Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12620000829910
Ethics application status
Approved
Date submitted
30/03/2020
Date registered
19/08/2020
Date last updated
23/06/2021
Date data sharing statement initially provided
19/08/2020
Date results information initially provided
23/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A Phase 1, Open-label Study to Determine the Safety, Tolerability, and Pharmacokinetics of Multiple Subcutaneous Doses of Pentosan Polysulfate Sodium (PPS) in Healthy Adult Participants
Scientific title
A Phase 1, Open-label Study to Determine the Safety, Tolerability, and Pharmacokinetics of Multiple Subcutaneous Doses of Pentosan Polysulfate Sodium (PPS) in Healthy Adult Participants
Secondary ID [1] 300890 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee Osteoarthritis 316823 0
Bone Marrow Lesion 316824 0
Condition category
Condition code
Musculoskeletal 315031 315031 0 0
Osteoarthritis
Musculoskeletal 315032 315032 0 0
Other muscular and skeletal disorders
Inflammatory and Immune System 315033 315033 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Cohort 1 - participants will receive a single subcutaneous(SC) dose of PPS at 2 mg/kg once weekly for a total of 6 weeks. Participants will visit the clinical trial centre once weekly for 6 weeks for treatment injections. Participants will remain confined until completion of the 24-hour post-dose assessments on Day 2 (Dose 1). For the remaining doses, participants will attend the CRU for pre-dose assessment, dosing, and post-dosing assessment as outpatients. Patients adherence to visits will be by reminder phone calls, emails and texts.

Cohort 2 - participants will receive a single subcutaneous(SC) dose of PPS at 2 mg/kg twice weekly for a total of 6 weeks. Participants will visit the clinical trial centre twice weekly for 6 weeks for treatment injections. Participants will remain confined until completion of the 24-hour post-dose assessments on Day 2 (dose 1). For the remaining doses, participants will attend the CRU for pre-dose assessment, dosing, and post-dosing assessment as outpatients.
Patients adherence to visits will be by reminder phone calls, emails and texts.
Intervention code [1] 317213 0
Treatment: Drugs
Comparator / control treatment
Cohort 1 - participants will receive a single subcutaneous(SC) dose of PPS at 2 mg/kg once weekly for a total of 6 weeks
Control group
Dose comparison

Outcomes
Primary outcome [1] 323332 0
To assess the pharmacokinetics (PK) of multiple SC doses of PPS in healthy adult participants

For Initial Dose
• Maximum observed concentration (Cmax)
• Time to maximum observed drug concentration (Tmax)
• AUC from time zero to the last measurable concentration (AUC0-last)
• AUC from time zero to infinity (AUC0-inf)
• Apparent terminal elimination rate constant (kel)
• Apparent elimination half life (t½)
• Apparent clearance (CL/F)
• Apparent terminal volume of distribution (Vz/F)
•
For repeated doses:
• Maximum plasma concentration during each dosing interval (Cmax).
• Time to maximum concentration (Tmax).
• Lowest concentration during each dosing interval (Cmin).
• Average concentration during each dosing interval (Cav).
• Concentration at the end of each dosing interval (Ctrough).
• Degree of fluctuation [(Cmax-Cmin)/Cav].
• Swing [(Cmax-Cmin)/Cmin].
• Areas under the plasma concentration-time curve during each dosing interval AUC0-last, and AUC0-inf, provided estimation of kel is possible.
• Apparent terminal elimination rate constant during each dosing interval, (kel) , provided estimation is possible
• Apparent clearance during each dosing interval (CL/F).
• Apparent terminal volume of distribution (Vz/F)
• Accumulation ratio (RA) during each dosing interval.
Timepoint [1] 323332 0
Cohort 1 -PK samples will be collected for Dose 1, 3, and 6, within 15 minutes prior to dosing and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 1 24, 36, and 48 hours post dose. For Dose 2, 4 and 5 PK samples are collected within 15 minutes pre-dose
Cohort 2 - PK samples will be collected for dose 1, 5 and 12 within 15 minutes prior to dosing and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 8, 1 24, 36, and 48 hours post dose. For Dose 2, 3, 4, 6, 7, 8, 9, 10, 11 PK samples are collected within 15 minutes pre-dose
Secondary outcome [1] 381595 0
To assess the safety and tolerability of multiple SC doses of PPS in healthy adult participants..
Safety and tolerability will be assessed by adverse event assessment (eg. Injection site pain or bruising, ), vital signs (including ECG’s), physical exams and laboratory blood monitoring.
Timepoint [1] 381595 0
Cohort 1- Safety and tolerability will be assessed at every clinic visit on Days 1, 2, 3, 7, 12, 14, 15, 16, 21, 28, 35, 36, 37 and 42
Cohort 2 - Safety and tolerability will be assessed at every clinic visit and on Days 1, 2, 3, 4, 5, 7, 10, 14, 15, 16, 17, 21, 24, 28, 31, 35, 38, 39, 40, 45

