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Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials

OBJECTIVES: Plasma 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. METHODS: We used clinical trial data from three cohorts of clinical t...

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Autores principales: van Eijk, Ruben P A, Eijkemans, Marinus J C, Ferguson, Toby A, Nikolakopoulos, Stavros, Veldink, Jan H, van den Berg, Leonard H
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800333/
https://www.ncbi.nlm.nih.gov/pubmed/29084868
http://dx.doi.org/10.1136/jnnp-2017-317077
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author van Eijk, Ruben P A
Eijkemans, Marinus J C
Ferguson, Toby A
Nikolakopoulos, Stavros
Veldink, Jan H
van den Berg, Leonard H
author_facet van Eijk, Ruben P A
Eijkemans, Marinus J C
Ferguson, Toby A
Nikolakopoulos, Stavros
Veldink, Jan H
van den Berg, Leonard H
author_sort van Eijk, Ruben P A
collection PubMed
description OBJECTIVES: Plasma 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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: Plasma 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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spelling pubmed-58003332018-02-09 Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials van Eijk, Ruben P A Eijkemans, Marinus J C Ferguson, Toby A Nikolakopoulos, Stavros Veldink, Jan H van den Berg, Leonard H J Neurol Neurosurg Psychiatry Neuromuscular OBJECTIVES: Plasma 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. METHODS: We 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. RESULTS: A 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. CONCLUSIONS: Plasma 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. BMJ Publishing Group 2018-02 2017-10-30 /pmc/articles/PMC5800333/ /pubmed/29084868 http://dx.doi.org/10.1136/jnnp-2017-317077 Text en © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
spellingShingle Neuromuscular
van Eijk, Ruben P A
Eijkemans, Marinus J C
Ferguson, Toby A
Nikolakopoulos, Stavros
Veldink, Jan H
van den Berg, Leonard H
Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials
title Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials
title_full Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials
title_fullStr Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials
title_full_unstemmed Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials
title_short Monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials
title_sort monitoring disease progression with plasma creatinine in amyotrophic lateral sclerosis clinical trials
topic Neuromuscular
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800333/
https://www.ncbi.nlm.nih.gov/pubmed/29084868
http://dx.doi.org/10.1136/jnnp-2017-317077
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