Efficacy Study of Intra-articular Hyaluronic Acid in the Knee Osteoarthritis

Efficacy Evaluation of Intra-articular Hyaluronic Acid (Sinovial®) vs Synvisc® in the Treatment of Symptomatic Knee Osteoarthritis. A Double-blind, Controlled, Randomised, Parallel-group Non-inferiority Study

The purpose of this study is to prove the non-inferiority of the intra-articular injection of hyaluronic acid (Sinovial®) in the symptomatic treatment of knee OA in comparison to Synvisc®.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis, Knee
• Intervention / Treatment: Device: Sinovial® (syringe containing sodium hyaluronate solution); Device: Synvisc® ( syringe containing Hylan G-F 20 solution)

• Study Type: Interventional
• Enrollment (Actual): 381
• Phase: Phase 4

Contacts and Locations

Study Locations

• Czech Republic
  • Brno - Bohunice, Czech Republic, 63900
    • Interni hemato-onkologická klinika, Fakultní nemocnice
  • Pardubice, Czech Republic, 53002
    • ARTHROMED s.r.o.
  • Praha, Czech Republic, 12850
    • Institute of Rheumatology
  • Praha, Czech Republic, 19061
    • Centrum léčby pohybového aparátu spol. s.r.o.
• France
  • Bois Guillaume, France, 76230
    • University Hospital Centre Bois-Guillaume
  • Limoges Cedex, France, 87042
    • University Hospital Centre of Limoges - Rheumatology Service
• Germany
  • Aachen, Germany, 52074
    • Orthopädische Universitätsklinik und Poliklinik der RWTH Aachen
  • Biberach an der Riss, Germany, 88400
    • Nova clinic
  • Stockach, Germany, 78333
    • Orthopädische Praxis
• Italy
  • Arezzo, Italy, 52100
    • Sezione Dipartimentale a valenza provinciale di Reumatologia - AzUSL 8
  • Bologna, Italy, 40138
    • Ospedale Privato Accreditato Nigrisoli
  • Lucca, Italy, 55100
    • Medicina e Traumatologia dello Sport - AzUSL 2 Lucca
  • Milano, Italy, 20122
    • Unità Operativa di Reumatologia - Istituto Ortopedico Gaetano Pini
  • Pisa, Italy, 56126
    • Rheumatology Unit Santa Chiara Hospital
  • Siena, Italy, 53100
    • Unità Operativa di Reumatologia - Az. Ospedaliera Universitaria Senese - Policlinico "Le Scotte"
• Slovakia
  • Banská Bystrica, Slovakia, 975 17
    • F.D. Roosevelt's University Hospital
  • Bratislava, Slovakia, 831 03
    • ROMJAN s.r.o.
  • Piest'any, Slovakia, 921 12
    • National Institute of Rheumatic Diseases
  • Trnava, Slovakia, 917 01
    • Rheumatology Clinic, Reumaglobal s.r.o
• Switzerland
  • Zürich, Switzerland, 8091
    • Department of Rheumatology and Institute of Physical Medicine - Zurich University

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:

• Age between 40 and 80 years
• Primary knee OA of the medial or lateral femoro-tibial compartment
• Symptoms for at least 3 months
• Diagnosis according to ACR criteria
• Kellgren & Lawrence radiological grade 2-3
• Patients who failed to respond sufficiently (not responders) to analgesics and/or NSAIDs taken regularly or responders intolerant to the regular use of analgesics and/or NSAIDs.
• Mean WOMAC pain subscore at the target knee >= 40 mm and < 80 mm on a VAS at baseline after wash-out from analgesics/NSAIDs· If bilateral knee OA: definition of the most symptomatic joint at screening based on patient's evaluation and Investigator's clinical judgment and mean WOMAC pain subscore at baseline in the contra-lateral knee < 30 mm
• Written informed consent
• Subject able to understand, co-operative and reliable

