Exploratory double-blind, parallel-group, placebo-controlled extension study of edaravone (MCI-186) in amyotrophic lateral sclerosis

Figures & data

Figure 1. Study design.

This article reports this results of the extension study (Double blind period: Cycles 7–12, and Open label period: Cycles 13–15) indicated by the bold frame.

*As unblinding of the first phase III study was performed during this extension study, the blind was only maintained for the patients who were assigned to the E group in the first phase III study, but not for the patients who were assigned to the P group in the first phase III study.

Figure 2. Disposition of patients.

FAS: Full analysis set, EESP: Efficacy-expected sub-population of ALS patients in the FAS (forced vital capacity of at least 80% before treatment and at least 2 points for all item scores in ALSFRS-R before treatment).

ALS: amyotrophic lateral sclerosis, ALSFRS-R: revised ALS functional rating scale.

Abbreviations of groups are as follows: E-E, edaravone group (the first phase III study) - edaravone group (this extension study); E-P, edaravone group (the first phase III study) - placebo group (this extension study); P-E, placebo group (the first phase III study) - edaravone group (this extension study).

Detailed reasons for discontinuation (numbers are numbers of patients):

*: patient's withdrawal request.

**: patient's request, E-E 2, E-P 4, P-E 5; adverse event, E-E 3, E-P 2, P-E 2; tracheotomy, E-E 7, E-P 1, P-E 6; patient's convenience, E-E 0, E-P 0, P-E 1; other reasons, E-E 2, E-P 0, P-E 2.

***: diagnosed as not having ALS. ****: patient's request, E-P 2, P-E 2; adverse event, E-E 1, tracheotomy, E-E 2, P-E 2; P-E 1; other reasons, P-E 2.

Table 1. Subject demographic characteristics in the FAS.

Item			E-E group(n = 48)		E-P group(n = 44)		P-E group(n = 88)
Sex*	Male	(%)	26	(54.2)	32	(72.7)	57	(64.8)
Age (years old)*	Mean	(min–max)	59.6	(29–73)	55.5	(31–73)	56.9	(28–75)
	<65	(%)	29	(60.4)	37	(84.1)	62	(70.5)
	≥65	(%)	19	(39.6)	7	(15.9)	26	(29.5)
Height (cm)*	Mean	(min–max)	161.8	(145–179)	164.5	(151–180)	163.5	(148–181)
Body weight (kg)*	Mean	(min–max)	57.2	(35–76)	59.7	(42–77)	59.4	(37–91)
Duration of disease (years)*	Mean	(min–max)	1.48	(0.5–2.9)	1.45	(0.6–2.8)	1.31	(0.3–3.0)
Initial symptom*	Limb	(%)	39	(81.3)	37	(84.1)	71	(80.7)
ALS diagnosis*	Sporadic	(%)	47	(97.9)	44	(100.0)	84	(95.5)
Diagnosis by modified El EscorialRevised Airlie House criteria*	Definite	(%)	14	(29.2)	11	(25.0)	18	(20.5)
	Probable	(%)	24	(50.0)	23	(52.3)	46	(52.3)
	Probable-laboratory-suppported	(%)	10	(20.8)	10	(22.7)	23	(26.1)
	Possible	(%)	0	(0.0)	0	(0.0)	1	(1.1)
	Suspected	(%)	0	(0.0)	0	(0.0)	0	(0.0)
Japan ALS severity classification
Before treatment Cycle 1	grade 1	(%)	17	(35.4)	16	(36.4)	36	(40.9)
	grade 2	(%)	31	(64.6)	28	(63.6)	52	(59.1)
Before treatment Cycle 7	grade 1	(%)	6	(12.5)	7	(15.9)	9	(10.2)
	grade 2	(%)	26	(54.2)	23	(52.3)	48	(54.5)
	grade 3	(%)	12	(25.0)	11	(25.0)	18	(20.5)
	grade 4	(%)	2	(4.2)	3	(6.8)	11	(12.5)
	grade 5	(%)	1	(2.1)	0	(0.0)	1	(1.1)
	missing data	(%)	1	(2.1)	0	(0.0)	1	(1.1)
Use of riluzole
Before treatment Cycle 1	Yes	(%)	42	(87.5)	39	(88.6)	80	(90.9)
Before treatment Cycle 7	Yes	(%)	42	(87.5)	38	(86.4)	79	(89.8)
ALSFRS-R Score
Before observation period (A)	Mean	(S.D.)	42.3	(3.9)	42.9	(2.9)	43.3	(2.6)
Before treatment Cycle 1 (B)	Mean	(S.D.)	40.5	(3.8)	40.9	(3.1)	41.3	(2.8)
Change from A to B	(−4, −3)	(%)	13	(27.1)	11	(25.0)	26	(29.5)
	(−2, −1)	(%)	35	(72.9)	33	(75.0)	62	(70.5)
Before treatment Cycle 7	Mean	(S.D.)	36.0	(6.1)	36.5	(5.5)	35.8	(7.0)

FAS: full analysis set.

ALS: amyotrophic lateral sclerosis.

ALSFRS-R: revised ALS functional rating scale.

Groups were as follows: E-E: edaravone group (the first phase III study) - edaravone group (this extension study); E-P, edaravone group (the first phase III study) - placebo group (this extension study);P-E: placebo group (the first phase III study) - edaravone group (this extension study).

*The value listed for each item was obtained at baseline in Cycle 1.

Table 2. Subject demographic characteristics in the EESP.

Item			E-E group(n = 27)		E-P group(n = 25)		P-E group(n = 44)
Sex*	Male	(%)	13	(48.1)	18	(72.0)	28	(63.6)
Age (years old)*	Mean	(min–max)	56.9	(29–72)	54.1	(31–73)	58.8	(28–75)
	<65	(%)	20	(74.1)	22	(88.0)	29	(65.9)
	≥ 65	(%)	7	(25.9)	3	(12.0)	15	(34.1)
Height (cm)*	Mean	(min–max)	161.3	(148–179)	164.8	(151–180)	163.5	(150–181)
Body weight (kg)*	Mean	(min–max)	56.6	(40–73)	61.8	(42–77)	59.5	(37–83)
Duration of disease (years)*	Mean	(min–max)	1.29	(0.5–2.8)	1.45	(0.6–2.8)	1.13	(0.3–2.3)
Initial symptom*	Limb	(%)	22	(81.5)	25	(100.0)	36	(81.8)
ALS diagnosis*	Sporadic	(%)	26	(96.3)	25	(100.0)	44	(100.0)
Diagnosis by modified EL EscorialRevised Airlie House criteria*	Definite	(%)	11	(40.7)	7	(28.0)	9	(20.5)
	Probable	(%)	13	(48.1)	13	(52.0)	21	(47.7)
	Probable-laboratory-supported	(%)	3	(11.1)	5	(20.0)	13	(29.5)
	Possible	(%)	0	(0.0)	0	(0.0)	1	(2.3)
	Suspected	(%)	0	(0.0)	0	(0.0)	0	(0.0)
Japan ALS severity classification
Before treatment Cycle 1	grade 1	(%)	15	(55.6)	11	(44.0)	22	(50.0)
	grade 2	(%)	12	(44.4)	14	(56.0)	22	(50.0)
Before treatment Cycle 7	grade 1	(%)	5	(18.5)	6	(24.0)	7	(15.9)
	grade 2	(%)	18	(66.7)	15	(60.0)	24	(54.5)
	grade 3	(%)	4	(14.8)	2	(8.0)	7	(15.9)
	grade 4	(%)	0	(0.0)	2	(8.0)	4	(9.1)
	grade 5	(%)	0	(0.0)	0	(0.0)	1	(2.3)
	missing data	(%)	0	(0.0)	0	(0.0)	1	(2.3)
Use of riluzole
Before treatment Cycle 1	Yes	(%)	24	(88.9)	23	(92.0)	38	(86.4)
Before treatment Cycle 7	Yes	(%)	24	(88.9)	22	(88.0)	37	(84.1)
ALSFRS-R Score
Before observation period (A)	Mean	(S.D.)	43.9	(2.5)	44.1	(2.4)	44.4	(1.9)
Before treatment Cycle 1 (B)	Mean	(S.D.)	42.2	(2.4)	42.4	(2.5)	42.4	(2.3)
Change from A to B	(−4, −3)	(%)	7	(25.9)	3	(12.0)	12	(27.3)
	(−2, −1)	(%)	20	(74.1)	22	(88.0)	32	(72.7)
Before treatment Cycle 7	Mean	(S.D.)	38.8	(4.9)	39.1	(4.7)	36.7	(8.3)

EESP: efficacy-expected sub-population in the FAS (forced vital capacity of at least 80% at baseline in Cycle 1 and at least 2 points for all item scores in ALSFRS-R at baseline in Cycle 1).

ALS: amyotrophic lateral sclerosis.

ALSFRS-R: revised ALS functional rating scale.

Groups were as follows: E-E: edaravone group (the first phase III study) - edaravone group (this extension study); E-P: edaravone group (the first phase III study) - placebo group (this extension study); P-E: placebo group (the first phase III study) - edaravone group (this extension study).

*The value listed for each item was obtained at baseline in Cycle 1.

Figure 3. Changes in ALSFRS-R score in the first phase III study and this extension study in the FAS (a) and the EESP (b).

FAS: full analysis set

EESP: efficacy-expected sub-population in the FAS (forced vital capacity of at least 80% at baseline in Cycle 1 and at least 2 points for all item scores in ALSFRS-R).

ALS: amyotrophic lateral sclerosis.

ALSFRS-R: revised ALS functional rating scale.

In the first phase III study (from before pre-registration to the end of Cycle 6), the groups were as follows: E, edaravone group; P, placebo group.

In this extension study (baseline in Cycle 7 to the end of Cycle 15), the groups were as follows: E-E, edaravone group (the first phase III study) - edaravone group (this extension study); E-P, edaravone group (the first phase III study) - placebo group (this extension study); P-E, placebo group (the first phase III study) - edaravone group (this extension study).

Table 3. Changes in endpoints from baseline in Cycle 7 to the end of Cycle 12 in the FAS and the EESP.

	FAS				EESP
	Adjusted mean changeLS Mean ± S.E.				Adjusted mean changeLS Mean ± S.E.
	E-E group	E-P group	Inter-group difference in adjusted mean changeLS Mean ± S.E.(95% C.I.)	p value	E-E group	E-P group	Inter-group difference in adjusted mean changeLS Mean ± S.E.(95% C.I.)	p value
ALSFRS-R	−4.42 ± 0.69(n = 44)	−5.58 ± 0.74(n = 41)	1.16 ± 0.93(−0.70, 3.01)	0.2176	−4.01 ± 0.86(n = 27)	−5.86 ± 0.98(n = 25)	1.85 ± 1.14(−0.45, 4.15)	0.1127
%FVC (%)	−13.33 ± 2.29(n = 44)	−10.15 ± 2.44(n = 41)	−3.17 ± 3.09(−9.32, 2.97)	0.3074	−9.92 ± 2.97(n = 27)	−7.55 ± 3.41(n = 25)	−2.37 ± 3.98(−10.36, 5.62)	0.5542
Modified Norris scale	−10.84 ± 1.68(n = 42)	−14.02 ± 1.76(n = 41)	3.19 ± 2.26(−1.32, 7.69)	0.1634	−10.88 ± 2.30(n = 25)	−15.08 ± 2.59(n = 25)	4.20 ± 3.08(−2.01, 10.40)	0.1801
ALSAQ-40	13.54 ± 2.89(n = 42)	18.99 ± 3.03(n = 41)	−5.45 ± 3.89(−13.19, 2.29)	0.1651	16.52 ± 3.97(n = 25)	20.94 ± 4.47(n = 25)	−4.42 ± 5.32(−15.12, 6.29)	0.4108
Grip strength (kg)	−3.10 ± 0.43(n = 44)	−3.47 ± 0.45(n = 41)	0.38 ± 0.58(−0.77, 1.52)	0.5173	−2.66 ± 0.55(n = 27)	−3.43 ± 0.63(n = 25)	0.77 ± 0.73(−0.71, 2.24)	0.3015
Pinch strength (kg)	−0.69 ± 0.12(n = 44)	−0.71 ± 0.13(n = 41)	0.01 ± 0.16(−0.31, 0.33)	0.9419	−0.58 ± 0.15(n = 27)	−0.51 ± 0.17(n = 25)	−0.07 ± 0.20(−0.47, 0.32)	0.7132

FAS: full analysis set; EESP: efficacy-expected sub-population in the FAS (forced vital capacity of at least 80% at baseline in Cycle 1 and at least 2 points for all item scores in ALSFRS-R at baseline in Cycle 1); LS Mean: least-squares mean; S.E: standard error: C.I: confidence interval.

ALS: amyotrophic lateral sclerosis.

ALSFRS-R: revised ALS functional rating scale.

%FVC: % forced vital capacity.

ALSAQ-40: ALS assessment questionnaire.

Groups were as follows: E-E: edaravone group (the first phase III study) - edaravone group (this extension study); E-P: edaravone group (the first phase III study) - placebo group (this extension study).

An analysis of variance was used with the treatment groups and the change in the ALSFRS-R score during the pre-observation period (–1, –2/–3, –4) used in one of dynamic randomisation as factors at the start of the first phase III study.

LOCF was used for patients who completed Cycle 9 (i.e. patients who reached 249 d after the baseline in Cycle 1).

Table 4. Events of death or a specified state of disease progression in the FAS and the EESP.

	FAS				EESP
Event name	E-E group(n = 48)	E-P group(n = 44)	P-E group(n = 88)	Total(n = 180)	E-E group(n = 27)	E-P group(n = 25)	P-E group(n = 44)	Total(n = 96)
Death	1	1	1	3	0	0	0	0
Disability of independent  ambulation	11	8	20	39	7	4	11	22
Loss of upper limbs function	5	3	7	15	1	2	2	5
Tracheotomy	0	0	2	2	0	0	0	0
Use of respirator	1	0	2	3	0	0	0	0
Use of tube feeding	1	1	8	10	0	0	5	5
Total events(Number of patients with events)	19(18)	13(11)	40(33)	72(62)	8(8)	6(5)	18(17)	32(30)

FAS: full analysis set; EESP: efficacy-expected sub-population in the FAS (forced vital capacity of at least 80% at baseline in Cycle 1 and at least 2 points for all item scores in ALSFRS-R at baseline in Cycle 1).

Groups were as follows: E-E: edaravone group (the first phase III study) - edaravone group (this extension study); E-P: edaravone group (the first phase III study) - placebo group (this extension study) P-E: placebo group (the first phase III study) - edaravone group (this extension study).

Events that occurred from the baseline of Cycle 7 to the end of Cycle 12.

Table 5. Adverse events in the Safety Analysis Set.

	AE
	Treatment
Name of AE (MedDRA: ver.11.1)	E-E group(n = 48)		E-P group(n = 45)		P-E group(n = 88)
Preferred Term	n	(%)	n	(%)	n	(%)
Total	44	(91.7)	44	(97.8)	81	(92.0)
Diarrhoea	3	(6.3)	1	(2.2)	6	(6.8)
Constipation	10	(20.8)	8	(17.8)	20	(22.7)
Dysphagia	9	(18.8)	7	(15.6)	22	(25.0)
Bronchitis	1	(2.1)	3	(6.7)	3	(3.4)
Tinea pedis	3	(6.3)	3	(6.7)	4	(4.5)
Nasopharyngitis	10	(20.8)	12	(26.7)	28	(31.8)
Arthralgia			3	(6.7)	2	(2.3)
Musculoskeletal disorder	6	(12.5)	5	(11.1)	12	(13.6)
Muscular weakness	1	(2.1)	3	(6.7)	5	(5.7)
Cough					5	(5.7)
Dyspnoea	3	(6.3)	3	(6.7)	4	(4.5)
Respiratory disorder	3	(6.3)	1	(2.2)	3	(3.4)
Respiratory failure	6	(12.5)	2	(4.4)	6	(6.8)
Upper respiratory tract inflammation	3	(6.3)	1	(2.2)	4	(4.5)
Contusion	3	(6.3)	7	(15.6)	8	(9.1)
Dyslalia			1	(2.2)	6	(6.8)
Insomnia	5	(10.4)	3	(6.7)	7	(8.0)
Pyrexia	3	(6.3)	1	(2.2)	2	(2.3)
Gait disturbance	14	(29.2)	9	(20.0)	32	(36.4)
Pruritus	1	(2.1)	1	(2.2)	8	(9.1)
Erythema	2	(4.2)	3	(6.7)	2	(2.3)
Eczema	3	(6.3)	3	(6.7)	3	(3.4)

AE: adverse event.

MedDRA: Medical Dictionary for Regulatory Activities. These are tabulated the Preferred Term, MedDRA version 11.1.

Groups were as follows: E-E: edaravone group (the first phase III study) - edaravone group (this extension study); E-P: edaravone group (the first phase III study): placebo group (this extension study); P-E: placebo group (the first phase III study) - edaravone group (this extension study).

AEs with incidence greater than 5% in the safety analysis population are tabulated.

Table 6. All serious adverse events in the Safety Analysis Set.

	SAE
				Treatment
	E-E group			E-P group			P-E group
Name of SAE (MedDRA ver.11.1)	(n = 48)			(n = 45)			(n = 88)
System Organ ClassPreferred Term	No. of patients	(%)	No. of events	No. of patients	(%)	No. of events	No. of patients	(%)	No. of events
Total	25	(52.1)	38	13	(28.9)	24	39	(44.3)	72
Gastrointestinal disorders	9	(18.8)	10	7	(15.6)	7	24	(27.3)	24
Gastric ulcer							1	(1.1)	1
Stomach discomfort	1	(2.1)	1
Colonic polyp							1	(1.1)	1
Enterocolitis				1	(2.2)	1
Dysphagia	9	(18.8)	9	6	(13.3)	6	22	(25.0)	22
Infections and infestations	3	(6.3)	3	2	(4.4)	2	3	(3.4)	4
Catheter site infection							1	(1.1)	1
Bronchitis	1	(2.1)	1	1	(2.2)	1
Bronchopneumonia	1	(2.1)	1
Diverticulitis				1	(2.2)	1
Herpes zoster							1	(1.1)	1
Pneumonia	1	(2.1)	1				2	(2.3)	2
Eye disorders							1	(1.1)	1
Retinal vein occlusion							1	(1.1)	1
Musculoskeletal and connective tissue disorders	6	(12.5)	7	4	(8.9)	4	13	(14.8)	13
Musculoskeletal disorder	6	(12.5)	6	4	(8.9)	4	10	(11.4)	10
Muscular weakness	1	(2.1)	1				3	(3.4)	3
Respiratory, thoracic and mediastinal disorders	12	(25.0)	12	6	(13.3)	7	12	(13.6)	14
Dyspnoea	3	(6.3)	3	2	(4.4)	2	2	(2.3)	2
Respiratory disorder	2	(4.2)	2	1	(2.2)	1	2	(2.3)	2
Respiratory arrest							1	(1.1)	1
Respiratory failure	6	(12.5)	6	2	(4.4)	2	6	(6.8)	6
Hypercapnia							1	(1.1)	1
Pneumonia aspiration	1	(2.1)	1	1	(2.2)	1	1	(1.1)	1
Sputum retention				1	(2.2)	1	1	(1.1)	1
Injury, poisoning and procedural complications				1	(2.2)	1	2	(2.3)	3
Joint sprain							1	(1.1)	1
Upper limb fracture				1	(2.2)	1
Head injury							1	(1.1)	1
Skin laceration							1	(1.1)	1
Cardiac disorders							1	(1.1)	1
Cardiac arrest							1	(1.1)	1
Nervous system disorders				2	(4.4)	2	6	(6.8)	6
Dyslalia				1	(2.2)	1	6	(6.8)	6
Dysarthria				1	(2.2)	1
General disorders and administration site conditions	5	(10.4)	5				6	(6.8)	6
Gait disturbance	4	(8.3)	4				5	(5.7)	5
Abasia	1	(2.1)	1				1	(1.1)	1
Neoplasms benign, malignant and unspecified (including cysts and polyps)	1	(2.1)	1	1	(2.2)	1
Prostate cancer				1	(2.2)	1
Bladder cancer	1	(2.1)	1

SAE: serious adverse event.

MedDRA: Medical Dictionary for Regulatory Activities. These are tabulated the System Organ Class and Preferred Term, MedDRA version 11.1.

Groups were as follows: E-E: edaravone group (the first phase III study) - edaravone group (this extension study); E-P: edaravone group (the first phase III study) - placebo group (this extension study); P-E: placebo group (the first phase III study) - edaravone group (this extension study).