Need for hip, knee replacement appears reduced with canakinumab, industry-funded study finds
An editorial noted that a novel entry criterion may have identified a subgroup of patients with accelerated joint degeneration.
Findings from an analysis of an industry-funded randomized controlled trial may support investigation of interleukin-1 beta inhibition for treatment of large-joint osteoarthritis.
To determine whether canakinumab, an interleukin-1 beta inhibitor, reduced incident total hip or knee replacement, researchers conducted an exploratory analysis of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS), conducted at 1,091 clinical sites in 39 countries. Patients were randomly assigned to placebo or a subcutaneous dose of canakinumab once every three months. The placebo group included 3,344 patients. In the treatment groups, 2,170 patients received a 50-mg dose, 2,284 received a 150-mg dose, and 2,263 received a 300-mg dose of canakinumab.
The study's primary and secondary outcomes were time to first hip or knee replacement and time to a first osteoarthritis-related adverse event. Data came from blinded trial clinical and safety databases. Because the parent trial was not designed to examine the efficacy of canakinumab in osteoarthritis, the researchers did not collect information on structural joint outcomes. Novartis Pharmaceuticals funded the study, and some of its authors work for the company. Results were published Aug. 4 by Annals of Internal Medicine.
Incidence rates for any hip or knee replacement during a median follow-up of 3.7 years were significantly lower among patients receiving canakinumab than those in the placebo group. Compared with placebo, hazard ratios (HRs) for incident hip or knee replacement were lower with all three doses: 0.60 (95% CI, 0.38 to 0.95) for 50 mg, 0.53 (95% CI, 0.33 to 0.84) for 150 mg, and 0.60 (95% CI, 0.38 to 0.93) for 300 mg. There were similar overall effects of canakinumab on arthroplasty outcomes stratified by sex. In comparisons with placebo, HRs for hip or knee replacements with canakinumab were 0.54 (95% CI, 0.36 to 0.81) among men (92 incident events) and 0.66 (95% CI, 0.38 to 1.12) among women (55 incident events).
In subgroup analyses that eliminated patients with a history of gout, gouty arthritis, or rheumatoid arthritis at trial entry, findings were statistically significant and consistent with the overall effect of canakinumab versus placebo. Among CANTOS participants with no history of any of these inflammatory conditions, incidence rates for large joint replacements were 0.31 and 0.52 events per 100 person-years in the pooled canakinumab and placebo groups, respectively (HR, 0.60; 95% CI, 0.42 to 0.84). Similar benefits of canakinumab versus placebo were seen in the subgroup of patients with a history of peripheral osteoarthritis at baseline (HR, 0.57; 95% CI, 0.39 to 0.83).
On the secondary end point of worsening osteoarthritis symptoms or new osteoarthritis adverse events, incidence rates were 1.17 and 1.63 events per 100 person-years in the pooled canakinumab and placebo groups, respectively (HR, 0.73; 95% CI, 0.61 to 0.87). Similar effects for the secondary end point were also seen in the subgroup of patients with a history of peripheral osteoarthritis at baseline (HR, 0.66; 95% CI, 0.51 to 0.87).
The study authors concluded, “This research is particularly relevant because large joint osteoarthritis is an increasingly common disorder with few effective and tolerated therapies other than joint replacement surgery, and for which no precision medicine structure-modifying drugs are currently available.”
An editorial noted that investigators used elevated high-sensitivity C-reactive-protein (CRP) level as an entry criterion, which may have identified a subgroup of osteoarthritis patients with accelerated joint degeneration due to inflammatory cytokines. A strength of the trial was that most other osteoarthritis trials have a much shorter duration, the editorial said.
“Further studies should evaluate the importance of elevated CRP levels as a factor affecting response to treatment, include more women to better reflect the osteoarthritis population, explore how to minimize infections, and try to better define the duration of therapy needed to detect treatment effects,” the editorial stated. “This unexpected finding deserves additional investigation in developing potential disease-modifying osteoarthritis drugs.”