Multiple sclerosis, the measurement of disability and access to clinical trial data

Background: Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Nevertheless, MS trials have been getting steadily shorter despite the lack of a consensus definition for the most important clinical outcome - unremitting progression of disability. Methods: We have examined widely used surrogate markers of disability progression in MS within a unique database of individual patient data from the placebo arms of 31 randomised clinical trials. Findings: Definitions of treatment failure used in secondary progressive MS trials include much change unrelated to the target of unremitting disability. In relapsing-remitting MS, disability progression by treatment failure definitions was no more likely than similarly defined improvement for these disability surrogates. Existing definitions of disease progression in relapsing-remitting trials encompass random variation, measurement error and remitting relapses and appear not to measure unremitting disability. Interpretation: Clinical surrogates of unremitting disability used in relapsing -remitting trials cannot be validated. Trials have been too short and/or degrees of disability change too small to evaluate unremitting disability outcomes. Important implications for trial design and reinterpretation of existing trial results have emerged long after regulatory approval and widespread use of therapies in MS, highlighting the necessity of having primary trial data in the public domain

On-treatment follow-up in real-world studies of direct oral anticoagulants in atrial fibrillation: Association with treatment effects.

Background Numerous observational studies support the safety and effectiveness of the direct oral anticoagulants (DOAC) for stroke prevention in atrial fibrillation (AF), but these data are often limited to short duration of follow-up. We aimed to assess the length of on-treatment follow-up in the accumulated real-world evidence and the relationship between follow-up duration and estimates of DOAC effectiveness and safety. Methods We searched the literature for observational studies reporting comparative effectiveness and safety outcomes of DOACs versus warfarin. In random-effects meta-analyses, we assessed associations of specific DOACs vs warfarin for stroke/systematic embolism (SE) and major bleeding. In meta-regression analyses, we assessed the correlation between the reported on-treatment follow-up with the effect sizes for stroke/SE and major bleeding outcomes. Results In 45 eligible observational studies, the average on-treatment follow-up was <1 year for all DOACs. In meta-analyses, all DOACs showed significantly lower risks of stroke/SE, but only dabigatran and apixaban showed lower risks for major bleeding compared to warfarin. There was no correlation between follow-up duration and magnitude of stroke/SE reduction for any of the DOACs. Longer follow-up correlated with greater major bleeding reduction for dabigatran (p = 0.006) and rivaroxaban (p = 0.033) as compared to warfarin, but it correlated with smaller major bleeding reduction for apixaban (p = 0.004). Conclusions The numerous studies of DOAC effectiveness and safety in the routine AF practice pertain to short treatment follow-up. Study follow-up correlates significantly with DOAC-specific vs warfarin associations for major bleeding

Functional electrical stimulation for foot drop in multiple sclerosis: a systematic review and meta-analysis of the effect on gait speed

Objective: To review the efficacy of functional electrical stimulation (FES) used for foot drop in people with multiple sclerosis (pwMS) on gait speed in short and long walking performance tests. Data sources: Five databases (Cochrane Library, CINAHL, Embase, MEDLINE, Pubmed) and reference lists were searched. Study selection: Studies of both observational and experimental design where gait speed data in pwMS could be extracted were included. Data extraction: Data were independently extracted and recorded. Methodological quality was assessed using the Effective Public Health Practice Project (EPHPP) tool. Data synthesis: Nineteen studies (described in 20 articles) recruiting 490 pwMS were identified and rated moderate or weak, with none gaining a strong rating. All studies rated weak for blinding. Initial and ongoing orthotic and therapeutic effects were assessed with regards to the impact of FES on gait speed in short and long walking tests. Meta-analyses of the short walk tests revealed a significant initial orthotic effect (t = 2.14, p = 0.016) with a mean increase in gait speed of 0.05 meters per second (m/s) and ongoing orthotic effect (t = 2.81, p = 0.003) with a mean increase of 0.08m/s. There were no initial or ongoing effect on gait speed in long walk tests and no therapeutic effect on gait speed in either short or long walk tests. Conclusions: FES used for foot drop has a positive initial and ongoing effect on gait speed in short walking tests. Further fully-powered randomized controlled trials comparing FES with alternative treatments are required

Intravenous immunoglobulin in the treatment of primary trigeminal neuralgia refractory to carbamazepine: a study protocol[ISRCTN33042138]

BACKGROUND: We have recently reported successful treatment of patients with chronic pain syndromes using human pooled intravenous immunoglobulin (IVIG) in a prospective, open-label cohort study. A randomised, placebo controlled, double blinded study is needed to confirm these results. We chose to study patients with carbamazepine resistant primary Trigeminal Neuralgia (rpTN), as these had responded particularly well to IVIG. A protocol involving the use of IVIG in rpTN is complex for three reasons: 1. The effect of IVIG does not follow simple dose-response rules; 2. The response pattern of patients to IVIG was variable and ranged between no effect at all and pain free remission between two weeks and >1 year; 3. TN is characterized by extremely severe pain, for which operative intervention is (if temporarily) helpful in most patients. DESIGN: A placebo controlled, parallel, add-on model was developed and the primary outcome variable defined as the length of time during which patients remain in the study. Study groups are compared using Kaplan-Maier survival analysis. Patients record their response to treatment ("severe, moderate, slight, no pain"). The study coordinator monitors pain diaries. Severe or moderate pain of three days duration will result in termination of the study for that patient. CONCLUSIONS: This study design utilizes a method of survival analysis and is novel in chronic pain research. It allows for both early departure from the study and voluntary crossover upon non-response. It may be applicable to the analysis of IVIG efficacy in other chronic pain syndromes

