Randomized, Double-Blind, Placebo-Controlled Trial of Intraarticular Trans-Capsaicin for Pain Associated With Osteoarthritis of the Knee

Abstract

Objective: To assess the efficacy and safety of high-purity synthetic trans-capsaicin (CNTX-4975) in patients with chronic moderate-to-severe osteoarthritis (OA)-associated knee pain.

Methods: In this phase II multicenter double-blind study, patients ages 45-80 years who had stable knee OA were randomized in a 2:1:2 ratio to receive a single intraarticular injection of placebo, CNTX-4975 0.5 mg, or CNTX-4975 1.0 mg. The primary efficacy end point was area under the curve (AUC) for change from baseline in daily Western Ontario and McMaster Universities Osteoarthritis Index pain with walking score (range 0-10, 0 = none and 10 = extreme) through week 12. Secondary efficacy end points included a similar AUC analysis of outcomes in patients treated with CNTX-4975 0.5 mg, and evaluations extending to 24 weeks.

Results: Efficacy was evaluated in 172 patients (placebo group, n = 69; CNTX-4975 0.5 mg group, n = 33; CNTX-4975 1.0 mg group, n = 70). At week 12, greater decreases in the AUC for the pain score were observed with CNTX-4975 in the 0.5 mg and 1.0 mg groups versus placebo (0.5 mg group least squares mean difference [LSMD] -0.79, P = 0.0740; 1.0 mg group LSMD -1.6, P < 0.0001). Significant improvements were maintained at week 24 in the 1.0 mg group (LSMD -1.4, P = 0.0002). Treatment-emergent adverse events were similar in the placebo and CNTX-4975 1.0 mg groups.

Conclusion: In this study, CNTX-4975 provided dose-dependent improvement in knee OA-associated pain. CNTX-4975 1.0 mg produced a significant decrease in OA knee pain through 24 weeks; CNTX-4975 0.5 mg significantly improved pain at 12 weeks, but the effect was not evident at 24 weeks.

Trial registration: ClinicalTrials.gov NCT02558439.

Figure 1

Disposition of the study patients. Reasons for exclusion at screening included Kellgren/Lawrence grade outside of range 2–4 (320 patients [60%]); inability to understand and follow study requirements, including diary entry via computer (64 [12%]); failure to meet the requirement for moderate‐to‐severe pain (29 [5%]); history of allergic reaction to the planned local anesthesia regimens, polyethylene glycol, or capsaicin (19 [3%]); baseline and screening scores outside of a 5–9 range on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain with walking assessment (12 [2%]); >2‐point difference in WOMAC pain with walking score between screening and baseline (11 [2%]); prior participation in an ALGRX4975 or CNTX‐4975 study (10 [2%]); and positive urine drug screen or active/past substance use disorder within prior year (10 [2%]). Other inclusion/exclusion criteria each contributed ≤1% to exclusions at screening. * = Number of patients in the safety analysis. † Three patients were excluded from the efficacy analysis (modified intent‐to‐treat population, n = 172). One patient was excluded (prior to unblinding) due to deviation/noncompliance, as this patient was injected at 2 different study sites (CNTX‐4975 1.0 mg, n = 1; placebo, n = 1). A third patient was lost to follow‐up in the CNTX‐4975 0.5 mg group.

Figure 2

Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain with walking on a flat surface (QA1) scores. Standardized area under the curve (AUC), normalized to the 0–10 rating scale, for change from baseline with CNTX‐4975 versus placebo in daily pain with walking scores through week 12 and in average weekly pain with walking scores through week 24 were evaluated. Analysis of covariance was performed in the modified intent‐to‐treat population. LSMD = least squares mean difference; 90% CI = 90% confidence interval.

Figure 3

Change in average weekly WOMAC pain with walking scores. Change from baseline in average weekly scores through week 24 in patients treated with CNTX‐4975 versus placebo is shown. A mixed model for repeated measures was used in the modified intent‐to‐treat population. Week 12 was the prespecified landmark end point; other P values were considered nominal and are presented for summary purposes only. Baseline scores (range 0–10): placebo 7.4, CNTX‐4975 0.5 mg 7.2, CNTX‐4975 1.0 mg 7.2. * = P < 0.1; † = P < 0.05; ‡ = P < 0.001, versus placebo. See Figure 2 for definitions.