A Study to Evaluate the Efficacy, Safety and Tolerability of EVI-01 Intra-Articular Injection in Osteoarthritis of the Knee

Study Overview
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Brief Summary
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Objective: Identifying the dose of EVI-01 with the best clinical response, balancing the efficacy, safety, and tolerability of the investigational product. Study design: Interventional, dose-finding, three arms, randomized (1:1:1), parallel assignment, double-blind, controlled by an active comparator.

Detailed Description
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Phase II, dose-finding, interventional, three-arm, randomized (1:1:1), double-blind, parallel, active-comparator-controlled clinical trial.

Official Title
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A Double-Blind, Randomized, Controlled, Three Parallel Arm, Dose-Finding Study to Evaluate the Efficacy, Safety and Tolerability of One Single Intra-Articular Injection of EVI-01 in Patients With Symptomatic Osteoarthritis of the Knee

Conditions
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Osteoarthritis, Osteoarthritis, Knee

Intervention / Treatment
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* Device: EVI-01
* Device: Active comparator Synvisc-One


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of both genders aged 18 years or older; Body Mass Index (BMI) < 35 kg/m2; Diagnosis of primary knee osteoarthritis, Kellgren-Lawrence Grade 2 to 4, according to American College of Rheumatology (ACR) criteria and confirmed radiologically within the previous 12 months, for which an intraarticular treatment is indicated; Moderate to severe pain measured by VAS (0-100mm) and >40mm in the knee to be treated, partially responsive to chronic doses of nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics, or weak opioids (codeine and tramadol); Ability to understand and provide signed consent through the Informed Consent Form (ICF). Exclusion Criteria: History of hypersensitivity/allergy to hyaluronic acid (HA) or other excipients of the IP or product; Pregnant or breastfeeding women; Women at menace who do not agree to use acceptable contraceptive methods (oral contraceptive, injectable contraceptive, IUD, hormonal implant, barrier methods, sexual abstinence, hormone transdermal patch and tubal ligation); except those who are surgically sterile (bilateral oophorectomy or hysterectomy); Emotional problems or any situation that, at the Investigator's discretion, places the safety of subjects at risk; Application of visco-supplementation to the knee less than four months prior to randomization; Corticosteroid IA injection less than 4 months prior to randomization and/or schedule during the course of the study; Knee infection and/or inflammation (e.g., bursitis), skin infection at or around the IA injection; Swelling, redness, warmth, or other clinically relevant inflammatory signs in the knee in the investigator's description Knee injury or trauma; Patients with bleeding diathesis or on anticoagulant therapy; Major knee malformations or deformities that the investigator deems pertinent; Active cancer at the Investigator's discretion; Continuous or frequent use (use for more than 2 weeks in the last 2 months) of corticosteroids by any route of administration (oral, IM, IV) Concomitant use of chondroprotective drugs such as glucosamine, chondroitin, or collagen. These medications should not be introduced during the study, but if the patient is already taking them may be included, but the medication will not change. Need for the use of strong opioids (methadone, fentanyl, morphine, and oxycodone) for pain management; Participation in a clinical trial within the last twelve months prior to enrollment (CNS Resolution 251, dated 07 August 1997, item III, item J), unless the investigator believes that there may be a benefit to the patient.

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EVI-01 - low dose<br>4 mL, one single EVI-01 intra-articular injection | Device: EVI-01<br>* Single intra-articular injection of high molecular weight hyaluronic acid<br>|
| Experimental: EVI-01 - high dose<br>6 mL, one single EVI-01 intra-articular injection | Device: EVI-01<br>* Single intra-articular injection of high molecular weight hyaluronic acid<br>|
| Active Comparator: Synvisc-One<br>6 mL, one single intra-articular injection | Device: Active comparator Synvisc-One<br>* Single intra-articular injection of active comparator Synvisc-One<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes to the questionnaire WOMAC A (Western Ontario and McMaster Universities) Numeric 3.1 | Questionnaire WOMAC A (Western Ontario and McMaster Universities) numeric scale, version 3.1, total knee pain score (pain, stiffness and physical function assessment) | from baseline to 180 days after randomization | 
| Comparison of treatment-related Adverse Events in the three groups | Incidence of treatment-emergent adverse events | from baseline to 180 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes to the WOMAC (Western Ontario and McMaster Universities) Total Numeric 3.1 score | WOMAC (Western Ontario and McMaster Universities) numeric scale, version 3.1 (pain, stiffness and physical function assessment) | from baseline to 180 days after randomization | 
| Changes to the WOMAC (Western Ontario and McMaster Universities) A score | WOMAC (Western Ontario and McMaster Universities) A numeric scale, version 3.1, total knee pain score (pain, stiffness and physical function assessment) | from Day 1 to Day 7 after randomization | 
| Response to the Euro Quality of Life Questionnaire | Euro Quality of Life Questionnaire version EQ-5D-5L | from baseline to 180 days after randomization | 
| Response rate, according to OMERACT-OARSI2 international criteria | OMERACT-OARSI2 (Outcome Measures in Rheumatology Committee - Osteoarthritis Research Society International) | from baseline to Days 28, 90 and 180 after randomization |