Neonatal scrotal wall necrotizing fasciitis (Fournier gangrene): a case report

<p>Abstract</p> <p>Introduction</p> <p>Necrotizing fasciitis in neonates is rare and is associated with almost 50% mortality. Although more than 80 cases of neonates (under one month of age) with necrotizing fasciitis have been reported in the literature, only six of them are identified as originating in the scrotum.</p> <p>Case presentation</p> <p>We report the case of a four-week-old, full-term, otherwise-healthy Caucasian baby boy who presented with an ulcerating lesion of his scrotal wall. His scrotum was explored because of a provisional diagnosis of missed torsion of the testis. He was found to have necrotizing fasciitis of the scrotum. We were able to preserve the testis and excise the necrotic tissue, and with intravenous antibiotics there was a successful outcome.</p> <p>Conclusions</p> <p>Fournier gangrene is rarely considered as part of the differential diagnosis in the clinical management of the acute scrotum. However, all doctors who care for small babies must be aware of this serious condition and, if it is suspected, should not hesitate in referring the babies to a specialist pediatric surgical center immediately.</p

Reducing bias in open-label trials where blinded outcome assessment is not feasible: strategies from two randomised trials

Background Blinded outcome assessment is recommended in open-label trials to reduce bias, however it is not always feasible. It is therefore important to find other means of reducing bias in these scenarios. Methods We describe two randomised trials where blinded outcome assessment was not possible, and discuss the strategies used to reduce the possibility of bias. Results TRIGGER was an open-label cluster randomised trial whose primary outcome was further bleeding. Because of the cluster randomisation, all researchers in a hospital were aware of treatment allocation and so could not perform a blinded assessment. A blinded adjudication committee was also not feasible as it was impossible to compile relevant information to send to the committee in a blinded manner. Therefore, the definition of further bleeding was modified to exclude subjective aspects (such as whether symptoms like vomiting blood were severe enough to indicate the outcome had been met), leaving only objective aspects (the presence versus absence of active bleeding in the upper gastrointestinal tract confirmed by an internal examination). TAPPS was an open-label trial whose primary outcome was whether the patient was referred for a pleural drainage procedure. Allowing a blinded assessor to decide whether to refer the patient for a procedure was not feasible as many clinicians may be reluctant to enrol patients into the trial if they cannot be involved in their care during follow-up. Assessment by an adjudication committee was not possible, as the outcome either occurred or did not. Therefore, the decision pathway for procedure referral was modified. If a chest x-ray indicated that more than a third of the pleural space filled with fluid, the patient could be referred for a procedure; otherwise, the unblinded clinician was required to reach a consensus on referral with a blinded assessor. This process allowed the unblinded clinician to be involved in the patient’s care, while reducing the potential for bias. Conclusions When blinded outcome assessment is not possible, it may be useful to modify the outcome definition or method of assessment to reduce the risk of bias

Blinded Outcome Assessment Was Infrequently Used and Poorly Reported in Open Trials

Objective Unblinded outcome assessment can lead to biased estimates of treatment effect in randomised trials. We reviewed published trials to assess how often blinded assessment is used, and whether its use varies according to the type of outcome or assessor. Design and setting A review of parallel group, individually randomised phase III trials published in four general medical journals (BMJ, Journal of the American Medical Association, The Lancet, and New England Journal of Medicine) in 2010. Main outcome measures Whether assessment of the primary outcome was blinded, and whether this differed according to outcome or assessor type. Results We identified 258 eligible trials. Of these, 106 (41%) were reported as double-blind, and 152 (59%) as partially or fully open-label (that is, they included some groups who were unblinded, such as patients, those delivering the intervention, or those in charge of medical care). Of the 152 open trials, 125 required outcome assessment. Of these 125 trials, only 26% stated that outcome assessment was blinded; 51% gave no information on whether assessment was blinded or not. Furthermore, 18% of trials did not state who performed the assessment. The choice of outcome type (e.g. instrument measured, rated, or naturally occurring event) did not appear to influence whether blinded assessment was performed (range 24-32% for the most common outcome types). However, the choice of outcome assessor did influence blinding; independent assessors were blinded much more frequently (71%) than participant (5%) or physician (24%) assessors. Despite this, open trials did not use independent assessors any more frequently than double-blind trials (17% vs. 18% respectively). Conclusions Blinding of outcome assessors is infrequently used and poorly reported. Increased use of independent assessors could increase the frequency of blinded assessment

Genetic predisposition for sudden cardiac death in myocardial ischaemia: the Arrhythmia Genetics in the NEtherlandS study

Sudden cardiac death from ventricular fibrillation during myocardial infarction is a leading cause of total and cardiovascular mortality. This multifactorial, complex condition clusters in families, suggesting a substantial genetic cause. We carried out a genomewide association study (GWAS) for sudden cardiac death, in the AGNES (Arrhythmia Genetics in the Netherlands) population, consisting of patients with (cases) and without (controls) ventricular fibrillation during a first ST-elevation myocardial infarction. The most significant association was found at chromosome 21q21 (rs2824292; odds ratio = 1.78, 95% CI 1.47–2.13, P = 3.3 × 10−10), 98 kb proximal of the CXADR gene, encoding the Coxsackie and adenovirus receptor. This locus has not previously been implicated in arrhythmia susceptibility. Further research on the mechanism of this locus will ultimately provide novel insight into arrhythmia mechanisms in this condition

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD