Article

The PRO-ACT database: Design, initial analyses, and predictive features

October 2014
Neurology 83(19)

DOI:10.1212/WNL.0000000000000951

Source
PubMed

Authors:

James Berry

Glasgow Caledonian University

Neta Zach

Prize4Life

Show all 11 authorsHide

Objective: To pool data from completed amyotrophic lateral sclerosis (ALS) clinical trials and create an open-access resource that enables greater understanding of the phenotype and biology of ALS. Methods: Clinical trials data were pooled from 16 completed phase II/III ALS clinical trials and one observational study. Over 8 million de-identified longitudinally collected data points from over 8,600 individuals with ALS were standardized across trials and merged to create the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. This database includes demographics, family histories, and longitudinal clinical and laboratory data. Mixed effects models were used to describe the rate of disease progression measured by the Revised ALS Functional Rating Scale (ALSFRS-R) and vital capacity (VC). Cox regression models were used to describe survival data. Implementing Bonferroni correction, the critical p value for 15 different tests was p = 0.003. Results: The ALSFRS-R rate of decline was 1.02 (±2.3) points per month and the VC rate of decline was 2.24% of predicted (±6.9) per month. Higher levels of uric acid at trial entry were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.02). Higher levels of creatinine at baseline were predictive of a slower drop in ALSFRS-R (p = 0.01) and VC (p < 0.0001), and longer survival (p = 0.01). Finally, higher body mass index (BMI) at baseline was associated with longer survival (p < 0.0001). Conclusion: The PRO-ACT database is the largest publicly available repository of merged ALS clinical trials data. We report that baseline levels of creatinine and uric acid, as well as baseline BMI, are strong predictors of disease progression and survival.

Timing and impact of percutaneous endoscopic gastrostomy insertion in patients with amyotrophic lateral sclerosis: a comprehensive analysis

Article

Full-text available

Mar 2024

Dysphagia is common in amyotrophic lateral sclerosis (ALS) patients, often requiring percutaneous endoscopic gastrostomy (PEG) for enteral nutrition. We retrospectively analyzed data from 188 Korean patients with ALS who underwent PEG tube insertion at five-time points: symptom onset (t1), diagnosis (t2), recommended time for gastrostomy (t3), PEG insertion (t4), and one-year post-insertion (t5). The recommended time point for gastrostomy (T-rec for gastrostomy) was defined as the earlier time point between a weight loss of more than 10% and advanced dysphagia indicated by the ALSFRS-R swallowing subscore of 2 or less. The T-rec for gastrostomy was reached at 22 months after symptom onset, followed by PEG insertion at 30 months, resulting in an 8-month delay. During the delay, the ALSFRS-R declined most rapidly at 1.7 points/month, compared to 0.8 points/month from symptom onset to diagnosis, 0.7 points/month from diagnosis to T-rec for gastrostomy, and 0.6 points/month after the PEG insertion. It is crucial to discuss PEG insertion before significant weight loss or severe dysphagia occurs and minimize the delay between the recommended time for gastrostomy and the actual PEG insertion. A stratified and individualized multidisciplinary team approach with careful symptom monitoring and proactive management plans, including early PEG insertion, should be prioritized to improve patient outcomes.

The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity

Preprint

Full-text available

Sep 2024

Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1 G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, β-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1 G93A or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.

MENSA: A Multi-Event Network for Survival Analysis under Informative Censoring

Preprint

Full-text available

Sep 2024

Given an instance, a multi-event survival model predicts the time until that instance experiences each of several different events. These events are not mutually exclusive and there are often statistical dependencies between them. There are relatively few multi-event survival results, most focusing on producing a simple risk score, rather than the time-to-event itself. To overcome these issues, we introduce MENSA, a novel, deep learning approach for multi-event survival analysis that can jointly learn representations of the input covariates and the dependence structure between events. As a practical motivation for multi-event survival analysis, we consider the problem of predicting the time until a patient with amyotrophic lateral sclerosis (ALS) loses various physical functions, i.e., the ability to speak, swallow, write, or walk. When estimating when a patient is no longer able to swallow, our approach achieves an L1-Margin loss of 278.8 days, compared to 355.2 days when modeling each event separately. In addition, we also evaluate our approach in single-event and competing risk scenarios by modeling the censoring and event distributions as equal contributing factors in the optimization process, and show that our approach performs well across multiple benchmark datasets. The source code is available at: https://github.com/thecml/mensa

Comparison of Demographics: National Amyotrophic Lateral Sclerosis Registry and Clinical Trials Data

Article

Full-text available

Jul 2024

Objective To characterize the participant demographics in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database compared with the web-portal National Amyotrophic Lateral Sclerosis (ALS) Registry (the Registry). Methods Demographics and ALS symptom information were compared between the self-reported registrant data in the Registry web portal (2010–2021) and the latest available PRO-ACT data (updated August 2022), which is a collection of clinical trials data. Results Greater percentages of younger (≤ 59 years old) but smaller percentages of older (60 + years old) participants were represented in PRO-ACT compared to Registry. Enrollment for minority race groups was greater in the Registry portal data, but race information was largely missing/unknown in PRO-ACT database. Median age at the time of diagnosis and age at the time of symptom onset were significantly higher for Registry enrollees compared to the participants of PRO-ACT. Symptom onset sites were similarly reported, but duration between self-noted symptom onset and diagnosis was slight, but significantly longer for the Registry enrollees (11 vs. 9 months). Hispanic were as likely as non-Hispanic to participate in research studies, based on the Registry data. Conclusion There was a notable difference in the age distribution and minority representation of enrollees between the PRO-ACT and Registry study populations. Age distribution in the PRO-ACT database skewed to a younger and less diverse cohort. Despite the clinical heterogeneity and complex disease mechanism of ALS, identifying the underrepresented demographic niche in the PRO-ACT and Registry study populations can help improve patient participation and criteria for patient selection to enhance generalizability.

Temporal stratification of amyotrophic lateral sclerosis patients using disease progression patterns

Article

Full-text available

Jul 2024

Identifying groups of patients with similar disease progression patterns is key to understand disease heterogeneity, guide clinical decisions and improve patient care. In this paper, we propose a data-driven temporal stratification approach, ClusTric, combining triclustering and hierarchical clustering. The proposed approach enables the discovery of complex disease progression patterns not found by univariate temporal analyses. As a case study, we use Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease with a non-linear and heterogeneous disease progression. In this context, we applied ClusTric to stratify a hospital-based population (Lisbon ALS Clinic dataset) and validate it in a clinical trial population. The results unravelled four clinically relevant disease progression groups: slow progressors, moderate bulbar and spinal progressors, and fast progressors. We compared ClusTric with a state-of-the-art method, showing its effectiveness in capturing the heterogeneity of ALS disease progression in a lower number of clinically relevant progression groups.

Time-restricted ketogenic diet in amyotrophic lateral sclerosis: a case study

Article

Full-text available

Jan 2024

Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder. The most devastating variant is bulbar-onset ALS, which portends a median survival of 24 months from the onset of symptoms. Abundant evidence indicates that neuron metabolism and mitochondrial function are impaired in ALS. Metabolic strategies, particularly fasting and ketogenic diet protocols, alter neuron metabolism and mitochondria function in a manner that may mitigate the symptoms of this disorder. We report the case of a 64-year-old man with a 21-month history of progressive, deteriorating bulbar-onset ALS, with an associated pseudobulbar affect, who implemented a time-restricted ketogenic diet (TRKD) for 18 months. During this time, he improved in ALS-related function (7% improvement from baseline), forced expiratory volume (17% improvement), forced vital capacity (13% improvement), depression (normalized), stress levels (normalized), and quality of life (19% improvement), particularly fatigue (23% improvement). His swallowing impairment and neurocognitive status remained stable. Declines were measured in physical function, maximal inspiratory pressure, and maximal expiratory pressure. Weight loss was attenuated and no significant adverse effects occurred. This case study represents the first documented occurrence of a patient with ALS managed with either a fasting or ketogenic diet protocol, co-administered as a TRKD. We measured improved or stabilized ALS-related function, forced expiratory volume, forced vital capacity, swallowing, neurocognitive status, mood, and quality of life. Measurable declines were restricted to physical function, maximal inspiratory pressure, and maximal expiratory pressure. Now over 45 months since symptom onset, our patient remains functionally independent and dedicated to his TRKD.

Analysis of sodium phenylbutyrate and taurursodiol survival effect in ALS using external controls

Article

Full-text available

Oct 2023

Objective Sodium phenylbutyrate and taurursodiol (PB and TURSO) was evaluated in amyotrophic lateral sclerosis (ALS) in the CENTAUR trial encompassing randomized placebo‐controlled and open‐label extension phases. On intent‐to‐treat (ITT) survival analysis, median overall survival (OS) was 4.8 months longer and risk of death 36% lower in those originally randomized to an initial 6‐month double‐blind period of PB and TURSO versus placebo. To estimate PB and TURSO treatment effect without placebo‐to‐active crossover, we performed a post hoc survival analysis comparing PB and TURSO‐randomized participants from CENTAUR and a propensity score–matched, PB and TURSO‐naïve external control cohort from the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) database. Methods Clinical trial control participants from the PRO‐ACT database who met prespecified eligibility criteria were propensity score matched 1:1 with PB and TURSO‐randomized CENTAUR participants using prognostically significant covariates in ALS. Results Baseline characteristics including propensity score–matched covariates were generally well balanced between CENTAUR PB and TURSO ( n = 89) and PRO‐ACT external control ( n = 85) groups. Estimated median (IQR) OS was 23.54 (14.56–39.32) months in the CENTAUR PB and TURSO group and 13.15 (9.83–19.20) months in the PRO‐ACT external control group; hazard of death was 52% lower in the former group (hazard ratio, 0.48; 95% CI, 0.31–0.72; p = 0.00048). Interpretation This analysis suggests potentially greater survival benefit with PB and TURSO in ALS without placebo‐to‐active crossover than seen on ITT analysis in CENTAUR. Analyses using well‐matched external controls may provide additional context for evaluating survival effects in future ALS trials.

Describing and characterising variability in ALS disease progression

Article

Oct 2023

Background, Objectives: Decrease in the revised ALS Functional Rating Scale (ALSFRS-R) score is currently the most widely used measure of disease progression. However, it does not sufficiently encompass the heterogeneity of ALS. We describe a measure of variability in ALSFRS-R scores and demonstrate its utility in disease characterization. Methods: We used 5030 ALS clinical trial patients from the Pooled Resource Open-Access ALS Clinical Trials database to calculate variability in disease progression employing a novel measure and correlated variability with disease span. We characterized the more and less variable populations and designed a machine learning model that used clinical, laboratory and demographic data to predict class of variability. The model was validated with a holdout clinical trial dataset of 84 ALS patients (NCT00818389). Results: Greater variability in disease progression was indicative of longer disease span on the patient-level. The machine learning model was able to predict class of variability with accuracy of 60.1-72.7% across different time periods and yielded a set of predictors based on clinical, laboratory and demographic data. A reduced set of 16 predictors and the holdout dataset yielded similar accuracy. Discussion: This measure of variability is a significant determinant of disease span for fast-progressing patients. The predictors identified may shed light on pathophysiology of variability, with greater variability in fast-progressing patients possibly indicative of greater compensatory reinnervation and longer disease span. Increasing variability alongside decreasing rate of disease progression could be a future aim of trials for faster-progressing patients.

Lessons Learned and Recommendations from a SCOPE Spinal Cord Injury Neurorestorative Clinical Trials Update

Article

Full-text available

Mar 2025

The Spinal Cord Outcomes Partnership Endeavors presented a clinical trials update (CTU) in collaboration with the International Spinal Research Trust as a precourse to their annual meeting. Selected trials adhered to a priori considerations, prioritizing novelty and a focus on neurorestorative approaches. The sessions featured 13 speakers, covering 4 in-preparation, 4 in-progress, and 4 recently completed trials. In addition to in-person attendance, individuals worldwide viewed a live stream of the presentations. Approximately 1600 participants, comprising clinicians, researchers, industry stakeholders, foundations, and individuals with lived experiences, engaged in the CTU through both in-person and virtual channels. Presentations represented a variety of approaches, including drug, biological, and device-based therapeutics. This summary provides high-level summaries of the trials presented and the resulting discussions including lessons learned. Rather than recapitulating published data, the presentations and discussions emphasized the novelty and strengths of each trial, practical aspects of translation, and lessons learned. Throughout the day, several discussion themes surfaced. These included reflections on the suitability of outcome measures and the distinction between statistically or clinically meaningful effects and meaningful changes in quality of life. Additional topics included novel trial designs, selection of inclusion criteria, recognizing the indispensable role of rehabilitation, tailoring approaches to individual needs, the importance of integrating lived experience, and emphasizing the importance of establishing robust pre-clinical data packages before venturing into clinical translation. Importantly, strategic directives are summarized to address these challenges, focusing resources and efforts to steer forthcoming trials effectively.

Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale as a Novel Tool to Measure Disease Progression

Article

Full-text available

Jan 2025

Background: A valuable outcome measure to monitor amyotrophic lateral sclerosis (ALS) disease progression is crucial in clinical trials. Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is a novel questionnaire assessing ALS disability. Currently, there are no studies on the relationship between ROADS and ALS survival. This study explored the value of Chinese ROADS as a novel tool for measuring disease progression and the correlation between ROADS and ALS survival. Methods: A total of 170 ALS participants were included in this study. Clinical characteristics and baseline ROADS, ΔROADS, ALSFRS-R, and ΔFRS of patients were collected. Participants were followed for 18 months to assess time to tracheostomy and survival. Scales were collected every 3 to 6 months. We evaluated the association of baseline ROADS and ΔROADS with survival using Cox regression analyses. Linear mixed effects models were used to assess changes over time in ROADS and ALSFRS-R. Results: Multivariate Cox models confirmed that baseline ROADS positively correlated with ALS survival (HR = 0.95, p < 0.001), while baseline ΔROADS negatively correlated with survival (HR = 1.26, p < 0.001). Additionally, linear mixed effects models suggested that ROADS, similar to ALSFRS-R, declined significantly over time, but there was no significant difference between these two. Conclusions: Our study indicates that Chinese ROADS is strongly related to ALS survival. Changes in ROADS with disease progression are similar to those in ALSFRS-R. These findings support Chinese ROADS as a reliable outcome measure for clinical trials, potentially enhancing the dimension of evaluating treatment effectiveness in ALS trials.

Prognostic factors affecting ALS progression through disease tollgates

Article

Full-text available

Dec 2024
J NEUROL

Background and objectives Understanding factors affecting the timing of critical clinical events in ALS progression. Methods We captured ALS progression based on the timing of critical events (tollgates), by augmenting 6366 patients’ data from the PRO-ACT database with tollgate-passed information using classification. Time trajectories of passing ALS tollgates after the first visit were derived using Kaplan–Meier analyses. The significant prognostic factors were found using log-rank tests. Decision-tree-based classifications identified significant ALS phenotypes characterized by the list of body segments involved at the first visit. Results Standard (e.g., gender and onset type) and tollgate-related (phenotype and initial tollgate level) prognostic factors affect the timing of ALS tollgates. For instance, by the third year after the first visit, 80–100% of bulbar-onset patients vs. 43–48% of limb-onset patients, and 65–73% of females vs. 42–49% of males lost the ability to talk and started using a feeding tube. Compared to the standard factors, tollgate-related factors had a stronger effect on ALS progression. The initial impairment level significantly impacted subsequent ALS progression in a segment while affected segment combinations further characterized progression speed. For instance, patients with normal speech (Tollgate Level 0) at the first visit had less than a 10% likelihood of losing speech within a year, while for patients with Tollgate Level 1 (affected speech), this likelihood varied between 23 and 53% based on additional segment (leg) involvement. Conclusions Tollgate- and phenotype-related factors have a strong effect on the timing of ALS tollgates. All factors should be jointly considered to better characterize patient groups with different progression aggressiveness.

A validated score to predict risk of severe weight loss in amyotrophic lateral sclerosis

Preprint

Full-text available

Oct 2024

Background Severe weight loss is common in amyotrophic lateral sclerosis (ALS) and associated with shortened survival. The ability to predict risk of severe weight loss from baseline clinical variables would enable targeted nutritional support. Methods This retrospective longitudinal clinical cohort study used data from a multi-centre ALS clinical trials repository (N=3,289 patients) to develop time-to-≥10% weight loss Cox proportional hazards and random survival forest models, which were then tested in validation data from a multi-centre ALS clinical resource (N=298) and a referral-based regional clinic (N=104). Predictor variables were recorded at time of first weight measurement: age, gender, time from symptom onset, diagnostic latency, onset site, body mass index, forced vital capacity (FVC), and Revised ALS Functional Rating Scale (ALSFRS-R) subscores. The most important variables from the most accurate model were used to create a simple weight loss risk score. Results The random survival forest outperformed the Cox proportional hazards model in validation data (concordance index=0.67). The two most important variables from the random survival forest– ALSFRS-R bulbar subscore and FVC– were used to create a weight loss risk score that categorised patients using these two baseline clinical variables into low (score=0), intermediate (score=1) and high (score=2) risk of ≥10% weight loss. Analysis of weight loss risk score as a continuous parameter by Cox regression in validation data demonstrated a significantly increased risk of severe weight loss with each point increase (HR 1.83, 95% CI 1.44-2.32, p <0.01). Conclusions Weight loss in ALS is associated with a combination of bulbar and respiratory dysfunction. A simple score identifies risk of severe weight loss for potentially more targeted support.

Efficacy of Radicava® IV (intravenous edaravone) in subjects with differing trajectories of disease progression in amyotrophic lateral sclerosis: Use of a novel statistical approach for post hoc analysis of a pivotal phase 3 clinical trial

Article

Nov 2024

Predicting clinical events characterizing the progression of amyotrophic lateral sclerosis via machine learning approaches using routine visits data: a feasibility study

Article

Full-text available

Oct 2024
BMC MED INFORM DECIS

Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that results in death within a short time span (3-5 years). One of the major challenges in treating ALS is its highly heterogeneous disease progression and the lack of effective prognostic tools to forecast it. The main aim of this study was, then, to test the feasibility of predicting relevant clinical outcomes that characterize the progression of ALS with a two-year prediction horizon via artificial intelligence techniques using routine visits data. Methods Three classification problems were considered: predicting death (binary problem), predicting death or percutaneous endoscopic gastrostomy (PEG) (multiclass problem), and predicting death or non-invasive ventilation (NIV) (multiclass problem). Two supervised learning models, a logistic regression (LR) and a deep learning multilayer perceptron (MLP), were trained ensuring technical robustness and reproducibility. Moreover, to provide insights into model explainability and result interpretability, model coefficients for LR and Shapley values for both LR and MLP were considered to characterize the relationship between each variable and the outcome. Results On the one hand, predicting death was successful as both models yielded F1 scores and accuracy well above 0.7. The model explainability analysis performed for this outcome allowed for the understanding of how different methodological approaches consider the input variables when performing the prediction. On the other hand, predicting death alongside PEG or NIV proved to be much more challenging (F1 scores and accuracy in the 0.4-0.6 interval). Conclusions In conclusion, predicting death due to ALS proved to be feasible. However, predicting PEG or NIV in a multiclass fashion proved to be unfeasible with these data, regardless of the complexity of the methodological approach. The observed results suggest a potential ceiling on the amount of information extractable from the database, e.g., due to the intrinsic difficulty of the prediction tasks at hand, or to the absence of crucial predictors that are, however, not currently collected during routine practice.

The Potential of Disease Progression Modeling to Advance Clinical Development and Decision Making

Article

Full-text available

Oct 2024
CLIN PHARMACOL THER

While some model‐informed drug development frameworks are well recognized as enabling clinical trials, the value of disease progression modeling (DPM) in impacting medical product development has yet to be fully realized. The Clinical Trials Transformation Initiative assembled a diverse project team from across the patient, academic, regulatory, and industry sectors of practice to advance the use of DPM for decision making in clinical trials and medical product development. This team conducted a scoping review to explore current applications of DPM and convened a multi‐stakeholder expert meeting to discuss its value in medical product development. In this article, we present the scoping review and expert meeting output and propose key questions that medical product developers and regulators may use to inform clinical development strategy, appreciate the therapeutic context and endpoint selection, and optimize trial design with disease progression models. By expanding awareness of the unique value of DPM, this article does not aim to be technical in nature but rather aims to highlight the potential of DPM to improve the quality and efficiency of medical product development.

Next-gen spinal cord injury clinical trials: lessons learned and opportunities for future success

Article

Full-text available

Oct 2024

Despite promising basic science discoveries and a surge in clinical trials, the quest for effective treatments that restore neurological function after spinal cord injury lags on. While “failed” in a conventional sense, emerging solutions to longstanding challenges represent promising steps towards a future with effective interventions. In this personal view, we highlight clinical trials implementing new solutions and their impact on the field. Our perspective is that, ultimately, the integration of shared knowledge, adaptive designs, and a deeper understanding of the intricacies of spinal cord injury holds promise of unlocking of major breakthroughs, leading to improved outcomes for people with spinal cord injury.

Longitudinal analysis of glymphatic function in amyotrophic lateral sclerosis and primary lateral sclerosis

Article

Full-text available

Sep 2024
BRAIN

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons in the brain and spinal cord. Accumulation of misfolded proteins is central in the pathogenesis of ALS and the glymphatic system is emerging as a potential therapeutic target to reduce proteinopathy. Using diffusion tensor imaging analysis along the perivascular spaces (DTI-ALPS) to assess glymphatic function, we perform a longitudinal analysis of glymphatic function in ALS and compare it to a disorder in the motor neuron disease spectrum, primary lateral sclerosis (PLS). From a cohort of 45 participants from the Calgary site in the CALSNIC study (Canadian ALS Neuroimaging Consortium), including 18 ALS, 5 PLS and 22 control participants, DTI-ALPS was analyzed and correlated to clinical features (age, sex, disease presentation, disease severity and progression rate), and white matter hyperintensity (WMH) burden. This included longitudinal measurements at three time points, 4 months apart. The DTI-ALPS index was reduced in ALS participants compared to PLS and control participants across all three time points. There was no association with clinical factors, however the index tended to decline with advancing age. Our study suggests heterogeneity in glymphatic dysfunction in motor neuron diseases that may be related to the underlying pathogenesis.

A low molecular weight dextran sulphate, ILB, for the treatment of amyotrophic lateral sclerosis (ALS): An open-label, single-arm, single-centre, phase II trial

Article

Full-text available

Jul 2024
PLOS ONE

Background Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig´s disease, is a rare neurological condition and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management by multidisciplinary clinics. Patients and methods This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. EudraCT number. 2018-000668-28 Findings Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection. Interpretation Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS. Trial registration EudraCT: 2018-000668-28. clinicaltrials.gov: NCT03705390. This trial adheres to the principles of GCP in the design, conduct, recording and reporting of clinical trials as listed in part 2, “Conditions and Principles which apply to all Clinical Trials” under the header “Principles based on Articles 2 to 5 of the EU GCP Directive” in the Medicines for Human Use Clinical Trials Regulations (as amended in SI 2006/1928). For clarity, the study did not conform to all aspects of the International Conference on Harmonisation (ICH) E6 R2 Guidelines for GCP (also known as ‘ICH GCP’). Of note, we did not use an external database, perform 100% source data verification, and only primary outcome data were analysed in parallel by a second, independent statistician.

Individualized predictions for clinical milestone in amyotrophic lateral sclerosis: A multialgorithmic approach

Article

Full-text available

Jun 2024

Objective The phenotypic heterogeneity and complex disease trajectory complicate the ability to predict specific clinical milestone for individual patients with amyotrophic lateral sclerosis (ALS). Here we developed individualized prediction models to estimate the time to the loss of autonomy in swallowing function. Methods Utilizing the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, we built three models of distinct time-to-event prediction algorithms: accelerated failure time (AFT), cox proportional hazard (COX) and random survival forest (RSF) for an individualized risk assessment of the swallowing milestone. The target variable was defined as the time to a decline in the ALSFRS-R swallowing item score to 1 or below, indicating a need for supplementary tube feeding. Results Internal cross-validation revealed the median concordance index (C-index) of 0.851 (IQR, 0.842–0.859) for AFT, 0.850 (0.841–0.859) for COX and 0.846 (0.839–0.854) for RSF, and all models demonstrated good distributional calibration with predicted and observed event probabilities closely matched across different time intervals. For external validation with a registry dataset with characteristics different from PRO-ACT, the discriminative power was replicated with comparable C-indices for all models, whereas the calibration revealed a left-skewed distribution suggesting a bias towards overestimation of event probabilities in real-world data. While all models were effective at stratifying patients, the results of RSF model, unlike AFT and COX, did not match well with the KM curves of the corresponding risk groups, supporting the importance of nuanced understanding of data structure and algorithmic properties. Conclusion Our models are implemented into a web application which could be applied to individualized counselling, management and clinical trial design for gastrostomy intervention. Further studies for model optimization will advance personalized care in patients with ALS.

Ensemble-imbalance-based classification for amyotrophic lateral sclerosis prognostic prediction: identifying short-survival patients at diagnosis

Article

Full-text available

Mar 2024
BMC MED INFORM DECIS

Prognosticating Amyotrophic Lateral Sclerosis (ALS) presents a formidable challenge due to patients exhibiting different onset sites, progression rates, and survival times. In this study, we have developed and evaluated Machine Learning (ML) algorithms that integrate Ensemble and Imbalance Learning techniques to classify patients into Short and Non-Short survival groups based on data collected during diagnosis. We aimed to identify individuals at high risk of mortality within 24 months of symptom onset through analysis of patient data commonly encountered in daily clinical practice. Our Ensemble-Imbalance approach underwent evaluation employing six ML algorithms as base classifiers. Remarkably, our results outperformed those of individual algorithms, achieving a Balanced Accuracy of 88% and a Sensitivity of 96%. Additionally, we used the Shapley Additive Explanations framework to elucidate the decision-making process of the top-performing model, pinpointing the most important features and their correlations with the target prediction. Furthermore, we presented helpful tools to visualize and compare patient similarities, offering valuable insights. Confirming the obtained results, our approach could aid physicians in devising personalized treatment plans at the time of diagnosis or serve as an inclusion/exclusion criterion in clinical trials. Supplementary Information The online version contains supplementary material available at 10.1186/s12911-024-02484-5.

Predicting amyotrophic lateral sclerosis (ALS) progression with machine learning

Article

Dec 2023

Objective: To predict ALS progression with varying observation and prediction window lengths, using machine learning (ML). Methods: We used demographic, clinical, and laboratory parameters from 5030 patients in the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database to model ALS disease progression as fast (at least 1.5 points decline in ALS Functional Rating Scale-Revised (ALSFRS-R) per month) or non-fast, using Extreme Gradient Boosting (XGBoost) and Bayesian Long Short Term Memory (BLSTM). XGBoost identified predictors of progression while BLSTM provided a confidence level for each prediction. Results: ML models achieved area under receiver-operating-characteristics curve (AUROC) of 0.570-0.748 and were non-inferior to clinician assessments. Performance was similar with observation lengths of a single visit, 3, 6, or 12 months and on a holdout validation dataset, but was better for longer prediction lengths. 21 important predictors were identified, with the top 3 being days since disease onset, past ALSFRS-R and forced vital capacity. Nonstandard predictors included phosphorus, chloride and albumin. BLSTM demonstrated higher performance for the samples about which it was most confident. Patient screening by models may reduce hypothetical Phase II/III clinical trial sizes by 18.3%. Conclusion: Similar accuracies across ML models using different observation lengths suggest that a clinical trial observation period could be shortened to a single visit and clinical trial sizes reduced. Confidence levels provided by BLSTM gave additional information on the trustworthiness of predictions, which could aid decision-making. The identified predictors of ALS progression are potential biomarkers and therapeutic targets for further research.

