Edaravone (Radicava)

Number: 0918

Policy

Notes: PRECERTIFICATION REQUIREDFootnotes for Precertification of edaravone^*

Site of Care Utilization Management Policy applies.  For information on site of service for edaravone, see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Aetna considers edaravone (Radicava) medically necessary for the treatment of individuals with amyotrophic lateral sclerosis (ALS) when all the following criteria are met:

• Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale-Revised (ALSFRS-R; see Appendix)); and
• Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] greater than or equal to 80%); and
• Definite or probable ALS based on El Escorial revised criteria (see Appendix); and
• Disease duration of 2 years or less

Aetna considers edaravone experimental and investigational for the following (not an all-inclusive list):

• Acute ischemic stroke
• Alzheimer's disease
• Autoimmune thyroiditis
• Brain radionecrosis
• Choroidal neovascularization
• Intra-cerebral hemorrhage
• Myocardial damage after ischemia and re-perfusion
• Nephropathy
• Osteoarthritis
• Parkinson disease
• Stroke
• Wound healing.

Continuation Criteria

Aetna considers continued use of edaravone medically necessary when the following criteria are met:

• There is documentation indicating that edaravone use has slowed the progression of ALS; and
• Overall function should be improved/superior relative to that projected for the natural course of ALS.

Footnotes^* Precertification of edaravone is required of all Aetna participating providers and members in applicable plan designs.  For precertification of edaravone, call (866) 503-0857, or fax (866) 267-3277. 

Background

Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig’s disease, is a progressive, neurodegenerative disease that destroys motor neurons.  Patients with ALS gradually lose their ability to control voluntary muscles that are involved in breathing, chewing, talking, and walking; resulting in paralysis and finally death.  The Centers for Disease Control and Prevention estimates that approximately 12,000 to 15,000 Americans have ALS; and the majority of patients with ALS die from respiratory failure, usually within 3 to 5 years from when the symptoms first commence.  Riluzole is the only currently approved mildly effective treatment; it received marketing authorization in the U.S. in 1995 in the U.S. and in Europe in 1996.  In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS.  Despite significant research efforts, the majority of clinical studies have failed to demonstrate clinical effectiveness.  In the past year, oral masitinib and intravenous (IV) edaravone (a synthetic-free radical scavenger) have emerged as promising new therapeutic agent for the treatment of ALS (Petrov et al, 2017). 

In a double-blind, parallel-group, placebo-controlled study, Abe and colleagues (2014) examined the safety and effectiveness of edaravone in patients with ALS.  These researchers conducted a 36-week clinical trial, consisting of 12-week pre-observation period followed by 24-week treatment period.  Patients received placebo (n = 104) or edaravone (n= 102) IV infusion over 60 minutes for the first 14 days in cycle 1, and for 10 of the first 14 days during cycles 2 to 6.  The efficacy primary end-point was changes in the revised ALS functional rating scale (ALSFRS-R) scores during the 24-week treatment period.  Changes in ALSFRS-R during the 24-week treatment period were -6.35 ± 0.84 in the placebo group and -5.70 ± 0.85 in the edaravone group, with a difference of 0.65 ± 0.78 (p = 0.411).  Adverse events (AEs) amounted to 88.5 % (92/104) in the placebo group and 89.2 % (91/102) in the edaravone group.  The authors concluded that the reduction of ALSFRS-R was smaller in the edaravone group than in the placebo group.  Levels and frequencies of reported AEs were similar in the 2 groups.  These investigators stated that although the elimination of free radicals by means of edaravone to inhibit the degeneration of motor neurons appeared to be a promising new strategy for the treatment of ALS, this study did not demonstrate effectiveness of edaravone in delaying the progression of ALS.  They noted that while the primary end-point was not attained, they considered that these findings were helpful to identify the patient population in which edaravone could be expected to show effectiveness.  On the basis of this information, these researchers designed a phase-III clinical trial.

Noto and associates (2016) stated that therapies that inhibit neuronal hyper-excitability may be effective in arresting the progression of ALS.  These investigators searched Medline and ClinicalTrials.gov and selected randomized controlled trials (RCTs) that covered neuro-protective therapy.  Riluzole has been established to reduce neuronal hyper-excitability.  More recently, initial studies of Na(+) channel blockers (mexiletine and flecainide) have been investigated.  Separately, a trial of a K(+) channel activator (retigabine) is underway, while edaravone is currently being considered for licensing by drug approval agencies based on a hypothesis that the elimination of free radicals may lead to protection of motor neurons.  The authors concluded that initial clinical trials with Na(+) channel blockers have not yet established effectiveness in ALS.  Currently, retigabine is under evaluation as a potential therapy; and edaravone has recently been approved as a new therapeutic option for ALS in Japan.

