ANZCTR - Registration

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

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]

None

Universal Trial Number (UTN)

Trial acronym

PN-10943A-01

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Ulcerative Colitis

Condition category

Condition code

Oral and Gastrointestinal

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]

Treatment: Drugs

Comparator / control treatment

50 mM sodium phosphate buffer solution at pH 7.4

Control group

Placebo

Outcomes

Primary outcome [1]

Safety and tolerability assessments including vital signs

Timepoint [1]

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]

Safety and tolerability assessments including clinical safety laboratory tests

Timepoint [2]

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]

Safety and tolerability assessments including electrocardiograms (ECGs)

Timepoint [3]

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]

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]

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]

2.. Pharmacodynamic assessment of PN-10943A as assessed by:
a. Changes in a4ß7 integrin expression in blood T cells.

Timepoint [2]

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]

b. Assessment of PN-10943A receptor occupancy in peripheral blood.

Timepoint [3]

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]

c. Number of a4ß7 cells in the blood

Timepoint [4]

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]

Safety and tolerability assessments including physical examinations. (This is a primary outcome)

Timepoint [5]

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]

Safety and tolerability assessments including adverse events. (This is a primary outcome)

Timepoint [6]

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

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]

Nucleus Network - Melbourne

Recruitment postcode(s) [1]

3004 - Melbourne

Funding & Sponsors

Funding source category [1]

Commercial sector/Industry

Name [1]

Protagonist Pty Ltd.

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Protagonist Pty Ltd.

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Country [1]

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

Alfred Hospital Ethics Committee

Ethics committee address [1]

 55 Commercial Rd, Melbourne, VIC 3004

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

03/10/2018

Approval date [1]

20/11/2018

Ethics approval number [1]

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

Public notes

Contacts

Principal investigator

Name

Dr Ben Snyder

Address

Nucleus Network Pty Ltd
5th Floor, Burnet Tower, AMREP Precinct
89 Commercial Road, Melbourne
VIC, 3004

Country

Australia

Phone

+61 3 9076 8960

Email

[email protected]

Contact person for public queries

Name

Chrishni Williams

Address

Nucleus Network Pty Ltd.
5th Floor, Burnet Tower, AMREP Precinct
89 Commercial Road, Melbourne
VIC, 3004

Country

Australia

Phone

+61 3 8593 9821

Email

[email protected]

Contact person for scientific queries

Name

Lucio A D Tozzi

Address

Protagonist Therapeutics Inc.,
7707 Gateway Blvd.,
Suite 140, Newark, CA 94560, USA

Country

United States of America

Phone

+1 (510) 474 0899

Email

[email protected]

Trial Review

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