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Trial registered on ANZCTR


Registration number
ACTRN12621000322831
Ethics application status
Approved
Date submitted
1/10/2020
Date registered
23/03/2021
Date last updated
23/03/2021
Date data sharing statement initially provided
23/03/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
Safety and tolerability Of Lysyl OxidAse InhibitoR (LOX) In the amelioration of acute and established scAr: SOLARIA I, a single centre Phase I study.
Scientific title
Safety and tolerability Of Lysyl OxidAse InhibitoR (LOX) In the amelioration of acute and established scAr: SOLARIA I, a single centre Phase I study in healthy male adults.
Secondary ID [1] 302450 0
NIL
Universal Trial Number (UTN)
U1111-1251-2394
Trial acronym
SOLARIA I
Linked study record

Health condition
Health condition(s) or problem(s) studied:
skin 319277 0
burns 319278 0
scar 319279 0
Condition category
Condition code
Skin 317245 317245 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Topical agent for reduction or prevention of scar formation following burn injury. Topical agent PXS6302 is a lysl oxidase inhibitor for collagen cross linking formation. The formation of cross-links is catalysed by a family of 5 lysyl oxidase (LOX) enzymes, with LOX and lysyl oxidase-like 1 (LOXL1) being the dominant forms in the skin. These enzymes catalyse the oxidation of lysine residues in collagen resulting in the formation of reactive aldehydes which spontaneously react, either with other aldehydes or with unmodified lysine residues. This results in the formation of cross-links between the collagen strands, making the collagen less soluble and more resistant against enzymatic degradation. Consequently, reducing cross-linking of collagen decreases stability and leads to increased degradation. Inhibiting LOX activity in scars may reduce collagen stability.

Investigational Products Administered

Part 1: Single Ascending Dose Arm
PXS-6302 Cream Topical
Cohort 1: 0.6 mg (0.3%) Single application on Day 1
Cohort 2: 2 mg (1.0%)
Cohort 3: 4 mg (2.0%)
Cohort 4: 8 mg (4.0%)
Part 2: Multiple Dose Arm
PXS-6302 Cream Topical Cohort 1: Dose TBC* Every day for 7 days
*The dose will be confirmed following the review of safety, tolerability, and PK findings from Part 1.

All doses of PXS-6302 will be applied by appropriately trained study center staff. The dose will be applied to the subject’s lateral thigh via a syringe.

The same volume will be provided per syringe for each dose level. Each syringe will contain 1 mL of PXS-6302. The first 200 µL is to be discarded, with the subsequent 200 µL applied to the subject’s skin. Any remaining study drug will be left within the syringe for accountability purposes. The cream should be spread using a gloved hand over an area of 10 cm2 (to an area 5 x 2 cm). The study drug should be allowed to absorb into the skin for at least 5 minutes following application, then no restrictions on touching or covering the area will apply.
Either leg may be selected for dosing and there will be no restrictions on hair density around dosing area and no restrictions on skin pigment/colour or minor blemishes for the dosing area. Areas containing tattoos, scars or moles should be avoided. Hair around dosing area may be trimmed to assist with visualizing the area, however, should not be shaved.

In Part 1, PXS-6302 will be applied as a single dose on Day 1. In Part 2, PXS-6302 will be applied at approximately the same time every day over the same skin area for 7 days (Days 1 to 7).
The Investigator or designee is responsible for the education of study staff as to the correct administration of the investigational product.
PXS-6302 will be removed from storage at 2-8°C and kept at room temperature for at least 30 minutes prior to being administered by the study staff.



Intervention code [1] 318745 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325307 0
To investigate the safety and tolerability of single ascending doses and multiple doses of PXS-6302 in healthy volunteers. Safety and tolerability will be assessed via the incidence and severity of adverse events (i.e, adverse event, serious adverse event, unexpected serious adverse reaction).
The Investigator will make an assessment of intensity for each AE and SAE reported during the study using the CTCAE V5.0 criteria. The assessments will be based on the Investigator’s clinical judgment. The severity of each AE and SAE recorded in the eCRF should be assigned to one of the following:

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated

Grade 2: Moderate; minimal, local or non-invasive intervention indicated; limiting age appropriate instrumental Activities of Daily Living (ADL)

Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL

Grade 4: Life-threatening consequences; urgent intervention indicated
Grade 5: Death related to AE.

Safety and tolerability is also assessed via participant self report and dermatological investigation performed by study principal investigator.
Timepoint [1] 325307 0
Day 7 post last dose.
Secondary outcome [1] 387463 0

To investigate the pharmacokinetics of PXS-6302 when administered as single ascending doses and multiple doses.
Timepoint [1] 387463 0
Blood samples collected at Day 1, Day 2 & Day 8 post dose
PART 1
Day 1: Pre-dose (within 30 minutes prior to dosing)
1 hour post dose (±2 minutes)
4 hours post dose (±5 minutes)
8 hours post dose (±5 minutes)
Day 2: 24 hours post dose (±10 minutes)

PART 2
Day 1 Pre-dose (within 30 minutes prior to dosing)
1 hour post dose (±2 minutes)
4 hours post dose (±5 minutes)
8 hours post dose (±5 minutes)
Day 2 Pre-dose (15 minutes prior to dosing)
Day 3 Pre-dose (15 minutes prior to dosing)
Day 4 Pre-dose (15 minutes prior to dosing)
Day 5 Pre-dose (15 minutes prior to dosing)
Day 6 Pre-dose (15 minutes prior to dosing)
Day 7 Pre-dose (15 minutes prior to dosing)
1 hour post dose (±2 minutes)
4 hours post dose (±5 minutes)
8 hours post dose (±5 minutes)
Day 8 24 hours post dose (±10 minutes)
Concentration of PXS-6302 and its metabolites in plasma;
• Pharmacokinetic parameters including:
- Area under the serum PXS-6302 concentration curve (AUC);
- Peak plasma concentration (Cmax);
- Time to peak plasma concentration (Tmax);
- Elimination half-life (t1/2);
- Clearance (Cl);
- Volume of distribution (Vz)
Secondary outcome [2] 392058 0
To investigate the pharmacodynamics of PXS-6302 when administered as single ascending doses and multiple doses
Timepoint [2] 392058 0
Biomarkers for PXS-6302 obtained from skin biopsy samples obtained pre dose Day-1 and post dose Day 7.

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 electrocardiogram (ECG); QTcF (QTc Fredericia’s correction) equal to 450 ms, PR interval of 120-210 ms and a QRS duration120 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 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 6 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 that, 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, that, 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. Presence of a currently healing wound, recent musculoskeletal injury, or currently healing fracture.

5. 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).

6. At Investigator discretion if systolic blood pressure less than 100 or greater than 160 mmHg, diastolic blood pressure <50 or >95 mmHg, and heart rate (HR) less than 45 or greater than 100 bpm.

7. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), or bilirubin less than 1.5 × upper limit of normal (ULN).

8. Hemoglobin, white blood cell, neutrophils, platelets greater than lower limit of normal (LLN).


9. 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.

10. Positive Screening test for Hepatitis B surface antigen or Hepatitis C antibody or HIV (human immunodeficiency virus).

11. History of drug abuse in the last 2 years.


12. Males who regularly drink more than 3 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]).

13. Used nicotine-containing products (eg, cigarettes, cigars, chewing tobacco, snuff, patches) within 6 weeks before Screening and unable to abstain from using these products until study completion.

14. Unable to abstain from consuming caffeine and/or xanthine products (eg, coffee, tea, chocolate, and caffeine-containing sodas, colas, etc.) for at least 48 hours prior to admission to the clinical facility, and while confined to the clinical facility.


15. 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.

16. 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.


17. Have participated in a clinical trial or have received an experimental therapy within 30 days or 5 half-lives of the drug, whichever is longer, prior to dosing.


