Attrition and discontinuation in amyotrophic lateral sclerosis clinical trials: a meta-analysis.

Objectives: Attrition due to adverse events and disease progression impacts the integrity and generalizability of clinical trials. The aim of this study is to provide evidence-based estimates of attrition for clinical trials in amyotrophic lateral sclerosis (ALS), and identify study-related predictors, through a comprehensive systematic review and meta-analysis.

Methods: We systematically reviewed the literature to identify all randomized, placebo-controlled clinical trials in ALS and determined the number of patients who discontinued the study per randomized arm.

Living systematic review and comprehensive network meta-analysis of ALS clinical trials: study protocol.

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurogenerative disease with no effective treatment to date. Despite numerous clinical trials, the majority of studies have been futile in their effort to significantly alter the course of the disease. However, these studies may still provide valuable information for identifying patient subgroups and generating new hypotheses for future research.

Do efficacy results obtained from randomized controlled trials translate to effectiveness data from observational studies for relapsing-remitting multiple sclerosis?

Background: Randomized controlled trials are considered the gold standard in regulatory decision making, as observational studies are known to have important methodological limitations. However, real-world evidence may be helpful in specific situations. This review investigates how the effect estimates obtained from randomized controlled trials compare to those obtained from observational studies, using drug therapy for relapsing-remitting multiple sclerosis as an example.

Exploring the Effectiveness of Self-Management Interventions in Type 2 Diabetes: A Systematic Review and Network Meta-Analysis.

Background: Chronic diseases are a leading cause of global morbidity and mortality. In response to this challenge, self-management interventions (SMIs) have emerged as an essential tool in improving patient outcomes. However, the diverse and complex nature of SMIs pose significant challenges in measuring their effectiveness.

Inconsistency identification in network meta-analysis via stochastic search variable selection.

The reliability of the results of network meta-analysis (NMA) lies in the plausibility of the key assumption of transitivity. This assumption implies that the effect modifiers' distribution is similar across treatment comparisons. Transitivity is statistically manifested through the consistency assumption which suggests that direct and indirect evidence are in agreement.

Development and Evaluation of a Simulation-Based Algorithm to Optimize the Planning of Interim Analyses for Clinical Trials in ALS.

Background And Objectives: Late-phase clinical trials for neurodegenerative diseases have a low probability of success. In this study, we introduce an algorithm that optimizes the planning of interim analyses for clinical trials in amyotrophic lateral sclerosis (ALS) to better use the time and resources available and minimize the exposure of patients to ineffective or harmful drugs.

Methods: A simulation-based algorithm was developed to determine the optimal interim analysis scheme by integrating prior knowledge about the success rate of ALS clinical trials with drug-specific information obtained in early-phase studies.

Graphical tools for visualizing the results of network meta-analysis of multicomponent interventions.

Network meta-analysis (NMA) is an established method for assessing the comparative efficacy and safety of competing interventions. It is often the case that we deal with interventions that consist of multiple, possibly interacting, components. Examples of interventions' components include characteristics of the intervention, mode (face-to-face, remotely etc.

Modeling Multicomponent Interventions in Network Meta-Analysis.

There is a rapid increase in trials assessing healthcare interventions consisting of a combination of drugs (polytherapies) or multiple components. In the latter type of interventions (also known as complex interventions), the aspect of complexity is of paramount importance. For example, nonpharmacological interventions, such as psychological interventions or self-management interventions, usually share common components that relate to the nature of intervention, who delivers it, or where and how.

Network Meta-Analysis Techniques for Synthesizing Prevention Science Evidence.

Network meta-analysis is a popular statistical technique for synthesizing evidence from studies comparing multiple interventions. Benefits of network meta-analysis, over more traditional pairwise meta-analysis approaches, include evaluating efficacy/safety of interventions within a single framework, increased precision, comparing pairs of interventions that have never been directly compared in a trial, and providing a hierarchy of interventions in terms of their effectiveness. Network meta-analysis is relatively underutilized in prevention science.

Innovating Clinical Trials for Amyotrophic Lateral Sclerosis: Challenging the Established Order.

Development of effective treatments for amyotrophic lateral sclerosis (ALS) has been hampered by disease heterogeneity, a limited understanding of underlying pathophysiology, and methodologic design challenges. We have evaluated 2 major themes in the design of pivotal, phase 3 clinical trials for ALS-(1) patient selection and (2) analytical strategy-and discussed potential solutions with the European Medicines Agency. Several design considerations were assessed using data from 5 placebo-controlled clinical trials (n = 988), 4 population-based cohorts (n = 5,100), and 2,436 placebo-allocated patients from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database.

Combined assessment of early and late-phase outcomes in orphan drug development.

In drug development programs, proof-of-concept Phase II clinical trials typically have a biomarker as a primary outcome, or an outcome that can be observed with relatively short follow-up. Subsequently, the Phase III clinical trials aim to demonstrate the treatment effect based on a clinical outcome that often needs a longer follow-up to be assessed. Early-phase outcomes or biomarkers are typically associated with late-phase outcomes and they are often included in Phase III trials.

An old friend who has overstayed their welcome: the ALSFRS-R total score as primary endpoint for ALS clinical trials.

The ALSFRS-R is limited by multidimensionality, which originates from the summation of various subscales. This prevents a direct comparison between patients with identical total scores. We aim to evaluate how multidimensionality affects the performance of the ALSFRS-R in clinical trials.

Endovascular treatment for basilar artery occlusion: A systematic review and meta-analysis.

