A Randomized, Placebo-Controlled Study of Methotrexate to Increase Response Rates in Patients with Uncontrolled Gout Receiving Pegloticase: Primary Efficacy and Safety Findings.

OBJECTIVE: To assess efficacy, safety, pharmacokinetics, and immunogenicity of pegloticase plus methotrexate (MTX) versus pegloticase plus placebo cotreatment for uncontrolled gout in a randomized, placebo-controlled, double-blind trial. METHODS: This study included adults with uncontrolled gout, defined as serum urate ≥7 mg/dl, oral urate-lowering therapy failure or intolerance, and presence of ongoing gout symptoms including ≥1 tophus, ≥2 flares in the past 12 months, or gouty arthritis. Key exclusion criteria included MTX contraindication, current immunosuppressant use, G6PDH deficiency, and estimated glomerular filtration rate <40 ml/minute/1.73 m2 . Patients were randomized 2:1 to 52 weeks of pegloticase (8 mg biweekly) with either oral MTX (15 mg/week) or placebo. The primary end point was the proportion of treatment responders during month 6 (defined as serum urate <6 mg/dl for ≥80% of visits during weeks 20-24). Efficacy was evaluated in all randomized patients (intent-to-treat population), and safety was evaluated in all patients receiving ≥1 blinded MTX or placebo dose. RESULTS: A total of 152 patients were randomized, 100 to receive pegloticase plus MTX, 52 to receive pegloticase plus placebo. Significantly higher treatment response occurred during month 6 in the MTX group versus the placebo group (71.0% [71 of 100 patients] versus 38.5% [20 of 52 patients], respectively; between-group difference 32.3% [95% confidence interval 16.3%, 48.3%]) (P < 0.0001 for between-group difference). During the first 6 months of pegloticase plus MTX or pegloticase plus placebo treatment, 78 (81.3%) of 96 MTX patients versus 47 (95.9%) of 49 placebo patients experienced ≥1 adverse event (AE), most commonly gout flare (64 [66.7%] of 96 MTX patients and 34 [69.4%] of 49 placebo patients). Reports of AEs and serious AEs were comparable between groups, but the infusion reaction rate was considerably lower with MTX cotherapy (4.2% [4 of 96 MTX patients, including 1 patient who had anaphylaxis]) than with placebo cotherapy (30.6% [15 of 49 placebo patients, 0 who had anaphylaxis]) (P < 0.001). Antidrug antibody positivity was also lower in the MTX group. CONCLUSION: MTX cotherapy markedly increased pegloticase response rate over placebo (71.0% versus 38.5%) during month 6 with no new safety signals. These findings verify higher treatment response rate, lower infusion reaction incidence, and lower immunogenicity when pegloticase is coadministered with MTX.

Idiopathic distal sensory polyneuropathy: ACTTION diagnostic criteria.

OBJECTIVE: To present standardized diagnostic criteria for idiopathic distal sensory polyneuropathy (iDSP) and its subtypes: idiopathic mixed fiber sensory neuropathy (iMFN), idiopathic small fiber sensory neuropathy (iSFN), and idiopathic large fiber sensory neuropathy (iLFN) for use in research. METHODS: The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities and Networks (ACTTION) public-private partnership with the Food and Drug Administration convened a meeting to develop consensus diagnostic criteria for iMFN, iSFN, and iLFN. After background presentations, a collaborative, iterative approach was used to develop expert consensus for new criteria. RESULTS: An iDSP diagnosis requires at least 1 small fiber (SF) or large fiber (LF) symptom, at least 1 SF or LF sign, abnormalities in sensory nerve conduction studies (NCS) or distal intraepidermal nerve fiber density (IENFD), and exclusion of known etiologies. An iMFN diagnosis requires that at least 1 of the above clinical features is SF and 1 clinical feature is LF with abnormalities in sensory NCS or IENFD. Diagnostic criteria for iSFN require at least 1 SF symptom and at least 1 SF sign with abnormal IENFD, normal sensory NCS, and the absence of LF symptoms and signs. Diagnostic criteria for iLFN require at least 1 LF symptom and at least 1 LF sign with normal IENFD, abnormal sensory NCS, and absence of SF symptoms and signs. CONCLUSION: Adoption of these standardized diagnostic criteria will advance research and clinical trials and spur development of novel therapies for iDSPs.

Taking Personalized Medicine Seriously: Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia.

The success rate in the development of psychopharmacological compounds is insufficient. Two main reasons for failure have been frequently identified: 1) treating the wrong patients and 2) using the wrong dose. This is potentially based on the known heterogeneity among patients, both on a syndromal and a biological level. A focus on personalized medicine through better characterization with biomarkers has been successful in other therapeutic areas. Nevertheless, obstacles toward this goal that exist are 1) the perception of a lack of validation, 2) the perception of an expensive and complicated enterprise, and 3) the perception of regulatory hurdles. The authors tackle these concerns and focus on the utilization of biomarkers as predictive markers for treatment outcome. The authors primarily cover examples from the areas of major depression and schizophrenia. Methodologies covered include salivary and plasma collection of neuroendocrine, metabolic, and inflammatory markers, which identified subgroups of patients in the Netherlands Study of Depression and Anxiety. A battery of vegetative markers, including sleep-electroencephalography parameters, heart rate variability, and bedside functional tests, can be utilized to characterize the activity of a functional system that is related to treatment refractoriness in depression (e.g., the renin-angiotensin-aldosterone system). Actigraphy and skin conductance can be utilized to classify patients with schizophrenia and provide objective readouts for vegetative activation as a functional marker of target engagement. Genetic markers, related to folate metabolism, or folate itself, has prognostic value for the treatment response in patients with schizophrenia. Already, several biomarkers are routinely collected in standard clinical trials (e.g., blood pressure and plasma electrolytes), and appear to be differentiating factors for treatment outcome. Given the availability of a wide variety of markers, the further development and integration of such markers into clinical research is both required and feasible in order to meet the benefit of personalized medicine. This article is based on proceedings from the "Taking Personalized Medicine Seriously-Biomarker Approaches in Phase IIb/III Studies in Major Depression and Schizophrenia" session, which was held during the 10th Annual Scientific Meeting of the International Society for Clinical Trials Meeting (ISCTM) in Washington, DC, February 18 to 20, 2014.

A randomized, double-blind, placebo-controlled trial of TAK-242 for the treatment of severe sepsis.

OBJECTIVE: To evaluate whether TAK-242, a small-molecule inhibitor of Toll-like receptor-4-mediated signaling, suppresses cytokine levels and improves 28-day all-cause mortality rates in patients with severe sepsis. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: A total of 93 intensive care units worldwide. PATIENTS: A total of 274 patients with severe sepsis and shock or respiratory failure. INTERVENTIONS: Patients were randomly assigned to receive a 30-min loading dose followed by 96-hr infusions of placebo, TAK-242 1.2 mg/kg/day, or TAK-242 2.4 mg/kg/day. MEASUREMENTS AND MAIN RESULTS: The primary pharmacodynamic end point was change in serum interleukin-6 levels relative to baseline, with 28-day all-cause mortality rate the primary clinical end point. The trial was terminated because of a lack of effect of TAK-242 in suppressing serum interleukin-6 levels. A total of 274 subjects were randomly assigned and treated. Clinical parameters at baseline were balanced across the three groups. TAK-242 did not suppress interleukin-6 as measured by 0- to 96.5-hr area under the interleukin-6 concentration curve at either dose. Specifically, the area under the effect curve increased by 9% and 26.9% in the TAK-242 1.2 and 2.4 mg/kg/day groups, respectively, which was not statistically different from placebo (p = .63 and .15, respectively). The 28-day mortality rate was 24% in the placebo, 22% in the low-dose, and 17% in the high-dose group (p = .26 for placebo vs. high dose). A nonsignificant reduction in mortality rate was observed in a subset of patients with both shock and respiratory failure (placebo [n = 51], 33%, vs. high dose [n = 52], 19%, p = .10). Transient, dose-related increases in methemoglobin levels were observed with TAK-242 treatment in 30.1% of the patients. CONCLUSIONS: TAK-242 failed to suppress cytokine levels in patients with sepsis and shock or respiratory failure. Treatment with TAK-242 resulted in mild increases in serum methemoglobin levels but was otherwise well tolerated. Although observed mortality rates in patients with both shock and respiratory failure were lower with the 2.4 mg/kg/day dose, differences were not significant.

Evaluation of the efficacy and safety of ramelteon in subjects with chronic insomnia.

OBJECTIVE: To evaluate efficacy and safety of ramelteon (MT1/MT2-receptor [corrected] agonist) in subjects with chronic primary insomnia. METHODS: Randomized, multicenter, double-blind, placebo-controlled trial of nightly ramelteon treatment (8 mg or 16 mg) in adults (N=405) with primary chronic insomnia (DSM-IV-TR). Latency to persistent sleep (LPS), TST, sleep efficiency, wake time after sleep onset, and number of awakenings were measured by polysomnography. Subject-reported measures were also assessed. RESULTS: LPS at Week 1 (primary measure) was significantly shorter with ramelteon 8 mg (32.2 min) or 16 mg (28.9 min) vs placebo (47.9 min; p <0.001). Significant improvements in LPS were maintained at Weeks 3 and 5. TST was significantly longer with both doses of ramelteon at Week 1 (p <0.001) vs placebo. Subject-reported sleep latency was significantly shorter with ramelteon 8 mg at Weeks 1, 3, and 5 (p <0.001) and ramelteon 16 mg at Weeks 1 and 3 (p < or =0.050) vs placebo. Wake time after sleep onset and number of awakenings were not significantly different with ramelteon 8 mg or 16 mg treatment vs placebo. Subjective TST was significantly longer with ramelteon 8 mg at Weeks 1, 3, and 5 (p < or =0.050) and ramelteon 16 mg at Week 1 (p = 0.003) vs placebo. Ramelteon had no clinically meaningful effect on sleep architecture, next-morning psychomotor tasks, alertness, or ability to concentrate. No withdrawal or rebound effects were observed. CONCLUSIONS: Ramelteon reduced LPS over 5 weeks of treatment in subjects with chronic insomnia, with no clinically meaningful sleep architecture alterations, next-morning residual pharmacologic effects, and no evidence of rebound insomnia or withdrawal. No numerical differences were observed between the 2 doses of ramelteon.

Effects of ramelteon on patient-reported sleep latency in older adults with chronic insomnia.

BACKGROUND AND PURPOSE: To assess the efficacy and safety of ramelteon, a selective MT(1)/MT(2) receptor agonist, for chronic insomnia treatment. PATIENTS AND METHODS: Randomized, double-blind, placebo-controlled 35-night outpatient trial with weekly clinic visits at multiple centers. Patients include older adults (>or=65 years; N=829) with chronic insomnia. Placebo, ramelteon 4mg, or ramelteon 8mg were taken nightly for five weeks, and patient-reported sleep data were collected using sleep diaries. Primary efficacy was sleep latency at week 1. Sustained efficacy was examined at weeks 3 and 5. Rebound insomnia and withdrawal effects were evaluated during a 7-day placebo run-out. RESULTS: Both doses of ramelteon produced statistically significant reductions in sleep latency vs. placebo at week 1 (ramelteon 4mg: 70.2 vs. 78.5min, P=.008; ramelteon 8mg: 70.2 vs. 78.5 min, P=.008). Patients continued to report reduced sleep latency at week 3 with ramelteon 8mg (60.3 vs. 69.3min, P=.003), and at week 5 with ramelteon 4 mg (63.4 vs. 70.6 min, P=.028) and ramelteon 8 mg (57.7 vs. 70.6 min; P<.001). Statistically significant increases in total sleep time were observed with ramelteon 4 mg at week 1 (324.6 vs. 313.9 min, P=.004) and week 3 (336.0 vs. 324.3min, P=.007) compared with placebo. There was no evidence of significant rebound insomnia or withdrawal effects following treatment discontinuation. The incidence of adverse events was similar among all treatment groups; most were mild or moderate. CONCLUSIONS: In older adults with chronic insomnia, ramelteon significantly reduced patient reports of sleep latency over five weeks of treatment with no significant rebound insomnia or withdrawal effects.

An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia.

BACKGROUND AND PURPOSE: To evaluate the efficacy, safety, and dose response of Ramelteon, a novel highly selective MT1/MT2 receptor agonist, in patients with chronic primary insomnia. PATIENTS AND METHODS: A randomized, multicenter, double-blind, placebo-controlled, five-period crossover study design was performed. A total of 107 patients, aged 18-64 years, were randomized into a dosing sequence that included 4, 8, 16, and 32 mg of Ramelteon and placebo. Patients received all five treatments, with a 5- to 12-day washout period between treatments, and served as their own controls. Medication was administered 30 min before habitual bedtime and polysomnographic monitoring. Next-day residual effects were assessed with two visual analog scales (mood and feeling), digit symbol substitution test (DSST), word-list memory tests (immediate recall and delayed recall), and a post-sleep questionnaire that ascertained patients' alertness and ability to concentrate. RESULTS: All tested doses of Ramelteon resulted in statistically significant reductions in latency to persistent sleep (LPS) and increases in total sleep time (TST). No next-day residual effects were apparent at any dose, as compared with placebo. There were no differences in the number or type of adverse events between any active treatment and placebo group. The most commonly reported adverse events were headache, somnolence, and sore throat. CONCLUSIONS: Ramelteon demonstrated a statistically significant reduction in LPS and a statistically significant increase in TST, with no apparent next-day residual effects, in patients with chronic primary insomnia.

Valdecoxib, a COX-2-specific inhibitor, does not affect cardiac repolarization.

This double-blind, four-way crossover study assessed the effect of valdecoxib on the QTc interval duration in 25 male and 9 female healthy adults. Subjects received placebo or 40 mg, 80 mg, or 120 mg valdecoxib once daily for 5 days. Serial ECGs were obtained for 24 hours before the first treatment (baseline) and on the 5th day of each treatment. The study was statistically powered to detect a difference of > or = 5.6 ms in the average daily QTc change from baseline and a > or = 7.8-ms difference in the average maximal daily change from baseline. No QTc prolongation versus placebo (Fridericia's or Bazett's correction) was observed for any valdecoxib dose. A 22% greater than proportional increase in valdecoxib AUC0-24 was observed over the 40- to 120-mg dose range, supporting the conclusiveness of the negative QTc risk assessment even at supratherapeutic doses (up to three times the maximum recommended dose of 40 mg per day) and concentrations. In conclusion, repeated administration of doses up to 120 mg valdecoxib had no effect on cardiac repolarization in healthy volunteers, suggesting that chronic administration of valdecoxib to patients would not increase the risk from cardiac arrhythmia associated with QT prolongation.