A Study to Evaluate the Clinical Performance and Safety of an Intra-articular Hyaluronic Acid in Knee Osteoarthritis

Study Overview
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Brief Summary
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This is a study to evaluate the Clinical Performance and Safety of a single intra-articular (i.a.) injection of hyaluronic acid product (as HL-01) in the treatment of pain due to osteoarthritis (OA) of the knee.

Official Title
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A Phase 3,Randomized,Double-blind,Placebo-controlled Study to Evaluate the Clinical Performance and Safety of an Intra-articular Solution of High and Low Molecular Weight Hyaluronic Acid (HL-01) in the Treatment of Pain in Symptomatic Knee Osteoarthritis

Conditions
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Knee Osteoarthritis

Intervention / Treatment
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* Device: HL-01: high and low molecular weight hyaluronic acid
* Device: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female and male subjects ≥40 to 80 years of age. Subjects with primary knee OA of the medial or lateral femoro-tibial compartment, documented according to ACR criteria with symptoms, at screening, from at least 3 months. Subjects with Kellgren & Lawrence (K-L) radiological grade 2-3. Subjects with at least one antero-posterior view X-Ray image of the target knee taken within 12 months prior to the screening. Subjects with OA pain intensity meeting the criteria below: If unilateral knee OA: Subjects demonstrating at screening pain intensity in the target knee measured by Visual Analogue Scale (VAS) ≥40 mm VAS, and ≤ 20 mm in the contralateral knee and confirmed at randomization after wash-out from analgesics/NSAIDs. If bilateral knee OA: definition of the most symptomatic joint at screening based on subject's evaluation and Investigator's clinical judgment with subjects demonstrating pain intensity in the target knee measured by Visual Analogue Scale (VAS) ≥40 mm VAS, and ≤ 20mm in the contralateral knee and confirmed at randomization after wash-out from analgesics/NSAIDs. Subjects are able to understand and are willing and able to comply with study procedures including usage of acetaminophen as the only analgesic. Subjects are able to provide informed consent. Any female subject of childbearing potential must agree to use adequate methods of contraception throughout the course of the study. Exclusion Criteria: Subjects with secondary (post-traumatic) knee OA of the target and non-target joints. Subjects with K-L radiological grade 4 knee OA. Subjects with a history of knee joint replacement/arthroplasty of the target knee. Subjects with a history of arthroscopy, osteotomy, or surgery of the target knee in the past 12 months. Subjects with any significant injury to the target knee in the last 6 months (as per Investigator judgment). Subjects with Body Mass Index (BMI) ≥32 kg/m2. Subjects with any musculoskeletal condition affecting the target knee that would impair proper assessment of the Investigational Medicinal Device (IMD) performance in the target knee as assessed by the Investigator and such as: severe varus/valgus deformity (>15°) predominantly patello-femoral pain/syndrome. Subjects with a history of symptomatic hip OA or other health condition i.e. associated with pain and interfering with adequate study endpoints evaluation. Subjects with a known history or present evidence of conditions which may affect the target knee assessments, like rheumatic disease and inflammatory, infective or metabolic joint diseases; recurrent clinical chondrocalcinosis; crystal arthropathies; osteo-articular pathologies differing from arthrosis; articular fracture; ochronosis; acromegaly; haemochromatosis; Wilson's disease; primary osteochondromatosis; heritable disorders; collagen gene mutations. Subjects with venous or lymphatic stasis in the relevant limb. Subjects with a history of the following treatments for knee OA: a) I. a. knee corticosteroids: i. target knee - in the past 3 months ii. non-target knee/other joints - in the past 4 weeks b) Systemic (both oral and parenteral) and topical corticosteroids at the target knee in the past 3 months. c) Topical anti-inflammatories and analgesics applied at the target knee in the past 48 hrs. d) Viscosupplementation with hyaluronic acid or joint-lavage in the target knee in the past year. e) Physical therapy started in the last 3 months in the target knee. f) Symptomatic Slow-Acting Drugs for OA (SYSADOA) such as glucosamine, chondroitin sulfate, diacerhein, or other medications like avocado/soya extracts, etc. in the past 3 months. g) Chronic or recurrent use of narcotic analgesics. h) Use of analgesic (other than acetaminophen) and NSAIDs for a time of 5-half-lives before the screening. Subjects with a history of chronic or recurrent use of NSAIDs/analgesics/narcotics because of diseases different from OA of the target knee. Subjects treated with drugs having an influence on pain: hypnotics, muscle relaxants, anxiolytics if the intake has started less than 8 days before the screening. Subjects who currently use heparin or anti-vitamin K (e. g. crystalline warfarin) anticoagulant therapy. Subjects with the presence of infection, skin diseases, other disease or trauma in the area of the injection site or joint. Subjects with a known history or suspected allergy or hypersensitivity to hyaluronic acid or to hyaluronate preparations. Subjects with a known history or suspected allergy or hypersensitivity to acetaminophen. Subjects with any major surgery scheduled in the next 6 months. Subjects who have participated in a clinical study / investigation in the last 3 months. Pregnant or lactating women and women of childbearing potential not willing to use adequate contraception.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HL-01<br>Single 2 ml intra-articular injection of HL-01 (solution of high and low molecular weight hyaluronic acid (HA)) | Device: HL-01: high and low molecular weight hyaluronic acid<br>* 2 ml intra-articular single injection<br>* Other names: Sinovial HL®;|
| Placebo Comparator: Placebo<br>Single 2 ml intra-articular injection of Placebo (physiological solution) | Device: Placebo<br>* 2 ml intra-articular single injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in VAS (Visual Analogue Scale) pain score | The primary efficacy variable will be the change from baseline of the VAS pain score calculated as a VAS measure ranging from 0 to 100 mm. A four- step analysis will be followed in order to assess superiority of HL-01 versus Placebo after 6, 12, 18 and 24 weeks. | Baseline-week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lequesne's Algofunctional Index | Change from baseline in Lequesne's Algofunctional Index at 6, 12, 18 and 24 weeks. | Baseline-Week 24 | 
| Change in global status assessed by subject (EQ-5D-5L EuroQol Group Health questionnaire) | Change from baseline in global status assessed by subject at 6, 12, 18 and 24 weeks (EQ-5D-5L) | Baseline-Week 24 | 
| Change in global status assessed by physician | Change from baseline in global status assessed by physician at 6, 12, 18 and 24 weeks (5-point verbal Likert scale), dichotomised to 'Improvement' and 'No change/Worsening' | Baseline -Week 24 | 
| Overall response rate according to OMERACT (Outcome Measures in Rheumatology)-OARSI (Osteoarthritis Research Society International) criteria | Overall response rate according to OMERACT-OARSI criteria at 6, 12, 18 and 24 weeks (this is a statistical analysis) | Week 6-Week 24 | 
| Rescue medication usage | Rescue medication usage assessed at 6, 12, 18 and 24 weeks. | Week 6-Week 24 |