Clinical trial NCT00556608: Efficacy Study of Intra-articular Hyaluronic Acid in the Knee Osteoarthritis
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Osteoarthritis, Knee
Lead sponsor: IBSA Institut Biochimique SA
Sponsor class: INDUSTRY
First posted: 2007-11-12
Enrollment: 381
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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®.


Eligibility criteria: 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

Primary outcomes:
measure: Improvement in WOMAC pain subscore from baseline
timeFrame: to week 26
Secondary outcomes:
measure: 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%
timeFrame: 26 weeks
Other outcomes:
Locations:
city: Brno - Bohunice
country: Czech Republic
facility: Interni hemato-onkologická klinika, Fakultní nemocnice
city: Pardubice
country: Czech Republic
facility: ARTHROMED s.r.o.
city: Praha
country: Czech Republic
facility: Institute of Rheumatology
city: Praha
country: Czech Republic
facility: Centrum léčby pohybového aparátu spol. s.r.o.
city: Bois Guillaume
country: France
facility: University Hospital Centre Bois-Guillaume
city: Limoges Cedex
country: France
facility: University Hospital Centre of Limoges - Rheumatology Service
city: Aachen
country: Germany
facility: Orthopädische Universitätsklinik und Poliklinik der RWTH Aachen
city: Biberach an der Riss
country: Germany
facility: Nova clinic
city: Stockach
country: Germany
facility: Orthopädische Praxis
city: Arezzo
country: Italy
facility: Sezione Dipartimentale a valenza provinciale di Reumatologia - AzUSL 8
city: Bologna
country: Italy
facility: Ospedale Privato Accreditato Nigrisoli
city: Lucca
country: Italy
facility: Medicina e Traumatologia dello Sport - AzUSL 2 Lucca
city: Milano
country: Italy
facility: Unità Operativa di Reumatologia - Istituto Ortopedico Gaetano Pini
city: Pisa
country: Italy
facility: Rheumatology Unit Santa Chiara Hospital
city: Siena
country: Italy
facility: Unità Operativa di Reumatologia - Az. Ospedaliera Universitaria Senese - Policlinico "Le Scotte"
city: Banská Bystrica
country: Slovakia
facility: F.D. Roosevelt's University Hospital
city: Bratislava
country: Slovakia
facility: Romjan s.r.o.
city: Piest'any
country: Slovakia
facility: National Institute of Rheumatic Diseases
city: Trnava
country: Slovakia
facility: Rheumatology Clinic, Reumaglobal s.r.o
city: Zürich
country: Switzerland
facility: Department of Rheumatology and Institute of Physical Medicine - Zurich University
Study officials:
affiliation: Institute of Rheumatology-Na Slupi 4 - 12850 Praha 2 (Czech Republic)
name: Karel PAVELKA, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Lockman LE. Practice tips. Knee joint injections and aspirations: the triangle technique. Can Fam Physician. 2006 Nov;52(11):1403-4. No abstract available.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: Allen E, Krohn K. Adverse reaction to Hylan GF-20. J Rheumatol. 2000 Jun;27(6):1572. No abstract available.
citation: 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.
citation: Zardawi IM, Chan I. Synvisc perisynovitis. Pathology. 2001 Nov;33(4):519-20. doi: 10.1080/00313020120083296.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.