Post-hoc analysis of MCI186-17, the extension study to MCI186-16, the confirmatory double-blind, parallel-group, placebo-controlled study of edaravone in amyotrophic lateral sclerosis

Figures & data

Table 1. Disposition of patients in each population.

	Number of patients (patients who discontinued from the study)
Treatment group	FAS	EESP	dpEESP2y
E-E	48 (14)	27 (3)	22 (3)
E-P	44 (7)	25 (2)	16 (2)
P-E	88 (16)	44 (7)	29 (6)
Total	180 (37)	96 (12)	67 (11)

E-E = patients were treated with edaravone in cycles 1 through 12.

E-P = patients were treated with edaravone in cycles 1 through 6 and placebo in cycles 7 through 12.

P-E = patients were treated with placebo in cycles 1 through 6 and edaravone in cycles 7 through 12.

Table 2. Demographics and baseline characteristics of the dpEESP2y population.

Item	E-E (n = 22)	E-P (n = 16)	P-E (n = 29)
	n (%)	n (%)	n (%)
Sex^a
Male	12 (54.5)	13 (81.3)	18 (62.1)
Female	10 (45.5)	3 (18.8)	11 (37.9)
Initial symptom^a
Bulbar	4 (18.2)	0 (0.0)	7 (24.1)
Limb	18 (81.8)	16 (100.0)	22 (75.9)
ALS diagnosis^a
Sporadic	21 (95.5)	16 (100.0)	29 (100.0)
Familial	1 (4.5)	0	0
Diagnosis (EL Escorial revised Airlie House diagnostic criteria)^a
Definite	10 (45.5)	7 (43.8)	9 (31.0)
Probable	12 (54.5)	9 (56.3)	20 (69.0)
Japan ALS severity classification
Grade 1	4 (18.2)	3 (18.8)	5 (17.2)
Grade 2	14 (63.6)	9 (56.3)	14 (48.3)
Grade 3	4 (18.2)	2 (12.5)	5 (17.2)
Grade 4	0	2 (12.5)	4 (13.8)
Grade 5	0	0	1 (3.4)
Use of riluzole
Yes	21 (95.5)	14 (87.5)	24 (82.8)
No	1 (4.5)	2 (12.5)	5 (17.2)
Change in ALSFRS-R score during pre-observation
-4, -3	6 (27.3)	1 (6.3)	9 (31.0)
-2, -1	16 (72.7)	15 (93.8)	20 (69.0)
Item	E-E (n = 22) median (min-max)	E-P (n = 16) median (min-max)	P-E (n = 29) median (min-max)
Age^a (years)	58.0 (38-72)	54.5 (31-64)	57.0 (28-75)
Body weight^a (kg)	55.0 (40-72)	64.0 (50-77)	57.0 (37-83)
Height^a (cm)	162.5 (148-179)	167.5 (154-180)	165.0 (150-181)
Duration of disease^a (years)	1.20 (0.5-1.8)	1.30 (0.6-2.0)	0.90 (0.3-1.8)
ALSFRS-R score
Before pre-observation period	44.5 (37-48)	44.5 (39-47)	44.0 (41-48)
At baseline	42.5 (36-47)	43.5 (37-46)	42.0 (37-47)
At the end of cycle 6	38.0 (27-45)	39.5 (28-46)	38.0 (14-47)
%FVC
At baseline	99.6 (80.5-124.0)	101.75 (84.2-124.6)	101.3 (80.8-143.4)
At the end of cycle 6	93.85 (47.2-119.1)	92.1 (81.1-118.1)	88.9 (38.4-127.1)

ALSFRS-R = the Revised ALS Functional Rating Scale.

%FVC = percent predicted forced vital capacity.

E-E = patients were treated with edaravone for cycles 1 through 12.

E-P = patients were treated with edaravone for cycles 1 through 6 and placebo for cycles 7 through 12.

^a Data obtained from baseline in cycle 1.

Figure 1. Forest plots of between-group differences in least-squares mean (Δ LS-mean) of ALSFRS-R change in the FAS, EESP, and dpEESP2y during double-blind treatment.

1a. From baseline to week 24 of study MCI186-16; 1b from week 24 to week 48 of study MCI186-17.

FAS = full analysis set; EESP = efficacy-expected sub-population of ALS patients (% forced vital capacity of ≥80% before treatment and ≥2 points for all item scores in the ALSFRS-R before treatment); dpEESP2y = subgroup of the EESP, containing patients with a diagnosis of ‘definite’ or ‘probable’ ALS according to the El Escorial revised Airlie House diagnostic criteria and with disease duration of ≤2 years; ALSFRS-R = revised ALS functional rating scale; CI = confidence interval; SE = standard error.

