Safety and efficacy of intra-articular injections of a combination of hyaluronic acid and mannitol (HAnOX-M) in patients with symptomatic knee osteoarthritis

Results of a double-blind, controlled, multicenter, randomized trial



      To compare both safety and efficacy of a novel intra-articular viscosupplement made of intermediate molecular weight (MW) hyaluronic acid (HA) mixed with high concentration of mannitol with a marketed high MW HA, in patients with knee osteoarthritis (OA).


      Patients with symptomatic knee OA, with radiological OARSI grades 1 to 3, were enrolled in a controlled, double-blind, parallel-group, non-inferiority trial. They were randomized to receive three intra-articular injections, at weekly intervals, of either HAnOX-M made of a combination of HA (MW one to 1.5 MDa, 31 mg/2 ml) and mannitol (70 mg/2 ml) or Bio-HA (MW 2.3 to 3.6 MDa, 20 mg/2 ml). The primary outcome was six-month change in the WOMAC pain subscale (0 to 20). Sample size was calculated according to a non-inferiority margin of 1.35. Secondary endpoints included six-month change in function and walking pain, analgesic consumption and safety.


      The intention-to-treat (ITT) and per-protocol (PP) populations consisted of 205 and 171 patients. HAnOX-M and Bio-Ha groups did not differ statistically at baseline. The primary analysis was conducted in the PP population, then in the ITT population. The average WOMAC pain score at baseline was 9.5 in both groups. Mean (SD) variations in WOMAC pain score were −4.4 (3.8) and −4.5 (4.3) mm, for HAnOX and Bio-HA respectively, satisfying the claim for non-inferiority. Similar results were obtained for all other secondary endpoints.


      Treatment with of HAnOX-M is effective to alleviate knee OA symptoms and to improve joint function over six months, with similar safety than conventional HA viscosupplement.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Knee
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Jordan K.M.
        • Arden N.K.
        • Doherty M.
        • Bannwarth B.
        • Bijlsma J.W.
        • Dieppe P.
        • et al.
        EULAR recommendations 2003: an evidence based approach to the management of knee osteoarthritis: report of a Task of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT).
        Ann Rheum Dis. 2003; 62: 1145-1155
        • Hochberg M.C.
        • Altman R.D.
        • April K.T.
        • Benkhalti M.
        • Guyatt G.
        • McGowan J.
        • et al.
        American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee.
        Arthritis Care Res. 2012; 64: 465-474
        • McAlindon T.E.
        • Bannuru R.R.
        • Sullivan M.C.
        • Arden N.K.
        • Berenbaum F.
        • Bierma-Zeinstra S.M.
        • et al.
        OARSI guidelines for the non-surgical management of knee osteoarthritis.
        Osteoarthritis Cartilage. 2014; 22: 363-388
        • Bruyère O.
        • Cooper C.
        • Pelletier J.P.
        • Branco J.
        • Luisa Brandi M.
        • Guillemin F.
        An algorithm recommendation for the management of knee osteoarthritis in Europe and internationally: a report from a Task Force of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).
        Semin Arthritis Rheum. 2014; 44: 253-263
        • Balazs E.A.
        • Denlinger J.L.
        Viscosupplementation: a new concept in the treatment of osteoarthritis.
        J Rheumatol Suppl. 1993; 39: 3-9
        • Balazs E.A.
        Viscosupplementation for treatment of osteoarthritis: from initial discovery to current status and results.
        Surg Technol Int. 2004; 12: 278-289
        • Wang C.T.
        • Lin Y.T.
        • Chiang B.L.
        • Lin Y.H.
        • Hou S.M.
        High molecular weight hyaluronic acid down-regulates the gene expression of osteoarthritis-associated cytokines and enzymes in fibroblast-like synoviocytes from patients with early osteoarthritis.
        Osteoarthritis Cartilage. 2006; 14: 1237-1247
        • Li P.
        • Raitcheva D.
        • Hawes M.
        • Moran N.
        • Yu X.
        • Wang F.
        • et al.
        Hylan G-F 20 maintains cartilage integrity and decreases osteophyte formation in osteoarthritis through both anabolic and anti-catabolic mechanisms.
        Osteoarthritis Cartilage. 2012; 20: 1336-1346
        • Li J.
        • Gorski D.J.
        • Anemaet W.
        • Velasco J.
        • Takeuchi J.
        • Sandy J.D.
        • et al.
        Hyaluronan injection in murine osteoarthritis prevents TGFbeta 1-induced synovial neovascularization and fibrosis and maintains articular cartilage integrity by a CD44-dependent mechanism.
        Arthritis Res Ther. 2012; 14: R151
        • Conrozier T.
        • Balblanc J.C.
        • Richette P.
        • Mulleman D.
        • Maillet B.
        • Henrotin Y.
        • et al.
        Early effect of hyaluronic acid intra-articular injections on serum and urine biomarkers in patients with knee osteoarthritis: an open-label observational prospective study.
        J Orthop Res. 2012; 30: 679-685
        • Henrotin Y.
        • Chevalier X.
        • Deberg M.
        • Balblanc J.C.
        • Richette P.
        • Mulleman D.
        • et al.
        Early decrease of serum biomarkers of type II collagen degradation (Coll2-1) and joint inflammation (Coll2-1 NO₂) by hyaluronic acid intra-articular injections in patients with knee osteoarthritis: a research study part of the Biovisco study.
        J Orthop Res. 2013; 31: 901-907
        • Wang Y.
        • Hall S.
        • Hanna F.
        • Wluka A.E.
        • Grant G.
        • Marks P.
        • et al.
        Effects of hylan G-F 20 supplementation on cartilage preservation detected by magnetic resonance imaging in osteoarthritis of the knee: a two-year single-blind clinical trial.
        BMC Musculoskelet Disord. 2011; 12: 195
        • Bannuru R.R.
        • Schmid C.H.
        • Kent D.M.
        • Vaysbrot E.E.
        • Wong J.B.
        • McAlindon T.E.
        Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis.
        Ann Intern Med. 2015; 162: 46-54
        • Miller L.E.
        • Block J.E.
        US-approved intra-articular hyaluronic acid injections are safe and effective in patients with knee osteoarthritis: systematic review and meta-analysis of randomized, saline-controlled trials.
        Clin Med Insights Arthritis Musculoskelet Disord. 2013; 6: 57-63
        • Rutjes A.W.
        • Jüni P.
        • da Costa B.R.
        • Trelle S.
        • Nüesch E.
        • Reichenbach S.
        Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis.
        Ann Intern Med. 2012; 157: 180-191
        • Vavken P.
        • Dorotka R.
        A systematic review of conflicting meta-analyses in orthopaedic surgery.
        Clin Orthop Relat Res. 2009; 467: 2723-2735
        • Campbell J.
        • Bellamy N.
        • Gee T.
        Differences between systematic reviews/meta-analyses of hyaluronic acid/hyaluronan/hylan in osteoarthritis of the knee.
        Osteoarthritis Cartilage. 2007; 15: 1424-1436
        • 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; 2CD005321
        • Lindqvist U.
        • Tolmachev V.
        • Kairemo K.
        • Aström G.
        • Jonsson E.
        • Lundqvist H.
        Elimination of stabilised hyaluronan from the knee joint in healthy men.
        Clin Pharmacokinet. 2002; 4: 603-613
        • Larsen N.E.
        • Dursema H.D.
        • Pollak C.T.
        • Skrabut E.M.
        Clearance kinetics of a hylan-based viscosupplement after intra-articular and intravenous administration in animal models.
        J Biomed Mater Res B Appl Biomater. 2012; 100: 457-462
        • Lindenhayn K.
        • Heilmann H.H.
        • Niederhausen T.
        • Walther H.U.
        • Pohlenz K.
        Elimination of tritium-labelled hyaluronic acid from normal and osteoarthritic rabbit knee joints.
        Eur J Clin Chem Clin Biochem. 1997; 35: 355-363
        • Stern R.
        • Kogan G.
        • Jedrzejas M.J.
        • Soltés L.
        The many ways to cleave hyaluronan.
        Biotechnol Adv. 2007; 25: 537-557
        • Mendoza G.
        • Alvarez A.I.
        • Pulido M.M.
        • Molina A.J.
        • Merino G.
        • Real R.
        • et al.
        Inhibitory effects of different antioxidants on hyaluronan depolymerization.
        Carbohydr Res. 2007; 342: 96-102
        • Grange L.
        • Nguyen M.V.
        • Lardy B.
        • Derouazi M.
        • Campion Y.
        • Trocme C.
        • et al.
        NAD(P)H oxidase activity of Nox4 in chondrocytes is both inducible and involved in collagenase expression.
        Antioxid Redox Signal. 2006; 8: 1485-1496
        • Rousset F.
        • Nguyen M.V.
        • Grange L.
        • Morel F.
        • Lardy B.
        Heme oxygenase-1 regulates matrix metalloproteinase MMP-1 secretion and chondrocyte cell death via Nox4 NADPH oxidase activity in chondrocytes.
        PLoS One. 2014; 8e66478
        • Conrozier T.
        • Mathieu P.
        • Rinaudo M.
        Mannitol allows to preserve the elasto-viscous properties of hyaluronic acid in an in vitro model of oxidative stress.
        Rheumatol Ther. 2014; 1: 45-54
        • Rinaudo M.
        • Lardy B.
        • Grange L.
        • Conrozier T.
        Effect of mannitol on hyaluronic acid stability in two in vitro models of oxidative stress.
        Polymers. 2014; 6 ([1007/s40744-014-0001-8])
        • Bannuru R.R.
        • Natov N.S.
        • Dasi U.R.
        • Schmid C.H.
        • McAlindon T.E.
        Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis-metaanalysis.
        Osteoarthritis Cartilage. 2011; 19: 611-619
        • 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; 14: 154-162
        • Altman R.D.
        • Rosen J.E.
        • Bloch D.A.
        • Hatoum H.T.
        • Korner P.
        A double blind, randomized, saline controlled study of the efficacy and safety of Euflexxa for treatment of painful osteoarthritis of the knee with an open-label safety extension (the Flexx trial).
        Semin Arthritis Rheum. 2009; 39: 1169-1175
        • Altman R.
        • Asch E.
        • Bloch D.
        • Bole G.
        • Borenstein D.
        • Brandt K.
        • 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; 29: 1039-1049
        • Altman R.D.
        • Hochberg M.
        • Murphy Jr., W.A.
        • Wolfe F.
        • Lequesne M.
        Atlas of individual radiographic features in osteoarthritis.
        Osteoarthritis Cartilage. 1995; 3: 3-70
        • Marty M.
        • Hilliquin P.
        • Rozenberg S.
        • Valat J.P.
        • Vignon E.
        • Coste P.
        • et al.
        Validation of the KOFUS (Knee Osteoarthritis Flare-ups Score).
        Joint Bone Spine. 2009; 76: 268-272
        • Bellamy N.
        • Buchanan W.W.
        • Goldsmith C.H.
        • Campbell J.
        • Stitt L.W.
        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; 15: 1833-1840
        • Salaffi F.
        • Stancati A.
        • Silvestri C.A.
        • Ciapetti A.
        • Grassi W.
        Minimal clinically important changes in chronic musculoskeletal pain intensity measured on a numerical rating scale.
        Eur J Pain. 2004; 8: 283-291
        • Tubach F.
        • Ravaud P.
        • Baron G.
        • Falissard B.
        • Logeart I.
        • Bellamy N.
        • et al.
        Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement.
        Ann Rheum Dis. 2005; 64: 29-33
        • Altman R.D.
        • Rosen J.E.
        • Bloch D.A.
        • Hatoum H.T.
        Safety and efficacy of retreatment with a bioengineered hyaluronate for painful osteoarthritis of the knee: results of the open-label extension study of the Flexx trial.
        Osteoarthritis Cartilage. 2011; 19: 1169-1175
        • Hatoum H.T.
        • Fierlinger A.L.
        • Lin S.J.
        • Altman R.D.
        Cost-effectiveness analysis of intra-articular injections of a high molecular weight bioengineered hyaluronic acid for the treatment of osteoarthritis knee pain.
        J Med Econ. 2014; 17: 326-337
        • Borras-Verdera
        • Calcedo-Bernal V.
        • Ojeda-Levenfeld J.
        • Clavel-Sainz C.
        Efficacy and safety of a single intra-articular injection of 2% hyaluronic acid plus mannitol in knee osteoarthritis over a 6-month period.
        Rev Esp Cir Ortop Traumatol. 2012; 56: 274-280
        • Conrozier T.
        • Bossert M.
        • Balblanc J.C.
        • Sondag M.
        • Walliser-Lohse A.
        Viscosupplementation with HAnOX-M-XL is effective in moderate hip osteoarthritis but is not an alternative to hip joint surgery in patients with severe disease. Results of a clinical survey in 191 patients treated in daily practice.
        EMJD. 2014; 3: 49-55
        • Heisel C.K.
        Safety and efficacy findings from a non-interventional study of a new hyaluronic acid/sorbitol formulation (Go-on ® Matrix) for intra-articular injection to relieve pain and disability in osteoarthritis patients.
        Drug Res. 2013; : 445-449
        • Lanas A.
        • Tornero J.
        • Zamorano J.L.
        Assessment of gastrointestinal and cardiovascular risk in patients with osteoarthritis who require NSAIDs: the LOGICA study.
        Ann Rheum Dis. 2010; 69: 1453-1458
        • Abdulla A.
        • Adams N.
        • Bone M.
        • Elliott A.M.
        • Gaffin J.
        • Jones D.
        • et al.
        British Geriatric Society guidance on the management of pain in older people.
        Age Ageing. 2013; 42: i1-57