Sawada (2017) noted that although the pathogenesis remains unresolved, oxidative stress is known to play a pivotal role.  Edaravone works in the central nervous system as a potent scavenger of oxygen radicals.  In ALS mouse models, edaravone suppresses motor functional decline and nitration of tyrosine residues in the cerebro-spinal fluid (CSF).  These investigators reviewed 3 clinical trials: 1 phase-II open-label trial and 2 phase-III RCTs.  In all trials, the primary outcome measure was the changes in scores on the ALSFRS-R to evaluate motor function of patients.  The phase-II, open-label trial suggested that edaravone is safe and effective in ALS, markedly reducing 3-nitrotyrosine levels in the CSF.  One of the 2 RCTs showed beneficial effects in ALSFRS-R, although the differences were not significant.  The last trial demonstrated that edaravone provided significant effectiveness in ALSFRS-R scores over 24 weeks where concomitant use of riluzole was permitted.  Eligibility was restricted to patients with a relatively short disease duration and preserved vital capacity.  Therefore, combination therapy with edaravone and riluzole should be considered earlier.

Martinez and colleagues (2017) reviewed all the ALS ongoing clinical trials (up to November 2016).  They described them in a comprehensive way and grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs.  Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials.  The authors noted that edaravone was recently approved in Japan and is pending in the U.S.

On May 5, 2017, the Food and Drug Administration (FDA) approved edaravone (Radicava) for the treatment of patients with ALS.  The effectiveness of edaravone for the treatment of ALS was demonstrated in a 6-month, randomized, placebo-controlled, double-blind study conducted in Japanese patients with ALS who were living independently and met the following criteria at screening:

• Functionality retained most activities of daily living (defined as scores of 2 points or better on each individual item of the ALS Functional Rating Scale – Revised [ALSFRS-R; described below])
• Normal respiratory function (defined as percent-predicted forced vital capacity values of [%FVC] greater than or equal to  80 %)
• Definite or Probable ALS based on El Escorial revised criteria
• Disease duration of 2 years or less.

The study enrolled 69 patients in the Radicava arm and 68 in the placebo arm.  Baseline characteristics were similar between these groups, with over 90 % of patients in each group being treated with riluzole.  Radicava was administered as an IV infusion of 60 mg given over a 60-minute period according to the following schedule:

• An initial treatment cycle with daily dosing for 14 days, followed by a 14-day drug-free period (Cycle 1)
• Subsequent treatment cycles with daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods (Cycles 2 to 6).

The primary efficacy end-point was a comparison of the change between treatment arms in the ALSFRS-R total scores from baseline to Week 24.  The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency).  Each item is scored from 0 to 4, with higher scores representing greater functional ability.  The decline in ALSFRS-R scores from baseline was significantly less in the Radicava-treated patients as compared to placebo.  The most common AEs reported by subjects receiving edaravone were contusion and gait disturbance.  Radicava is also associated with serious risks that require immediate medical care, such as hives, swelling, or shortness of breath, and allergic reactions to sodium bisulfite, an ingredient in the drug.  Sodium bisulfite may cause anaphylactic symptoms that can be life-threatening in people with sulfite sensitivity.  The FDA granted Radicava orphan drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

Mitsubishi Tanabe Pharma Corporation’s Package Insert on “Radicut Injection” (2015) lists 3 clinical studies regarding the use of edaravone injection for the treatment of ALS.

1st Confirmatory Study:

When edaravone or placebo was intravenously administered at 60 mg in patients with ALS (warranting “Definite”, “Probable” or “Probable-laboratory-supported” according to the El Escorial and the revised Airlie House diagnostic criteria for ALS, rated as grade 1 or 2 in Japan ALS severity classification, having %FVC not less than 70 %, and illness duration within 3 years) in 6 cycles of treatmentFootnotes for 6 cycles treatment^*1, mean changes from baseline in the ALSFRS-R as primary end-point were not significantly different between the edaravone-treated and placebo-treated groups (-5.70 ± 0.85 versus -6.35 ± 0.84; p = 0.411).

2nd Confirmatory Study:

When edaravone or placebo was intravenously administered at 60 mg in patients with ALS (warranting “Definite” or “Probable” according to the El Escorial and the revised Airlie House diagnostic criteria for ALS, rated as grade 1 or 2 in Japan ALS severity classification, having %FVC not less than 80 % and illness duration within 2 years) in 6 cycles of treatmentFootnotes for 6 cycles of treatment^*1, there were significant differences in mean changes from baseline in the ALSFRS-R as primary end-point between the edaravone-treated and placebo-treated groups (-5.01 ± 0.64 versus -7.50 ± 0.66; p = 0.0013).

A Placebo-Controlled Double-Blind Comparative Study in Patients with Japan ALS Severity Classification of Grade 3:

When edaravone or placebo was intravenously administered at 60 mg in patients with Japan ALS severity classification of grade 3 ALS in 6 cycles of treatmentFootnotes for 6 cycles treatment^*1, mean changes from baseline in the ALSFRS-R as primary end-point were significantly different between the edaravone-treated and placebo-treated groups (-6.52 ± 1.78 versus -6.00 ± 1.83; p = 0.8347).

Footnotes^*1: Once-daily consecutive administration for 14 days and subsequent cessation for 14 days of this product were combined in the 1st cycle of treatment.  After completion of the 1st cycle, this product was administered for 10 of 14 days followed by cessation for 14 days from the 2nd to 6th cycle (the treatment cycle was repeated 5 times).

Edaravone is also being investigated in the treatment of various conditions/diseases (e.g., acute ischemic stroke, choroidal neovascularization, intra-cerebral hemorrhage, myocardial damage after ischemia and re-perfusion, nephropathy, and osteoarthritis); however, its effectiveness for these indications has not been established.

Acute Stroke (e.g., Acute Ischemic Stroke and Intra-Cerebral Hemorrhage)

Yang and colleagues (2015) evaluated the effectiveness of edaravone for acute stroke including acute ischemic stroke (AIS) and intra-cerebral hemorrhage (ICH).  These investigators identified RCTs with comprehensive searches and performed systematic reviews according to the Cochrane methods of systematical reviews.  Edaravone can reduce the rate of death or long-term disability significantly for AIS (relative risk [RR] = 0.65; 95 % confidence intervals [CI]: 0.48 to 0.89, p = 0.007).  However, sensitivity analysis yielded a different result.  Edaravone can also improve the short-term neurological impairment of AIS (mean difference (MD) = 7.09; 95 % CI: 5.12 to 9.05, p < 0.00001), and ICH (MD = -4.32; 95 % CI: -5.35 to -3.29, p < 0.00001).  The authors concluded that edaravone is beneficial in improving neurological impairment resulting from AIS and ICH.  However, there is currently insufficient evidence that edaravone reduces death or long-term disability for AIS and ICH.

Choroidal Neovascularization

Masuda and colleagues (2016) stated that choroidal neo-vascularization (CNV) is a main characteristic in exudative type of age-related macular degeneration.  These researchers examined the effects of edaravone on laser-induced CNV, which was induced by laser photocoagulation to the subretinal choroidal area of mice and common marmosets.  Edaravone was administered either intra-peritoneally (IP) twice-daily for 2 weeks or intravenously just once after laser photocoagulation.  The effects of edaravone on laser-induced CNV were evaluated by fundus fluorescein angiography, CNV area measurements, and the expression of 4-hydroxy-2-nonenal (4-HNE) modified proteins, a marker of oxidative stress.  Furthermore, the effects of edaravone on the production of hydrogen peroxide (H2O2)-induced reactive oxygen species (ROS) and vascular endothelial growth factor (VEGF)-induced cell proliferation were evaluated using human retinal pigment epithelium cells (ARPE-19) and human retinal microvascular endothelial cells, respectively.  Choroidal neo-vascularization areas in the edaravone-treated group were significantly smaller in mice and common marmosets.  The expression of 4-HNE modified proteins was up-regulated 3 hours after laser photocoagulation, and intravenously administered edaravone decreased it.  In in-vitro studies, edaravone inhibited H2O2-induced ROS production and VEGF-induced cell proliferation.  The authors concluded that these findings suggested that edaravone may protect against laser-induced CNV by inhibiting oxidative stress and endothelial cell proliferation.

Myocardial Damage After Ischemia and Re-Perfusion

Zheng and associates (2015) evaluated the safety and effectiveness of edaravone for myocardial damage during myocardial ischemia and reperfusion (I/R).  These researchers included RCTs that compared edaravone with placebo or no intervention in patients with acute myocardial infarction (MI) or undergoing coronary artery bypass.  Two authors selected eligible trials, assessed trial quality and independently extracted the data.  A total of 7 clinical trials were eventually included and analyzed in this study, involving 148 participants; 4 trials were defined as waiting assessment.  All of the 3 remaining trials compared edaravone and another treatment combined with other treatment alone, used the same dose of edaravone injections (60 mg/day) and course of treatment (14 days), evaluated the effect of edaravone at different times, applied different methods, reported AEs, and showed no differences between the treatment group and the control group.  When pooling all of the trials in 1 dataset, edaravone appeared to decrease the proportion of participant with marked myocardial damage during I/R as compared with the control group.  The meta-analysis also revealed decreased cardiac markers such as creatine kinase myocardial b fraction (CK-MB), cardiac troponin I (cTnI) and erythrocyte membrane malonyldialdehyde (MDA), and increased content of superoxide dismutase (SOD).  The authors concluded that as a consequence of the moderate risk of bias and small sample, the observation of an effective treatment trend of edaravone for I/R requires future larger, high-quality trials to confirm.

Nephropathy

Varatharajan and colleagues (2016) stated that edaravone has been reported to reduce ischemia-reperfusion-induced renal injury by improving tubular cell function, and lowering serum creatinine (Cr) and renal vascular resistance.  These researchers examined the effect of edaravone in diabetes mellitus-induced nephropathy in rats.  A single administration of streptozotocin (STZ, 55 mg/kg, IP) was employed to induce diabetes mellitus in rats.  The STZ-administered diabetic rats were allowed for 10 weeks to develop nephropathy.  Mean body weight, lipid alteration, renal functional and histopathology were analyzed.  Diabetic rats developed nephropathy as evidenced by a significant increase in serum Cr and urea, and marked renal histopathological abnormalities like glomerulo-sclerosis and tubular cell degeneration.  The kidney weight to body weight ratio was increased.  Moreover, diabetic rats showed lipid alteration as evidenced by a significant increase in serum triglycerides and decrease in serum high-density lipoproteins (HDLs).  Edaravone (10 mg/kg, IP, last 4-weeks) treatment markedly prevented the development of nephropathy in diabetic rats by reducing serum Cr and urea and preventing renal structural abnormalities.  In addition, this treatment, without significantly altering the elevated glucose level in diabetic rats, prevented diabetes mellitus-induced lipid alteration by reducing serum triglycerides and increasing serum HDLs.  Interestingly, the reno-protective effect of edaravone was comparable to that of lisinopril (5 mg/kg, P.O. 4 weeks, standard drug).  The authors concluded that edaravone prevented renal structural and functional abnormalities and lipid alteration associated with experimental diabetes mellitus; it has the potential to prevent nephropathy without showing an anti-diabetic action, implicating its direct reno-protection in diabetic rats.

Osteoarthritis

Huang and colleagues (2016) stated that osteoarthritis (OA) is a degenerative joint disease affecting millions of people.  The degradation and loss of type II collagen induced by pro-inflammatory cytokines secreted by chondrocytes, such as tumor necrosis factor-alpha (TNF-α) is an important pathological mechanism to the progression of OA.  Whether edaravone has a protective effect in articular cartilage has not been reported.  These researchers examined the chondrocyte protective effects of edaravone on TNF-α induced degradation of type II collagen, and found that TNF-α treatment resulted in degradation of type II collagen, which can be ameliorated by treatment with edaravone in a dose-dependent manner.  It  was found that the inhibitory effects of edaravone on TNF-α-induced reduction of type II collagen were mediated by matrix metalloproteinase 3 (MMP-3) and MMP-13.  The authors concluded that edaravone alleviated TNF-α induced activation of signal transducer and activator of transcription 1 (STAT1) and expression of interferon regulatory factor 1 (IRF-1); these findings suggested a potential protective effect of edaravone in OA.

Alzheimer's Disease

Parikh and associates (2018) stated that Alzheimer's disease (AD) is a devastating neurodegenerative disorder that lacks any disease-modifying drug for the prevention and treatment.  Edaravone (EDR), an approved free radical scavenger, has proven to have potential against AD by targeting multiple key pathologies including amyloid-beta (Aβ), tau phosphorylation, oxidative stress, and neuro-inflammation.  To enable its oral use, novel edaravone formulation (NEF) was previously developed.  These researchers evaluated the safety and efficacy of NEF by using in-vitro/in-vivo disease model.  In-vitro therapeutic potential of NEF over EDR was studied against the cytotoxicity induced by copper metal ion, H2O2 and Aβ42 oligomer, and cellular uptake on SH-SY5Y695 amyloid-β precursor protein (APP) human neuroblastoma cell line.  For i- vivo safety and efficacy assessment, a total of 7 groups of APP/PS1 (5 treatment groups, 1 each as a basal and sham control) and 1 group of C57BL/6 mice as a positive control for behavior tests were used; 3 groups were orally treated for 3 months with NEF at an equivalent dose of EDR 46, 138, and 414 µmol/kg, whereas 1 group was supplied with each Donepezil (5.27 µM/kg) and Soluplus (amount present in NEF of 414 µmol/kg dose of EDR).  Behavior tests were conducted to assess motor function (open-field), anxiety-related behavior (open-field), and cognitive function (novel objective recognition test, Y-maze, and Morris water maze).  For the safety assessment, general behavior, adverse effects, and mortality were recorded during the treatment period.  Moreover, biochemical, hematological, and morphological parameters were determined.  Compared to EDR, NEF showed superior cellular uptake and neuroprotective effect in SH-SY5Y695 APP cell line.  Furthermore, it showed nontoxicity of NEF up to 414 µM/kg dose of EDR and its potential to reverse AD-like behavior deficits of APP/PS1 mice in a dose-dependent manner.  The authors concluded that these findings indicated that oral delivery of NEF holds promise as a safe and effective therapeutic agent for AD.

Autoimmune Thyroiditis

Li and co-workers (2018) noted that autoimmune thyroiditis is among the most prevalent of all the auto-immunities in population.  It is characterized as both cellular immune responses with T, B cells infiltrating to the thyroid gland followed by hypothyroidism as a result of destruction of the thyroid follicles and fibrous replacement of the parenchymal tissue, as well as immune response for TPO and Tg-antibody production.  Experimental autoimmune thyroiditis (EAT) has been proven to be an ideal model to study autoimmune thyroiditis.  In the present study, these researchers induced an EAT model in rats and examined the effect of edaravone on EAT severity and explored the mechanism.  The results showed that edaravone reduced the severity score of thyroiditis dose-dependently and the levels of serum TPOAb, TgAb, T3 and T4.  Edaravone significantly decreased the mRNA level of IL-17, but increased the mRNA level of IL-10, IL-4, TNF-α and IFN-γ.  EAT model significantly induced oxidative stress, which was inhibited by the treatment of 10 mg/kg, 20 mg/kg or 40 mg/kg of edaravone.  The EAT model significantly increased the Akt and STAT3 phosphorylation, but when rats were treated with 20 mg/kg or 40 mg/kg edaravone, they were significantly inhibited.  The HO-1 expression was greatly increased by 20 mg/kg or 40 mg/kg edaravone.  The PI3K inhibitor LY294002, Akt inhibitor triciribine or STAT3 inhibitor WP1066 all significantly decreased the severity score of thyroiditis in the EAT model group, while the HO-1 inhibitor ZnPP-IX increased the severity score of thyroiditis.  The authors concluded that these findings confirmed the involvement of ROS and HO-1-dependent STAT3/PI3K/Akt pathway in the process of Hashimoto's thyroiditis and suggested the potential usage of edaravone in the therapy of it.

