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Summary Objective CR4056 is a selective imidazoline-2 (I2) receptor ligand with potent analgesic activity in animal pain models. This proof-of-concept study tested CR4056 efficacy and safety in patients with knee osteoarthritis (OA) and different phenotypes. Design This is a multicenter, randomized, double-blind, placebo-controlled trial. Knee OA patients with moderate to severe pain received CR4056 (women 100 mg bid; men 200 mg bid) or placebo (both genders) for 14 days. The primary outcome was the change in WOMAC pain score (0–100 scale) compared to placebo, analyzed in the intention-to-treat population and pre-defined OA phenotypes. Results 213 patients were treated with CR4056 (92 women; 52 men) or placebo (69 overall). After 14 days, median WOMAC pain improvements were 10 points on placebo and 14, 20 and 16 in women, men, and pooled CR4056 groups (P = 0.184, 0.030 and 0.070 vs placebo, respectively). Pre-specified subgroup analysis in the metabolic OA phenotype (BMI ≥ 27.5 kg/m2, N = 156) showed statistically significant differences in all CR4056-treated groups vs placebo of 12–18 points. Conversely, there were too few patients with a neuropathic or inflammatory phenotype for a meaningful analysis. CR4056 was well tolerated; the most common adverse event was mild headache. Conclusions Although the primary endpoint was met in males only, this exploratory phase 2 trial shows that CR4056 might be an effective analgesic against knee OA pain, especially in overweight patients representing the metabolic OA phenotype. These findings, along with the broad-spectrum analgesic activity of CR4056 in animal models, warrant further clinical investigation in OA and other pain conditions. Clinical trial registration number EudraCT 2015-001136-37.

Objective To investigate the relationship between baseline radiographic severity of knee osteoarthritis (OA) and the importance of long-term joint space narrowing.DesignSub-analysis from a three-year randomized, placebo-controlled, prospective study, of 212 patients with knee OA, recruited in an osteoarthritic outpatient clinic and having been part of a study evaluating the effect of glucosamine sulfate on symptom and structure modification in knee OA.Material and Methods Measurements of mean joint space width (JSW), assessed by a computer-assisted method, were performed at baseline and after 3 years, on weightbearing anteroposterior knee radiographs.Results In the placebo group, baseline JSW was significantly and negatively correlated with the joint space narrowing observed after 3 years (r=−0.34, P=0.003). In the lowest quartile of baseline mean JSW (6.2mm), a joint space narrowing of 14.9% (17.9) occurred in the placebo group after 3 years while patients from the glucosamine sulfate group only experienced a narrowing of 6.0% (15.1). Patients with the most severe OA at baseline had a RR of 0.42 (0.17–1.01) to experience a 0.5mm joint space narrowing over 3 years, compared to those with the less affected joint. In patients with mild OA, i.e. in the highest quartile of baseline mean JSW, glucosamine sulfate use was associated with a trend (P=0.10) towards a significant reduction in joint space narrowing.Conclusion These results suggest that patients with the less severe radiographic knee OA will experience, over 3 years, the most dramatic disease progression in terms of joint space narrowing. Such patients may be particularly responsive to structure-modifying drugs. Copyright 2003 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved.