Reconsidering the revised amyotrophic lateral sclerosis functional rating scale for ALS clinical trials

ObjectivesPlasma creatinine is a predictor of survival in amyotrophic lateral sclerosis (ALS). It remains, however, to be established whether it can monitor disease progression and serve as surrogate endpoint in clinical trials.MethodsWe used clinical trial data from three cohorts of clinical trial participants in the LITRA, EMPOWER and PROACT studies. Longitudinal associations between functional decline, muscle strength and survival with plasma creatinine were assessed. Results were translated to trial design in terms of sample size and power.ResultsA total of 13 564 measurements were obtained for 1241 patients. The variability between patients in rate of decline was lower in plasma creatinine than in ALS functional rating scale–Revised (ALSFRS-R; p<0.001). The average rate of decline was faster in the ALSFRS-R, with less between-patient variability at baseline (p<0.001). Plasma creatinine had strong longitudinal correlations with the ALSFRS-R (0.43 (0.39–0.46), p<0.001), muscle strength (0.55 (0.51–0.58), p<0.001) and overall mortality (HR 0.88 (0.86–0.91, p<0.001)). Using plasma creatinine as outcome could reduce the sample size in trials by 21.5% at 18 months. For trials up to 10 months, the ALSFRS-R required a lower sample size.ConclusionsPlasma creatinine is an inexpensive and easily accessible biomarker that exhibits less variability between patients with ALS over time and is predictive for the patient’s functional status, muscle strength and mortality risk. Plasma creatinine may, therefore, increase the power to detect treatment effects and could be incorporated in future ALS clinical trials as potential surrogate outcome.

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Variation in noninvasive ventilation use in amyotrophic lateral sclerosis

Neurology ◽

10.1212/wnl.0000000000007776 ◽

2019 ◽

Vol 93 (3) ◽

pp. e306-e316 ◽

Cited By ~ 3

Author(s):

Nimish J. Thakore ◽

Brittany R. Lapin ◽

Erik P. Pioro ◽

Loutfi S. Aboussouan

Keyword(s):

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Noninvasive Ventilation ◽

Rating Scale ◽

Factors Affecting ◽

Cox Proportional Hazard ◽

Bulbar Onset ◽

Cox Proportional Hazard Models ◽

R Factors ◽

Lateral Sclerosis

ObjectiveWe sought to examine prevalence and predictors of noninvasive ventilation (NIV) in a composite cohort of patients with amyotrophic lateral sclerosis (ALS) followed in a clinical trials setting (Pooled Resource Open-Access ALS Clinical Trials database).MethodsNIV initiation and status were ascertained from response to question 12 of the revised ALS Functional Rating Scale (ALSFRS-R). Factors affecting NIV use in patients with forced vital capacity (FVC) ≤50% of predicted were examined. Predictors of NIV were evaluated by Cox proportional hazard models and generalized linear mixed models.ResultsAmong 1,784 patients with 8,417 simultaneous ALSFRS-R and FVC% measures, NIV was used by 604 (33.9%). Of 918 encounters when FVC% ≤50%, NIV was reported in 482 (52.5%). Independent predictors of NIV initiation were lower FVC% (hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.17–1.37 for 10% drop), dyspnea (HR 2.62, 95% CI 1.87–3.69), orthopnea (HR 4.09, 95% CI 3.02–5.55), lower bulbar and gross motor subscores of ALSFRS-R (HRs 1.09 [95% CI 1.03–1.14] and 1.13 [95% CI 1.07–1.20], respectively, per point), and male sex (HR 1.73, 95% CI 1.31–2.28). Adjusted for other variables, bulbar onset did not significantly influence time to NIV (HR 0.72, 95% CI 0.47–1.08). Considerable unexplained variability in NIV use was found.ConclusionNIV use was lower than expected in this ALS cohort that was likely to be optimally managed. Absence of respiratory symptoms and female sex may be barriers to NIV use. Prospective exploration of factors affecting adoption of NIV may help bridge this gap and improve care in ALS.

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Clinical Determinants of Disease Progression in Amyotrophic Lateral Sclerosis—A Retrospective Cohort Study

Journal of Clinical Medicine ◽

10.3390/jcm10081623 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1623

Author(s):

Maria Viktoria Requardt ◽

Dennis Görlich ◽

Torsten Grehl ◽

Matthias Boentert

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Motor Neuron ◽

Disease Progression ◽

Rating Scale ◽

Rapid Decline ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Hazard Ratios ◽

