A safety analysis of edaravone (MCI-186) during the first six cycles (24 weeks) of amyotrophic lateral sclerosis (ALS) therapy from the double-blind period in three randomized, placebo-controlled studies

Figures & data

Table 1. Three phase III clinical trials of edaravone included in the integrated safety analysis.

Study #	Design	Population	Number of Patients (Safety Analysis)
MCI186-16	Randomized, double-blind, placebo-controlled, parallel group, comparative study	Japan ALS severity classification, grade 1 or 2	206 patientsP group: 104 patientsE group: 102 patients
MCI186-18	Randomized, double-blind, placebo-controlled, parallel group, comparative, exploratory study	Japan ALS severity classification, grade 3	25 patientsP group: 12 patientsE group: 13 patients
MCI186-19	Randomized, double-blind, placebo-controlled, parallel group, comparative study with 6-month active treatment period	Japan ALS severity classification, grade 1 or 2	137 patients (double-blind period only)P group: 68 patientsE group: 69 patients

E: edaravone; P: placebo.

Table 2. Demographics and other baseline characteristics, integrated safety analysis (cycle 1 through 6).

Parameter	Edaravone (N = 184)	Placebo (N = 184)
Gender, n (%)
Male	109 (59.2)	116 (63.0)
Female	75(40.8)	68 (37.0)
Age (years)
No. of patients	184	184
Mean (SD)	58.8 (9.8)	58.7 (9.9)
Min, Max	29, 75	28, 75
Median	60.0	60.0
<65 years, n (%)	131 (71.2)	127 (69.0)
≥65 years, n (%)	53 (28.8)	57 (31.0)
Body weight (kg)
No. of patients	184	184
Mean (SD)	57.8 (10.7)	58.3 (10.9)
Min, Max	35, 105	37, 109
Median	56.0	57.0
Disease duration (years)
No. of patients	184	184
Mean (SD)	1.34 (0.59)	1.26 (0.62)
Min, Max	0.3, 2.9	0.2, 3.0
Median	1.30	1.20
<1 year, n (%)	57 (31.0)	71 (38.6)
≥1 year, n (%)	127 (69.0)	113 (61.4)
Initial symptoms, n (%)
Bulbar	37 (20.1)	34 (18.5)
Limb s	147 (79.9)	150 (81.5)
ALS diagnosis, n (%)
Sporadic	182 (98.9)	177 (96.2)
Familial	2 (1.1)	7 (3.8)
El Escorial revised Airlie House diagnostic criteria, n (%)
Definite ALS,	64 (34.8)	50 (27.2)
Probable ALS,	97 (52.7)	103 (56.0)
Probable ALS - Laboratory supported	22 (12.0)	30 (16.3)
Possible ALS	0 (0.0)	1 (0.5)
Suspected ALS	1 (0.5)	0 (0.0)
Not rated	0 (0.0)	0 (0.0)
ALS Severity Grade, n (%)
1	58 (31.5)	56 (30.4)
2	113 (61.4)	116 (63.0)
3	13 (7.1)	12 (6.5)
ALS Functional Rating Scale-Revised (ALSFRS-R) Score
Pre-registration
No. of patients	184	184
Mean (SD)	42.4 (3.9)	43.0 (3.0)
Min, Max	25, 48	29, 48
Median	43.0	43.0
At baseline in cycle 1
No. of patients	184	184
Mean (SD)	40.5 (4.0)	41.0 (3.2)
Min, Max	23, 47	28, 47
Median	41.0	42.0

Table 3. Overview of TEAEs, integrated safety analysis (cycle 1 through 6).

	Edaravone		Placebo
	N = 184		N = 184
	n (%)	No. of Events	n (%)	No. of Events
Adverse events (AEs)	161 (87.5)	487	160 (87.0)	501
AEs leading to discontinuation	4 (2.2)	4	10 (5.4)	10
Adverse drug reactions (ADRs)	19 (10.3)	23	26 (14.1)	30
ADRs leading to discontinuation	1 (0.5)	1	3 (1.6)	3
Serious AEs (SAEs)	32 (17.4)	46	41 (22.3)	60
Serious ADRs	0 (0.0)	0	0 (0.0)	0
Death	4 (2.2)	4	2 (1.1)	2

ADRs were based on investigator assessment of AEs (and SAEs).

Table 4. Incidence of TEAEs occurring in at least 2% of patients in any treatment group, integrated safety analysis (cycle 1 through 6).

	Edaravone (N = 184)		Placebo (N = 184)
SOC PT	n	(%)	n	(%)
Any adverse event^a	161	(87.5)	160	(87.0)
Infections and infestations^a	63	(34.2)	57	(31.0)
Nasopharyngitis	27	(14.7)	29	(15.8)
Pharyngitis	5	(2.7)	5	(2.7)
Tinea pedis	4	(2.2)	2	(1.1)
Upper respiratory tract infection	5	(2.7)	3	(1.6)
Blood and lymphatic system disorders			4	(2.2)
Anaemia			4	(2.2)
Psychiatric disorders^a	14	(7.6)	20	(10.9)
Insomnia	14	(7.6)	15	(8.2)
Nervous system disorders	26	(14.1)	23	(12.5)
Dizziness	3	(1.6)	4	(2.2)
Headache	15	(8.2)	10	(5.4)
Respiratory, thoracic and mediastinal disorders^a	26	(14.1)	24	(13.0)
Pneumonia aspiration			4	(2.2)
Respiratory failure	2	(1.1)	5	(2.7)
Respiratory disorder	8	(4.3)	2	(1.1)
Upper respiratory tract inflammation	6	(3.3)	3	(1.6)
Gastrointestinal disorders^a	57	(31.0)	68	(37.0)
Constipation	23	(12.5)	24	(13.0)
Diarrhoea	8	(4.3)	9	(4.9)
Dysphagia	18	(9.8)	21	(11.4)
Nausea	4	(2.2)	1	(0.5)
Stomatitis	2	(1.1)	8	(4.3)
Hepatobiliary disorders	5	(2.7)	6	(3.3)
Hepatic function abnormal	2	(1.1)	5	(2.7)
Skin and subcutaneous tissue disorders^a	47	(25.5)	37	(20.1)
Dermatitis contact	11	(6.0)	6	(3.3)
Eczema	12	(6.5)	4	(2.2)
Erythema	5	(2.7)	3	(1.6)
Haemorrhage subcutaneous	3	(1.6)	4	(2.2)
Pruritus			7	(3.8)
Rash	7	(3.8)	4	(2.2)
Musculoskeletal and connective tissue disorders^a	36	(19.6)	39	(21.2)
Back pain	7	(3.8)	7	(3.8)
Muscular weakness	8	(4.3)	10	(5.4)
Musculoskeletal pain	2	(1.1)	5	(2.7)
Myalgia	4	(2.2)	2	(1.1)
Musculoskeletal disorder	4	(2.2)	6	(3.3)
General disorders and administration site conditions^a	41	(22.3)	37	(20.1)
Gait disturbance	23	(12.5)	17	(9.2)
Pyrexia	1	(0.5)	4	(2.2)
Investigations^a	13	(7.1)	14	(7.6)
Glucose urine present	7	(3.8)	3	(1.6)
Injury, poisoning and procedural complications^a	39	(21.2)	36	(19.6)
Laceration	2	(1.1)	4	(2.2)
Ligament sprain	5	(2.7)	4	(2.2)
Excoriation	5	(2.7)	3	(1.6)
Contusion	27	(14.7)	16	(8.7)

SOC: system organ class; PT: preferred term.

MedDRA version 17.0. A patient reporting more than 1 treatment-emergent adverse event (TEAE) for a particular PT or SOC was counted only once for that PT or SOC. Includes TEAEs with an incidence ≥2% in the pooled edaravone group.

^a Count for all patients who had at least 1 TEAE.

Table 5. Incidence of treatment-emergent adverse events (TEAEs) by cycle, integrated safety analysis (cycle 1 through 6).

	Edaravone (N = 184)		Placebo (N = 184)
Cycle No.	No. of Patients^a	Patients with TEAE(s) n (%)^b	No. of Patients^a	Patients with TEAE(s) n (%)^b
1	184	66 (35.9)	184	71 (38.6)
2	183	59 (32.2)	182	65 (35.7)
3	182	56 (30.8)	179	53 (29.6)
4	182	60 (33.0)	174	57 (32.8)
5	178	49 (27.5)	168	54 (32.1)
6	174	60 (34.5)	167	63 (37.7)

^aNumber of patients who received at least one treatment in the cycle.

