Tetrodotoxin for Chemotherapy-Induced Neuropathic Pain: A Randomized, Double-Blind, Placebo-Controlled, Parallel-Dose Finding Trial.

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.

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

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.

Opioid-sparing Effects of SoluMatrix Indomethacin in a Phase 3 Study in Patients With Acute Postoperative Pain.

OBJECTIVES: To report the opioid-sparing effects of SoluMatrix indomethacin, developed using SoluMatrix Fine Particle Technology, in a phase 3 study in patients with acute pain following bunionectomy. METHODS: This phase 3, placebo-controlled study randomized 462 patients with moderate-to-severe pain following bunionectomy surgery to receive SoluMatrix indomethacin 40 mg 3 times daily, SoluMatrix indomethacin 40 mg twice daily, SoluMatrix indomethacin 20 mg 3 times daily, celecoxib 400-mg loading dose followed by 200 mg twice daily, or placebo. Patients were permitted to receive opioid-containing rescue medication throughout the study. The proportion of patients who used rescue medication and the amount of rescue medication used on the first (0 to 24 h) and second (>24 to 48 h) days following initial dose of study medication, as well as time to first rescue medication use, were assessed. RESULTS: Significantly fewer patients who received SoluMatrix indomethacin 40 or 20 mg 3 times daily used opioid-containing rescue medication on day 1 compared with those receiving placebo (P≤0.034), and fewer patients in all active treatment groups used rescue medication during the second day compared with those in the placebo group (P<0.001). All active treatment groups used significantly fewer rescue medication tablets on days 1 and 2 following randomization compared with placebo (P<0.001). The most common adverse events were nausea, postprocedural edema, and headache. DISCUSSION: SoluMatrix indomethacin was associated with opioid-sparing effects in patients with acute postoperative pain.

A Double-Blind, Placebo Controlled, Randomized Phase 1 Cross-Over Study with ALLN-177, an Orally Administered Oxalate Degrading Enzyme.

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.

Low-dose SoluMatrix diclofenac in the treatment of osteoarthritis: A 1-year, open-label, Phase III safety study.

INTRODUCTION: Diclofenac is used for the treatment of osteoarthritis (OA); however, like other nonsteroidal anti-inflammatory drugs (NSAIDs) it can be associated with serious dose-related adverse events (AEs). Low-dose SoluMatrix® diclofenac has been developed to provide efficacy at lower diclofenac doses. A recently published Phase III study evaluated the efficacy and safety of SoluMatrix diclofenac 35 mg twice daily (b.i.d.) and thrice daily (t.i.d.) in patients with OA pain treated for 12 weeks. METHODS: This Phase III multicenter, open-label study assessed the safety of SoluMatrix diclofenac in patients with OA dosed up to 52 weeks (ClinicalTrials.gov: NCT01510912). The study enrolled 602 chronic NSAID/acetaminophen users, aged ≥40 years with OA of the knee or hip. Patients received SoluMatrix diclofenac 35 mg b.i.d., which could be increased to t.i.d. and subsequently reduced to b.i.d. as needed. Safety assessments included AEs, vital signs, physical examination findings, 12-lead electrocardiogram, and clinical laboratory test results. Patient-reported outcomes were evaluated by the Short Form-36 (SF-36). RESULTS: A total of 601 patients received SoluMatrix diclofenac; 373 of 601 patients (62.1%) received treatment for ≥11 months. The most frequent AEs included upper respiratory tract infection, headache, urinary tract infection, diarrhea, nasopharyngitis, and nausea. Serious gastrointestinal, cardiovascular, renal, and hepatic AEs were uncommon. A small proportion (99 patients, 16.5%) of patients discontinued participation in the study due to AEs. Clinically meaningful improvements from baseline in Physical Component Summary Scores of the SF-36 were noted at week 12 and were sustained through week 52. Improvements in six of the eight individual physical and mental SF-36 domains were also noted. CONCLUSION: SoluMatrix diclofenac treatment for up to 1 year was generally well tolerated in patients with OA pain and associated with improvement in quality of life measures. TRIAL REGISTRATION: www.clinicaltrials.gov identifier: NCT01510912.