A randomized clinical trial to evaluate two doses of an intra-articular injection of LMWF-5A in adults with pain due to osteoarthritis of the knee

David Bar-Or, Kristin M Salottolo, Holli Loose, Matthew J Phillips, Brian McGrath, Nathan Wei, James L Borders, John E Ervin, Alan Kivitz, Mark Hermann, Tammi Shlotzhauer, Melvin Churchill, Donald Slappey, Vaughan Clift, David Bar-Or, Kristin M Salottolo, Holli Loose, Matthew J Phillips, Brian McGrath, Nathan Wei, James L Borders, John E Ervin, Alan Kivitz, Mark Hermann, Tammi Shlotzhauer, Melvin Churchill, Donald Slappey, Vaughan Clift

Abstract

Objective: The Low Molecular Weight Fraction of 5% human serum Albumin (LMWF-5A) is being investigated as a treatment for knee pain from osteoarthritis.

Methods: This was a multicenter randomized, vehicle-controlled, double-blind, parallel study designed to evaluate the safety and efficacy of two doses of an intra-articular injection of LMWF-5A. Patients with symptomatic knee osteoarthritis were randomized 1∶1∶1∶1 to receive a single 4 mL or 10 mL intra-articular knee injection of either LMWF-5A or vehicle control (saline). The primary efficacy endpoint was the difference between treatment groups in the Western Ontario and McMaster Universities (WOMAC) pain change from baseline over 12 weeks. Safety was examined as the incidence and severity of adverse events (AEs).

Results: A total of 329 patients were randomized and received treatment. LMWF-5A resulted in a significant decrease in pain at 12 weeks compared to vehicle control (-0.93 vs -0.72; estimated difference from control: -0.25, p = 0.004); an injection volume effect was not observed (p = 0.64). The effect of LMWF-5A on pain was even more pronounced in patients with severe knee OA (Kellgren Lawrence Grade IV): the estimated difference from control was -0.42 (p = 0.02). Adverse events were generally mild and were similar in patients who received vehicle control (47%) and LMWF-5A (41%).

Conclusions: This clinical trial demonstrated that LMWF-5A is safe and effective at providing relief for the pain of moderate to severe OA of the knee over 12 weeks when administered by intra-articular injection into the knee.

Trial registration: ClinicalTrials.gov NCT01839331.

Conflict of interest statement

Competing Interests: The authors have the following interests: Financial support for this study was provided by Ampio Pharmaceuticals, Inc., the employer of David Bar-Or, Kristin M. Salottolo, Vaughan Clift and Holli Loose who have stock/stock options in the company. David Bar-Or is also a board member, and inventor of patents (not paid) at Ampio Pharmaceuticals, Inc. Brian McGrath and Matthew Phillips have stock/stock options in the company. Ampion (LMWF-5A) is a product of Ampio Pharmaceuticals. There are no marketed products related to this work. There are several patents and products in development related to this work. Please see the supporting information file for more details. Donald Slappey is an employee of Alabama Clinical Therapeutics, LLC. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. CONSORT Flow diagram.
Figure 1. CONSORT Flow diagram.
Figure 2. Summary of the percent improvement…
Figure 2. Summary of the percent improvement in the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) pain subscore.

