305 study slides

Report
305 Study
Randomised, Double Blind, Placebo Controlled Phase
III Safety and Efficacy Study (8 and 12 mg OD)
Conducted in Europe, Asia, North America, Australia,
and South Africa
1
Study design:
Phase III study number: E2007-G000-305 (NCT00699582)
Design
•
Randomized, double-blind, placebo-controlled, multicenter study of the efficacy and safety
of perampanel when added to 1–3 approved AEDs in patients with uncontrolled partialonset seizures (POS)
•
6-week baseline phase followed by a 19-week double-blind treatment phase (6-week
titration and 13-week maintenance)
•
4-week follow up, or entry into open-label extension (OLE)
Participants
•
Patients ≥12 years of age with refractory (uncontrolled) POS, with or without secondary
generalization
•
Uncontrolled seizures (SZs) despite treatment with ≥2 different AEDs within the past
2 years
•
During 6-week baseline phase had ≥5 POS and receive stable doses of 1–3 AEDs
•
78 centers in Africa, America, Asia, Australia, Europe, and Russia
Treatments
•
8 or 12 mg of perampanel or matched placebo once daily
French JA et al. Epilepsia 2012;
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Study objectives and endpoints
Study objectives
•
Primary: evaluate efficacy of 2 doses of perampanel (8 and 12 mg)
•
Secondary: evaluate the safety and tolerability of perampanel
Primary efficacy endpoints
•
Responder rate (% of patients with ≥50% reduction from baseline in SZ
frequency)
•
Median % change from baseline in SZ frequency per 28 days
Secondary efficacy endpoints
•
Median % change from baseline in frequency of CP+SG SZs
Safety assessments
•
Prior and concomitant medication use, AEs, discontinuations, vital signs, clinical
labs, ECGs, physical and neurological examinations, photosensitivity and
withdrawal questionnaires
CP: complex partial; SG: secondarily generalized; CP+SG: seizures that are either complex partial or
secondarily generalized. French JA et al. Epilepsia 2012
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Study design
Prerandomization
Follow-up
phase or
OLE
Double-blind phase
6-week titration period
6 weeks
13-week maintenance period
12
Baseline
4 weeks
12 mg/day
10
8
6
4
2
8 mg/day
8
6
4
2
Placebo arm
Visit 1
Enrolment
2
3
Randomization
French JA et al. Epilepsia 2012;
4
5
6
7
8
OLE
9
Follow-up
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Patient flow and disposition
Patient flow and disposition
Placebo
Perampanel
8 mg
12 mg
Assessed for eligibility
N
496
Randomized
N
389a
Randomized, not treated
N
3
ITT analysis set
N
136
129
121
Safety analysis set
N
136
129
121
Completed (% of safety analysis set)
88%
84%
77%
Discontinued (% of safety analysis set)
12%
16%
23%
3%
9%
19%
Discontinued due to AEs
%
aIncludes
8 patients who were screen failures and inappropriately randomized to a treatment group.
ITT: intent-to-treat analysis set (all randomized patients who received study drug and had any seizure frequency
data collected from the double-blind phase).
French JA et al. Epilepsia 2012;
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Patient demographics
Patient demographics and baseline characteristics
Placebo
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
34.4
36.7
35.5
47.8%
49.6%
58.7%
White
84.6%
82.9%
82.6%
Asian
8.8%
10.9%
13.2%
Black or African American
<1%
1.6%
<1%
Other
5.9%
4.7%
3.3%
Mean age
Female gender
years
%
Race, %
Safety analysis set.
French JA et al. Epilepsia 2012;
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Epilepsy-specific medical history
Epilepsy-specific medical history
Placebo
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
22.0
22.5
21.3
11.8
13.0
13.7
3.4, 358.4
3.3, 652.2
1.4, 598.4
SP without motor signs
35.3%
38.0%
29.8%
SP with motor signs
22.1%
30.2%
31.4%
CP
83.8%
88.4%
82.6%
SG
69.9%
69.8%
63.6%
Mean time since diagnosis
years
Baseline seizure frequencya
median
min, max
SZ type, %
aITT
population. All other variables are repeated for the safety analysis set.
CP: complex partial; SP: simple partial; SG: secondarily generalized.
French JA et al. Epilepsia 2012;
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Concomitant AEDs
Most patients were taking 2–3 AEDs
% of patients taking 1, 2, and 3 concomitant AEDs, or inducing AEDs,
at baseline
Placebo
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
1 AED
%
12.5%
12.4%
7.4%
2 AEDs
%
47.1%
52.7%
52.1%
3 AEDs
%
40.4%
34.9%
40.5%
Perampanel-inducing AEDsa
%
52.2%
64.3%
66.1%
aAEDs
shown to induce clearance of perampanel were carbamazepine, oxcarbazepine, and phenytoin.
Safety analysis set.
Mean number of concomitant AEDs at baseline was 2.3
French JA et al. Epilepsia 2012;
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Concomitant AEDs
% of patients taking the most commonly used AEDsa as 1 of their
1–3 concomitant AEDs
Placebo
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
Levetiracetam
38.2%
38.0%
38.0%
Carbamazepine
31.6%
33.3%
38.8%
Lamotrigine
27.2%
31.0%
22.3%
Valproic acid
23.5%
19.4%
21.5%
Oxcarbazepine
16.9%
19.4%
19.8%
Topiramate
17.6%
19.4%
18.2%
Clobazam
13.2%
10.9%
14.0%
Zonisamide
14.0%
9.3%
9.1%
Safety analysis set.
aData
shown for AEDs used ≥10% of all patients.
French JA et al. Epilepsia 2012;
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Primary efficacy endpoint:
Responder rate
Responder ratea
45
Placebo
40
** ***
33
% patients
35
34
Perampanel 8 mg
Perampanel 12 mg
30
25
20
15
Mean compliance was ≥98% in
each treatment group
15
N=121
0
N=129
5
N=136
10
All POS
(N=386)
*P≤0.05; **P≤0.01 ***P≤0.001, vs placebo.
a% of patients achieving ≥50% reduction from baseline in SZ frequency, ITT population. Maintenance LOCF.
French JA et al. Epilepsia 2012;
Study 305
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Primary and secondary efficacy endpoints:
Median % change in SZ frequency
Median % change from baseline in SZ frequency/28 days
by seizure type
Median % change
N=113
N=119
N=126
(Secondary endpoint)
N=121
(Primary endpoint)
N=129
-5
CP+SG
N=136
0
All POS
Perampanel 8 mg
Perampanel 12 mg
-8
-10
Placebo
-10
-15
Median differences in % change in SZ
frequency (all POS) vs placebo
-18
-20
*
**
Median
difference %
-30
-31
-35
Perampanel
-22
-25
***
-33
***
95% CI
*P≤0.05; **P≤0.01 ***P≤0.001, vs placebo. ITT population. Double-blind phase.
French JA et al. Epilepsia 2012;
8 mg
12 mg
-19.1%
-13.7%
-29.2, -8.4
-25.2, -2.3
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Exploratory efficacy endpoints
≥75% seizure reduction and seizure-free rates
Placebo
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
4.4%
15.5%
16.5%
% patients seizure free, excluding drop-outsb
1.7%
2.8%
6.5%
% patients seizure free, pragmatic calculationc
1.5%
2.3%
5.0%
≥75% reduction in seizure frequency1
% patientsa
SZ-free status1
aMaintenance
period.
completers who were seizure free, as a % of the maintenance completer population.
cMaintenance completers who were seizure free, as a % of the ITT population, conforming to the “pragmatic ITT”
suggested by Gazzola et al.2
bMaintenance
1French
JA et al. Epilepsia 2012; 2Gazzola et al. Epilepsia 2007;48:1303–1307.
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Exploratory efficacy endpoint
Global impression of change
Global impression of change: proportion of patients with
improvement and worsening
Placebo
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
17.2%
28.8%*
27.3%*
% patients “very much”, or “much” improved
21.8%
36.7%*
30.6%
% patients “minimally”, “much”, or “very much” worse
11.3%
12.5%
20.4%
CGIC, %
% patients “very much”, or “much” improved
PGIC, %
*P≤0.05 vs placebo. ITT population.
CGIC: clinician global impression of change; PGIC: patient global impression of change.
French JA et al. Epilepsia 2012;
Study 305
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Safety: overview of AEs
Incidence of AEs1
Placebo
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
68.4%
86.8%
86.0%
Mild AEs
%
31.6%
39.5%
28.9%
Moderate AEs
%
30.1%
38.0%
46.3%
Severe AEs
%
6.6%
9.3%
10.7%
AEs considered treatment-related
%
47.8%
69.0%
77.7%
7 (5.1%)
10 (7.8%)
12 (9.9%)
Patients with any AE
Patients with SAEs
(%)
%
n
AEs: treatment-emergent adverse events (an adverse event that began on or after the date of first study drug and
occurred up to 30 days after the date of the last study drug dose, or began before the date of first study drug and
increased in severity during the treatment period).2
1French JA et al. Epilepsia 2012; (In press); 2Data on file, Eisai Inc.
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Safety: most common AEs (1)
Incidence of AEs occurring in ≥10% of patients in any treatment
group
Placebo
(N=136)
Perampanel
8 mg
(N=129)
12 mg
(N=121)
AEs occurring in ≥10% of patients in any group, %
Dizziness
7.4%
32.6%
47.9%
Somnolence
2.9%
12.4%
18.2%
Fatigue
8.1%
13.2%
16.5%
Headache
13.2%
8.5%
13.2%
Safety analysis set.
Majority of AEs were mild or moderate
Despite longer duration of maintenance period,
incidence of AEs was no higher during
maintenance than titration
French JA et al. Epilepsia 2012;
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Safety: (2)
Incidence of AEs occurring in >5% of perampanel-treated patients
and in at least twice as many perampanel patients than placebo1
Placebo
(N=136)2
Perampanel
(N=250)
Dizziness
7.4%
40.0%
Somnolence
2.9%
15.2%
Fatigue
8.1%
14.8%
Irritability
3.7%
9.2%
Nausea
3.7%
9.2%
Fall
2.9%
6.0%
Weight increase
2.2%
5.6%
AEs occurring in >5% of perampanel patients, %
Safety analysis set.
Dose–response relationship observed with the
exception of weight increase and irritability
1French
JA et al. Epilepsia 2012; 2Data on file, Eisai Inc.
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Safety: AEs leading to discontinuation
Rates of discontinuation due to AEs
Placebo
Discontinuation due to AEs, %
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
Total
(N=250)
4.4%
9.3%
19.0%
14.0%
Discontinuation >2% of patients, in any treatment group, %
Dizziness
Somnolence
Convulsion
<1%
2.3%
5.0%
3.6%
0
<1%
3.3%
2.0%
2.2%
1.6%
<1%
1.2%
Safety analysis set.
• Rash led to discontinuation in 4 (1.6%) perampanel patients vs none in
the placebo group
French JA et al. Epilepsia 2012
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Safety: AEs leading to dose adjustments
Rates of drug interruption or dose reduction due to AEs
Placebo
Dose interruption/reduction due to AEs, %
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
Total
(N=250)
3.7%
20.9%
28.1%
24.4%
Dose interruption/reduction >2% of patients in any treatment group, %
Dizziness
0
7.8%
17.4%
12.4%
Somnolence
0
3.9%
4.1%
4.0%
Headache
0
0
3.3%
1.6%
Fatigue
0
3.9%
2.5%
3.2%
Ataxia
0
1.6%
2.5%
2.0%
Asthenia
0
2.3%
<1%
1.6%
Safety analysis set.
French JA et al. Epilepsia 2012
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Safety: AEs of interest
Psychiatric AEs
Incidence of psychiatric AEs
Placebo
Psychiatric AEs, %
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
14.0%
14.0%
17.4%
Psychiatric AEs occurring in >1% of patients, and more frequent in any
perampanel group than placebo, %
Sleep disorder
%
<1%
2.3%
1.7%
Anxiety
%
0
1.6%
1.7%
Aggression
%
<1%
1.6%
<1%
Confusional state
%
0
0
2.5%
Anger
%
0
0
1.7%
Safety analysis set.