Sum Score ◽

Lateral Sclerosis

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that is ultimately fatal but characterized by substantial phenotypic heterogeneity, which is known to impact long-term course and survival. This study investigated clinical determinants of disease progression and outcome in a large cohort of patients with ALS. Methods: Retrospective analysis included comprehensive data from 625 patients who attended a tertiary ALS centre at least twice. Patients were stratified according to five distinct clinical phenotypes: classical ALS; bulbar ALS; ALS with frontotemporal dementia (ALS-FTD); upper motor neuron predominant (UMNP); and lower motor neuron predominant (LMNP). Results: This study confirmed higher age at symptom onset, shorter latency to diagnosis and more rapid decline in the revised ALS Functional Rating Scale sum score as predictors of poor prognosis. Hazard ratios for shorter survival were higher in patients with ALS-FTD versus classical ALS, and in patients with versus without chronic obstructive pulmonary disease (COPD). Mean survival was longest in the UMNP phenotype group. Conclusions: This study confirmed established predictors of shorter survival in ALS and showed that concomitant COPD in particular relates to poor outcome.

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A systematic review of non-motor symptom evaluation in clinical trials for amyotrophic lateral sclerosis

Journal of Neurology ◽

10.1007/s00415-021-10651-1 ◽

2021 ◽

Author(s):

Emily Beswick ◽

Deborah Forbes ◽

Zack Hassan ◽

Charis Wong ◽

Judith Newton ◽

...

Keyword(s):

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Sleep Disturbances ◽

Neuropsychiatric Symptoms ◽

Behavioural Change ◽

Motor Symptom ◽

Motor Symptoms ◽

Behavioural Changes ◽

Non Motor Symptoms ◽

Lateral Sclerosis

Abstract Background Amyotrophic lateral sclerosis (ALS) is increasingly recognised as a multi-system disorder, presenting with common and impactful non-motor symptoms, such as neuropsychiatric symtpoms, cognitive and behavioural changes, pain, disordered sleep, fatigue and problematic saliva. Aim/hypothesis We aimed to systematically review 25 years of ALS clinical trials data to identify if non-motor features were evaluated, in addition to the traditional measures of motor functioning and survival, and where evaluated to describe the instruments used to assess. We hypothesised that assessment of non-motor symptoms has been largely neglected in trial design and not evaluated with ALS-suitable instruments. Methods We reviewed clinical trials of investigative medicinal products in ALS, since the licensing of riluzole in 1994. Trial registry databases including WHO International Trials Registry, European Clinical Trials Register, clinicaltrials.gov, and PubMed were systematically searched for Phase II, III or IV trials registered, completed or published between 01/01/1994 and 16/09/2020. No language restrictions were applied. Results 237 clinical trials, including over 29,222 participants, were investigated for their use of non-motor outcome measures. These trials evaluated neuropsychiatric symptoms (75, 32%), cognitive impairment (16, 6.8%), behavioural change (34, 14%), pain (55, 23%), sleep disturbances (12, 5%) and fatigue (18, 8%). Problematic saliva was assessed as part of composite ALS-FRS(R) scores in 184 trials (78%) but with no focus on this as an isolated symptom. 31 (13%) trials including 3585 participants did not include any assessment of non-motor symptoms. Conclusions Non-motor symptoms such as neuropsychiatric, cognitive and behavioural changes, pain, disordered sleep, fatigue, and problematic saliva have not been consistently evaluated in trials for people with ALS. Where evaluated, non-symptoms were primarily assessed using instruments and impairment thresholds that are not adapted for people with ALS. Future trials should include non-motor symptom assessments to evaluate the additional potential therapeutic benefit of candidate drugs. PROPSERO registration CRD42020223648.

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Informal Caregiving in Amyotrophic Lateral Sclerosis (ALS): A High Caregiver Burden and Drastic Consequences on Caregivers’ Lives

Brain Sciences ◽

10.3390/brainsci11060748 ◽

2021 ◽

Vol 11 (6) ◽

pp. 748

Author(s):

Pavel Schischlevskij ◽

Isabell Cordts ◽

René Günther ◽

Benjamin Stolte ◽

Daniel Zeller ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Functional Status ◽

Disease Severity ◽

Caregiver Burden ◽

Rating Scale ◽

Depression Scale ◽

Anxiety And Depression ◽

Daily Routine ◽

Work Lives ◽

Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive autonomy loss and need for care. This does not only affect patients themselves, but also the patients’ informal caregivers (CGs) in their health, personal and professional lives. The big efforts of this multi-center study were not only to evaluate the caregivers’ burden and to identify its predictors, but it also should provide a specific understanding of the needs of ALS patients’ CGs and fill the gap of knowledge on their personal and work lives. Using standardized questionnaires, primary data from patients and their main informal CGs (n = 249) were collected. Patients’ functional status and disease severity were evaluated using the Barthel Index, the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and the King’s Stages for ALS. The caregivers’ burden was recorded by the Zarit Burden Interview (ZBI). Comorbid anxiety and depression of caregivers were assessed by the Hospital Anxiety and Depression Scale. Additionally, the EuroQol Five Dimension Five Level Scale evaluated their health-related quality of life. The caregivers’ burden was high (mean ZBI = 26/88, 0 = no burden, ≥24 = highly burdened) and correlated with patients’ functional status (rp = −0.555, p < 0.001, n = 242). It was influenced by the CGs’ own mental health issues due to caregiving (+11.36, 95% CI [6.84; 15.87], p < 0.001), patients’ wheelchair dependency (+9.30, 95% CI [5.94; 12.66], p < 0.001) and was interrelated with the CGs’ depression (rp = 0.627, p < 0.001, n = 234), anxiety (rp = 0.550, p < 0.001, n = 234), and poorer physical condition (rp = −0.362, p < 0.001, n = 237). Moreover, female CGs showed symptoms of anxiety more often, which also correlated with the patients’ impairment in daily routine (rs = −0.280, p < 0.001, n = 169). As increasing disease severity, along with decreasing autonomy, was the main predictor of caregiver burden and showed to create relevant (negative) implications on CGs’ lives, patient care and supportive therapies should address this issue. Moreover, in order to preserve the mental and physical health of the CGs, new concepts of care have to focus on both, on not only patients but also their CGs and gender-associated specific issues. As caregiving in ALS also significantly influences the socioeconomic status by restrictions in CGs’ work lives and income, and the main reported needs being lack of psychological support and a high bureaucracy, the situation of CGs needs more attention. Apart from their own multi-disciplinary medical and psychological care, more support in care and patient management issues is required.

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Current clinical trials in amyotrophic lateral sclerosis

Expert Opinion on Investigational Drugs ◽

10.1517/13543784.16.8.1197 ◽

2007 ◽

Vol 16 (8) ◽

pp. 1197-1207 ◽

Cited By ~ 23

Author(s):

Jaydeep M Bhatt ◽

Paul H Gordon

Keyword(s):

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Lateral Sclerosis

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Urate levels predict survival in amyotrophic lateral sclerosis: Analysis of the expanded Pooled Resource Open-Access ALS clinical trials database

Muscle & Nerve ◽

10.1002/mus.25950 ◽

2017 ◽

Vol 57 (3) ◽

pp. 430-434 ◽

Cited By ~ 14

Author(s):

Sabrina Paganoni ◽

Katharine Nicholson ◽

James Chan ◽

Amy Shui ◽

David Schoenfeld ◽

...

Keyword(s):

Clinical Trials ◽

Amyotrophic Lateral Sclerosis ◽

Open Access ◽

Lateral Sclerosis

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Plasma exchange with albumin replacement and disease progression in amyotrophic lateral sclerosis: a pilot study

Neurological Sciences ◽

10.1007/s10072-021-05723-z ◽

2021 ◽

Author(s):

Mónica Povedano ◽

Andrés Paipa ◽

Miquel Barceló ◽

Michael K. Woodward ◽

Sandra Ortega ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Pilot Study ◽

Disease Progression ◽

Plasma Exchange ◽

Rating Scale ◽

Open Label ◽

Primary Endpoints ◽

Rate Of Decline ◽

Post Hoc ◽

Lateral Sclerosis

Abstract Background Plasma exchange (PE) is used to treat a range of neurological disorders. Based on results demonstrated in Alzheimer’s disease, we theorized that PE with albumin replacement (PE-A) might alter the metabolic profile of plasma and cerebrospinal fluid in patients with amyotrophic lateral sclerosis (ALS) by removing disease-inducing molecules. The aim of this study was to evaluate the effect of PE-A on disease progression in ALS. Methods In this open-label, non-controlled, single-arm, prospective pilot study, 13 adults with ALS had 6 months’ treatment with PE-A 5% and 6 months’ follow-up. Primary endpoints were changes from baseline in the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score and forced vital capacity (FVC) through 48 weeks. A post hoc analysis compared individual patient data with the expected ALSFRS-R progression slope. Results The median ALSFRS-R score declined throughout the study, although the rate of decline was slower than expected in seven patients at treatment end and in five patients at study end. Six patients remained in the same baseline slope progression category, and four patients improved their slope category at treatment end. Median FVC decreased significantly during the study. Treatment was well tolerated. Of 330 PE-A procedures, 0.9% were associated with potentially related adverse events. Conclusion Although functional impairment progressed, about two-thirds of patients showed a slower than expected rate of decline at treatment end. Most patients had unaltered (54.5%) or reduced (36.4%) ALSFRS-R slope progression at treatment end. Further evaluation of PE-A in controlled studies involving more patients is warranted. EudraCT number 2013-004842-40. Trial registration ClinicalTrials.gov identifier: NCT02479802.

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