1. 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

2. Demographics and Characteristics
similar

3. 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 35
5-item physical-impairment (MPFID-PI): scores range from 5 to 25
Daily 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 migraine
Safety: reports of adverse events and serious adverse events throughout trial, labs, VS, EKG, anti-erenumab Abs
7 + 5 ><13 ?

4. 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 scale with the highest numbers representing highest migraine burden (btw baseline and averaged over the final 3 mos of double-blind treatment phase)

5. 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

6. Type I error: reject null hyp when true
Type II error: accept null hyp when false

8. Same rates of adverse events
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 days
0.2 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

10. Definitions
Episodic migraine = < 15 migraine or HA days per mo, wwo aura. 90% pts w migraine
Chronic 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

12. 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.

13. 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)
Design
Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial conducted at 121 sites across North America, Europe, and Turkey from 07/2015 until 09/2016
4 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