Exclusion Criteria:

• BMI >= 32 kg/m2
• Secondary (post-traumatic) knee OA
• Predominantly patello-femoral pain/syndrome
• No remaining joint space width
• Symptomatic hip OA or other interfering health condition
• Severe varus/valgus deformity (>15°)
• History/present evidence of (target knee): inflammatory, infective or metabolic joint diseases; recurrent clinical chondrocalcinosis; crystal arthropaties; osteo-articular pathologies differing from arthrosis; articular fracture; ochronosis; acromegaly; haemochromatosis; Wilson's disease; primary osteochondromatosis; heritable disorders; collagen gene mutations.
• Concomitant rheumatic disease
• Significant injury to the target knee in the last 6 months
• Previous joint replacement/arthroplasty (target knee)
• Arthroscopy/osteotomy/surgery in the past 1 year (target knee)
• Any surgery scheduled in the next 6 months
• Venous or lymphatic stasis in the relevant limb
• Skin infection/disease/trauma at the injection site
• Systemic or i.a. (target knee) corticosteroids in the past 3 months
• I.a. corticosteroids (non-target joint) in the past 4 weeks
• Viscosupplementation (target knee) in the past year
• Recently started (in the last 3 months) physical therapy (target knee)
• Recently (in the last 3 months) started therapy or change in dosage of SYSADOAs
• Ongoing anticoagulant therapy
• Chronic or recurrent use of NSAIDs/analgesics/narcotics because of diseases different from OA of the target knee
• History of allergy or hypersensitivity to hyaluronic acid or paracetamol or avian proteins
• Participation in a clinical study in the last 3 months
• Pregnant or lactating women, and women of childbearing potential not willing to use adequate contraception
• Patients unable to stay in the study for 6 months, non-cooperating, not able to understand

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sinovial; 3 intra-articular injections of Sinovial®	Device: Sinovial® (syringe containing sodium hyaluronate solution); 2 mL 0.8% sodium hyaluronate (16 mg) solution. 3 intra-articular injections once-a-week.; Other Names: Sinovial®: Class III medical device(CE mark n° 0499)
Active Comparator: Sinvisc	Device: Synvisc® ( syringe containing Hylan G-F 20 solution); 2 mL 0.8% Hylan G-F 20 (16 mg) solution. 3 intra-articular injections once-a-week.; Other Names: Synvisc®: class III medical device (CE mark n° 0088)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Improvement in WOMAC pain subscore from baseline	to week 26

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in WOMAC OA Index total score and pain, function and stiffness subscores;Change in Lequesne's algofunctional index; Change in global pain (visit assessment); Change in global status by the patient;Change in global status by the Investigator;SPID%	26 weeks

Collaborators and Investigators

• Sponsor: IBSA Institut Biochimique SA
• Investigators: Principal Investigator: Karel PAVELKA, MD, Institute of Rheumatology-Na Slupi 4 - 12850 Praha 2 (Czech Republic)