Background And Purpose: Independent randomized controlled clinical trials (RCTs) have provided robust evidence for endovascular treatment (EVT) as the standard of care treatment for acute large vessel occlusions in the anterior circulation. We examined available studies specific to posterior cerebral circulation ischemic strokes to see if any conclusions can be drawn regarding EVT options.

Methods: We performed a systematic literature search to identify studies evaluating the safety and efficacy of EVT versus standard medical treatment for patients with acute basilar artery occlusion (BAO).

Prior distributions for variance parameters in a sparse-event meta-analysis of a few small trials.

In rare diseases, typically only a small number of patients are available for a randomized clinical trial. Nevertheless, it is not uncommon that more than one study is performed to evaluate a (new) treatment. Scarcity of available evidence makes it particularly valuable to pool the data in a meta-analysis.

Prevention of severe infectious complications after colorectal surgery using oral non-absorbable antimicrobial prophylaxis: results of a multicenter randomized placebo-controlled clinical trial.

Background: Surgical site infections (SSIs) are common complications after colorectal surgery. Oral non-absorbable antibiotic prophylaxis (OAP) can be administered preoperatively to reduce the risk of SSIs. Its efficacy without simultaneous mechanical cleaning is unknown.

Misuse of the sign test in narrative synthesis of evidence.

In narrative synthesis of evidence, it can be the case that the only quantitative measures available concerning the efficacy of an intervention is the direction of the effect, that is, whether it is positive or negative. In such situations, the sign test has been proposed in the literature and in recent Cochrane guidelines as a way to test whether the proportion of positive effects is favorable. I argue that the sign test is inappropriate in this context as the data are not generated according to the binomial distribution it employs.

A short, 8-week course of imiquimod 5% cream versus podophyllotoxin in the treatment of anogenital warts: A retrospective comparative cohort study.

Background: Studies comparing head-to-head treatment modalities for anogenital warts are lacking.

Aim: We sought to compare a short, 8-week course of imiquimod 5% cream to versus the standard 4 week course of podophyllotoxin in the treatment of anogenital warts and to assess factors that may affect response to treatment.

Methods: This was a retrospective cohort study.

Pharmacogenetic interactions in amyotrophic lateral sclerosis: a step closer to a cure?

Genetic mutations related to amyotrophic lateral sclerosis (ALS) act through distinct pathophysiological pathways, which may lead to varying treatment responses. Here we assess the genetic interaction between C9orf72, UNC13A, and MOBP with creatine and valproic acid treatment in two clinical trials. Genotypic data was available for 309 of the 338 participants (91.

Critical design considerations for time-to-event endpoints in amyotrophic lateral sclerosis clinical trials.

Background: Funding and resources for low prevalent neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) are limited, and optimising their use is vital for efficient drug development. In this study, we review the design assumptions for pivotal ALS clinical trials with time-to-event endpoints and provide optimised settings for future trials.

Methods: We extracted design settings from 13 completed placebo-controlled trials.

Neuropathy associated with immunoglobulin M monoclonal gammopathy: A combined sonographic and nerve conduction study.

Introduction: We assessed the specific sonographic pattern of structural nerve abnormalities in immunoglobulin M (IgM) neuropathy and disease controls.

Methods: We enrolled 106 incident patients-32 patients with IgM neuropathy, 42 treatment-naive patients with chronic inflammatory demyelinating polyneuropathy, and 32 patients with axonal neuropathies. All patients underwent standardized ancillary testing in addition to standardized sonography of the brachial plexus and the large arm and leg nerves bilaterally.

Effectiveness of a school food aid programme in improving household food insecurity; a cluster randomized trial.

Background: Aim of this cluster randomized trial was to examine the impact of a school feeding programme combining healthy meals provision and educational activities to reduce food insecurity.

Methods: Schools participating in the DIATROFI Program in Greece during the 2014-2015 school year were randomly allocated between a multicomponent intervention (MI: each student received a daily healthy meal along with educational actions; 28 schools) and an educational intervention (EI; 23 schools). A linear-mixed model was used to examine intervention effect on change from baseline in the food insecurity score, as measured via the Food Security Survey Module (FSSM).

Refining eligibility criteria for amyotrophic lateral sclerosis clinical trials.

Objective: To assess the effect of eligibility criteria on exclusion rates, generalizability, and outcome heterogeneity in amyotrophic lateral sclerosis (ALS) clinical trials and to assess the value of a risk-based inclusion criterion.

Methods: A literature search was performed to summarize the eligibility criteria of clinical trials. The extracted criteria were applied to an incidence cohort of 2,904 consecutive patients with ALS to quantify their effects on generalizability and outcome heterogeneity.

Nerve ultrasound: A reproducible diagnostic tool in peripheral neuropathy.

Objective: To determine interobserver variability of nerve ultrasound in peripheral neuropathy in a prospective, systematic, multicenter study.

Methods: We enrolled 20 patients with an acquired chronic demyelinating or axonal polyneuropathy and 10 healthy controls in 3 different centers. All participants underwent an extensive nerve ultrasound protocol, including cross-sectional area measurements of median, ulnar, fibular, tibial, and sural nerves, and brachial plexus.

Applicability and added value of novel methods to improve drug development in rare diseases.

Background: The ASTERIX project developed a number of novel methods suited to study small populations. The objective of this exercise was to evaluate the applicability and added value of novel methods to improve drug development in small populations, using real world drug development programmes as reported in European Public Assessment Reports.

Methods: The applicability and added value of thirteen novel methods developed within ASTERIX were evaluated using data from 26 European Public Assessment Reports (EPARs) for orphan medicinal products, representative of rare medical conditions as predefined through six clusters.