3. ALS is a life-threatening, progressive neurodegenerative
disease affecting upper and lower motor neurons.
Most patients with ALS are sporadic, but 5% to 10% of
patients present with familial ALS.
Mutations – Superoxide dismutase type 1 (SOD1) – ROS
formed - superoxide anion, nitric oxide and hydrogen
peroxide
4. Edaravone
Edaravone, is a potent free radical scavenger
MOA - enhancement of prostacyclin production,
hydroxyl radical trapping, suggesting that it may
provide neuroprotection against oxidative stress in
motor neurons.
MOA in ALS is not known
5. Storage and Handling
Store at up to 25°C (77°F).
Protect from light.
Store in overwrapped package to protect from oxygen
degradation until time of use.
The oxygen indicator will turn blue or purple if the
oxygen has exceeded acceptable levels.
Once the overwrap package is opened, use within 24
hours.
6. DOSAGE
Iv infusion of 60 mg 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
Subsequent treatment cycles with daily dosing for 10
days out of 14-day periods, followed by 14-day drug-
free periods.
7. Administration
60 mg dose as two consecutive 30 mg infusions over a
total of 60 minutes (infusion rate approximately 1 mg
per minute).
Discontinue on the first observation of any signs of
hypersensitivity reaction
9. Pharmacokinetics
C max - reached by the end of infusion.
With multiple-dose administration, does not
accumulate in plasma.
92 % bound to albumin
half-life is 4.5 to 6 hours
10. Pharmacokinetics
Metabolism - metabolized to a sulfate and glucuronide
conjugate - pharmacologically inactive.
excreted mainly in the urine as its glucuronide form
(70-90% of the dose), sulfate form (5-10%) , 1% as
unchanged form.
No age, gender, race effects on pharmacokinetics has
been found
Not found to induce or inhibit enzymes,
No drug interactions.
11. Pregnancy
no adequate data
In animal studies - developmental effects
In the general population, the risk of major birth
defects and miscarriage is 2-4% and 15-20%,
respectively.
The risk in patients with ALS is unknown.
12. Lactation
no data on the presence in human milk, the effects on
the infant, or the effects of the drug on milk
production.
Pediatric
Not known
13. Geriatric
No overall differences in safety or effectiveness were
observed between these patients and younger patients
Renal Impairment
not studied.
but, renal impairment is not expected to significantly
affect the exposure to edaravone, so no dose
adjustment is needed in these patients.
14. Hepatic Impairment
not studied.
No dose adjustment is needed for patients with mild
or moderate hepatic impairment.
No specific dosing recommendation known for
patients with severe hepatic impairment.
16. Evidence before this study - Phase II clinical trial
Yoshino and Kimura - in 20 ALS patients - two-arm 30
and 60 mg/day
Results - Changes in ALSFRS-R scores were significant,
The CSF levels of 3-nitrotyrosine decreased to
undetectable levels after the treatment
No significant differences were found in both arms
17. Evidence before this study - Phase III clinical trial
(Abe et al., 2014).
206 patients - placebo: 104; edaravone: 102.
inclusion criteria included –
FVC of at least 70%
time since disease onset of <3 years,
probable laboratory supported El Escorial
criteria.
18. Evidence before this study - Phase III clinical trial
(Abe et al., 2014).
the primary endpoint - ALSFRS-R
Results - The study has failed to demonstrate
statistically significant treatment effect in any of the
functional endpoints
19. Evidence before this study - Phase III clinical trial
(Abe et al., 2014).
A trend was noted that edaravone appeared to show
possible treatment effect in patients with most severe
and moderate disease progression
no treatment effect was observed in patients with least
severe disease.
20. Evidence before this study-Phase III clinical trial
(Tanaka et al., 2016b)
The second confirmatory Phase 3 study
25 patients with severe ALS, with
The study failed to demonstrate any treatment effect
between placebo and edaravone arms.
