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Trial registered on ANZCTR


Registration number
ACTRN12621000136808
Ethics application status
Approved
Date submitted
4/12/2020
Date registered
10/02/2021
Date last updated
8/02/2022
Date data sharing statement initially provided
10/02/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
An Exploratory Phase 2, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Treatment Effect of Pentosan Polysulfate Sodium Compared with Placebo on Synovial Fluid Biomarkers in Participants with Knee Osteoarthritis Pain
Scientific title
A Phase 2, Randomised, Double-blind, Placebo-controlled Study to Evaluate the Treatment Effect of Pentosan Polysulfate Sodium Compared to Placebo on Synovial Fluid Biomarkers in Participants with Knee Osteoarthritis Pain
Secondary ID [1] 302922 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee Osteoarthritis 319939 0
Condition category
Condition code
Musculoskeletal 317876 317876 0 0
Osteoarthritis
Musculoskeletal 317877 317877 0 0
Other muscular and skeletal disorders
Inflammatory and Immune System 317878 317878 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be administered twice weekly, subcutaneous (SC) injections of investigational product (IP) calculated for ideal body weight (IBW) of either:
• PPS twice weekly: 2.0 mg/kg IBW PPS twice weekly for 6 weeks
• PPS once weekly: 2.0 mg/kg IBW PPS once weekly + placebo (0.9% saline) once weekly for 6 weeks
• Placebo: placebo (0.9% saline) twice weekly for 6 weeks
Participants will visit the clinical trial centre twice weekly for 6 weeks for treatment injections. For the remaining doses, participants will attend the clinical trial centre 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] 319207 0
Treatment: Drugs
Comparator / control treatment
Saline (0.9% saline solution) placebo, administered by subcutaneous injection, twice weekly for 6 weeks in the same dosing regimen (by equivalent volume) as the active treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 325894 0
To evaluate the effect of PPS on synovial fluid biomarkers associated with inflammation in participants with knee osteoarthritis (OA) pain. (Method of assessment is via synovial fluid biopsy).
Timepoint [1] 325894 0
Change from Baseline at Day 56 in one or more synovial fluid biomarkers, including but not limited to cartilage oligomeric matrix protein (COMP), C terminal telopeptide (CTX) -II, NGF, interleukin (IL) -1ß, TNFa, IL-6, a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), ARGS (aggrecan cleavage fragments, tissue inhibitor matrix metalloproteinase 1 (TIMP-1), CTX-I, and type II collagen (C2C). Synovial fluid biomarker samples will be taken at Baseline and Day 56.
Primary outcome [2] 326211 0
To evaluate the effect of PPS on synovial fluid biomarkers associated with Osteoarthritis (OA) disease progression in participants with knee OA pain. . (Method of assessment is via synovial fluid biopsy).
Timepoint [2] 326211 0
Change from Baseline at Day 56 in one or more synovial fluid biomarkers, including but not limited to cartilage oligomeric matrix protein (COMP), C terminal telopeptide (CTX) -II, NGF, interleukin (IL) -1ß, TNFa, IL-6, a disintegrin and metalloproteinase with thrombospondin motif 5 (ADAMTS-5), ARGS (aggrecan cleavage fragments, tissue inhibitor matrix metalloproteinase 1 (TIMP-1), CTX-I, and type II collagen (C2C). Synovial fluid biomarker samples will be taken at Baseline and Day 56 Method of assessment is testing for biomarkers is by synovial fluid biopsy.
Secondary outcome [1] 389447 0
To evaluate the effect of PPS 6 months after initiation of treatment on synovial fluid biomarkers associated with inflammation in participants with knee OA pain. Method of assessment is testing for biomarkers in synovial fluid.
Timepoint [1] 389447 0
Change from Baseline at Day 168 in synovial fluid biomarkers, including but not limited to COMP, CTX-II, NGF, IL-1ß, TNFa, IL-6, ADAMTS-5, ARGS (aggrecan cleavage fragments), TIMP-1, CTX-I, and C2C Synovial fluid biomarker samples will be taken at Baseline and Day 168.
Secondary outcome [2] 389544 0
To evaluate the effect of PPS on change in pain in participants with knee OA.
Timepoint [2] 389544 0
Change from baseline at Days 11, 25, 39, 56, 84, 112, 140, 168, 266, and 365 in knee pain as assessed by the average pain subscale score of the WOMAC® NRS 3.1 Index.
Reduction in knee pain of greater than or equal to 25% and greater than or equal to 50% as assessed by the average pain subscale score of the WOMAC® NRS 3.1 Index at Days 11, 25, 39, 56, 84, 112, 140, 168, 266, and 365.
Secondary outcome [3] 389545 0
To evaluate the effect of PPS on change in function in participants with knee OA pain.
Timepoint [3] 389545 0
Change from baseline at Days 11, 25, 39, 56, 84, 112, 140, 168, 266, and 365 in function as assessed by the average functional subscale score of the WOMAC® NRS 3.1 Index. Improvement in function of greater than or equal to 25% and greater than or equal to 50% as assessed by the average functional subscale score of the WOMAC® NRS 3.1 Index from baseline at Days 11, 25, 39, 56, 84, 112, 140, 168, 266, and 365.
Secondary outcome [4] 389546 0
To evaluate the effect of PPS on change in stiffness in participants with knee OA pain.
Timepoint [4] 389546 0
Change from baseline at Days 11, 25, 39, 56, 84, 112, 140, 168, 266, and 365 in knee stiffness as assessed by the average stiffness subscale score of the WOMAC® NRS 3.1 Index.
Secondary outcome [5] 389547 0
To evaluate the effect of PPS on quality of life in participants with knee OA pain.
Timepoint [5] 389547 0
PGIC scores at Days 11, 25, 39, 56, 84, 112, 140, 168, 266, and 365.
Secondary outcome [6] 389548 0
To evaluate the effect of PPS on serum biomarkers associated with inflammation in participants with knee OA pain. (Assessed blood serum sample).
Timepoint [6] 389548 0
Change from Baseline at Days 56 and 168 in serum biomarkers, including but not limited to, COMP, CTX-II, ADAMTS-5, ARGS (aggrecan cleavage fragments), TIMP-1, CTX-I, and C2C
Secondary outcome [7] 389549 0
To evaluate the effect of PPS on urine biomarkers associated with inflammation in participants with knee OA pain.
Timepoint [7] 389549 0
Change from baseline at Days 56 and 168 in urine biomarkers, including but not limited to CTX-II
Secondary outcome [8] 389553 0
To evaluate the effect of PPS on consumption of rescue medication in participants with knee OA pain. Rescue medication will be collected electronically via a rescue medication log.
Timepoint [8] 389553 0
Number of days of rescue medication used from Day 1 to Day 365.
Secondary outcome [9] 389554 0
To evaluate the safety and tolerability of PPS in participants with knee OA pain.
Timepoint [9] 389554 0
Incidence of Treatment Emergent Adverse Events (TEAEs), including serious adverse events (SAEs) Day 1 to Day 168.
Number of discontinuations for TEAE Day 1 to Day 168.
Treatment-emergent clinical laboratory abnormalities Day 1 to Day 168.
Number of PPS-treated participants with detection of ADA in serum Day 1 to Day 168.
Secondary outcome [10] 390526 0
To evaluate the effect of PPS 6 months after initiation of treatment on synovial fluid biomarkers associated with OA disease progression in participants with knee OA pain. Method of assessment is testing for biomarkers in synovial fluid.
Timepoint [10] 390526 0
Change from Baseline at Day 168 in synovial fluid biomarkers, including but not limited to COMP, CTX-II, NGF, IL-1ß, TNFa, IL-6, ADAMTS-5, ARGS (aggrecan cleavage fragments), TIMP-1, CTX-I, and C2C Synovial fluid biomarker samples will be taken at Baseline and Day 168..
Secondary outcome [11] 390528 0
To evaluate the effect of PPS on serum biomarkers associated with OA disease progression in participants with knee OA pain. (Assessed by blood serum sample).
Timepoint [11] 390528 0
Change from Baseline at Days 56 and 168 in serum biomarkers, including but not limited to, COMP, CTX-II, ADAMTS-5, ARGS (aggrecan cleavage fragments), TIMP-1, CTX-I, and C2C
Secondary outcome [12] 391725 0
To evaluate the effect of PPS on urine biomarkers associated with OA disease progression in participants with knee OA pain.
Timepoint [12] 391725 0
Change from baseline at Days 56 and 168 in urine biomarkers, including but not limited to CTX-II

Eligibility
Key inclusion criteria
Subjects with a clinical diagnosis of osteoarthritis in one or both knees and a radiographic diagnosis of knee osteoarthritis showing a Kellgren-Lawrence score 2, 3 or 4
Symptomatic pain for at least 6 months preceding screening
Males and females aged greater than or equal to 18 years, who are willing and able to comply with study requirements
Subjects must be able to provide written informed consent
Body Mass Index (BMI) of 18 to 35.0 kg/m2 inclusive
Females of non child-bearing potential or females and males willing to comply with medically acceptable contraceptive requirements of the study
Additional inclusion criteria apply.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Documented or reported history of increased bleeding in the absence of anticoagulant or antiplatelet drugs, or prior history of major bleeding episode in the presence of anticoagulant or antiplatelet therapy.
History of idiopathic or immune-mediated thrombocytopenia including history of or laboratory-confirmed heparin-induced thrombocytopenia (HIT; positive or equivocal antibodies against platelet factor 4 [ie, PF4]).
Current treatment with anticoagulants or antiplatelet drugs, excluding aspirin less than or equal to 100 mg/day.
Previous treatment with PPS in any form.
Currently active or recent history (within preceding 12 months) of a gastric or duodenal ulcer, or suspicion of gastrointestinal tract bleeding.
Activated partial thromboplastin time [aPTT]) > upper limit of normal (ULN), platelets <150,000/µL, or liver enzyme tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) greater than or equal to 2 × ULN at screening.
Additional exclusion criteria apply.

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)
Central randomisation by phone/computer
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
The randomisation schedule will be computer-generated using a permuted block algorithm and will randomly allocate IP to randomisation numbers. The randomisation numbers will be assigned sequentially through a central interactive web response system (IWRS) as participants are entered into 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
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
No formal statistical sample size estimation has been performed due to the exploratory nature of this study. Rather, the sample size is based on clinical and practical considerations.

This study is descriptive in nature, and no formal hypothesis testing will be performed.

The descriptive summary for the categorical variables will include counts and percentages. The descriptive summary for the continuous variables will include number of subjects (n), means, medians, standard deviations, and minimum and maximum values. All data will be listed for all subjects.
For the summary statistics, the number of decimal places will be the same as for the source data for minimum and maximum. Mean will be presented with 1 more decimal place than the source data and SD with 2 more decimal places. Percentages will be presented with 1 decimal place.
For all primary, secondary and exploratory analyses, 95% CI will be presented unless stated otherwise.
Change from baseline in biomarkers in synovial fluid at Days 56, will be analysed using a restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) approach. Change from baseline in biomarkers in synovial fluid at Days 168, and in biomarkers in serum and in urine at Days 56 and 168 will be analysed using the same REML-based MMRM approach.
For the analysis of change from baseline using WOMAC Osteoarthritis Index NRS (Total index, pain, functional, stiffness subscale) at Days 11, 25, 39, 56, 84, 112, 140, 168, 266, and 365 it will be analysed using a REML-based MMRM approach. For analysis involving improvement and reduction in subscale from Baseline, logistic regression will be used with treatment as factor and baseline score as covariate will be used.
Other associations between biomarkers and outcomes will be explored.
Pearson correlation coefficient will be used to examine the strength of linear association between the variables of interest. Checks on the normality assumption of these variables will be done before using Pearson correlation coefficient. In the case of skewed data, Spearman correlation coefficient will be used instead.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
15/03/2021
Actual
12/04/2021
Date of last participant enrolment
Anticipated
25/03/2022
Actual
Date of last data collection
Anticipated
24/03/2023
Actual
Sample size
Target
60
Accrual to date
30
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 18134 0
Sportsmed Biologic - Box Hill
Recruitment hospital [2] 21669 0
Novatrials - Kotara
Recruitment postcode(s) [1] 32127 0
3128 - Box Hill
Recruitment postcode(s) [2] 36716 0
2289 - Kotara

Funding & Sponsors
Funding source category [1] 307342 0
Commercial sector/Industry
Name [1] 307342 0
Paradigm Biopharmaceuticals Pty Ltd
Country [1] 307342 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Paradigm Biopharmaceuticals Pty Ltd
Address
Level 15, 500 Collins Street, Melbourne Vic 3000
Country
Australia
Secondary sponsor category [1] 307983 0
None
Name [1] 307983 0
Address [1] 307983 0
Country [1] 307983 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307431 0
Bellberry Ltd
Ethics committee address [1] 307431 0
123 Glen Osmond Rd, Eastwood SA 5063
Ethics committee country [1] 307431 0
Australia
Date submitted for ethics approval [1] 307431 0
23/12/2020
Approval date [1] 307431 0
12/02/2021
Ethics approval number [1] 307431 0
2020-10-1014

Summary
Brief summary
Paradigm Biopharmaceuticals Ltd (Paradigm) is evaluating Pentosan Polysulfate Sodium (PPS) for the treatment of symptoms (pain and diminished function) and mitigation of underlying tissue degeneration associated with osteoarthritis (OA) of the knee.. This study is designed to measure synovial fluid biomarkers indicative of the inflammation and cartilage degradation present in symptomatic knee OA, and to determine quantitative changes in individual biomarkers resulting from treatment with PPS. The results from this study will enhance understanding of the PPS mechanism of action and will provide information on the effect of PPS on joint inflammation and on the processes responsible for OA disease progression.
Trial website
Trial related presentations / publications
Public notes
Additional recruitment site:
Dr Oscar Cumming
Novatrials
Suite 7, Level 2, OTP House
10 Bradford Close, Kotara NSW 2289 Australia
Phone: +61 2 4063 3381
Email: [email protected]

Contacts
Principal investigator
Name 107214 0
Dr Philip Bloom
Address 107214 0
Sportsmed Biologic
1G/116 -118 Thames St, Box Hill VIC 3128
Country 107214 0
Australia
Phone 107214 0
+61 3 8539 6504
Fax 107214 0
Email 107214 0
[email protected]
Contact person for public queries
Name 107215 0
Melanie Duiker
Address 107215 0
Paradigm Biopharmaceuticals
Level 15, 500 Collins St, Melbourne Vic 3000
Country 107215 0
Australia
Phone 107215 0
+61 492 922 860
Fax 107215 0
Email 107215 0
[email protected]
Contact person for scientific queries
Name 107216 0
Ravi Krishnan
Address 107216 0
Paradigm Biopharmaceuticals
Level 15, 500 Collins St, Melbourne Vic 3000
Country 107216 0
Australia
Phone 107216 0
+61 492 922 860
Fax 107216 0
Email 107216 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
Not required


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.