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Supplements Edaravone in the Treatment of Amyotrophic Lateral Sclerosis: Efficacy and Access to Therapy - A Roundtable Discussion
Edaravone in the Treatment of Amyotrophic Lateral Sclerosis: Efficacy and Access to Therapy - A Roundtable Discussion
Benjamin Rix Brooks, MD; James A. Jorgenson, MS, RPh, FASHP; Barbara J. Newhouse, MS, BSW; Jeremy M. Shefner, MD, PhD; and Wendy Agnese, PharmD
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Edaravone in the Treatment of Amyotrophic Lateral Sclerosis: Efficacy and Access to Therapy - A Roundtable Discussion Appendix
Benjamin Rix Brooks, MD; James A. Jorgenson, MS, RPh, FASHP; Barbara J. Newhouse, MS, BSW; Jeremy M. Shefner, MD, PhD; and Wendy Agnese, PharmD

Edaravone in the Treatment of Amyotrophic Lateral Sclerosis: Efficacy and Access to Therapy - A Roundtable Discussion Appendix

Benjamin Rix Brooks, MD; James A. Jorgenson, MS, RPh, FASHP; Barbara J. Newhouse, MS, BSW; Jeremy M. Shefner, MD, PhD; and Wendy Agnese, PharmD
APPENDIX I. Development and Clinical Relevance of ALSFRS-R

The original Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS), developed in the 1990s, was designed as a clinical tool to help with the clinical assessment of patients with ALS.44,45 Prior to the development of the original version of the ALSFRS, several instruments for measuring disease status and progression in ALS were used in clinical trials and practice, such as the Norris scale, Baylor scale, and Tufts Quantitative Neuromuscular Examination. However, these metrics failed to consider all areas of functionality that may be impacted by ALS.25 The developers of the ALSFRS sought to create a scale that was easy to use and assessed multiple clinically relevant factors, including a patient’s ability to conduct activities of daily living (ADLs).25 The original ALSFRS, like the later revised version, was a questionnaire-based scale that measured physical function in carrying out ADLs of patients with ALS.25 It posed a series of questions regarding a patient’s ability to carry out functions in 4 domains: gross motor tasks, fine motor tasks, bulbar function, and respiratory function.25

The ALSFRS was validated and employed in both clinical trials and practice; however, over time, it became evident that respiratory function was not weighted in the overall assessment as well as the other 3 domains were.25 Therefore, a revised ALSFRS (ALSFRS-R) was developed in 1999 to include additional considerations relevant to a patient’s respiratory function.25 It consists of 12 questions, 3 for each of the 4 domains, and the scoring for each question ranges from 0 (no ability) to 4 (normal ability), producing a potential total maximum score of 48 (Table 2).25

The ALSFRS-R is now established not only for clinical use to measure disease progression and patient status, but also as a standard outcome measure employed across ALS trials.3,24

The Significance of Change in ALSFRS-R Measurement

A key issue discussed by the roundtable participants was the difficulty that individuals who are not ALS experts have in understanding the clinical significance of changes in ALSFRS-R scores. Studies have sought to translate changes in ALSFRS-R scores into more tangible clinically relevant terms. One such study showed that a 16.5% improvement in the rate of decline in ALSFRS-R scores was associated with an increase in median survival of 4 to 5 months.26,46 Another study, by Kaufmann and colleagues, found that a 1-point decline in the total baseline ALSFRS-R was associated with a 7% increase in mortality risk.47 While these study findings are informative, they do not actually provide guidance on how to determine if ALSFRS-R score changes are clinically significant.

Castrillo-Viguera and colleagues attempted to define a threshold for clinical significance of ALSFRS-R score changes.26 They conducted a survey of members of the Northeast ALS Consortium, asking these experienced ALS clinical investigators to rate the level of clinical meaningfulness of 10% to 50% changes in the ALSFRS-R slope (score vs time).26 A total of 93% of respondents stated that a 20% suppression of the ALSFRS-R slope decline was at least somewhat clinically meaningful, while 100% of respondents agreed that a 25% or greater change in the slope of decline was meaningful.26

Strengths and Weaknesses of the ALSFRS-R

Using the ALSFRS-R as an outcome measure has several advantages. The ALSFRS-R provides a uniform measure of efficacy that is easily administered in person or remotely, which may improve patient retention since it minimizes the number of clinic visits.24 It has a high inter-rater and intra-rater reliability, and scores are strongly correlated with quality of life.2,24,25

Although the ALSFRS-R encompasses many clinically relevant features of disease progression, it has limitations.2 It provides a uniform efficacy measurement, but the scoring metric remains subjective.2 It may also have a potential floor effect in advanced disease. Further, the questionnaire includes inquiries regarding symptoms that can be potentially resolved by supportive treatment; thus, it is difficult to compare patients’ scores since some symptoms may be masked by therapy.2 The ALSFRS-R has also been challenged on the basis of inconsistency between steps of change (ie, point scoring) within each domain, as it is a nominal scale. Support for this contention was provided in a study showing that the motor subscore deteriorated at earlier time point in spinal-onset disease compared with bulbar-onset, and the bulbar subscore deteriorated both earlier and more rapidly in bulbar-onset disease.44,48 The risk of specific features of change being concealed due to inconsistent equivalence between domains of the ALSFRS-R may be more intrinsic in a disease with heterogeneous patterns of progression like ALS.44 Notably, Franchignoni and colleagues have demonstrated evidence of multidimensionality in the ALSFRS-R, suggesting that subscores presented separately rather than combined as 1 single score might better reflect patient status.48,49

While the ALSFRS-R score is a well-validated scoring metric used in clinical trials, its limitations should be considered when evaluating clinical trial data.

APPENDIX II. Clinical Trials of Edaravone in the Treatment of ALS

Mitsubishi Tanabe Pharma America sponsored an edaravone clinical development program with the goal of both bringing effective treatments to patients with ALS and uncovering methods to develop more efficient clinical trials to advance the treatment of ALS and globally aid future clinical trials.7 Spanning 13-plus years, the edaravone clinical development program was a multi-study program involving a series of randomized clinical trials, extension trials, and post hoc analysis studies. Post hoc analyses were conducted to determine the limitations of a given trial and how to improve trial designs of subsequent trials. The details of each trial are discussed below.

Study 16 (MCI 186-16): The First Phase 3 Trial of Edaravone in ALS

Methods

Study 16 was a randomized, double-blind, parallel-group, placebo-controlled phase 3 trial conducted at 29 sites in Japan from May 2006 to September 2008.28 It was a 2-phase, 36-week study, including a 12-week pre-observation period and a 24-week treatment period.28

Patients were eligible if they met the following inclusion criteria:28
  • Aged 20 to 75 years
  • Diagnosis of “definite,” “probable,” or “laboratory-supported-probable” ALS
  • % predicted forced vital capacity (%FVC) ≥70%
  • Disease duration ≤3 years
  • Change in ALSFRS-R score during the pre-observational period of –1 to –4 points
  • Japanese ALS severity classification of 1 or 2
Japanese ALS severity classification scores 1 to 5 are defined as follows: (1) able to work or perform housework; (2) independent living but unable to work; (3) requiring assistance for eating, excretion, or ambulation; (4) presence of respiratory insufficiency, difficulty in coughing out sputum, or dysphagia; and (5) using a tracheostomy tube, tube feeding, or tracheostomy positive pressure ventilation.28

Patients were excluded if any of the following were met:28
  • Deteriorated general condition as judged by investigators
  • Reduced respiratory function or dyspnea
  • Creatinine clearance of ≤50 ml/min within 28 days of study treatment initiation
  • Complications that might substantially influence evaluation of drug efficacy or require hospitalization
  • Infection requiring antibiotic therapy
  • Undergoing cancer treatment
Patients were randomized to receive edaravone 60 mg once-daily intravenous (IV) infusion or placebo for the 24-week treatment period.28 There were 6 total treatment cycles, where each cycle is 4 weeks (cycles 1 to 6). The first cycle consisted of 14 days of drug adminstration followed by 14 days off drug. All subsequent cycles (cycles 2-6) were 10 of 14 days on drug, followed by 14 days off drug.28

The primary efficacy end point was change in ALSFRS-R score. Secondary end points included changes in %FVC, grip strength, pinch strength, Modified Norris Scale score, 40-item ALS Assessment Questionnaire (ALSAQ-40), and time to death or specified state of disease progression. Evaluations were conducted prior to the pre-observation period, prior to the start of the first treatment cycle, and at the end of each treatment cycle after the 14-day observation period.28 Safety outcomes were assessed in terms of number and severity of adverse events (AEs), adverse drug reactions, and the results of clinical laboratory tests and sensory tests.28

Results

Baseline characteristics. A total of 206 patients were randomized; however, 1 was excluded due to misdiagnosis. Of the 205 patients who were studied, 101 patients were treated with edaravone and 104 patients received placebo.28 Baseline characteristics between the 2 study groups were fairly similar. Approximately 64% of the patients were male, and median age was about 58 years. The vast majority of the patients initially presented with limb-onset disease (81%-82% versus 18%-19% bulbar-onset), and median duration of disease was 1.2 to 1.3 years. A total of 88.8% of patients reported use of riluzole. Median ALSFRS-R scores prior to treatment period were 42.0 for the edaravone group and 41.0 for the placebo group. 28  

Efficacy. The adjusted mean change in ALSFRS-R score from baseline to the end of treatment period was –5.70 ± 0.85 in the edaravone group and –6.35 ± 0.84 in the placebo group. The between-group difference was 0.65 ± 0.78 (95% CI, –0.90 to 2.19).28 Although there was less of a decline in ALSFRS-R score seen in the edaravone group than the placebo group, no statistically significant difference was found (P = .411).28

Safety. There was no significant difference in AEs reported between the edaravone group and placebo group.28 The most common AEs reported in the edaravone and placebo groups, respectively, were nasopharyngitis (21.6% vs 21.2%), gait disturbance (19.6% vs 15.4%), constipation (12.7% vs 16.3%), dysphagia (7.8% vs 11.5%), and contusion (11.8% vs 4.8%).28 A total of 17.6% of patients in the edaravone group versus 23.1% in the placebo group reported experiencing serious AEs (SAEs), which included dysphagia (7.8% vs 10.6%), gait disturbance (2.9% vs 1.9%), and muscular weakness (1% in each group).28 A total of 5 deaths, secondary to respiratory dysfunction, were reported (3 in the edaravone group and 2 in the placebo group); however, the investigators attributed the deaths to the underlying disease rather than the study drug.28 No serious adverse drug reactions (ADRs) occurred in either group.28

Study 16 Post Hoc Analysis

 
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