Abstract
Background: There continues to be a need for new therapies to treat ALS. Objective: Provide an overview of safety for edaravone in ALS patients during the first six cycles of treatment. Methods: Analysis was based on three randomised, placebo-controlled clinical trials. Endpoints included treatment-emergent adverse events (TEAEs), including AEs leading to discontinuation, serious adverse events (SAEs), and deaths. Results: The analysis included a total of 368 patients (184 in the edaravone group and placebo group, respectively). Of those, 94.6% of the edaravone group and 90.2% of placebo group completed six cycles of therapy. Baseline characteristics were comparable between the two groups. TEAE incidence in the edaravone group and placebo group was 87.5% and 87.0%, respectively. TEAEs ocurring at ≥2% incidence in the edaravone group compared to placebo were contusion (14.7% vs. 8.7%), gait disturbance (12.5% vs. 9.2%), headache (8.2% vs. 5.4%), eczema (6.5% vs. 2.2%), dermatitis contact (6.0% vs. 3.3%), respiratory disorder (4.3% vs. 1.1%), and glucose urine present (3.8% vs. 1.6%). There was no imbalance in TEAEs leading to discontinuation (2.2% [edaravone], and 5.4% [placebo]). SAE incidence was 17.4% in the edaravone group and 22.3% in placebo group. Treatment-emergent deaths occurred in 2.2% in the edaravone group and 1.1% in placebo group, all respiratory in nature and attributed to worsening ALS. Conclusion: Data collected from three double-blind assessments found that while some TEAEs were more common in the edaravone group compared to placebo, the overall incidences of SAEs, deaths, and discontinuations due to AEs were similar or less for edaravone compared to placebo.
Introduction
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Rapid progression of symptoms directly results from degeneration in motor neurons causing the loss of motor function. Most patients will need assistance with activities of daily living, with subsequent progression leading to respiratory compromise and eventual respiratory failure, which is a leading cause of death in ALS (Citation1). Median survival times are consistently reported as 2–3 years from the diagnosis (or 3–4 years from the first onset of symptom) (Citation2–5). About 10% of ALS patients live over 10 years (Citation6).
Edaravone (MCI-186), hypothesised as a free-radical scavenger, was initially developed for acute ischaemic stroke (Citation7–9). The development rationale for edaravone in ALS is based upon multiple lines of preclinical evidence affirming protection of neuronal cell damage against high oxidative stress. Studies have confirmed that edaravone scavenges radical species, including the hydroxyl radical (•OH), while other studies confirm that edaravone can ameliorate oxidative stress that damages endothelial and neuronal cells. Taken in context, these studies show that edaravone protects astrocytes, oligodendrocytes, and endothelial cells from oxidative stress damage (Citation10,Citation11). Furthermore, clinical studies have suggested edaravone can slow the progression of disability in patients with ALS (Citation12–14).
The clinical development programme of edaravone for ALS included five completed studies conducted in Japan. These were one phase II study (MCI186-12) and four phase III studies (MCI186-16, MCI186-17, MCI186-18, and MCI186-19). The dosing regimen for edaravone in the phase III studies included 60 mg administered intravenously (IV) over 60 min daily for 14 consecutive days, followed by a two-week drug-free period (cycle 1), and then 60 mg administered IV over 60 min daily for 10 d within a 14-d period followed by a two-week drug-free period (cycle 2 and thereafter).
The integrated safety analysis reported here was based on the first six cycles (24 weeks) of three randomised, placebo-controlled trials (MCI186-16, MCI186-18, and MCI186-19 [double-blind period]).
Methods
Integrated safety analysis
Three completed clinical studies conducted in Japan for ALS were included in this integrated analysis set:
Study MCI186-16 (phase III) was the first randomised, placebo-controlled study (n = 206) conducted to evaluate the efficacy and safety of edaravone in ALS patients, and enrolled patients with ALS severity grade 1 or 2 according to the Japanese ALS severity classification (based on Specified Disease Treatment Research Program for ALS of the Ministry of Health, Labour, and Welfare [MHLW] of Japan Severity Scale).
Study MCI186-18 (phase III) was an exploratory, randomised, placebo-controlled study (n = 25) in a limited number of patients with a more advanced stage of ALS (Japanese ALS grade 3 severity).
Study MCI186-19 (phase III) comprised two study periods, a randomised, placebo-controlled period for six cycles (n = 137) and then an active, extension period of six cycles of edaravone (n = 123). This study enrolled patients in the early stage of ALS (Japanese ALS grade 1 or 2 severity with normal respiratory function).
Safety data from the first six cycles (24 weeks) of studies MCI186-16, MCI186-18, and MCI186-19 (double-blind period) were pooled for this integrated analysis (). Patients in the three studies received edaravone or placebo. This dataset was used to characterise the overall six cycles (24 weeks) safety of edaravone for patients with ALS. Studies MCI186-16, MCI186-18, and MCI186-19 had similar study designs and safety endpoints for their first six cycles. Studies MCI186-16 and MCI186-19 were conducted in patients with grade 1 or grade 2 ALS severity, whereas patients in MCI186-18 had grade 3 ALS severity. Safety results for the three studies have been previously published (Citation13–15). All three studies were conducted in compliance with the Japanese Ministerial Ordinance on Good Clinical Practice and in accordance with the ethics principles of the Declaration of Helsinki, and all patients gave written informed consent. The studies are registered with clinicaltials.gov as NCT00330681 (MCI186-16), NCT00415519 (MCI186-18), and NCT01492686 (MCI186-19).
Table 1. Three phase III clinical trials of edaravone included in the integrated safety analysis.
Safety endpoints
The safety endpoints considered here were treatment-emergent adverse events (TEAEs), including adverse events (AEs) leading to discontinuation, serious adverse events (SAEs), and deaths.
Demographics and baseline characteristics
Baseline demographics and characteristics of the dataset were tabulated by treatment group. Mean, median, minimum and maximum, and standard deviation (SD) were used to describe continuous variables, such as body weight. Frequency distributions were used to describe categorical variables.
ALS severity classification was the ‘Specified Disease Treatment Research Program for ALS of the MHLW of Japan’ Severity Scale, which grades functional severity as follows:
Grade 1: Able to work or perform housework;
Grade 2: Independent living but unable to work;
Grade 3: Requiring assistance for eating, excretion, or ambulation;
Grade 4: Presence of respiratory insufficiency, difficulty in coughing out sputum, or dysphagia;
Grade 5: Using a tracheostomy tube, tube feeding, or tracheostomy positive-pressure ventilation.
Adverse events
AEs in each study were recorded from the start of treatment to the end of the treatment period or three weeks after the last dose of the study drug. All AEs were considered as treatment-emergent unless onset date was before the first dose of study drug or more than three weeks after the last dose.
The incidence of TEAEs was summarised by treatment group and in a separate summary by treatment cycle of first onset.
The incidence rate of a TEAE was calculated by dividing the number of patients with any report of the TEAE by the number of patients exposed to study drug. Thus, if a TEAE was recorded more than once in a patient in the study it was counted only once in the incidence summary.
In studies MCI186-16 and MCI186-18, the causality relationship of AEs to the study drug was determined by the investigator as none/not related, remote/unlikely related, possibly related, or probably related; in these two studies, with those possibly or probably related tabulated as ‘adverse drug reactions (ADRs)’. In Study MCI186-19, the investigator chose from two categories of causality: ‘a reasonable possibility’ or ‘not a reasonable possibility’; those categorised as ‘a reasonable possibility’ were tabulated as ‘ADRs.’
A serious AE was defined as one that resulted in death, was life threatening, required hospitalisation or prolongation of the hospitalisation period for treatment, had potential for causing disability, was any AE that the clinical investigator considered medically significant, or was any congenital disease or anomaly in the offspring of a treated patient.
All of the AEs reported by the investigators or subinvestigators were coded using the Medical Dictionary for Regulatory Activities/Japanese (MedDRA/J) and summarised by system organ class (SOC) and Preferred Term (PT). MedDRA/J version 17 was used for the integrated safety analysis.
Results
Exposure
The integrated safety analysis included a total of 368 patients (184 patients each in the edaravone group and placebo group). Of those, 94.6% of patients in the edaravone group and 90.2% of patients in the placebo group completed six cycles of therapy.
Demographics and baseline characteristics
Demographics and other baseline characteristics are summarised in . The percentage of male patients was 59.2% in the edaravone group and 63.0% in the placebo group. The proportion of elderly patients (≥65 years) was 28.8% in the edaravone group and 31.0% in the placebo group.
Table 2. Demographics and other baseline characteristics, integrated safety analysis (cycle 1 through 6).
The mean disease duration was 1.3 years in both treatment groups. The proportion of patients with initial limb symptoms was comparable in the two treatment groups (79.9% in the edaravone group and 81.5% in the placebo group). The proportion of patients with definite ALS as defined by El Escorial and the revised Airlie House diagnostic criteria was 34.8% in the edaravone group and 27.2% in the placebo group, and the proportion of patients with ‘probable ALS’ was 52.7% in the edaravone group and 56.0% in the placebo group.
The proportion of patients with ALS severity grade 1 was 31.5% in the edaravone group and 30.4% in the placebo group and the proportion of patients with ALS severity grade 2 was 61.4% in the edaravone group and 63.0% in the placebo group. The proportion of patients with ALS severity grade 3 was 7.1% in the edaravone group and 6.5% in the placebo group.
The mean ALSFRS-R score in the pre-observation period (12 weeks before first dose in cycle 1) was 42.4 in the edaravone group and 43.0 in the placebo group. The ALSFRS-R mean scores had decreased slightly at cycle 1 baseline and were 40.5 in the edaravone group and 41.0 in the placebo group.
Overview of treatment-emergent adverse events
An overview of TEAEs is presented in . The overall incidence of TEAEs was comparable between edaravone and placebo (87.5% vs. 87.0%, respectively). The overall incidences of AEs leading to discontinuation, ADRs, and treatment-emergent SAEs were higher in the placebo group compared to the edaravone group. TEAEs with a fatal outcome (four deaths with edaravone compared to two with placebo) were due to respiratory failure or respiratory disorder that occurred in patients with advanced ALS.
Table 3. Overview of TEAEs, integrated safety analysis (cycle 1 through 6).
Commonly reported adverse events
summarises the TEAEs with an incidence ≥2% in any treatment group. TEAEs that were reported at a higher incidence (≥2%) in the edaravone group compared to placebo were contusion (14.7% vs. 8.7%), gait disturbance (12.5% vs. 9.2%), headache (8.2% vs. 5.4%), eczema (6.5% vs. 2.2%), dermatitis contact (6.0% vs. 3.3%), respiratory disorder (4.3% vs. 1.1%), and glucose urine present (3.8% vs. 1.6%). The incidences of all other TEAEs in the edaravone group were either within 2% of the placebo rate or below it. TEAEs in the skin and subcutaneous tissue disorders SOC was >5% higher in the edaravone group compared to the placebo group (25.5% vs. 20.1%). All were mild to moderate in intensity, with none reported as severe. None was reported as serious.
Table 4. Incidence of TEAEs occurring in at least 2% of patients in any treatment group, integrated safety analysis (cycle 1 through 6).
Incidence of adverse events by cycle
Incidence of TEAEs is summarised by cycle in . The incidence of TEAEs per cycle for cycle 1 through 6 did not increase over time with edaravone-treated patients (cycle 1: 35.9% and cycle 6: 34.5%). The overall incidence of TEAEs by cycle was similar between the two treatment groups.
Table 5. Incidence of treatment-emergent adverse events (TEAEs) by cycle, integrated safety analysis (cycle 1 through 6).
Adverse events leading to discontinuation
TEAEs that led to discontinuation of study drug are summarised by treatment group in . The incidence was 2.2% (4/184) of patients in the edaravone group and 5.4% (10/184) of patients in the placebo group. No differences in incidence or type of TEAEs leading to discontinuation were observed between the two treatment groups.
Table 6. Incidence of treatment-emergent adverse events (TEAEs) that led to discontinuation of study medication, integrated safety analysis (cycle 1 through 6).
In both treatment groups, the SOC with the highest incidence of TEAEs leading to discontinuation was respiratory, thoracic and mediastinal disorders. All these TEAEs were considered by investigators to be unrelated to study drug. Their overall incidence as well as the individual terms was lower in the edaravone group than in the placebo group.
Serious adverse events
summarises the treatment-emergent SAEs by treatment group. The incidence of treatment-emergent SAEs was 17.4% (32/184) of patients in the edaravone group and 22.3% (41/184) of patients in the placebo group. There was no imbalance observed in the overall incidence of treatment-emergent SAEs between the two treatment groups. In both treatment groups, the SOCs with the highest incidence of treatment-emergent SAEs were the respiratory, thoracic and mediastinal disorders SOC and gastrointestinal disorders SOC. The incidence of treatment-emergent SAEs in the gastrointestinal disorders SOC, and for the individual PTs within this SOC, was similar for the two treatment groups. Although the overall incidence of treatment-emergent SAEs in respiratory, thoracic and mediastinal disorders SOC was similar for the two treatment groups (6.0% in the edaravone group vs. 6.5% in the placebo group), the incidences of dyspnoea (1.6% vs. 0.5%) and respiratory disorder (3.3% vs. 1.1%), were more frequent in the edaravone group compared to placebo, and pneumonia aspiration (0.0% vs. 1.6%) and respiratory failure (1.1% vs. 2.7%) were more frequent in the placebo group compared to edaravone.
Table 7. Incidence of treatment-emergent serious adverse events (SAEs), integrated safety analysis (cycle 1 through 6).
Deaths
The incidence of treatment-emergent death was 2.2% (4/184) of patients in the edaravone group and 1.1% (2/184) of patients in the placebo group. The two fatal TEAEs in the placebo group were those of respiratory failure and the four fatal TEAEs in the edaravone group were those of respiratory disorder and respiratory failure (two each). None were considered by the investigator to be related to study drug, and all were attributed to worsening of ALS.
Discussion
During the first six cycles (24 weeks) of three randomised, placebo-controlled clinical studies of ALS, the total number of TEAEs was similar between edaravone-treated patients and placebo-treated patients. Incidence of TEAEs per cycle did not increase over time in edaravone-treated patients. In addition, no imbalance was observed in the incidence of TEAEs leading to discontinuation between the two treatment groups. However, the overall incidence of TEAEs in the skin and subcutaneous tissue disorders category was higher in the edaravone group than in the placebo group (25.5% vs. 20.1%). Although there was a numerical imbalance in the incidence of skin TEAEs between the two treatment groups, a review of the skin TEAEs did not suggest any discernible pattern in the incidence or type of events between the two treatment groups. In the edaravone group, the most frequent skin TEAEs were eczema, dermatitis contact, rash, and erythema. Skin TEAEs that occurred more frequently in the placebo group were pruritus and haemorrhage subcutaneous () . None of the skin TEAEs in either treatment group was serious or severe. Review of skin TEAEs did not suggest a risk for developing an edaravone-induced skin effect that would impact patient health.
The incidence of reported treatment-emergent SAEs was similar between edaravone-treated patients and placebo-treated patients. The most common treatment-emergent SAEs were in the respiratory, thoracic and mediastinal category and gastrointestinal category, both of which primarily developed as a result of worsening of ALS symptoms.
There were six deaths in this integrated safety analysis, four (2.2%) in the edaravone group and two (1.1%) in the placebo group. The deaths were all from respiratory causes and occurred in cycles 3, 4, 5 and 6. None was considered by the investigator to have a reasonable possibility of causal association with the study drug, and all were attributed to worsening ALS. Three of the four patients in the edaravone group who died had post-baseline assessments for ALS severity; all three of these patients had evidence of worsening ALS severity prior to death (one progressed to grade 3, and two progressed to grade 5).
Overall, it can be concluded that although some TEAEs were more common in the edaravone group compared to the placebo group, the overall incidences of AEs leading to discontinuation, SAEs, and deaths were similar to or less for edaravone compared to placebo. The findings of this pooled analysis, which was focussed on placebo-controlled edaravone studies of 24 weeks duration, enhance and confirm the earlier safety findings of the individual studies.
Declaration of interest
AK, EP, AK, YZ, and TS are employees of Mitsubishi Tanabe Pharma Development America, Inc. KI and MW are employees of Mitsubishi Tanabe Pharma Corporation (MTPC). The authors take full responsibility for the content of and the decision to submit this manuscript. The edaravone MCI186 clinical trials were funded by Mitsubishi Tanabe Pharma Corporation. This article and the others in the ALSFTD supplement, Edaravone (MCI-186) in Amyotrophic Lateral Sclerosis (ALS), were funded by Mitsubishi Tanabe Pharma America, Inc.
Acknowledgements
We thank David Hartree under contract with Mitsubishi Tanabe Pharma America, Inc. for editorial and coordination support for this article.
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