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.

Background: Hyperoxaluria may result from increased endogenous production or overabsorption of dietary oxalate in the gastrointestinal tract leading to nephrolithiasis and, in some, to oxalate nephropathy and chronic kidney disease. ALLN-177 is an oral formulation of a recombinant, oxalate specific, microbial enzyme oxalate decarboxylase intended to treat secondary hyperoxaluria by degrading dietary oxalate in the gastrointestinal tract, thereby reducing its absorption and subsequent excretion in the urine. Methods: This double-blind, placebo controlled, randomized, cross-over, phase 1 study of ALLN-177 evaluated the tolerability of ALLN-177 and its effect on urinary oxalate excretion in 30 healthy volunteers with hyperoxaluria induced by ingestion of a high oxalate, low calcium (HOLC) diet. The primary end point was the difference in the mean 24-hour urinary oxalate excretion during the ALLN-177 treatment period compared with the placebo treatment period. Results: The daily urinary oxalate excretion increased in the study population from 27.2 ± 9.5 mg/day during screening to 80.8 ± 24.1 mg/day (mean ± SD) on the HOLC diet before introducing ALLN-177 or placebo therapy for 7 days. Compared to placebo, ALLN-177 treatment reduced urinary oxalate by 11.6 ± 2.7 mg/day, p = 0.0002 (least squares mean ± SD). Conclusions: In healthy volunteers, with diet-induced hyperoxaluria treatment with ALLN-177, when compared to placebo, significantly reduced urinary oxalate excretion by degrading dietary oxalate in the gastrointestinal tract and thereby reducing its absorption. ALLN-177 may represent a new approach for managing secondary hyperoxaluria and its complications.

Tetrodotoxin (TTX) has emerged as a potentially efficacious agent for chemotherapy-induced neuropathic pain (CINP), a prevalent, debilitating condition often resistant to analgesics. This randomized, double-blind, dose-finding study was undertaken to explore safety and trends in efficacy of four TTX doses and to identify a dose for further study. One hundred and twenty-five patients with taxane- or platinum-related CINP received subcutaneous placebo or TTX (7.5 µg twice daily (BID), 15 µg BID, 30 µg once daily (QD), 30 µg BID) for four consecutive days. Primary outcome measure was average patient-reported Numeric Pain Rating Scale (NPRS) score during Days 21–28 post-treatment. Changes in mean NPRS score were not statistically different between cohorts, due to small trial size and influence of a few robust placebo responders. Cumulative responder analysis showed significant difference from placebo with 30 µg BID cohort using the maximum response at any timepoint (p = 0.072), 5-day (p = 0.059), 10-day (p = 0.027), and 20-day (p = 0.071) rolling averages. In secondary quality of life (QOL) outcomes, 30 µg BID cohort also differed significantly from placebo in a number of SF-36 and CIPN20 subscales. Most adverse events (AE) were mild or moderate with oral paresthesia (29.6%) and oral hypoesthesia (24.8%) as most common.

www.clinicaltrials.gov identifier: NCT01510912.

BackgroundOsteoarthritis causes joint pain, stiffness, and reduced function, leading to disability. CNTX-4975, a highly purified, synthetic trans-capsaicin, targets the transient receptor potential vanilloid 1, producing analgesia via reversible deactivation of end terminals of primary afferent pain fibers within the joint and capsule.ObjectivesThis 24-week dose-ranging study evaluated CNTX-4975 efficacy and safety in subjects with chronic, moderate to severe osteoarthritis-associated knee pain.MethodsSubjects aged 45–80 years with chronic knee osteoarthritis, stable moderate to severe knee pain, and intolerability to oral or intra-articular analgesics were randomized to a single injection of placebo, CNTX-4975 0.5 mg, or CNTX-4975 1.0 mg. The primary efficacy endpoint was the area under the curve (AUC) for change from baseline in daily Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A1 score through week 12. Least squares mean differences (LSMD) for CNTX-4975 vs placebo were calculated for the primary endpoint and the average weekly AUC WOMAC A1 scores using analysis of covariance. Additional efficacy endpoints, mean change from baseline in weekly WOMAC A1 score, WOMAC B stiffness subscale, and WOMAC C physical function subscale through week 24, were analyzed using a mixed model for repeated measures (MMRM). Statistical tests were 2-sided (alpha, P=0.10). Safety assessments included treatment-emergent adverse events (TEAEs).ResultsEfficacy was evaluated in 172 subjects (placebo, n=69; CNTX-4975 0.5 mg, n=33; CNTX-4975 1.0 mg, n=70). Mean WOMAC A1 pain scores at baseline were 7.4 (placebo), 7.2 (CNTX-4975 0.5 mg), and 7.2 (CNTX-4975 1.0 mg). In the primary efficacy analysis, significant improvements vs placebo in WOMAC A1 scores were observed at week 12 with CNTX-4975 0.5 mg (LSMD: −0.8; P=0.07) and CTNX-4975 1.0 mg (LSMD: −1.6; P<0.0001). Significant improvements vs placebo were also observed at week 24 with CNTX-4975 1.0 mg (LSMD: −1.35; P=0.0002). In the MMRM analysis, significant improvements in WOMAC A1 scores vs placebo were demonstrated with CNTX-4975 0.5 mg at week 12 (LSMD: −0.9; P=0.087) but not week 24 (LSMD: −0.5; P=0.41), and with CNTX-4975 1.0 mg at weeks 12 (LSMD: −1.5; P=0.0003) and 24 (LSMD: −0.9; P=0.067). CNTX-4975 1.0 mg significantly improved WOMAC B (LSMD: −2.5; P=0.0013) and WOMAC C scores vs placebo (LSMD: −18.3; P=0.004) at week 12. Numerically greater improvements were observed in WOMAC B and C at week 24, but differences were not significant (WOMAC B LSMD: −1.2; P=0.14; WOMAC C LSMD: −7.2; P=0.28). In the safety population, the incidence of TEAEs was 30% for placebo or CNTX-4975 1.0 mg, and 47% for CNTX-4975 0.5 mg at week 24. Most TEAEs were considered unrelated to study treatment. Arthralgia was the most common TEAE with CNTX-4975 1.0 mg (placebo, 5.7%; CNTX-4975 1.0 mg, 7.0%).ConclusionsA single injection of CNTX-4975 1.0 mg improved pain with walking, knee stiffness, and physical function, and was well tolerated in subjects with moderate to severe osteoarthriti...