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

Abstract

Background: There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between different countries and regions. Objective: To assess similarities and differences in clinical practice and treatment guidelines for ALS, and also to compare the demographics and rate of progression of disease in patients with ALS enrolled in clinical trials in Japan, the US, and Europe. Methods: We performed a review of clinical studies published since 2000 to compare the demographics and characteristics of patients with ALS. Progression of ALS disease was assessed in patients receiving placebo. The changes per month in ALSFRS-R score were calculated and compared between the studies. Results: Overall, diagnostic criteria, recognition of ALS symptoms, comorbidities, use of riluzole, and nutritional, and respiratory support were similar. Regarding demographics and characteristics, there were no clear differences in the incidence of sporadic ALS (range 91–98%), bulbar onset (range 11–41%), and median time from onset to diagnosis (range 9–14 months) among the populations despite the difference in race between regions. However, use of tracheostomy-based invasive respiratory support was higher in Japan (29–38%) than in the US (4%) and Europe (1–31%). Rate of progression of disease was similar between the US and Europe study populations (range –0.89 to –1.60 points/month), and the Japanese study populations (range –1.03 to –1.21 points/month). Conclusion: There is evidence to support the generalisability of data from the Japanese ALS trial experience to the US and Europe populations in early to mid-stage of ALS.

Keywords:

• Amyotrophic lateral sclerosis
• guideline
• treatment patterns
• disease progression
• edaravone

Introduction

Edaravone (MCI-186) has been hypothesised to be a free radical scavenger, and was developed as a treatment for amyotrophic lateral sclerosis (ALS). Phase II and phase III clinical studies of edaravone have suggested edaravone may slow the progression of functional disability in Japanese patients with ALS (1–5).

Increased oxidative stress in ALS patients, demonstrated by high level biomarkers for oxidised DNA (6–11), lipids (10–13) and proteins (14–18) or by low level of uric acid (19–24), has been extensively reported in Asia, the US, and Europe. Increased oxidative stress appears to be a common and underlying phenomenon in ALS, independent of sporadic or familial aetiology (9,16). Multiple studies suggest that oxidative stress may play a major role in the progression of motor neuron degeneration and astrocyte dysfunction, leading to progressive deterioration in motor neurons (25,26).

In the preceding article, the authors describe similar PK profiles of edaravone between Japanese and Caucasian populations. To further assess that the Japanese ALS trial experience can be generalised in the US and Europe, similarities and differences among patients with ALS in Japan, the US, and Europe were compared with regard to clinical practice and treatment guidelines, demographics and baseline characteristics, and progression of disease (evaluated by ALSFRS-R score). We here describe the results of this comparison.

Methods

Clinical practice and treatment guidelines

To assess the similarities and differences that might exist in the care of patients with ALS, region-specific practice guideline documents were reviewed and compared for Japan (27,28), the US (29–33), and Europe (34) by the authors. Japanese guideline documents were translated into English and each item was compared among guidelines.

Demographics and characteristics

An informal literature review was performed to compare published data regarding demographics and characteristics for ALS patients including, but not limited to: age, gender, race, family history of ALS, site of onset, time to onset, and use of medical interventions (e.g. pharmacological, gastrostomy, respiratory/ventilation support). The informal search was conducted in PubMed using common terms associated with ALS, for example ‘amyotrophic lateral sclerosis’, ’motor neuron disease’, ‘tracheostomy’, ‘TIV’, ‘NIV’, and ‘PEG’, as well as other relevant terms such as ‘epidemiology’, ‘prevalence’, ‘survival’, ‘prognosis’, and ‘quality of life’. We also manually searched the literature referenced in internet sites or articles focussed on ALS epidemiology. Articles published after 2000 were considered for inclusion.

Progression of disease

To compare the disease course of ALS among Japanese and the US and European populations, a brief literature search was conducted in PubMed using the search strings ‘amyotrophic lateral sclerosis’ and ‘controlled trial’. Articles published after 2000 were considered for inclusion. The results of this brief literature search were further reviewed to identify those which examined an investigational therapy in a double-blind, placebo-controlled study design. The data from these studies (described here as reference studies) were compared with data from two Japanese phase III clinical studies of edaravone (MCI186-16 (3,4), and MCI186-19 (5)). Published studies that had a placebo withdrawal phase or had <20 patients were not included as part of the reference study comparison. Studies with a treatment period >1 year and those conducted prior to 2000 were also excluded.

To compare the slope of the ALSFRS-R (change per month) in patients receiving placebo between the reference and edaravone studies, we used the results from a random coefficient model using the intercept and slope for each treatment group as fixed effects, and the intercept and slope of each patient as random effects. These two random effects were assumed to be a bivariate normal distribution with an unstructured covariance matrix. The assumption of this model is that the ALSFRS-R score declines in a linear fashion by individual patient. To determine the clinical relevance of the calculation, the results were compared with data in published literature from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database (35). The database comprises longitudinal data in more than 8000 patients with ALS who had enrolled in 17 unique clinical studies.

Furthermore, to compare change from baseline in ALSFRS-R score between a recent phase III study of dexpramipexole (36) and the edaravone studies, we used the results of a mixed model for repeated measurements (MMRM) with treatment group, time, treatment group-by-time interaction and stratified factors using dynamic randomisation, and baseline value of ALSFRS-R score as the covariate when considering the edaravone studies.

Results

Clinical practice and treatment guidelines

Overall, the treatment of ALS in Japan, the US, and Europe is nearly identical in both guidelines and practice, in terms of identification, diagnosis, prognosis, culture of care, and management of disease progression (Table 1). There is consensus to confirm the presence of upper and lower neuron degenerations with progressive symptoms (or signs) and diagnosis by exclusion (El Escorial criteria) and the use of a physical examination to support a diagnosis of ALS. There is also recognition of symptoms associated with ALS and the acknowledgement of its complications including cognitive and behavioural impairment, sialorrhoea, impaired communication, and impaired swallowing. The importance of coordinated interdisciplinary care is also emphasised in the practice guidelines. For example, the US based guidance recognises increased survival when interdisciplinary care is available in specialty centres, while the Japan based guidance highlights the enhancement of quality of life associated with the availability of interdisciplinary care. The Europe-based guideline recommends that attendance at multidisciplinary clinics may extend survival, decrease complications, and improve quality of life.

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.

Riluzole is recommended as first line therapy for the treatment of ALS in Japan, the US, and Europe. Currently, no other drugs are globally approved for slowing the progression of ALS. There may be modest differences in some of the medications that are prescribed for secondary complications and symptomatic relief, likely the result of availability of products in the different regions. There is also a similar awareness of the requirements for nutritional support in patients with ALS, with advice regarding the most appropriate time for different interventions, including percutaneous endoscopic gastrostomy (PEG) placement.

Non-invasive ventilation (NIV) and tracheostomy-invasive ventilation (TIV) are similarly recommended in the practice guidelines, in addition to various methods of manual and mechanical therapeutic interventions. However, there appears to be less flexibility in the Japanese guidelines about the terminal choice of discontinuation of TIV compared to that noted in the US and European guidelines.

Demographics and characteristics

Published literature suggests demographics and characteristics of patients with ALS to be similar in Japan, the US, and Europe (Table 2) (37–67). Patients ranged from 55 to 66 years of age (mean) at onset of the disease and time to diagnosis ranged from nine to 14 months (median). More than half of patients with ALS were male (range 54%–63%).

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.

A majority of patients with ALS were receiving riluzole (range 49%–86%), the only primary pharmacological treatment approved to treat ALS in Japan, the US, and Europe. There was no published literature describing prevalence of symptomatic therapies for ALS.

Use of PEG appeared to be highly variable in US and European centers. Generally, the prevalence of PEG use appeared to be slightly higher in Japan than noted for the US or European countries. Prevalences of NIV were also reported with large variabilities even in the same region, but might be relatively higher in the US than Japan and European countries. On the other hand, the prevalence of TIV in Japan was clearly higher than reported for the US or Europe. However, the uptake for use of this invasive respiratory support varied by European country. For example, in the United Kingdom the prevalence of TIV was quite low (1%) while the method appeared to be more common in Italy (10%–31%).

Progression of disease

Through a targeted PubMed search, we identified 159 citations to be of interest. Of these, a total of 10 reference studies investigating nine compounds for ALS were identified to assess the disease course of ALS (36,68–76). The reference studies were compared with the results from three Japanese clinical studies of edaravone (3–5).

As anticipated, the reference studies included a majority of Caucasian patients, while the edaravone studies comprised solely Japanese patients. On average, BMI was less in the edaravone studies compared to the reference studies. In general, the use of riluzole was greater in the edaravone studies than that reported in the reference studies. The duration of disease was less in the edaravone studies compared to the reference studies, likely related to a specific inclusion criterion requiring patients to be within two years of first symptom of ALS. A summary of demographics and baseline characteristics is provided in Table 3(a,b).

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.

Despite these differences in demographics, the progression of disease in patients who received placebo, as assessed by slope changes in the ALSFRS-R score, was similar between the reference studies (range across 10 studies –0.89 to –1.60 points/month) and the edaravone studies (range across two studies –1.03 to –1.21 points per four weeks) (Table 4(a,b)). These results correspond with published longitudinal data from the PRO-ACT database (–1.02 points/month).

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.

Additionally, we compared the change from baseline in ALSFRS-R score using MMRM analyses because the most recent phase III study of dexpramipexole focussed on the change from baseline in ALSFRS-R score using this methodology rather than change in the slopes of ALSFRS-R score. Although the published literature of the dexpramipexole study describes only the change in ALSFRS-R score at 12 months, we estimated the six-month data from a figure in the literature showing a change of approximately –7 points from baseline in the placebo group. This is very similar with changes from baseline on placebo calculated by MMRM in the full analysis set in the study MCI186-19 (–7.37 points) and the definite or probable/EESP/2y population from the study MCI186-16 (–6.97 points).

Discussion

Clinical practice and treatment guidelines for ALS in Japan, the US, and Europe appeared to be similar in terms of diagnosis, symptoms, medical treatment, non-invasive and invasive mechanical support, and multidisciplinary care. This was not unexpected given the most recent ALS guidelines from Japan and Europe make reference to the US based guidance. However, given the similarities among the regions, it is interesting that the tone and emphasis of each guideline appeared modestly different, reflecting potential cultural differences. For example, the US based guidance tends to recognise increased survival for ALS patients when interdisciplinary care is available in specialty centers and the Japan based guidance highlights the enhancement of quality of life with the availability of interdisciplinary care. The Europe based guideline emphasises importance to maintain the patient's ability to communicate and patient autonomy with every possible effort.

For the treatment of ALS, riluzole is the only drug indicated for the treatment of ALS in all three regions – Japan, the US, and Europe. Other drugs may be used for symptomatic therapy of ALS such as botulinum toxin injections or anticholinergic medications for sialorrhoea, mucolytic for bronchial secretions, antidepressant for depression in the different regions; however, it is unlikely such symptomatic therapies affect the primary course of disease in ALS or measures of functional loss over time (as commonly assessed by the ALSFRS-R).

The use of PEG and NIV appeared to be highly variable in US and European centers, making it difficult to compare the prevalence of its use among the three regions. On the other hand, Japan had a higher prevalence of TIV than that reported in the US and Europe. This could possibly be due to more frequent introduction of TIV as well as less flexibility to terminate mechanical support in Japan.

Although there were expected differences in both race and body weight in Japan, the US, and Europe, the demographics of ALS patients were similar in terms of age, gender, onset of disease, and diagnosis. Despite demographic differences, the progression of disease in patients who received placebo, as assessed by slope changes in the ALSFRS-R score, was similar between the reference studies (conducted in the US and Europe) and the edaravone studies (conducted in Japan). These results correspond with published longitudinal data from the PRO-ACT database. Taken together, the consistency in reported rates of disease progression may suggest similarity of ALS in Japan, the US, and Europe.

There are some limitations for this analysis. First, the review of the literature was not designed to be systematic. This was partly due to the information being sought for analysis: specifically, details about regional treatment practices and specific demographics. With that in mind, using targeted search terms may have narrowed the pool of relevant articles for review. Subsequently, our informal review methodology means that selection bias in the literature search cannot be ruled out.

One limitation is the post-hoc nature of the performed statistical analyses. We used standard methods to calculate slopes of ALSFRS-R change or change from baseline (i.e. random coefficient model and MMRM, which were used for the majority of reference studies). However, this is not a cohort study with prospectively planned statistical analyses; such comparisons among studies with different backgrounds may need to be interpreted with caution. Even with these limitations, the results obtained with our analysis were fairly consistent.

Another limitation is a difference between general patient populations and specific clinical study populations. Clinical trials are usually conducted to enrol patients who meet specific inclusion and exclusion criteria, in order to reduce variability of patient characteristics when evaluating a drug effect. Edaravone studies included only patients in whom all individual item of the ALSFRS-R were 2 points or greater, with almost normal respiratory function (%FVC 80% or greater) at baseline, definite or probable ALS and within two years after initial symptom, to show measurable disease progression over 24 weeks. Other reference studies also appear to have included patients with relatively early to mid-stage ALS. Although inclusion and exclusion criteria of edaravone studies may be stricter, rates of disease progression rate were similar to other reference studies. Therefore, the question as to whether or not the results of the edaravone studies might be generalisable to the larger population of individuals, who may not necessarily meet typical study inclusion criteria for registration studies in ALS, will need to be confirmed over time.

Edaravone, described as a free radical scavenger, was developed for ALS in Japan. High oxidative stress in ALS patients has been extensively reported in Japan, the US and Europe. Therefore, ethnic differences in response to edaravone may be considered to be unlikely. Furthermore, the preceding article demonstrated the similarity of PK profile of edaravone between Japanese and Caucasian subjects, the latter predominating in ALS populations in Europe and the US.

In conclusion, there is evidence to suggest that medical practice and progression of disease are similar between Japan, the US and Europe with the exception of tracheostomy-based invasive ventilation (TIV) in late stage ALS. The Japanese clinical trial experience, including data obtained in patients with early to mid-stage ALS, may be generalisable to patients at similar stages of ALS in the US and Europe.

Declaration of interest

KT and KT are employees of Mitsubishi Tanabe Pharma Development America (MTDA). FT and MH are employees of Mitsubishi Tanabe Pharmaceutical Corporation (MTPC). JP is an employee of MTDA and MTPC. The authors take full responsibility for the content of and the decision to submit this manuscript but thank Teresa A. Oblak, of Covance Market Access Services Inc. for providing research support, coordination assistance, and editorial contributions.

MTPC and MTDA were responsible for the oversight of the literature reviews and statistical contributions for this analysis. MTDA also provided medical writing support for this article. The edaravone (MCI-186) clinical trials were funded by MTPC. The ALSFTD supplement, Edaravone (MCI-186) in amyotrophic lateral sclerosis (ALS), was funded by Mitsubishi Tanabe Pharma America, Inc.