A Study to Investigate The Duration of Treatment Effect and Re-treatment With Subcutaneous Injections of Pentosan Polysulfate Sodium Compared With Placebo in Adult Participants With Knee Osteoarthritis Pain

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to measure the duration of treatment effect and response to re-treatment with subcutaneous injections of pentosan polysulfate sodium (PPS) compared with placebo in adult participants with knee osteoarthritis (OA) pain. Study details include: The study duration will be up to 28, 56, 68, or 80 weeks depending on treatment received in the parent study and response to treatment. If participating in the Treatment Part of the study: The treatment duration will be up to 6 weeks The visit frequency will be twice weekly during the Treatment Period.

Detailed Description
-----------------
This is a follow-up extension study to determine duration of treatment effect and assess long-term safety and response to re-treatment with PPS in participants with knee OA pain who completed the parent study study (PARA_OA_002). Study PARA_OA_006 consists of Follow-up Part 1 and Part 2 and a Treatment Part Eligible participants will be enrolled in Study PARA_OA_006 at the completion of the parent study and will enter the 6-month Follow-up Part 1. At the end of Follow-up Part 1, participants will begin the Treatment Part of the study, continue to Follow-up Part 2, or end the study depending on the treatment received in the parent study, their response to treatment during the parent study, and/or their response status at the end of the Follow-up Part 1 Participants in the Treatment Part will be administered twice weekly subcutaneous (SC) injections for 6 weeks: The PPS dose regimen will be 1 of the 3 dose regimens evaluated in Stage 1 of the parent study and selected by the independent data monitoring committee (DMC). Placebo will be 0.9% w/v sodium chloride injection. The maximum duration of study participation will be approximately: 28 weeks for participants who complete Follow-up Part 1 and are not eligible to continue to Follow-up Part 2 or the Treatment Part 56 weeks for participants who complete Follow-up Part 1 and the Treatment Part 68 weeks for participants who complete Follow-up Part 1, Follow-up Part 2 up to Week 40, and the Treatment Part 80 weeks for participants who complete Follow-up Parts 1 and 2 or Follow-up Part 1, Follow-up Part 2 up to Week 52 and the Treatment Part

Official Title
-----------------
An Extension Study to Evaluate Duration of Treatment Effect and Re-treatment of Pentosan Polysulfate Sodium in Participants With Knee Osteoarthritis Pain

Conditions
-----------------
Osteoarthritis, Knee

Intervention / Treatment
-----------------
* Drug: Pentosan Polysulphate Sodium
* Drug: Placebo (Sodium Chloride Injection, 0.9%)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Participants who completed Day 168 of Study PARA_OA_002 (ie, did not discontinue/withdrew prematurely from the parent study). Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Agrees to continue use of paracetamol or topical analgesics (topical NSAIDs are prohibited) as rescue therapy, if required. Exclusion Criteria: Major surgery or anticipated surgery during the study. Currently hospitalised or any planned hospitalisations during the study. Plan for total knee reconstruction in affected knee(s) during the study. Contraindication to MRI scans. An employee of the Sponsor, clinical research organisations 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. Treatment Inclusion Criteria: Body mass index of >=18 to <=39.0 kg/m2 Willing to abstain from use of oral and topical NSAIDs, opioids, and all other systemic pain medications (except acetaminophen/paracetamol per rescue protocol) from 2 weeks before Treatment Day 1 to end of study. Agrees to continue to use acetaminophen/paracetamol or topical analgesics (topical NSAIDs are prohibited) as rescue therapy if required Treatment Exclusion Criteria Major surgery or anticipated surgery during the study. Currently hospitalised or any planned hospitalisations during the study. Plan for total knee reconstruction in affected knee(s) during the study. Contraindication to MRI scans. An employee of the Sponsor, clinical research organisations 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. 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 (HIT) including history of or laboratory confirmed HIT (positive or equivocal antibodies against platelet factor 4 (anti-PF4). Currently active or recent history (within preceding 12 months) of a gastric or duodenal ulcer, or suspicion of gastrointestinal tract bleeding. Fibromyalgia, regional pain caused by lumbar or cervical compression with radiculopathy, or other moderate to severe pain that may confound assessments or self-evaluation of the pain associated with osteoarthritis. Participants with a present (current) history of sciatica are not eligible for participation. Participants with a history of sciatica who have been asymptomatic for >= 3 months and who have no evidence of radiculopathy or sciatic neuropathy on thorough neurologic examination are eligible for participation. History of hypersensitivity to PPS, heparin or heparin-like drugs, or drugs of a similar chemical or pharmacological class. Current clinically significant medical conditions, medical history, physical findings, or laboratory abnormality that, in the Investigator's opinion, makes the participant unsuitable for the study. Chronic medical conditions will be allowed at the discretion of the Investigator but must be stable without necessitating medication changes within 30 days before Treatment Day 1. 