18. Systemic infection other than common cold in the week prior to dosing.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised 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
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
This will be a single centre, open label single arm phase I study of Lysyl OxidAse InhibitoR (LOX).
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Baseline descriptive statistics

Variables will be analysed to determine whether the criteria for the study conduct are met. This will include a description of volunteers who did not meet all the eligibility criteria, an assessment of protocol violations, study drug accountability and other data that impact on the general conduct of the study.


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)
WA
Recruitment hospital [1] 17733 0
Linear Clinical Research - Nedlands
Recruitment postcode(s) [1] 31588 0
6009 - Nedlands

Funding & Sponsors
Funding source category [1] 306879 0
Commercial sector/Industry
Name [1] 306879 0
Pharmaxis Ltd
Address [1] 306879 0
Pharmaxis Ltd
20 Rodborough Road
Frenchs Forest
NSW 2086, AUSTRALIA
Country [1] 306879 0
Australia
Primary sponsor type
University
Name
University of Western Australia
Address
University of Western Australia
Hackett Drive
Crawley WA 6009
Country
Australia
Secondary sponsor category [1] 307435 0
None
Name [1] 307435 0
Address [1] 307435 0
Country [1] 307435 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307034 0
Bellberry Ltd
Ethics committee address [1] 307034 0
123 Glen Osmond Road
EastWood
South Australia 5063
Ethics committee country [1] 307034 0
Australia
Date submitted for ethics approval [1] 307034 0
15/10/2020
Approval date [1] 307034 0
17/02/2021
Ethics approval number [1] 307034 0
2020-12-1296-A-2

Summary
Brief summary
Scar formation following a burn for skin injury is a considerable health issue worldwide, After an injury, humans are unable to regenerate normal skin. Instead the repair process leads to scar formation. Scars are both aesthetically and functionally inferior to normal skin, leading to significant psychological and physical problems. A key factor in the poor appearance and pliability of scars, and in particular hypertrophic scars, is the changes to collagen in the dermal layer. In scar tissue the collagen (predominantly Collagen I) is more densely packed and closely aligned in parallel bundles. In normal skin collagen is not densely packed and is more of a ‘basket-weave’ structure. These changes both in structure and quantity of collagen largely underlie the poor appearance of scar and lead to loss of pliability, discomfort and functional problems. Lysyl oxidase is an enzyme that, in humans, is encoded by the LOX gene. Lysl oxidase catalyzes the conversion of lysine molecules into highly reactive aldehydes that form cross-links in extracellular matrix proteins and are key to regulating collagen structure.
Under normal physiological conditions, cross-links are essential for the stabilisation of collagen. However, the correct balance of cross-linking and stability is essential to normal matrix being established post-injury and being maintained through life. The cross-links bind the collagen tightly, stabilize the bundles of collagen in the scar and reduce physiological degradation of scar tissue. This sentinel Phase I first in human trial will determine the safety and tolerability of a novel topical compound for the inhibition of Lysl Oxidase. This phase I study will inform the recommended phase 2 dose for a subsequent Phase II trial for safety and efficacy.

Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 59786 0
Dr Lara Hatchuel
Address 59786 0

Linear Clinical Research
Level 1, B Block, Hospital Ave
Nedlands WA 6009
Country 59786 0
Australia
Phone 59786 0
+610433552206
Fax 59786 0
Email 59786 0
lhatchuel@linear.org.au
Contact person for public queries
Name 59787 0
Dr Kylie Sandy-Hodgetts
Address 59787 0
University of Western Australia
Hackett Drive, Crawley WA 6009
Country 59787 0
Australia
Phone 59787 0
+61435436747
Fax 59787 0
Email 59787 0
kylie.sandy-hodgetts@uwa.edu.au
Contact person for scientific queries
Name 59788 0
Dr Mark Fear
Address 59788 0
University of Western Australia
Hackett Drive, Crawley WA 6009
Country 59788 0
Australia
Phone 59788 0
+61 411355944
Fax 59788 0
Email 59788 0
mark.fear@fionawoodfoundation.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
IPD will not be available due to the Privacy Act and confidentiality of individual participants. Aggregated non identifiable data will be published via academic peer review journals as part of the dissemination plan.
What supporting documents are/will be available?
No other documents available
Summary results
No Results