Rapid Onset of Effect of Galcanezumab for the Prevention of Episodic Migraine: Analysis of the EVOLVE Studies.

Objective: To evaluate onset of effect of galcanezumab in patients with episodic migraine.

Background: Galcanezumab is a monoclonal antibody that binds to calcitonin gene-related peptide and is indicated for preventive treatment of migraine.

Design/methods: Data on the primary outcome measure were analyzed from 2 previously published double-blind, Phase 3 studies (EVOLVE-1 [N = 858] and EVOLVE-2 [N = 915]) wherein adult patients with episodic migraine were randomized to receive monthly subcutaneous injections of galcanezumab 120 mg (with 240-mg loading dose) or 240 mg or placebo for up to 6 months.

Trial of Galcanezumab in Prevention of Episodic Cluster Headache.

Background: Episodic cluster headache is a disabling neurologic disorder that is characterized by daily headache attacks that occur over periods of weeks or months. Galcanezumab, a humanized monoclonal antibody to calcitonin gene-related peptide, may be a preventive treatment for cluster headache.

Methods: We enrolled patients who had at least one attack every other day, at least four total attacks, and no more than eight attacks per day during a baseline assessment, as well as a history of cluster headache periods lasting at least 6 weeks, and randomly assigned them to receive galcanezumab (at a dose of 300 mg) or placebo, administered subcutaneously at baseline and at 1 month.

Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial.

Introduction Galcanezumab is a humanized monoclonal antibody binding calcitonin gene-related peptide, used for migraine prevention. Methods A global, double-blind, 6-month study of patients with episodic migraine was undertaken with 915 intent-to-treat patients randomized to monthly galcanezumab 120 mg (n = 231) or 240 mg (n = 223) or placebo (n = 461) subcutaneous injections. Primary endpoint was overall mean change from baseline in monthly migraine headache days.

Multiplicity considerations in subgroup analysis.

This paper deals with the general topic of subgroup analysis in late-stage clinical trials with emphasis on multiplicity considerations. The discussion begins with multiplicity issues arising in the context of exploratory subgroup analysis, including principled approaches to subgroup search that are applied as part of subgroup exploration exercises as well as in adaptive biomarker-driven designs. Key considerations in confirmatory subgroup analysis based on one or more pre-specified patient populations are reviewed, including a survey of multiplicity adjustment methods recommended in multi-population phase III clinical trials.

Nutrition for the Prevention of Chronic Diseases.

Chronic non-communicable diseases (NCDs) are the leading causes of morbidity and mortality in the United States and globally, and are attributable largely to poor nutrition and suboptimal lifestyle behaviors. The 2015-2020 Dietary Guidelines for Americans promote healthy eating and lifestyle patterns across the lifespan to reduce risk of NCDs. Physicians are well positioned to provide lifestyle preventive interventions that are personalized to their patients' biological needs and cultural preferences through multidisciplinary team activities or referral to professional nutrition and physical activity experts.

The 2015 Dietary Guidelines Advisory Committee Scientific Report: Development and Major Conclusions.

The Dietary Guidelines for Americans (DGA) is published every 5 y jointly by the Department of Health and Human Services (HHS) and the USDA and provides a framework for US-based food and nutrition programs, health promotion and disease prevention initiatives, and research priorities. Summarized in this report are the methods, major conclusions, and recommendations of the Scientific Report of the 2015 US Dietary Guidelines Advisory Committee (DGAC). Early in the process, the DGAC developed a conceptual model and formulated questions to examine nutritional risk and determinants and impact of dietary patterns in relation to numerous health outcomes among individuals aged ≥2 y.

Serotonin 2A Receptor SNP rs7330461 Association with Treatment Response to Pomaglumetad Methionil in Patients with Schizophrenia.

This study aims to confirm the initial pharmacogenetic finding observed within the clinical proof-of-concept trial of an enhanced response to treatment with pomaglumetad methionil (LY2140023 monohydrate) in Caucasian schizophrenia patients homozygous for T/T at single nucleotide polymorphism rs7330461 in the serotonin (5-hydroxytryptamine) 2A receptor gene compared to A/A homozygous patients. The effect of the rs7330461 genotype on the response to pomaglumetad methionil treatment was assessed in three additional clinical trials and in an integrated analysis. Overall, this study includes data from 1115 Caucasian patients for whom genotyping information for rs7330461 was available, consisting of 513 A/A homozygous, 466 A/T heterozygous and 136 T/T homozygous patients.

Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia.

Background: Accumulating evidence indicates that glutamatergic tone in schizophrenia may vary as a function of illness duration or medication history. We conducted an exploratory analysis of the existing clinical trial database of pomaglumetad methionil (pomaglumetad) to demonstrate treatment response in targeted patient populations.

Methods: Results of the H8Y-MC-HBBM (HBBM) study and an integrated analysis based on five placebo-controlled trials were summarized.

A Double-Blind, Placebo-Controlled Comparator Study of LY2140023 monohydrate in patients with schizophrenia.

Background: Pomaglumetad methionil (LY2140023 monohydrate) is a potent and highly selective agonist for the metabotropic glutamate mGluR2 and mGluR3 receptors. We present results of a pivotal clinical study H8Y-MC-HBBM assessing the efficacy of LY2140023 in improving symptoms as a monotherapy in patients with an acute exacerbation of schizophrenia.

Methods: Enrolled adult patients (ages 18-65) with schizophrenia who had experienced an exacerbation of symptoms within 2 weeks prior to study entry.

Multipopulation Tailoring Clinical Trials: Design, Analysis, and Inference Considerations.

Several recent publications have focused on statistical considerations that arise in multipopulation tailoring clinical trials that evaluate treatment effect in an overall patient population as well as one or more predefined subpopulations. This paper presents a decision-making framework applicable to these trials and evaluates the operating characteristics of this framework versus one based solely on the results of primary hypothesis tests. The operating characteristics are presented as rates of applicable errors, known as influence errors and interaction errors.

Bayesian assessment of the influence and interaction conditions in multipopulation tailoring clinical trials.

Multipopulation tailoring trials provide a trial design option that supports the realization of tailored therapeutics or personalized medicine. Several recent publications have focused on statistical and clinical considerations that arise in these trials that are designed to study the overall treatment effect in a population of interest as well as one or more prospectively defined subpopulations. Millen et al.

A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia.

Background: We compared the time to discontinuation due to lack of tolerability over 24 weeks in patients suffering from schizophrenia treated with pomaglumetad methionil (LY2140023 monohydrate, the prodrug of metabotropic glutamate 2/3 receptor agonist, LY404039) or standard of care (SOC: olanzapine, risperidone, or aripiprazole).

Methods: Study HBBR was a multicenter, randomized, open-label study comparing the long-term safety and tolerability of LY2140023 with SOC for schizophrenia. Patients had moderate symptomatology with prominent negative symptoms and evidence of functional impairment.

On the practical application of mixed effects models for repeated measures to clinical trial data.

The use of mixed effects models for repeated measures (MMRM) for clinical trial analyses has recently gained broad support as a primary analysis methodology. Some questions of practical implementation detail remain, however. For example, whether and how to incorporate clinical trial data that is collected at nonprotocol-specified timepoints or clinic visits has not been systematically studied.

Methodology for adding glycemic index to the National Health and Nutrition Examination Survey nutrient database.

Generating valid estimates of dietary glycemic index (GI) and glycemic load (GL) has been a challenge in nutritional epidemiology. The methodologic issues may have contributed to the wide variation of GI/GL associations with health outcomes observed in existing literature. We describe a standardized methodology for assigning GI values to items in the National Health and Nutrition Examination Survey (NHANES) nutrient database using the new International Tables to develop research-driven, systematic procedures and strategies to estimate dietary GI/GL exposures of a nationally representative population sample.