Evidence map›Paper›PMID 34433481›Full record

ArticleTranslational neurodegeneration2021

Neurofilament light and heterogeneity of disease progression in amyotrophic lateral sclerosis: development and validation of a prediction model to improve interventional trials.

Simon Witzel, Felix Frauhammer, Petra Steinacker, David Devos, Pierre-François Pradat, Vincent Meininger, Steffen Halbgebauer, Patrick Oeckl, Joachim Schuster, Simon Anders and 3 more

2 registry-linked trialsAbstract readValidation Study
PubMed Full text at PMC Publisher
In one paragraph

Article in Translational neurodegeneration, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 26 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
26citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT00868166 phase3completednot on this map

Phase II/III, Multicenter, Randomized, Parallel Group, Double-blind, Placebo Controlled Study to Assess Safety and Efficacy of TRO19622 in Amyotrophic Lateral Sclerosis (ALS) Patients Treated With Riluzole

TypeinterventionalSponsorHoffmann-La RocheRan2009 to 2011Enrolled512ConditionsAmyotrophic Lateral SclerosisArmsOlesoxime, Placebo Comparator, Riluzole
NCT02306590 nacompletednot on this map

Efficacy, Safety and Tolerability of High Lipid and Calorie Supplementation in Amyotrophic Lateral Sclerosis

TypeinterventionalSponsorUniversity of UlmRan2015 to 2018Enrolled207ConditionsAmyotrophic Lateral SclerosisArmsCalogen, Placebo
3 · Its place in the literature

Who cites it

26 citing papers in PubMed, 1 synthesis or guideline pooled it.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors.

Simon Witzel *Department of Neurology, University of Ulm, Ulm, Germany. simon.witzel@uni-ulm.de.ORCID 0000-0003-1841-954X
Felix Frauhammer *Center for Molecular Biology, Heidelberg University, Heidelberg, Germany.
Petra SteinackerDepartment of Neurology, University of Ulm, Ulm, Germany.
David DevosDepartment of Medical Pharmacology, Expert center for Parkinson, CHU-Lille, Lille Neuroscience and Cognition, Inserm, UMR-S1172, LICEND, NS-Park Network, University of Lille, Lille, France.
Pierre-François PradatLaboratoire D'Imagerie Biomédicale, Sorbonne Université, CNRS, INSERM, Paris, France.
Vincent MeiningerAPHP, Département de Neurologie, Hôpital Pitié-Salpêtrière, Paris, France.
Steffen HalbgebauerDepartment of Neurology, University of Ulm, Ulm, Germany.
Patrick OecklDepartment of Neurology, University of Ulm, Ulm, Germany.
Joachim SchusterDepartment of Neurology, University of Ulm, Ulm, Germany.
Simon AndersCenter for Molecular Biology, Heidelberg University, Heidelberg, Germany.
Johannes DorstDepartment of Neurology, University of Ulm, Ulm, Germany.
Markus Otto *Department of Neurology, University of Ulm, Ulm, Germany.
Albert C Ludolph *Department of Neurology, University of Ulm, Ulm, Germany.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundInterventional trials in amyotrophic lateral sclerosis (ALS) suffer from the heterogeneity of the disease as it considerably reduces statistical power. We asked if blood neurofilament light chains (NfL) could be used to anticipate disease progression and increase trial power.

methodsIn 125 patients with ALS from three independent prospective studies-one observational study and two interventional trials-we developed and externally validated a multivariate linear model for predicting disease progression, measured by the monthly decrease of the ALS Functional Rating Scale Revised (ALSFRS-R) score. We trained the prediction model in the observational study and tested the predictive value of the following parameters assessed at diagnosis: NfL levels, sex, age, site of onset, body mass index, disease duration, ALSFRS-R score, and monthly ALSFRS-R score decrease since disease onset. We then applied the resulting model in the other two study cohorts to assess the actual utility for interventional trials. We analyzed the impact on trial power in mixed-effects models and compared the performance of the NfL model with two currently used predictive approaches, which anticipate disease progression using the ALSFRS-R decrease during a three-month observational period (lead-in) or since disease onset (ΔFRS).

resultsAmong the parameters provided, the NfL levels (P < 0.001) and the interaction with site of onset (P < 0.01) contributed significantly to the prediction, forming a robust NfL prediction model (R = 0.67). Model application in the trial cohorts confirmed its applicability and revealed superiority over lead-in and ΔFRS-based approaches. The NfL model improved statistical power by 61% and 22% (95% confidence intervals: 54%-66%, 7%-29%).

conclusionThe use of the NfL-based prediction model to compensate for clinical heterogeneity in ALS could significantly increase the trial power. NCT00868166, registered March 23, 2009; NCT02306590, registered December 2, 2014.

Indexed as

Amyotrophic Lateral SclerosisDisease ProgressionModels, NeurologicalNeurofilament ProteinsAgedBiomarkersClinical Trials as TopicCohort StudiesFemaleHumansMaleMiddle AgedObservational Studies as TopicPredictive Value of TestsProspective StudiesReproducibility of ResultsBiomarkersneurofilament protein LNeurofilament ProteinsAmyotrophic lateral sclerosisDisease progressionInterventional trialsNeurofilament lightPrediction modelStatistical power

Identifiers

PMID34433481
PMCPMC8390195

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.