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Litwin J.S.,ERT | Benedict M.S.,PPD Inc | Thorn M.D.,Statistical Resources | Lawrence L.E.,Melinta Therapeutics | And 2 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2015

A randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Mundt J.C.,Center For Psychological Consultation | Greist J.H.,Healthcare Technology Systems, Llc | Jefferson J.W.,Healthcare Technology Systems, Llc | Federico M.,ERT | And 2 more authors.
Journal of Clinical Psychiatry | Year: 2013

Objective: To evaluate whether lifetime suicidal ideation with intention to act and/or suicidal behaviors reported at baseline predict risk of prospectively reporting suicidal behavior during subsequent study participation. Method: Data from studies using the electronic Columbia-Suicide Severity Rating Scale (eC-SSRS) to prospectively monitor suicidal ideation and behaviors between September 2009 and May 2011 were analyzed. Studies included patients with major depressive disorder, insomnia, posttraumatic stress disorder, epilepsy, and fibromyalgia. Records for 35,224 eC-SSRS assessments were extracted. Incomplete assessments and eC-SSRS records from patients missing a baseline assessment or with no prospective follow-up assessments were excluded. Baseline lifetime eC-SSRS reports were categorized as negative (no lifetime ideation with intent to act or prior suicidal behavior) or positive (lifetime ideation with intent to act but no prior behavior, no ideation with intent to act but prior behavior, or both lifetime ideation with intent and prior behavior). Results: 3,776 patients completed a baseline and 1 or more follow-up assessments. The mean follow-up period was 64 days. Of patients with negative lifetime reports, 2.4% subsequently reported suicidal behavior during study participation, compared to 12.0% of patients with lifetime ideation with intent only (OR = 5.55; 95% CI, 2.65-11.59), 9.6% of patients with lifetime behavior only (OR = 4.33; 95% CI, 2.94-6.39), and 18.3% of patients with both (OR = 9.13; 95% CI, 6.47-12.88). Sensitivity and specificity of positive reports for identifying suicidal behaviors were 0.67 and 0.76, respectively. Conclusions: Patients reporting lifetime suicidal ideation with intent to act and/or prior suicidal behavior at baseline are 4 to 9 times more likely to prospectively report suicidal behavior during study participation. © Copyright 2013 Physicians Postgraduate Press, Inc.

Reaney M.,ERT | Yu M.,Eli Lilly and Company | Lakshmanan M.,Eli Lilly and Company | Pechtner V.,Eli Lilly and Company | Van Brunt K.,Eli Lilly and Company
Diabetes, Obesity and Metabolism | Year: 2015

Aims: To compare treatment satisfaction among people with type 2 diabetes receiving dulaglutide 1.5mg and dulaglutide 0.75mg (a once-weekly, long-acting, glucagon-like peptide-1 receptor agonist) with those receiving either exenatide or placebo (AWARD-1 study) or metformin (AWARD-3 study) over 52weeks. Methods: The Diabetes Treatment Satisfaction Questionnaire status version (DTSQs) and change version (DTSQc) were used to evaluate total treatment satisfaction and perceived frequency of hyperglycaemia and hypoglycaemia. Results: In the AWARD-1 study, significant improvements from baseline were observed in total DTSQs score for both dulaglutide doses (26 and 52weeks) and exenatide (26weeks). The improvement was significantly greater with both dulaglutide doses compared with placebo (26weeks) and exenatide (26 and 52weeks). The perceived frequency of hyperglycaemia was lower for all groups at 26 and 52weeks compared with baseline. The improvement was greater with both dulaglutide doses and exenatide compared with placebo at 26weeks, and was also greater with both dulaglutide doses compared with exenatide at 26 and 52weeks. The exenatide group had an increase in perceived frequency of hypoglycaemia at 26 and 52weeks. In the AWARD-3 study, significant improvements from baseline were observed for total DTSQs scores in all groups at 26 and 52weeks. Perceived frequency of hyperglycaemia was lower for all groups at 26 and 52weeks compared with baseline, and this improvement was greater with both dulaglutide doses compared with metformin at 52weeks. Conclusions: Dulaglutide was associated with improvements in treatment satisfaction and a decrease in perceived frequency of hyperglycaemia. © 2015 John Wiley & Sons Ltd.

McHorney C.A.,ERT | Crivera C.,Janssen Scientific Affairs LLC | Laliberte F.,Groupe dAnalyse Ltee | Nelson W.W.,Janssen Scientific Affairs LLC | And 6 more authors.
Current Medical Research and Opinion | Year: 2015

Background: CMS Star Ratings help inform beneficiaries about the performance of health and drug plans. Medication adherence is currently weighted at nearly half of a Part D plans Star Ratings. Including the adherence to non-vitamin-K-antagonist oral anticoagulants (NOACs) as a measure in the Star Ratings program may increase a plan's incentives to improve patient adherence. Objective: To assess the adherence to medication of patients who used the NOACs rivaroxaban, dabigatran, or apixaban in 2014 based on the Pharmacy Quality Alliance (PQA) adherence measure. Methods: Healthcare claims from the Humana database between July 2013 and December 2014 were analyzed. Adult patients with ≥2 dispensings of NOAC agents in 2014, at least 180 days apart, with460 days of supply, and ≥180 days of continuous enrollment prior to the index NOAC were identified. The PQA measure was calculated as the percentage of patients who had a proportion of days covered (PDC) ≥0.8. Multivariate logistic regression analyses were also conducted adjusting for baseline confounders. Results: A total of 11,095 rivaroxaban, 6548 dabigatran, and 3532 apixaban users were identified. Based on the PQA adherence measure (PDC ≥0.8), a significantly higher proportion of rivaroxaban users (72.7%) was found to be adherent compared to dabigatran (67.2%: p50.001) and apixaban (69.5%: p50.001) users. Compared to apixaban users, the adjusted likelihood of being adherent was significantly higher for rivaroxaban users (unadjusted OR [95% CI]: 1.17 [1.08-1.27], p50.001; adjusted OR [95% CI]: 1.20 (1.10-1.31), p50.001) and significantly lower for dabigatran users (unadjusted OR [95% CI]: 0.90 [0.82- 0.98], p 0.019; adjusted OR [95% CI]: 0.85 [0.77-0.93], p50.001). Limitations: Limitations of the study are potential inaccuracies in claims data, possible change in patterns over time, and the impossibility of knowing whether all supplied tablets were taken. Conclusion: Using the PQA's adherence measure, rivaroxaban users were found to have significantly higher adherence compared to apixaban and dabigatran users. © 2015 Taylor & Francis.

Del Corral A.,Novartis | Dutreix C.,Novartis | Huntsman-Labed A.,Novartis | Lorenzo S.,Novartis | And 3 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose Midostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization. Here we evaluated midostaurin's effect on cardiac repolarization. Methods This phase I study evaluated the effect of midostaurin (75 mg twice daily for 2 days; 75 mg once on day 3) on the heart rate-corrected QT (QTc) interval in a parallel design with active (moxifloxacin) and placebo control arms in healthy volunteers. Results The maximum mean QTc change from baseline corrected using Fridericia's correction (QTcF) for midostaurin compared with placebo was 0.7 ms at 24 h post dose on day 3. The highest upper bound of the 1-sided 95% CI was 4.7 ms, which excluded 10 ms, demonstrating a lack of QTcF prolongation effect. Assay sensitivity was demonstrated by modeling the moxifloxacin plasma concentration versus QTcF change from baseline, which showed a clear positive increase in QTcF with increasing moxifloxacin plasma concentrations, as expected based on previous studies. In the 4-day evaluation period, a minority of participants (34.6%) experienced an adverse event; 97.0% were grade 1. No grade 3 or 4 adverse events were reported. Conclusion Midostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram. © Springer-Verlag 2012.

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