Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine

Background: Calcitonin gene–related peptide (CGRP) may have a causative role in migraine. We therefore hypothesized that a CGRP-receptor antagonist might be effective in the treatment of migraine attacks. Methods: In an international, multicenter, double-blind, randomized clinical trial of BIBN 4096 BS, a highly specific and potent nonpeptide CGRP-receptor antagonist, 126 patients with migraine received one of the following: placebo or 0.25, 0.5, 1, 2.5, 5, or 10 mg of BIBN 4096 BS intravenously over a period of 10 minutes. A group-sequential adaptive treatment-assignment design was used to minimize the number of patients exposed. Results: The 2.5-mg dose was selected, with a response rate of 66 percent, as compared with 27 percent for placebo (P=0.001). The BIBN 4096 BS group as a whole had a response rate of 60 percent. Significant superiority over placebo was also observed with respect to most secondary end points: the pain-free rate at 2 hours; the rate of sustained response over a period of 24 hours; the rate of recurrence of headache; improvement in nausea, photophobia, phonophobia, and functional capacity; and the time to meaningful relief. An effect was apparent after 30 minutes and increased over the next few hours. The overall rate of adverse events was 25 percent after the 2.5-mg dose of the drug and 20 percent for the BIBN 4096 BS group as a whole, as compared with 12 percent for placebo. The most frequent side effect was paresthesia. There were no serious adverse events. Conclusions: The CGRP antagonist BIBN 4096 BS was effective in treating acute attacks of migraine

Biomarker and Clinical Trial Design Support for Disease-Modifying Therapies: Report of a Survey of the EU/US: Alzheimer's Disease Task Force

BACKGROUND: Disease-modifying therapies are urgently needed for the treatment of Alzheimer’s disease (AD). The European Union/United States (EU/US) Task Force represents a broad range of stakeholders including biopharma industry personnel, academicians, and regulatory authorities. OBJECTIVES: The EU/US Task Force represents a community of knowledgeable individuals who can inform views of evidence supporting disease modification and the development of disease-modifying therapies (DMTs). We queried their attitudes toward clinical trial design and biomarkers in support of DMTs. DESIGN/SETTING/PARTICIANTS: A survey of members of the EU/US Alzheimer’s Disease Task Force was conducted. Ninety-three members (87%) responded. The details were analyzed to understand what clinical trial design and biomarker data support disease modification. MEASUREMENTS/RESULTS/CONCLUSIONS: Task Force members favored the parallel group design compared to delayed start or staggered withdrawal clinical trial designs to support disease modification. Amyloid biomarkers were regarded as providing mild support for disease modification while tau biomarkers were regarded as providing moderate support. Combinations of biomarkers, particularly combinations of tau and neurodegeneration, were regarded as providing moderate to marked support for disease modification and combinations of all three classes of biomarkers were regarded by a majority as providing marked support for disease modification. Task Force members considered that evidence derived from clinical trials and biomarkers supports clinical meaningfulness of an intervention, and when combined with a single clinical trial outcome, nearly all regarded the clinical trial design or biomarker evidence as supportive of disease modification. A minority considered biomarker evidence by itself as indicative of disease modification in prevention trials. Levels of evidence (A,B,C) were constructed based on these observations. CONCLUSION: The survey indicates the view of knowledgeable stakeholders regarding evidence derived from clinical trial design and biomarkers in support of disease modification. Results of this survey can assist in designing clinical trials of DMTs

Spatial and temporal trends in nutrient concentrations in the Belgian Continental area of the North Sea during the period 1993-2000

Statistical analysis of nutrient data obtained during 8 years of monitoring indicated strong seasonal and spatial variability, with highest concentrations in winter and significantly higher concentrations (on average >2 times higher) in the salinity zone S < 33 than in the salinity zone S = 33. In the North Sea ammonium concentrations significantly decreased from 1995 on (47% in zone S < 33 and 64% in zone S = 33), while for nitrate no significant decrease was observed in the zone S = 33. Despite a drastic reduction (50%) in the riverine inputs of phosphorus to the North Sea during the last decade, phosphate concentrations decreased only slightly in the zone S < 33 (<20%). This observation was somewhat similar to what happened with nitrate. Phosphate concentrations were generally low (mean: 0.75 µM; maximum: 2.4 µM) compared to the other dissolved nutrients. Mean nitrate concentrations were about 18 µM but some extreme concentrations, up to 140 µM were observed. Finally, the dissolved organic nitrogen (DON) content represented a major fraction of the total dissolved nitrogen (TDN) (median of 72% for all data), especially in the zone S = 33, but no significant spatial differences in the DON concentrations were found in the Belgian area of the North Sea

