 8, 12, 13, 16, and 20 hours, Days 2-4 at 0 hour, Day 5 at 0, 1, 4, 8, 12, 13, 16, 20, and 24 hours (Day 6).
Secondary outcome [5] 353917 0
Safety and tolerability assessments including physical examinations. (This is a primary outcome)
Timepoint [5] 353917 0
In Single ascending dose, Multiple ascending and cross over dose, the directed physical examination will be performed pre-dose: In Single Ascending Dose: Day 1, through to Day 7 The participants will remain in the clinical trial unit post-dose through to the completion of all scheduled post-dose procedures 48 hours after dosing. This will include Directed physical examination as follows at 8, 24 and 48 hours. In Multiple Ascending Dose: Day 1, through to Day 21,. The participants will remain in the clinical trial unit post-1st dose through to the completion of all scheduled procedures 48 hours after last dosing. This will include Directed physical examination at 8 hours and days 3 to 13. In cross over Dose: Day 1, through to Day 17,. The participants will remain in the clinical trial unit post last dose through to the completion of all scheduled procedures 48 hours after last dosing. This will include Directed physical examination on Day 1 8-hour post dose, Day 12 8-hour post dose, Days 2-6, Days 13-17 and End of Study visit (7 days after last dose)
Secondary outcome [6] 353918 0
Safety and tolerability assessments including adverse events. (This is a primary outcome)
Timepoint [6] 353918 0
In Single Ascending Dose: Day 1, through to Day 7 The participants will remain in the clinical trial unit post-dose through to the completion of all scheduled post-dose procedures 48 hours after dosing. This will include Adverse Events and concomitant medications continually monitored and specifically reviewed at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36 and 48 hours. In Multiple Ascending Dose: Day 1, through to Day 21. The participants will remain in the clinical trial unit post-1st dose through to the completion of all scheduled procedures 48 hours after last dosing. This will include Adverse Events and concomitant medications continually monitored and specifically reviewed at 0.25. 0.5, 1, 2, 4, 8 and 12 hours and daily. In cross over Dose: Day 1, through to Day 17,. The participants will remain in the clinical trial unit post last dose through to the completion of all scheduled procedures 48 hours after last dosing. This will include Adverse Events and concomitant medications continually monitored and specifically reviewed at Day 1(0.25. 0.5, 1, 2, 4, 8 and 12 hours) on Day 2-Days 6, Days 13-17 and End of study visit (7 days after last dose).

Eligibility
Key inclusion criteria
Normal healthy volunteers 18-55 years
Good general health,
BMI 18-30kg/m2
Non-smokers
Lab values within normal range. Willing to consume standard meal provided.
Ability and willingness to attend visits to the site and provide written informed consent prior to entry into the study.
Minimum age
18 Years
Maximum age
55 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
History of significant abnormalities or diseases
Clinical significant lab or ECG abnormalities
Mentally or legally incapacitated
History of substance abuse, severe allergic or anaphylactic reactions. Regular Alcohol consumption (>21units per week).
Inability to comply with the requirements of the study protocol

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)
A randomisation list will be generated by the unblinded statistician and be transferred electronically to the pharmacist on site
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation provided by the biostatistician.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving 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
26/11/2018
Actual
10/12/2018
Date of last participant enrolment
Anticipated
28/06/2019
Actual
6/06/2019
Date of last data collection
Anticipated
31/07/2019
Actual
28/06/2019
Sample size
Target
100
Accrual to date
Final
97
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 12140 0
Nucleus Network - Melbourne
Recruitment postcode(s) [1] 24310 0
3004 - Melbourne

Funding & Sponsors
Funding source category [1] 300816 0
Commercial sector/Industry
Name [1] 300816 0
Protagonist Pty Ltd.
Country [1] 300816 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Protagonist Pty Ltd.
Address
306 Carmody Road,
St Lucia, Brisbane, QLD 4067 Australia
Country
Australia
Secondary sponsor category [1] 300456 0
None
Name [1] 300456 0
Address [1] 300456 0
Country [1] 300456 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 301585 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 301585 0
55 Commercial Rd, Melbourne, VIC 3004
Ethics committee country [1] 301585 0
Australia
Date submitted for ethics approval [1] 301585 0
03/10/2018
Approval date [1] 301585 0
20/11/2018
Ethics approval number [1] 301585 0

Summary
Brief summary
Protagonist Therapeutics, Inc. is developing PN-10943A as a potential oral therapy for patients with ulcerative colitis (UC).
This study will be conducted in upto 80 normal healthy male subjects who meet all of the inclusion criteria and none of the exclusion criteria. The study is to assess the safety and tolerability of PN-10943A to normal healthy volunteers.
This includes vital signs, safety labs, ECGs, and physical examinations

The drug will be given in single ascending then multiple ascending doses.

The study will also evaluate the PK and PD of the drug after dose administration.
Participants will be entered into standard study cohorts.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 87474 0
Dr Ben Snyder
Address 87474 0
Nucleus Network Pty Ltd
5th Floor, Burnet Tower, AMREP Precinct
89 Commercial Road, Melbourne
VIC, 3004
Country 87474 0
Australia
Phone 87474 0
+61 3 9076 8960
Fax 87474 0
Email 87474 0
[email protected]
Contact person for public queries
Name 87475 0
Ms Chrishni Williams
Address 87475 0
Nucleus Network Pty Ltd.
5th Floor, Burnet Tower, AMREP Precinct
89 Commercial Road, Melbourne
VIC, 3004
Country 87475 0
Australia
Phone 87475 0
+61 3 8593 9821
Fax 87475 0
Email 87475 0
[email protected]
Contact person for scientific queries
Name 87476 0
Mr Lucio A D Tozzi
Address 87476 0
Protagonist Therapeutics Inc.,
7707 Gateway Blvd.,
Suite 140, Newark, CA 94560, USA
Country 87476 0
United States of America
Phone 87476 0
+1 (510) 474 0899
Fax 87476 0
Email 87476 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
It’s a healthy volunteer study and the individual participant results are not useful to the participants or to others outside of the sponsor.


What supporting documents are/will be available?

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1    



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