^b Number (and percent) of patients who had at least one TEAE.

Table 6. Incidence of treatment-emergent adverse events (TEAEs) that led to discontinuation of study medication, integrated safety analysis (cycle 1 through 6).

	Edaravone (N = 184)		Placebo (N = 184)
	n	(%)	n	(%)
Any adverse event^a	4	(2.2)	10	(5.4)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Gastric cancer			1	(0.5)
Psychiatric disorders
Depression			1	(0.5)
Respiratory, thoracic and mediastinal disorders
Respiratory disorder	1	(0.5)	1	(0.5)
Respiratory failure	2	(1.1)	4	(2.2)
Hepatobiliary disorders
Hepatic function abnormal			1	(0.5)
Skin and subcutaneous tissue disorders
Drug eruption			1	(0.5)
Rash			1	(0.5)
Toxic skin eruption	1	(0.5)

MedDRA version 17.0. A patient reporting more than one TEAE for a particular term was counted only once for that term.

^a Count for all patients who had at least one TEAE that led to discontinuation of study drug.

Table 7. Incidence of treatment-emergent serious adverse events (SAEs), integrated safety analysis (cycle 1 through 6).

	Edaravone (N = 184)		Placebo (N = 184)
SOC PT	n	(%)	n	(%)
Any SAE^a	32	(17.4)	41	(22.3)
Infections and infestations	3	(1.6)	2	(1.1)
Cellulitis			1	(0.5)
Gastroenteritis	1	(0.5)
Pneumonia	1	(0.5)
Bacterial infection	1	(0.5)	1	(0.5)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)			1	(0.5)
Gastric cancer			1	(0.5)
Metabolism and nutrition disorders			1	(0.5)
Hypoproteinaemia			1	(0.5)
Psychiatric disorders			3	(1.6)
Anxiety			1	(0.5)
Depression			2	(1.1)
Nervous system disorders	1	(0.5)	3	(1.6)
Dyslalia	1	(0.5)	2	(1.1)
Speech disorder			1	(0.5)
Ear and labyrinth disorders			1	(0.5)
Vertigo positional			1	(0.5)
Vascular disorders			1	(0.5)
Pelvic venous thrombosis			1	(0.5)
Respiratory, thoracic and mediastinal disorders	11	(6.0)	12	(6.5)
Aspiration			1	(0.5)
Dyspnoea	3	(1.6)	1	(0.5)
Haemoptysis			1	(0.5)
Pneumonia aspiration			3	(1.6)
Respiratory disorder	6	(3.3)	2	(1.1)
Respiratory failure	2	(1.1)	5	(2.7)
Sputum retention	1	(0.5)
Gastrointestinal disorders	19	(10.3)	21	(11.4)
Abdominal pain	1	(0.5)
Ascites			1	(0.5)
Colitis ischaemic	1	(0.5)
Dysphagia	18	(9.8)	19	(10.3)
Lower gastrointestinal haemorrhage			1	(0.5)
Hepatobiliary disorders			1	(0.5)
Drug-induced liver injury			1	(0.5)
Musculoskeletal and connective tissue disorders	4	(2.2)	7	(3.8)
Mastication disorder			1	(0.5)
Muscle spasms			1	(0.5)
Muscular weakness	1	(0.5)	1	(0.5)
Musculoskeletal disorder	4	(2.2)	5	(2.7)
General disorders and administration site conditions	5	(2.7)	3	(1.6)
Gait disturbance	3	(1.6)	2	(1.1)
Oedema peripheral			1	(0.5)
Abasia	2	(1.1)
Injury, poisoning and procedural complications			2	(1.1)
Subdural haematoma			1	(0.5)
Contusion			1	(0.5)

SOC: system organ class; PT: preferred term.

MedDRA version 17.0. A patient reporting more than one treatment-emergent adverse event for a particular PT or SOC was counted only once for that PT or SOC.

^a Count for all patients who had at least one treatment-emergent SAE.