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Trial registered on ANZCTR


Trial ID
ACTRN12617001311347
Ethics application status
Approved
Date submitted
5/09/2017
Date registered
13/09/2017
Date last updated
27/09/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
A phase 2b, randomised double blind placebo controlled multicentre study to evaluate the effects of pentosan polysulfate sodium on treating pain in subjects with osteoarthritis of the knee and subchondral bone marrow lesions
Scientific title
A phase 2b, randomised double blind placebo controlled multicentre study to evaluate the effects of pentosan polysulfate sodium on treating pain in subjects with osteoarthritis of the knee and subchondral bone marrow lesions
Secondary ID [1] 292557 0
PARA_005
Universal Trial Number (UTN)
Trial acronym
PARA_005
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Knee Osteoarthritis 304214 0
Bone Marrow Lesion 304215 0
Condition category
Condition code
Musculoskeletal 303564 303564 0 0
Osteoarthritis
Musculoskeletal 303565 303565 0 0
Other muscular and skeletal disorders
Inflammatory and Immune System 303566 303566 0 0
Other inflammatory or immune system disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
2mg/kg Pentosan Polysulfate Sodium (100mg/ml injectable solution), administered by subcutaneous injection, twice weekly for 6 weeks. Patients will visit the clinical trial centre twice weekly for 6 weeks for treatment injections, which will be given by experienced clinical trial nurses.
Intervention code [1] 298757 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 regime (by equivalent volume) as the active treatment.
Control group
Placebo

Outcomes
Primary outcome [1] 302926 0
Change in KOOS Pain score from baseline to Day 53
Timepoint [1] 302926 0
Baseline (day 1 of treatment), days 11, 25, 39, 53 (repeated measures)
Secondary outcome [1] 337445 0
Changes in KOOS Symptom score
Timepoint [1] 337445 0
baseline to Days 11, 25, 39, 53, 81, 109 and 165
Secondary outcome [2] 337446 0
Changes in KOOS Function scores
Timepoint [2] 337446 0
baseline to Days 11, 25, 39, 53, 81, 109 and 165
Secondary outcome [3] 337447 0
Changes in KOOS Quality of Life score
Timepoint [3] 337447 0
baseline to Days 11, 25, 39, 53, 81, 109 and 165
Secondary outcome [4] 337448 0
Patient Global impression of change
Timepoint [4] 337448 0
Day 53
Secondary outcome [5] 337449 0
Changes in Bone marrow lesion volume as assessed by MRI
Timepoint [5] 337449 0
Baseline and day 53
Secondary outcome [6] 338623 0
Any Adverse Events (including reported symptoms or physical examination findings) as observed at clinic visits or reported by the patient (regardless of possible causality).
Timepoint [6] 338623 0
All adverse events will be collected from Day 1 of treatment until day 165..
Secondary outcome [7] 338624 0
Haematology - complete blood cell count (laboratory test on blood sample)
Timepoint [7] 338624 0
Baseline, day 11, 25, 39, 53.
Secondary outcome [8] 338625 0
Coagulation parameters (blood clotting time APTT and INR) (laboratory test on blood sample)
Timepoint [8] 338625 0
Baseline, day 11, 25, 39, 53.

Eligibility
Key inclusion criteria
jects 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 40 to 75 years inclusive, 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

Presence of bone marrow lesions of the distal femur or proximal tibia on sagittal or coronal MRI slices, confirmed by radiologist at screening
Minimum age
40 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Documented or reported history of increased bleeding tendency or thrombocytopenia

Current treatment with anticoagulants or anti platelet drugs according to Protocol requirements

Current or prior use of medicines which are prohibited for the duration of the study according to the Prohibited medicines and withhold periods in the study Protocol,

Currently active or recent history (within preceding 12 months) of a gastric or duodenal ulcer, or suspicion of GI tract bleeding

History or evidence of, or positive test for HIV, hepatitis B or hepatitis C

Major surgery within 2 months preceding Day 1 or anticipated surgery in the study period

Medical history or evidence of any active or chronic condition including autoimmune disease involving musculoskeletal system

Currently hospitalised or any planned hospitalisations during the study period

Knee surgery or trauma within 6 months preceding Day 1

Participation in another clinical trial or administration of any investigational product within 8 weeks or 5 half-lives (whichever is longer) preceding Day 1

Contraindications to MRI scans

History of significant allergy to PPS or similar drugs

Any clinically significant abnormalities on clinical chemistry, haematology, urinalysis, physical examination, medical history, 12-lead ECG, or vital signs as judged by the investigator and/or sponsor (at Screening)

History of or current clinically-significant gastrointestinal, hepatic, renal, cardiovascular, respiratory, endocrine, oncological, immunological, neurological, ophthalmological, haematological or psychiatric disorder or any other condition, which in the opinion of the investigator or sponsor would jeopardise the safety of the subject or the validity of the study results

An employee of the sponsor or research site personnel directly affiliated with this study or their immediate family members defined as a spouse, parent, sibling, or child, whether biological or legally adopted.

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)
Patients will be randomly allocated (computer generated) to Placebo or PPS in a ratio of 1:1. Randomisation will be conducted by an electronic central randomisation system within the study electronic data capture system.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation numbers will be generated electronically, allocated in blocks for each site. Patients will be randomised in 2 strata based on severity of symptoms using NRS pain score at screening (NRS 4-6; NRS 7-8)
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
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The sample size estimation is based on the following assumptions:
• A power of 80%
• A type I error rate a of 0.05
• The test is two-sided
• Standard deviation of KOOS pain sub scale of 15
• No change from baseline for the placebo group
• A change from baseline of 10 points for treated group. Hence a difference of 10 points for the changes from baseline of the treated group compared to the placebo group.

The statistical analysis principles described below will be supplemented by a comprehensive statistical analysis plan (SAP) which will be finalised before the database is locked. Any changes to the statistical analyses will be described and justified in the final report.
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.
Any confidence intervals (CIs) generated will be 95%, unless stated otherwise.

Recruitment
Recruitment status
Not yet 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
Current
Final
Recruitment in Australia
Recruitment state(s)
SA,WA,VIC
Recruitment hospital [1] 8660 0
Emeritus Research - Malvern East
Recruitment hospital [2] 8661 0
Linear Clinical Research - Nedlands
Recruitment hospital [3] 8662 0
Sportsmed SA Hospital - Stepney
Recruitment postcode(s) [1] 16771 0
3145 - Malvern East
Recruitment postcode(s) [2] 16772 0
6009 - Nedlands
Recruitment postcode(s) [3] 16773 0
5069 - Stepney

Funding & Sponsors
Funding source category [1] 297136 0
Commercial sector/Industry
Name [1] 297136 0
Paradigm Biopharmaceuticals Pty Ltd
Address [1] 297136 0
Level 2
517 Flinders Lane
Melbourne
Vic 3000
Country [1] 297136 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] 296146 0
None
Name [1] 296146 0
Address [1] 296146 0
Country [1] 296146 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 298305 0
Bellberry Human Research Ethics Commitee
Ethics committee address [1] 298305 0
129 Glen Osmond Road Eastwood
South Australia 5063
Ethics committee country [1] 298305 0
Australia
Date submitted for ethics approval [1] 298305 0
26/07/2017
Approval date [1] 298305 0
05/09/2017
Ethics approval number [1] 298305 0

Summary
Brief summary
The investigational product pentosan polysulfate (PPS) has various effects which suggest it may be useful in osteoarthritis. Preclinical (laboratory and animal studies) and clinical (human) studies have supported its potential role in OA. PPS has been shown to:;
1.Inhibit the cartilage degrading enzymes which play a key role in OA progression
2 Have anti-inflammatory effects including blocking the effects of the pro-inflammatory cytokines which are involved in osteoarthritis
3. Have antithrombic, antifibrotic and antilipidaemic effects which may assist with improved blood circulation in the bone.

In this trial, patients with Osteoarthritis of the knee and associated Bone marrow lesions, who meet the study inclusion criteria, will be treated with either PPS or placebo, in a ratio of 1:1 according to a computer generated randomisation. The treatment will be given in double-blinded fashion (so that neither the patient, nor the person administering the treatment and assessing responses will know which treatment the patient received)

The treatment will be given by subcutaneous injection, twice weekly for 6 weeks. Patients will visit the clinic according the the study schedule for the duration of treatment and up until Day 81, for monitoring and assessment of treatment responses, safety and adverse events recording.

Treatment responses will be measured by changes in symptom scores according to KOOS questionnaire and NRS pain score at various time-points, and evolution of MRI images before treatment and at day 53.

Patients will be further followed up with a phone call and symptom questionnaire on day 109 and 165.
Trial website
https://www.ctc.asn.au/trials/oaknee
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 76658 0
A/Prof Andrew Ostor
Address 76658 0
Emeritus Research
291 Wattletree Road
Malvern East, VIC 3145
Country 76658 0
Australia
Phone 76658 0
+61395096166
Fax 76658 0
Email 76658 0
andrewostor@emeritusresearch.com
Contact person for public queries
Name 76659 0
Mrs Melanie Duiker
Address 76659 0
Paradigm Biopharmaceuticals
Level 2
517 Flinders Lane
Melbourne
VIC 3000
Country 76659 0
Australia
Phone 76659 0
+61478694464
Fax 76659 0
Email 76659 0
mduiker@paradigmbiopharma.com
Contact person for scientific queries
Name 76660 0
Dr Ravi Krishnan
Address 76660 0
Paradigm Biopharmaceuticals
Level 2
517 Flinders Lane
Melbourne
VIC 3000
Country 76660 0
Australia
Phone 76660 0
+61412095125
Fax 76660 0
Email 76660 0
rkrishnan@paradigmbiopharma.com