Publications and helpful links

General Publications

• Jordan KM, Arden NK, Doherty M, Bannwarth B, Bijlsma JW, Dieppe P, Gunther K, Hauselmann H, Herrero-Beaumont G, Kaklamanis P, Lohmander S, Leeb B, Lequesne M, Mazieres B, Martin-Mola E, Pavelka K, Pendleton A, Punzi L, Serni U, Swoboda B, Verbruggen G, Zimmerman-Gorska I, Dougados M; Standing Committee for International Clinical Studies Including Therapeutic Trials ESCISIT. EULAR Recommendations 2003: an evidence based approach to the management of knee osteoarthritis: Report of a Task Force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT). Ann Rheum Dis. 2003 Dec;62(12):1145-55. doi: 10.1136/ard.2003.011742.
• Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988 Dec;15(12):1833-40.
• Tubach F, Ravaud P, Baron G, Falissard B, Logeart I, Bellamy N, Bombardier C, Felson D, Hochberg M, van der Heijde D, Dougados M. Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement. Ann Rheum Dis. 2005 Jan;64(1):29-33. doi: 10.1136/ard.2004.022905. Epub 2004 Jun 18.
• Theiler R, Bruhlmann P. Overall tolerability and analgesic activity of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis. Curr Med Res Opin. 2005 Nov;21(11):1727-33. doi: 10.1185/030079905X65547.
• Castellacci E, Polieri T. Antalgic effect and clinical tolerability of hyaluronic acid in patients with degenerative diseases of knee cartilage: an outpatient treatment survey. Drugs Exp Clin Res. 2004;30(2):67-73.
• Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Arthritis Rheum. 2000 Sep;43(9):1905-15. doi: 10.1002/1529-0131(200009)43:93.0.CO;2-P. No abstract available.
• Altman RD. Status of hyaluronan supplementation therapy in osteoarthritis. Curr Rheumatol Rep. 2003 Feb;5(1):7-14. doi: 10.1007/s11926-003-0077-6.
• Lo GH, LaValley M, McAlindon T, Felson DT. Intra-articular hyaluronic acid in treatment of knee osteoarthritis: a meta-analysis. JAMA. 2003 Dec 17;290(23):3115-21. doi: 10.1001/jama.290.23.3115.
• Wang CT, Lin J, Chang CJ, Lin YT, Hou SM. Therapeutic effects of hyaluronic acid on osteoarthritis of the knee. A meta-analysis of randomized controlled trials. J Bone Joint Surg Am. 2004 Mar;86(3):538-45. doi: 10.2106/00004623-200403000-00012.
• Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev. 2006 Apr 19;2006(2):CD005321. doi: 10.1002/14651858.CD005321.pub2.
• Recommendations for the registration of drugs used in the treatment of osteoarthritis. Group for the respect of ethics and excellence in science (GREES): osteoarthritis section. Ann Rheum Dis. 1996 Aug;55(8):552-7. doi: 10.1136/ard.55.8.552. No abstract available.
• Altman R, Brandt K, Hochberg M, Moskowitz R, Bellamy N, Bloch DA, Buckwalter J, Dougados M, Ehrlich G, Lequesne M, Lohmander S, Murphy WA Jr, Rosario-Jansen T, Schwartz B, Trippel S. Design and conduct of clinical trials in patients with osteoarthritis: recommendations from a task force of the Osteoarthritis Research Society. Results from a workshop. Osteoarthritis Cartilage. 1996 Dec;4(4):217-43. doi: 10.1016/s1063-4584(05)80101-3. No abstract available.
• Strand V, Kelman A. Outcome measures in osteoarthritis: randomized controlled trials. Curr Rheumatol Rep. 2004 Feb;6(1):20-30. doi: 10.1007/s11926-004-0080-6.
• Kirchner M, Marshall D. A double-blind randomized controlled trial comparing alternate forms of high molecular weight hyaluronan for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage. 2006 Feb;14(2):154-62. doi: 10.1016/j.joca.2005.09.003. Epub 2005 Oct 19.
• Bellamy N. WOMAC: a 20-year experiential review of a patient-centered self-reported health status questionnaire. J Rheumatol. 2002 Dec;29(12):2473-6. No abstract available.
• KELLGREN JH, LAWRENCE JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis. 1957 Dec;16(4):494-502. doi: 10.1136/ard.16.4.494. No abstract available.
• Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M, et al. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Diagnostic and Therapeutic Criteria Committee of the American Rheumatism Association. Arthritis Rheum. 1986 Aug;29(8):1039-49. doi: 10.1002/art.1780290816.
• Lockman LE. Practice tips. Knee joint injections and aspirations: the triangle technique. Can Fam Physician. 2006 Nov;52(11):1403-4. No abstract available.
• Lequesne MG, Mery C, Samson M, Gerard P. Indexes of severity for osteoarthritis of the hip and knee. Validation--value in comparison with other assessment tests. Scand J Rheumatol Suppl. 1987;65:85-9. doi: 10.3109/03009748709102182. Erratum In: Scand J Rheumatol 1988;17(3):following 241. Scand J Rheumatol Suppl 1988;73:1.
• Lequesne M, Samson M, Gerard P, Mery C. [Pain-function indices for the follow-up of osteoarthritis of the hip and the knee]. Rev Rhum Mal Osteoartic. 1990 Oct 30;57(9 ( Pt 2)):32S-36S. French.
• Ali Y, Weinstein M, Jokl P. Acute pseudogout following intra-articular injection of high molecular weight hyaluronic acid. Am J Med. 1999 Dec;107(6):641-2. doi: 10.1016/s0002-9343(99)00255-7. No abstract available.
• Luzar MJ, Altawil B. Pseudogout following intraarticular injection of sodium hyaluronate. Arthritis Rheum. 1998 May;41(5):939-40. doi: 10.1002/1529-0131(199805)41:53.0.CO;2-D. No abstract available.
• Maillefert JF, Hirschhorn P, Pascaud F, Piroth C, Tavernier C. Acute attack of chondrocalcinosis after an intraarticular injection of hyaluronan. Rev Rhum Engl Ed. 1997 Oct;64(10):593-4. No abstract available.
• Allen E, Krohn K. Adverse reaction to Hylan GF-20. J Rheumatol. 2000 Jun;27(6):1572. No abstract available.
• Chen AL, Desai P, Adler EM, Di Cesare PE. Granulomatous inflammation after Hylan G-F 20 viscosupplementation of the knee : a report of six cases. J Bone Joint Surg Am. 2002 Jul;84(7):1142-7.
• Zardawi IM, Chan I. Synvisc perisynovitis. Pathology. 2001 Nov;33(4):519-20. doi: 10.1080/00313020120083296.
• Hamburger MI, Lakhanpal S, Mooar PA, Oster D. Intra-articular hyaluronans: a review of product-specific safety profiles. Semin Arthritis Rheum. 2003 Apr;32(5):296-309. doi: 10.1053/sarh.2002.50008.
• Ehrich EW, Davies GM, Watson DJ, Bolognese JA, Seidenberg BC, Bellamy N. Minimal perceptible clinical improvement with the Western Ontario and McMaster Universities osteoarthritis index questionnaire and global assessments in patients with osteoarthritis. J Rheumatol. 2000 Nov;27(11):2635-41.
• Angst F, Aeschlimann A, Michel BA, Stucki G. Minimal clinically important rehabilitation effects in patients with osteoarthritis of the lower extremities. J Rheumatol. 2002 Jan;29(1):131-8.
• Bijlsma JW. Patient centred outcomes in osteoarthritis. Ann Rheum Dis. 2005 Jan;64(1):1-2. doi: 10.1136/ard.2004.025072. No abstract available.
• Pavelka K, Uebelhart D. Efficacy evaluation of highly purified intra-articular hyaluronic acid (Sinovial((R))) vs hylan G-F20 (Synvisc((R))) in the treatment of symptomatic knee osteoarthritis. A double-blind, controlled, randomized, parallel-group non-inferiority study. Osteoarthritis Cartilage. 2011 Nov;19(11):1294-300. doi: 10.1016/j.joca.2011.07.016. Epub 2011 Aug 16.

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: November 9, 2007
• First Submitted That Met QC Criteria: November 9, 2007
• First Posted (Estimate): November 12, 2007

Study Record Updates

• Last Update Posted (Estimate): December 4, 2012
• Last Update Submitted That Met QC Criteria: December 3, 2012
• Last Verified: November 1, 2012

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; Pharmaceutical Solutions; Hyaluronic Acid; Hylan
• Other Study ID Numbers: 06CZIFCH/Hai06