A Randomized, Double-blind, Placebo-controlled, Crossover Study to Investigate the Mechanism of Action of an Oral Enzyme Treatment with Bromelain, Trypsin and Rutoside versus Placebo in Subjects with OsTeoarthritis (WOBE-SMART)

INTERVENTION: Trade Name: WOBENZYM®, enteric‐coated tablet Product Name: Wobenzym Pharmaceutical Form: Gastro‐resistant tablet INN or Proposed INN: Bromelains CAS Number: 37189‐34‐7 Other descriptive name: Bromelain Concentration unit: mg milligram(s) Concentration type: range Concentration number: 67.5‐76.5 INN or Proposed INN: Trypsin CAS Number: 9002‐07‐7 Concentration unit: mg milligram(s) Concentration type: range Concentration number: 32‐48 INN or Proposed INN: Rutoside trihydrate CAS Number: 250249‐75‐3 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 100‐ Pharmaceutical form of the placebo: Gastro‐resistant tablet Route of administration of the placebo: Oral use CONDITION: Subjects suffering from knee Osteoarthitis ; MedDRA version: 20.0 Level: PT Classification code 10031161 Term: Osteoarthritis System Organ Class: 10028395 ‐ Musculoskeletal and connective tissue disorders Therapeutic area: Diseases [C] ‐ Musculoskeletal Diseases [C05] PRIMARY OUTCOME: Main Objective: The primary objective of this study is to evaluate the pharmacodynamic profile of an oral enzyme treatment with Bromelain, Trypsin and Rutoside in subjects with Osteoarthritis. Primary end point(s): The primary endpoints for evaluation of the pharmacodynamic profile are:; • Effects on cartilage biomarkers using immunoassays;; • Effects on markers of innate immune response;; • Effects on systemic inflammatory markers using immunoassays;; • Effects on cellular pathways identified by changes in proteomic profile. Secondary Objective: The secondary objectives are to evaluate: ; ; • Vital signs and anthropomorphic measurements;; • Knee pain;; • Knee function;; • Patient global assessment of disease activity (PGADA);; • Patient physical activity;; • Body metabolism;; • Clinical chemistry;; • Joint structure modification; ; • Volume of joint effusion;; • Tolerance;; • Compliance; ; • Responder to treatment. Timepoint(s) of evaluation of this end point: At four timepoints for the entire treatment period (cross‐over design, 2 parallel arms):; ; During the first treatment period:; ‐ at V0 (baseline); ‐ at V2 (8 weeks post‐baseline); ; During the second treatment period:; ‐ at V3 (12 weeks post‐baseline and including 4 weeks wash out); ‐ at V5 (20 weeks post‐baseline) SECONDARY OUTCOME: Secondary end point(s): The secondary endpoints are:; • Blood Pressure (BP), Heart Rate (HR), Temperature, Weight, Height and ; BMI; ; • Knee pain at rest and while walking using a Visual Analogue Scale (VAS);; • Global score and each of the five subscales scores of the Knee Injury and ; Osteoarthritis Outcome Score (KOOS) using a self‐administered ; questionnaire;; • PGADA using a VAS;; • Global physical activity using a connected device;; • Concentration of growth factors in serum (e.g. TGF‐ß1_ß2_ß3) using ; immunoassays;; • Clinical chemistry measurements using immunoassays:; ‐ Concentration of myokines (e.g. myostatin); ; ‐ Concentration of hemoglobin, hematocrit, erythrocyte count, Triglyceride (TG), Total cholesterol (TC), LDL, HDL, glucose, hsCRP, uric acid, coagulation markers and key hepatic enzymes;; • Semi‐quantitative joint assessment of knee OA features using MOAKS (MRI ; Osteoarthritis Knee Score) or WORMS (Whole‐Organ Magnetic Resonance ; Imaging Score); ; • Volume of joint effusion by magnetic resonance imaging (MRI);; • Adverse Events (AE) and drop out;; • Tablet count;; • Responder rate to treatment defined as changes in knee pain and/or knee ; function and/or subjects disease activity according to OMERACT OARSI ; criteria. Timepoint(s) of evaluation of this end point: To be evaluated at each visit except: ; ; ‐ Immunoassays and clinical chemistry which are evaluated at two timepoints for each treatment period (V0, V2 and V3, V5);; ‐ MRI which is evaluated at two timepoints for the second treatment period only (V3 and V6). INCLUSION CRITERIA: Subjects must fulfill all of the following inclusion criteria to be eligible for participation in the study: 1. Male or female = 40 years of age and with BMI = 35 kg/m2; 2. Uni‐ or bilateral femorotibial knee OA : a. Responding to clinical and radiological criteria of American College of Rheumatology (ACR); b. Symptomatic for more than 6 months in the index knee; c. Radiological Kellgren & Lawrence (K&L) grade II‐III in standing x‐rays from less than 12 months. 3. Mild‐to‐Moderate mean knee pain score at rest or at walking over the last 24 hours on the index knee evaluated on VAS (0‐100) = 40 at baseline; 4. Able to follow the instructions of the study; 5. Having signed an informed consent. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18‐64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 2