Pramipexole in patients with Parkinson's disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study

Objective: To compare the tremorlytic properties of pramipexole, a non-ergoline dopamine agonist to those of placebo as add on medication in patients with Parkinson's disease. Methods: Eighty four patients with early or advanced Parkinson's disease and marked, drug resistant tremor under a stable and optimised antiparkinsonian medication were included in a double blind, randomised, placebo controlled, multicentre study and assigned to add on treatment (7 week dose titration interval, 4 week maintenance period) with either pramipexole (n=44) or placebo (n=40) as adjunct. The primary end point was the absolute change in tremor score, defined as the sum of tremor related items (16, 20, 21) of the unified Parkinson's disease rating scale (UPDRS) in "on" periods. Secondary end points included the percentage change in tremor score, the absolute and percentage changes in long term EMG tremor registration, and the change in tremor self rating scales. Safety and tolerability were assessed on the basis of adverse events, laboratory tests, ECG, and vital signs. Results: Pramipexole was significantly superior to placebo with a difference between treatment groups in the mean absolute change in tremor score of -4.4 (95% confidence interval (95% CI) -6.2 to -2.5) (p<0.0001), corresponding to a difference in the mean percentage change of -34.7% in favour of pramipexole. The secondary end points were consistent with the significant change in tremor score and provided further evidence for the benefit of pramipexole compared with placebo. Long term EMG registration as an objective measure showed a difference in mean absolute change in tremor occurrence of -15.2% (95%CI -21.4 to -9.0) (p<0.0001), and a difference in the mean percentage change of -45.7% in favour of pramipexole. The treatment effects increased during dose titration and remained stable during the 4 week maintenance dose period until the end of the study. The average daily pramipexole dose during maintenance was 4.1 (SD 0.9) mg. Safety analysis showed an increased rate of fatigue, insomnia, nausea, abdominal pain, and headache under pramipexole, comparable with previous studies. Conclusion: Pramipexole proved to be an effective agent for patients with Parkinson's disease and drug resistant tremor

Social dysfunction in mood disorders and schizophrenia: Clinical modulators in four independent samples

Introduction: Social dysfunction is a common symptom of several neuropsychiatric disorders. However, only in the last few years research began to systematically investigate clinical aspects of this relevant outcome. Interestingly, its distribution and link with other clinical variables is still unclear. This study investigated social dysfunction in 4 different cohorts of patients affected by mood disorders and schizophrenia to evaluate 1) the degree of social dysfunction in these populations; 2) the associations among social dysfunction and socio-demographic and psychopathological features. Methods: Data from 4 independent studies (CATIE, GSRD ES1, ES2 and ES3, STAR*D, STEP-BD) were investigated. Behavioural and affective indicators of social dysfunction were derived and operationalized from scales or questionnaire items related to the interaction with relatives, friends and significant people in patients affected by schizophrenia (N = 765) and mood disorders (N = 2278 + 1954 + 1829). In particular the social dysfunction indicator was derived from Sheehan Disability Scale (SDS) for GSRD sample, from the Work and Social Adjustment Scale (WSAS) for STAR*D sample, from the Life-Range of Impaired Functioning Tool (LRIFT) for STEP-BD sample, and from the Quality of Life Scale (QOLS) for CATIE sample. The distribution of social dysfunction was described and association with socio-demographic and psychopathological characteristics were analysed. Results: Social dysfunction indicators showed a broad distribution in all samples investigated. Consistently across studies, social dysfunction was associated with higher psychopathological severity (all samples except CATIE) and suicide risk (GSRD ES1 and ES2, STAR*D, and STEP-BD) that explain up to 47% of the variance, but also to lower education level (GSRD ES2, STAR*D, CATIE, and STEP-BD), poorer professional/work status (GSRD ES2 and ES3, STAR*D, CATIE, and STEP-BD), marital status (STAR*D and CATIE), age (younger age in GSRD ES1 and STAR*D, older age in CATIE), higher BMI (GSRD ES2 and ES3, and STEP-BD), and smoking (GSRD ES2 and ES3). Conclusion: Our results demonstrated that a significant percentage of patients affected by both mood disorders and schizophrenia shows relevant social dysfunction. Social dysfunction is related, but not completely explained by psychopathological severity. In several patients, it tends to persist also during remission state. Socio-demographic and lifestyle factors were also found to play a role and should therefore be taken into consideration in further studies investigating social dysfunction