Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12614001326684
Ethics application status
Approved
Date submitted
17/11/2014
Date registered
17/12/2014
Date last updated
27/06/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
Single Ascending Dose and Multiple Ascending Dose Phase I study of PXS-4728A Administered Orally in Healthy Adult Males.
Scientific title
Single Ascending Dose and Multiple Ascending Dose
Phase 1 Study to determine the safety, tolerability, pharmacokinetic and pharmacodynamic parameters of PXS-4728A Administered Orally in
Healthy Adult Males
Secondary ID [1] 285691 0
Nil
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Obstructive Pulmonary Disease 293548 0
Cystic Fibrosis 293596 0
Condition category
Condition code
Respiratory 293824 293824 0 0
Chronic obstructive pulmonary disease
Respiratory 293825 293825 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The interventional product, PXS-4728A, is a powder which will be dissolved in water for irrigation (stock solution). The final product will be formulated at 1-20 mg/100 mL in flavoured water at room temperature for oral administration.

The study is divided into 2 parts:

Part A - Single Ascending Dose (SAD) study in which PXS-4728A will be administered as a single dose (1/ 3/ 6/ 10/ 15 or 20 mg).

Part B - Multiple Ascending Dose (MAD) study in which PXS-4728A will be administered once daily from Day 1 up to Day 14. However the dose for this part of the study will be decided based on the results of the SAD study.

The interventional product will be administered to the healthy volunteers while they are confined in the clinical facility under the direct supervision of the study team. This will ensure that strict adherence to the intervention are followed.
Intervention code [1] 290631 0
Treatment: Drugs
Comparator / control treatment
The comparator/ control for this trial is 100 mL of flavoured water at room temperature which will be administered as an oral solution.
Control group
Placebo

Outcomes
Primary outcome [1] 293609 0
1. To evaluate the safety and tolerability of single ascending or repeated oral doses of PXS-4728A:
a) Recording of adverse events throughout the study.
b) Change from baseline in:
- Electrocardiogram (ECG) readings
- Clinical monitoring of blood pressure (BP)
- Heart rate (HR)
- Laboratory assessments
Timepoint [1] 293609 0
Part A (SAD): Measurements to be taken daily up to Day 5 following dosing on Day 1.

Part B (MAD): Measurements to be taken daily up to Day 21 following dosing on Day 1. Dosing will be once daily from Day until Day 14.
Secondary outcome [1] 311467 0
1. To evaluate plasma pharmacokinetic parameters after single and repeat oral dosing of PXS-4728A:
a) AUC (0-t) and AUC (0-inf)
b) Cmax – maximum concentration
c) Tmax – time to maximum observed plasma drug concentration
d) t1/2 – Terminal half-life
e) Accumulation ratio (For Part B only)
Timepoint [1] 311467 0
Blood and urine assessments were carried out for PK analysis.

Part A: To be assessed 11 times on Day 1 and once on Day 2, 3, 4 and 5.

Part B: To be assessed 11 times on Day 1 and Day 14 and once on Day 2 and Day 15.
Secondary outcome [2] 311468 0
2. Assessment of plasma pharmacodynamic parameters after single and repeat dosing of PXS-4728A:
a) SSAO activity in plasma using enzymatic assay
b) SSAO concentration in plasma using ELISA method
Timepoint [2] 311468 0
Blood assessments were carried out for PD parameters.

Part A (SAD): To be assessed 11 times on Day 1 and once on Day 2, 3, 4 and 5.

Part B (MAD): To be assessed 11 times on Day 1, once on Day 2 and Day 3 and 7 times on Day 14.

Eligibility
Key inclusion criteria
- healthy males.
- BMI - 18.5 to 30 kg/m2.
- no clinically relevant abnormality in an ECG; QTcF (QTc Fredericia’s correction) less than or equal to 450 ms, PR interval of 120-210 ms and a QRS duration less than or equal to 120 ms.
- adequate venous access.
- agree to use two approved methods of contraception from screening and until 30 days after administration of the study drug.
- has given written informed consent.
Minimum age
18 Years
Maximum age
60 Years
Sex
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
- clinically significant abnormal findings on the physical examination or medical history.
- clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, skin or cardiovascular disease.
- history of significant drug allergies/ allergic reaction or currently suffers from clinically significant systemic allergic disease.
- abnormal wound healing as the result of surgery or trauma.
- received or is anticipated to receive any prescription systemic or topical medication within 14 days prior to the start of dosing or within 5 half lives of the drug, whichever is greater, or use any complimentary or alternative medicine 48 hours prior to the start of dosing or within 5 half
lives of the drug whichever is greater (excluding paracetamol).
- systolic blood pressure <100 or >140 mmHg, diastolic blood pressure <50 or >90 mmHg and heart rate (HR) <55 or >95 bpm.
- ALT, AST or bilirubin >2x ULN.
- significant renal insufficiency, with an estimated
creatinine clearance less than 60 mL/min at screening.
- positive screening test for HbsAg or Hep C.
- history of drug abuse in the last 2 years.
- drink more than three (3) units of alcohol daily
- used nicotine-containing products within 6 weeks before screening and unable to abstain until study completion.
- consumed caffeine and/or xanthine products for at least 48 hours prior to admission to the clinical facility, and whilst confined to the clinical facility.
- consumption of grapefruit, grapefruit juice, star fruit, oranges, orange juice, Seville oranges, red wine or other alcohol within 7 days prior to administration of study drug.
- positive urine screen for drugs of abuse and alcohol breath test at screening and study check-in.
- receipt of blood or blood products, or loss or donation of 450 mL or more of blood within 90 days before the first dose administration.
- clinically significant abnormality detected on telemetry pre-dose.
- systemic infection other than coryza in the last week prior to dosing

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)
After informed consent has been obtained, all screening tests establishing subject eligibility will be performed within a period of 21 days before dosing. Subjects will be admitted to the clinical facility on Day -1.

In this study there are 6 cohorts for Part A and 3 cohorts for Part B. Each Cohort will have 8 subjects. Subjects within a cohort will be randomly assigned to one of the 2 groups (PXS-4728A or placebo) in a 3:1 ratio respectively such that there are 6 subjects receiving PXS-4728A and 2 subjects receiving placebo within each cohort.

Sentinel dosing will be conducted for the first cohort of Part A. However sentinel dosing is not planned for the remaining cohorts but can be conducted if required based on the discretion of the Principal Investigator.

In Part A, single dose of PXS-4728A/ placebo will be administered to healthy males. In Part B, PXS-4728A/ placebo will be administered once daily from Day 1 to Day 14.

Allocation will be concealed by use of pre-labelled plastic bottles containing subject randomization numbers and use of sealed opaque envelopes.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The investigational product (test or placebo) received by each volunteer will be determined according to the randomization schedule.

Block randomisation using computerised software will be used for generating randomisation sequence.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

Intervention assignment
Other
Other design features
Dose Escalating Study
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis
Demographics and baseline characteristics will be tabulated and summarised by SAD/MAD dose level. Physical examination and medical/surgical history data will be listed by subject.
All clinical safety and tolerability data will be listed for each subject and summarised by dose. Vital signs and ECG parameters will be tabulated and summarised by SAD/MAD dose level.
Laboratory values will be listed, along with comments as to clinical significance for values outside the laboratory’s normal ranges.
Treatment-emergent adverse events, following the investigational product dosing, will be listed and summarised by dose level. All adverse events reported in this study will be coded using MedDRA.
Individual plasma concentrations and blood collection times will be listed by subject. Summaries of concentration data will include mean, standard deviation and coefficient of variation by SAD/MAD dose level at each scheduled collection time.
Summaries of PK parameters by SAD/MAD dose level will include mean, SD and CV.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
14/01/2015
Actual
14/01/2015
Date of last participant enrolment
Anticipated
1/05/2015
Actual
11/05/2015
Date of last data collection
Anticipated
Actual
Sample size
Target
72
Accrual to date
Final
72
Recruitment in Australia
Recruitment state(s)
SA
Recruitment postcode(s) [1] 8930 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 290261 0
Commercial sector/Industry
Name [1] 290261 0
Pharmaxis Ltd.
Country [1] 290261 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Pharmaxis Ltd.
Address
20 Rodborough Rd, Frenchs Forest, NSW 2086
Country
Australia
Secondary sponsor category [1] 288967 0
None
Name [1] 288967 0
Address [1] 288967 0
Country [1] 288967 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291957 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 291957 0
Ethics committee country [1] 291957 0
Australia
Date submitted for ethics approval [1] 291957 0
12/11/2014
Approval date [1] 291957 0
15/12/2014
Ethics approval number [1] 291957 0
2014-11-599

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

Contacts
Principal investigator
Name 52854 0
Dr Sepehr Shakib
Address 52854 0
CMAX, a division of Institute of Drug Technology (IDT) Australia Ltd, Level 5, East Wing, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000
Country 52854 0
Australia
Phone 52854 0
+61 8 8222 2763
Fax 52854 0
+61 8 8222 2907
Email 52854 0
[email protected]
Contact person for public queries
Name 52855 0
Sepehr Shakib
Address 52855 0
CMAX, a division of Institute of Drug Technology (IDT) Australia Ltd, Level 5, East Wing, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000
Country 52855 0
Australia
Phone 52855 0
+61 8 8222 2763
Fax 52855 0
+61 8 8222 2907
Email 52855 0
[email protected]
Contact person for scientific queries
Name 52856 0
Brett Charlton
Address 52856 0
Pharmaxis Ltd.
20 Rodborough Rd, Frenchs Forest, NSW 2086
Country 52856 0
Australia
Phone 52856 0
+61 2 9454 7210
Fax 52856 0
+61 2 9451 3622
Email 52856 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

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