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. Current treatment with anticoagulants or antiplatelet drugs, excluding aspirin ≤100 mg/day. Activated partial thromboplastin time (aPTT) > upper limit of normal (ULN), platelets < 150,000/µL, or liver enzyme tests (aspartate aminotransferase (AST) or alanine aminotransferase (ALT)) >= 2 × ULN at Screening. Values of aPTT at Screening that are below the lower limit of normal should be discussed with the Medical Monitor. Active or chronic hepatitis B virus, hepatitis C virus, or uncontrolled HIV infection (detectable virus or diagnosis of AIDS); participants with HIV infection must be on chronic suppressive antiviral medication. Any clinically significant abnormalities on clinical chemistry, haematology, urinalysis, physical examination, medical history, 12-lead electrocardiogram (ECG), or vital signs as judged by the Investigator (at Screening). Resting, supine blood pressure (BP) ≥ 160 mmHg in systolic pressure or >= 100 mmHg in diastolic pressure at Screening. If a participant is found to have uncontrolled and/or untreated significant hypertension at Screening and anti-hypertensive treatment is initiated, assessment for study eligibility should be deferred until BP and anti-hypertensive medication have been stable for at least 1 month. For participants with previously diagnosed hypertension, anti-hypertensive medications must be stable for at least 1 month before Screening. Largely or wholly incapacitated (eg, bedridden or confined to a wheelchair, permitting little or no self-care). Major surgery within 12 weeks before treatment Day1or anticipated surgery. Currently hospitalised or any planned hospitalisations during the treatment part. Plan for total knee reconstruction in affected knee(s) during the treatment part. Knee surgery or trauma to the index knee within 1 year before treatment Day 1. A history of drug or alcohol abuse and/or dependence within the 12 months before Screening that, in the opinion of the investigator, may affect participant ability to comply with study requirements. Contraindication to MRI scans. An employee of the Sponsor, clinical research organisations 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentosan Polysulfate Sodium<br>Pentosan Polysulfate Sodium (PPS) at Dose and frequency selected in Stage 1 of Parent Study for 6 weeks | Drug: Pentosan Polysulphate Sodium<br>* Subcutaneous Injection (100mg/ml)<br>|
| Placebo Comparator: Placebo<br>Placebo for 6 weeks | Drug: Placebo (Sodium Chloride Injection, 0.9%)<br>* Placebo to match PPS<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time from initial response in the parent study (PARA_OA_002) to loss of OMERACT-OARSI response through Follow-up Week 28 (Part 1) | Time taken to loose response from participants considered OMERACT- OARSI responders in the parent study. Participants are considered as an OMERACT-OARSI responder: if the change (improvement) from baseline to day of interest was greater than or equal to >= 50 percent and >= 2 units in either WOMAC pain sub-scale or physical function sub-scale score; if change (improvement) from baseline to week of interest was >=20 percent and >=1 unit in at least 2 of the following: 1) WOMAC pain sub-scale score, 2) WOMAC physical function sub-scale score, 3) Patient Global Impression of Change (PGIC). | From initial response time in parent study upto Week 28 | 
| Time from initial response in the parent study (PARA_OA_002) to loss of OMERACT-OARSI response through Follow-up Week 80 (Part 2) | Time taken to loose response from participants considered OMERACT- OARSI responders in the parent study. | From initial response time in parent study upto Week 80 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants meeting Outcomes Measures in Arthritis Clinical Trials-Osteoarthritis Research Society International - Osteoarthritis Research Society International (OMERACT-OARSI) Responder Index at Week 12, 28, 40, 52 and 80 | Percentage of participants considered OMERACT- OARSI responders at each timepoint.. | Week 12, 28, 40, 52 and 80 | 
| Percentage of participants meeting OMERACT-OARSI Responder Index at Treatment Days 11, 25, 39, 56, 84, 112, 140 and 168 | Percentage of participants considered OMERACT- OARSI responders at each timepoint following treatment/re-treatment | Baseline, Days 11, 25, 39, 84, 112, 140 and 168 | 
| Change from baseline of the parent study in knee pain as assessed by the average pain sub-scale score of the Western Ontario and McMaster Universities (WOMAC®) numeric rating scale (NRS) 3.1 Index at Weeks 12, 28, 40, 52, and 80 | WOMAC: The WOMAC pain sub-scale is a 5-item questionnaire used to assess the amount of pain experienced due to OA of index joint (knee) during the past 48 hours. | Baseline (Parent Study), Weeks 12, 28, 40, 52 and 80 | 
| Change from baseline of the parent study in function as assessed by the average function sub-scale score of the Western Ontario and McMaster Universities (WOMAC®) numeric rating scale (NRS) 3.1 Index at Weeks 12, 28, 40, 52, and 80 | WOMAC: Physical function refers to participant's ability to move around and perform usual activities of daily living. The WOMAC physical function sub-scale is a 17-item questionnaire used to assess the degree of difficulty experienced due to OA in index joint (knee) during the past 48 hours. | Baseline (Parent Study), Weeks 12, 28, 40, 52 and 80 | 
| Change from baseline of the parent study in knee pain of >=25% and >=50% as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index at Weeks 12, 28, 40, 52, and 80 | Percentage of participants with reduction in WOMAC pain intensity of at least >=25% or >=50% compared to baseline in the parent study as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index at Weeks 12, 28, 40, 52 and 80 | Baseline (Parent Study), Weeks 12, 28, 40, 52 and 80 | 
| Change from baseline of the parent study in function of >=25% and >=50% as assessed by the average function sub-scale score of the WOMAC® NRS 3.1 Index at Weeks 12, 28, 40, 52, and 80 | Percentage of participants with improvement in WOMAC function of at least >=25% or >=50% compared to baseline in the parent study | Baseline (Parent Study), Weeks 12, 28, 40, 52 and 80 | 
| Change from baseline of the parent study in stiffness as assessed by the average stiffness sub-scale score of the Western Ontario and McMaster Universities (WOMAC®) numeric rating scale (NRS) 3.1 Index at Weeks 12, 28, 40, 52, and 80 | WOMAC: The WOMAC stiffness sub-scale is a 2-item questionnaire used to assess the amount of stiffness experienced due to OA in the index joint (knee) during the past 48 hours | Baseline (Parent Study), Weeks 12, 28, 40, 52 and 80 | 
| Change from baseline of the parent study as assessed by the average overall score of the Western Ontario and McMaster Universities (WOMAC®) numeric rating scale (NRS) 3.1 Index at Weeks 12, 28, 40, 52, and 80 | WOMAC: The WOMAC® NRS 3.1 Index consists of 24 questions and produces 3 sub-scales scores for pain (5 questions), stiffness (2 questions), and function (17 questions) and a total score that summarizes overall disability | Baseline (Parent Study), Weeks 12, 28, 40, 52 and 80 | 
| Patient Global Impression of Change (PGIC) at Weeks 12, 28, 40, 52 and 80 | The PGIC is a self-administered question that rates participants overall improvement in chronic pain since beginning treatment from 1 no change (or condition has worsened) to 7 a great deal better in response to the question Since beginning treatment, how would you describe the change (if any) in activity, limitation, symptoms, emotions, and overall QoL related to your arthritis. | Weeks 12, 28, 40, 52 and 80 | 
| Change from baseline of the parent study at Weeks 12, 28, 40, 52 and 80 in Quality of Life (QoL) as assessed by Short Form-36 General Health Survey (SF-36) | The SF-36 v2 is a 36-item, patient-reported survey of patient health, consisting of 8 scaled scores, which are the weighted sums of the questions in their section. The 1-week recall form asks the respondent to answer the questions as they pertain to the way he or she felt or acted during the past week. | Weeks 12, 28, 40, 52 and 80 | 
| Change from baseline of the parent study at Weeks 12, 28, 40, 52 and 80 in Work Productivity and Activity Impairment (WPAI) questionnaire. | This WPAI questionnaire (WPAI:OA-knee) is a validated self-administered questionnaire that assesses work impairment due to OA . The questionnaire gathers information on employment status, hours worked, hours missed due to OA, and hours missed for any other reasons | Weeks 12, 28, 40, 52 and 80 | 
| Change from baseline at Treatment Days 11, 25, 39, 84, 112, 140 and 168 in knee pain as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index. | Change from baseline following treatment/re-treatment. WOMAC: The WOMAC pain sub-scale is a 5-item questionnaire used to assess the amount of pain experienced due to OA of index joint (knee) during the past 48 hours. | Baseline, Days 11, 25, 39, 56, 84 112, 140 and 168 | 
| Change from baseline at Treatment Days 11, 25, 39, 84, 112, 140 and 168 in function as assessed by the average function sub-scale score of the WOMAC® NRS 3.1 Index. | Change from baseline of function following treatment/re-treatment. WOMAC: Physical function refers to participant's ability to move around and perform usual activities of daily living. | Baseline, Days 11, 25, 39, 56, 84 112, 140 and 168 | 