Epidemiological Surveillance of Amyotrophic Lateral Sclerosis: A Review

Preprint

Nov 2023

Background: Registries and clinical databases are important tools to systematically record and collect information about individuals with rare diseases and to monitor disease patterns in populations. Through a review of the published literature on strategies used for surveillance of Amyotrophic Lateral Sclerosis (ALS), our objective was to better delineate the varied approaches used to monitor ALS at a population level. Further, we sought to determine the potential of registries to enhance knowledge on the epidemiology of ALS using a case study comparing epidemiological outputs from registries in the United States, United Kingdom, and Italy. Summary: We searched Medline, Embase, Global Health, PsycInfo, Cochrane Library, and CINAHL identifying articles published between January 1st, 2010, and May 12th, 2021. Studies describing population registries, cohorts of individuals with ALS, or large-scale studies aimed at systematically identifying people with ALS, were eligible for inclusion. 1,447 publications were found, of which 141 were selected for full text review, and 41 of those were selected for data extraction. We identified ALS registries and pertinent databases in 4 continents (North America, Europe, Asia, and Oceania). Stated objectives of the registries/databases shaped their framework, methodology, and follow-up. The US National Registry demonstrates substantial research outputs and methodological strengths, producing many descriptive epidemiological outputs (n=5 studies) and several methodological papers (n=12 studies). The UK and Italy overall each produced a similar number of studies (albeit with fewer methodological papers), across several different registries and regions. Key Messages: Due to challenges inherent to the surveillance of rare diseases, registries are a vital tool in determining and assessing the global impact of ALS. Nevertheless, the development and implementation of registries is not feasible everywhere in the world. There are advantages and drawbacks to structuring registries at a national or regional level, often dictated by funding availability, resources and health care infrastructure, and research objectives. To fully assess the epidemiological burden of ALS globally, collaborative initiatives are needed to fill gaps in knowledge, and there is a critical need to harmonize and optimize the development, collection, and sharing of data across registries.

A low molecular weight dextran sulphate, ILB®, for the treatment of amyotrophic lateral sclerosis (ALS): an open-label, single-arm, single-centre, phase II trial

Preprint

Full-text available

Aug 2023

Background Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is a rare neurological disease and is the most common motor neurone disease. It is a fatal disease with specific loss of motor neurons in the spinal cord, brain stem, and motor cortex leading to progressive paralysis and usually death within five years of diagnosis. There remains no cure for ALS, and management is focused on a combination of neuroprotective medication, respiratory support, and management be multidisciplinary clinics. Patients and Methods This prospective, single-arm, open-label phase II clinical trial of sustained weekly administration of 2 mg/kg ILB® (a low-molecular weight dextran sulphate) was conducted in a single UK hospital. Eligible patients were at least 18 years and had a definite diagnosis of ALS according to El Escorial Criteria. The co-primary outcomes were safety, tolerability, and quantity of ILB® administered. All evaluable patients were analysed in a modified intention-to-treat analysis. EudraCT number. 2018-000668-28 Findings Between 18-Apr-2019 and 27-Mar-2020, 11 patients were recruited and treated for up to 38 weeks. There were no treatment terminations or withdrawals. One serious adverse event was reported, which was not related to ILB® and resolved without sequalae. 270 mild/moderate adverse events were reported with no intolerable events occurring during the trial. The total number of ILB® treatments administered per patient ranged from 4 to 38, with a cumulative dose ranging from 745 to 6668 mg. As a result of the COVID-19 pandemic and the high-risk status of study participants, recruitment and treatment was suspended early in Mar-2020. At the long-term follow-up, three patients had died after the trial was halted, between 53 and 62 weeks after their final ILB® injection. Interpretation Long-term weekly ILB® injections of 2 mg/kg was well tolerated and had an acceptable safety profile in patients with ALS.

Interaction of sex and onset site on the disease trajectory of amyotrophic lateral sclerosis

Article

Full-text available

Aug 2023
J NEUROL

Background: Studies showed the impact of sex and onset site (spinal or bulbar) on disease onset and survival in ALS. However, they mainly result from cross-sectional or survival analysis, and the interaction of sex and onset site on the different proxies of disease trajectory has not been fully investigated. Methods: We selected all patients with repeated observations in the PRO-ACT database. We divided them into four groups depending on their sex and onset site. We estimated a multivariate disease progression model, named ALS Course Map, to investigate the combined temporal changes of the four sub-scores of the revised ALS functional rating scale (ALSFRSr), the forced vital capacity (FVC), and the body mass index (BMI). We then compared the progression rate, the estimated age at onset, and the relative progression of the outcomes across each group. Results: We included 1438 patients from the PRO-ACT database. They were 51% men with spinal onset, 12% men with bulbar onset, 26% women with spinal onset, and 11% women with bulbar onset. We showed a significant influence of both sex and onset site on the ALSFRSr progression. The BMI decreased 8.9 months earlier (95% CI [3.9, 13.8]) in women than men, after correction for the onset site. Among patients with bulbar onset, FVC was impaired 2.6 months earlier (95% CI [0.6, 4.6]) in women. Conclusion: Using a multivariable disease modelling approach, we showed that sex and onset site are important drivers of the progression of motor function, BMI, and FVC decline.

Akt Activation With IPL344 Treatment for Amyotrophic Lateral Sclerosis: First in Human, Open‐Label Study

Article

Mar 2025
MUSCLE NERVE

Introduction/Aims Akt intracellular signal transduction pathway dysfunction has been reported in people with amyotrophic lateral sclerosis (ALS) providing a novel target for intervention in this devastating progressive disease. This first‐in‐human study evaluated the safety, tolerability, and preliminary efficacy of the Akt pathway activator, IPL344, in people with ALS. Methods Nine participants with ALS and a progression rate > 0.55 points/month on the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS‐R) received open‐label IPL344 treatment (once‐daily) for up to 36 months. Safety was assessed through adverse event (AE) reporting. Plasma neurofilament light chain (NfL) concentrations were measured before and after treatment. Clinical outcomes were compared to historical data. Results The mean ± SD duration of IPL344 follow‐up was 14.0 ± 12.5 months. One participant developed drug hypersensitivity, two had central venous catheter‐related AEs, and two had serious pneumonia AEs. The unadjusted mean ± SE slope of decline in ALSFRS‐R was −0.53 ± 0.15 (48% slower progression vs. historical controls, p = 0.028). Adjustment for disease stage and rate‐indicating covariates indicated a 64% slower ALSFRS‐R progression ( p = 0.034), with increased rather than reduced body weight ( p = 0.02). Eight of nine IPL344‐treated participants had a significantly improved slope compared to the median slope of a matched control group ( p = 0.04). Plasma NfL concentrations were lowered by 27% ( n = 6). Unadjusted median survival for participants in the IPL344 group was 43.4 months [95% CI: 20.5, NA] compared with 19.1 months [17.4, 23.0] in the historical control group. Discussion These preliminary data indicate that IPL344 was safe and well‐tolerated, and possibly effective. Our findings may merit further investigation in a larger placebo‐controlled clinical trial.

The Amyotrophic Lateral Sclerosis Multidisciplinary Clinic: Broke but Not Broken

Article

Jan 2025
NEUROLOGY

Frequency of orthostatic hypotension in the Pooled Resource Open-Access ALS Clinical Trials database

Article

Full-text available

Jan 2025

Purpose To explore the frequency of orthostatic hypotension (OH) in a large sample of amyotrophic lateral sclerosis patients (ALS). Methods From the PRO-ACT database, data of 1,240 ALS patients were analyzed, focusing on blood pressure and heart rate before and after standing. OH was defined as a drop in systolic/diastolic blood pressure > 20/10 mm Hg within 3 min of standing. Neurogenic OH was diagnosed when the heart rate increase was below 15 bpm in patients not taking medications that could affect this response. Results At baseline, 138 (11.1%) patients showed OH, 76.1% of whom had neurogenic OH. At follow-up, 163 patients (13.1%) had OH, 71.2% with neurogenic OH. Only 22.5% of the patients with OH at baseline had OH at follow-up. Conclusion In a large sample of ALS patients, OH occurred in 11–13%, pointing to a subgroup that might require special care to avoid related complications.

Motor Neuron Disorders

Chapter

Jan 2025

Disorders of motor neurons include amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), spinobulbar muscular atrophy (SBMA, or Kennedy’s disease), spinal muscular atrophy (SMA), poliomyelitis, and monomelic amyotrophy (Hirayama disease). Although the pathology, genetics, and clinical features of ALS are well-established, neither a unifying etiology nor a highly effective treatment have been identified. Because of this, as well as its inexorable progression and numerous clinical manifestations, the management of ALS currently requires multidisciplinary care. People living with ALS, PLS and SBMA have overlapping needs and are commonly cared for in the same multidisciplinary setting. The differential diagnosis of ALS, including conditions that can mimic ALS, are discussed as well.

Model-based Recursive Partitioning for Subgroup Analyses

Preprint

May 2016

The identification of patient subgroups with differential treatment effects is the first step towards individualised treatments. A current draft guideline by the EMA discusses potentials and problems in subgroup analyses and formulated challenges to the development of appropriate statistical procedures for the data-driven identification of patient subgroups. We introduce model-based recursive partitioning as a procedure for the automated detection of patient subgroups that are identifiable by predictive factors. The method starts with a model for the overall treatment effect as defined for the primary analysis in the study protocol and uses measures for detecting parameter instabilities in this treatment effect. The procedure produces a segmented model with differential treatment parameters corresponding to each patient subgroup. The subgroups are linked to predictive factors by means of a decision tree. The method is applied to the search for subgroups of patients suffering from amyotrophic lateral sclerosis that differ with respect to their Riluzole treatment effect, the only currently approved drug for this disease.

Routine blood biochemical biomarkers in amyotrophic lateral sclerosis: Systematic review and cohort analysis

Article

Dec 2024

Introduction: Blood biochemical biomarkers, including urate, creatinine, albumin, and creatine kinase, have been shown to be useful in ALS. To provide further information about the roles of these four biomarkers roles we performed a systematic review. In addition, we also performed a new study of the role of these biomarkers in predicting survival, using data from our local ALS cohort. Methods: (1) Using established databases and other sources, we searched for papers about the use of urate, creatinine, albumin, and creatine kinase as biomarkers in ALS. Included articles were reviewed for information about biomarker levels in ALS and controls, association with markers of functional decline, and survival. (2) For our local ALS cohort, we performed survival analysis, Cox-proportionate-hazard ratio and ROC curves to investigate the use of these biomarkers in predicting survival. Results: (1) For systematic review, 104 papers were included. There was some variability in the findings. For urate, there was evidence of decreased levels in ALS, with higher levels associated ith longer survival. For creatinine, there was evidence of decreased levels in ALS, and higher levels correlated with longer survival. For albumin, some reports of reduced levels in ALS, but no consistent association with survival. For creatine kinase, some reports of increased levels in ALS, with inconsistent association with survival. (2) For the local ALS cohort there was evidence that urate and creatinine were associated with survival, but no significant association with survival. There was less evidence for albumin and CK. Discussion: This study provides support for further studies of these readily available biochemical measurement as bioamerkers in ALS.

The Long Path to Usable AI

Chapter

May 2024

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

Article

Full-text available

Nov 2024

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. Additionally, synthesising evidence from these studies may help overcome the limitations of individual studies. Network meta-analysis may refine the assessment of efficacy in specific patient subgroups, evaluate intervention characteristics such as mode of administration or biological mechanisms of action, and rank order promising therapeutic areas of interest. Therefore, we aim to synthesise the available evidence from ALS clinical trials. Methods and analysis We will conduct a systematic review to identify all clinical trials that assessed disease-modifying pharmaceutical therapies, cell therapies, or supplements in patients with ALS. Outcomes of interest are clinical disease progression outcomes and survival. We will conduct this search in the period Q4 2024 in three databases: PubMed, Embase and ClinicalTrials.gov for studies from 1999 to 2023. Individual patient data and aggregate data will be collected and subsequentially synthesised in meta-analytical models. The final model will be presented as an open-source web application with biannual updates of the underlying data, thereby providing a ‘living’ overview of the ALS clinical trial landscape. Ethics and dissemination No ethics approvals are required. Findings will be presented at relevant conferences and submitted to peer-reviewed journals. Data will be stored anonymously in secure repositories.

Spanish adaptation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS)

Article

Oct 2024

Amyotrophic lateral sclerosis (ALS) is characterized functional decline, traditionally measured by the ALS Functional Rating Scale-Revised (ALSFRS-R). The Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) is an alternative comprehensive, detailed functional disability measure for people with ALS (pwALS), not yet translated to Spanish. The aim of this study was to translate and validate the Spanish ROADS. 53 Spanish speaking pwALS were recruited. They completed the ALSFRS-R and Spanish ROADS. Reliability (internal consistency, intra-class correlation) and validity (ALSFRS-R total and item-total correlations) were determined. The Spanish ROADS internal consistency reliability was excellent (Cronbach's standardized alpha = 0.94), the test-retest reliability intra-class correlation value was 0.93. There was a strong significant correlation between the Spanish ROADS and ALSFRS-R totals (rs(52) = .89, p < .001). Additionally, the ALSFRS-R subscales and ROADS items correlations showed domain-to-item specific expected significant correlations. The Spanish ROADS is a psychometrically robust, valid and reliable measure for quantifying functional disability for pwALS.

White matter integrity mediated the effect of plasma uric acid levels on cognitive function in ALS patients

Preprint

Full-text available

Oct 2024

Objective: To investigate the association between plasma uric acid levels and white matter microstructural changes in amyotrophic lateral sclerosis (ALS) patients and to explore the potential mediating role of white matter microstructural changes in the protective effect of plasma uric acid on cognitive function in ALS patients. Methods: 73 right-handed ALS patients were recruited for this study. Plasma uric acid levels were measured, diffusion tensor imaging scans were performed to assess white matter integrity, and cognition was evaluated using the Edinburgh Cognitive and Behavioral Screen. The relationships among plasma uric acid, white matter integrity, and cognitive function were examined through multivariate linear regression analysis. Additionally, mediation analysis was performed to investigate whether white matter integrity mediated the relationship between uric acid levels and cognitive function. Results: The findings revealed a positive correlation between plasma uric acid levels and extensive preservation of white matter microstructural in various regions, including the cerebellar, internal capsule, and frontotemporal lobe bundles among ALS patients. Mediation analysis indicated that fractional anisotropy in the hippocampal portion of the cingulum fully mediated the effects of plasma uric acid level on global cognitive function and executive function in ALS patients. Interpretation: Our results suggested that elevated plasma uric acid may preserve the integrity of white matter microstructure in ALS patients. Furthermore, we have identified evidence supporting the mediating influence of the hippocampal portion of the cingulum in linking plasma uric acid levels to cognitive function among ALS patients.

TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive amyotrophic lateral sclerosis through a haploinsufficiency mechanism

Article

Aug 2024

Background TBK1 variants have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia spectrum disorder. The current study elucidated the clinical and molecular genetic features of a novel TBK1 variant identified in a patient with young-onset, rapidly progressive ALS. Methods The coding regions of TBK1 , SOD1 , TARDBP , and FUS were genetically analyzed using Sanger sequencing. Repeat-primed PCR was used to survey the GGGGCC repeat in C9ORF72 . The study participant underwent a comprehensive clinical evaluation. The functional effects of the TBK1 variant were analyzed through in vitro transfection studies. Results We identified a novel frameshift truncating TBK1 variant, c.456_457delGT (p.Y153Qfs*9), in a man with ALS. The disease initially manifested as right hand weakness at the age of 39 years but progressed rapidly, with the revised ALS Functional Rating Scale score declining at an average monthly rate of 1.92 points in the first year after diagnosis. The patient had no cognitive dysfunction. However, Technetium-99m single photon emission tomography indicated hypoperfusion in his bilateral superior and middle frontal cortices. In vitro studies revealed that the p.Y153Qfs*9 variant resulted in a truncated TBK1 protein product, reduced TBK1 protein expression, loss of kinase function, reduced interaction with optineurin, and impaired dimerization. Conclusion The heterozygous TBK1 p.Y153Qfs*9 variant may be associated with young-onset, rapidly progressive ALS through a haploinsufficiency mechanism.

A Model-Based Economic Evaluation of Hypothetical Treatments for Amyotrophic Lateral Sclerosis in the UK: Implications for Pricing of New and Emerging Health Technologies

Article

May 2024
PHARMACOECONOMICS

Amyotrophic lateral sclerosis (ALS) is a devastating disease which leads to loss of muscle function and paralysis. Historically, clinical drug development has been unsuccessful, but promising disease-modifying therapies (DMTs) may be on the horizon. The aims of this study were to estimate survival, quality-adjusted life-years (QALYs) and costs under current care, and to explore the conditions under which new therapies might be considered cost effective. We developed a health economic model to evaluate the cost effectiveness of future ALS treatments from a UK National Health Service and Personal Social Services perspective over a lifetime horizon using data from the ALS-CarE study. Costs were valued at 2021/22 prices. Two hypothetical interventions were evaluated: a DMT which delays progression and mortality, and a symptomatic therapy which improves utility only. Sensitivity analysis was conducted to identify key drivers of cost effectiveness. Starting from King’s stage 2, patients receiving current care accrue an estimated 2.27 life-years, 0.75 QALYs and lifetime costs of £68,047. Assuming a 50% reduction in progression rates and a UK-converted estimate of the price of edaravone, the incremental cost-effectiveness ratio for a new DMT versus current care is likely to exceed £735,000 per QALY gained. Symptomatic therapies may be more likely to achieve acceptable levels of cost effectiveness. Regardless of efficacy, DMTs may struggle to demonstrate cost effectiveness, even at a low price. The cost effectiveness of DMTs is likely to be strongly influenced by drug price, the magnitude and durability of relative treatment effects, treatment starting/stopping rules and any additional utility benefits over current care.

Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Article

May 2024
LANCET NEUROL

Sex Differences in Amyotrophic Lateral Sclerosis Survival and Progression: A Multidimensional Analysis

Article

Apr 2024
ANN NEUROL

Objective To investigate sex‐related differences in amyotrophic lateral sclerosis (ALS) prognosis and their contributing factors. Methods Our primary cohort was the Piemonte and Aosta Register for ALS (PARALS); the Pooled Resource Open‐Access ALS Clinical Trials (PRO‐ACT) and the Answer ALS databases were used for validation. Survival analyses were conducted accounting for age and onset site. The roles of forced vital capacity and weight decline were explored through a causal mediation analysis. Survival and disease progression rates were also evaluated after propensity score matching. Results The PARALS cohort included 1,890 individuals (44.8% women). Men showed shorter survival when stratified by onset site (spinal onset HR 1.20, 95% CI 1.00–1.44, p = 0.0439; bulbar onset HR 1.36, 95% CI 1.09–1.70, p = 0.006917), although women had a steeper functional decline (+0.10 ALSFRS‐R points/month, 95% CI 0.07–0.15, p < 0.00001) regardless of onset site. Instead, men showed worse respiratory decline (−4.2 forced vital capacity%/month, 95% CI −6.3 to −2.2, p < 0.0001) and faster weight loss (−0.15 kg/month, 95% CI −0.25 to −0.05, p = 0.0030). Causal mediation analysis showed that respiratory function and weight loss were pivotal in sex‐related survival differences. Analysis of patients from PRO‐ACT ( n = 1,394, 40.9% women) and Answer ALS ( n = 849, 37.2% women) confirmed these trends. Interpretation The shorter survival in men is linked to worse respiratory function and weight loss rather than a faster disease progression. These findings emphasize the importance of considering sex‐specific factors in understanding ALS pathophysiology and designing tailored therapeutic strategies. ANN NEUROL 2024

ALSFRS-R decline rate prior to baseline is not useful for stratifying subsequent progression of functional decline

Article

Feb 2024

Objective: One of the difficulties in developing a novel drug for patients with amyotrophic lateral sclerosis (ALS) is the significant variation in the clinical course. To control this variation, a 12-week run-in period is used in some clinical trials. Based on the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) change during the run-in period, only moderate progressors are selected in some clinical trials. Some reports showed that the ALSFRS-R progression rate was associated with survival. However, it is unclear whether the ALSFRS-R change in the run-in period is a useful prognostic factor of the ALSFRS-R change from baseline. In addition, we explore the inclusion criteria that could control the variability in ALS-function progression without setting a run-in period. Methods: We utilized the Japanese and US ALS registry databases (JaCALS and PRO-ACT). Patients were classified into three populations (rapid, moderate, and slow progressors) based on the ALSFRS-R change prior to baseline. We also classified patients into three prognostic populations based on the ALSFRS-R change from baseline. We confirmed whether each of the three populations were matched with their respective three prognostic populations. Results: Our data showed that the three groups classified by the ALSFRS-R change during the 12 weeks prior to baseline or by the rate of progression from onset to baseline did not accord with the three prognostic groups. Conclusions: Our results showed that the ALSFRS-R change in the run-in period or from onset to baseline is not useful for stratifying subsequent progression of functional decline in clinical trials.

Giving Breath to Motor Neurons: Noninvasive Mechanical Ventilation Slows Disease Progression in Amyotrophic Lateral Sclerosis

Article

Jan 2024
ANN NEUROL

Objective Noninvasive mechanical ventilation (NIMV) improves amyotrophic lateral sclerosis (ALS) quality of life and survival. However, data about its effect on disease progression are still lacking. Here, we test whether NIMV use changed the rate of functional decline among ALS patients. Methods In this retrospective observational study, we included 448 ALS patients followed up at the ALS Center in Turin, Italy, who underwent NIMV during the disease course. The primary outcome was the change in functional decline after NIMV initiation adjusting for covariates. Functional decline was based on the nonrespiratory items of the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS‐R). Results NIMV initiation resulted in a slower functional decline (mean improvement = 0.16 points per month, 95% confidence interval = 0.12–0.19, p < 0.001), with consistent effects observed across various demographic factors, including sex, age at diagnosis, and disease duration before NIMV initiation. This finding was replicated using the PRO‐ACT (Pooled Resource Open‐Access ALS Clinical Trials) dataset. The favorable impact of NIMV on ALSFRS‐R progression was evident independently of disease stages. Notably, NIMV benefits were not dose‐dependent but were particularly prominent for nighttime respiratory support. Interpretation NIMV significantly influences the rate of motor progression in ALS, and this effect is not determined by the nonlinearity of ALSFRS‐R trajectory. The functional decline slowed following NIMV initiation, independently of the site of disease onset or disease severity at the time of NIMV initiation. Our findings underscore the importance of timely NIMV initiation for all ALS patients and highlight the need to consider NIMV‐induced slowing of disease progression when evaluating clinical trial outcomes. ANN NEUROL 2024

Feasibility assessment of using the MiToS Staging System for Conducting Economic Evaluation in amyotrophic lateral sclerosis

Article

Full-text available

Jan 2024

Objectives: This study assessed the feasibility of using the Milano-Torino staging (MiToS) system for conducting economic evaluation to measure health outcomes in amyotrophic lateral sclerosis (ALS). Methods: A Markov model was developed using the MiToS system and evaluated with a hypothetical treatment versus standard of care. Health utilities and transition probabilities were derived from the literature. Four-time horizons (1, 5, 10, and 20 years) were examined. Treatment effects of 20-35% relative risk reduction (RRR) of progressing to the next MiToS stage were assessed. Three patient distribution scenarios were tested: (1) all patients began in stage 0; (2) patient distribution based on real-world TONiC study; (3) distribution based on the PRO-ACT database. Health outcomes (quality-adjusted life-years [QALYs], life-years [LYs]) were reported with a 3% discount rate. Results: A time horizon of 10 years fully captured treatment benefits: incremental QALYs were 0.28-0.60, 0.21-0.45, and 0.26-0.55 for scenarios 1-3, respectively; incremental LYs were 0.56-1.17, 0.46-0.97, and 0.53-1.11, respectively. Conclusion: MiToS-based staging can be used for conducting economic analyses in ALS. Estimated incremental QALY and LY gains were meaningful within the context of ALS, for hypothetical treatments with RRR of 20-35%.

Higher Glycemic Index and Glycemic Load Diet Is Associated with Slower Disease Progression in Amyotrophic Lateral Sclerosis

Article

Nov 2023
ANN NEUROL

Objective High‐caloric diets may slow the progression of amyotrophic lateral sclerosis; however, key macronutrients have not been identified. We examined whether dietary macronutrients are associated with the rate of progression and length of survival among the prospective cohort study participants. Methods Participants with a confirmed diagnosis of sporadic amyotrophic lateral sclerosis enrolled in the Multicenter Cohort Study of Oxidative Stress were included (n=304). We evaluated baseline macronutrient intake assessed by food frequency questionnaire in relation to change in revised amyotrophic lateral sclerosis functional rating scale total‐score, and tracheostomy‐free survival using linear regression and Cox proportional hazard models. Baseline age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised amyotrophic lateral sclerosis functional rating scale total‐score, and forced vital capacity were included as covariates. Results Baseline higher glycemic index and load were associated with less decline of revised amyotrophic lateral sclerosis functional rating scale total‐score at 3‐month follow‐up (β= ‐0.13, 95% Confidence Interval [‐0.2, ‐0.01], p=0.03) and (β= ‐0.01, [‐0.03, ‐0.0007], p=0.04) respectively. Glycemic index second‐quartile, third‐quartile, and fourth‐quartile groups were associated with less decline at 3‐month by 1.9 ([‐3.3, ‐0.5], p=0.008), 2.0 ([‐3.3, ‐0.6], p=0.006), and 1.6 ([‐3.0, ‐0.2], p=0.03) points compared to the first‐quartile group; glycemic load fourth‐quartile group had 1.4 points less decline compared to the first‐quartile group ([‐2.8, 0.1], p=0.07). Higher glycemic index was associated with a trend toward longer tracheostomy‐free survival (Hazard ratio 0.97, [0.93, 1.00], p=0.07). Interpretation Higher dietary glycemic index and load are associated with slower disease progression in amyotrophic lateral sclerosis. This article is protected by copyright. All rights reserved.

Induced pluripotent stem cells‐based disease modeling, drug screening, clinical trials, and reverse translational research for amyotrophic lateral sclerosis

Article

Full-text available

Nov 2023
J NEUROCHEM

It has been more than 10 years since the hopes for disease modeling and drug discovery using induced pluripotent stem cell (iPSC) technology boomed. Recently, clinical trials have been conducted with drugs identified using this technology, and some promising results have been reported. For amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, several groups have identified candidate drugs, ezogabine (retigabine), bosutinib, and ropinirole, using iPSCs‐based drug discovery, and clinical trials using these drugs have been conducted, yielding interesting results. In our previous study, an iPSCs‐based drug repurposing approach was utilized to show the potential of ropinirole hydrochloride (ROPI) in reducing ALS‐specific pathological phenotypes. Recently, a phase 1/2a trial was conducted to investigate the effects of ropinirole on ALS further. This double‐blind, randomized, placebo‐controlled study confirmed the safety and tolerability of and provided evidence of its ability to delay disease progression and prolong the time to respiratory failure in ALS patients. Furthermore, in the reverse translational research, in vitro characterization of patient‐derived iPSCs‐motor neurons (MNs) mimicked the therapeutic effects of ROPI in vivo, suggesting the potential application of this technology to the precision medicine of ALS. Interestingly, RNA‐seq data showed that ROPI treatment suppressed the sterol regulatory element‐binding protein 2‐dependent cholesterol biosynthesis pathway. Therefore, this pathway may be involved in the therapeutic effect of ROPI on ALS. The possibility that this pathway may be involved in the therapeutic effect of ALS was demonstrated. Finally, new future strategies for ALS using iPSCs technology will be discussed in this paper.

Nutritional Consequences of Amyotrophic Lateral Sclerosis

Chapter

Dec 2018

Nutritional Consequences of Amyotrophic Lateral Sclerosis

Chapter

Mar 2019

Efficacy and Safety of Ravulizumab, a Complement C5 Inhibitor, in Adults With Amyotrophic Lateral Sclerosis: A Randomized Clinical Trial

Article

Full-text available

Sep 2023

Importance: Additional therapies for amyotrophic lateral sclerosis (ALS) are urgently needed. Immune-mediated complement activation may be involved in ALS pathogenesis as evidenced by the upregulation of terminal components; thus, complement inhibition could potentially slow progression. Objective: To evaluate the safety and efficacy of the terminal complement C5 inhibitor ravulizumab in adults with ALS. Design, setting, and participants: This double-blind, placebo-controlled, parallel-group, multinational, randomized, phase 3 clinical trial was conducted from March 30, 2020, to October 17, 2021, in 81 ALS specialty centers across 17 countries. A preplanned, unmasked, nonbinding interim futility analysis was conducted when 33% of participants had completed week 26, wherein a conditional power of less than 10% would halt the trial. A total of 478 individuals were screened, and 96 were excluded. Inclusion criteria were weight of 40 kg or more, fulfillment of the El Escorial diagnostic criteria, and a minimal prestudy Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) progression score of -0.3 points per month. Interventions: Study treatment consisted of placebo or a weight-based dose of intravenous ravulizumab every 8 weeks until week 42. Participants could continue standard-of-care treatment. Main outcomes and measures: The primary end point was change from baseline in ALSFRS-R score at week 50 based on the Combined Assessment of Function and Survival (CAFS). Results: A total of 382 participants were randomly assigned 2:1 to receive ravulizumab (n = 255; mean [SD] age, 58.6 [10.6] years; 94 female [36.9%] and 161 male [63.1%]) or placebo (n = 127; mean [SD] age, 58.0 [11.0] years; 58 female [45.7%] and 69 male [54.3%]). The interim analysis showed that the observed mean change from baseline in ALSFRS-R at week 50 was -14.67 points (SE, 0.89 points; 95% CI, -16.42 to -12.91 points) for ravulizumab and -13.33 points (SE, 1.22 points; 95% CI, -15.72 to -10.93 points) for placebo, with no significant difference between the groups (mean [SE] difference, -1.34 [1.46] points; 95% CI, -4.21 to 1.53 points). Based on these data, the trial was terminated for futility. The primary analysis at week 50 showed no significant difference in CAFS between groups (mean [SE], 5.5 [10.8] points; 95% CI, -15.7 to 26.6 points; P = .61). Overall incidence rates for treatment-emergent adverse events were similar for ravulizumab (204 participants [80.0%]) and placebo (108 participants [85.0%]). Conclusions and relevance: This trial rapidly showed that terminal complement C5 inhibition with ravulizumab did not slow functional decline in participants with ALS and that the safety profiles of ravulizumab and placebo were similar. Highly effective, novel treatments are critically needed to slow functional decline and extend survival in patients with ALS. Trial registration: ClinicalTrials.gov Identifier: NCT04248465.

