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Trial registered on ANZCTR


Registration number
ACTRN12617001444370
Ethics application status
Approved
Date submitted
3/10/2017
Date registered
11/10/2017
Date last updated
24/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A study of the safety and pharmacokinetics and pharmacodynamics of the LOXL2 inhibitor PXS-5338K in healthy male subjects given single and repeated doses.
Scientific title
Single Ascending Dose and Multiple Ascending Dose Phase I Study of PXS-5338K Administered Orally in Healthy Adult Males.
Secondary ID [1] 293058 0
PXS-5338K-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Nonalcoholic steatohepatitis (NASH) 304746 0
Other fibrotic diseases 304747 0
Condition category
Condition code
Inflammatory and Immune System 304125 304125 0 0
Other inflammatory or immune system disorders
Oral and Gastrointestinal 304308 304308 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
PXS-5338K has been developed to be an anti-fibrotic medication for once daily oral administration in patients for the treatment of NASH (non-alcoholic steatohepatitis) and other fibrosis based diseases.

Subjects will be randomised to receive PXS-5338K (active) or matching placebo in single ascending doses (SAD) or multiple ascending doses (MAD).

PXS-5388K will be in a capsule form and will be administered orally followed by 200ml of water.

Dose levels for SAD will begin at 10 mg and increase to 400 mg over 6 Cohorts. Dose for each cohort are as follows:
Cohort 1 – PXS-5338K = 10 mg
Cohort 2 – PXS-5338K = 30 mg
Cohort 3 – PXS-5338K = 60 mg
Cohort 4 – PXS-5338K = 100 mg
Cohort 5 – PXS-5338K = 200 mg
Cohort 6 – PXS-5338K = 400 mg

The doses for the MAD phase will be chosen based on the safety/tolerability data collected from the SAD phase.

Cohort 7, Cohort 8 and Cohort 9 of MAD study will be planned following consideration of safety, tolerability and PK assessment of preceding SAD and/or repeat dose cohorts. However the most likely doses for MAD study will be between 60 and 200 mg for 14 days once daily.

For the SAD, there will be outpatient visits on Day 3 and 4. For the MAD Phase, follow up visits will be done on Day, 16, 17 and 18. The Exit Evaluation visit will be done at Day 5 for the SAD and Day 21 for the MAD.
Intervention code [1] 299169 0
Treatment: Drugs
Comparator / control treatment
Matching Placebo will be used as the comparator/control treatment for this study. The placebo will be in gelatin capsule containing mannitol and sodium stearate
Control group
Placebo

Outcomes
Primary outcome [1] 303445 0
To evaluate the safety and tolerability of single ascending or repeated oral doses of PXS-5338K
Timepoint [1] 303445 0
14 days

Incidence of adverse events.
Physical examination: At Screening, check-in and also at discharge from the study centre (Day 2 for single dose, Day 15 for multiple dose) and Exit Evaluation Visit (i.e. Day 5 and Day 21 for SAD and MAD respectively).

12-lead ECG
SAD: At screening, on Day 1 at pre-dose (-30 minutes), and 1, 2 and 4 hours post-dose and on Day 2 (24 hours post dose) and on Day 3 (48 hours post dose) and on Day 5 (Exit Evaluation Visit).

MAD: At screening and on Day 1 at
pre-dose (-30 minutes), and 1, 2 and 4 hours post-dose and on Day
4, Day 8, Day 14 and on Day 21 (Exit Evaluation Visit).

Cardiac telemetry
SAD: commencing approx. 12 hours prior to dosing and continued for at least 24 hours post Day 1 dose.
MAD: commencing approx. 12 hours prior to dosing on Day 1 and Day 14 and continued for at least 24 hours post Day 1 and Day 14 dosing respectively.

Vital signs
SAD: Screening, check-in and on Day 1 at pre-dose (-30 minutes), 0.25, 0.5, 1, 2, 4, 6, 8 and 12 hours and then on Day 2, Day 3 and Day 4 and on Day 5 (Exit Evaluation Visit).
MAD: Screening, check-in and on Day 1 at pre-dose (-30 minutes), 0.25, 0.5, 1, 2, 4, 6, 8 and 12 hours and then on Day 2, Day 3, Day 4, Day 6, Day 8, Day 10, Day 12 and Day 14 (1 hour post dose on each of these days) and on Day 18 and Day 21 (Exit Evaluation Visit).

Clinical laboratory samples include urinalysis, biochemistry, haematology and coagulation.
SAD: Screening, check-in (Day -1), on day of discharge (Day 2) and on Exit Evaluation Visit (Day 5).
MAD: Screening, check-in (Day -1), Day 7, on day of discharge (Day 15) and on Exit Evaluation Visit (Day 21).
Secondary outcome [1] 338943 0
To evaluate plasma pharmacokinetic parameters after single and repeat oral dosing of PXS-5338K

For SAD, PK parameters to be determined will include:
1. AUC (0-24) and AUC (0-inf)
2. Cmax – maximum concentration
3. Tmax – time to maximum observed plasma drug concentration
4. t1/2 – Terminal half-life

For MAD, PK parameters to be determined will include:
1. Cmax, Tmax, AUC (0-24), AUC (0-inf) on Day 1
2. Cmax, Tmax, AUC (0-24), t1/2 on Day 7 and 14.
3. Accumulation ratio, AUC (0-24, Day 7/14)/ AUC (0-24, Day 1) along with
Cmax (Day 7/14)/ Cmax (Day 1)
Timepoint [1] 338943 0
SAD (Part A): assessed by collection of pharmacokinetic blood and urine samples up to Day 5 (End of Study).

Blood samples for plasma PK analysis will be taken on Day 1 at pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post dose (15 samples total).

Voided urine samples will be collected for PK analysis for up to 24 hours post Day 1, Day 7 and Day 14 dosing over intervals of 0-4, 4-8, 8-12 and 12-24 hours.


MAD (Part B): assessed by collection of pharmacokinetic blood and urine samples up to Day 15.

Blood samples for plasma PK analysis will be taken on Days 1,7, and 14 at pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, and 12 hours post dose, on Day 2 and Day 8 at 23.5 hours post and Day 15 at 24 hours post Day 14 dose, respectively (36 samples in total).

Voided urine samples will be collected for PK analysis for up to 24 hours post Day 1, Day 7 and Day 14 dosing over intervals of 0-4, 4-8, 8-12 and 12-24 hours.
Secondary outcome [2] 339055 0
Assessment of plasma pharmacodynamic parameters after single and repeat dosing of PXS-5338K.

Serum levels of LOXL2 and target engagement of LOXL2 by PXS-5338K
Timepoint [2] 339055 0
SAD (Part A): assessed by collection of pharmacodynamic blood samples up to Day 5 (End of Study).
Blood samples for plasma PD analysis will be taken on Day 1 at pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72 and 96 hours post dose (15 samples in total).

MAD (Part B): assessed by collection of pharmacodynamic blood samples up to Day 21 (End of Study).
Blood samples for plasma PD analysis will be taken at pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 23.5 and 47.5 hours post-Day 1 dose, Day 7 at pre-dose, and at 6, 12 and 23.5 hours post dose. Day 14 at pre-dose and at 2, 24, 48, 72, 96 and 168 hours post dose (24 samples in total).

Eligibility
Key inclusion criteria
1. Male and aged between 18 and 60 years (inclusive).
2. Body Mass Index (BMI) between 18.5 kg/m2 and 30 kg/m2 inclusive.
3. 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.
4. Adequate venous access in the left or right arm to allow collection of a number of blood samples.
5. Agrees to use a condom, and in the case of partner who is potentially childbearing at least one other method of contraception, from Screening and until 30 days after administration of the study drug. Agreed methods of contraception may include approved birth control pills, patches, implants or injections by the subject’s partner, use of an IUD (intra uterine device) by the subject’s partner and/or surgical sterilisation of the participant (vasectomy at least six months prior to dosing).
6. Have given written informed consent to participate in this study in accordance with local regulations.
Minimum age
18 Years
Maximum age
60 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. Clinically significant abnormal findings on the physical examination or medical history which, in the opinion of the Principal Investigator, would jeopardize the safety of the subject or impact the validity of the study results.
2. Clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, skin or cardiovascular disease or any other condition, which, in the opinion of the Principal Investigator, would jeopardize the safety of the subject or impact the validity of the study results.
3. History of immediate hypersensitivity to any medication or currently suffers from clinically significant systemic allergic disease.
4. Evidence of abnormal wound healing (e.g. hypertrophic scars) as the result of surgery or trauma as deemed by the Principal Investigator or delegate.
5. Presence of a currently healing wound, recent musculoskeletal injury or currently healing fracture
6. Have 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 of any over-the-counter, complementary or alternative medicine 48 hours prior to the start of dosing
(excluding paracetamol).
7. At investigator discretion if Systolic blood pressure <100 or >160 mmHg, diastolic blood pressure <50 or >95 mmHg and heart rate (HR) <45 or >100 bpm.
8. ALT, AST or bilirubin >1.5x ULN.
9. Hb, WBC, neutrophils, platelets < LLN
10. Evidence of significant renal insufficiency, as indicated by an estimated creatinine clearance using the Cockcroft-Gault formula of less than 60 mL/min at Screening.
11. Positive Screening test for Hepatitis B surface antigen or Hepatitis C antibody or HIV (human immunodeficiency virus).
12. History of drug abuse in the last 2 years.
13. Males who regularly drink more than three (3) units of alcohol daily (1 unit = 285 mL beer (4.9% Alc./Vol), 100 mL wine (12% Alc./Vol), 30mL spirit (40% Alc./Vol)).
14. Used nicotine-containing products (e.g., cigarettes, cigars, chewing tobacco, snuff) within 6 weeks before screening and unable to abstain from using these products until study completion.
15. Unable to abstain from consuming caffeine and/or xanthine products (i.e., coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.) for at least 48 hours prior to admission to the clinical facility, and whilst confined to the clinical facility.
16. Consumption of grapefruit, grapefruit juice, star fruit, oranges, orange juice, Seville oranges, apple juice, red wine or other alcohol within 7 days prior to administration of study drug and during the conduct of the study.
17. Positive urine screen for drugs of abuse and alcohol breath test at screening and study check-in. Subjects may undergo a repeat urine drug screen or alcohol breath test at the discretion of the Principal Investigator.
18. 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.
19. Any condition that would interfere with drug absorption (e.g. chronic diarrhoea).
20. Have participated in a clinical trial or have received an experimental therapy within 30 days or 10 half-lives of the drug, whichever is the longer, prior to dosing.
21. Clinically significant abnormality detected on telemetry pre-dose.
22. Systemic infection other than common cold in the week prior to dosing.
23. Have received any vaccines (e.g. influenza) within 30 days before the first dose administration and during the conduct of the study.

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Other design features
Phase
Phase 1
Type of endpoint(s)
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 9078 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 17571 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 297449 0
Commercial sector/Industry
Name [1] 297449 0
Pharmaxis Ltd
Address [1] 297449 0
20 Rodborough Rd
Frenchs Forest, NSW 2086
Country [1] 297449 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] 296445 0
None
Name [1] 296445 0
Address [1] 296445 0
Country [1] 296445 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298557 0
Bellberry Human Research Ethics Committee
Ethics committee address [1] 298557 0
129 Glen Osmond Road
Eastwood SA 5063
Ethics committee country [1] 298557 0
Australia
Date submitted for ethics approval [1] 298557 0
06/09/2017
Approval date [1] 298557 0
06/10/2017
Ethics approval number [1] 298557 0

Summary
Brief summary
Groups of healthy male subjects will be administered escalating single doses of PXS-5338K to examine the safety, pharmacokinetic and pharmacodynamic profiles of PXS-5338K. This study will also investigate the safety, pharmacokinetic and pharmacodynamic profiles after repeated doses of PXS-5338K over a 14 day period.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 77458 0
Prof Sepehr Shakib
Address 77458 0
CMAX Clinical Research Pty Ltd
Level 5, 18a North Terrace
Adelaide SA 5000
Country 77458 0
Australia
Phone 77458 0
+61870887900
Fax 77458 0
Email 77458 0
Sepehr.Shakib@sa.gov.au
Contact person for public queries
Name 77459 0
Mr David McGarvey
Address 77459 0
Pharmaxis Ltd,
20 Rodborough Rd,
Frenchs Forest, NSW 2086
Country 77459 0
Australia
Phone 77459 0
+61 2 9454 7203
Fax 77459 0
Email 77459 0
David.Mcgarvey@pharmaxis.com.au
Contact person for scientific queries
Name 77460 0
Dr Brett Charlton, MBBS, FRACP
Address 77460 0
Pharmaxis Ltd,
20 Rodborough Rd,
Frenchs Forest, NSW 2086
Country 77460 0
Australia
Phone 77460 0
+61 2 9454 7210
Fax 77460 0
Email 77460 0
brett.charlton@pharmaxis.com.au

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary