Demographic comparison of subjects in FDA approval trials in the United States to disorder specific demographics using Real World Data.

The Food and Drug Administration (FDA) has recommended that clinical trial study populations accurately reflect the patients likely to use the product, if approved. The FDA has not provided specific guidance on how cohort sizes of clinically relevant demographic characteristics should be determined. Therefore, the present study was designed to compare demographic characteristics reported in US-only FDA approval trials to the demographic characteristics of the related medical disorders in an electronic health records database of >150 M patients in the United States (US). The results demonstrate that comparative disparities in demographic cohort proportions are common, yet inconsistent, and highlight the need to define disorder specific demographic cohort proportion goals in future clinical trials.

Real world data analysis of frontotemporal dementia: Implications for future clinical research.

Frontotemporal dementia (FTD) is a progressive decline of cognitive abilities associated with other neuropsychiatric comorbidities. A real-world data (RWD) analysis of a large electronic healthcare records (EHR) database identified the comorbidities of FTD. Deidentified EHRs in the TriNetX Network database from >155,000,000 individuals in the United States established an FTD Cohort (ICD-10 Code G31.0) of adult patients who visited a healthcare provider in 2022. The non-FTD cohort were age-matched individuals who had not received a diagnosis of ICD-10 Code G31.0, and who had visited a healthcare provider in 2022. The median age of both cohorts was 73 years. A comparative analysis was performed between the FTD and non-FTD cohorts. There were 6660 individuals (aged ≥18) with FTD and 11,810,060 individuals (aged ≥63) without a diagnosis of FTD, with healthcare visits in 2022. There were 25 ICD-10 Codes for disorders that were present in >10% of FTD patients, with a Relative Risk (RR) of ≥2.0 compared the non-FTD cohort. Multiple neuropsychiatric disorders had RRs ≥ 2.0, with minimal evidence for significant involvement of other organ systems. These data document that FTD, as known previously, is associated with multiple neuropsychiatric comorbidities. There was minimal evidence of comorbid involvement of other organ systems. These data provide a baseline of general FTD symptoms for the rapidly evolving analysis of genetic subvariants of FTD. These data also provide insights into the clinical management of FTD, as well as recommendations for specific endpoints in clinical trials.

Defining demographic cohorts in clinical trial populations using large electronic health records databases.

The Food and Drug Administration (FDA) has stressed the need to ensure that clinical trial study populations accurately reflect the patients likely to use the product, if approved. However, the FDA has not provided specific guidance on how clinically relevant demographic characteristics might be defined. Therefore, the present study was designed to develop a framework that could be used to rapidly identify population demographics for any medical condition. Then, these real-world data were used as the basis to calculate acceptable demographic parameters (with 95% confidence intervals) for clinical trial populations. Data on Alzheimer's Disease were used as an example of the proposed approach.

Clinical trials update 2015: Year in review.

This section of Headache annually reviews the status of recently completed and ongoing major clinical trials involving common headache disorders. The review will focus on multicenter trials of new therapies, as well as novel formulations of previously approved therapeutics. The Table summarizes the major therapeutic headache trials that were ongoing at the end of 2015, according to data obtained from both the "ClinicalTrials.Gov" website and from corporate press releases and presentations.

Clinical trials update 2014: year in review.

This section of Headache annually reviews the status of recently completed and ongoing major clinical trials involving common headache disorders. The review will focus on multicenter trials of new therapies as well as novel formulations of previously approved therapeutics. Table 1 summarizes the major therapeutic headache trials that were ongoing at the end of 2014, according to data obtained from both the "ClinicalTrials.Gov" website and from corporate press releases and presentations.

What turns on a migraine? A systematic review of migraine precipitating factors.

Migraine attacks rarely occur spontaneously in the absence of any possible precipitating factors. A systematic literature review of 25 publications revealed a consistent set of stimuli that have been identified as factors associated with the onset of a migraine attack. The weighted average of the "Top 10" trigger factors was determined. Stress was cited as the overall most common migraine precipitating factor, which was identified as a trigger factor by 58 % of 7187 migraineurs. The incidence of migraine precipitating factors, across various populations globally, demonstrates the clinical consistency of migraine in the human population. Future efforts aimed at mitigating these precipitating factors have the potential to significantly improve migraine management. However, the current healthcare system is unlikely to be able to develop detailed personalized management plans. There is a need to develop a novel approach to the identification and management of multiple trigger factors in individual migraineurs.

Calcitonin gene-related peptide targeted immunotherapy for migraine: progress and challenges in treating headache.

A role for calcitonin gene-related peptide (CGRP) in the pathophysiology of migraine has been established over the past 25 years. There have now been at least five different small-molecule CGRP antagonists that have demonstrated statistical proof of efficacy in the acute treatment of migraine. At present, multiple clinical trials are underway that are assessing the ability of long-acting antibodies against CGRP to prevent frequent migraine attacks. This review summarizes the existing data concerning the role of CGRP in migraine and attempts to highlight some possible outcomes from the ongoing anti-CGRP antibody trials.

Clinical trials update. 2013: year in review.

This section of Headache annually reviews the status of recently completed and ongoing major clinical trials involving common headache disorders. The review will focus on multicenter trials of new therapies, as well as novel formulations of previously approved therapeutics. Table 1 summarizes the major therapeutic headache trials that are ongoing at the present time, according to data obtained from both the "ClinicalTrials.Gov" website and from corporate press releases and presentations.

2010: year in review.

This section of Headache annually reviews the status of recently completed and ongoing clinical trials involving headache disorders. The review will focus on multicenter trials of new therapies as well as novel formulations of previously approved therapeutics. Table 1 summarizes major migraine therapeutic trials that have been completed recently, according to data obtained from the "ClinicalTrials.Gov" website as well as from corporate press releases. Table 2 summarizes the major therapeutic trials that are ongoing at the present time.

Neurogenic inflammation and migraine: implications for the therapeutics.

Significant recent advances in molecular pharmacology have elucidated the molecular pathways involved in neurogenic inflammation (NI). The release of tachykinins and endothelin-3 (ET-3) from trigeminal neurons induces dural vascular permeability and vasodilatation via activation of tachykinin receptor 1 (Tacr1) and endothelin receptor type B (Ednrb) on endothelial cells. Endothelial cell receptor stimulation results in cellular contraction, leading to plasma protein extravasation (PPE), which is the most recognized physiological hallmark of NI, and nitric oxide-induced vasodilatation. By contrast, the release of calcitonin gene-related peptide (CGRP) from trigeminal neurons--also a key physiological component of NI--does not affect vascular permeability but does induce neurogenic vasodilatation (NV) via the direct, (i.e., endothelium-independent) relaxation of vascular smooth muscle. The molecular pharmacology of NI is discussed within the context of migraine research and assesses the putative role of the two key physiological components of NI (i.e., PPE and NV) in migraine pathophysiology. The data indicate that the PPE component of NI plays no significant role in migraine but that NV is likely to be involved in migraine pathophysiology.

Analgesic safety and efficacy of diclofenac sodium softgels on postoperative third molar extraction pain.

PURPOSE: The purpose of this single-blind, placebo-controlled, 3-arm parallel, randomized study was to compare the analgesic efficacy and tolerability of a single dose of 100 mg diclofenac potassium (Cataflam; Novartis, Stein, Switzerland), 100 mg diclofenac sodium softgel, and placebo in patients experiencing moderate to severe postoperative pain after third molar extraction. PATIENTS AND METHODS: Seventy-five patients (67% female with a mean age of 23, age range 18 to 34.5 years) participated in the study following removal of at least 1 impacted mandibular third molar. Patients received a single dose of study medication when their postoperative pain reached a moderate or severe intensity. Analgesic efficacy measures included the time to meaningful pain relief measured using a stopwatch and time to rescue medication. Pain relief (PR) and Pain intensity (PI) ratings were recorded at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8, and 24 hours postdosing. Summary analgesic measures, including Summed Pain Relief Score (TOTPAR) and Summed Pain Intensity Differences (SPID), were calculated from the 0.25- to 6-hour responses. The time between pain relief and rescue and a global evaluation for the effectiveness of the study medications were recorded at the end of the study. Seven scheduled blood samples were collected from each patient for determining plasma concentrations of diclofenac anion. RESULTS: Both diclofenac sodium softgel and Cataflam were significantly more effective than placebo (P <.0001) for all summary analgesic measures. The average overall pain relief was substantially better from diclofenac sodium softgel than from Cataflam, but the difference was not statistically significant (P =.14). In patients taking diclofenac sodium softgel, 50% of the patients experienced a time to onset of analgesic activity within 18 minutes and the median analgesic duration was 5 hours (302 minutes). Fifty percent of the patients taking Cataflam had a time to onset of action within 38 minutes, and the median duration of analgesia was 4.5 hours (272 minutes). At the time of rescue drug administration or 6 hours, whichever was earlier, 72% of the patients given diclofenac sodium softgel rated the medication as a very good or excellent pain reliever, whereas only 45% of the patients taking Cataflam gave these ratings. No serious adverse events were observed in this study. The mean concentrations of diclofenac from the diclofenac sodium softgel formulation were significantly different from the Cataflam formulation. The mean C(max) for the softgel was almost twice that of Cataflam and C(max) was reached an hour earlier, on average. CONCLUSIONS: More diclofenac anion was absorbed at a quicker rate using the formulation diclofenac sodium softgel 100 mg than Cataflam. The softgel provided a very rapid onset of analgesic activity, a prolonged analgesic duration, and an acceptable side-effect profile in the postoperative third molar surgery pain model. In an acute pain situation, the rapid absorption of nonsteroidal anti-inflammatory drugs from a formulation like the Softgel may positively affect the time of onset and duration of inflammatory pain compared with other commercially available nonsteroidal anti-inflammatory drug formulations.

Migraine: a chronic sympathetic nervous system disorder.

OBJECTIVES: To determine the degree of diagnostic and clinical similarity between chronic sympathetic nervous system disorders and migraine. BACKGROUND: Migraine is an episodic syndrome consisting of a variety of clinical features that result from dysfunction of the sympathetic nervous system. During headache-free periods, migraineurs have a reduction in sympathetic function compared to nonmigraineurs. Sympathetic nervous system dysfunction is also the major feature of rare neurological disorders such as pure autonomic failure and multiple system atrophy. There are no known reports in the medical literature, however, comparing sympathetic nervous system function in individuals with migraine, pure autonomic failure, and multiple system atrophy. METHODS: A detailed review of the literature was performed to compare the results of a wide variety of diagnostic tests and clinical signs that have been described in these 3 heretofore unrelated disorders. RESULTS: The data indicate that migraine shares significant diagnostic and clinical features with both pure autonomic failure and multiple system atrophy, yet represents a distinct subtype of chronic sympathetic dysfunction. Migraine is most similar to pure autonomic failure in terms of reduced supine plasma norepinephrine levels, peripheral adrenergic receptor supersensitivity, and clinical symptomatology directly related to sympathetic nervous system dysfunction. The peripheral sympathetic nervous system dysfunction is much more severe in pure autonomic failure than in migraine. Migraine differs from both pure autonomic failure and multiple system atrophy in that migraineurs retain the ability, although suboptimal, to increase plasma norepinephrine levels following physiological stressors. CONCLUSIONS: The major finding of the present study is that migraine is a disorder of chronic sympathetic dysfunction, sharing many diagnostic and clinical characteristics with pure autonomic failure and multiple system atrophy. However, the sympathetic nervous system dysfunction in migraine differs from pure autonomic failure and multiple system atrophy in that occurs in an anatomically intact system. It is proposed that the sympathetic dysfunction in migraine relates to an imbalance of sympathetic co-transmitters. Specifically, it is suggested that a migraine attack is characterized by a relative depletion of sympathetic norepinephrine stores in conjunction with an increase in the release of other sympathetic cotransmitters such as dopamine, prostaglandins, adenosine triphosphate, and adenosine. An enhanced understanding of the sympathetic dysfunction in migraine may help to more effectively diagnose, prevent, and/or treat migraine and other types of headache.

Efficacy of diclofenac sodium softgel 100 mg with or without caffeine 100 mg in migraine without aura: a randomized, double-blind, crossover study.

OBJECTIVE: A phase II, randomized, double-blind, crossover study was designed to evaluate the efficacy of 100-mg diclofenac sodium softgel (formulated using ProSorb technology) with or without 100-mg caffeine versus placebo in migraineurs during migraine attacks. BACKGROUND: Diclofenac has been demonstrated to be an effective migraine treatment in several placebo-controlled studies. A rapidly absorbed softgel of diclofenac has been shown to be effective in the rapid relief of acute pain, and may have advantages in migraine treatment. In addition, caffeine has consistently been shown to increase both the efficacy and speed of onset of concurrently administered analgesics. The ability of caffeine to both enhance and accelerate analgesic effects has been documented with a variety of different medications (ie, aspirin, acetaminophen, ibuprofen, and ergotamine). METHODS: The 3-period crossover study was designed to compare diclofenac softgel 100 mg, diclofenac softgel 100 mg plus caffeine 100 mg, and placebo in the acute treatment of migraine. Subjects treated one moderate or severe attack with each study medication. The primary efficacy parameter was the percentage of subjects with headache relief at 60 minutes as defined by a reduction of headache severity from moderate or severe at baseline to absent or mild compared with placebo. Though the sample size estimate required that 72 subjects treat 3 separate attacks, 51 subjects treated 1 migraine attack, 44 treated 2 attacks, and 39 treated 3 attacks. Results.-In the placebo group, 6 (14%) of 43 subjects reported headache relief at 60 minutes versus 12 (27%) of 45 subjects in the diclofenac softgel group, and 19 (41%) of 46 subjects in the diclofenac softgel plus caffeine group. Differences were statistically significant for the diclofenac softgel plus caffeine group versus placebo (odds ratio, 4.2; 95% confidence interval, 1.3 to 13.7). Rescue medication was used by 27 (63%) of 43 subjects treated with placebo, 15 (33%) of 45 subjects treated with diclofenac softgel, and 14 (30%) of 46 subjects treated with diclofenac softgel plus caffeine. This result is highly statistically significant (chi22= 11.56, P=.003). Both the diclofenac plus caffeine (P <.03) and diclofenac only (P <.03) groups were significantly different from the placebo group in terms of the visual analog scale score at 60 minutes. CONCLUSIONS: The major finding of the present study is that diclofenac softgel plus caffeine produces statistically significant benefits relative to placebo at 60 minutes. Diclofenac softgel alone did not differ significantly from placebo, perhaps due to limits in sample size. Nonsignificant trends support the analgesic adjuvant benefit of caffeine when added to diclofenac softgels.

Glucose regulation in headache: implications for dietary management.

Dietary factors are frequently cited as 'triggers' of migraine and other types of headache. A review of the literature indicates that two specific dietary factors frequently induce headache: fasting and the relatively mild reactive hypoglycemia that can follow large carbohydrate ingestions. The maintenance of serum glucose levels to supply the energy for the nervous system is a primary responsibility of the sympathetic nervous system. It is suggested that migraine and other headache attacks may, at least in part, result from or be exacerbated by the sympathetic nervous system activation required to provide a steady supply of serum glucose for brain energy needs. Dietary patterns that provide a steady source of serum glucose, while minimizing serum glucose fluctuations, are hypothesized to help prevent and/or treat migraine and other headache attacks.