Bilateral intra-articular injection of CNTX-4975 for management of painful osteoarthritis of the knee: results at 6 weeks from an open-label trial

Abstract

Purpose: A prior double-blind, randomized, placebo-controlled trial with a single 1 mg intra-articular injection of CNTX-4975 (highly purified trans-capsaicin) into one knee for management of moderate to severe pain associated with osteoarthritis of the knee revealed a statistically significant decrease in pain with walking vs placebo through 24 weeks post-dose. The present study evaluated cooling parameters to mitigate procedure pain from a single intra-articular injection of CNTX-4975 1 mg into the osteoarthritic knee, and the efficacy and safety of a water-soluble, ready-to-use formulation of CNTX-4975 in a prefilled syringe. Here we present the efficacy and safety outcomes determined 6 weeks after bilateral osteoarthritic knee injections. Methods: Subjects with bilateral moderate to severe painful knee osteoarthritis for ≥3 months prior to study entry consented to receive a single intra-articular injection of CNTX-4975 1 mg into each knee (left knee followed by the right), with 7 days (±2 days) between intra-articular injections. Intra-articular lidocaine 2% (without epinephrine, 15 mL) was given 3-30 minutes before injection of CNTX-4975. Before the injection of lidocaine and throughout the procedure, the skin around the knee was cooled using different techniques. Temperature changes in the knee joint were documented with an intra-articular temperature probe. Pain with walking over the past 24 hours was rated on a Numeric Pain Rating Scale (NPRS, 0-10) at baseline (4-9 inclusive required for enrollment) and at 6 weeks for each knee. Subjects also rated the change in pain in each knee using the Patient Global Impression of Change (PGIC) scale (7-point scale from very much improved to very much worse). Knees were examined to determine the presence of injection site issues, and adverse events were recorded. Results: Fifteen subjects with bilateral knee osteoarthritis, 12 male and 3 female, were enrolled; mean age was 57 years (range, 47-71). There were no discontinuations and no missing data in the outcome measures. As shown in the Table, the baseline and 42-day post-injection NPRS pain scores were averaged across both knees and ranged from 4 to 8. The mean pain with walking score decreased from a baseline value of 6.0 to 1.5 at day 42, for a 75% reduction in pain overall (P<0.00001, two-tailed, paired t-test). Of the 15 subjects, 10 reported a pain level of 2 or less, and 6 subjects reported no pain in either knee 6 weeks post intra-articular injection. A similar pattern of improvement was evident with the PGIC: in 26 of 30 recordings (15 subjects, both knees), subjects described pain at 6 weeks post injection as much improved or very much improved. No subject reported pain as being unchanged or worse in either knee. One subject developed a large ecchymosis at the site of insertion of the intra-articular temperature probe that was deemed related to insertion of the temperature probe. Treatment-emergent adverse events (TEAEs) reported on the day of injection were nausea (n=3), headache (n=2), vasovagal attack, dizziness, elevated blood pressure, and tachycardia (n=1 each); all were reported to be mild and 2 (vasovagal attack and 1 report of nausea) were deemed possibly related to treatment. TEAEs reported after the day of injection were insect bite (n=2) and hay fever, vasovagal attack, back pain, acid reflux (esophageal), allergic conjunctivitis, and bruise (n=1 each); all were mild and deemed unlikely or not related to study treatment. Conclusions: Pain reduction in this open-label trial following bilateral injection of CNTX-4975 1 mg into painful osteoarthritic knees was statistically significant and similar to the pain reduction reported in a prior double-blind, randomized, controlled trial involving injection into one painful osteoarthritic knee (TRIUMPH study). These data support the continued development of intra-articular CNTX-4975 1 mg as a therapy to manage moderate to severe pain associated with knee osteoarthritis.