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

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

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.

Study Overview

• Status: Completed
• Conditions: Knee Osteoarthritis
• Intervention / Treatment: Device: HL-01: high and low molecular weight hyaluronic acid; Device: Placebo

• Study Type: Interventional
• Enrollment (Actual): 692
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Liège, Belgium
    • CHU Centre Ville (Brull) - Bone Metabolism Unit
• Germany
  • Bad Doberan, Germany
    • Rheumazentrum Prof. Dr. med. Gunther Neeck
  • Berlin, Germany
    • Klinische Forschung Berlin-Mitte GmbH
  • Eichstätt, Germany
    • DGS Schmerzzentrum Eichstätt
  • Leipzig, Germany
    • AmBeNet GmbHDas Ambulante BehandlungsNetz
• Hungary
  • Budapest, Hungary
    • Revita Rendelo
  • Budapest, Hungary
    • Semmelweis Egyetem - Ortopediai Klinika
  • Budapest, Hungary
    • Szent Margit Rendelointézet
  • Debrecen, Hungary
    • DEEK University
  • Kiskunfélegyháza, Hungary
    • MEDIDEA Egeszsegugyi es Szolgaltato Beteti Tarsasag
  • Létavértes, Hungary
    • Swan Med SMO
• Italy
  • Milano, Italy
    • Istituto Ortopedico Gaetano Pini
  • Napoli, Italy
    • Fisiatria Policlinico di Napoli
  • Roma, Italy
    • Ospedale San Pietro - FATEBENEFRATELLI
• Poland
  • Bydgoszcz, Poland
    • NZOZ VITAMED Gałaj i Cichomski Sp. j.
  • Chełm, Poland
    • ETG Chełm
  • Chojnice, Poland
    • Centrum Medyczne Lukamed
  • Elbląg, Poland
    • Centrum Kliniczno-Badawcze
  • Gdańsk, Poland
    • Gdanskie Centrum Zdrowia
  • Lublin, Poland
    • ETG Lublin
  • Ostróda, Poland
    • SOLB - Zbigniew Zegota
  • Siedlce, Poland
    • ETG Siedlce
  • Sochaczew, Poland
    • RCMed
  • Warszawa, Poland
    • ETG Warszawa
  • Warszawa, Poland
    • Europejskie Centrum leczenia Chorob Cywilizacyjnych
  • Warszawa, Poland
    • NZOZ Wilmed
  • Warszawa, Poland
    • Wasilczyk Medical Clinic Indywidualna Praktyka Lekarska Cezary Wasilczyk
  • Zamość, Poland
    • ETG Zamość
  • Łódź, Poland
    • ETG Łódz
  • Łódź, Poland
    • Klinika Zdrowej Kości
  • Świdnik, Poland, 21-040
    • Lubelskie Centrum Diagnostyczne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. severe varus/valgus deformity (>15°)
  2. 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HL-01; 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; 2 ml intra-articular single injection; Other Names: Sinovial HL®
Placebo Comparator: Placebo; Single 2 ml intra-articular injection of Placebo (physiological solution)	Device: Placebo; 2 ml intra-articular single injection

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Incidence and frequency of AEs (adverse events)	Screening -Week 24
Level of treatment satisfaction	Level of treatment satisfaction - assessed by subject at baseline (within 15 minutes after the i. a. injection), in 24 hours (+/- 1 hour) after the injection, at week 1 and week 6	Baseline-Week 6

Collaborators and Investigators

• Sponsor: IBSA Institut Biochimique SA

Publications and helpful links

General Publications

• Migliore A, Blicharski T, Plebanski R, Zegota Z, Gyula G, Rannou F, Reginster JY. Knee Osteoarthritis Pain Management with an Innovative High and Low Molecular Weight Hyaluronic Acid Formulation (HA-HL): A Randomized Clinical Trial. Rheumatol Ther. 2021 Dec;8(4):1617-1636. doi: 10.1007/s40744-021-00363-3. Epub 2021 Aug 30.
• Bruyere O, Dardenne N, Donneau AF, Reginster JY. Responder Profile to Pharmaceutical-Grade Chondroitin Sulfate: An Analysis of the CONCEPT Trial. Adv Ther. 2020 Nov;37(11):4641-4648. doi: 10.1007/s12325-020-01484-x. Epub 2020 Sep 21.

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2017
• Primary Completion (Actual): June 27, 2018
• Study Completion (Actual): October 30, 2018

Study Registration Dates

• First Submitted: June 21, 2017
• First Submitted That Met QC Criteria: June 23, 2017
• First Posted (Actual): June 27, 2017

Study Record Updates

• Last Update Posted (Actual): November 16, 2021
• Last Update Submitted That Met QC Criteria: November 15, 2021
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee; Physiological Effects of Drugs; Immunologic Factors; Protective Agents; Adjuvants, Immunologic; Viscosupplements; Hyaluronic Acid
• Other Study ID Numbers: 16EU-Hai13

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No