An assessment of treatment guidelines, clinical practices, demographics, and progression of disease among patients with amyotrophic lateral sclerosis in Japan, the United States, and Europe

Figures & data

Table 1. Clinical practice and treatment guidelines for ALS in Japan, the United States, and Europe.

	Japan	US	Europe
Diagnosis	1) The presence of upper and lower motor neuron involvement;2) Progressive clinical course; 3) Diagnosis by exclusion. Diagnosis is based on overall clinical findings and complementary test findings (electrophysiological tests, neuroimaging) (Grade C1)El Escorial diagnostic criteria were revised (1998). More sensitive Awaji criteria were proposed (2008).	El Escorial revisited criteriaThe diagnosis of ALS requires:(A) the presence of:(1) evidence of lower motor neuron degeneration by clinical, electrophysiological or neuropathologic examination(2) evidence of upper motor neuron degeneration by clinical examination(3) progressive spread of symptoms or signs within a region or to other regionstogether with:(B) the absence of(1) electrophysiological or pathological evidence of other disease processes(2) neuroimaging evidence of other disease processes	The diagnosis of ALS requiresthe presence of: (positive criteria)- Lower motor neuron signs (including EMG features in clinically unaffected muscles)- Upper motor neuron signs- Progression of symptoms and signs the absence of (diagnosis by exclusion):sensory signs, sphincter disturbances, visual disturbances, autonomic features, basal ganglion, dysfunction, Alzheimer-type dementia, ALS ‘mimic’ syndromes
Care	Multidisciplinary team care improves patient QOL.	Multidisciplinary clinic referral should be considered for managing patients with ALS to optimise health care delivery and prolong survival (Level B) and may be considered to enhance QOL (Level C).	Multidisciplinary care should be available for people affected by ALS. Attendance at multidisciplinary clinics may extend survival, decrease medical complications (level B) and improve quality of life (Level C).
Medication	At present, only oral riluzole is recommended (Grade A)	Riluzole should be offered to slow disease progression (Level A).	Patient with ALS should be offered treatment with riluzole (Level A). Treatment should be initiated as early as possible after diagnosis.
Symptom management	Symptomatic therapy, such as pain, spasms, sialorrhea, insomnia, depression/anxiety, dementia, pressure sores, constipation, compulsive laughter and compulsive crying should be handled.	Effective management of symptoms (sialorrhea, pseudobulbar affect, fatigue, cramps, spasticity, depression/anxiety, insomnia and cognitive/behavioural impairment) is one of the primary goals of ALS patient care.	Control of symptoms such as sialorrhoea, thick mucus, emotional lability, cramps, spasticity and pain should be attempted.
Nutrition support(when oral intake becomes  difficult)	Discontinue oral food intake, or continue it only for the patient's enjoyment, and use enteral nutrition as the primary nutrition source (Grade C1).The risk of PEG placement is lower when %FVC ≥50% (Grade C1).	PEG should be considered to stabilise weight and to prolong survival (Level B). The risk of PEG placement increased when the FVC decline was below 50% of predicted.	PEG feeding improves nutrition and QOL. Gastrostomy tubes should be placed before respiratory insufficiency develops.
Respiratory support	It is recommended that NIV be introduced from the early stages of respiratory disorder (Grade B).Consider tracheostomy if airway clearance deteriorates because of bulbar palsy, or if invasive ventilation is selected (Grade C1).	NIV should be considered to treat respiratory insufficiency in order to lengthen survival (Level B), and may be considered to slow decline of forced vital capacity (Level C) and improve QOL (Level C). Early initiation of NIV may increase compliance (Level C). Tracheostomy invasive ventilation is possibly effective in preserving QOL for patients with ALS, but possibly with a greater burden for their caregivers.	NIV improves survival and QOL. Invasive mechanical ventilation has a major impact upon caregivers and should be initiated only after informed discussion.
Palliative care	Implement preventative measures in advance to avoid painful symptoms during terminal care. If such symptoms appear, provide adequate treatment to relieve each symptom (Grade C1).	As ALS progresses, the goal of patient care changes from maximising function to providing effective and compassionate palliative care.	Advance directives for palliative end-of-life care should be discussed early with the patient and carers.

Japanese guideline.

Grade A; Based on strong scientific evidence; strongly recommended.

Grade B; Scientific evidence available; recommended.

Grade C1; Scientific evidence is lacking, but recommended.

US guideline.

Level A; Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population.

Level B; Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population.

Level C; Possibly effective, ineffective or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population.

European guideline.

Level A; Established as useful/predictive or not useful/predictive.

Level B; Established as probably useful/predictive or not useful/predictive.

Level C; Established as possibly useful/predictive or not useful/predictive.

QOL: quality of life; PEG: percutaneous endoscopic gastrostomy; NIV: non-invasive ventilation; TIV: tracheostomy with invasive ventilation.

Table 2. Demographics and baseline characteristics for ALS in Japan, the United States, and Europe.

Characteristic	Japan (37–44)	US (44–54)	EU (55–67)
Sex (%)^a
Male	57	56–63	54–58^b
Female	43	37–44	42–46^b
Age at onset, mean (years)	61–65	55–62	62–66^b
Race (%)^a
White	0	75–77	66^c
Oriental/Asian	100	4	3^c
Others and Unknown	0	21	31^c
Time from onset to diagnosis, median (months)	11	11–14	9^d
Sporadic ALS, range (%)	93	93–96	91–98^d
Bulbar onset, range (%)	25–30	11–32	19–41^e
Riluzole use, range (%)	59–85	49–72	58–86^f
PEG use, range (%)	29–58	8–43	6–45^f
NIV use, range (%)	7–46	19–87	3–44^g
TIV use, range (%)	29–38	4	1–31^g

^aData generated from references 37, 45, 46, 55 and 56 (race only, including primary lateral sclerosis or progressive muscular atrophy).

^b Ireland, the Netherlands, UK, and Italy.

^c UK.

^d Ireland, UK, and Italy.

^e Ireland, the Netherlands, UK, Italy and Denmark.

^f UK and Italy.

^g UK, Italy, Denmark and Sweden.

PEG: percutaneous endoscopic gastrostomy; NIV: non-invasive ventilation; TIV: tracheostomy with invasive ventilation.

Table 3a. Comparison of demographics and baseline characteristics between reference studies (Placebo group).

Study drug	Creatine (68)	Glatiramer (69)	Acetyl-L- carnitine (70)	Celecoxib (71)	Minocycline (72)	TCH346 (73)	Ceftriaxone (74)	NP001 (75)	Dexpramipexole (36,76)		PRO-ACT Database (35)
Type of study	–	–	–	–	Phase III	Phase II/III	Phase I--III	Phase II	Phase II	Phase III	Phase II--III
Study period (months)
Run-in	NA	NA	NA	NA	4	4	NA	NA	NA	NA	–
Double-blind	12	12	11	12	9	6	12	6	3	12	12 (avg)
Sex (%)
Male	71	60	65	67	64	63.9	58	69	51.9	64	60
Female	29	40	35	33	36	36.1	42	31	49.1	36	40
Age, years (Mean ± SD)	58.4 ± 10.9	56.7 ± 12.1	63^d	55.0 ± 12.4	57.7 ± 10.9	55.5 ± 11.5	55 ± 10	53.7 ± 9.52	55.8 ± 9.07	57.3 ± 11.3	56.2 ± 11.8
Race (%)
White	–	–	–	91	94	95.4	94	97.6	–	94	94.9
Oriental/Asian	–	–	–	–	<1	2.8	3	0	–	1	–
Other	–	–	–	–	5	1.9	2	2.4	–	3	–
BMI (kg/m^2)	–	25.1 ± 3.9	24.0^d	26.95 ± 4.96	–	–	–	–	25.66 ± 3.93	26.2 ± 4.3	25.4 ± 4.4
Disease duration (years^a)	–	1.68 ± 0.68	–	1.91 ± 1.23	1.51 ± 0.79	1.47 ± 0.72	1.50 ± 0.7	1.43 ± 0.74	1.29 ± 0.46	1.29 ± 0.45	1.9 ± 1.4
Initial symptom (%)
Bulbar	19.5	–	22.5	–	20	17.6	20	16.7	25.9	24	NA
Limb	–	–	77.5	82.8	80	82.4	79	83.3	–	–
Diagnostic criteria for ALS	D, P, PLS	D, P, PLS	D, P, PLS	NA	D, P, PLS	D, P, PLS	D, P, PLS, POS	D, P	D, P, PLS, POS		–
Baseline FVC (%)	89 ± 18.4^b	93.8 ± 16.0^b	94^d	85.36 ± 15.13^b	93.8 ± 14.7	–	91 ± 18^b	–	90.4 ± 14.39^b	89.1 ± 17.7^c	86 ± 24^b
Concomitant riluzole (%)	–	–	100	71	66	83.3	74	69	59.3	75	77.5

^aMean time since symptom onset (years); ^bVital capacity data; ^cSlow vital capacity data. ^dMedian.

avg: average; D: definite ALS (as given by El Escorial revised Airlie House criteria); FVC: forced vital capacity; NA: not available; P: probable ALS (as given by El Escorial revised Airlie House); PLS: probable laboratory-supported ALS (as given by El Escorial revised Airlie House criteria); POS: possible ALS (as given by El Escorial revised Airlie House criteria); SD: standard deviation.

Table 3b. Comparison of demographics and baseline characteristics between edaravone studies (Placebo group).

Study Drug	Edaravone MCI186-16 (3)	Edaravone MCI186-16 (4)	Edaravone MCI186-19 (5)
Type of study/Population (Mean ± SD)	Phase III/FAS	Phase III/dpEESP2y	Phase III/FAS
Study period (months)
Run-in	3	3	3
Double-blind	6	6	6
Sex (%)
Male	66.3	62.5	60.3
Female	33.7	37.5	39.7
Age (years)	57.7 ± 10.2	57.5 ± 10.4	60.1 ± 9.6
Race (%)
White	0	0	0
Oriental/Asian	100	100	100
Other	0	0	0
BMI (kg/m^2)	22.0 ± 3.2	21.7 ± 2.7	21.8 ± 2.7
Disease duration (years^a)	1.30 ± 0.63	1.03 ± 0.41	1.06 ± 0.47
Initial symptom (%)
Bulbar	19.2	21.9	20.6
Limb	80.8	78.1	79.4
Diagnostic criteria for ALS	D, P, PLS	D, P	D, P
Baseline FVC (%)	95.8 ± 17.0	101.8 ± 15.2	97.4 ± 13.6
Concomitant riluzole (%)	88.5	78.1	91.2

^aMean time since symptom onset (years).

D: definite ALS (as given by El Escorial revised Airlie House criteria); FVC: forced vital capacity; P: probable ALS (as given by El Escorial revised Airlie House criteria); PLS: probable laboratory-supported ALS (as given by El Escorial revised Airlie House criteria); SD: standard deviation.

Study MCI186-16 was the first phase III study. Study MCI186-19 was the second phase III study using dpEESP2y inclusion criteria that showed drug effect in post-hoc analyses of study MCI186-16. The dpEESP2y inclusion criteria are as follows: a baseline score of 2 points or better on each individual item of the ALSFRS-R; normal respiratory function (%FVC ≥ 80%) at baseline; definite or probable ALS; and within 2 years after initial symptom.

Table 4a. Slope of time dependent change in ALSFRS-R score between reference studies (Placebo group).

Study Drug	Creatine (68)	Glatiramer (69)	Acetyl-L- carnitine (70)	Celecoxib (71)	Minocycline (72)	TCH346 (73)	Ceftriaxone (74)	NP001 (75)	Dexpramipexole (36,76)		PRO-ACT Database (35)
Type of Study	–	–	–	–	Phase III	Phase II/III	Phase I/III	Phase II	Phase II	Phase III	Phase II--III
n	87	182	40	99	206	108	173	42	27	468	4838
Baseline ALSFRS-R score  (Mean ± SD)	30.74 ± 4.9	38.1 ± 5.4	42	43.24 ± 5.17	37.9 ± 5.17	–	36.9 ± 5.4	38.2 ± 5.6	37.3 ± 5.14	37.9 ± 5.7	38.37 ± 5.22
Slope (change/month)  (LS Mean ± SE)	−1.02^a	−1.00 ± 0.06	−1.60 ± 1.39	−1.078 ± 0.907	−1.04 ± 0.07	−0.942	−1.22 ± 0.06	−0.89	−1.28	−1.12^b	−1.02 ± 2.3

^aMedian; ^bIn publication, mixed model for repeated measures data for 12 months (–13.42) is presented. Data were derived from the MMRM result assuming a linear change for 12 months (–13.42/12 months = –1.12/month).

LS Mean: least-squares mean; SD: standard deviation; SE: standard error.

Table 4b. Slope of time dependent change in ALSFRS-R score between edaravone studies (Placebo group).

Study Drug	Edaravone MCI186-16 (3)	Edaravone MCI186-16 (4)	Edaravone MCI186-19 (5)
Type of study/population	Phase III/FAS	Phase III/dpEESP2y	Phase III/FAS
n	104	32	68
Baseline ALSFRS-R score (Mean ± SD)	41.2 ± 2.9	42.2 ± 2.2	41.8 ± 2.2
Slope (change/4 weeks) (LS Mean ± SE)	−1.03 ± 0.10	−1.21 ± 0.21	−1.21 ± 0.11

LS Mean: least-squares mean; SD: standard deviation; SE: standard error.

Study MCI186-16 was the first phase III study. Study MCI186-19 was the second phase III study using dpEESP2y inclusion criteria that showed drug effect in post-hoc analyses of study MCI186-16. The dpEESP2y inclusion criteria are as follows: a baseline score of 2 points or better on each individual item of the ALSFRS-R; normal respiratory function (%FVC ≥ 80%) at baseline; definite or probable ALS; and within two years after initial symptom.

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