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BRIEF COMMUNICATIONS: F. Kimura, C. Fujimura, S. Ishida, H. Nakajima, D. Furutama, H. Uehara, K. Shinoda, M. Sugino, and T. Hanafusa Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS Neurology 2006; 66: 265-267 [Abstract] [Full text] [PDF]

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Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS

Paul H. Gordon, Ying Kuen Cheung   (24 May 2006)

Reply from the Author

Fumiharu Kimura   (24 May 2006)

Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS 24 May 2006
Paul H. Gordon, Columbia University Neurological Institute, 9th Floor, 710 West 168th St, New York, NY 10032, Ying Kuen Cheung Send Correspondence to journal: Re: Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS phg8{at}columbia.edu Paul H. Gordon, et al.	We read with interest the article by Kimura et al [1] describing assessment of progression rate at time of diagnosis using the ALS Functional Rating Scale (ALSFRS-R). It is difficult to measure progression in ALS trials because there are no biomarkers, and the standard outcomes are clinical. Six months are needed to detect changes in the ALSFRS-R because of variability, due principally to differing rates of progression among patients. Stratified enrollment lowers variability by reducing heterogeneity in the treatment arms. While site of onset and riluzole treatment may impart modest effects, the person’s rate of progression is the most important predictor of outcome. [2] It is theoretically possible to assign strata using historical information on progression at the baseline visit of a trial using the DeltaFS. [1] We measured the DeltaFS for our clinic patients to find the cutoff value that best dichotomizes the population into two groups for an upcoming phase II trial. We used DeltaFS = (48-"baseline" ALSFRS-R) / time from onset to "baseline" (months). We took first visit to clinic as baseline. Unlike Kimura et al who considered survival as primary endpoint, our primary outcome is the 6- month change in ALSFRS-R. Of 442 patients with information on DeltaFS (median=0.55, inter-quartile range=[0.269, 1.11]), 112 patients had ASLFRS -R scores at baseline and 6 months later. The reduction in variance was maximized when the cutoff 0.50 per month was used to separate fast and slow progression: The mean of the 6-month score in the fast progression group was 4.11 points lower than that in the slow progression group (p<0.0001). Using the cutoff suggested by Kimura et al (0.67), variance reduction was significant (p=0.0005) with mean for fast progression 3.67 lower than that for slow progression. The DeltaFS is an excellent measure to determine rate of progression at first encounter, and can be used for stratification in clinical trials. Both 0.50 and 0.67 are acceptable points of dichotomization in terms of reducing heterogeneity in the study population, although 0.50 provides slightly better reduction and is slightly easier arithmetically. We recommend that individual studies choose a dichotomization cutoff based on their data, as the value could change slightly from region to region. Further analysis may provide a global value of dichotomization for stratification in clinical trials. References 1. Kimura F, Fujimura C, Ishida S, et al. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 2006;66:265- 267. 2. Armon C, Moses D. Linear estimates of rates of disease progression as predictors of survival in patients with ALS entering clinical trials. J Neurol Sci 1998;160:S37-41. Disclosure: The authors report no conflicts of interest.
Reply from the Author 24 May 2006
Fumiharu Kimura, Osaka Medical College Daigaku-machi 2-7, Takatsukishi, Osaka, Japan 569-8686 Send Correspondence to journal: Re: Reply from the Author in1110{at}poh.osaka-med.ac.jp Fumiharu Kimura	We thank Drs. Gordon and Cheung you for their correspondence and confirmation that our progression rate (DFS) at first encounter is a significant clinical marker measuring future progression in ALS trials. A dichotomization of DFS value at baseline in their study of 442 ALS patients was 0.55, compared to our DFS of 0.67 in 82 subjects. A one point reduction per each two months of ALSFRS-R score until diagnosis of ALS was an average. We also appreciate their investigation of DFS values in the upcoming ALS phase II trial and anticipate that future analyses at various facilities and trials may provide a global standard value. A comparison of detailed clinical characteristics would be necessary to determine whether the difference between our DFS of 0.67 and their indicated DFS value of 0.55 was due to differences in study populations (i.e., racial factors, clinical profiles or facility characteristics). One possible explanation is that we enrolled patients who had progressed to definite ALS after observing state of progression up to the endpoint, which you used 6 months after diagnosis. Patients with still probable or possible ALS who did not progress to definite ALS, some of whom tended to display low DFS were not included. We also took a value of DFS=0.5 as an important cut-off point and discussed prognosis for the following three arbitrary groupings of DFS in our paper: < 0.5, 0.5-1.0 and †1.0. In our study, mean duration from initial onset to diagnosis was about 14.2 months, and setting the DFS=0.55 produces an ALSFRS-R score at diagnosis of 40.19 (48-0.55x14.2). This score was higher than the actual our ALSFRS-R score at diagnosis of 38.7, indicating the inclusion of milder cases at diagnosis. A mean ALSFRS-R score of 38 at diagnosis was previously reported [3] and was almost identical to our data. We concur that progression rate (DFS) at diagnosis represents sequential progression of ALS until respiratory failure and that it is a valid predictor of prognosis. We anticipate the adoption of this simple and meaningful clinical marker in future ALS clinical trials. References 3. Kaufmann P, Levy G, Thompson JLP, et al. The ALSFRSr predicts survival time in an ALS clinic population. Neurology 2005;64:38-43. Disclosure: The author reports no conflicts of interest.