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

Abstract

Objective

One of the difficulties in developing a novel drug for patients with amyotrophic lateral sclerosis (ALS) is the significant variation in the clinical course. To control this variation, a 12-week run-in period is used in some clinical trials. Based on the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) change during the run-in period, only moderate progressors are selected in some clinical trials. Some reports showed that the ALSFRS-R progression rate was associated with survival. However, it is unclear whether the ALSFRS-R change in the run-in period is a useful prognostic factor of the ALSFRS-R change from baseline. In addition, we explore the inclusion criteria that could control the variability in ALS-function progression without setting a run-in period.

Methods

We utilized the Japanese and US ALS registry databases (JaCALS and PRO-ACT). Patients were classified into three populations (rapid, moderate, and slow progressors) based on the ALSFRS-R change prior to baseline. We also classified patients into three prognostic populations based on the ALSFRS-R change from baseline. We confirmed whether each of the three populations were matched with their respective three prognostic populations.

Results

Our data showed that the three groups classified by the ALSFRS-R change during the 12 weeks prior to baseline or by the rate of progression from onset to baseline did not accord with the three prognostic groups.

Conclusions

Our results showed that the ALSFRS-R change in the run-in period or from onset to baseline is not useful for stratifying subsequent progression of functional decline in clinical trials.

Keywords:

• JaCALS
• PRO-ACT, ALSFRS-R, clinical trial
• heterogeneity

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Correction

Introduction

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which both upper and lower motor neurons degenerate progressively (1). Neurodegeneration leads to bulbar palsy, limb muscular atrophy, and death due to dysphagia or respiratory muscular palsy, with a median survival time of 2–4 years from onset (1). It has been reported that different phenotypes of ALS might have different rates of progression (2).

Treatment options for ALS are very limited, although riluzole (3, 4), edaravone (5, 6), sodium phenylbutyrate and taurursodiol (PB-TURSO) (7–9), and tofersen (10, 11) are available in the US. In the meantime, the degree of difficulty in developing new drugs is high as evidenced by the fact that more than 50 clinical trials have failed to find an effective form of treatment in the last 50 years (12). However, due to the progress in ALS research, drug development for this condition has been active internationally, and the number of new clinical trials is increasing.

To monitor disease progression, the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) is commonly used. It consists of 12 items to evaluate bulbar function, motor function, and respiratory function, and each item is evaluated from 0 (unable) to 4 (normal). The total points (0–48) also serve as the gold standard for primary efficacy outcomes in clinical trials (13). Edaravone has successfully completed a phase 3 trial using the ALSFRS-R as the primary endpoint measure. The Phase 3 trial targeted early-stage patients and included subjects who had a 1- to 4-point worsening in the ALSFRS-R total score during the 12-week run-in period prior to the treatment period (6). The variability in ALS progression is thought to have been controlled and the study appeared to be successful. Since then, a 12-week run-in period prior to the treatment period has been commonly used in clinical trials in Japan (14–18). In the US and EU, a 12-week run-in period is not common in clinical studies because a run-in period of this duration is not considered suitable for ALS patients given their short life expectancy. Some reports showed that the ALSFRS-R progression rate was associated with survival (19–22). Thakore et al reported that the run-in slope correlated with the post-baseline slope (23). Although estimated the run-in slope is a predictor, another group reported the rate of change in the ALSFRS-R was frequently non-linear (24). When the impact of predicting post-baseline slope using the run-in slope to set inclusion criteria is small, it would be better to intervene earlier rather than setting a run-in period. Therefore, it is important to evaluate the value of setting a run-in period.

In this study, we aimed to confirm whether the rate of deterioration in the 12 weeks before the treatment period was useful for controlling the heterogeneity of ALSFRS-R progression or not. In addition, we explored the inclusion criteria that could control the variability in ALS-symptom progression without setting a 12-week run-in period. In conducting the present research, we utilized Japanese and US ALS registry databases. The Japanese Consortium for Amyotrophic Lateral Sclerosis Research (JaCALS) has been utilized in the search for clinical markers, biomarkers, and modifier genes related to the course and prognosis of ALS (2, 21, 22, 25–27). It is the largest ALS registry in Japan. The Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database is a publicly available repository that merges data from existing publicly and privately conducted ALS clinical trials (28). By using both databases, we planned to evaluate whether or not the change in ALSFRS-R during the 12 weeks prior to baseline is useful to control ALSFRS-R heterogeneity after baseline in clinical trials.

Materials and methods

Datasets

The JaCALS and PRO-ACT databases were used. For JaCALS database research, data were collected from 38 sites in Japan from January 2006 to the beginning of the analysis (24 August 2022). The protocol for our JaCALS research was approved by the School of Medicine Ethical Review Board of Aichi Medical University. This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and in compliance with the protocol, and Ethical Guidelines for Medical and Biological Research Involving Human Subjects. PRO-ACT represents the largest aggregation of placebo and treatment-arm data from 29 Phase II/III clinical trials. As of 1 August 2022, 111,675 de-identified clinical patient records were included. We obtained the dataset in August 2022 via a web-based application (available at https://ncri1.partners.org/ProACT).

Eligibility criteria for JaCALS database research

All of the following criteria should be met; 1) Patients aged 18 years or older and less than 80 years at the time of onset, 2) Patients with an ALSFRS-R total score at baseline (baseline was defined in each patient as the time point closest to week 78 between weeks 52 and 104 after onset), 3) Definite, probable, laboratory-supported probable, or possible ALS according to the El Escorial criteria, 4) Patients with an ALSFRS-R total score at baseline and 12 weeks (±8 weeks) prior to baseline, 5) Patients who had at least one ALSFRS-R total score recorded during the 48 weeks after baseline. In addition, patients were not included if they met either of the following criteria: 1) Patients undergoing tracheostomy at baseline, 2) Patients who are considered unsuitable for analysis identified by data review.

Eligibility criteria for PRO-ACT database research

All of the following criteria should be met; 1) Patients aged 18 years or older and less than 80 years at the time of onset, 2) Patients with an ALSFRS-R total score at baseline (baseline was defined in each patient as the time point closest to week 78 between weeks 52 and 104 after onset), 3) Patients with an ALSFRS-R total score at baseline and 12 weeks (±8 weeks) prior to baseline, 4) Patients who had at least one ALSFRS-R total score recorded during the 48 weeks after baseline, 5) Patients in the placebo group. Patients were not included if they met either of the following criteria: 1) Patients undergoing tracheostomy at baseline, 2) Suspected ALS according to the El Escorial criteria.

Formula for calculating change/slope of ALSFRS-R total score

The change in ALSFRS-R total score during the 12 weeks prior to baseline was calculated using the ALSFRS-R total score closest to week 12, within the period from week 4 to week 20, prior to baseline, using the following equation: $$[\{(\text{total score at baseline})-(\text{total score 12 weeks prior to baseline})\}/\text{day difference between two measured days}]\times \text{84}$$

The rate of progression of the ALSFRS-R total score from onset to baseline was calculated by the following equation: $$\left[\left\{(\text{total score at baseline})-(\text{total score at onset})\right\}/\text{day difference between two measured days}\right]\times \text{3}0$$

Patients’ classification (rapid, moderate, and slow progression population)

Patients were classified into the following three populations based on the change in ALSFRS-R total score during the 12 weeks prior to baseline. This categorization was same as that used in the edaravone phase 3 studies (5, 6).

• Rapid progressors with ALSFRS-R total score change in the 12 weeks prior to baseline faster than -4

• Moderate progressors with ALSFRS-R total score change of -1 to -4 during the 12 weeks prior to baseline

• Slow progressors with ALSFRS-R total score change in the 12 weeks prior to baseline slower than -1

Patients were classified into the following three prognostic populations based on the change in ALSFRS-R total score from baseline at Weeks 24 and 48.

• Rapid progressors whose ALSFRS-R total score change from baseline at Week 48 is faster than −16 (ALSFRS-R total score change from baseline at Week 24 is faster than −8)

• Moderate progressors whose ALSFRS-R total score change from baseline at Week 48 is -4 to -16 (ALSFRS-R total score change from baseline at Week 24 is − 2 to −8)

• Slow progressors whose ALSFRS-R total score change from baseline at Week 48 is slower than –4 (ALSFRS-R total score change from baseline at Week 24 is slower than –2)

For calculating the slope from onset to baseline, ALSFRS-R total score at onset and baseline were used. In the event there was no score at onset, 48 points was adopted as the onset score.

Statistical analysis

Continuous variables were summarized using number of cases (n), mean, standard deviation (S.D.), and number of missing data cases. Discrete variables were presented as percentage of the number of cases and the number of cases included in the analysis as needed.

Cross tabulations were performed examine the distribution of the two different classifications of populations, as before and after the baseline. In order to evaluate whether the change in ALSFRS-R during the 12 weeks prior to baseline is not useful for stratifying subsequent progression, the consistency between three populations classified by ALSFRS-R total score change during 12 weeks prior to baseline and three prognostic populations at Week 48 was evaluated by the weighted kappa coefficient for ordinal scales. Quadratic weighting was used to calculate the weighted kappa coefficient. As a sensitivity analysis, the data up to Week 24 was analyzed in a same manner. In addition, for the exploration the inclusion criteria without setting a 12-week run-in period, the cutoff for rate of progression of ALSFRS-R total score from onset to baseline with the highest kappa coefficient is selected as the best control for the variability of ALS-functional progression. When ALSFRS-R total score at Week 48 (or Week 24) was missing, the change in ALSFRS-R total score from baseline at Week 48 (or Week24) was calculated based on the score at the time point closest to Week 48. Statistical analyses of JaCALS and PRO-ACT data were performed using SPSS Statistics 28.0 for Windows (IBM SPSS Statistics; Chicago, IL, USA) and SAS software, version 9.4 (SAS Institute; Cary, NC, USA), respectively.

Patients

Patient dispositions from the JaCALS and PRO-ACT databases are presented in Figure 1. In terms of the JaCALS database, the analysis dataset included 246 ALS patients. For PRO-ACT database research, 585 ALS patients were used for the analysis. Patients were classified into three patient populations (rapid, moderate, and slow progressors) based on the change in ALSFRS-R total score during the 12 weeks prior to baseline. In JaCALS, the proportions of rapid, moderate, and slow progressors were 32.9% (81/246), 32.1% (79/246), and 35.0% (86/246). In PRO-ACT, the proportions of rapid, moderate, and slow progressors were 31.1% (182/585), 33.3% (195/585), and 35.6% (208/585). These proportions were well balanced between the two databases. The characteristics and baseline of the included patients are shown in Table 1. Male patients accounted for 58.5% in JaCALS and 62.6% in PRO-ACT. The mean age of all patients was 62.1 years and 56.5 years, respectively. The mean of the ALSFRS-R total score at baseline (± SD) was 32.6 ± 10.9 in JaCALS and 33.6 ± 8.0 in PRO-ACT. The main demographic and baseline data in JaCALS were similar to those in PRO-ACT.

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.

Results

ALSFRS-R total score from onset to Week 48

Figure 2 showed the individual plots in the JaCALS and PRO-ACT databases. The ALSFRS-R total score for each population was analyzed up to 48 weeks from onset (Table 2). At Week 24, the percentage of patients who had ALSFRS-R data was 72.0% (177/246) in JaCALS and 72.8% (426/585) in PRO-ACT. At Week 48, the percentage of patients who had ALSFRS-R data was 52.8% (130/246) and 28.7% (168/585), respectively. The baseline score in the rapid progression group was lower than that of the slow progression group in JaCALS and PRO-ACT. However, the progression rate was not significantly different between either group at Week 24 and Week 48 in both databases.

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.

Prognosis of the populations classified by ALSFRS-R total score change during the 12 weeks prior to baseline

Table 3 showed that three groups classified by the change during the 12 weeks prior to baseline were not in concordance with the three prognostic groups in JaCALS (Kappa coefficient 0.126). Of the patients in the moderate group, 49.4% (39/79) showed a moderate decline (-4 to −16 points for 48 weeks) after baseline. The other 50.6% (40/79) showed a slow (less than −4 points for 48 weeks) or rapid (more than −16 points for 48 weeks) progression. The analysis of PRO-ACT produced similar results (Kappa coefficient: 0.180). Of the patients in the moderate group, 48.2% (94/195) showed a moderate decline (-4 to −16 points decrease for 48 weeks). In the total population without categorization based on the ALSFRS-R change prior to baseline, 45.9% (113/246) of JaCALS patients and 48.2% (282/585) of PRO-ACT patients in the moderate group showed a decline of −4 to −16 points over 48 weeks. As a sensitivity analysis, the data up to Week 24 were analyzed in the same manner. The results were consistent with those obtained using the data up to Week 48 (Supplementary Table 1).

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.

Prognosis of the populations classified by ALSFRS-R total score from onset to baseline

Cutoffs for the rate of progression of the ALSFRS-R total score from onset to baseline similar to the three classifications based on the change in the ALSFRS-R total score during the 12 weeks prior to baseline (rapid, moderate, slow progression populations) were explored. The cutoffs with the highest Kappa coefficients were Rapid (change per month < −1.20), Moderate (−1.20 ≦change per month ≦–0.45), and Slow (change per month > −0.45) in JaCALS (Supplementary Table 2). However, the concordance between the three populations classified by the rate of progression from ALS onset to baseline and the three prognostic populations (those with a change from baseline to 48 weeks faster than −16, ranging from −16 to −4, and slower than −4, respectively) was low (Kappa factor 0.036) (Table 4A). The same analysis was conducted using the PRO-ACT data. The cutoffs with the highest Kappa coefficients were Rapid (change per month <–1.10), Moderate (–1.10≦change per month ≦–0.50), and Slow (change per month > −0.50) in PRO-ACT (Supplementary Table 2). The concordance between the three populations classified by the rate of progression from onset to baseline and the three prognostic populations was low (Table 4B).

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.

Discussion

Our database research is the first study to evaluate whether the ALSFRS-R change during the 12 weeks prior to baseline is useful to control ALSFRS-R heterogeneity in clinical trials. We conducted our study using the JaCALS and PRO-ACT databases. The main demographic and baseline data were similar in both databases in our analysis population. Our data showed that three groups classified by the change during the 12 weeks prior to baseline were not in concordance with the three prognostic groups in JaCALS (Kappa coefficient 0.126). The analysis using 24-week data was conducted to minimize the impact of missing data. The results obtained using 24-week data were similar to those using 48-week data. In addition, the results from the PRO-ACT database research were robustly consistent with those of JaCALS. In the JaCALS database research, 49.4% (39/79) of patients in the moderate group showed moderate progression after baseline. However, 45.9% (113/246) of all subjects also showed moderate decline without classification based on the change in the 12 weeks prior to baseline. Given the above, ALSFRS-R change during the 12 weeks prior to baseline would not be a key factor to stratify subsequent decline of ALSFRS-R in the setting of clinical trials although a previous research reported that estimated the run-in slope correlated with the post-baseline slope (23). We focused on the likely target population in clinical trial and directly evaluated the usefulness of the run-in slope as a single factor. It might be a potential reason for the divergent conclusions. Our research also showed that 40-50% of slow progressors and rapid progressors classified by the ALSFRS-R change in the 12 weeks prior to baseline became moderate progressors after baseline. Thus, patients might lose the opportunity to participate clinical trials due to the eligibility criteria based on the ALSFRS-R change in the run-in period.

PB-TURSO was approved by the FDA based on the positive ALSFRS-R results (7). In the trial, early ALS patients who were within 18 months of symptom onset were enrolled without a run-in period. In Japan, an ultrahigh-dose methylcobalamin phase 3 study showed the effect of treatment on ALSFRS-R (14). In the phase 3 study, patients within 12 months of symptom onset were enrolled. In addition, post-hoc analysis of dexpramipexole and edaravone studies showed that targeting early ALS patients is important to detect the therapeutic effects of treatment (29, 30). Given these results, intervention at the early stage of ALS appears to be a critical factor. A post-hoc survival analysis of the PB-TURSO phase 2 study (CENTAUR) also clarified the advantage of early intervention (8, 9). In CENTAUR, patients with ALS were randomized 2:1 to PB-TURSO or placebo. CENTAUR consisted of a 24-week double-blind randomized phase and an open-label extension in which all subjects were administered PB-TURSO. A survival benefit was observed among participants originally randomized to PB-TURSO compared to those originally randomized to placebo. This indicates that 6-month early intervention is important to detect a survival benefit and highlights the fact that a 12-week run-in period delays intervention by 12 weeks. This could have the effect of impairing the results of ALS clinical trials.

The alternative eligibility criteria using the slope from onset to baseline have been used in several clinical trials (11, 31, 32). Our study showed that the concordance between the three populations classified by the rate of progression from ALS onset to baseline and the three prognostic populations (those with a change from baseline to 48 weeks faster than −16, those with a change ranging from −16 to −4, and those with a change slower than −4) was low based on the JaCALS and PRO-ACT database research. Given these results, eligibility criteria using the slope from onset to baseline does not appear to be a key factor to stratify subsequent progression of ALSFRS-R after baseline. Post-hoc analyses also showed that the correlation coefficients between the change during 12 weeks prior to baseline and the change from baseline at Week 48 were low (Pearson: 0.014, Spearman: 0.118) in JaCALS. The correlation was also low (Pearson: −0.103, Spearman: 0.006) for the rate of progression from onset to baseline. Results in PRO-ACT were similar to those in JaCALS (Supplementary Table 3). A previous report showed that the rate of change in the ALSFRS-R was frequently non-linear from onset (24). The non-linearity was observed in our research as well although the research focus was different. The previous work did not mimic the setting of recent clinical trials. On the other hand, we set a similar baseline point to other clinical trials and evaluated the slope between pre- and post-baseline. Therefore, our results showed the impact of non-linearity on the clinical trial design. In the setting of clinical trials, a 12-week run-in period, which requires extra time, would not have an additional value in the setting of clinical trials compared to the index (the rate of progression from onset to baseline) obtained in a single baseline assessment.

The present study has some limitations. First, this was a retrospective study. Second, data were insufficient to confirm robustness in certain subgroups such as a subgroup population with forced vital capacity of more than 80%. A run-in period might be useful in these subgroup populations. Third, the baseline was set arbitrarily in our study because there is no baseline timepoint in JaCALS’s real-world data. The baseline was defined in each patient as the time point closest to week 78 between weeks 52 and 104 after onset given the mean of ALS duration in the edaravone phase 3 studies (5, 6). This could be a potential source of bias. Fourth, in our research, the total ALSFRS-R score at baseline was relatively severe than other clinical trials (5–7).

In conclusion, our research results showed that the ALSFRS-R change during the 12 weeks prior to baseline or from onset to baseline is not useful to for stratifying subsequent progression of functional decline in clinical trials. It would be better to intervene early rather than setting a run-in period.

Acknowledgements

We would like to thank the doctors and staff as well as all the patients with ALS who participated in JaCALS and PRO-ACT. We would also like to extend our thanks to Ariko Takanashi, Shinichi Kanazawa, Yoshinori Imokawa and Takahiro Higuchi from A2 Healthcare Corporation who supported the analysis of the data from JaCALS.

Disclosure statement

No potential conflict of interest was reported by the author(s).

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.

Correction Statement

This article was originally published with errors, which have now been corrected in the online version. Please see Correction (http://dx.doi.org/10.1080/21678421.2024.2320987).

Additional information

Funding

Tatsuto Hamatani and Fumiya Sano are employees of Sumitomo Pharma Co., Ltd. This study was supported by Sumitomo Pharma Co., Ltd. The other authors report that they have no competing interests to declare.