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Trial registered on ANZCTR


Registration number
ACTRN12617001564347
Ethics application status
Approved
Date submitted
2/11/2017
Date registered
21/11/2017
Date last updated
13/02/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Single Ascending Dose and Multiple Ascending Dose Phase I Study of PXS-5382A Administered Orally
Scientific title
A Single Ascending Dose and Multiple Ascending Dose Phase I Study of PXS-5382A Administered Orally in Healthy Male Adult Volunteers
Secondary ID [1] 293265 0
SG200
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Idiopathic Pulmonary Fibrosis 305324 0
Non- alcoholic Steatohepatitis 305325 0
Liver Fibrosis 305326 0
Kidney Fibrosis 305327 0
Condition category
Condition code
Oral and Gastrointestinal 304618 304618 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon
Respiratory 304619 304619 0 0
Other respiratory disorders / diseases
Renal and Urogenital 304695 304695 0 0
Other renal and urogenital disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a randomised, double-blind, placebo controlled, dose escalating Phase 1 study. The study will follow a sequential dose-escalating design and will have two phases; the Single Ascending Dose phase and the Multiple Ascending Dose phase.

Sentinel dosing will be conducted for each cohort, such that;
Sentinel dosing – Total N = 2, where
N=1 = PXS-5382A
N=1 = Placebo

Main Cohort – Total N = 6, where
N=5 = PXS-5382A
N=1 = Placebo

SAD Phase
Cohort 1 PXS-5382A = 5mg
Cohort 2 PXS-5382A= 10 mg
Cohort 3 PXS-5382A= 20 mg
Cohort 4 PXS-5382A= 50 mg
Cohort 5 PXS-5382A= 100 mg
Cohort 6 PXS-5382A=200 mg

MAD Phase
The exact number of cohorts in the MAD phase of the study will be determined after review of the SAD phase data. It is likely that there will be 3 cohorts consisting of 8 subjects each per cohort in the MAD phase of the study.

The selection of appropriate doses, dosing duration and study population for the MAD phase will be confirmed upon evaluation of the PK data and all safety information as well as any other relevant data that is available from the SAD phase.

Possible dose range for MAD is between 60 and 200 mg. The mode of administration will be oral tablet. The anticipated duration is 7-14 days.

For each subject, the duration of the study clinic visits from screening (allowing 28 days) to the Day 14 (± 2) Follow-Up Visit is approximately 6 weeks.
For each subject in SAD, clinical facility confinement will be approximately 4 days, starting on Day -1, with discharge following the 72 hour post-dose assessments on the morning of Day 4. Subjects will return for out-patient visits on Days 5 and 14.

MAD:
The duration of dosing for the MAD phase will be determined post review of the SAD phase data, however this will be no longer than 14 days but could be shorter for example 5 half-lives of PXS-5382A. Subjects will remain in the unit for the entire duration of the MAD dosing and will comply with follow-up visits as planned.

Intervention code [1] 299524 0
Treatment: Drugs
Comparator / control treatment
Placebo is made up of 50.5 mg mannitol and 0.15 Mg-stearate with a total capsule weight of 0.59.
Control group
Placebo

Outcomes
Primary outcome [1] 303851 0
To evaluate the safety and tolerability of single and repeated ascending oral doses of PXS-5382A.

SAD:
Physical examination: Full physical examination at Screening, on Day -1 and Day 1. Symptom directed physical examination on Day 2, Day 3, Day 4, Day 5 (at 24, 48, 72 and 96 hours post dose, respectively) and on Day 14.

12-lead ECG (taken in triplicate 1 minute apart after laying for 5 minutes in semi-supine position): At Screening, on Day 1 at pre-dose (-2 hours), 1, 2, 4, 6, 8, 12 hours post dose and on Day 2, Day 3 , Day 5 (at 24, 48 and 96 hours post dose, respectively) and on Day 14.

Cardiac Telemetry: commencing pre-dose (-2 hours) and continuing for 24 hours post-dose (Day 2).

Vital signs: At Screening, on Day -1, on Day 1 at pre-dose (-2 hours), 0.25, 0.5, 1, 2, 4, 6, 8 and 12 hours post dose and then on Day 2, Day 3, Day 4 Day 5 (at 24, 48, 72 and 96 hours post dose, respectively) and on Day 14.

Adverse Events: AEs will be monitored from the time of signed informed consent until the Follow-Up Visit.

SAD: At Screening, Day -1, on Day 2, on Day 5 and on Day 14. Clinical laboratory samples include urinalysis, biochemistry, haematology and coagulation.

MAD:
Physical examination: Full physical examination at Screening, on Day -1 and Day 1. Symptom directed physical examination will be performed on all treatment days, at the Exit Evaluation Visit and Follow-Up Visit.

12-lead ECG (taken in triplicate 1 minute apart after laying for 5 minutes in semi-supine position): At Screening, on Day 1 at pre-dose (-2 hours), 1, 2, 4, 6, 8, 12 hours post dose, at the Exit Evaluation Visit and at the Follow-Up Visit. The timing of further ECG measurements will be determined by the duration of dosing and will be decided upon post review of the SAD phase data.

Cardiac Telemetry: commencing pre-dose (-2 hours) and continuing for 24 hours post Day 1. The timing of further cardiac telemetry will be determined by the duration of dosing and will be decided upon post review of the SAD phase data.

Vital signs: At Screening, on Day -1, on Day 1 at pre-dose (-2 hours), 0.25, 0.5, 1, 2, 4, 6, 8 and 12 hours post dose, at the Exit Evaluation Visit and at the Follow-Up Visit. The timing of further vital sign measurements will be determined by the duration of dosing and will be decided upon post review of the SAD phase data.

Adverse Events: AEs will be monitored from the time of signed informed consent until the Follow-Up Visit.

MAD: At Screening, Day -1,at the Exit Evaluation Visit and Follow-Up Visit. The timing of further clinical laboratory analysis will be determined by the duration of dosing and will be decided upon post review of the SAD phase data. Clinical laboratory samples include urinalysis, biochemistry, haematology and coagulation.

SAD: On Day -1, on Day 2 and on Day 5.
MAD: Day -1 and at the Exit Evaluation Visit. The timing of further biomarker analysis will be determined by the duration of dosing and will be decided upon post review of the SAD phase data.
Timepoint [1] 303851 0
SAD:
For each subject, the duration of the study clinic visits from screening (allowing 28 days) to the Day 14 (± 2) Follow-Up Visit is approximately 6 weeks.
For each subject in SAD, clinical facility confinement will be approximately 4 days, starting on Day -1, with discharge following the 72 hour post-dose assessments on the morning of Day 4. Subjects will return for out-patient visits on Days 5 and 14.

MAD:
On Day 1, blood samples for plasma PK analysis will be taken at pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8 and 12 hours post-dose and on Day 2 at 24 hours post dose. Further PK blood sample timings will be determined by the duration of dosing and will be decided upon post review of the SAD phase data.
Secondary outcome [1] 340276 0
For PK:
o AUC (0-t) and AUC (0-inf)
o Cmax – maximum concentration
o Tmax – time to maximum observed plasma drug concentration
o Terminal half-life (t1/2)
o Accumulation ratio (For MAD phase only)
Timepoint [1] 340276 0
Study Procedures - Blood PK sampling times
SAD:
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 in total).
MAD:
On Day 1, blood samples for plasma PK analysis will be taken at pre-dose and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8 and 12 hours post-dose and on Day 2 at 24 hours post dose. Further PK blood sample timings will be determined by the duration of dosing and will be decided upon post review of the SAD phase data.

Urine PK sampling times
SAD:
Voided urine will be collected pre-dose and for up to 24 hours post Day 1 dosing over intervals of 0 – 4, 4 – 8, 8 – 12 and 12 – 24 hours.

MAD:
Voided urine will be collected pre-dose and for up to 24 hours post Day 1 over intervals of 0 – 4, 4 – 8, 8 – 12 and 12 – 24 hours. Further urine sample collection timings will be determined by the duration of dosing and will be decided upon post review of the SAD phase data.
Secondary outcome [2] 340415 0
For PD (subject to the availability of an assay which at the time of writing is currently being developed)
o Active LOXL2 concentration in serum using validated assay
o Total LOXL2 concentration in serum using enzyme linked immunosorbent assay (ELISA) method
Timepoint [2] 340415 0
PD sampling times
SAD:
Blood samples for serum 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:
Blood samples for serum PD analysis will be taken at pre-dose and at, 6, 8, 12, 24 post-dose Day 1. Further PD blood sample timings will be determined by the duration of dosing and will be decided upon post review of the SAD phase data.

Eligibility
Key inclusion criteria
Healthy males, aged between 18 and 60 years (inclusive).
2. Eligibility of the subjects will be based on clinical history, physical examination, ECG and Lab results
3. BMI between 18.5 kg/m2 and 30.0 kg/m2 inclusive.
4. No clinically relevant abnormality in an ECG; QTcF (Fredericia’s corrected QT) > or equals to 450 ms, PR interval of 120-210 ms and a QRS duration < or equals to 120 ms.
5. Adequate venous access in the left or right arm to allow collection of a number of blood samples.
6. Male subjects with female partners of childbearing potential may be enrolled if they:
a. are documented to be surgically sterile (vasectomy at least six months prior to dosing), or
b. practice true abstinence for 30 days after the study drug administration, or
c. agree to use a barrier method of contraception (e.g. condom) from Screening and until 30 days after administration of the study. Additionally, the female partner must use a highly effective hormonal method, such as birth control pills, patches, implants or injections; or use an intra uterine device (IUD).
Contraceptive requirements do not apply to subjects who are exclusively in same-sex relationships.
7. 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
Clinically significant abnormal findings on the physical examination, medical history, ECG or laboratory results as deemed by the PI (or delegate).
2. Clinically significant gastrointestinal, renal, hepatic, neurologic, haematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, skin or cardiovascular disease or any other condition, which, in the opinion of the PI (or delegate), would jeopardise the safety of the subject or impact the validity of the study results.
3. History of significant drug allergies or significant allergic reaction or currently suffers from clinically significant systemic allergic disease. Mild hay fever is acceptable.
4. Evidence of abnormal wound healing (e.g. hypertrophic scars) as the result of surgery or trauma as deemed by the PI or delegate.
5. Have received or is anticipated to receive any prescription systemic or topical medication, or any over the counter, complimentary or alternative medicine 7 days prior to the start of dosing or within 5 half-lives of the drug whichever is longer (excluding paracetamol).
6. Systolic BP <90 or >140 mmHg, diastolic BP <40 or >90 mmHg and HR <40 or >100 beats per minute (BPM).
7. ALT, AST or bilirubin >1.5x ULN.
8. Gilbert’s syndrome sufferers are not eligible.
9. Evidence of significant renal insufficiency, as indicated by an estimated creatinine clearance using the Cockcroft-Gault formula of less than 80 mL/min at Screening.
10. Positive Screening test for Hepatitis B surface antigen or Hepatitis C antibody or human immunodeficiency virus (HIV)
11. Any condition directly or indirectly caused by or associated with Transmissible Spongiform Encephalopathy (TSE) Creutzfeldt-Jakob Disease (CJD) variant Creutzfeldt-Jakob Disease (vCJD) or new variant Creutzfeldt-Jakob Disease (nvCJD)
12. History of drug abuse in the last 2 years
Males who regularly drink more than four (4) units of alcohol daily (1 unit = 285 mL beer (4.9% Alc./Vol), 100 mL wine (12% Alc./Vol), 30 mL spirit (40% Alc./Vol)).
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 defined periods (e.g., for at least 48 hours prior to admission to the clinical facility, and whilst confined to the clinical facility).
16. Consumption of:
a. Grapefruit, grapefruit juice, star fruit, oranges, orange juice, Seville oranges (CYP450 enzymes) within 7 days prior to administration of the study drug.
b. Poppy seeds and poppy seed products within 7 days prior to administration of the study drug.
c. Alcohol within 48 hours 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 PI (or delegate).
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 3 months or 5 half-lives of the drug, whichever is the longer, prior to dosing.
21. Clinically significant abnormality detected on cardiac telemetry pre-dose.
22. Systemic infection other than coryza in the last 4 weeks 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)
To ensure maximal safety, each strength and the related placebo will have its own unique colour code.

The randomisation codes will be maintained under controlled access. As the study is double-blinded, sealed subject-specific code break envelopes will be produced by the statistician and will be kept at the clinical study site in a secure location with controlled access.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computerised sequence generation will be used to create the randomisation for the study.

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
This is a randomised, double-blind, placebo controlled, dose escalating Phase 1 study. The study will follow a sequential dose-escalating design and will have two phases; the SAD phase and the MAD phase
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A sample size of 8 subjects in each cohort (6 active, 2 placebo) has been chosen as an appropriate number of subjects required to evaluate safety and tolerability and to estimate systemic PK of PXS-5382A. This is typical of subject numbers in similar first-in-human SAD/MAD studies. This number of subjects receiving active and placebo is sufficient to show statistical significance at 5% level if an assessment of concern is reported in 5 of the 6 subjects who receive active and in no subjects who receive placebo.

Quantitative data will be summarised by descriptive statistics, including mean, standard deviation (SD), minimum and maximum. Summaries will include median for quantitative data that is not continuous. Qualitative data will be summarised by counts in relevant categories.
Summaries of PXS-5382A plasma and urine concentrations over time and pharmacokinetic parameters will include mean, SD and coefficient of variation (CV), and also median or geometric mean where appropriate.

Recruitment
Recruitment status
Recruiting
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,WA
Recruitment hospital [1] 9333 0
Linear Clinical Research - Nedlands
Recruitment hospital [2] 9613 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 18002 0
6009 - Broadway Nedlands
Recruitment postcode(s) [2] 18370 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 297895 0
Commercial sector/Industry
Name [1] 297895 0
Pharmaxis
Address [1] 297895 0
Pharmaxis Ltd
20 Rodborough Rd
Frenchs Forest
NSW 2086
Country [1] 297895 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Pharmaxis
Address
Pharmaxis Ltd
20 Rodborough Rd
Frenchs Forest
NSW 2086
Country
Australia
Secondary sponsor category [1] 296948 0
None
Name [1] 296948 0
Address [1] 296948 0
Country [1] 296948 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298944 0
Bellberry
Ethics committee address [1] 298944 0
129 Glen Osmond Rd
Eastwood SA 5063
Ethics committee country [1] 298944 0
Australia
Date submitted for ethics approval [1] 298944 0
30/08/2017
Approval date [1] 298944 0
12/09/2017
Ethics approval number [1] 298944 0
2017-08-638

Summary
Brief summary
The primary purpose of the study is to determine the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of PXS-5382A after oral administration

SAD
This is a randomised, double-blind, placebo controlled, dose escalating study with single ascending dose of PXS-5382A.
There will be 6 cohorts consisting of 8 subjects each. Subjects within a cohort will be randomly assigned to one of the two groups (PXS-5382A or placebo) in a 3:1 ratio respectively. Sentinel dosing will be conducted for each cohort, such that;
Sentinel dosing – Total N = 2, where
N=1 = PXS-5382A
N=1 = Placebo
Main Cohort – Total N = 6, where
N=5 = PXS-5382A
N=1 = Placebo

Doses will be escalated across the cohorts but not within each cohort. The starting dose and incremental dose increase through the cohorts has been determined based on the results of the pre-clinical studies.
MAD
Multiple ascending doses of PXS-5382A will be assessed during the MAD phase of the study. Within each cohort, each subject will be randomly assigned to one of the two groups (PXS-5382A or placebo) in a 3:1 ratio respectively wherein each subject will receive the active drug or placebo once daily. The doses and dosing duration chosen for MAD will be based on evaluation of the PK data and all safety information as well as any other relevant data that is available from the SAD phase
Trial website
None
Trial related presentations / publications
None
Public notes
None

Contacts
Principal investigator
Name 78738 0
Dr Angela Molga
Address 78738 0
CMAX Clinical Research
Level 5, 18a North Terrace | Adelaide SA 5000 | AUSTRALIA
Country 78738 0
Australia
Phone 78738 0
+61 8 7088 1900
Fax 78738 0
Email 78738 0
Angela.Molga@sa.gov.au
Contact person for public queries
Name 78739 0
Dr Brett Charlton
Address 78739 0
Pharmaxis Ltd
20 Rodborough Rd
Frenchs Forest
NSW 2086
Country 78739 0
Australia
Phone 78739 0
+61 414 987 338
Fax 78739 0
Email 78739 0
Brett.Charlton@pharmaxis.com.au
Contact person for scientific queries
Name 78740 0
Dr Brett Charlton
Address 78740 0
Pharmaxis Ltd
20 Rodborough Rd
Frenchs Forest
NSW 2086
Country 78740 0
Australia
Phone 78740 0
+44 (0)118 963 7846
Fax 78740 0
Email 78740 0
Brett.Charlton@pharmaxis.com.au

No data has been provided for results reporting
Summary results
Not applicable