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

Abstract

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.

Keywords: amyotrophic lateral sclerosis; clinical trials; disease progression; plasma creatinine.

Figure 1

Longitudinal decline in ALSFRS-R total score and plasma creatinine level. Matched longitudinal ALSFRS-R and laboratory data from 50 patients in the LITRA study, 936 patients in the EMPOWER study and 255 patients in the PROACT database. The red solid line is the mean rate of decline over time. Both the ALSFRS-R and plasma creatinine declined significantly over time (all p<0.001; LR test). The red shaded area is 1 SD around the mean rate of decline and represents the variability between patients over time. Note the severe funnelling out in ALSFRS-R total scores and the more homogenous pattern of decline in plasma creatinine, best seen in the EMPOWER and PROACT cohorts. ALSFRS-R, amyotrophic lateral sclerosis functional rating scale–revised; LR test, likelihood ratio test.

Figure 2

Longitudinal relationship between muscle strength and plasma creatinine during a 12-month follow-up period. Mean values with bootstrapped 95% CIs are given for plasma creatinine and muscle strength at bimonthly follow-up moments for the first 12 months in the EMPOWER study.

Figure 3

Sample size and power calculations for plasma creatinine and the ALSFRS-R. Sample size calculations were performed for the ALSFRS-R and plasma creatinine, with varying total follow-up durations (ranging 6–18 months) and with either bimonthly or monthly return visits. All calculations were based on an expected standardised 30% reduction in slope during follow-up, with a two-sided alpha of 5% and power of 90%. For short trials (up to 10 months), the smaller between-patient variability at baseline and relatively faster rate of decline of the ALSFRS-R (see online supplementary eTable 1) resulted in smaller sample sizes. For longer trials (>10 months), sample size calculations for plasma creatinine, when determined in micromoles per litre, resulted in smaller sample sizes due to the lower variability between patients in rate of decline (A). When plasma creatinine levels were determined in micrograms per decilitre, this advantage was lost (B). The utility of plasma creatinine seems higher in spinal-onset patients (C) as compared with bulbar-onset patients (D). ALSFRS-R, amyotrophic lateral sclerosis functional rating scale–revised.