The study is a randomized, double-blinded, placebo-controlled, parallel group-study. The duration will be approximately 127 days (4 weeks screening; 12 weeks treatment; 2 weeks follow-up. Currently, Approximately 9 sites in Taiwan and 6 sites in the United States have been selected. Approximately 500 evaluable patients will be enrolled and randomly assigned to receive IBUMR or placebo at a fixed ratio of 1:1. The treatment regimen will be dosing twice a day (BID) for a total of 12 weeks.. The randomized, IP-treated subject with baseline value for primary analysis will be considered evaluable. Considering an estimated randomization failure rate of 10%, approximately 556 eligible patients will be recruited.
For Primary Endpoint, WOMAC Pain will be measured using visual analogue scale (VAS) ranging from 0 mm (no pain) to 100 mm (extreme pain) at baseline week (Day -6 to Day 1) and at Day 8, 15, 22, 29, 43, 57 and Week 12 (Day 79 to Day 85).
For secondary endpoint, WOMAC Physical function will be measured using VAS ranging from 0 mm (no difficulty) to 100 mm (extreme difficulty) at baseline (Day 1) and at Day 8, 15, 22, 29, 43, 57 and 85. WOMAC stiffness will be measured using VAS ranging from 0 mm (no stiffness) to 100 mm (maximum stiffness) at baseline (Day 1) and at Day 8, 15, 22, 29, 43, 57 and 85. WOMAC Total Index will be calculated at baseline (Day 1) and Day 8, 15, 22, 29, 43, 57 and 85 as sum of scores of all 24 WOMAC questions.
For other secondary endpoints, Patients will perform a PGADS via a 0-100 mm VAS, ranging from 0 mm (best ever) to 100 mm (worst ever) with respect to "Considering all the ways your arthritis conditionhas affected you, how do you feel your arthritis is today? " PGADS will be calculated periodically, at baseline (Day 1) and at Day 8, 15, 22, 29, 43, 57 and 85. The degree of the patient's disease status, based on the Investigator's judgment, in terms of pain intensity, joint swelling and tenderness, functional capacity and ability to flex the knee will be assessed by an established IGADS (0-4 point Likert scale), ranging from 0 (very well) to 4 (very poor). IGADS scores will be calculated periodically, at baseline (Day 1) and at Day 8, 15, 22, 29, 43, 57 and 85.
Safety will also be monitored and evaluated by changes occurring at the baseline and during treatment periods.
Subjects may withdraw from this study due to reasons. A withdrawal occurs when an enrolled patient ceases to participate in the study, regardless of the circumstances, prior to completion of the protocol. The investigators should try their best to complete the evaluation items for the final evaluation visit upon a patient's withdrawal. The reason for a patient withdrawn from the study will be recorded in the case report form (CRF) and in the patient's medical record.
The sample size of this study was based on results from a previous study (Puopolo et al., 2007(2)) which suggested that the least-square mean (95% CI) change in WOMAC pain scores (WOMAC-PS) from baseline is -24.10 (-27.20, -20.99) for treatment group (2400 mg/day; 800 mg TID) and -16.47 (-20.55, -12.40) for placebo group, respectively.
Considering the regimen of our study product (1600 mg; 800 mg BID) and the primary estimand which imputes efficacy data with baseline values for subjects with intercurrent events, we adjusted the treatment effect to -6.005 which is conditional under a 20% reduction in the treatment effect from the study by Puopolo et al. in 2007 (i.e., -7.63 = -24.10 - (-16.47)) and the effect of data imputation, which the proportions of missing data are assumed to be 15% in treatment group and 20% in control group.
A sample size of 250 in each group will have ≥ 85% power to detect a difference in means of -6.005 between treatment and control groups, assuming that the standard deviation for treatment group (t) is 22.879 and the standard deviation for placebo group (p) is 21.463, using a two group Satterthwaite t-test with a 0.050 two-sided significance level.
Analyses on efficacy endpoints will utilize mITT population. A sensitivity analysis using PP population to analyze efficacy endpoints will be conducted if more than 20% of patients are excluded from PP population. Safety evaluation will be performed on mITT population. The conclusion of efficacy (i.e., primary endpoint analysis) of the study will be made according to the results of mITT analysis.
