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Edaravone ALS 19 Study

Safety and Efficacy of Edaravone in Well Defined Patients with Amyotrophic Lateral Sclerosis: A Randomised, Double-Blind, Placebo-Controlled Trial

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Year of Publication: 2017

Authors: Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group

Journal: Lancet Neurology

Citation: Lancet Neurol. 2017;16(7):505-512

Link: https://pubmed.ncbi.nlm.nih.gov/28522181/

Clinical Question

Does edaravone slow functional decline in a well-defined subgroup of early-stage ALS patients?

Bottom Line

Edaravone significantly reduced functional decline on ALSFRS-R over 24 weeks in carefully selected early ALS patients (difference 2.49 points, p=0.0013). However, strict inclusion criteria limited applicability to a small fraction of ALS patients.

        Major Points
        Edaravone reduced ALSFRS-R decline by 33% compared to placebo (-5.01 vs -7.50 points)
Highly restrictive inclusion criteria: only 137 of 213 screened patients randomized
Required 12-week pre-randomization observation period to confirm decline rate
Led to FDA approval in 2017 (Radicava)
Conducted exclusively in Japan

      

Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled trial

Randomization: 1

Blinding: Double-blind

Enrollment Period: November 2011 to September 2014

Follow-up Duration: 24 weeks preceded by 12-week observation period

Centers: 31

Countries: Japan

Sample Size: 137

Analysis: Full analysis set; last observation carried forward (LOCF)

Inclusion Criteria

Age 20 to 75 years
Definite or probable ALS per revised El Escorial criteria
Disease duration 2 years or less
Forced vital capacity (FVC) 80% or greater of predicted
ALSFRS-R score of 2 or more on ALL 12 items (ensuring no severely affected domain)
Japan ALS Severity Classification grade 1 or 2 (living independently at baseline)
ALSFRS-R decline of 1 to 4 points during 12-week pre-randomization observation period (confirming active but not rapidly progressive disease)
Able to provide informed consent

Exclusion Criteria

FVC less than 80% predicted
Tracheostomy or mechanical ventilation
ALSFRS-R decline of 0 points (too stable) or >4 points (too rapid) during 12-week observation period
Reduced creatinine clearance
Any ALSFRS-R item score <2 (severe impairment in any domain)
Japan ALS Severity Classification grade 3 or higher

Arms

Field	Edaravone	Control
Intervention	Edaravone 60 mg IV in repeated 2-week cycles for 24 weeks	Matching saline placebo IV on identical schedule
Duration	24 weeks	24 weeks

Outcomes

Outcome	Type	Control	Intervention	P-value
Change in ALSFRS-R score from baseline to week 24	Primary	-7.50 (SE 0.66)	-5.01 (SE 0.64)	p=0.0013
Modified Norris Scale	Secondary		Trend favoring edaravone but not significant	NS
FVC change	Secondary		No significant difference	NS
Any AE	Adverse	84% (placebo)	84% (edaravone)
Serious AE	Adverse	24%	16%
AE leading to withdrawal	Adverse	6%	1%
Contusion	Adverse	9%	15%
Gait disturbance	Adverse	9%	13%
Headache	Adverse	6%	10%
Dermatitis	Adverse	5%	8%
Eczema	Adverse	4%	7%
Respiratory disorder	Adverse	4%	6%
Glycosuria	Adverse	2%	4%

Subgroup Analysis

Study population (ALS 19) was derived from post-hoc analysis of a prior failed trial (ALS 16). In ALS 16, the overall population showed no benefit, but the subgroup meeting ALS 19 criteria (all ALSFRS-R items >=2, 1-4 point decline in observation) showed a treatment effect, forming the basis for ALS 19's restrictive enrollment.

Criticisms

Very restrictive inclusion criteria: only ~7% of screened ALS patients qualified, severely limiting real-world applicability
Study population derived from post-hoc subgroup analysis of a failed prior trial (ALS 16) -- raises concerns about data-driven patient selection
Conducted exclusively in Japan with all Japanese patients; racial/ethnic generalizability uncertain
Relatively short 24-week treatment period; long-term benefit unknown
IV administration requiring repeated 60-minute infusions in 2-week cycles creates substantial treatment burden
Secondary endpoints (Modified Norris Scale, FVC) did not reach statistical significance
>90% of patients on concurrent riluzole; cannot assess edaravone monotherapy effect
Industry-funded (Mitsubishi Tanabe Pharma) with potential conflict of interest

Funding

Mitsubishi Tanabe Pharma Corporation

Based on: Edaravone ALS 19 Study (Lancet Neurology, 2017)

Authors: Writing Group on behalf of the Edaravone (MCI-186) ALS 19 Study Group

Citation: Lancet Neurol. 2017;16(7):505-512

Content summarized and formatted by NeuroTrials.ai.