Brain Radionecrosis

Chung and colleagues (2018) stated that brain radionecrosis can occur following high-dose radiotherapy to brain tissue and can have a significant impact on a person's quality of life (QOL) and function.  The underlying pathophysiological mechanism remains unclear for this condition, which makes establishing effective treatments challenging.  In a Cochrane review, these investigators evaluated the effectiveness of interventions used for the treatment of brain radionecrosis in adults over 18 years old.  In October 2017, these researchers searched the Cochrane Register of Controlled Trials (CENTRAL), Medline, Embase and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) for eligible studies.  They also searched unpublished data through Physicians Data Query, www.controlled-trials.com/rct, www.clinicaltrials.gov, and www.cancer.gov/clinicaltrials for ongoing trials and hand-searched relevant conference material.  These investigators included RCTs of any intervention directed to treat brain radionecrosis in adults over 18 years old previously treated with radiation therapy to the brain.  These investigators anticipated a limited number of RCTs, so they also planned to include all comparative prospective intervention trials and quasi-randomized trials of interventions for brain radionecrosis in adults as long as these studies had a comparison group that reflects the standard of care (i.e., placebo or corticosteroids).  Selection bias was likely to be an issue in all the included non-randomized studies therefore results were interpreted with caution.  Two review authors independently extracted data from selected studies and completed a “risk of bias” assessment.  For dichotomous outcomes, the odds ratio (OR) for the outcome of interest was reported.  For continuous outcomes, treatment effect was reported as MD between treatment arms with 95 % CIs.  Two RCTs and 1 prospective non-randomized study evaluating pharmacological interventions met the inclusion criteria for this review.  As each study evaluated a different drug or intervention using different end-points, a meta-analysis was not possible.  There were no trials of non-pharmacological interventions that met the inclusion criteria.  A very small randomized, double-blind, placebo-controlled trial of bevacizumab versus placebo reported that 100 % (7/7) of participants on bevacizumab had reduction in brain edema by at least 25 % and reduction in post-gadolinium enhancement, whereas all those receiving placebo had clinical or radiological worsening or both.  This was an encouraging finding but due to the small sample size these researchers did not report a relative effect.  The authors also failed to provide adequate details regarding the randomization and blinding procedures.  Therefore, the certainty of this evidence was low and a larger RCT adhering to reporting standards is needed.  An open-label RCT demonstrated a greater reduction in brain edema (T2 hyper-intensity) in the edaravone plus corticosteroid group than in the corticosteroid alone group (MD was 3.03 (95 % CI: 0.14 to 5.92; low-certainty evidence due to high risk of bias and imprecision); although the result approached borderline significance, there was no evidence of any important difference in the reduction in post-gadolinium enhancement between arms (MD = 0.47, 95 % CI: - 0.80 to 1.74; low-certainty evidence due to high risk of bias and imprecision).  In the RCT of bevacizumab versus placebo, all 7 participants receiving bevacizumab were reported to have neurological improvement, whereas 5 of 7 participants on placebo had neurological worsening (very low-certainty evidence due to small sample size and concerns over validity of analyses).  While no AEs were noted with placebo, 3 severe AEs were noted with bevacizumab, which included aspiration pneumonia, pulmonary embolus and superior sagittal sinus thrombosis.  In the RCT of corticosteroids with or without edaravone, the participants who received the combination treatment were noted to have significantly greater clinical improvement than corticosteroids alone based on LENT/SOMA scale (OR = 2.51, 95 % CI: 1.26 to 5.01; low-certainty evidence due to open-label design).  No differences in treatment toxicities were observed between arms.  One included prospective non-randomized study of alpha-tocopherol (vitamin E) versus no active treatment was found but it did not include any radiological assessment.  As only 1 included study was a double-blinded RCT, the other studies were prone to selection and detection biases.  None of the included studies reported QOL outcomes or adequately reported details about corticosteroid requirements.  A limited number of prospective studies were identified but subsequently excluded as these studies had a limited number of participants evaluating different pharmacological interventions using variable end-points.  The authors concluded that there is a lack of good certainty evidence to help quantify the risks and benefits of interventions for the treatment of brain radionecrosis after radiotherapy or radiosurgery.  In an RCT of 14 patients, bevacizumab showed radiological response that was associated with minimal improvement in cognition or symptom severity.  Although it was a randomized trial by design, the small sample size limited the quality of data.  A trial of edaravone plus corticosteroids versus corticosteroids alone reported greater reduction in the surrounding edema with combination treatment but no effect on the enhancing radionecrosis lesion.  Due to the open-label design and wide CIs in the results, the quality of this data was also low.  There was no evidence to support any non-pharmacological interventions for the treatment of radionecrosis.  They stated that further prospective randomized studies of pharmacological and non-pharmacological interventions are needed to generate stronger evidence; 2 ongoing RCTs, 1 evaluating bevacizumab and 1 evaluating hyperbaric oxygen therapy were identified.

Parkinson Disease

Karba and colleagues (2018) noted that Parkinson's disease (PD) is one of the most common neurodegenerative disorder with intricate progressive pathology.  Currently, available conventional options for PD have certain limitations of their own, and as a result, patient compliance and satisfaction are low.  Current therapeutic options provide only symptomatic relief with limited control to prevent disease progression, resulting in poor patient compliance and satisfaction.  Several emerging pharmacotherapies for PD are in different stages of clinical development.  These therapies include adenosine A2A receptor antagonists, glutamate receptor antagonists, monoamine oxidase inhibitors, anti-apoptotic agents, and antioxidants such as coenzyme Q10, N-acetyl cysteine, and edaravone.  Other emerging non-pharmacotherapies include viral vector gene therapy, microRNAs, transglutaminases, RTP801, stem cells and glial-derived neurotrophic factor (GDNF).  In addition, surgical procedures including deep brain stimulation, pallidotomy, thalamotomy and Gamma Knife surgery have emerged as alternative interventions for advanced PD patients who have completely utilized standard treatments and still suffer from persistent motor fluctuations.  Complementary and alternative medicine (CAM) modalities such as Yoga, acupuncture, Tai Chi, music therapies etc. are highly practiced in several countries, offer some of the safer and effective treatment modalities for PD.  While several of these therapies hold much promise in delaying the onset of the disease and slowing its progression, more pharmacotherapies and surgical interventions need to be investigated in different stages of PD.  It is hoped that these emerging therapies and surgical procedures will strengthen our clinical armamentarium for improved treatment of PD.

Stroke

Bao and associates (2018) stated that cerebral vasculature and neuronal networks will be largely destroyed due to the oxidative damage by over-produced reactive oxygen species (ROS) during a stroke, accompanied by the symptoms of ischemic injury and blood-brain barrier (BBB) disruption.  Ceria nanoparticles, acting as an effective and recyclable ROS scavenger, have been shown to be highly effective in neuro-protection.  However, the brain access of nanoparticles can only be achieved by targeting the damaged area of BBB, leading to the disrupted BBB being unprotected and to turbulence of the micro-environment in the brain.  Nevertheless, the integrity of the BBB will cause very limited accumulation of therapeutic nanoparticles in brain lesions.  This dilemma is a great challenge in the development of efficient stroke nano-therapeutics.  These researchers developed an effective stroke treatment agent based on monodisperse ceria nanoparticles, which were loaded with edaravone and modified with Angiopep-2 and poly(ethylene glycol) on their surface (E-A/P-CeO2).  The as-designed E-A/P-CeO2 features highly effective BBB crossing via receptor-mediated transcytosis to access brain tissues and synergistic elimination of ROS by both the loaded edaravone and ceria nanoparticles.  As a result, the E-A/P-CeO2 with low toxicity and excellent hemo-/histo-compatibility can be used to effectively treat strokes due to great intra-cephalic uptake enhancement and, in the meantime, effectively protect the BBB, holding great potentials in stroke therapy with much mitigated harmful side effects and sequelae.

Oguru and co-workers (2018) noted that argatroban is a thrombin inhibitor agent for acute non-cardioembolic ischemic stroke in Japan.  These researchers studied the prognosis in patients with acute stroke treated by argatroban in comparison with the control group with ozagrel.  A total of 513 patients with acute non-cardioembolic ischemic stroke were enrolled retrospectively from the authors’ hospital database.  Of all patients with stroke, 353 were administered with argatroban.  The other 160 control patients were administered with ozagrel.  Patients were examined as to their stroke types, the neurological severity according to the National Institutes of Health Stroke Scale (NIHSS), and clinical outcomes on discharge were determined according to the modified Rankin Scale (mRS).  A total of 353 patients with acute non-cardioembolic stroke, including 138 with lacunar infarction (LIs) and 215 with athero-thrombotic infarction (ATI) showed functional recovery by argatroban, but the effectiveness of argatroban was not superior to ozagrel therapy defined by the control group.  A total of 255 patients with ATI who were treated with both argatroban and ozagrel showed improvement by 1 point.  These investigators could not find any significant difference between argatroban and ozagrel in the 2 stroke subtypes, LI and ATI.  They also found that combination therapy of argatroban and edaravone was not superior to argatroban monotherapy in clinical outcome.  The authors concluded that argatroban therapy was not superior to control with ozagrel therapy in acute non-cardioembolic ischemic stroke, including LI and ATI, regardless of the use of edaravone.

Naganuma and associates (2018) stated that uric acid (UA), an anti-oxidant with neuroprotective effects, favorably affects stroke outcome.  However, the effect has not been examined in patients treated with edaravone, a frequently used free radical scavenger.  These investigators examined if the use of edaravone affected the relationship between UA levels and outcome in acute ischemic stroke (AIS).  They retrospectively evaluated 1,114 consecutive ischemic stroke patients with pre-morbid mRS scores of less than 2 admitted within 24 hours of onset (mean age of 74 years; median UA levels, 333 μmol/L).  These researchers divided the patients into 2 groups using the median UA value as a cut-off, a low UA group (less than or equal to 333 μmol/L; n = 566) and a high UA group (greater than 333 μmol/L; n = 548), and compared their clinical characteristics and favorable outcomes (mRS less than 2) at 90 days.  These researchers examined the associations between UA levels and 90-day stroke outcome in patients with and without edaravone treatment.  The high UA group had a higher proportion of men, hypertension, atrial fibrillation, and cardio-embolic stroke than the low UA group.  The high UA group also had a higher proportion of patients with mRS of less than 2 at 90 days (61.5 versus 54.1 %, p = 0.013), but the significance was diminished in multi-variate analysis (OR 1.30, 95 % CI: 0.94 to 1.71).  In subgroup analysis, the high UA group without edaravone exhibited a higher proportion of patients with mRS of less than 2 at 90 days than the low UA group (OR 2.87, 95 % CI: 1.20 to 7.16).  The high UA group with edaravone did not exhibit this difference.  The authors concluded that in AIS, the favorable association between high UA levels and outcome at 90 days was not evident in patients treated with edaravone.