Table 3. Changes in ALSFRS-R scores in study MCI186-16 and subsequent study MCI186-17 in FAS, subpopulation of each criterion in FAS, EESP and dpEESP2y (LOCF).

Study number and population (evaluation period)			Adjusted mean	Δ
	Group	n (LOCF)	LS mean ± SE	LS mean ± SE (95% CI)	p-value
MCI186-16 FAS (baseline to cycle 6)	E	100	−5.70 ± 0.85	0.65 ± 0.78 (-0.90, 2.19)	0.4108
	P	99	−6.35 ± 0.84
Scores of ≥2 points on all 12 items of ALSFRS-R (baseline of cycle 6)	E	64	−5.83 ± 1.27	1.35 ± 1.04 (-0.71, 3.42)	0.1969
	P	65	−7.18 ± 1.18
%FVC ≥80% (baseline to cycle 6)	E	79	−4.82 ± 0.86	1.11 ± 0.77 (-0.42, 2.63)	0.1548
	P	74	−5.93 ± 0.82
Definite or probable ALS based on El Escorial revised criteria (baseline to cycle 6)	E	80	−6.46 ± 0.99	0.97 ± 0.95 (-0.90, 2.84)	0.3057
	P	71	−7.43 ± 0.98
Disease duration of ≤2 years after the first symptom (baseline to cycle 6)	E	80	−6.4 ± 0.95	0.32 ± 0.86 (-1.37, 2.01)	0.7088
	P	86	−6.72 ± 0.94
MCI186-16 EESP (baseline to cycle 6)	E	53	−4.85 ± 1.24	2.20 ± 1.03 (0.15, 4.26)	0.0360
	P	46	−7.06 ± 1.13
MCI186-16 dpEESP2y (baseline to cycle 6)	E	39	−4.58 ± 1.55	3.01 ± 1.33 (0.35, 5.67)	0.0270
	P	29	−7.59 ± 1.34
MCI186-17 FAS (baseline of cycle 7 to cycle 12)	E-E	44	−4.42 ± 0.69	1.16 ± 0.93 (-0.70, 3.01)	0.2176
	E-P	41	−5.58 ± 0.74
Scores of ≥2 points on all 12 items of ALSFRS-R (baseline of cycle 7 to cycle 12)	E-E	29	−4.15 ± 0.91	2.1 ± 1.18 (-0.26, 4.47)	0.0805
	P-E	28	−6.25 ± 1.03
%FVC ≥80% (baseline of cycle 7 to cycle 12)	E-E	41	−4.11 ± 0.69	1.03 ± 0.96 (-0.89, 2.94)	0.2884
	P-E	33	−5.13 ± 0.78
Definite or probable ALS based on El Escorial revised criteria (baseline of cycle 7 to cycle 12)	E-E	35	−4.52 ± 0.78	1.89 ± 1.05 (-0.21,3.98)	0.0765
	P-E	32	−6.4 ± 0.85
Disease duration of ≤2 years after the first symptom (baseline of cycle 7 to cycle 12)	E-E	34	−4.58 ± 0.83	1.46 ± 1.10 (-0.75, 3.66)	0.1911
	P-E	33	−6.04 ± 0.89
MCI186-17 EESP (baseline of cycle 7 to cycle 12)	E-E	27	−4.01 ± 0.86	1.85 ± 1.14 (-0.45, 4.15)	0.1127
	E-P	25	−5.86 ± 0.98
MCI186-17 dpEESP2y (baseline of cycle 7 to cycle 12)	E-E	22	−4.22 ± 1.04	2.79 ± 1.51 (-0.26, 5.85)	0.0719
	E-P	16	−7.02 ± 1.39

Δ = between-group difference.

LS Mean = least-squares mean.

SE = standard error.

CI = confidence interval.

ALSFRS-R = the Revised ALS Functional Rating Scale.

%FVC = percent predicted forced vital capacity.

E = Edaravone.

P = Placebo.

E-E = Patients were treated with edaravone in Cycle 1 through 12.

E-P = Patients were treated with edaravone for cycles 1 through 6 and placebo for cycles 7 through 12.

For study MCI186-16, patients who did not complete cycle 3 were excluded from the analysis. For study MCI186-17, patients who did not complete cycle 9 were excluded from the analysis.

EESP = efficacy-expected sub-population of ALS patients (% forced vital capacity of ≥80% before treatment and ≥2 points for all item scores in the ALSFRS-R before treatment).

dpEESP2y = subgroup of the EESP, containing patients with a diagnosis of ‘definite’ or ‘probable’ ALS according to the El Escorial revised Airlie House diagnostic criteria and with disease duration of ≤2 years.

Figure 2. Mean ALSFRS-R score ± standard deviation (SD) by treatment cycle in the dpEESP2y in studies MCI186-16 and MCI186-17.

Table 4. Analysis of other efficacy endpoints in the dpEESP2y (Change from baseline of cycle 7 to the end of cycle 12) (LOCF).

Efficacy endpoint	Group	n (LOCF)	Adjusted mean value LS mean ± SE	Δ LS mean ± SE (95% CI)	p-value
%FVC (%)	E-E	22	−11.85 ± 3.36	−1.91 ± 4.88 (−11.83, 8.00)	0.6979
	E-P	16	−9.94 ± 4.50
Modified Norris Scale	E-E	20	−11.19 ± 2.45	8.01 ± 3.58 (0.73, 15.29)	0.0321
	E-P	16	−19.20 ± 3.22
ALSAQ-40	E-E	20	14.80 ± 4.63	−2.84 ± 6.77 (−16.61, 10.93)	0.6777
	E-P	16	17.64 ± 6.08
Grip strength (kg)	E-E	22	−2.78 ± 0.69	0.57 ± 1.00 (−1.45, 2.59)	0.5715
	E-P	16	−3.34 ± 0.92
Pinch strength (kg)	E-E	22	−0.59 ± 0.18	−0.19 ± 0.26 (−0.71, 0.33)	0.4649
	E-P	16	−0.40 ± 0.24

Δ = between-group difference.

LS Mean = least-squares mean.

SE = standard error.

CI = confidence interval.

ALSFRS-R = the Revised ALS Functional Rating Scale.

%FVC = percent predicted forced vital capacity.

ALSAQ-40 = the 40 item ALS Assessment Questionnaire.

LOCF = last observation carried forward.

E-E = Patients were treated with edaravone in cycles 1 through 12.

E-P = Patients were treated with edaravone in cycles 1 through 6 and placebo in cycles 7 through 12.

Patients who did not complete cycle 9 were excluded from the analysis of variance.

Table 5. Adverse events reported in at least two patients in any treatment group: cycle 7 to cycle 15.

	E-E (n = 22)	E-P (n = 16)	P-E (n = 29)
	n (%)	n (%)	n (%)
Total	20 (90.9)	15 (93.8)	27 (93.1)
Gait disturbance	7 (31.8)	2 (12.5)	14 (48.3)
Constipation	4 (18.2)	1 (6.3)	9 (31.0)
Dysphagia	4 (18.2)	1 (6.3)	9 (31.0)
Nasopharyngitis	4 (18.2)	4 (25.0)	6 (20.7)
Diarrhoea	2 (9.1)	1 (6.3)	3 (10.3)
Eczema	2 (9.1)		1 (3.4)
Gastritis	2 (9.1)		1 (3.4)
Insomnia	2 (9.1)	1 (6.3)
Musculoskeletal disorder	2 (9.1)	2 (12.5)	5 (17.2)
Nocturia	2 (9.1)
Contusion	1 (4.5)	2 (12.5)	4 (13.8)
Respiratory failure	1 (4.5)		2 (6.9)
Upper respiratory tract inflammation	1 (4.5)		2 (6.9)
Abasia			2 (6.9)
Abdominal pain upper		2 (12.5)	1 (3.4)
Back pain		1 (6.3)	3 (10.3)
Cough			3 (10.3)
Depression		2 (12.5)	2 (6.9)
Dyslalia			3 (10.3)
Gastric ulcer		2 (12.5)
Muscular weakness		1 (6.3)	2 (6.9)
Pain in extremity			2 (6.9)
Pruritus		1 (6.3)	2 (6.9)
Rash			3 (10.3)
Seasonal allergy			2 (6.9)
Skin laceration		1 (6.3)	2 (6.9)
Stomach discomfort		2 (12.5)
Stomatitis			2 (6.9)
Vertigo		1 (6.3)	2 (6.9)

Table 6. Serious adverse events reported in any treatment group: cycle 7 to cycle 15.

	E-E (n = 22)	E-P (n = 16)	P-E (n = 29)
	n (%)	n (%)	n (%)
Total	10 (45.5)	3 (18.8)	14 (48.3)
Dysphagia	4 (18.2)		9 (31.0)
Musculoskeletal disorder	2 (9.1)	2 (12.5)	4 (13.8)
Bronchopneumonia	1 (4.5)
Dyspnoea	1 (4.5)	1 (6.3)
Gait disturbance	1 (4.5)		4 (13.8)
Pneumonia	1 (4.5)		1 (3.4)
Pneumonia aspiration	1 (4.5)	1 (6.3)
Respiratory failure	1 (4.5)		2 (6.9)
Abasia			1 (3.4)
Catheter site infection			1 (3.4)
Diverticulitis		1 (6.3)
Dysarthria		1 (6.3)
Dyslalia			3 (10.3)
Enterocolitis		1 (6.3)
Herpes zoster			1 (3.4)
Joint sprain			1 (3.4)
Muscular weakness			1 (3.4)