Empowering Interpretable, Explainable Machine Learning Using Bayesian Network Classifiers

Chapter

Feb 2023

Boaz Lerner

Even before the deep learning era, the machine learning (ML) community commonly believed that while decision trees, neural networks (NNs), support vector machines, and ensemble (bagging and boosting) methods are the ultimate tools for highly accurate classification, graphical models and their flagship Bayesian networks (BNs) are only appropriate for knowledge representation. This chapter challenges the belief that the unsupervised graphical model is inferior to the supervised classifier and provides evidence to the contrary. Moreover, it demonstrates how the graphical models’ knowledge representation capability promotes a level of interpretability and explainability that is not found in conventional ML classifiers. This chapter further challenges the ML community to invest even 1% of the efforts currently focused on increasing the accuracy of deep and non-deep ML classifiers and to equip them with the means for visualization and interpretation, on instead developing BN learning algorithms that would allow graphical models to complement and integrate with these classifiers to foster interpretability and explainability. One example could be to utilize the natural interpretability provided by conditional (in)dependencies among the nodes and causal pathways in the BN classifier to visualize, interpret, and explain deep NN results and important interactions among network units, layers, and activities that may be responsible for right and wrong classification decisions made by the network. Another example could be development of graphical user interface tools encouraging, promoting, and supporting human–machine interaction by which both users’ inquiries will help manipulate and extend the learned BN model to better address these and further inquiries, and the tools will inspire users’ curiosity to further investigate the model to enrich their understanding of the domain. Such efforts will further contribute to the attempts of the ML community to not only increase its impact on advancing and supporting the many fields that strive for innovation, but also to meet growing criticism concerning lack of explainability, transparency, and accountability in AI—criticism that may undermine and hinder the tremendous societal benefits that ML can bring.

Amyotrophic Lateral Sclerosis Quality Measurement Set 2022 Update: Quality Improvement in Neurology

Article

Full-text available

Aug 2023
NEUROLOGY

The natural history of ALS: Baseline characteristics from a multicenter clinical cohort

Article

Jul 2023

Background: Amyotrophic lateral sclerosis (ALS) is a rare disease with urgent need for improved treatment. Despite the acceleration of research in recent years, there is a need to understand the full natural history of the disease. As only 40% of people living with ALS are eligible for typical clinical trials, clinical trial datasets may not generalize to the full ALS population. While biomarker and cohort studies have more generous inclusion criteria, these too may not represent the full range of phenotypes, particularly if the burden for participation is high. To permit a complete understanding of the heterogeneity of ALS, comprehensive data on the full range of people with ALS is needed. Methods: The ALS Natural History Consortium (ALS NHC) consists of nine ALS clinics and was created to build a comprehensive dataset reflective of the ALS population. At each clinic, most patients are asked to participate and about 95% do. After obtaining consent, a minimum dataset is abstracted from each participant's electronic health record. Participant burden is therefore minimal. Results: Data on 1925 ALS patients were submitted as of 9 December 2022. ALS NHC participants were more heterogeneous relative to anonymized clinical trial data from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database. The ALS NHC includes ALS patients of older age of onset and a broader distribution of El Escorial categories, than the PRO-ACT database. Conclusions: ALS NHC participants had a higher diversity of diagnostic and demographic data compared to ALS clinical trial participants.Key MessagesWhat is already known on this topic: Current knowledge of the natural history of ALS derives largely from regional and national registries that have broad representation of the population of people living with ALS but do not always collect covariates and clinical outcomes. Clinical studies with rich datasets of participant characteristics and validated clinical outcomes have stricter inclusion and exclusion criteria that may not be generalizable to the full ALS population.What this study adds: To bridge this gap, we collected baseline characteristics for a sample of the population of people living with ALS seen at a consortium of ALS clinics that collect extensive, pre-specified participant-level data, including validated outcome measures.How this study might affect research, practice, or policy: A clinic-based longitudinal dataset can improve our understanding of the natural history of ALS and can be used to inform the design and analysis of clinical trials and health economics studies, to help the prediction of clinical course, to find matched controls for open label extension trials and expanded access protocols, and to document real-world evidence of the impact of novel treatments and changes in care practice.

Portable fixed dynamometry enables home-based, reliable assessment of muscle strength in patients with amyotrophic lateral sclerosis: a pilot study

Article

Jul 2023

Objective: To determine the feasibility, reliability, and sensitivity of remotely monitoring muscle strength loss of knee extensors using a novel portable fixed dynamometer (PFD) in patients with amyotrophic lateral sclerosis (ALS). Methods: We conducted a pilot study with a newly developed device to measure knee extension strength. Patients performed unsupervised PFD measurements, biweekly, for 6 months at home. We evaluated feasibility using adherence and a device-specific questionnaire. Reliability was assessed by (1) comparing unsupervised and supervised measurements to identify systematic bias, and (2) comparing consecutive unsupervised measurements to determine test-retest reliability expressed as intraclass correlation coefficient (ICC) and standard error of measurement (SEM). Sensitivity to detect longitudinal change was described using linear mixed-effects models. Results: We enrolled 18 patients with ALS. Adherence was 86%, where all patients found that the device suitable to measure muscle strength at home; 4 patients (24%) found the measurements burdensome. The correlation between (un)supervised measurements was excellent (Pearson's r 0.97, 95%CI; 0.94 - 0.99) and no systematic bias was present (mean difference 0.13, 95%CI; -2.22 - 2.48, p = 0.91). Unsupervised measurements had excellent test-retest reliability with an average ICC of 0.97 (95%CI: 0.94 - 0.99) and SEM of 5.8% (95%CI: 4.8 - 7.0). Muscle strength declined monthly by 1.9 %predicted points (95%CI; -3.0 to -0.9, p = 0.001). Conclusions: Using the PFD, it proved feasible to perform knee extension strength measurements at home which were reliable and sensitive for detecting muscle strength loss. Larger studies are warranted to compare the device with conventional outcomes.

Infrastructure resources for clinical research in amyotrophic lateral sclerosis

Article

Full-text available

May 2013

Clinical trial networks, shared clinical databases, and human biospecimen repositories are examples of infrastructure resources aimed at enhancing and expediting clinical and/or patient oriented research to uncover the etiology and pathogenesis of amyotrophic lateral sclerosis (ALS), a rapidly progressive neurodegenerative disease that leads to the paralysis of voluntary muscles. The current status of such infrastructure resources, as well as opportunities and impediments, were discussed at the second Tarrytown ALS meeting held in September 2011. The discussion focused on resources developed and maintained by ALS clinics and centers in North America and Europe, various clinical trial networks, U.S. government federal agencies including the National Institutes of Health (NIH), the Agency for Toxic Substances and Disease Registry (ATSDR) and the Centers for Disease Control and Prevention (CDC), and several voluntary disease organizations that support ALS research activities. Key recommendations included 1) the establishment of shared databases among individual ALS clinics to enhance the coordination of resources and data analyses; 2) the expansion of quality-controlled human biospecimen banks; and 3) the adoption of uniform data standards, such as the recently developed Common Data Elements (CDEs) for ALS clinical research. The value of clinical trial networks such as the Northeast ALS (NEALS) Consortium and the Western ALS (WALS) Consortium was recognized, and strategies to further enhance and complement these networks and their research resources were discussed.

Predicting Survival of Patients with Amyotrophic Lateral Sclerosis at Presentation: A 15-Year Experience

Article

Full-text available

Aug 2012
NEURODEGENER DIS

Objective: To describe the clinical features at first evaluation that best predict survival of the amyotrophic lateral sclerosis (ALS) population from the Salpêtrière Hospital between 1995 and 2009. Methods: Data are collected and entered into a clinical database from all patients seen at the Paris ALS Center. Variables analyzed were demographic and baseline information, strength testing (manual muscle testing; 1995-2009), the revised ALS Functional Rating Scale (ALSFRS-R; 2002-2009) and survival status. The χ(2) test and ANOVA assessed differences in variables by region and across time period. Univariate and multivariate Cox proportional hazards models determined which variables best predicted survival. Flexible modeling of continuous predictors (splines) assessed trends in survival for different variables. Results: 3,885 patients with ALS were seen in 1995-2009, of whom 2,037 had ALSFRS-R scores. Age, weight, strength, and site of onset varied by region of residence. The proportion of patients living outside Paris, the time to first visit, patient age, and motor function differed across time periods. In Cox models, site of onset, time to first visit greater than 18 months, strength and the year of visit after 2006 predicted survival (all p values <0.0001). Compared to patients first seen between 1999 and 2002, the hazard ratio of death was 1.04 (95% CI = 0.95-1.14) for 2003-2006, and 0.76 (95% CI = 0.66-0.87) after 2006, while adjusting for other predictors of survival. The use of noninvasive ventilation increased during 2004-2008 from 16 to 51% of patients. Conclusions: Older age, bulbar onset, shorter delay to first visit and poor motor function at first visit predicted shorter survival rates in this large center-based sample from France, showing marked consistency across time and region of residence. Survival improved after 2006, concurrent with increasing rates of noninvasive ventilation use. Clinicopathologic correlation could better define subgroups, but identification of etiologies may be needed to elucidate individual forms of ALS with unique survival patterns.

Biochemical alterations associated with ALS

Article

Full-text available

Nov 2011
AMYOTROPH LATERAL SC

Our objective was to identify metabolic pathways affected by ALS using non-targeted metabolomics in plasma, comparing samples from healthy volunteers to those from ALS patients. This discovery could become the basis for the identification of therapeutic targets and diagnostic biomarkers of ALS. Two distinct cross-sectional studies were conducted. Plasma was collected from 62 (Study 1) and 99 (Study 2) participants meeting El Escorial criteria for possible, probable, or definite ALS; 69 (Study 1) and 48 (Study 2) healthy controls samples were collected. Global metabolic profiling was used to detect and evaluate biochemical signatures of ALS. Twenty-three metabolites were significantly altered in plasma from ALS patients in both studies. These metabolites include biochemicals in pathways associated with neuronal change, hypermetabolism, oxidative damage, and mitochondrial dysfunction, all of which are proposed disease mechanisms in ALS. The data also suggest possible hepatic dysfunction associated with ALS. In conclusion, the data presented here provide insight into the pathophysiology of ALS while suggesting promising areas of focus for future studies. The metabolomics approach can generate novel hypotheses regarding ALS disease mechanisms with the potential to identify therapeutic targets and novel diagnostic biomarkers.

Urate as a Predictor of the Rate of Clinical Decline in Parkinson Disease

Article

Full-text available

Oct 2009

The risk of Parkinson disease (PD) and its rate of progression may decline with increasing concentration of blood urate, a major antioxidant. To determine whether serum and cerebrospinal fluid concentrations of urate predict clinical progression in patients with PD. Eight hundred subjects with early PD enrolled in the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) trial. The pretreatment urate concentration was measured in serum for 774 subjects and in cerebrospinal fluid for 713 subjects. Treatment-, age-, and sex-adjusted hazard ratios (HRs) for clinical disability requiring levodopa therapy, the prespecified primary end point of the original DATATOP trial. The HR of progressing to the primary end point decreased with increasing serum urate concentrations (HR for highest vs lowest quintile = 0.64; 95% confidence interval [CI], 0.44-0.94; HR for a 1-SD increase = 0.82; 95% CI, 0.73-0.93). In analyses stratified by alpha-tocopherol treatment (2000 IU/d), a decrease in the HR for the primary end point was seen only among subjects not treated with alpha-tocopherol (HR for a 1-SD increase = 0.75; 95% CI, 0.62-0.89; vs HR for those treated = 0.90; 95% CI, 0.75-1.08). Results were similar for the rate of change in the Unified Parkinson's Disease Rating Scale score. Cerebrospinal fluid urate concentration was also inversely related to both the primary end point (HR for highest vs lowest quintile = 0.65; 95% CI, 0.44-0.96; HR for a 1-SD increase = 0.89; 95% CI, 0.79-1.02) and the rate of change in the Unified Parkinson's Disease Rating Scale score. As with serum urate concentration, these associations were present only among subjects not treated with alpha-tocopherol. Higher serum and cerebrospinal fluid urate concentrations at baseline were associated with slower rates of clinical decline. The findings strengthen the link between urate concentration and PD and the rationale for considering central nervous system urate concentration elevation as a potential strategy to slow PD progression.

Low uric acid levels in serum of patients with ALS: Further evidence for oxidative stress?