21. narrowed the inclusion criteria even further
excluded both the patients with more severe disease
and the patient population with the least severe
disease
Safety and efficacy of edaravone in well defined
patients with amyotrophic lateral sclerosis
(MCI-186) ALS 19 Study Group (Tanaka et al., 2016a)
22. Eligibility criteria
• age 20−75 years
• ALS of grade 1 or 2 in the Japan ALS Severity
Classification
• scores of at least 2 points on all 12 items of
ALSFRS-R,
23. Eligibility criteria
• forced vital capacity of 80% or more
• definite or probable ALS acc to the revised El
Escorial criteria
• disease duration of 2 years or less
• decrease in the ALSFRS-R score of 1–4 during a 12-
week observation
24. Exclusion criteria
score of 3 or less on ALSFRS-R items for dyspnoea ,orthopnea, or
respiratory insufficiency
history of spinal surgery after onset of ALS; or creatinine
clearance 50 mL/min or less.
initiation of riluzole after the start of the observation period was
prohibited.
25. Trial Design
Phase 3
Multicenter - 31 hospitals in Japan.
randomized,
Double blind
parallel-group study
( funded by Mitsubishi Tanabe Pharma Corporation )
26. Randomisation
After the 12-week observation period, eligible patients
were randomly assigned to receive edaravone or
placebo (1:1) by the independent registration centre.
Stratification - definite vs probable ALS
- change in ALSFRS-R score during the
observation period
- age (65–75 vs 20–64 years).
28. Primary end points Time Frame: 24 weeks
The primary efficacy endpoint was the change in
ALSFRS-R score from the baseline to the end of cycle 6
29. secondary outcome Time Frame: 24 weeks
change in FVC
Modified Norris Scale scores (limb, bulbar, and total)
ALS severity classification
grip and pinch strength
Time to death or time to a specified state of disease
progression occurring during the 6 cycles
(defined as disability of independent ambulation, loss of upper-limb function,
tracheotomy, use of a respirator, use of tube feeding, or loss of useful speech)
30. Safety end points
incidence of adverse events
adverse drug reactions
clinical laboratory tests (haematology, blood
biochemistry, and urinalysis)
31. Statistical analysis (SAS 9.3)
sample size of 128 patients (64 per group) was required
to provide 80% power to detect an adjusted mean
difference between groups of 3·0 points on the
ALSFRS-R score at cycle 6 (24 weeks) for analysis of
the primary endpoint.
39. Discussion
The difference in the ALSFRS-R score was significant
after treatment with edaravone compared with placebo
in a well defined population of patients with ALS.
A survey of clinicians by Castrillo- Viguera and
colleagues suggested that suppression of ALSFRS-R
score by 20% or more is clinically meaningful. (33% in
this study)
40. Limitations
the inclusion criteria were stringent
the study duration was short
The effect of edaravone - long term survival rate,
- efficacy in a wider population
- efficacy in patients with
advanced disease were not
considered in this study.
Measurement of CSF 3-nitrotyrosine, which showed a
decrease after treatment in the phase 2 trial, was not
included
41. Limitations
all CTs with edaravone were conducted in Japanese
population.
Previous epidemiological studies point to significant
difference in ALS incidence in populations of Asian
versus European/North American descents
the treatment regimen of intravenous infusions for 10–
14 days each month is inconvenient, require a hospital
setting for administration and potentially costly
47. Diagnostic Categories
Clinically Definite ALS:
is defined on clinical evidence alone by the presence of UMN, as
well as LMN signs, in three 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 limbs, with proper application of neuroimaging and
clinical laboratory protocols to exclude other causes.
48. Diagnostic Categories
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
Clinically Suspected ALS:
it is a pure LMN syndrome, wherein the diagnosis of ALS could
not be regarded as sufficiently certain to include the patient in a
research study. Hence, this category is deleted from the revised
El Escorial Criteria for the Diagnosis of ALS.
