title: Efficacy, tolerability, and safety of an oral enzyme combination vs diclofenac in osteoarthritis of the knee: results of an individual patient-level pooled reanalysis of data from six randomized controlled trials.
abstract: OBJECTIVE
  To compare efficacy, safety, and tolerability of an oral enzyme combination (OEC) containing proteolytic enzymes and bioflavonoid vs diclofenac (DIC), a nonselective nonsteroidal anti-inflammatory drug in the treatment of osteoarthritis of the knee.
  
  
  METHODS
  This was an individual patient-level pooled reanalysis of patient-reported data from prospective, randomized, double-blind, parallel-group studies in adult patients with moderate-to-severe osteoarthritis of the knee treated for at least 3 weeks with OEC or DIC. Appropriate trials were identified with a systemic literature and database search. Data were extracted from the original case-report forms and reanalyzed by a blinded evaluation committee. The primary end point was the improvement of the Lequesne algofunctional index (LAFI) score at study end vs baseline. Secondary end points addressed LAFI response rates, treatment-related pain-intensity changes, adverse events, and laboratory parameters.
  
  
  RESULTS
  Six trials were identified that enrolled in total 774 patients, of whom 759 had post-baseline data for safety analysis, 697 (n=348/349 with OEC/DIC) for intent to treat, 524 for per protocol efficacy analysis, and 500 for laboratory evaluation. LAFI scores - the primary efficacy end point - decreased comparably with both treatments and improved with both treatments significantly vs baseline (OEC 12.6±2.4 to 9.1±3.9, DIC 12.7±2.4 to 9.1±4.2, effect size 0.9/0.88;P<0.001 for each). In parallel, movement-related 11-point numeric rating-scale pain intensity improved significantly (P<0.001) and comparably with both treatments from baseline (6.4±1.9/6.6±1.8) to study end (3.8±2.7/3.9±2.5). Overall, 55/81 OEC/DIC patients of the safety-analysis population (14.7%/21.1%,P=0.022) reported 90/133 treatment-emergent adverse events, followed by premature treatment discontinuations in 22/39 patients (5.9%/10.2%,P=0.030). Changes in laboratory parameters were significantly less with OEC vs DIC: on average 18.8% vs 86.3% of patients presented a decrease with respect to hemoglobin, hematocrit, or erythrocyte count (P<0.001), and 28.2% vs 72.6% showed an increase in AST, ALT, or GGT (P<0.001).
  
  
  CONCLUSIONS
  When compared with DIC, OEC showed comparable efficacy and a superior tolerability/safety profile associated with a significantly lower risk of treatment-emergent adverse events, related study discontinuations, and changes in laboratory parameters.
authors.affiliation: Institute of Neurological Sciences, Nuremberg.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Ueberall
authors.affiliation: Interdisciplinary Center for Pain and Palliative Care Medicine, Göppingen.
authors.forename: Gerhard Hh
authors.initials: GH
authors.lastname: Mueller-Schwefe
authors.affiliation: Interdisciplinary Center for Rheumatology and Immunology, Frankfurt.
authors.forename: Rainer
authors.initials: R
authors.lastname: Wigand
authors.affiliation: O.Meany Consultancy, Hamburg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Essner
keywords: diclofenac; meta-analysis; oral enzyme combination; osteoarthritis; randomized controlled trial