Article

Full-text available

Jun 2009

The exact cause of amyotrophic lateral sclerosis (ALS) is unknown. Oxidative stress is one of the factors implicated in the etiology of ALS as well as in that of other neurodegenerative diseases. Uric acid is an important natural antioxidant that may reduce oxidative stress. The objective of this study was to prospectively determine the serum uric acid levels in ALS patients and allegedly healthy individuals and to correlate those values with measures of ALS disease progression among the patients. The ALS patients and well-matched controls underwent blood tests for serum uric acid levels which were then correlated with the patients' disability status, as expressed by the ALS Functional Rating Scale (ALSFRS-R). Eighty-six ALS patients and 86 well-matched controls participated. The ALS patients' mean+/-SD uric acid level was significantly lower (4.78+/-1.3 mg/dl) than that of the controls (5.76+/-1.26 mg/dl) (p<0.0001). The findings were similar for a second examination performed after an interval of at least 6 months. There was a correlation between the relative decrease of serum uric acid levels among patients (the difference between the patients' level and the controls' level) and the rate of disease progression (ALSFRS-R decline) (p<0.0001, r=0.624). ALS patients had lower serum uric acid levels than healthy individuals. The decreased uric acid levels were correlated to the rate of disease progression (ALSFRS-R decline), further demonstrating the possible role of oxidative stress in the induction and propagation of the disease.

The Multiple Sclerosis Functional Composite measure (MSFC): an integrated approach to MS clinical outcome assessment

Article

Full-text available

Sep 1999

Clinical outcome assessment in Multiple Sclerosis (MS) is challenging due to the diversity and fluctuating nature of MS symptoms. Traditional clinical scales such as the EDSS are inadequate in their assessment of key clinical dimensions of MS (e.g., cognitive function), and they have psychometric limitations as well. Based on analyses of pooled data from natural history studies and from placebo groups in clinical trials, the National MS Society's Clinical Outcomes Assessment Task Force recently proposed a new multidimensional clinical outcome measure, the MS Functional Composite (MSFC). The MSFC comprises quantitative functional measures of three key clinical dimensions of MS: leg function/ambulation, arm/hand function, and cognitive function. Scores on component measures are converted to standard scores (z-scores), which are averaged to form a single MSFC score. Preliminary analyses confirm that: (1) the three clinical dimensions of the MSFC are relatively independent; (2) the MSFC is sensitive to clinical changes over 1- and 2-year intervals; and (3) the MSFC has acceptable criterion validity (i.e., predicts both concurrent and subsequent EDSS change). The advantages and potential limitations of incorporating quantitative functional outcome measures such as the MSFC into collaborative databases are discussed.

Amyotrophic Lateral Sclerosis

Article

Full-text available

Jun 2001

Serum Urate as a Predictor of Clinical and Radiographic Progression in Parkinson Disease

Article

Full-text available

Jul 2008

To determine whether concentration of serum urate, a purine metabolite and potent antioxidant that has been linked to a reduced risk of Parkinson disease (PD), predicts prognosis in PD. Prospective study. The Parkinson Research Examination of CEP-1347 Trial (PRECEPT) study, which investigated the effects of a potential neuroprotectant on rates of PD progression, was conducted between April 2002 and August 2005 (average follow-up time 21.4 months). Eight hundred four subjects with early PD enrolled in the PRECEPT study. The primary study end point was progression to clinical disability sufficient to warrant dopaminergic therapy. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching end point according to quintiles of baseline serum urate concentration, adjusting for sex, age, and other potential covariates. Change in striatal uptake of iodine I 123-labeled 2-beta-carbomethoxy-3-beta-(4-iodophenyl)tropane ([(123)I]beta-CIT), a marker for the presynaptic dopamine transporter, was assessed with linear regression for a subset of 399 subjects. The adjusted HR of reaching end point declined with increasing baseline concentrations of urate; subjects in the top quintile reached the end point at only half the rate of subjects in the bottom quintile (HR, 0.51; 95% confidence interval [CI], 0.37-0.72; P for trend < .001). This association was markedly stronger in men (HR, 0.39; 95% CI, 0.26-0.60; P for trend < .001) than in women (HR, 0.77; 95% CI, 0.39-1.50; P for trend = .33). The percentage of loss in striatal [(123)I]beta-CIT uptake also improved with increasing serum urate concentrations (overall P for trend = .002; men, P = .001; women, P = .43). These findings identify serum urate as the first molecular factor directly linked to the progression of typical PD and suggest that targeting urate or its determinants could be an effective disease-modifying therapy in PD. Trial Registration clinicaltrials.gov Identifier: NCT00040404.

A Controlled Trial of Riluzole in Amyotrophic Lateral Sclerosis

Article

Mar 1994
NEW ENGL J MED

Amyotrophic lateral sclerosis is a progressive motor neuron disease for which there is no adequate treatment. Some research suggests that the excitatory amino acid neurotransmitter glutamate may be involved in the pathogenesis. To evaluate the efficacy and safety of the antiglutamate agent riluzole, we conducted a prospective, double-blind, placebo-controlled trial in 155 outpatients with amyotrophic lateral sclerosis. The dose of riluzole was 100 mg per day. Randomization was stratified according to the site of disease onset (the bulbar region or the limbs). The primary end points were survival and rates of change in functional status. The main secondary end point was change in muscle strength. Analyses were undertaken after 12 months of treatment and at the end of the placebo-controlled period (median follow-up, 573 days). After 12 months, 45 of 78 patients (58 percent) in the placebo group were still alive, as compared with 57 of 77 patients (74 percent) in the riluzole group (P = 0.014). For patients with bulbar-onset disease, one-year survival rates were 35 percent (6 of 17) with placebo and 73 percent (11 of 15) with riluzole (P = 0.014), whereas for those with limb-onset disease one-year survival was 64 percent and 74 percent, respectively (P = 0.17). The survival advantage with riluzole was smaller (37 percent [29 of 78] with placebo vs. 49 percent [38 of 77] with riluzole) at the end of the placebo-controlled period, but it remained significant in the overall population (P = 0.046) as well as in the patients with bulbar-onset disease (18 percent [3 of 17] vs. 53 percent [8 of 15], P = 0.013). The deterioration of muscle strength was significantly slower in the riluzole group than in the placebo group (P = 0.028). Adverse reactions to riluzole included asthenia, spasticity, and mild elevations in aminotransferase levels. Twenty-seven patients in the riluzole group withdrew from the study, as compared with 17 in the placebo group. The antiglutamate agent riluzole appears to slow the progression of amyotrophic lateral sclerosis, and it may improve survival in patients with disease of bulbar onset.

The Direct Likelihood Method

Chapter

May 2007

IntroductionIgnorable Analyses in PracticeThe Linear Mixed ModelAnalysis of the Toenail DataThe Generalized Linear Mixed ModelThe Depression TrialsThe Analgesic Trial

A controlled trial of recombinant methionyl human BDNF in ALS: the BDNF Study Group (Phase III)

Article

Jan 1999

The BDNF Study Group

A controlled trial of recombinant methionyl human BDNF in ALS

Article

Apr 1999
NEUROLOGY

Walter George Bradley

Objective: To replicate the beneficial effect of brain-derived neurotrophic factor (BDNF) in 1,135 ALS patients in a multicenter trial. Background: In a phase I through II study, BDNF appeared to increase survival and retard loss of pulmonary function in ALS patients. Methods: Patients were randomized to placebo, or 25 or 100 microg/kg BDNF for 9 months. Results: The study failed to show benefit of BDNF treatment for the primary end points. Survival in patients treated with 25 microg/kg BDNF was identical to placebo, but there was a trend toward increased survival in the 100-microg/kg group. As a whole, survival was better than anticipated when planning the study. The 9-month probability of survival was approximately 85% across all groups. This diminished the power of the study. Among the 60% of patients with baseline forced vital capacity of < or = 91%, survival was significantly greater for 100 microg/kg BDNF versus placebo. For the 20% of patients treated with 100 microg/kg BDNF reporting altered bowel function as an adverse effect of BDNF in the first 2 weeks of dosing, defined as BDNF "responders," 9-month survival was significantly better than for placebo (97.5% versus 85%). Conclusions: Although the primary end point analysis failed to demonstrate a statistically significant survival effect of BDNF in ALS, post hoc analyses showed that those ALS patients with early respiratory impairment and those developing altered bowel function showed statistically significant benefit. Further clinical trials of BDNF using either intrathecal delivery or high-dose subcutaneous administration are in progress.

A double-blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis

Article

May 1996

Ciliary neurotrophic factor (CNTF) is a neuroactive cytokine found in Schwann cells, which appears to be released in response to nerve injury. The ALS CNTF Treatment Study (ACTS) clinical trial was a phase II-III randomized, placebo-controlled, double-blind study designed to evaluate the safety, tolerability, and efficacy of subcutaneous administration of recombinantly produced human CNTF (rHCNTF) in slowing disease progression in 730 patients with amyotrophic lateral sclerosis (ALS). Patients were randomized to receive 30 μg/kg or 15 μg/kg rHCNTF or placebo subcutaneously three times a week for 9 months. The primary endpoint of the study, the slope of decline of isometric muscle strength in treated versus placebo patients, showed no statistically significant difference between rHCNTF and placebo-treated patients, and was complicated by an initial statistically significant decrease in strength early in rHCNTF-treated patients. Mortality was similar in all three study arms. There were no statistically significant treatment effects among the secondary measures. Side effects of rHCNTF included anorexia, weight loss, and cough and were sufficient to limit dosing in many patients.

Amyotrophic lateral sclerosis disease progression model

Article

Sep 2013

Our objective was to develop: 1) a longitudinal model to describe amyotrophic lateral sclerosis (ALS) disease progression using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R); and 2) a probabilistic model to estimate the presence of clusters of trajectories in ALS progression over 12 months of treatment. Three hundred and thirty-eight patients treated with placebo from the PRO-ACT database were included in the analyses. A non-linear Weibull model best described the ALS disease progression, and a stepwise logistic regression approach was used to select the variables predicting a slow or fast disease progression. Results identified two clusters of trajectories: 1) slow disease progressors (46% of patients with a change from baseline of 13%); 2) fast disease progressors (54% of patients with a change from baseline of 49%). ROC curve analysis estimated the optimal cut-off for classifying patients as slow or fast disease progressors given ALSFRS-R measurements at 2-4 weeks. Results showed that the degree of ALS disease progression quantified by the ALSFRS-R symptomatic change on placebo is highly heterogeneous. In conclusion, this finding indicates the potential interest of disease progression models for implementing a population enrichment strategy to control the level of heterogeneity in the patients included in new trials.

Biomedicine. Pharma firms push for sharing of cancer trial data

Article

Oct 2012
SCIENCE

Yudhijit Bhattacharjee

A consortium of pharmaceutical companies hopes to improve the success rate of experimental cancer therapies by getting cancer researchers to share data from clinical trials. Called DataSphere, the effort aims to create a repository of data sets from cancer trials. The initiative has been kick-started with two data sets contributed by pharma giant Sanofi. Other companies, as well as universities, are expected to contribute data in the coming months. The architects of the effort hope to make the repository available to outside researchers by April of next year.

A double-blind, placebo-controlled randomized clinical trial of ??-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis

Article

Jul 2009

INTRODUCTION: Increasing evidence suggests that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E ( f -tocopherol) has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS. The current study was designed to determine whether a-tocopherol (500 mg b.i.d.) may be efficacious in the treatment of ALS. METHODS: Two hundred and eighty-nine patients with ALS of less than 5 years duration, treated with riluzole, were enrolled in this study, and were randomly assigned to receive either a-tocopherol or placebo daily for one year. The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale. Patients were assessed at entry, and every 3 months thereafter during the study period. Survival was also recorded. Biochemical markers of oxidative stress were measured in a subset of patients on entry and after 3 months of treatment. RESULTS: After 12 months of treatment, a-tocopherol had no effect on the primary outcome measure. Survival was not influenced by treatment. Among secondary outcome measures, patients given a-tocopherol were less likely to progress from the milder state A to the more severe state B ( P = 0.046) of the ALS Health State scale. After 3 months treatment, analysis of oxidative stress markers showed an increase in glutathione peroxidase activity in plasma ( P = 0.0389) and a decrease in plasma levels of thiobarbituric acid reactive species ( P = 0.0055) in the group of patients given f -tocopherol in combination with riluzole. CONCLUSION: Although f -tocopherol did not appear to affect the survival and motor function in ALS, patients receiving riluzole plus f -tocopherol remained longer in the milder states of the ALS Health State scale and showed, after 3 months, changes in biochemical markers of oxidative stress. Further studies are required to confirm the greater sensitivity of the ALS Health State scale over other clinical endpoints. (ALS 2001; 2: 9-18)

Relationships between Disease Progression and Serum Levels of Lipid, Urate, Creatinine and Ferritin in Japanese Patients with Amyotrophic Lateral Sclerosis: A Cross-Sectional Study

Article

Jun 2012
INTERNAL MED

Previous studies have reported distinct serological profiles of lipid, urate and ferritin in Western patients with amyotrophic lateral sclerosis (ALS). We aimed to examine the levels of these serological factors and their relationship to disease progression in Japanese ALS patients. Ninety-two patients with definite or probable ALS who fulfilled the revised El Escorial criteria were analyzed for clinical and serological variables. Serological data at the time diagnosed with ALS were compared to those of 92 age/sex/body mass index-matched healthy controls. Compared to controls, urate and creatinine (Cr) levels were decreased and ferritin levels were increased significantly in sera of male and female patients with ALS. Significant increases of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels were found in female ALS patients. The annual decline of ALS Functional Rating Scale-Revised (ALS-FRS) and forced vital capacity (FVC) were inversely correlated with serum TC, LDL-C, Cr and urate levels, and were positively correlated with serum ferritin levels. Multivariate analysis showed that the rapid worsening of annual ALS-FRS and FVC was associated with serum levels of TC, LDL-C, Cr, urate and ferritin. The present study indicated that serum levels of TC, LDL-C, Cr, urate and ferritin were correlated with clinical deterioration in ALS patients. These results are similar to those in Western patients. Metabolic and nutritional conditions of lipid, urate and iron could contribute to disease progression in ALS patients. Further studies investigating high nutrition diets and iron chelation for the treatment of ALS are warranted.

Urate in Parkinson’s Disease: More Than a Biomarker?

Article

May 2012
CURR NEUROL NEUROSCI

Parkinson's disease (PD) is a progressive neurodegenerative disease with characteristic motor manifestations. Although appreciation of PD as a multisystem disorder has grown, loss of dopaminergic neurons in the substantia nigra remains a pathological and neurochemical hallmark, accounting for the substantial symptomatic benefits of dopamine replacement therapies. However, currently no treatment has been shown to prevent or forestall the progression of the disease in spite of tremendous efforts. Among multiple environmental and genetic factors that have been implicated in the pathogenesis of PD, oxidative stress is proposed to play a critical role. A recent confluence of clinical, epidemiological, and laboratory evidence identified urate, an antioxidant and end product of purine metabolism, as not only a molecular predictor for both reduced risk and favorable progression of PD but also a potential neuroprotectant for the treatment of PD. This review summarizes recent findings on urate in PD and their clinical implications.

Uric acid levels predict survival in men with amyotrophic lateral sclerosis

Article

Feb 2012
J NEUROL

Elevated uric acid levels have recently been found to be associated with slower disease progression in Parkinson's disease, Huntington's disease, multiple system atrophy, and mild cognitive impairment. The aim of this study is to determine whether serum uric acid levels predict survival in amyotrophic lateral sclerosis (ALS). A total of 251 people with ALS enrolled in two multicenter clinical trials were included in our analysis. The main outcome measure was survival time, which was calculated as time to death, tracheostomy, or permanent assistive ventilation, with any event considered a survival endpoint. Cox proportional hazards models were used to estimate the hazard ratio (HR) of reaching a survival endpoint according to baseline uric acid levels after adjusting for markers of disease severity (FVC, total ALSFRS-R score, time since symptom onset, diagnostic delay, BMI, bulbar vs. spinal onset, age, and riluzole use). There was a dose-dependent survival advantage in men, but not women, with higher baseline uric acid levels (logrank test: p = 0.018 for men, p = 0.81 for women). There was a 39% reduction in risk of death during the study for men with each 1 mg/dl increase in uric acid levels (adjusted HR: 0.61, 95% CI 0.39-0.96, p = 0.03). This is the first study to demonstrate that serum uric acid is associated with prolonged survival in ALS, after adjusting for markers of disease severity. Similar to previous reports in Parkinson's disease, this association was seen in male subjects only.

ALS clinical trials Do enrolled patients accurately represent the ALS population?

Article

Sep 2011
NEUROLOGY

To assess the effect of eligibility criteria in amyotrophic lateral sclerosis (ALS) clinical trials on the representativeness of the enrolled population. Patients enrolled in 8 placebo-controlled clinical trials in our ALS center from 2003 to 2008 were compared 1) to the patients included a prospective epidemiologic register (Piemonte and Valle d'Aosta register for ALS, PARALS) in the same period and 2) the subset of PARALS patients who met the usual criteria for inclusion in clinical trials (PARALS-ct) (definite, probable, probable laboratory-supported ALS; age between 18 and 75 years; disease duration <36 months; vital capacity at diagnosis ≥70%; score ≥3 at the items swallowing and respiratory insufficiency at the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised scale; riluzole therapy). A total of 164 patients were enrolled in 8 different clinical trials. The PARALS cohort included 813 patients, of whom 539 (66.3%) met the entry criteria for clinical trials. Patients enrolled in clinical trials were different from both epidemiologic cohorts, since they were younger, had a longer diagnostic delay, and were more likely to have a spinal onset, and to be men. Tracheostomy-free survival was significantly longer in the group of patients enrolled in clinical trials (median survival time, trial patients, 3.9 years [95% confidence interval (CI) 3.4-4.4]; PARALS, 2.6 [2.4-2.8]; PARALS-ct, 2.9 [2.7-3.1]). Patients enrolled in clinical trials do not satisfactorily represent the ALS population; consequently, the findings of ALS trials lack of external validity (generalizability). Efforts should be made to improve patients' recruitment in trials, particularly enrolling incident rather than prevalent cases.

Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis

Article

Jul 2011
MUSCLE NERVE

Recent studies have provided conflicting data regarding the role of dyslipidemia in amyotrophic lateral sclerosis (ALS). The aim of this study was to determine whether cholesterol level are an independent predictor of survival in ALS. Cholesterol levels were measured in 427 ALS subjects from three clinical trial databases. The LDL/HDL ratio did not decrease over time, despite significant declines in body mass index (BMI), forced vital capacity (FVC), and ALSFRS-R. After adjusting for BMI, FVC, and age, the lipid ratio was not associated with survival. There was a "U"-shaped association between BMI and mortality, with the highest survival at 30-35 kg/m(2). The adjusted hazard ratio for the linear association between BMI and survival was 0.860 (95% CI 0.80-0.93, P = 0.0001). We found that dyslipidemia is not an independent predictor of survival in ALS. BMI is an independent prognostic factor for survival after adjusting for markers of disease severity.

Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial

Article

Apr 2010

In a pilot study, lithium treatment slowed progression of amyotrophic lateral sclerosis (ALS). We aimed to confirm or disprove these findings by assessing the safety and efficacy of lithium in combination with riluzole in patients with ALS. We did a double-blind, placebo-controlled trial with a time-to-event design. Between January and June, 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned (1:1) by a centralised computer to receive either lithium or placebo. Patients, caregivers, investigators, and all site study staff with the exception of site pharmacists were masked to treatment assignment. The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death. Interim analyses were planned for when 84 patients had been allocated treatment, 6 months later or after 55 events, and after 100 events. Analysis was by intention to treat. The stopping boundary for futility at the first interim analysis was a p value of at least 0.68. We used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. This trial is registered with ClinicalTrials.gov, NCT00818389. At the first interim analysis, 22 of 40 patients in the lithium group had an event compared with 20 of 44 patients in the placebo group (log rank p=0.51). The hazard ratio of reaching the primary endpoint was 1.13 (95% CI 0.61-2.07). The study was stopped at the first interim analysis because criterion for futility was met (p=0.78). The difference in mean decline in the ALS functional rating scale score between the lithium group and the placebo group was 0.15 (95% CI -0.43 to 0.73, p=0.61). There were no major safety concerns. Falls (p=0.04) and back pain (p=0.05) were more common in the lithium group than in the placebo group. We found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone. The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly. This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS. National Institute of Neurological Disorders and Stroke, ALS Association, and ALS Society of Canada.

The Relationship Between Uric Acid Levels and Huntington's Disease Progression

Article

Jan 2010
MOVEMENT DISORD

Uric acid (UA) may be associated with the progression of Parkinson's disease and related neurodegenerative conditions; however, its association with Huntington's disease (HD) progression has not been explored. A secondary analysis of 347 subjects from the CARE-HD clinical trial was performed to examine the relationship between baseline UA levels and the level of functional decline in HD. Outcomes included change in scores at 30 months for the Unified Huntington's Disease Rating Scale components. There was less worsening of total functional capacity over time with increasing baseline UA levels (adjusted mean worsening in scores: 3.17, 2.99, 2.95, 2.28, 2.21, from lowest to highest UA quintile, P = 0.03). These data suggest a possible association between higher UA levels and slower HD progression, particularly as measured by total functional capacity. If confirmed, UA could be an important predictor and potentially modifiable factor affecting the rate of HD progression.

Oxidative stress in ALS: Key role in motor neuron injury and therapeutic target

Article

Dec 2009

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by death of motor neurons leading to muscle wasting, paralysis, and death, usually within 2-3 years of symptom onset. The causes of ALS are not completely understood, and the neurodegenerative processes involved in disease progression are diverse and complex. There is substantial evidence implicating oxidative stress as a central mechanism by which motor neuron death occurs, including elevated markers of oxidative damage in ALS patient spinal cord and cerebrospinal fluid and mutations in the antioxidant enzyme superoxide dismutase 1 (SOD1) causing approximately 20% of familial ALS cases. However, the precise mechanism(s) by which mutant SOD1 leads to motor neuron degeneration has not been defined with certainty, and the ultimate trigger for increased oxidative stress in non-SOD1 cases remains unclear. Although some antioxidants have shown potential beneficial effects in animal models, human clinical trials of antioxidant therapies have so far been disappointing. Here, the evidence implicating oxidative stress in ALS pathogenesis is reviewed, along with how oxidative damage triggers or exacerbates other neurodegenerative processes, and we review the trials of a variety of antioxidants as potential therapies for ALS.

A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis

Article

Dec 2009
AMYOTROPH LATERAL SC

Our objective was to determine if chronic treatment with the non-competitive AMPA antagonist talampanel is efficacious and safe in subjects with ALS. A double-blind, placebo-controlled, multicenter, randomized clinical trial of nine months treatment duration was conducted in 59 subjects with ALS, with 40 subjects receiving talampanel 50 mg p.o. t.i.d, and 19 subjects receiving placebo. Primary outcome measure was rate of decline in isometric arm strength (as measured by change in arm strength megaslope of the Tufts Quantitative Neuromuscular Exam (TQNE)). Other efficacy endpoints included rate of decline in respiratory function, isometric leg strength, bulbar function, fine motor function, the ALS Functional Rating Scale (ALSFRS), and survival. Secondary safety outcome measures were frequency of adverse events, neurological status, plasma concentration of talampanel, vital signs, routine laboratory tests, and electrocardiograms. Decline in muscle strength was 15% less in talampanel treated subjects, and decline in ALSFRS was 30% slower in talampanel treated subjects. Talampanel was safe in subjects with ALS. Mortality rates (8% talampanel, 5% placebo) and drug discontinuation rates (25% talampanel, 16% placebo) were similar in active treatment and placebo groups. Dizziness and somnolence occurred significantly more often in talampanel treated subjects. Although no efficacy measure reached statistical significance, there was a repeated trend toward slower decline in ALSFRS and isometric muscle strength in talampanel treated subjects. Talampanel was well tolerated in subjects with ALS. Although certain adverse events occurred more frequently in the active treatment group, the rate of subject drop-out after nine months did not exceed that seen in other trials. These findings provide strong support for a phase III trial to determine the efficacy of talampanel in subjects with ALS.

Toward more efficient clinical trials for amyotrophic lateral sclerosis

Article

Dec 2009
AMYOTROPH LATERAL SC

More than 30 phase II or III clinical trials have been carried out in amyotrophic lateral sclerosis (ALS). Only riluzole, however, has been shown to extend survival and/or time to tracheostomy. Many early ALS trials lacked solid pharmacodynamic and pharmacokinetic data for the treatment being tested, challenging the interpretation of the efficacy and pathway relevance. Understanding of the genetics and pathophysiology of ALS has improved considerably in the past decade, but biomarkers of disease activity remain lacking. A more efficient approach to early phase clinical trials is needed to accelerate the identification of useful agents for ALS. Here we summarize our current thinking about phase II design options and the potential benefits of a clinical trial network for phase II trials in ALS.

MRI as an outcome in multiple sclerosis clinical trial

Article

Feb 2009
NEUROLOGY

T2-weighted and gadolinium enhanced T1-weighted MRI scans measure plaque burden and breakdown of the blood-brain barrier, respectively, in multiple sclerosis (MS) lesions. These have become widely used outcome measures for monitoring disease activity in clinical trials and clinical practice. However, their use as surrogates or biomarkers for disability and relapses, key clinical outcome measures, has remained incompletely validated. In a clinical trial database comprised of 31 relapsing-remitting and secondary progressive MS trial placebo groups, we assessed relationships between 1) T2 lesion load (TLL) change and disability change and 2) gadolinium enhancement of MS lesions and on-study relapses with univariate and multivariate analyses. In relapsing-remitting MS, TLL change (n = 223) made no independent contribution to predicting change in disability from baseline to trials' end. Similarly, inclusion of gadolinium enhancing lesions (n = 170) into multivariate models did not independently contribute to the predictive value for on-trial relapses. In secondary progressive MS, a small effect of TLL was found for disability change (n = 355) but in multivariate analysis this accounted for less than 5% of the variance in end-of-trial disability. Results were replicated in independent datasets, more than doubling effective sample sizes. MRI measures widely used in trials of relapsing-remitting and progressive multiple sclerosis add little if anything independently to the clinically relevant relapse and disability outcomes. These results reemphasize the importance of validating potential surrogate markers against clinical measures and highlight the need for better MRI markers of disease activity and progression.

Incidence of amyotrophic lateral sclerosis in three counties in western Washington State

Article

Sep 1996

We conducted a population-based study of amyotrophic lateral sclerosis (ALS) in King, Pierce, and Snohomish counties in western Washington state. Between April 1, 1990 and March 31, 1995, neurologists diagnosed 235 patients with ALS, including 127 men (54%) and 108 women (46%). The incidence rate, age-adjusted to the 1990 total U.S. population, was higher for men at 2.1 per 100,000 per year (95% CI, 1.3 to 2.9) than for women at 1.9 (95% CI, 1.1, 2.7) and increased with age for both men and women. These incidence rates are consistent with other studies from northern latitudes. NEUROLOGY 1996;47: 571-573

Placebo-controlled trial of gabapentin in patients with amyotrophic lateral sclerosis. WALS Study Group. Western Amyotrophic Lateral Sclerosis Study Group

Article

Jan 1997

We designed a phase II trial to evaluate the efficacy of gabapentin in slowing the rate of decline in muscle strength of patients with amyotrophic lateral sclerosis (ALS) and to assess safety and tolerability. Gabapentin (800 mg) or placebo was administered t.i.d. in a randomized, double-blinded, placebo-controlled, trial for 6 months. We enrolled 152 patients at eight sites in the United States. The primary outcome measure was the slope of the arm megascore, the average maximum voluntary isometric strength from eight arm muscles standardized against a reference ALS population. A secondary outcome measure was forced vital capacity. Slopes of arm megascores for patients on gabapentin were compared with slopes of those taking placebo using a two-way ANOVA. We observed a nonstatistically significant trend (p = 0.057-0.08) toward slower decline of arm strength in patients taking gabapentin compared with those taking placebo (mean difference 24%, median 37%). We observed no treatment effect on forced vital capacity. Gabapentin was well tolerated by patients with ALS. These results suggest that further studies of gabapentin in ALS are warranted.

The ALS patient care database: goals, design, and early results. ALS C.A.R.E. Study Group

Article

Feb 2000

The ALS Patient Care Database was created to improve the quality of care for patients with ALS by 1) providing neurologists with data to evaluate and improve their practices, 2) publishing data on temporal trends in the care of patients with ALS, and 3) developing hypotheses to be tested during formal clinical trials. Substantial variations exist in managing ALS, but there has been no North American database to measure outcomes in ALS until now. This observational database is open to all neurologists practicing in North America, who are encouraged to enroll both incident and prevalent ALS patients. Longitudinal data are collected at intervals of 3 to 6 months by using standard data collection instruments. Forms are submitted to a central data coordinating center, which mails quarterly reports to participating neurologists. Beginning in September 1996 through November 30, 1998, 1,857 patients were enrolled at 83 clinical sites. On enrollment, patients had a mean age of 58.6 years +/-12.9 (SD) years (range, 20.1 to 95.1 years), 92% were white, and 61% were men. The mean interval between onset of symptoms and diagnosis was 1.2+/-1.6 years (range, 0 to 31.9 years). Riluzole was the most frequently used disease-specific therapy (48%). Physical therapy was the most common nonpharmacologic intervention (45%). The primary caregiver was generally the spouse (77%). Advance directives were in place at the time of death for 70% of 213 enrolled patients who were reported to have died. The ALS Patient Care Database appears to provide valuable data on physician practices and patient-focused outcomes in ALS.

Increased oxidative damage to DNA in ALS patients

Article

Nov 2000
FREE RADICAL BIO MED

Although the cause of amyotrophic lateral sclerosis (ALS) is unknown, substantial evidence indicates that oxidative toxicity is associated with neuronal death in this disease. We examined levels of a well-established marker of oxidative damage to DNA, 8-hydroxy-2'-deoxyguanosine (8OH2'dG) in plasma, urine, and cerebrospinal fluid (CSF) at a single time point from subjects with ALS, other neurological diseases, or no known disorders. We also measured the rate of change of 8OH2'dG levels in plasma and urine from ALS and in urine from control subjects over 9 months and examined the relationship to disease severity. In each fluid, 8OH2'dG levels were significantly elevated in the ALS group as compared to control subjects. In all subjects, the plasma and CSF 8OH2'dG levels increased with age, providing further evidence for a role of oxidative damage in normal aging. Plasma and urine 8OH2'dG levels increased significantly with time in the ALS group only. The rate of increase in urine 8OH2'dG levels with time was significantly correlated with disease severity. These findings are consistent with the hypothesis that oxidative pathology accompanies the neurodegenerative process in ALS and suggest that 8OH2'dG may provide a useful tool for monitoring therapeutic interventions in this disease.

A double-blind, placebo-controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group

Article

Apr 2001

Increasing evidence suggests that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of paralysis in transgenic mice expressing a mutation in superoxide dismutase found in certain forms of familial ALS. The current study was designed to determine whether alpha-tocopherol (500 mg b.i.d.) may be efficacious in the treatment of ALS. Two hundred and eighty-nine patients with ALS of less than 5 years duration, treated with riluzole, were enrolled in this study, and were randomly assigned to receive either alpha-tocopherol or placebo daily for one year. The primary outcome measure was the rate of deterioration of function assessed by the modified Norris limb scale. Patients were assessed at entry, and every 3 months thereafter during the study period. Survival was also recorded. Biochemical markers of oxidative stress were measured in a subset of patients on entry and after 3 months of treatment. After 12 months of treatment, alpha-tocopherol had no effect on the primary outcome measure. Survival was not influenced by treatment. Among secondary outcome measures, patients given alpha-tocopherol were less likely to progress from the milder state A to the more severe state B (P=0.046) of the ALS Health State scale. After 3 months treatment, analysis of oxidative stress markers showed an increase in glutathione peroxidase activity in plasma (P = 0.0389) and a decrease in plasma levels of thiobarbituric acid reactive species (P = 0.0055) in the group of patients given alpha-tocopherol in combination with riluzole. Although alpha-tocopherol did not appear to affect the survival and motor function in ALS, patients receiving riluzole plus alpha-tocopherol remained longer in the milder states of the ALS Health State scale and showed, after 3 months, changes in biochemical markers of oxidative stress. Further studies are required to confirm the greater sensitivity of the ALS Health State scale over other clinical endpoints.

A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis

Article

Jun 2002

Treatment with the neuroprotective drug riluzole has previously been shown to increase the probability of survival in patients with amyotrophic lateral sclerosis. This report describes a placebo-controlled, double-blind randomised clinical trial of riluzole carried out in ALS patients with advanced stage disease or aged over 75 years. The primary objective was to enable access to treatment to patients excluded from the pivotal trial which was run in parallel. Another goal was to assess the safety of riluzole in patients with advanced-stage disease. One hundred and sixty-eight patients were included, randomised to either riluzole 50 mg b. i. d. or to placebo, and treated for eighteen months. Riluzole was well-tolerated in this patient population, and the adverse events observed were similar in nature and frequency to those observed in previously published clinical trials in patients included in pivotal trials. The study could not include enough patients to reach adequate power to detect differences in survival between the two treatment groups, and no such difference was in fact observed. In conclusion, riluzole is well-tolerated in ALS patients with advanced stage disease.

A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis

Article

Sep 2003
NEUROLOGY

To determine if long-term topiramate therapy is safe and slows disease progression in patients with ALS. A double-blind, placebo-controlled, multicenter randomized clinical trial was conducted. Participants with ALS (n = 296) were randomized (2:1) to receive topiramate (maximum tolerated dose up to 800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function as measured by the maximum voluntary isometric contraction (MVIC) strength of eight arm muscle groups. Secondary endpoints included safety and the rate of decline of forced vital capacity (FVC), grip strength, ALS functional rating scale (ALSFRS), and survival. Patients treated with topiramate showed a faster decrease in arm strength (33.3%) during 12 months (0.0997 vs 0.0748 unit decline/month, p = 0.012). Topiramate did not significantly alter the decline in FVC and ALSFRS or affect survival. Topiramate was associated with an increased frequency of anorexia, depression, diarrhea, ecchymosis, nausea, kidney calculus, paresthesia, taste perversion, thinking abnormalities, weight loss, and abnormal blood clotting (pulmonary embolism and deep venous thrombosis). At the dose studied, topiramate did not have a beneficial effect for patients with ALS. High-dose topiramate treatment was associated with a faster rate of decline in muscle strength as measured by MVIC and with an increased risk for several adverse events in patients with ALS. Given the lack of efficacy and large number of adverse effects, further studies of topiramate at a dose of 800 mg or maximum tolerated dose up to 800 mg/day are not warranted.

Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: Results of two phase III trials

Article

Jun 2004

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive and fatal motor neuron disease. We carried out two randomized, double-blind, placebo-controlled, multi-centre, multi-national studies with xaliproden (a drug with neurotrophic effect) to assess drug efficacy and safety at two doses. Patients with clinically probable or definite ALS of more than 6 months and less than 5 years duration were randomly assigned to placebo, 1 mg or 2 mg xaliproden orally once daily as monotherapy in Study 1 (n=867); or to the same regimen with addition of riluzole 50 mg bid background therapy in Study 2 (n=1210 patients). The two primary endpoints were defined as: 1. Time to death, tracheostomy, or permanent assisted ventilation (DTP), and 2. Time to vital capacity (VC)<50% or DTP before (log-rank test) and after adjustment using a Cox proportional hazard model for prespecified prognostic factors. Secondary endpoints were rates of change of various functional measures. In Study 1, primary outcome measures did not reach statistical significance. For the 2 mg group, for time to VC<50% analysis (without DTP) a significant 30% RRR was obtained (95% confidence interval [CI]: 8.46, P=0.009). In Study 2, no significant results were obtained. However, there was a trend in favour of add-on 1 mg dose xaliproden vs. placebo (RRR 15% [-6.31, ns] for time to VC<50%; RRR 12% [CI: -6.27, ns] for time to VC<50% or DTP). Adjusted RR ratios were consistently more favourable for the xaliproden groups. Tolerability was good, and dose-dependent side effects were largely associated with the serotonergic properties of xaliproden. An effect of xaliproden on functional parameters, especially VC, was noted. Although this effect did not reach statistical significance, xaliproden had a small effect on clinically noteworthy aspects of disease progression in ALS.

A clinical trial of creatine in ALS

Article

Dec 2004
NEUROLOGY

Mitochondrial dysfunction occurs early in the course of ALS, and the mitochondria may be an important site for therapeutic intervention. Creatine stabilizes the mitochondrial transition pore, and is important in mitochondrial ATP production. In a transgenic mouse model of ALS, administration of creatine prolongs survival and preserves motor function and motor neurons. The authors conducted a randomized double-blind, placebo controlled trial on 104 patients with ALS from 14 sites to evaluate the efficacy of creatine supplementation in ALS. The primary outcome measure was maximum voluntary isometric contraction of eight upper extremity muscles, with secondary outcomes including grip strength, ALS Functional Rating Scale-Revised, and motor unit number estimates. Patients were treated for 6 months, and evaluated monthly. Creatine was tolerated well, but no benefit of creatine could be demonstrated in any outcome measure. CI analysis showed that the study, although powered to detect a 50% or greater change in rate of decline of muscle strength, actually made an effect size of greater than 23% unlikely. It was also demonstrated that motor unit number estimation was performed with acceptable reproducibility and tolerability, and may be a useful outcome measure in future clinical trials. Any beneficial effect of creatine at 5 g per day in ALS must be small. Other agents should be considered in future studies of therapeutic agents to address mitochondrial dysfunction in ALS. In addition, motor unit number estimation may be a useful outcome measure for future clinical trials in ALS.

Prognostic factors for survival in amyotrophic lateral sclerosis patients treated with riluzole

Article

Apr 2005

The objective of this study was to identify prognostic factors for survival in amyotrophic lateral sclerosis from a large prospective observational study performed in France. The study included a cohort of 2069 patients fulfilling broad entry criteria treated with riluzole. Over 100 demographic, biological, clinical and quality-of-life variables were monitored and assessed for their effect on survival. Patients were randomized post hoc into two groups: one group (two-thirds of the patients) to generate the prognostic models and one group (one-third of the patients) to validate the resulting models. Thirteen variables were found to affect survival independently and were used to construct a survival prediction score, RL401. These included age, disease duration, slow vital capacity, intensity of tiredness (visual analogue scale), number of body levels with spasticity, atrophy and/or fasciculations, cough, distal muscle strength, household income, depression and two biological parameters, plasma creatinine levels and neutrophil counts. A simplified score, RL401S, was constructed, designed to be easy to use and interpret. The predictive powers of the two scores were similar.

Trial of Celecoxib in Amyotrophic Lateral Sclerosis

Article

Jul 2006

To determine whether chronic treatment with celecoxib, a cyclooxygenase-2 inhibitor that has been shown to be beneficial in preclinical testing, is safe and effective in amyotrophic lateral sclerosis (ALS). A double-blind, placebo-controlled, clinical trial was conducted. Three hundred research subjects with ALS were randomized (2:1) to receive celecoxib (800 mg/day) or placebo for 12 months. The primary outcome measure was the rate of change in upper extremity motor function measured by the maximum voluntary isometric contraction strength. Secondary end points included safety, survival, change in cerebrospinal fluid prostaglandin E(2) levels, and changes in the rate of decline of leg and grip strength, vital capacity, ALS Functional Rating Scale-Revised, and motor unit number estimates. Celecoxib did not slow the decline in muscle strength, vital capacity, motor unit number estimates, ALS Functional Rating Scale-Revised, or affect survival. Celecoxib was well tolerated and was not associated with an increased frequency of adverse events. Prostaglandin E(2) levels in cerebrospinal fluid were not elevated at baseline and did not decline with treatment. At the dosage studied, celecoxib did not have a beneficial effect on research subjects with ALS, and it was safe. A biological effect of celecoxib was not demonstrated in the cerebrospinal fluid. Further studies of celecoxib at a dosage of 800 mg/day in ALS are not warranted.

Phase II/III randomized trial of TCH346 in patients with ALS

Article

Sep 2007
NEUROLOGY

TCH346 exerts antiapoptotic effects by binding to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and blocking the apoptotic pathway in which GAPDH is involved. Apoptosis is considered to be a key pathogenic mechanism in neurodegenerative diseases including ALS. Patients were randomly assigned in a double-blind fashion to receive either placebo or one of four doses of TCH346 (1.0, 2.5, 7.5, or 15 mg/day) administered orally once daily for at least 24 weeks. The primary outcome measure was the rate of change in the revised ALS functional rating scale (ALSFRS-R). The trial design included a 16-week lead-in phase to determine each patient's rate of disease progression. The between treatment comparison was adjusted for the individual pretreatment rates of progression. The study was powered to detect a 25% reduction in the rate of decline of the ALSFRS-R as compared with placebo. Secondary outcome measures included survival, pulmonary function, and manual muscle testing (MMT). Five hundred ninety-one patients were enrolled at 42 sites in Europe and North America. There were no differences in baseline variables. There were no significant differences between placebo and active treatment groups in the mean rate of decline of the ALSFRS-R or in the secondary outcome measures (survival, pulmonary function, and MMT). The trial revealed no evidence of a beneficial effect of TCH346 on disease progression in patients with ALS.

Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis

Article

Jul 2008

Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the half-life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood-brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned.

Outcome measures and prognostic indicators in patients with amyotrophic lateral sclerosis

Article

Jul 2008
AMYOTROPH LATERAL SC

The purpose of the study was to assess frequency and predictors of disability measures in ALS. One hundred and fourteen newly diagnosed patients resident in eight administrative districts of Lombardy, Italy (population 4,947,554), included in a population-based registry, were followed for 2570 person-months (mean 22.5 months). The cumulative time-dependent risk of wheelchair, percutaneous endoscopic gastrostomy, and assisted ventilation was estimated according to the Kaplan-Meier method. Predictors of disability (age, sex, disease duration at diagnosis, type of onset, El-Escorial diagnosis) were assessed with the Cox proportional hazard function. During follow-up, 29 patients (25.4%) became wheelchair bound, 51 (44.7%) received gastrostomy, and 47 (41.2%) received assisted ventilation. The median time to loss of ambulation was 46.7 months (95% CI 36.5-56.8). The median time to gastrostomy and assisted ventilation was 31.1 months (95% CI 26.8-35.4) and 34.6 months (95% CI 29.6-39.6), respectively. Spinal onset ALS was the only predictor of loss of ambulation. Predictors of gastrostomy were older age, definite ALS, and shorter disease duration. Shorter disease duration was the only predictor of assisted ventilation. In conclusion, patients with ALS differ in terms of measures and predictors of disability. These factors are sources of bias and confounding in randomized clinical trials.

Placebocontrolled trial of gabapentin in patients with amyotrophic lateral sclerosis

Jan 1996
NEUROLOGY
1383-1388

R Miller
D H Moore
L Young
W S Group

Miller R, Moore DH, Young L, Group WS. Placebocontrolled trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 1996;47:1383-1388.