Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620001244998
Ethics application status
Approved
Date submitted
23/09/2020
Date registered
20/11/2020
Date last updated
22/11/2021
Date data sharing statement initially provided
20/11/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase 1 Study to Evaluate a Tablet Formulation of PBT434 in Healthy Volunteers
Scientific title
A phase 1, single-center, randomized, open-label, 3-way crossover study to evaluate the systemic exposure after administration of a tablet formulation of PBT434 in the fed and fasted states compared to a powder in capsule formulation in healthy volunteers
Secondary ID [1] 302369 0
Alterity protocol PBT434-102
Universal Trial Number (UTN)
U1111-1258-5815
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Multiple System Atrophy 319152 0
Parkinson's disease 319463 0
Condition category
Condition code
Neurological 317112 317112 0 0
Neurodegenerative diseases
Neurological 317113 317113 0 0
Parkinson's disease

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
In Part I, each subject will receive three treatments (Treatments A, B, C) once each in a random sequence during Periods 1, 2, 3, as follows:
Treatment A: Single dose of PBT434 200 mg PIC (1x200 mg capsule) in the fasted state (after a minimum 10-hr fast), followed by a 4-hr fast
Treatment B: Single dose of PBT434 200 mg tablet (2x100 mg tablets) in the fasted state (after a minimum 10-hr fast), followed by a 4-hr fast
Treatment C: Single dose of PBT434 200 mg tablet (2x100 mg tablets) in the fed state (30 minutes following the start of a high-fat, high-calorie meal), followed by a 4-hr fast

In Part II, each subject will receive three treatments (Treatments D, E, F) once each in a random sequence during Periods 1, 2, 3, as follows:

Treatment D: Single dose of PBT434 75 mg tablet (1x75 mg tablet) in the fasted state (after a minimum 10-hr fast), followed by a 4-hr fast
Treatment E: Single dose of PBT434 75 mg tablet (1x75 mg tablet) in the fed state (30 minutes following the start of a high-fat, high-calorie meal), followed by a 4-hr fast
Treatment F: Single dose of PBT434 75 mg tablet (1x75 mg tablet) in the fed state (30 minutes following the start of a low-fat meal), followed by a 4-hr fast

In Part III, subjects will receive 75 mg PBT434 twice daily for 8 days.
Intervention code [1] 318655 0
Treatment: Drugs
Comparator / control treatment
In a crossover trial, participants act as their own control. Their data is analysed by comparing participants to themselves in each study period. Treatment A (PBT434 200mg PIC) is the comparator treatment in this crossover study.
Control group
Active

Outcomes
Primary outcome [1] 325200 0
Pharmacokinetic (PK) parameters for PBT434 and potential metabolites after administration of a tablet formulation compared to a powder in capsule (PIC) formulation, including AUC, Cmax, Tmax, CL/F, Vz/F and t1/2
Timepoint [1] 325200 0
Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 10, 16, 24, 32, and 48 hrs post dose
Primary outcome [2] 325201 0
Pharmacokinetic (PK) parameters for PBT434 and potential metabolites after administration of a tablet formulation of PBT434 under fed and fasting conditions, including AUC, Cmax, Tmax, CL/F, Vz/F and t1/2
Timepoint [2] 325201 0
Pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 6, 10, 16, 24, 32, and 48 hrs post dose
Secondary outcome [1] 387163 0
Safety and tolerability of PBT434 when administered as tablet and PIC formulations as measured by adverse events (AEs), Physical examination, Vital signs, Safety 12-lead Electrocardiograms (ECGs) and Clinical laboratory values
Timepoint [1] 387163 0
AEs are collected starting at signing of informed consent through the final study visit
Physical examinations: pre-dose, 24 and 48 hrs post dose. Physical examinations for Part III: pre-dose and final study visit
Vital signs: pre-dose, 0.5, 1, 1.5, 2, 4, 10, 24 and 48 hrs post dose. Vital signs for Part III: daily throughout study.
ECGs: day -1 of each study period and at the final study visit (Period 3 Day 3 OR Early Termination visit). ECGs for Part III: day -1, day 8 after end of dosing, and at the final study visit.
Clinical labs: day -1 of each study period and 24 hrs post dose. Clinical labs for Part III: day -1, 4, 8, 9

Eligibility
Key inclusion criteria
1. Male or female between 18 and 65 years old (inclusive) (Parts I and II) or 18-75 years old (Part III) at the time of consent.
Note: Part III will include at least 4 subjects =50 years old

2. In good general health, free from clinically significant medical or psychiatric illness
based on medical/surgical history, physical examination, 12-lead ECG, and clinical laboratory tests

3. Vital signs within ranges and stable (measured in supine position after 5 minutes rest)

4. Body Mass Index greater than or equal to 18kg/m2 and less than or equal to 30 kg/m2

5. Adequate venous access in the left or right arm to allow collection of the required number of blood samples

6. Provides written informed consent

7. Willing to comply with all study procedures and requirements, including consumption of a standardized high-fat, high calorie meal

8. Women of childbearing potential are using two acceptable methods of contraception through 90 days after the final dose

9. Male subjects must be using an acceptable birth control method through 90 days after the final dose

10. Female subjects must agree to not donate ova for 90 days after the final dose. Male subjects must agree to not donate sperm for 90 days after the final dose

11. No significant changes to diet within the 30 days prior to dosing through study completion

12. Willing and able to abstain from caffeine from 48 hours prior to check-in through 48 hours after dosing in each study period
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Women who are pregnant or breastfeeding

2. History or presence of malignancy, with the exception of adequately treated localized skin cancer (basal cell or squamous cell carcinoma) or carcinoma in-situ of the cervix, which are allowed

3. Evidence of any clinically relevant medical illness, including cardiovascular, hematological, gastrointestinal, hepatic, renal, rheumatologic, endocrine, pulmonary, neurologic, psychiatric or skin disorders

4. Clinically significant surgical procedure within 3 months prior to screening or anticipated surgery during the study

5. History of epilepsy (other than febrile seizures during childhood)

6. History of head trauma with loss of consciousness, amnesia or skull fracture

7. Currently suffers from clinically significant systemic allergic disease or has a history of significant drug allergies including a history of anaphylactic reaction; allergic reaction due to any drug which led to significant morbidity

8. Unable to swallow study medication

9. History or presence of cardiac arrhythmia or congenital long QT syndrome

10. QTcF >450 msec for men or >470 msec for women on screening or baseline ECG

11. Use of any tobacco or nicotine containing products (including social use) in the 3 months prior to dosing or a positive urine cotinine test prior to dosing

12. Regular alcohol consumption >2 units/day (1 unit = 250 mL of beer, 100 mL of wine, or 30 mL of distilled spirits or liquor) or alcohol consumption within 24 hours prior to dosing until study completion

13. Positive urine drug or alcohol breathalyzer test prior to study entry (during screening or Day -1) or during the study, or history of alcohol or drug abuse in the 12 months prior to dosing

14. Evidence of renal insufficiency, as indicated by an estimated creatinine clearance <90 mL/min using the Cockcroft-Gault equation

15. Any of the following abnormalities in liver enzymes at Screening or Baseline:
a. Aspartate transaminase (AST) or alanine aminotransferase (ALT) >1.5 times the upper limit of normal (ULN)
b. Alkaline phosphatase (ALP) or total bilirubin (TBil) >2 times the ULN

16. Hemoglobin value less than the lower limit of normal

17. Positive results of serology screening for hepatitis B (hepatitis B surface antigen [HBsAg]), hepatitis C (anti-hepatitis C virus [HCV] antibodies) or HIV (HIV antibodies type 1 and 2)

18. Any acute illness, clinically significant infection or clinically significant abnormal laboratory result within 28 days prior to dosing

19. Use of any prescription medication within 28 days prior to dosing

20. Use of any non-prescription medication (including non-steroidal anti-inflammatory drugs), herbal remedy (including St. John’s Wort) or vitamin supplement, within 14 days prior to dosing and throughout the study
Note: Approved doses of paracetamol (acetaminophen, up to a maximum of 2,000 mg/day) may be permitted during Screening and while on study at the investigator’s discretion.

21. Use of an investigational drug or device within 28 days or 10 half-lives of the drug, whichever is longer, prior to start of dosing (or within 6 months prior to Day -1 if investigational drug was a biologic)

22. Clinically significant blood loss or blood or plasma donation >550 mL within 90 days prior to start of dosing

23. As a result of history and physical examination, the Investigator considers the subject unfit for the study

24. Any condition (e.g., chronic diarrhea, inflammatory bowel disease) or prior surgery (including surgery of the gastrointestinal and/or biliary tract) that could interfere with drug absorption, distribution, metabolism, or excretion of the IP

25. The subject has previously participated in a clinical trial of PBT434 within 28 days prior to dosing or experienced a clinically significant adverse event in a previous clinical trial of PBT434
Note: Subjects who have previously participated in a clinical trial of PBT434 may be enrolled only if approved by the Medical Monitor

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)
Permuted block randomisation
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Pharmacokinetics
Statistical methods / analysis
Up to 42 male and female who meet all eligibility criteria will be dosed. The sample size is not based on statistical considerations. The sample size chosen is based on clinical and regulatory considerations and precedence for similar studies. The number of subjects proposed is considered sufficient to evaluate the formulation effect and food effect on the pharmacokinetics of PBT434 and potential metabolites.

Safety
All subjects who have received at least one dose of PBT434 will be evaluated for safety. Incidence of AEs by severity, relationship to treatment, and outcome will be provided. Laboratory parameters, vital signs and other safety parameters will be listed by subject and presented using descriptive summary statistics.
Demographic variables such as age, race, etc. and baseline status (medical history, physical examination, disease and treatment history, etc.) will be summarized. Treatment-emergent adverse events and laboratory, vital sign, and Safety 12-lead ECG parameters will be summarized. In addition, change from baseline will be summarized for laboratory and vital sign parameters. Shift tables will be provided for clinical laboratory results. ECG results will be classified as normal and abnormal and summarized. Cardiac intervals, including the corrected QT, PR and QRS, will be analyzed for absolute outliers based on criteria set forth in the SAP.

Pharmacokinetic Analysis

PK parameters will be summarized graphically and tabularly by treatment using descriptive statistics.
The effect of formulation (tablet vs capsule) and food (tablet fed vs tablet fasted) on PK will be assessed by comparing the ln-transformed PK parameters of interest (AUC and Cmax) using a linear mixed-effects model with sequence, treatment and period as fixed effects and subject nested within sequence as a random effect.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
2/11/2020
Date of last participant enrolment
Anticipated
30/11/2021
Actual
Date of last data collection
Anticipated
10/12/2021
Actual
Sample size
Target
42
Accrual to date
12
Final
Recruitment in Australia
Recruitment state(s)
SA,WA
Recruitment hospital [1] 17605 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment hospital [2] 21155 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 31350 0
5000 - Adelaide
Recruitment postcode(s) [2] 36014 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 306799 0
Commercial sector/Industry
Name [1] 306799 0
Alterity Therapeutics Limited
Country [1] 306799 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Alterity Therapeutics Limited
Address
Level 3, 460 Bourke Street, Melbourne, Victoria, 3000
Country
Australia
Secondary sponsor category [1] 307353 0
None
Name [1] 307353 0
Address [1] 307353 0
Country [1] 307353 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 306957 0
Bellberry Limited
Ethics committee address [1] 306957 0
123 Glen Osmond Road, Eastwood, South Australia, 5063
Ethics committee country [1] 306957 0
Australia
Date submitted for ethics approval [1] 306957 0
12/08/2020
Approval date [1] 306957 0
16/09/2020
Ethics approval number [1] 306957 0

Summary
Brief summary
This is a phase 1, single-center, randomized, open-label, 3-way crossover study to evaluate the pharmacokinetics of PBT434 after administration of a tablet formulation in the fed and fasted states and a powder in capsule formulation which has been utilized in previous Phase 1 investigations
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 105582 0
Dr Nicholas Farinola
Address 105582 0
CMAX Clinical Research
Level 5, 18a North Terrace
Adelaide, South Australia, 5000
Country 105582 0
Australia
Phone 105582 0
+61 8 7088 7900
Fax 105582 0
Email 105582 0
[email protected]
Contact person for public queries
Name 105583 0
Ms Cynthia Wong
Address 105583 0
Alterity Therapeutics
39899 Balentine Drive, Suite 360, Newark, CA 94560
Country 105583 0
United States of America
Phone 105583 0
+1 650 3002141
Fax 105583 0
Email 105583 0
[email protected]
Contact person for scientific queries
Name 105584 0
Dr David Stamler
Address 105584 0
Alterity Therapeutics
39899 Balentine Drive, Suite 360, Newark, CA 94560
Country 105584 0
United States of America
Phone 105584 0
+1650 3002141
Fax 105584 0
Email 105584 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


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
No additional documents have been identified.