References

    1. Lawrence RC, Felson DT, Helmick CG, Arnold LM, Choi H, et al. (2008) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis and rheumatism 58: 26–35.
    1. Dillon CF, Rasch EK, Gu Q, Hirsch R (2006) Prevalence of knee osteoarthritis in the United States: arthritis data from the Third National Health and Nutrition Examination Survey 1991-94. The Journal of rheumatology 33: 2271–2279.
    1. Quintana JM, Arostegui I, Escobar A, Azkarate J, Goenaga JI, et al. (2008) Prevalence of knee and hip osteoarthritis and the appropriateness of joint replacement in an older population. Archives of internal medicine 168: 1576–1584.
    1. American Academy of Orthopaedic Surgeons (2013) Treatment of osteoarthritis of the knee: Evidence-based guideline. 2nd ed. Rosemont, IL: American Academy of Orthopaedic Surgeons.
    1. Dunlop DD, Manheim LM, Song J, Chang RW (2001) Arthritis prevalence and activity limitations in older adults. Arthritis and rheumatism 44: 212–221.
    1. Guccione AA, Felson DT, Anderson JJ, Anthony JM, Zhang Y, et al. (1994) The effects of specific medical conditions on the functional limitations of elders in the Framingham Study. American journal of public health 84: 351–358.
    1. Zhang W, Nuki G, Moskowitz RW, Abramson S, Altman RD, et al. (2010) OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society 18: 476–499.
    1. Bar-Or D, Bar-Or R, Rael LT, Gardner DK, Slone DS, et al. (2005) Heterogeneity and oxidation status of commercial human albumin preparations in clinical use. Critical care medicine 33: 1638–1641.
    1. Evans TW (2002) Review article: albumin as a drug–biological effects of albumin unrelated to oncotic pressure. Alimentary pharmacology & therapeutics 16 Suppl 56–11.
    1. Quinlan GJ, Martin GS, Evans TW (2005) Albumin: biochemical properties and therapeutic potential. Hepatology 41: 1211–1219.
    1. Bar-Or D, Rael LT, Lau EP, Rao NK, Thomas GW, et al. (2001) An analog of the human albumin N-terminus (Asp-Ala-His-Lys) prevents formation of copper-induced reactive oxygen species. Biochemical and biophysical research communications 284: 856–862.
    1. Bar-Or D, Thomas GW, Bar-Or R, Rael LT, Scarborough K, et al. (2006) Commercial human albumin preparations for clinical use are immunosuppressive in vitro. Critical care medicine 34: 1707–1712.
    1. Shimonkevitz R, Thomas G, Slone DS, Craun M, Mains C, et al. (2008) A diketopiperazine fragment of human serum albumin modulates T-lymphocyte cytokine production through rap1. The Journal of trauma 64: 35–41.
    1. Bar-Or D, Slone DS, Mains CW, Rael LT (2013) Dipeptidyl peptidase IV activity in commercial solutions of human serum albumin. Analytical biochemistry 441: 13–17.
    1. Rael LT, Bar-Or R, Shimonkevitz R, Mains CW, Slone DS, et al. (2010) Anti-inflammatory effect of a diketopiperazine by-product of commercial albumin in TBI patients [abstract]. J Neurotrauma 27: A1–A97.
    1. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW (1988) 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. The Journal of rheumatology 15: 1833–1840.
    1. Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M (2008) The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Annals of the rheumatic diseases 67: 1716–1723.
    1. Bellamy N (2002) WOMAC Osteoarthritis Index User Guide. Version V. Brisbane, Australia.
    1. Kersten P, White PJ, Tennant A (2010) The visual analogue WOMAC 3.0 scale–internal validity and responsiveness of the VAS version. BMC musculoskeletal disorders 11: 80.
    1. Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, et al. (2010) CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 340: c869.
    1. Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 340: c332.
    1. Cole BJ, Schumacher Jr HR (2005) Injectable corticosteroids in modern practice. The Journal of the American Academy of Orthopaedic Surgeons 13: 37–46.
    1. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, et al. (2006) Intraarticular corticosteroid for treatment of osteoarthritis of the knee. Cochrane database of systematic reviews: CD005328.
    1. Arrich J, Piribauer F, Mad P, Schmid D, Klaushofer K, et al. (2005) Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. CMAJ: Canadian Medical Association journal = journal de l'Association medicale canadienne 172: 1039–1043.
    1. Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, et al. (2006) Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane database of systematic reviews: CD005321.
    1. Lo GH, LaValley M, McAlindon T, Felson DT (2003) Intra-articular hyaluronic acid in treatment of knee osteoarthritis: a meta-analysis. JAMA: the journal of the American Medical Association 290: 3115–3121.
    1. Printz JO, Lee JJ, Knesek M, Urquhart AG (2013) Conflict of Interest in the Assessment of Hyaluronic Acid Injections for Osteoarthritis of the Knee: An Updated Systematic Review. The Journal of arthroplasty.
    1. (2007) Three Treatments for Osteoarthritis of the Knee: Evidence Shows Lack of Benefit. Comparative Effectiveness Review Summary Guides for Clinicians. Rockville (MD).
    1. Tubach F, Ravaud P, Baron G, Falissard B, Logeart I, et al. (2005) Evaluation of clinically relevant changes in patient reported outcomes in knee and hip osteoarthritis: the minimal clinically important improvement. Annals of the rheumatic diseases 64: 29–33.
    1. Bannuru RR, Natov NS, Dasi UR, Schmid CH, McAlindon TE (2011) Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis–meta-analysis. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society 19: 611–619.
    1. Kellgren JH, Lawrence JS (1957) Radiological assessment of osteo-arthrosis. Annals of the rheumatic diseases 16: 494–502.

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