ALSFRS-R decline rate prior to baseline is not useful for stratifying subsequent progression of functional decline

Figures & data

Figure 1. Disposition. A: JaCALS; B: PRO-ACT. Abbreviations: ALS: amyotrophic lateral sclerosis; ALSFRS-R: amyotrophic lateral sclerosis functional rating scale - Revised.

Table 1. Patient characteristics and baseline.

A: JaCALS
		Rapid		Moderate		Slow		All
N		81		79		86		246
Sex, n (%)	Male	48	(59.3)	47	(59.5)	49	(57.0)	144	(58.5)
	Female	33	(40.7)	32	(40.5)	37	(43.0)	102	(41.5)
Age, years (at baseline)	Mean	61.26		62.73		62.28		62.09
	S.D.	9.757		10.511		11.585		10.639
ALS duration from onset, days (at baseline)	Mean	540.0		543.6		549.0		544.3
	S.D.	39.3		39.5		40.3		39.7
Diagnostic criteria (at baseline), n (%)	Definite	15	(18.5)	13	(16.5)	11	(12.8)	39	(15.9)
	Probable	42	(51.9)	33	(41.8)	36	(41.9)	111	(45.1)
	Probable- Laboratory supported	19	(23.5)	30	(38.0)	30	(34.9)	79	(32.1)
	Possible	5	(6.2)	3	(3.8)	9	(10.5)	17	(6.9)
ALS diagnosis, n (%)	Familial ALS	2	(2.5)	5	(6.3)	3	(3.5)	10	(4.1)
	Sporadic ALS	79	(97.5)	74	(93.7)	83	(96.5)	236	(95.9)
Riluzole use (within 1 year after baseline), n (%)	Yes	58	(71.6)	54	(68.4)	58	(67.4)	170	(69.1)
	No	23	(28.4)	25	(31.6)	28	(32.6)	76	(30.9)
ALSFRS-R total score (at baseline)	Mean	25.4		35.6		36.7		32.6
	S.D.	9.5		8.5		10.8		10.9
% Forced vital capacity (at baseline)	n	22		15		15		52
	Mean	67.8		77.1		92.6		77.6
	S.D.	23.2		17.8		20.8		23.1
	Missing	59		64		71		194
B: PRO-ACT
		Rapid		Moderate		Slow		All
N		182		195		208		585
Sex, n (%)	Male	106	(58.2)	130	(66.7)	130	(62.5)	366	(62.6)
	Female	76	(41.8)	65	(33.3)	78	(37.5)	219	(37.4)
Age, years (at baseline)	Mean	58.3		56.1		55.4		56.5
	S.D.	10.7		10.8		11.2		11.0
ALS duration from onset, days (at baseline)	Mean	546.7		542.2		545.9		544.9
	S.D.	15.4		21.3		17.0		18.2
Diagnostic criteria (El Escorial criteria) (at baseline), n (%)	Definite	48	(26.4)	49	(25.1)	46	(22.1)	143	(24.4)
	Probable	46	(25.3)	52	(26.7)	51	(24.5)	149	(25.5)
	Probable- Laboratory supported	13	(7.1)	23	(11.8)	27	(13.0)	63	(10.8)
	Possible	6	(3.3)	4	(2.1)	11	(5.3)	21	(3.6)
	Missing	69	(37.9)	67	(34.4)	73	(35.1)	209	(35.7)
ALS diagnosis, n (%)	Familial ALS	0	(0.0)	0	(0.0)	0	(0.0)	0	(0.0)
	Sporadic ALS	182	(100.0)	195	(100.0)	208	(100.0)	585	(100.0)
Riluzole use (at screening of each trial), n (%)	Yes	145	(79.7)	147	(75.4)	155	(74.5)	447	(76.4)
	No	14	(7.7)	25	(12.8)	30	(14.4)	69	(11.8)
	Missing	23	(12.6)	23	(11.8)	23	(11.1)	69	(11.8)
ALSFRS-R total score (at baseline)	Mean	27.7		34.9		37.6		33.6
	S.D.	7.4		6.4		6.7		8.0
% Forced vital capacity (at baseline)	n	71		84		79		234
	Mean	69.7		80.8		81.4		77.7
	S.D.	21.0		20.3		20.4		21.1
	Missing	111		111		129		351

Data are presented as n (%) or mean ± SD. Abbreviations: ALS: amyotrophic lateral sclerosis; ALSFRS-R: amyotrophic lateral sclerosis functional rating scale – Revised; S.D.: standard deviation.

Figure 2. ALSFRS-R individual plot. A: JaCALS; B: PRO-ACT. Abbreviations: ALSFRS-R: amyotrophic lateral sclerosis functional rating scale - Revised.

Table 2. ALSFRS-R total score from onset to Week 48.

A: JaCALS
		Onset		12-week prior to baseline		Baseline	Week 12		Week 24		Week 36		Week 48
		Observed score	Change per month	Observed score	Change (Change per month)	Observed score	Observed score	Change (Change per month)	Observed score	Change (Change per month)	Observed score	Change (Change per month)	Observed score	Change (Change per month)
Rapid	N	81		81		81	58		65		52		39
	Mean	48.0	−1.23	34.1	−8.39 (–3.00/M)	25.4	21.3	−3.66 (–1.31/M)	20.7	−5.54 (–1.00/M)	16.6	−9.19 (–1.09/M)	15.9	−10.60 (–0.95/M)
	S.D.	0.00	0.55	8.13	4.18	9.52	10.23	3.71	10.40	5.48	11.65	7.55	10.41	8.52
Moderate	N	79		79		79	55		57		50		41
	Mean	48.0	−0.67	38.2	−2.28 (–0.81/M)	35.6	32.5	−2.92 (–1.04/M)	29.8	−7.00 (–1.25/M)	28.8	−9.15 (–1.09/M)	26.4	−10.96 (–0.98/M)
	S.D.	0.00	0.46	8.34	0.81	8.52	9.72	3.29	9.55	6.26	9.38	8.29	9.53	8.17
Slow	N	86		86		86	66		55		55		50
	Mean	48.0	−0.61	36.9	−0.10 (–0.04/M)	36.7	33.6	−2.47 (–0.88/M)	30.7	−5.33 (–0.95/M)	30.2	−6.45 (–0.77/M)	29.3	−7.98 (–0.71/M)
	S.D.	0.00	0.60	10.88	0.70	10.82	11.50	3.22	11.67	6.38	13.54	7.25	12.45	8.39
All	N	246		246		246	179		177		157		130
	Mean	48.0	−0.83	36.4	−3.53 (–1.26/M)	32.6	29.3	−2.99 (–1.07/M)	26.7	−5.94 (–1.06/M)	25.2	−8.22 (–0.98/M)	24.3	−9.71 (–0.87/M)
	S.D.	0.00	0.61	9.37	4.30	10.94	11.88	3.42	11.46	6.03	13.14	7.75	12.31	8.41
B: PRO-ACT
		Onset		12-week prior to baseline		Baseline	Week 12		Week 24		Week 36		Week 48
		Observed score	Change per month	Observed score	Change (Change per month)	Observed score	Observed score	Change (Change per month)	Observed score	Change (Change per month)	Observed score	Change (Change per month)	Observed score	Change (Change per month)
Rapid	N	182		182		182	174		122		76		41
	Mean	48.00	−1.12	34.2	−6.86 (–2.45/M)	27.7	23.9	−3.73 (–1.33/M)	20.8	−7.61 (–1.36/M)	19.1	−9.53 (–1.14/M)	17.8	−11.45 (–1.02/M)
	S.D.	0.00	0.41	6.63	2.59	7.38	8.71	3.68	8.96	5.37	9.86	6.75	8.75	6.80
Moderate	N	195		195		195	185		144		103		57
	Mean	48.00	−0.73	37.3	−2.52 (–0.90/M)	34.9	32.1	−2.87 (–1.02/M)	30.6	−5.21 (−0.93/M)	28.6	−7.98 (–0.95/M)	26.4	−10.00 (–0.89/M)
	S.D.	0.00	0.35	6.25	0.90	6.39	8.09	3.50	7.49	4.24	8.97	5.67	10.00	7.57
Slow	N	208		208		208	197		160		113		70
	Mean	48.00	−0.57	37.2	0.61 (0.22/M)	37.6	34.7	−3.00 (–1.07/M)	33.4	−4.91 (–0.88/M)	30.5	−8.02 (–0.96/M)	28.2	−10.72 (–0.96/M)
	S.D.	0.00	0.37	6.76	1.6	6.66	7.90	3.14	8.64	4.59	8.92	5.96	9.90	8.21
All	N	585		585		585	556		426		292		168
	Mean	48.00	−0.79	36.3	−2.76 (–0.99/M)	33.6	30.4	−3.19 (–1.14/M)	28.8	−5.79 (–1.03/M)	26.9	−8.40 (–1.00/M)	25.1	−10.66 (–0.95/M)
	S.D.	0.00	0.44	6.69	3.54	7.97	9.37	3.45	9.86	4.85	10.29	6.09	10.50	7.64

Abbreviation: S.D.: standard deviation.

Table 3. Prognosis of the populations classified by changes during 12 weeks prior to baseline.

A: JaCALS
		Three prognostic groups based on changes in ALSFRS-R total score from baseline to week 48
		Rapid progression <-16		Moderate progression -16≦　≦-4		Slow progression -4<
	Total N = 246	65	26.4%	113	45.9%	68	27.6%	Kappa
Three groups based on changes in ALSFRS-R total score during 12 weeks prior to baseline	Rapid progression (N = 81)	22	27.2%	40	49.4%	19	23.5%	0.126
	Moderate progression (N = 79)	25	31.6%	39	49.4%	15	19.0%
	Slow progression (N = 86)	18	20.9%	34	39.5%	34	39.5%
B: PRO-ACT
		Three prognostic groups based on changes in ALSFRS-R total score from baseline to week 48
		Rapid progression <-16		Moderate progression -16≦　≦-4		Slow progression -4<
	Total N = 585	186	31.8%	282	48.2%	117	20.0%	Kappa
Three groups based on changes in ALSFRS-R total score during 12 weeks prior to baseline	Rapid progression (N = 182)	75	41.2%	87	47.8%	20	11.0%	0.180
	Moderate progression (N = 195)	60	30.8%	94	48.2%	41	21.0%
	Slow progression (N = 208)	51	24.5%	101	48.6%	56	26.9%

Data are presented as n, % or kappa coefficient. Cross tabulations were performed examine the distribution of the two different classifications of populations, as before and after the baseline. The consistency between three populations classified by ALSFRS-R total score change during 12 weeks prior to baseline and three prognostic populations at Week48 was evaluated by the weighted kappa coefficient for ordinal scales in JaCALS(A) and PRO-ACT(B). Quadratic weighting was used to calculate the weighted kappa coefficient. Abbreviations: ALSFRS-R: amyotrophic lateral sclerosis functional rating scale - Revised.

Table 4. Prognosis of the population classified by ALSFRS-R total score from onset to baseline.

A: JaCALS
		Three prognostic groups based on changes in ALSFRS-R total score from baseline to week 48
		Rapid progression < −16		Moderate progression −16≦　≦−4		Slow progression −4<
	Total N = 246	65	26.4%	113	45.9%	68	27.6%	Kappa
Three groups based on the rate of progression from onset to baseline	Rapid progression: change per month <-1.20 (N = 57)	11	19.3%	28	49.1%	18	31.6%	0.036
	Moderate progression: −1.20≦change per month≦-0.45 (N = 115)	38	33.0%	55	47.8%	22	19.1%
	Slow progression: change per month >-0.45 (N = 74)	16	21.6%	30	40.5%	28	37.8%
B: PRO-ACT
		Three prognostic groups based on changes in ALSFRS-R total score from baseline to week 48
		Rapid progression <-16		Moderate progression −16≦　≦-4		Slow progression −4<
	Total N = 585	186	31.8%	282	48.2%	117	20.0%	Kappa
Three groups based on the rate of progression from onset to baseline	Rapid progression: change per month <-1.10 (N = 131)	52	39.7%	67	51.1%	12	9.2%	0.240
	Moderate progression: −1.10≦change per month ≦-0.50 (N = 283)	105	37.1%	131	46.3%	47	16.6%
	Slow progression: change per month >-0.50 (N = 171)	29	17.0%	84	49.1%	58	33.9%

Data are presented as n, % or kappa coefficient. Cross tabulations were performed examine the distribution of the two different classifications of populations, as before and after the baseline. The consistency between three populations classified by the rate of progression from ALS onset to baseline and three prognostic populations at Week48 was evaluated by the weighted kappa coefficient for ordinal scales in JaCALS(A) and PRO-ACT(B). Quadratic weighting was used to calculate the weighted kappa coefficient. Abbreviations: ALSFRS-R: amyotrophic lateral sclerosis functional rating scale - Revised.

Data availability statement

PRO-ACT data are openly available at https://ncri1.partners.org/ProACT. The participants of JaCALS did not give written consent for their data to be shared publicly, so due to the sensitive nature of the research supporting data is not available.