A 5-Year Observational Study of Patients With Treatment-Resistant Depression Treated With Vagus Nerve Stimulation or Treatment as Usual: Comparison of Response, Remission, and Suicidality.

OBJECTIVE: The Treatment-Resistant Depression Registry investigated whether adjunctive vagus nerve stimulation (VNS) with treatment as usual in depression has superior long-term outcomes compared with treatment as usual only. METHOD: This 5-year, prospective, open-label, nonrandomized, observational registry study was conducted at 61 U.S. sites and included 795 patients who were experiencing a major depressive episode (unipolar or bipolar depression) of at least 2 years' duration or had three or more depressive episodes (including the current episode), and who had failed four or more depression treatments (including ECT). Patients with a history of psychosis or rapid-cycling bipolar disorder were excluded. The primary efficacy measure was response rate, defined as a decrease of ≥50% in baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score at any postbaseline visit during the 5-year study. Secondary efficacy measures included remission. RESULTS: Patients had chronic moderate to severe depression at baseline (the mean MADRS score was 29.3 [SD=6.9] for the treatment-as-usual group and 33.1 [SD=7.0] for the adjunctive VNS group). The registry results indicate that the adjunctive VNS group had better clinical outcomes than the treatment-as-usual group, including a significantly higher 5-year cumulative response rate (67.6% compared with 40.9%) and a significantly higher remission rate (cumulative first-time remitters, 43.3% compared with 25.7%). A subanalysis demonstrated that among patients with a history of response to ECT, those in the adjunctive VNS group had a significantly higher 5-year cumulative response rate than those in the treatment-as-usual group (71.3% compared with 56.9%). A similar significant response differential was observed among ECT nonresponders (59.6% compared with 34.1%). CONCLUSIONS: This registry represents the longest and largest naturalistic study of efficacy outcomes in treatment-resistant depression, and it provides additional evidence that adjunctive VNS has enhanced antidepressant effects compared with treatment as usual in this severely ill patient population.

Novel drug OMS103HP reduces pain and improves joint motion and function for 90 days after arthroscopic meniscectomy.

PURPOSE: This phase 2 study compared OMS103HP (Omeros, Seattle, WA) with control (lactated Ringer's) irrigation solution in patients undergoing arthroscopic partial meniscectomy. METHODS: This was a prospective, multicenter, double-blind, randomized, vehicle-controlled, parallel-group study. Safety and postoperative pain, range of motion, and self-reported function were evaluated for 90 days. Statistical results were based on univariate analysis of variance and repeated-measures analyses. RESULTS: Mean visual analog scale (VAS) pain scores within 24 hours after discharge from the recovery room showed more pain in the control group beginning at 2 hours and peaking at 8 hours. Univariate analysis of variance of mean VAS scores over the 24-hour period did not meet statistical significance. Repeated-measures analysis yielded a statistically significant difference (P = .004) for time-by-treatment interaction, showing a clear drug benefit over time based on VAS scores. There were statistically significant differences at day 7 between the groups in passive flexion without pain (P = .022). The proportion of patients achieving flexion of 95° or greater, 110°, and 125° was greater for the OMS103HP group. The Knee Injury and Osteoarthritis Outcome Score (KOOS) showed statistically significant differences (P ≤ .05) between the OMS103HP and control groups for 4 of 5 outcomes (symptoms, pain, sport and recreation, and knee-based quality of life but not activities of daily living). All scores showed a treatment effect through day 90. The overall incidence of adverse events and abnormal laboratory values for the OMS103HP and control groups was similar. Serious adverse events occurred in 1 control patient. CONCLUSIONS: In this study of patients with meniscal tears who underwent simple debridement, the use of OMS103HP resulted in reduced acute postoperative pain (measured by VAS over the first 24 hours postoperatively), reduced pain during recovery (measured by the KOOS pain subscale, which measures both background levels of pain and exacerbations caused by movements or activities), improved postoperative knee motion, and improved functional outcomes as assessed with the KOOS Knee Survey. Clinical benefits of OMS103HP were consistent and sustained throughout 90 days of postoperative follow-up. LEVEL OF EVIDENCE: Level I, prospective, randomized, controlled trial.

A phase II open-label trial of apomine (SR-45023A) in patients with refractory melanoma.

Metastatic melanoma continues to be a very difficult disease to treat. Options are limited and often have very little impact on the course of the disease. The objective of the current study was to evaluate the efficacy and safety of continuously administered Apomine (SR-45023A), a novel bisphosphonate, in patients with previously treated metastatic malignant melanoma. Adult patients with previously treated metastatic melanoma received Apomine 100 mg orally, twice daily (total dose 200 mg per day) continuously for 28 days (defined as a cycle). Treatment was continued until disease progression or unacceptable toxicity. A total of 42 patients received at least one dose of Apomine. Stable disease was achieved in 2 patients (5%). No complete or partial responses were observed. Progression free survival of at least 16 weeks was observed in 6 patients (14%). The median overall survival was 6.1 months (95% CI, 4.9-9.4 months). Time to treatment failure was 1.7 months (95% CI, 1.6-1.8 months) with Apomine therapy. By cycle 2, Apomine concentrations reached steady-state. Apomine was well tolerated with only 37% of patients experiencing any drug-related event. Abdominal pain was the most frequent adverse event occurring in 26% of patients. In conclusion, Apomine, at the current dose studied, failed to produce a 30% progression free survival rate at 16 weeks considered to be a meaningful benefit for further development.

Phase I and pharmacokinetic study of the dolastatin-15 analogue tasidotin (ILX651) administered intravenously on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors.

PURPOSE: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors. PATIENTS AND METHODS: Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modified Fibonacci scheme ranging from 3.9 to 45.7 mg/m(2). Pharmacokinetic samples were collected during the first course. RESULTS: Neutropenia was the principal DLT at the 45.7 mg/m(2)/d dose level. In addition, one patient also experienced grade 3 neutropenia complicated with grade 3 esophageal candidiasis and grade 3 dehydration. Only 1 of 11 patients treated at the MTD, 34.4 mg/m(2), experienced dose-limiting neutropenia. Other common, drug-related toxicities included mild to moderate fatigue, anemia, nausea, anorexia, emesis, alopecia, and diarrhea. The best observed antitumor response consisted of stable disease and was noted in 10 patients (31%); the median duration on study for those patients with stable disease was 99.5 days compared with 37.5 days for those patients with progressive disease. Tasidotin plasma concentrations declined biphasically with an effective half-life of < or =55 minutes, and approximately 11% was excreted unchanged in the urine. CONCLUSION: The recommended dose for phase II studies and the MTD when tasidotin is administered on days 1, 3, and 5 every 3 weeks is 34.4 mg/m(2). The favorable toxicity profile of tasidotin compared with other antitubulin agents, including other dolastatin analogues, and its novel mechanism of action support further disease-directed evaluation of this agent.