| Change from baseline at Treatment Days 11, 25, 39, 84, 112, 140 and 168 in stiffness as assessed by the average function sub-scale score of the WOMAC® NRS 3.1 Index. | Change from baseline of stiffness following treatment/re-treatment. WOMAC: The WOMAC stiffness sub-scale is a 2-item questionnaire used to assess the amount of stiffness experienced due to OA in the index joint (knee) during the past 48 hours | Baseline, Days 11, 25, 39, 56, 84 112, 140 and 168 | 
| Change from baseline at Treatment Days 11, 25, 39, 84, 112, 140 and 168 as assessed by the average overall score of the WOMAC® NRS 3.1 Index. | Change from baseline of WOMAC overall score following treatment/re-treatment. WOMAC: The WOMAC® NRS 3.1 Index consists of 24 questions and produces 3 sub-scales scores for pain (5 questions), stiffness (2 questions), and function (17 questions) and a total score that summarizes overall disability | Baseline, Days 11, 25, 39, 56, 84 112, 140 and 168 | 
| Patient Global Impression of change at Day 39, 84, 112, 140 and 168 | The PGIC is a self-administered question that rates participants overall improvement in chronic pain since beginning treatment from 1 no change (or condition has worsened) to 7 a great deal better in response to the question Since beginning treatment, how would you describe the change (if any) in activity, limitation, symptoms, emotions, and overall QoL related to your arthritis. | Days 39, 56, 84 112, 140 and 168 | 
| Change from baseline at Treatment Days 11, 25, 39, 56, 84, 112, 140, and 168 in Quality of Life (QoL) as assessed by Short Form-36 General Health Survey (SF-36) | The SF-36 v2 is a 36-item, patient-reported survey of patient health, consisting of 8 scaled scores, which are the weighted sums of the questions in their section. The 1-week recall form asks the respondent to answer the questions as they pertain to the way he or she felt or acted during the past week. | Baseline, Days 11, 25, 39, 56, 84 112, 140 and 168 | 
| Change from baseline at Treatment Days 56, 84, 112, 140, and 168 in Work Productivity and Activity Impairment (WPAI) questionnaire score | This WPAI questionnaire (WPAI:OA-knee) is a validated self-administered questionnaire that assesses work impairment due to OA . The questionnaire gathers information on employment status, hours worked, hours missed due to OA, and hours missed for any other reasons.. | Days 56, 84 112, 140 and 168 | 
| Change from baseline in knee pain of >=25% and >=50% as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index at Treatment Days 11, 25, 39, 84, 112, 140 and 168 | Percentage of participants with reduction in WOMAC pain intensity of at least >=25% or >=50% compared to baseline as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index at Days 11, 25, 39, 56, 84 112, 140 and 168 | Baseline, Days 11, 25, 39, 46, 84 112, 140 and 168 | 
| Change from baseline in function of >=25% and >=50% as assessed by the average function sub-scale score of the WOMAC® NRS 3.1 Index at Treatment Days 11, 25, 39, 84, 112, 140 and 168 | Percentage of participants with improvement in WOMAC function of at least >=25% or >=50% compared to baseline as assessed by the average pain sub-scale score of the WOMAC® NRS 3.1 Index at Days 11, 25, 39, 56, 84 112, 140 and 168 | Baseline, Days 11, 25, 39, 46, 84 112, 140 and 168 | 
| Number of days of rescue medication used from through followup to end of study | In case of inadequate pain relief, either acetaminophen/paracetamol up to 3000 mg per day or topical analgesics, up to 4 days in a week could be taken as rescue medication. Number of participants with any use of rescue medication will be summarized | Baseline up to Week 80 | 
| Number of days of rescue medication used from Treatment Day 1 through Day 168 | In case of inadequate pain relief, either acetaminophen/paracetamol up to 3000 mg per day or topical analgesics, up to 4 days in a week could be taken as rescue medication between Treatment Day 1 and Day 168. Number of participants with any use of rescue medication will be summarized | Day 1 through Day 168 | 
| Incidence of Serious Adverse Events (SAE), Adverse Events (AE) related to the Investigational Product (IP), and AEs related to any intervention for knee pain through followup to end of study | An SAE is any untoward medical occurrence that at any dose results in one or more of the following outcomes: death; life-threatening; requires in-patient hospitalization or prolongation of an existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; is an important medical event. | Baseline up to Week 80 | 
| Incidence of Treatment Emergent Adverse Events (TEAE) through Treatment to Day 168 | Treatment-emergent are events between the first dose of study drug and up to Day 168 that were absent before treatment or that worsened relative to pre-treatment state. | Baseline up to Day 168 | 
| Incidence of Treatment-emergent clinical laboratory abnormalities from treatment to end of study | Treatment-emergent clinical laboratory abnormalities are deemed clinically significant abnormalities in labs between the first dose of study drug and up to Day 168 that were absent before treatment or that worsened relative to pre-treatment state. | Baseline up to Day 168 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Knee, Osteoarthritis