Effect of Edaravone Therapy on Amyotrophic Lateral Sclerosis Functional Rating Score (ALS-FRS) in Patients of Amyotrophic Lateral Sclerosis (ALS) in Central India: A Retrospective Open Label Study

Abstract

Abstracts

Background

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder affecting motor neurons and is characterised by a diverse range of clinical manifestations. With the understanding of its pathophysiology, many treatments have emerged in last two decades. This study aims to evaluate the impact of intravenous Edaravone on Amyotrophy Lateral Sclerosis Functional Rating Scale (ALS-FRS) scores and patient survival outcomes of Amyotrophic Lateral Sclerosis patients in Central India.

Methods

This retrospective study was conducted over a span of 2.5 years and included patients diagnosed with definitive or probable ALS, as per the revised El Escorial criteria. The effects of intravenous (IV) Edaravone on ALS-FRS-R scores were compared between two groups: the intervention group (patients who received IV Edaravone) and the non-intervention group (patients who did not receive IV Edaravone). Data collected included demographic details and ALS-FRS-R scores that were recorded at baseline after each treatment cycle, for a total six cycles. These scores were compared with those of the control group at the corresponding time points. Survival outcomes were also evaluated between the two groups and side effect profile of the drug was also noted.

Results

Data of ALS patients (definitive and probable) were screened, and 62 patients were enrolled, of which 12 were excluded, thus there were 25 ALS patients in the intervention group and 25 patients in the non-intervention group. The two groups were matched for demographic parameters and the ALS-FRS scores were noted at the baseline at each cycle till 6 cycles and compared. It was inferred that the scores were not significant statistically (p > .001) among the two groups, nor did the survival rates vary significantly.

Conclusion

Intravenous Edaravone therapy had no beneficial effect on the ALS-FRS score in the intervention group when compared to the non-intervention group, nor did the survival rates improve. Keywords: Amyotrophic lateral sclerosis, Edaravone Therapy, ALS FRS Score.

Keywords

Behaviour physiology clinical neuroscience clinical medicine

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder that selectively affects motor neurons of the brain and spinal cord, which are essential for controlling voluntary muscle movements. The disease manifests with progressive muscle weakness and wasting in both upper and lower limbs, along with bulbar involvement leading to dysarthria and dysphagia. Eventually, it leads to respiratory failure, typically resulting in death within 2 to 3 years following diagnosis. The median survival period ranges from 1.5 to 4 years,^{1, 2} with approximately 50% mortality occurring within the initial 30 months after onset of symptoms. As the disease advances, up to half of the affected individuals experience cognitive and behavioural disturbances, and about 13% present with coexisting behavioural variant frontotemporal dementia (bvFTD).^3–5

The mechanism underlying degeneration of motor neurons in ALS remains unclear; however, oxidative stress has been widely accepted to play a prominent role. Various other contributing mechanisms include accumulation of intranuclear and cytoplasmic protein and RNA aggregates, impairments in protein degradation pathways, defects in nucleocytoplasmic transport mechanisms, mitochondrial function impairment, endoplasmic reticulum stress, and altered excitability of neurons that disrupt axonal transport associated with motor degeneration. However, excessive oxidative stress reduces the capability of regeneration and scavenging properties and has been implicated in the pathogenesis and progression of ALS.⁶

Furthermore, reactive oxygen species (ROS) cause genetic mutations by changing the actions of superoxide dismutase and glutamate synthetase^{7, 8} responsible for the functional impairment of neurons. Increase in the levels of the 3 nitrotyrosine (3 - NT) have been reported as a biomarker for oxidative stress ALS patients.⁹

Many drugs gained insight in delaying the progression and improving the survival span, Riluzole is one. Edaravone also known as MCI-186 came in existence as a potent scavenger of oxygen radicals that prevents motor neural damage by eliminating hydroxyl radicals and lipid peroxides^{10, 11} and received FDA approval in 2017 for management of ALS, as it claimed to slow the rate of functional decline.¹² As limited studies have investigated the efficacy of Edaravone on ALS-FRS scores with no such study in Central part of India, the present study is designed to evaluate the impact of Edaravone on ALS-FRS scores and the improvement in the survival outcomes, if any.

The rationale is to determine the efficacy of IV Edaravone on ALS-FRS scores in the ALS patients of Central India, which has not been done till now, and to know exactly whether Edaravone in an injectable form has any benefits worth spending money on this drug. Also, patients taking long cycles (cost benefit) and outcomes were measured by comparing the ALS-FRS scores as well as the survival rates among the two groups.

Methods

Study Design and Population

The study was retrospective, observational, open label study done on clinically definite/probable ALS patients admitted in the neurology department of AIIMS, Bhopal, during the period June 2021 to December 2023 (2.5 years) after IHEC approval.

Participants

Inclusion Criteria

Patients of age ≥18 years diagnosed with of clinically definite/probable ALS by applying Revised El Escorial classification of ALS.

Patients may or may not have been treated with Riluzole.

Patients with clinically definite/probable ALS who have not received intravenous (iv) Edaravone serve as the control group.

Revised El Escorial classification of ALS. Four anatomical regions, bulbar, cervical, thoracic, and lumbar are included for disease stratification.

Exclusion Criteria

Patients without clinically definite/probable ALS diagnosis were excluded.

It included all ALS mimics.

Severe diseases involving respiratory muscles or needing ventilation in any form.

Data Collection

We collected data retrospectively for the above-mentioned duration (June 2021 to December 2023 (2.5 years) for ALS patients who were enrolled from the neurology OPD and were admitted in the neurology ward. Patients with clinically definitive/probable ALS were extensively worked up for ruling out mimics, through medical records and family history. A physical examination as a part of the neurologic work-up, along with neuroimaging and relevant blood laboratory workup of cerebrospina fluid (CSF) analysis including autoimmune and paraneoplastic profile were analysed in relevant cases. Electromyography (EMG) confirming LMN signs consisted of neurogenic potentials, incomplete interference pattern and presence of spontaneous activities such as fasciculations and fibrillations. The Patients were divided based on the onset of clinical symptoms into limb-onset, bulbar-onset and respiratory onset types.

They were grouped into patients that received IV Edaravone therapy (cases) and those who did not receive Edaravone therapy (controls). They were matched for similarities with respect to demographic and clinical parameters including race, age, region, sex, duration of illness, Riluzole prescription, ventilation support (invasive/non-invasive) and all-cause hospitalisation. The patients having respiratory dysfunction, requiring any form of ventilation or oxygenation, were excluded from the study.

The date from when the IV Edaravone was started was considered as the therapy start date.

For controls, it was the date when IV Edaravone was not administered because they did not consent to receive it due to personals beliefs, financial constraints or lack of caregiver support.

Data included demographic profiles such as onset age, gender, habitat and clinical profile phenotype at presentation and during progression and functional disabilities. ALSFRS-R scores were calculated at baseline and post IV Edaravone treatment after each cycle. This was also done for the non-Edaravone group.

The scores were calculated at the same time when the intervention group received Edaravone and were compared. The difference in longevity (survival rate) were also compared and analysed. These details were retrieved from the medical records.

Out of the 62 patients of ALS enrolled, 50 patients of clinically definite/probable ALS were matched for baseline characteristics at 1 month of the diagnosis. They were selected based on 25 in each group (IV Edaravone therapy group and non-IV Edaravone therapy group) (Figure 1). Twenty one were limb onset, 4 were bulbar onset in intervention group, 20 were limb onset and 5 were bulbar onset in the non-intervention group. Patients who did not meet the criteria of clinically definite/probable ALS were as following: 4 (3-males,1-female) were possible ALS, 4 (2-males, 2-females) ALS Mimic, 4 (3-males,1-female) did not consent for the study. The patients with definitive and probable ALS who were screened and had doubt of being an ALS mimic were ruled out after relevant and necessary investigations (radiology, UMN dominant (iPTH) and LMN dominant (GM1) antibodies).

Figure 1.

Flowchart Showing Sequence of Events in Our Study.

ALS patients’ phenotype was grouped as limb onset/bulbar onset or respiratory onset. Symptom severity was compared between the ALS patients who were administered IV Edaravone therapy and those who did not receive IV Edaravone therapy, using the ALSFRS score, which was applied at the baseline in both the groups (IV Edaravone therapy recipient group and IV Edaravone therapy non-recipient group). The scoring was done at the end of each cycle in the recipient group and at the same time in the non-recipient group. Edaravone was given in a dosage of 60 mg by intravenous infusion over 60 minutes once daily for fourteen consecutive days for initial treatment cycle and provided a drug-free interval of 2 weeks. In the subsequent cycles, patients were administered the drug for 10 days as per the standard protocol.¹³ Each cycle of treatment was followed by a 14-day drug free phase. The ALSFRS-R scale comprises 12 items grouped into four domains: bulbar function (items 1–3), fine motor skills (items 4–6), gross motor abilities (items 7–9) and respiratory function (items 10–12).¹⁴

Statistical Analysis

Descriptive analyses of demographics and clinical variables were performed using counts and percentages for categorical variables, and measures of central tendency (mean, median, SD, interquartile range) for continuous variables. We applied the chi square for qualitative ratios and the 2-way Anova test for comparison of differences in ALS-FRS scores (to check variance of the two groups). Survival differences between IV Edaravone-treated patients and untreated controls were analysed using Kaplan–Meier survival curves.

To estimate the potential benefit of IV Edaravone, a shared frailty Cox regression analysis was conducted, adjusting for hidden heterogeneity across matched cohorts.

Results

Sixty-two (62) ALS patients, 25 case, 25 control group, 4-ALS mimics, 4-possible ALS, 4- did not consent or did not receive the therapy. Sixty-two patients were screened, 12 were excluded, 25 patients fulfilled ALS criteria and received IV Edaravone and 25 patients fulfilled ALS criteria and did not receive IV Edaravone. ALS-FRS scores were calculated at baseline and after each treatment cycle—from cycle 1 through cycle 6. (shown in flow chart below).

Demographic and Clinical Variables of Case and Control Groups

The baseline characteristics of both the groups were compared. The mean age of the 211 participants was 49 ± 5.3 years in the case group and 47 ± 4.8 years in the control group. The majority were males, comprising 20 participants (80.8%). Limb onset was observed in 21 patients (84.0%), followed by bulbar onset in 4 patients (16%), as shown in Table 1 below.

Table 1.

Clinico-demographic Profile of Cases and Controls.

	Case (n = 25)	Control (n = 25)	p Value
Sex (male/female)	20/5	20/5	>.89
Age (year) (mean ± SD)	49 ± 5.3	47 ± 4.8	>.81
Disease onset (limb/bulb)	21/4	20/5	>.84
Disease type (sporadic/familial)	25/0	25/0	>.75
Mean duration(months)	26.7 ± 3.3	25.9 ± 2.8	>.91
Residence	All from MP
Riluzole consumption during study (month) (mean ± SD)	12.6 ± 7.31	12.95 ± 8.1	>.89

Note: SD: Standard deviation.

ALS-FRS scores were compared between the group that received Edaravone (case group) and the group that did not receive Edaravone (control group) measured at baseline and after each treatment cycle in the case group and at the same interval in the non- intervention group. Differences in ALS-FRS scores were not statistically significant among the two groups as shown in Table 2.

Table 2.

Effect of Edaravone on ALSFRS-R Scores in Intervention Group at Each Cycle and Control Group.

ALS-FRS Score (mean ± SD)	Intervention (mean ± SD)	Control (mean ± SD)	p Value
Cycle 1	35.08 ± 5.8	34.50 ± 2.6	>.99
Cycle 2	35.08 ± 5.8	34.54 ± 2.6	>.99
Cycle 3	34.88 ± 5.9	34.67 ± 2.5	>.98
Cycle 4	34.88 ± 5.9	34.67 ± 2.7	>.99
Cycle 5	34.60 ± 6.1	34.67 ± 2.7	>.99
Cycle 6	34.76 ± 6.0	34.63 ± 2.6	>.99

ALS FRS-R scores on presentation were normally distributed hence a repeated measures ANOVA was applied. The repeated measures ANOVA was performed to assess the impact of Edaravone therapy on the ALSFRS-R scores in patients with ALS. The effect of Edaravone over time was evaluated across cycles in the intervention group and was not significant either in the intervention or in non-intervention group, Wilk’s lambda = 0.87, F (5,19) = 0.556, p = .732, ƞ² = 0.13. Thus, the null hypothesis is to be retained. Follow-up comparisons indicated that each pairwise difference was not significant. There was no significant increase in the score over the cycles (Table 2 and Figures 2, 3).

Figure 2.

Bar Chart Showing ALS FRS R Scores in Both Treatment Arms After Each Treatment Cycle.

Figure 3.

Profile Plot Showing the ALS FRS R Score Across the Cycles of IV Edaravone Administered in Both the Intervention and the Control Group.

The survival rates were assessed in both the intervention and the non-intervention groups at the end of the study, and it was concluded that the survival rates did not differ between the two groups. The median survival was 25.5 months (95% CI, 20.4–24.9) for patients treated with IV Edaravone, compared to 23.5 months (95% CI, 20.0–28.0) for those who did not receive IV Edaravone.

Adverse events (if any): Adverse events (AEs) and serious adverse events (SAEs) were recorded throughout the study duration wherein one patient developed sensitivity on Edaravone administration at onset and one patient developed Riluzole induced pancreatitis during the study. Fatigue was noted in five patients from day 1 to day 5, which resolved by itself, and constipation was noted in three patients and gait disturbance in two. None reported hyperglycaemia, anaemia or myalgias.

Discussion

This retrospective observational open label study compared the effect of IV Edaravone in definite or probable ALS patients using R-El Escorial criteria and found no significant benefit of adding IV Edaravone, nor did it improve the survival rates. Various studies have shown preserved functional status in Edaravone recipient patients using Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALS-FRS-R)]. Hiide Yoshino et al., in their 2006 phase 2 study, demonstrated a reduction in ALSFRS-R scores over a 6-month treatment period with the administration of 60 mg of Edaravone as per the standard protocol, suggesting that Edaravone may delay the progression of functional disturbances in ALS patients.^15–17

A small retrospective, open-label study demonstrated a modest reduction of ALSFRS-R scores without any significant reported adverse events. The study also suggested a significant slowing of ALSFRS-R score decline, regardless of gender, site of onset or ethnicity. Furthermore, it highlighted the importance of initiating Edaravone treatment early, particularly in patients with a forced vital capacity (FVC) ≥60%, to observe optimal therapeutic efficacy.¹⁸

A phase 3 randomised, double-blind study was conducted to evaluate the safety and efficacy of Edaravone (60 mg/day administered intravenously for 2 weeks each month) in patients with early-stages of ALS. The study demonstrated a reduction in ALS Functional Rating Scale-Revised (ALSFRS-R) scores in favour of Edaravone compared to the placebo group. In 2020, Shefner et al. reported the long-term benefits of Edaravone in ALS patients through a phase 3 open-label study involving 123 participants—65 received Edaravone for 48 weeks, while 58 initially received a placebo for 24 weeks before switching to Edaravone for the subsequent 24 weeks. The analysis suggests that Edaravone remains beneficial even when initiated after receiving a placebo for 6 months while also being able to maintain the efficacy for 1 year.¹⁹ Other long-term (18 month) effects of Edaravone were favourable for ALSFRS-R scores and survival rates.²⁰ A recent meta-analysis study of 183 patients who received Edaravone showed an efficacious result without significant adverse events, further strengthening the clinical evidence supporting the use of Edaravone in ALS management.²¹ Our results were not favourable for the use of Edaravone. There were no improvements in functional scores nor were the survival benefits seen when assessed over 6 cycles of Edaravone. Our study is similar to a parallel-group single-blind trial in a subgroup of Iranian patients with ALS done by Eishi-Oskouei A et al. that evaluated amyotrophic lateral sclerosis ALSAQ-40, ALSFRS-R and MMT scores in 20 ALS patients in each group and found no significant difference between cases and control groups across five different time points. But it did show its safety for administration in ALS patients. It explained the non-efficacy of Edaravone as a result of different ethnicity.²² Another phase 3 clinical trial (first) with the name, the MCI186-16 study and its extension the MCI186-17 study, which was a 2-year study on probable or definite ALS, done in 2014, also showed lack of Edaravone response for ALS patients.

They used the definition efficacy-expected subpopulation (EESP), FVC ≥ 80% and a score ≥2 for all items of ALSFRS-R at baseline and post treatment. The MCI186-19 study phase 3 clinical trial in 2017 showed efficacy of Edaravone but only in selected subgroups comprising those who had an independent living status and had a preserved functional status.²³ Thus they drew the conclusion that when Edaravone was started early and administered continuously, it had some beneficial response.²⁴ Other studies, namely Phase 3 ADORE clinical trial of Oral Edaravone (FAB122), conducted in Europe in ALS patients, recently declared its results as being negative, stating no significant benefit from daily treatment of Oral Edaravone over a 48-week period.²⁵ They measured changes in the ALS-FRS-R score. Measurement of survival by the Combined Assessment of Function and Survival (CAFS) did not show survival benefits as well. It did prove it as a safe and well tolerated drug. A randomised, double-blind placebo-controlled study in a group of 25 patients with advanced ALS enrolled patients with clinically definite, probable or probable-laboratory supported ALS, FVC >60% and disease duration <36 months. It did not achieve clinical benefits of Edaravone at the end of 6 months, though no serious adverse events were noted.²⁶ The above data suggests that we need to re-explore more about the pathophysiological role of Edaravone on ALS patients and which group it can be beneficial to needs more critical re-evaluation for the neurophysicians involved in treating ALS patients. ENCALS, European Network for the Cure of ALS, shared some concerns about the potential benefits of Edaravone,²⁷ where the sample size, specific subgroup of ALS patients and the duration of Edaravone treatment were important parameters that must be addressed while selecting patients for Edaravone therapy.²⁸ The analysis showed a better clinical outcome in long-term administration (12 months) compared to a short-term Edaravone administration (6-month treatment). What the author can conclude is that Edaravone may require appropriate selection of ALS subgroup of patients and a careful time-line plan to start the therapy. Edaravone requires an invasive route of administration, relatively long-term continuous cyclical treatments and high costs. Therefore, one needs to be confirmed about its definite role in ALS before administering it in all patients of ALS.²⁹ Our patients received IV Edaravone for 6 cycles (24 weeks) continuously, which is a standard therapy protocol, and patients were followed for the next 3 months. No improvement in either physical or functional status were noted during this period. The adverse effect profile was comparable with the previous studies of phase 3 trials.^30–33 One patient had hypersensitivity to Edaravone infusion and was managed successfully with intravenous hydrocortisone and anti-histamines. This observation may be consistent with the hypothesis that Edaravone has only a modest effect and is in keeping with various other drugs tried in past 2–3 decades. Our study patients had moderate disease when assessed with the ALS-FRS scores, which may be a reason that Edaravone did not prove to be efficacious as it may be effective in mild diseases. This study gives insight into the fact that more work is required for knowing the mechanisms of action of Edaravone on various cellular function levels to validate the efficacy of Edaravone in neurodegenerative disease like ALS, especially in the context of disease severity -mild/moderate. Whether more cycles of Edaravone infusion can result in improvement is another area of interest which needs to be answered. Unlike Riluzole that has a mild effect on survival (9% increase in 1-year survival), survival rates did not differ in both the groups. So, with this observation, the role of Edaravone in prolongation of life remains to be answered in the future.

Conclusion

The authors conclude that Edaravone did not improve the functional scores in definite/probable ALS patients, nor did it show survival benefits when tried as 6 cycle regimes.

It is a safe and tolerable drug. More research at molecular and cellular levels to identify the causative factors related to ALS and role of Edaravone needs to be re-explored apart from its ‘free radical scavenging property’. Limitations-We did not include patients with respiratory involvement, and vital capacity (FVC) was not measured in contrast to other studies who took it as at least 80%. Instead, we relied on clinical respiratory function assessment parameters such as single breath count, Breath Holding Time and chest expansion, which were measured in all patients of ALS and were compared at baseline and at end of each cycle in both intervention and non-intervention group. Another limitation is small number of study participants.

Footnotes

Abbreviation

ALS-FRS-Amyotrophy Lateral Sclerosis Functional Rating Scale

ALS-Amyotrophy Lateral Sclerosis

IV-intravenous

3-NT-3nitrotyrosine

FDA-Food & Drug authority

IHEC-Institutional Human Ethics Committee

EMG-Electromyography

CSF-Cerebrospinal fluid

CAFS-Combined Assessment of Function and Survival

ENCALS-European Network for the Cure of ALS

FVC-Force vital capacity

Acknowledgement

We acknowledge the patients’ participation, their faith and their support in conducting the study.

Authors’ Contribution

PVK: Conceptualising, designing, framing and conducting the study, reviewing literature and writing manuscript.

DS: Clinical evaluation and calculating the functional rating scale and comparison.

AN: Tabulating the data, Literature search, editing manuscript, AAJ-Statistical analysis, table and chart preparation.

VP: Editing tables and graphs.

Statement of Ethics

Taken IHEC approval LOP-P24/018.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.

Funding

The authors received no financial support for the research, authorship and/or publication of this article.

ICMJE Statement

Yes.

Patient Consent

Taken. Patients and their tireless caregivers are heartily acknowledged for their participation in this study.

ORCID iD

Priyanka V Kashyap

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