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.
- amyotrophic lateral sclerosis
- plasma creatinine
- disease progression
- clinical trials
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Contributors RPAvE: study concept, design, analysis, interpretation of data and drafting manuscript. MJCE: study concept, design, analysis and interpretation of data. TAF: acquisition of data, critical revision of manuscript for intellectual content. SN: analysis and critical revision of manuscript for intellectual content. JHV: study concept, critical revision of manuscript for intellectual content. LHvdB: study supervision and critical revision of manuscript for intellectual content.
Disclaimer RPAvE reports no disclosures, MJCE reports no disclosures, TAF is an employee of Biogen Idec and hold shares in Biogen Idec, SN reports no disclosures, JV reports no disclosures, LHvd serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen Idec and Cytokinetics; received an educational grant from Baxter International; serves on the editorial board of Amyotrophic Lateral Sclerosis and the Journal of Neurology, Neurosurgery and Psychiatry; and receives research support from the Prinses Beatrix Spierfonds, Netherlands ALS Foundation, The European Community’s Health Seventh Framework Programme (grant agreement n° 259867), The Netherlands Organization for Health Research and Development (Vici Scheme, JPND (SOPHIA,STRENGTH)).
Competing interests None declared.
Patient consent Obtained.
Ethics approval Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
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