PDF: REGAIN - Galcanezumab
(2018)Objective
Galcanezumab - To evaluate the efficacy and safety of galcanezumab for the prevention of chronic migraine.
Study Summary
โข High rates of โฅ50% response observed, with early onset of effect.
โข Treatment was ๐๐ฒ๐น๐น ๐๐ผ๐น๐ฒ๐ฟ๐ฎ๐๐ฒ๐ฑ, with low discontinuation and AE rates.
Intervention
Phase 3, randomized, double-blind, placebo-controlled trial (REGAIN). Adults with chronic migraine (โฅ15 headache days/month, โฅ8 migraine days) were randomized 2:1:1 to monthly placebo, galcanezumab 120 mg (with 240 mg loading), or 240 mg. Study period was 3 months, followed by a 9-month open-label extension.
Inclusion Criteria
Adults aged 18โ65 with chronic migraine per ICHD-3 beta criteria, โฅ15 headache days/month (โฅ8 migraine), and onset before age 50. Patients with medication overuse were included; those with prior failure of >3 preventive classes were excluded.
Study Design
Arms: Placebo, Galcanezumab 120 mg, Galcanezumab 240 mg
Patients per Arm: Placebo: 558; Galcanezumab 120 mg: 278; Galcanezumab 240 mg: 277
Outcome
โข โฅ50% response rate: placebo 15.4%, 120 mg 27.6%, 240 mg 27.5%; both p<0.001
โข โฅ75% response: 4.5%, 7.0%, and 8.8% respectively; p<0.05 and p<0.001
โข Injection site reactions more frequent in 240 mg group
โข Serious adverse events: โค2% in all groups; no deaths
โข MIDAS score improved by 20.3 in 120 mg group vs. 11.5 in placebo
โข MSQ Role-Function-Restrictive improved by 21.8 (120 mg) vs. 16.8 (placebo)
Bottom Line
Both doses of galcanezumab (120mg with loading dose and 240mg) were superior to placebo in reducing monthly migraine headache days in patients with chronic migraine over 3 months, with a clinically meaningful reduction of approximately 2 days beyond placebo. Galcanezumab was safe and well tolerated with high study completion rates (>90%) and low discontinuation rates, though injection-site reactions occurred more frequently with the 240mg dose. These findings support CGRP pathway inhibition as an effective, biologically-targeted approach to chronic migraine prevention
Major Points
- Phase 3, randomized, double-blind, placebo-controlled trial conducted at 116 sites in 12 countries from January 2016 to March 2017
- 1,113 patients with chronic migraine randomized 2:1:1 to placebo, galcanezumab 120mg (with 240mg loading dose), or galcanezumab 240mg for 3-month double-blind phase
- Patients had mean 19.4 monthly migraine headache days at baseline and mean MIDAS score of 65.8, indicating very severe disability
- Primary endpoint: Both galcanezumab doses demonstrated significantly greater overall mean reduction in monthly MHDs compared to placebo (placebo -2.7, galcanezumab 120mg -4.8, galcanezumab 240mg -4.6, p<0.001 for both)
- Difference from placebo was approximately 2 MHDs, representing a clinically meaningful change
- Monthly reductions in MHDs were statistically significant from month 1 and maintained through month 3 for both galcanezumab doses
- โฅ50% responder rates significantly higher with galcanezumab: 27.6% (120mg) and 27.5% (240mg) vs 15.4% placebo (p<0.001 for both)
- โฅ75% responder rates: 7.0% (120mg) and 8.8% (240mg) vs 4.5% placebo; 240mg dose showed significance after multiplicity adjustment
- Galcanezumab 240mg showed statistical improvements on all key secondary endpoints except 100% response rate after multiplicity adjustment
- Galcanezumab 120mg showed statistical improvements on primary endpoint and โฅ50% response rate after multiplicity adjustment
- Mean increase in MSQ Role Function-Restrictive domain was 23 points for galcanezumab 240mg, representing clinically important functional improvement
- High study completion rates: 91% placebo, 95% galcanezumab 120mg, 96% galcanezumab 240mg
- Safety profile favorable: treatment-emergent AEs in 50% placebo, 58% galcanezumab 120mg, 57% galcanezumab 240mg, mostly mild-moderate
- Injection-site reactions more common with galcanezumab 240mg; most common AE was injection-site pain (4-7% across groups)
- Very low discontinuation rates due to AEs: 1% placebo, 1% galcanezumab 120mg, <1% galcanezumab 240mg
- No clinically meaningful differences in laboratory values, vital signs, weight, or ECGs between groups
- Treatment-emergent anti-drug antibodies occurred in 1.5% placebo, 2.7% galcanezumab 120mg, 2.6% galcanezumab 240mg with no discernible effect on efficacy or tolerability
- Results consistent with other CGRP pathway blockers in chronic migraine and represent advance in biologically-targeted migraine prevention
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind, placebo-controlled trial with 2:1:1 allocation ratio
- Randomization
- Yes
- Blinding
- Double-blind: patients and investigators masked to treatment assignment; all groups received two 1-mL injections at each visit using blinded prefilled syringes to maintain masking
- Sample Size
- 1113
- Follow-up
- 3-month double-blind placebo-controlled phase (reported here), followed by 9-month open-label extension and 4-month posttreatment washout (to be reported separately)
- Centers
- 116
- Countries
- Argentina, Canada, Czech Republic, Germany, Israel, Italy, Mexico, Netherlands, Spain, Taiwan, United Kingdom, United States
Primary Outcome
Definition: Overall mean change from baseline in number of monthly migraine headache days (MHDs) during 3-month double-blind treatment phase. MHD defined as calendar day with headache lasting โฅ30 minutes with features meeting ICHD-3 beta criteria for migraine or probable migraine, or headache believed to be migraine at onset and relieved by triptan or ergot
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| -2.7 days (SE 0.4) | Galcanezumab 120mg: -4.8 days (SE 0.4); Galcanezumab 240mg: -4.6 days (SE 0.4) | - (Galcanezumab 120mg vs placebo difference: -2.1 (95% CI -2.9 to -1.3); Galcanezumab 240mg vs placebo difference: -1.9 (95% CI -2.7 to -1.1)) | Galcanezumab 120mg vs placebo: p<0.001 (significant after multiplicity adjustment); Galcanezumab 240mg vs placebo: p<0.001 (significant after multiplicity adjustment) |
Limitations & Criticisms
- Relatively short 3-month duration may not be sufficient to demonstrate ultimate treatment effects or long-term safety profile
- Exclusion of patients with significant treatment-resistance (failed โฅ3 preventive medication classes) limits generalizability to most refractory population
- Exclusion of patients with serious and unstable medical conditions limits real-world applicability
- No head-to-head comparison with other approved chronic migraine preventives like onabotulinumtoxinA or topiramate
- Long-term efficacy and safety beyond 3 months requires analysis of 9-month open-label extension (not yet reported)
- Higher percentage of patients who failed โฅ2 preventives in galcanezumab 240mg group (35%) vs 120mg group (24%) could represent baseline imbalance
- Few statistical differences between galcanezumab 240mg and placebo at baseline (e.g., age, migraine duration, MHDs with acute meds) though stated as not clinically meaningful
- No assessment of whether benefits persist after discontinuation or duration of washout period needed
- Study population predominantly white (77-81%) and female (82-87%), limiting generalizability to more diverse populations
- Multiplicity adjustment procedure meant some nominally significant secondary endpoints (e.g., MIDAS) were not tested after ฮฑ was expended
- No comparison between 120mg and 240mg doses showed statistical differences on any efficacy measure, raising questions about optimal dosing
- Study excluded patients who could not washout preventives 30 days prior, potentially missing population needing continuous prevention
- Cost-effectiveness analysis not performed; monthly injections may have economic implications vs oral preventives
- Mechanism of sustained benefit beyond drug half-life not fully elucidated
- Unclear if patients with medication overuse headache require detoxification before starting galcanezumab or can start concurrently
Citation
Neurology 2018;91:e2211-e2221