A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee.

OBJECTIVE: To determine if inhibition of inducible nitric oxide synthase (iNOS) with cindunistat hydrochloride maleate slows progression of osteoarthritis (OA) METHODS: This 2-year, multinational, double-blind, placebo-controlled trial enrolled patients with symptomatic knee OA (Kellgren and Lawrence Grade (KLG) 2 or 3). Standard OA therapies were permitted throughout. Patients were randomly assigned to cindunistat (50 or 200 mg/day) or placebo. Randomisation was stratified by KLG. Radiographs to assess joint space narrowing (JSN) were acquired using the modified Lyon-schuss protocol at baseline, week 48 and 96. RESULTS: Of 1457 patients (50 mg/day, n=485; 200 mg/day, n=486; placebo, n=486), 1048 (71.9%) completed the study. Patients were predominantly women; 56% had KLG3. The primary analysis did not demonstrate superiority of cindunistat versus placebo for rate of change in JSN. In KLG2 patients, JSN after 48 weeks was lower with cindunistat 50 mg/day versus placebo (p=0.032). Least-squares mean±SE JSN with cindunistat 50 mg/day ( -0.048±0.028 mm) and 200 mg/day (-0.062±0.028 mm) were 59.9% (95% CI 6.8% to 106.9%) and 48.7% (95% CI -8.4% to 93.9%) of placebo, improvement was not maintained at 96 weeks. No improvement was observed for KLG3 patients at either time-point. Cindunistat did not improve joint pain or function, but was generally well tolerated. CONCLUSIONS: Cindunistat (50 or 200 mg/day) did not slow the rate of JSN versus placebo. After 48-weeks, KLG2 patients showed less JSN; however, the improvement was not sustained at 96-weeks. iNOS inhibition did not slow OA progression in KLG3 patients. CLINICAL TRIAL LISTING: NCT00565812.

Considerations when designing a disease-modifying osteoarthritis drug (DMOAD) trial using radiography.

OBJECTIVE: Using placebo data from a recently completed disease-modifying osteoarthritis (OA) drug trial, we seek to inform study design of future radiographic studies. METHODS: Eligible patients aged ≥40 years, with body mass index (BMI) 25-40kg/m(2) and symptomatic knee OA diagnosed by modified Kellgren and Lawrence grade (KLG) 2 or 3 and pain/stiffness and/or use of medication for knee pain in the past year, were assessed by radiography using a modified Lyon-schuss (mL/S) protocol for joint space narrowing (JSN) (primary outcome variable) at baseline and weeks 48 and 96. Multifaceted quality control was conducted throughout. Repeat images were requested when the medial tibial plateau (MTP) was not aligned (inter-margin distance [IMD] >1.5mm) or for other quality issues. Data are given mean ± standard deviation. RESULTS: Patients (74.9% female; 61.3 ± 9.1 years) had BMI 31.6 ± 4.1kg/m(2) at baseline; 222 (173 females) had KLG2, 264 (191 female) KLG3. A significant loss in joint space width (JSW) from baseline to week 48 (-0.13 ± 0.36mm) and to week 96 (-0.22 ± 0.45mm) was observed for all randomised placebo patients (p < 0.001 for both), and at both time points when stratified by KLG2 or KLG3. Standard deviations were small relative to mean changes, providing standardised response means for all placebo patients of 0.35 (week 48) and 0.48 (week 96). CONCLUSIONS: Using a tightly controlled radiographic technique, JSN is a viable outcome variable for determining disease progression in mild-to-moderate knee OA. The mL/S protocol is a sensitive and feasible method for OA studies aiming to assess rate of JSN in the knee.