ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12618000541202

Ethics application status

Approved

Date submitted

21/03/2018

Date registered

11/04/2018

Date last updated

19/09/2019

Date data sharing statement initially provided

18/01/2019

Type of registration

Prospectively registered

Titles & IDs

Public title

A Phase 1 clinical trial to assess the safety, tolerability and pharmacokinetics of PBT434 in healthy volunteers.

Scientific title

A randomised, Phase 1, double-blind, placebo-controlled single and multiple ascending dose study to assess the safety, tolerability and pharmockinetics of PBT434 in healthy volunteers.

Secondary ID [1]

None

Universal Trial Number (UTN)

U1111-1211-0052

Trial acronym

PBT434-101

Linked study record

Health condition

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

Atypical Parkinsonism

Idiopathic Parkinson's Disease

Condition category

Condition code

Neurological

Parkinson's disease

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

PBT434 is supplied as 50mg and 200 mg immediate release oral capsules. The doses in the SAD phase are: 50 mg, 100 mg, 300 mg, and 600 mg, given as a single dose. Up to two additional dose levels may be evaluated if supported by available toxicology data and approved by the SRT.

Up to four dosage regimens of PBT434 will be evaluated in the MAD portion of the study; 100 mg twice a day (200 mg Total Daily Dose (TDD), 300 mg twice a day (600 mg TDD). Up to two additional dose regimens may be evaluated based on available PK, safety, and toxicological data. The dose in the multiple ascending dose (MAD) phase is given twice daily for Days 1-7, and once daily on Day 8.

Participants do not take part in both the SAD and MAD phases. The phases are independently randomised.

In both the SAD and MAD phases, hand and mouth checks will be performed after each dose to assure that IP has been swallowed by the subject.

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Placebo is supplied as an identical looking, immediate release capsule. The single ascending dose and multiple ascending dose phases of the study are both placebo-controlled. The composition of the placebo is microcrystalline cellulose in hard gelatin capsule

Control group

Placebo

Outcomes

Primary outcome [1]

To evaluate the safety and tolerability of PBT434 after single and multiple oral dose administration by measuring adverse events (AEs), Physical examination, Vital signs, Safety 12-lead Electrocardiograms (ECGs) and Clinical laboratory values

Timepoint [1]

Single Ascending Dose Phase: Days 1, 2,3, 4, 6 post administration of dose on Day 1
Multiple Ascending Dose Phase, Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 post administration of first dose on Day 1

Secondary outcome [1]

To determine the pharmacokinetics (PK) of PBT434 (and potential metabolites) after single and multiple dose administration; by measuring plasma the following PK parameters:

• AUC(0-t)
• AUC(inf)
• %AUCextrap
• Cmax
• tmax
• t½
• Vz/F
• CL/F (parent only)
• Apparent terminal elimination rate constant

Timepoint [1]

Single Ascending Dose Phase: Plasma samples are collected on days 1, 2,3, 4, and 6 post administration of dose on Day 1. The specific plasma collection time-points are pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 4.5, 5, 5.5, 6, 8, 10, 12, 16, 24, 30, 36, 48, 72, and 120h post administration of the dose on Day 1, Multiple Ascending Dose Phase: Plasma samples are collected on Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 post administration of first dose on Day 1. The specific plasma collection time-points are: Day 1: pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 8 and 12 hour post administration of the dose on Day 1. Day 6: pre-dose following dose administration on Day 6 Day 7: pre-dose following dose administration on Day 7 Days 8, 9, 10 & 12: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, 24, 30, 36, 48 and 96 hour post administration of the dose on Day 8.

Secondary outcome [2]

To evaluate the pharmacokinetics of PBT434 (and potential metabolites) after multiple oral dose administration in healthy elderly subjects by measurement of the following plasma PK parameters:

• AUC
• Cmax
• Cmin
• Cavg
• Tmax
• t½
• PTF% (Percent Fluctuation)
• Accumulation index (Cmax SS/Cmax FD)
• Accumulation index (AUCSS/AUCFD)

Timepoint [2]

Multiple Ascending Dose Phase: Plasma samples are collected on Days 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12 post administration of first dose on Day 1. The specific plasma collection time-points are: Day 1: pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 4, 6, 8 and 12 hour post administration of the dose on Day 1. Day 6: pre-dose following dose administration on Day 6 Day 7: pre-dose following dose administration on Day 7 Days 8, 9, 10 & 12: pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, 12, 16, 24, 30, 36, 48 and 96 hour post administration of the dose on Day 8.

Secondary outcome [3]

To evaluate the preliminary effect of food on the pharmacokinetics of PBT434 (and potential metabolites) after single dose administration by measuring the following plasma PK parameters:

• AUC(0-t)
• AUC(inf)
• %AUCextrap
• Cmax
• tmax
• t½
• Vz/F
• CL/F (parent only)
• Apparent terminal elimination rate constant

Timepoint [3]

Secondary outcome [4]

To evaluate the preliminary effect of smoking on the pharmacokinetics of PBT434 (and potential metabolites) after single dose administration by measuring the following plasma PK parameters: • AUC(0-t) • AUC(inf) • Cmax (smoker versus non smoker).

Timepoint [4]

Eligibility

Key inclusion criteria

SAD and MAD phases require healthy male and female adult volunteers aged between 18 and 55 (n=106 total in this age group).

One cohort of the MAD phase will be conducted in healthy elderly participants. The elderly cohort in MAD will be comprised of healthy male and female (not of childbearing potential) volunteers aged greater than or equal to 65 years (n=10 participants in this age group).

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

History or presence of malignancy, clinically relevent medical illness, including cardiovascular, GI, hepatic, renal endocrine, neurologic and psychiatric, systemic allergic disease.

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)

Central randomisation

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

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

Intervention assignment

Other

Other design features

Single Ascending Dose Phase:
This phase will contain up to 6 dose escalation cohorts, each comprising 8 subjects per cohort randomized in a ratio of 6:2 (PBT434:placebo). Each dose cohort will use a sentinel group of 2 subjects randomized in a ratio of 1:1 (PBT434:placebo). The sentinel group will be dosed 1 day prior to the remaining subjects in each cohort. The preliminary effects of food on the PK of PBT434 will also be evaluated in one of the cohorts (dose level up to 900 mg to be selected by the Safety Review Team), as a fixed-sequence crossover. The preliminary effects of smoking on the PK of PBT434 will also be evaluated in one of the cohorts (dose to be selected by the Safety Review Team),

Multiple Ascending Dose:
There will be up to 4 dose regimens, each comprising 10 subjects per cohort randomized in a ratio of 8:2 (PBT434:placebo). The MAD phase will contain 1 cohort of elderly subjects, comprising 10 subjects randomised in a ratio of 8:2 (PBT434:placebo).

Phase

Phase 1

Type of endpoint/s

Safety

Statistical methods / analysis

Approximately 106 volunteers (96 healthy young adults, 10 healthy elderly adults) who meet all eligibility criteria will be dosed. The sample size is not based on statistical considerations . The sample sizes chosen are based on clinical and regulatory considerations and precedence for first-in-human studies. The number of subjects proposed is considered sufficient to investigate the initial safety, tolerability and PK profile of PBT434.

Recruitment

Recruitment status

Completed

Date of first participant enrolment

Anticipated

7/05/2018

Actual

21/06/2018

Date of last participant enrolment

Anticipated

4/03/2019

Actual

8/04/2019

Date of last data collection

Anticipated

29/03/2019

Actual

24/05/2019

Sample size

Target

106

Accrual to date

Final

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]

Alterity Therapeutics

Address [1]

Level 3, 460 Bourke St, Melbourne, Victoria, 3000

Country [1]

Australia

Primary sponsor type

Commercial sector/Industry

Name

Alterity Therapeutics

Address

Level 3, 460 Bourke St, Melbourne, Victoria, 3000

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [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]

28/03/2018

Approval date [1]

01/05/2018

Ethics approval number [1]

Summary

Brief summary

This is a Phase 1 Single and Multiple Ascending Dose Study of PBT434 in Healthy Volunteers.   The first in human study consists of two parts, both of which are randomised, double-blind, and placebo-controlled:  The single ascending dose (SAD) and the multiple ascending dose (MAD) parts of the study will be conducted in sequential stages.  Key safety and PK data from the SAD portion will be reviewed before progressing to the MAD part of the study.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Dr Jason Lickliter

Address

Nucleus Network
Level 5 Burnet Building AMREP Precinct
89 Commercial Rd
Melbourne, Vic, 3004

Country

Australia

Phone

+61390768960

Fax

[email protected]

Contact person for public queries

Name

Cynthia Wong

Address

Alterity Therapeutics, 39899 Balentine Drive, Suite 360, Newark, CA 94560

Country

United States of America

Phone

+16503002141

Fax

[email protected]

Contact person for scientific queries

Name

David Stamler

Address

Alterity Therapeutics, 39899 Balentine Drive, Suite 360, Newark, CA 94560

Country

United States of America

Phone

+16503002141

Fax

[email protected]

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

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

Source	Title	Year of Publication	DOI
Dimensions AI	Current experimental disease-modifying therapeutics for multiple system atrophy	2021	https://doi.org/10.1007/s00702-021-02406-z

N.B. These documents automatically identified may not have been verified by the study sponsor.

Trial Review

Documents added manually

Documents added automatically