Suicidal ideation occurred in 1 patient
in the placebo group
French JA et al. Epilepsia 2012;
Study 305
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Safety: AEs of interest
Falls
Incidence of fall – 31 falls were reported in 19 patients
•
Placebo: 4 falls in 4 placebo patients (2.9%)
•
Perampanel: 27 falls in 15 perampanel patients (6.0%)
–
7 out of 15 patients in the perampanel group had multiple episodes of fall (up to 5 in total)
–
5 perampanel patients experienced falls at daily doses lower than 8 mg
Timing of falls – exact timing not recorded in case report forms
•
3 of 4 falls in placebo patients and 9 of 27 falls in perampanel patients occurred on the
same day as secondarily generalized seizures
AEs in patients with falls – Many patients also complained of other CNS side effects
•
Unsteady gait, ataxia, dizziness, and slurred speech
Relationship to exposure – increased with plasma concentration
•
PK/PD analysis showed probability of fall (grouped with gait disturbance and balance
disorder), increased with increasing average plasma concentration of perampanel
Discontinuation – No discontinuations were related to falls or injury
Concomitant AEDs in patients with falls
•
Similar distribution to overall trial population
French JA et al. Epilepsia 2012
Study 305
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Safety: serious adverse events
Placebo
Serious adverse events
Perampanel
(N=136)
8 mg
(N=129)
12 mg
(N=121)
7 (5.1%)
10 (7.8%)
12 (9.9%)
SAEs
Patients with SAEs
n (%)
Patients discontinuing due to SAEs
n
0
4a
3b
Deaths
n
0
0
0
aPsychotic
disorder, ischemic stroke, convulsion, dizziness, nausea, somnolence.
epilepticus/urinary incontinence, somnolence, and belligerence.
Safety analysis set.
bStatus
•
The only SAEs occurring in >1% of patients were epilepsy related
– Occurred in 6 patients: 2 (1.5%) placebo, 3 (2.3%) 8 mg, and 1 (<1%) 12 mg
perampanel
•
Six patients had SAEs related to injury: 0, 3, and 3, respectively, in the placebo
and perampanel 8 mg and 12 mg groups
– Result of fall (n=3) or seizure with fall (n=3)
– Injury was the only SAE seen more than twice (7 SAEs of injury occurring in
6 patients)
French JA et al. Epilepsia 2012;
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Safety: serious adverse events
• Non-epilepsy-related SAEs
– There were 29 non-epilepsy-related SAEs in 25 patients (5 patients in the
placebo group, and 8 in the 8 mg and 12 in the 12 mg perampanel groups)
• Psychiatric SAEs were uncommon
– Occurred in 5 patients (<2% of total) and were evenly distributed between
placebo and perampanel groups
• Dermatological SAEs
– No reports of dermatological SAEs
– No reports of Stevens–Johnson syndrome
• Perampanel-related SAEs
– No specific event was consistently considered to be perampanel related with the
exception of 2 SAEs of convulsion in the 8 mg group
French JA et al. Epilepsia 2012;
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Safety: additional considerations
•
Laboratory values, ECGs, vital signs, physical/neurological exams
– No clinically important changes
•
Increases in weight
– >7% increase from baseline: 4.4% (placebo), 11.6% (perampanel), no apparent dose
effect
– Mean weight changes from baseline: −0.1 kg (placebo), +1.1 kg (8 mg), +1.3 kg
(12 mg perampanel)
•
Seizure worsening (>50% increase in seizure frequency from baseline)
– 10% (placebo), 8% (8 mg), 9% (12 mg perampanel)
•
Abuse and diversion
– No reports of abuse or diversion of perampanel
•
Overdose: all 10 were accidental; 8 were blister pack mistakes
– 2 (placebo), 5 (8 mg), and 3 (12 mg perampanel)
•
Photosensitivity questionnaire: 8 positive responses
– 2 (2.2%) placebo; 4 (4.9%) 8 mg, 2 (2.4%) 12 mg perampanel
– No dose changes or discontinuations required
French JA et al. Epilepsia 2012;
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Conclusions
•
In patients with refractory POS, adjunctive therapy with perampanel 8 mg/day
and 12 mg/day significantly reduced seizure frequency compared with placebo
•
Secondary and exploratory efficacy endpoints support the primary findings
– Seizure freedom was attained in up to 6.5% of patients
– More than 3-times as many perampanel patients achieved ≥75% seizure reductions
than placebo patients
– Both the CGIC and PGIC showed significant improvement with perampanel (PGIC
for perampanel 8mg only)
•
The most common AEs were predominantly CNS related (dizziness,
somnolence, fatigue and headache)
– Discontinuation rates due to AEs were low and comparable with other AED trials
– Falls occurred at a greater rate in perampanel-treated patients, although exposure
adjusted rates were low
•
There were few positive responses on the photosensitivity questionnaire
•
The results of this study add to the encouraging clinical evidence for the value
of AMPA receptor antagonists in the epilepsy armamentarium
French JA et al. Epilepsia 2012; (In press).
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