Methods Subjects : 18-65 PowerPoint Presentation, PPT

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yo. w migraine . wwo. aura (defined by ICHD3beta) for at least 1yr . ≥4 and <15 migraine days /. mo. during the 3-month period before screening and during a 4-week baseline phase assessed w handheld electronic diary (ERT) completed daily by the patient (≥ 80% adherence to reporting). ID: 720387

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Methods Subjects : 18-65

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Methods
Subjects
:
18-65
yo
w migraine
wwo
aura (defined by ICHD3beta) for at least 1yr
≥4 and <15 migraine days /
mo
during the 3-month period before screening and during a 4-week baseline phase assessed w handheld electronic diary (ERT) completed daily by the patient (≥ 80% adherence to reporting)
Subjects can use concomitantly one migraine-preventive medication taken at a stable dose (no dose changes within 2
mos
before the baseline phase or at any time during the trial)
Exclusion: >50yo at migraine onset,
hemiplegic migraine
or cluster headache, had received
botox
within 4
mos
before or during the baseline phase, used devices or procedures for migraine prevention within 2
mos
before the baseline phase, or had had
no therapeutic response to more than two migraine-preventive treatment
categories
Reportedly, 38.7% pts had not had beneficial effect from prior preventive
Slide2
Demographics and Characteristics
similar
Slide3
Methods
Assessments
During baseline and double-blind treatment phases:
electronic diary
w info about their migraine and non-migraine headaches (date, time of onset and resolution, pain severity and features, associated symptoms, and use of abortive and analgesic meds.
Migraine Physical Function Impact Diary (MPFID):
13-item survey of physical functioning in the past 24 hrs, on migraine and nonmigraine days. 7-item everyday-activities (MPFID-EA): scores range from 7 to 355-item physical-impairment (MPFID-PI): scores range from 5 to 25Daily scores averaged over a period of 1 month and then linearly transformed to a 100-point scale. Global question to assess the overall effect of migraineSafety: reports of adverse events and serious adverse events throughout trial, labs, VS, EKG, anti-erenumab Abs
7 + 5 ><13 ?
Slide4
Methods
Endpoints
Primary
: change in mean # migraine days /
mo
from baseline to the final 3
mos (mos 4 through 6) of the double-blind Rx phase. Secondary: (avged over the last 3 mos) ≥50% reduction from baseline in mean # migraine days /mo Change in mean # days / mo of use of acute migraine–specific medication (including triptans or ergotamine derivatives) Change in both the MPFID (migraine physical function impact diary)-physical impairment
and MPFID-every day activity scores on a 0-100 scale with the highest numbers representing highest migraine burden (btw baseline and averaged over the final 3 mos
of double-blind treatment phase)
Slide5
Methods
Statistics
Continuous end points analyzed w
linear mixed-effects model
wo any imputation of missing
data
“Linear mixed-effects models are extensions of linear regression models for data that are collected and summarized in groups. They describe the relationship between a response variable and independent variables, w coefficients that can vary w respect to one or more grouping variables. They consist of two parts: 1) fixed effects (the conventional linear regression part) and 2) random effects (associated w individual experimental units drawn at random from a population, w prior distributions). They can represent the covariance structure related to the grouping of data by associating the common random effects to observations that have the same level of a grouping variable
.” Easier to deal w missing variable than repeated ANOVAs. Sensitivity analyses w multiple
imputation
under missing-at-random and missing-not-at-random assumptions
.
Deleting all missing data might introduce bias, so imputation
preserves all cases by replacing missing data with an estimated value based on other available information.
For
≥50% reduction from baseline in mean # migraine days /
mo
:
stratified Cochran–Mantel–
Haenszel
test
after imputation of missing data as nonresponse.
Tests association btw
a binary
treatment
and
binary while
taking into account the stratification
Sensitivity analyses included a generalized linear mixed-effects model wo any imputation of missing data.
Significance of the between-group differences
for primary and secondary endpoints was determined
after
multiplicity adjustment
with a
prespecified
hierarchical gatekeeping procedure
and
Hochberg-based testing
procedures to maintain the
two-sided, study-wise, type I error rate at an alpha level of 0.05
.
Multiplicity adjustment: adjustment in alpha level for multiple tests (more than 1 dose vs placebo, multiple endpoints)
Hochberg tests see next slides
Primary end point was tested separately for each erenumab dose at an alpha of 0.04 for 70 mg and of 0.01 for 140 mg.
Efficacy analysis set: pts who received ≥1 dose of
erenumab
or placebo and ≥1
postbaseline
measurement for migraine days /
mo
during the double-blind Rx phase according to randomization trial regimen
Safety analysis set: pts who underwent randomization and received ≥1dose of
erenumab
or placebo regardless of assigned treatment
Slide6
Type I error: reject null
hyp
when true
Type II error: accept null
hyp
when false
Slide7
Slide8
Total 955 pts w baseline mean # HA days/
mo
of 8.3, 858 (89.8%) completed 6
mo
double blind Rx
# days to use abortive
1.1 day decreased
1.6 days0.2 day
Phys impairment
4.2 pts better
4.8 pts better
2.4 pts better
Daily activities
5.5 pts better
5.9 pts better
3.3 pts better
Same rates of adverse events
Slide9
Slide10
Definitions
Episodic migraine
= < 15 migraine or HA days per
mo
,
wwo
aura. 90% pts w migraineChronic migraine = at least 15 HA days per month (of which ≥8 are migraine days wwo aura). 5%-8% of pts w migraine Migraine day = any calendar day on which the patient had onset, continuation, or recurrence of a migraine (≥30 min, w ≥2 pain features, ≥1 associated nonpain feature) or any day on which acute migraine–specific medication was taken Candidate for migraine preventive therapy: sufficient migraine attacks to be disabled
Slide11
Slide12
Background
Current preventive therapy: sometimes not entirely effective, sometimes side effects
Goal: Evaluate erenumab for prevention episodic migraine (reduce frequency and severity)
Erenumab
= fully human monoclonal antibody that selectively and potently inhibits the canonical calcitonin gene–related peptide receptor
Phase 2 trials: significantly reduce # migraine days /
mo in pts w episodic migraine at a monthly dose of 70 mg and in patients with chronic migraine at doses of 70 mg and 140 mg in the last month of a 3-month double-blind treatment phase.
Slide13
Methods
STRIVE
(Study to Evaluate the Efficacy and Safety of Erenumab in Migraine Prevention)
phase 3 trial of erenumab at doses of 70 mg and 140 mg in patients with episodic migraine.
Funded by Amgen and Novartis (
codevelopers
of erenumab) DesignMulticenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial conducted at 121 sites across North America, Europe, and Turkey from 07/2015 until 09/20164 phases:
1. screening (≤3
wks
of initial screening and a 4-wk baseline phase)
2. double-blind treatment phase (24
wks
)
After 4-wk baseline phase, eligible pts randomly assigned in a 1:1:1 ratio to receive monthly
subQ
70 mg erenumab vs 140 mg erenumab vs placebo at day 1 and
wks
4, 8, 12, 16, and 20.
Randomization based on a schedule generated by the sponsor before initiation of the trial and was stratified according to region (North America vs. other) and according to the use of migraine-preventive medication (current use, previous use only, or no previous or current use)
3. active-treatment phase:
repeat randomization to receive 70 mg or 140 mg of erenumab (28
wks
)
4. safety follow-up phase
(12
wks
)
Results not analyzed yet