Wound Healing

Tamer and colleagues (2018) noted that a novel wound healing material composed of chitosan (Ch) and hyaluronan (HA) boosted with edaravone (Ed) as an anti-inflammatory drug was developed.  The fabricated membranes were verified using FT-IR, and the thermal properties were estimated employing TGA instrument.  Moreover, physical characterizations of the prepared membranes demonstrated a decrease in the membrane wettability, whereas an increase in membrane roughness was monitored due to the effect of edaravone supplementation.  A comparative study of free-radical scavenging activity of edaravone itself was carried out by 2 in-vitro approaches: uninhibited/inhibited hyaluronan degradation and de-colorization of ABTS methods in normal and simulated inflammation condition (acidic condition).  Accordingly, the scavenging activity of edaravone was significantly diminished to OH and peroxy-/alkoxy-type radicals in acidic conditions in compared to the neutral reactions.  The biochemical studies evidenced the hemo-compatibility of the examined membranes.  The consequence of membranes composed of Ch/HA/Ed on the wound healing of the rat's skin was studied, and the macroscopic and microscopic investigations revealed remarkable healing at 21st day post-surgery compared with injuries treated with cotton gauze as a negative control in addition to Ch/HA membrane without edaravone.  For these reasons, the Ch/HA/Ed membrane could be implemented as wound dressing material.

Appendix

The recommended dosage of edaravone (Radicava) is 60 mg administered as an IV infusion over 60 minutes as follows:

• Initial treatment cycle: Daily dosing for 14 days followed by a 14-day drug-free period
• Subsequent treatment cycles: Daily dosing for 10 days out of 14-day periods, followed by 14-day drug-free periods.

ALS Functional Rating Scale-Revised [ALSFRS-R]

The ALSFRS-R scale consists of 12 questions that evaluate the fine motor, gross motor, bulbar, and respiratory function of patients with ALS (speech, salivation, swallowing, handwriting, cutting food, dressing/hygiene, turning in bed, walking, climbing stairs, dyspnea, orthopnea, and respiratory insufficiency).  Each item is scored from 0 to 4, with higher scores representing greater functional ability.

ALSFRS-R Scale and Calculator

Revised El Escorial Schema for the Clinical Diagnosis of ALS

• Clinically Definite ALS: Defined on clinical evidence alone by the presence of UMN, as well as LMN signs, in 3 regions.
• Clinically Probable ALS: Defined on clinical evidence alone by UMN and LMN signs in at least 2 regions with some UMN signs necessarily rostral to (above) the LMN signs.
• Clinically Probable-Laboratory-Supported ALS: Defined when clinical signs of UMN and LMN dysfunction are in only 1 region, or when UMN signs alone are present in 1 region, and LMN signs defined by EMG criteria are present in at least 2 limbs, with proper application of neuroimaging and clinical laboratory protocols to exclude other causes.
• Clinically Possible ALS: Defined when clinical signs of UMN and LMN dysfunction are found together in only 1 region or UMN signs are found alone in 2 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.
• Clinically Suspected ALS: Defined as a pure LMN syndrome, wherein the diagnosis of ALS could not be regarded as sufficiently certain to include the patient in a research study.

LMN: lower motor neuron sign(s); UMN: upper motor neuron sign(s).

Source: Elman LB, McCluskey L. Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease. UpToDate Inc., April 2017.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB:
96365	Intravenous infusion, for therapy, prophylaxis, or diagnosis(specify substance or drug); initial, up to 1 hour
HCPCS codes covered if selection criteria are met:
J1301	Injection, edaravone, 1 mg
ICD-10 codes covered if selection criteria are met:
G12.21	Amyotrophic lateral sclerosis
ICD-10 codes not covered for indications listed in the CPB:
E06.3	Autoimmune thyroiditis
G20	Parkinson's disease
G30.0 - G30.9	Alzheimer's disease
H31.8	Other specified disorders of choroid [choroidal neovascularization]
I25.5	Ischemic cardiomyopathy [myocardial damage after ischemia and re-perfusion]
I61.0 - I61.9	Nontraumatic intracerebral hemorrhage
I63.00 - I63.9	Cerebral infarction
M15.0 - M19.93	Osteoarthritis
N00.0 - N08	Glomerular diseases [nephropathy]
N10 - N16	Renal tubulo-interstitial diseases [nephropathy]
N17.0 - N19	Acute kidney failure and chronic kidney disease [nephropathy]
N25.0 - N29	Other disorders of kidney and ureter [nephropathy]
Numerous Options	Wound healing
S06.340A - S06.369S	Traumatic hemorrhage of cerebrum
T66.xxxA - T66.xxxS	Radiation sickness [brain radionecrosis]

The above policy is based on the following references: