This document addresses the use of edaravone (Radicava) (Mitsubishi Tanabe Pharma Development America, Inc., Jersey City, NJ). Edaravone is a free radical scavenger approved by the U.S. Food and Drug Administration (FDA) for the treatment of amyotrophic lateral sclerosis (ALS).
Edaravone is considered medically necessary for the treatment of amyotrophic lateral sclerosis when all of the following criteria are met:
Investigational and Not Medically Necessary:
Edaravone is considered investigational and not medically necessary when the criteria above are not met and for all other indications.
*See definition section below for description
On May 5th, 2017 the U.S. Food and Drug Administration (FDA) approved Radicava (edaravone injection) for the treatment of ALS, a rapidly progressive neurological disease. Radicava is administered as an intravenous infusion by a health care professional.
Results of an early phase II clinical trial (Yoshino, 2006) indicated that edaravone may delay the progression of symptoms in some individuals with ALS. A 36-week confirmatory study (Abe, 2014) was conducted to further evaluate the efficacy and safety of edaravone in subjects with ALS. A total of 206 subjects were randomized to receive either placebo (saline) or edaravone IV infusion. The trial consisted of a 12-week pre-observation period followed by 24-week treatment period between May 2006 and September 2008 at 29 Japanese sites. Inclusion criteria were: age 20-75 years, diagnosis of definite, probable or probable laboratory-supported ALS, forced vital capacity (FVC) of at least 70%, duration of disease within 3 years, and change in revised ALS functional rate scale (ALSFRS-R) score during the pre-observation period of -1 to -4 points. Exclusion criteria included: reduced respiratory function and complaints of dyspnea; complications that might impact evaluation of drug efficacy, such as Parkinson's disease, schizophrenia and dementia; complications that require hospitalization such as liver, cardiac and renal diseases; infections requiring antibiotics; deteriorated general condition; creatinine clearance 50 ml/min or below; and undergoing cancer treatment. The primary efficacy endpoint was change in ALSFRS-R scores during the 24 weeks of treatment. Upon study completion, data failed to demonstrate the efficacy of edaravone for treatment of ALS. Adverse events occurred in 88.5% (92/104) of subjects in the placebo group and 89.2% (91/102) of subjects the edaravone group. The authors indicated that the results of this trial would be helpful to identify the population which edaravone could be expected to show efficacy. On the basis of that information, a phase III study was designed.
A phase III trial evaluated the efficacy and safety of edaravone in a 24-week open-label extension period after a 24-week double-blind period (NCT01492686). A total of 137 subjects were randomized 1:1 to receive edaravone or placebo after a 12-week pre-observation period. Selection criteria included: definite or probable ALS; Japan ALS severity classification grade less than 3; scoring 2 or more points on each single ALSFRS-R item at screening; forced vital capacity 80% or greater; and ALS duration 2 years or less. Subjects were treated with six cycles of 60-mg edaravone or a matching placebo treatment. Primary efficacy endpoint was change in ALSFRS-R score at week 24. Safety endpoints included adverse events and laboratory tests. Upon study completion, the mean change in ALSFRS-R score was -7.50 ± 0.66 (placebo) and -5.01 ± 0.64 (edaravone). Adverse events were similar in both groups (84.1% in the edaravone group and 83.8% in the placebo group). The most common adverse events were contusion, and dysphagia (16% and 13% of subjects, respectively). Incidence of adverse drug reactions was 2.9% (edaravone) and 7.4% (placebo). There were no serious adverse drug reactions or adverse events that resulted in death. Investigators concluded that subjects meeting the protocol inclusion criteria had less functional loss at 6 months, and less quality of life deterioration compared to those receiving placebo treatment.
Although the published evidence focuses on the use of edaravone for treatment of ALS, it has also been studied for other indications including, but not limited to, treatment of acute stroke (Nakase, 2011) and acute myocardial infarction (Tsujita, 2006). However, at this time the published evidence is insufficient to support the safety and efficacy of edaravone for any indication other than as treatment for certain cases of ALS.
ALS (commonly known as Lou Gehrig's disease) is a refractory and progressive neuromuscular disease that attacks nerve cells in the spine and brain responsible for controlling voluntary movement. It is estimated that approximately 5 persons per 100,000 in the United States are affected with ALS. The cause of the disease is not known; although, some scientific evidence suggests that genetics and environment may have a role. Median survival from onset to death in ALS is reported to vary from 20 to 48 months.
There is no known cure for ALS. However, there are treatments available that can help control symptoms and manage the disease. To date, only one other ALS disease modifying drug has been approved by the U.S. FDA (riluzole [Rilutek® ]). Other treatments may include nutritional support, breathing support, physical therapy and speech therapy.
ALS functional rating scale (revised) (ALSFRS-R): A commonly used functional rating system for persons with ALS (Cedarbaum, 1999):
Awaji-Shima criteria: Diagnostic criteria used for ALS (Douglass, 2010; Hardiman, 2011) consisting of the following categories:
Clinically definite ALS is defined on clinical or electrophysiological evidence, demonstrated by the presence of upper and lower motor neuron signs in the bulbar region and at least two spinal regions, or the presence of upper and lower motor neuron signs in three spinal regions.
Clinically probable ALS is defined on clinical or electrophysiological evidence, demonstrated by upper and lower motor neuron signs in at least two spinal regions, with some upper motor neuron signs necessarily rostral to the lower motor neuron signs.
Clinically possible ALS is defined on clinical or electrophysiological signs of upper and lower motor neuron dysfunction in only one region, or upper motor neuron signs alone in two or more regions, or lower motor neuron signs rostral to upper motor neuron signs.
El Escorial/revised Airlie House criteria (El Escorial is also known as Airlie House): Diagnostic criteria for ALS (Brooks, 2000; Douglass, 2010). Designed for research purposes to ensure appropriate inclusion of subjects into clinical trials. Consists of the following categories:
Clinically Definite ALS is defined on clinical evidence alone by the presence of upper motor neuron (UMN), as well as lower motor neuron (LMN) signs, in the bulbar region and at least two spinal regions or the presence of UMN and LMN signs in three spinal regions.
Clinically Probable ALS is defined on clinical evidence alone by UMN and LMN signs in at least two regions with some UMN signs necessarily rostral to (above) the LMN signs.
Clinically Probable - Laboratory-Supported ALS is defined when clinical signs of UMN and LMN dysfunction are in only one region, or when UMN signs alone are present in one region, and LMN signs defined by EMG criteria are present in at least two regions, with proper application of neuroimaging and clinical laboratory protocols to exclude other causes.
Clinically Possible ALS is defined when clinical signs of UMN and LMN dysfunction are found together in only one region or UMN signs are found alone in two or more regions; or LMN signs are found rostral to UMN signs and the diagnosis of Clinically Probable - Laboratory-supported ALS cannot be proven by evidence on clinical grounds in conjunction with electrodiagnostic, neurophysiologic, neuroimaging or clinical laboratory studies. Other diagnoses must have been excluded to accept a diagnosis of clinically possible ALS.
Japan ALS severity classification grade: A Japanese ALS classification grade based on the severity of the disease. The grade ranges from 1 to 5 as follows (Abe, 2014):
The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.
When services may be Medically Necessary when criteria are met:
|C9493||Injection, edaravone, 1 mg [Radicava]|
|J3490||Unclassified drugs [when specified as edaravone (Radicava)]|
|G12.21||Amyotrophic lateral sclerosis|
When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
|Websites for Additional Information|
The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.
|10/01/2017||The document header wording updated from “Current Effective Date” to “Publish Date. Updated Coding section with 10/01/2017 HCPCS coding changes.|
|New||05/15/2017||Medical Policy & Technology Assessment Committee (MPTAC) review. Initial document development.|
|Preliminary Discussion||05/04/2017||MPTAC review. Pre-FDA approval review.|