Edaravone ALS 19 Study

(2017)

Objective

To evaluate the safety and efficacy of edaravone (MCI-186) in a well-defined subgroup of early-stage ALS patients

Study Summary

• Edaravone reduced ALSFRS-R decline by 33% vs placebo (-5.01 vs -7.50 points, difference 2.49, 95% CI 0.99-3.98, p=0.0013); led to FDA approval in 2017 (Radicava)
• Highly restrictive criteria (FVC >=80%, all ALSFRS-R items >=2, 1-4 point decline in observation) meant only ~7% of ALS patients would qualify; secondary endpoints (Modified Norris Scale, FVC) did not reach significance; population derived from post-hoc subgroup analysis of prior failed trial (ALS 16)

Intervention

Intravenous edaravone (MCI-186) 60 mg vs placebo in repeated 2-week treatment cycles for 24 weeks

Inclusion Criteria

Age 20-75, definite/probable ALS, disease duration <=2 years, FVC >=80%, ALSFRS-R >=2 on all 12 items, 1-4 point decline during 12-week observation period

Study Design

Arms: Edaravone 60 mg IV vs Placebo

Patients per Arm: Edaravone: 68, Placebo: 66

Outcome

• ALSFRS-R change at 24 weeks: Edaravone -5.01 (SE 0.64) vs Placebo -7.50 (SE 0.66), difference 2.49 (95% CI 0.99-3.98, p=0.0013) -- 33% reduction in functional decline
• AEs similar (84% both); SAEs lower with edaravone (16% vs 24%); more contusion (15% vs 9%), headache (10% vs 6%), gait disturbance (13% vs 9%)
• FDA approval 2017 (Radicava); applicability limited: only ~7% of ALS patients meet strict criteria; secondary endpoints (Norris Scale, FVC) not significant

Bottom Line

Major Points

Edaravone reduced ALSFRS-R decline by 33% compared to placebo (-5.01 vs -7.50 points)
Highly restrictive inclusion criteria: only 137 of 213 screened patients randomized
Required 12-week pre-randomization observation period to confirm decline rate
Led to FDA approval in 2017 (Radicava)
Conducted exclusively in Japan

Study Design

Study Type: Phase 3, randomized, double-blind, placebo-controlled trial
Randomization: Yes
Blinding: Double-blind
Sample Size: 137
Follow-up: 24 weeks preceded by 12-week observation period
Centers: 31
Countries: Japan

Primary Outcome

Definition: Change in ALSFRS-R score from baseline to week 24

Control	Intervention	HR/OR	P-value
-7.50 (SE 0.66)	-5.01 (SE 0.64)	- (Difference: 2.49 (95% CI 0.99 to 3.98))	p=0.0013

Limitations & Criticisms

Very restrictive inclusion criteria: only ~7% of screened ALS patients qualified, severely limiting real-world applicability
Study population derived from post-hoc subgroup analysis of a failed prior trial (ALS 16) -- raises concerns about data-driven patient selection
Conducted exclusively in Japan with all Japanese patients; racial/ethnic generalizability uncertain
Relatively short 24-week treatment period; long-term benefit unknown
IV administration requiring repeated 60-minute infusions in 2-week cycles creates substantial treatment burden
Secondary endpoints (Modified Norris Scale, FVC) did not reach statistical significance
>90% of patients on concurrent riluzole; cannot assess edaravone monotherapy effect
Industry-funded (Mitsubishi Tanabe Pharma) with potential conflict of interest

Citation

Lancet Neurol. 2017;16(7):505-512

View Original Publication →

Edaravone ALS 19 Study

Safety and Efficacy of Edaravone in Well Defined Patients with Amyotrophic Lateral Sclerosis: A Randomised, Double-Blind, Placebo-Controlled Trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

Ask about Edaravone ALS 19 Study