Eligibility
Key inclusion criteria
Healthy male or female volunteers, aged grater than or equal to 18 years and less than or equal to 75 years (at the time of informed consent);
Participants must be in good general health, with no significant medical history, have no clinically significant abnormalities on physical examination at Screening and/or before administration of the initial dose of study drug;
Participants must have a minimum body weight of 50 kg and a Body Mass Index (BMI) greater than or equal to 18.0 and less than or equal to 35.0 kg/m2 at Screening
Participants who smoke no more than 10 cigarettes or equivalent per week can be included in the study but must agree to abstain from smoking and all nicotine containing products from 48 hours before each visit
Must agree to abstain from alcohol intake from 48 hours before each visit
Subjects must be able to provide written informed consent
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
History of severe allergic or anaphylactic reactions
Pregnant or lactating at Screening or planning to become pregnant (self or partner) at any time during the study, including the follow-up period
Prior or ongoing medical conditions, medical history, physical findings, or laboratory abnormality that, in the Investigator’s (or delegate’s) opinion, could adversely affect the safety of the participant
Presence of any underlying physical or psychological medical condition that, in the opinion of the Investigator, would make it unlikely that the participant will comply with the protocol or complete the study per protocol
Any surgical or medical condition that could interfere with the absorption, distribution, metabolism, or excretion of the study drug
Blood donation or significant blood loss within 60 days prior to the first study drug administration
History of malignancy except for non-melanoma skin cancer excised more than 2 years ago and cervical intraepithelial neoplasia that has been successfully cured more than 5 years prior to Screening
History of heparin induced thrombocytopenia
Participants undergoing invasive procedures or having signs/symptoms of underlying coagulopathy or other increased risk of bleeding (due to other therapies such as coumarin anticoagulants, heparin, tissue plasminogen activator (t-PA), streptokinase, high dose aspirin, or nonsteroidal anti-inflammatory drugs [NSAID]). Participants may be enrolled if they satisfy the following criteria with regard to NSAID:
• Participants taking NSAIDs continuously (i.e., daily) agree to a washout period of at least 7 days prior to admission on Day -1;
• Participants taking NSAIDs intermittently (i.e., less than daily) agree to a washout period of at least 24 hours prior to admission on Day -1;
• NSAIDs are not permitted from Day -1 through to the EOS visit

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)
Open Label Study
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
9/09/2020
Actual
9/09/2020
Date of last participant enrolment
Anticipated
17/09/2020
Actual
22/09/2020
Date of last data collection
Anticipated
30/10/2020
Actual
5/11/2020
Sample size
Target
24
Accrual to date
Final
23
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 17122 0
CMAX Clinical Research Pty Ltd - Adelaide
Recruitment postcode(s) [1] 30798 0
5000 - Adelaide

Funding & Sponsors
Funding source category [1] 305341 0
Commercial sector/Industry
Name [1] 305341 0
Paradigm Biopharmaceuticals Pty Ltd
Country [1] 305341 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Paradigm Biopharmaceuticals Pty Ltd
Address
Level 2, 517 Flinders Lane, Melbourne Vic 3000
Country
Australia
Secondary sponsor category [1] 306744 0
None
Name [1] 306744 0
Address [1] 306744 0
Country [1] 306744 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305674 0
Bellberry Ltd
Ethics committee address [1] 305674 0
123 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [1] 305674 0
Australia
Date submitted for ethics approval [1] 305674 0
17/06/2020
Approval date [1] 305674 0
27/07/2020
Ethics approval number [1] 305674 0
2020-06-534

Summary
Brief summary
Paradigm Biopharmaceuticals Ltd (Paradigm) is focusing on Pentosan Polysulfate Sodium (PPS) for the treatment of conditions that are associated with inflammation and progress chronically with tissue degeneration, including the treatment of Osteoarthritis Knee pain. Previous studies demonstrate that PPS is tolerated at the proposed dose (2 mg/kg) and duration (once or twice weekly for 6 weeks). While most of the clinical data obtained were acquired using a twice weekly regimen, a once weekly SC injection program, if effective and safe, would be ideal for feasibility.
This study is will assess safety, tolerability, and pharmacokinetic responses of multiple sub-cutaneous doses of PPS in a healthy western population to support the development program.
The clinical and nonclinical evidence demonstrate that PPS is tolerated at the proposed dose (2 mg/kg) and duration (once or twice weekly for 6 weeks). In two studies evaluating dose limiting toxicity, maximum tolerated doses were determined to be 3 mg/kg/day continuous infusion (Pluda et al., 1993) and 22.5 mg/m2 SC injection every 6 hours (Swain et al., 1995). Assuming an average male of 60 kg and 1.9 m, these doses are roughly equivalent to 180 mg/day and 171 mg/day, respectively. These levels are greater than the Sponsor’s current proposed dosing regimen of 2 mg/kg (approximately 120 mg) SC once or twice per week.
The PK sampling design in this study will allow comparison with an earlier PK study which evaluated 50 mg to 300 mg PPS administered by SC injection once weekly for 4 weeks.
While most of the clinical data obtained were acquired using a twice weekly regimen, a once weekly SC injection program, if effective and safe, would be ideal for feasibility. Therefore, PK data obtained from once and twice weekly dosing regimens will support the development program.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 101182 0
Dr Nicholas Farinola
Address 101182 0
CMAX Clinical Research
Level 5, East Wing
18a North Terrace
Adelaide, SA 5000, Australia
Country 101182 0
Australia
Phone 101182 0
+61 421 570 586
Fax 101182 0
Email 101182 0
[email protected]
Contact person for public queries
Name 101183 0
Ms Melanie Duiker
Address 101183 0
Paradigm Biopharmaceuticals
Level 15, 500 Collins St, Melbourne Vic 3000, Australia
Country 101183 0
Australia
Phone 101183 0
+61 434 553 011
Fax 101183 0
Email 101183 0
[email protected]
Contact person for scientific queries
Name 101184 0
Dr Ravi Krishnan
Address 101184 0
Paradigm Biopharmaceutical
Level 15, 500 Collins St, Melbourne Vic 3000, Australia
Country 101184 0
Australia
Phone 101184 0
+61 434 553 011
Fax 101184 0
Email 101184 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.