REGAIN MO
(2021)Objective
To evaluate whether galcanezumab is effective for preventive treatment of episodic and chronic migraine in patients with baseline acute medication overuse, via subgroup analysis of three phase 3 placebo-controlled trials (EVOLVE-1, EVOLVE-2, REGAIN).
Study Summary
• EVOLVE-1/-2 (episodic migraine) overall LS mean change in MMHD: placebo −2.7, galcanezumab 120 mg −6.3, galcanezumab 240 mg −5.8
• Treatment-by-subgroup interaction (medication overuse yes vs no) was significant in EVOLVE pooled analysis (p < 0.001 for 120 mg; p = 0.001 for 240 mg)
• Both galcanezumab doses reduced average monthly medication overuse rates vs placebo (p < 0.001) in both episodic and chronic migraine populations
• Baseline medication overuse prevalence: ~17–19% in EVOLVE-1/-2, ~63–64% in REGAIN
Intervention
Monthly subcutaneous galcanezumab 120 mg or 240 mg vs placebo for 6 months (EVOLVE-1/-2) or 3 months (REGAIN).
Inclusion Criteria
Adults with episodic migraine (4–14 monthly migraine headache days; EVOLVE-1/-2) or chronic migraine (≥15 monthly headache days with ≥8 migraine features for >3 months; REGAIN). Subgroup defined by baseline acute medication overuse per IHS criteria.
Study Design
Arms: Placebo (EVOLVE n=173 MO; REGAIN n=353 MO) vs Galcanezumab 120 mg SC monthly (EVOLVE n=77 MO; REGAIN n=178 MO) vs Galcanezumab 240 mg SC monthly (EVOLVE n=84 MO; REGAIN n=177 MO)
Patients per Arm: EVOLVE-1/-2 with MO: PBO 173 / GMB120 77 / GMB240 84; REGAIN with MO: PBO 353 / GMB120 178 / GMB240 177
Outcome
• In EVOLVE patients without MO: placebo −2.5, galcanezumab 120 mg −4.1, galcanezumab 240 mg −4.0 (both p < 0.001 vs placebo)
• Both galcanezumab doses significantly reduced monthly medication overuse rates vs placebo (p < 0.001) in both episodic and chronic migraine
• Significant treatment-by-MO subgroup interaction in EVOLVE (p < 0.001 for 120 mg, p = 0.001 for 240 mg) suggesting greater benefit in MO subgroup
Bottom Line
Galcanezumab 120 mg and 240 mg monthly are effective for preventive treatment of both episodic and chronic migraine in patients with baseline acute medication overuse, significantly reducing monthly migraine headache days and rates of medication overuse compared with placebo.
Major Points
- Subgroup analysis of three phase 3 RCTs: EVOLVE-1 and EVOLVE-2 (episodic migraine; pooled, post hoc) and REGAIN (chronic migraine; a priori stratified).
- Baseline medication overuse prevalence was 17.3–19.4% across EVOLVE arms and 63.4–64.3% across REGAIN arms.
- In EVOLVE pooled patients with MO, overall LS mean change in monthly migraine headache days was −2.7 (placebo), −6.3 (galcanezumab 120 mg), and −5.8 (galcanezumab 240 mg); both doses p < 0.001 vs placebo.
- In EVOLVE patients without MO, LS mean changes were −2.5 (placebo), −4.1 (120 mg), −4.0 (240 mg); both doses p < 0.001 vs placebo.
- In REGAIN patients with MO, overall LS mean change in monthly migraine headache days was −2.3 (placebo), −4.8 (galcanezumab 120 mg), and −4.5 (galcanezumab 240 mg); both doses p < 0.001 vs placebo.
- Treatment-by-subgroup interaction (MO yes vs no) was significant in EVOLVE (p < 0.001 for 120 mg; p = 0.001 for 240 mg), suggesting larger absolute benefit in patients with medication overuse; no significant interaction was seen in REGAIN (p = 0.172 for 120 mg; p = 0.243 for 240 mg).
- In both episodic and chronic migraine populations with baseline MO, galcanezumab 120 mg and 240 mg significantly reduced average monthly medication overuse rates vs placebo (p < 0.001).
- Galcanezumab appears effective for preventive treatment of migraine in patients who overuse acute medications, even without a structured withdrawal program.
Study Design
- Study Type
- Subgroup analysis of three phase 3, double-blind, randomized, placebo-controlled trials (EVOLVE-1, EVOLVE-2, REGAIN)
- Randomization
- Yes
- Blinding
- Double-blind
- Sample Size
- 1042
- Follow-up
- 6 months (EVOLVE-1/-2); 3 months (REGAIN)
- Countries
- North America, Europe, Other
Primary Outcome
Definition: Overall least squares mean change from baseline in the number of monthly migraine headache days in patients with baseline medication overuse
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| EVOLVE pooled placebo (MO, n=169): −2.7 (SE 0.5); REGAIN placebo (MO, n=344): −2.3 (SE 0.5) | EVOLVE pooled galcanezumab 120 mg (MO, n=74): −6.3 (SE 0.6); EVOLVE pooled galcanezumab 240 mg (MO, n=82): −5.8 (SE 0.6); REGAIN galcanezumab 120 mg (MO, n=177): −4.8 (SE 0.5); REGAIN galcanezumab 240 mg (MO, n=175): −4.5 (SE 0.5) | - (EVOLVE 120 mg vs PBO −4.7 to −2.4; EVOLVE 240 mg vs PBO −4.2 to −2.0; REGAIN 120 mg vs PBO −3.6 to −1.5; REGAIN 240 mg vs PBO −3.3 to −1.2) | p < 0.001 for both galcanezumab 120 mg and 240 mg vs placebo in EVOLVE pooled MO subgroup; p < 0.001 for both doses vs placebo in REGAIN MO subgroup |
Limitations & Criticisms
- Subgroup analysis in EVOLVE-1/-2 was post hoc; only REGAIN had a priori stratification by medication overuse.
- Patients with formal diagnosis of medication overuse headache in the 3 months before screening were excluded from EVOLVE, limiting generalizability of episodic-migraine findings to confirmed MOH patients.
- Short follow-up (3 months in REGAIN; 6 months in EVOLVE) limits assessment of durability and impact on long-term medication overuse behavior.
- Different durations and pooling approaches between episodic (EVOLVE) and chronic (REGAIN) cohorts complicate cross-population comparisons.
- Small sample sizes in EVOLVE galcanezumab arms with medication overuse (n=77 and n=84) reduce precision of subgroup estimates.
- Study not designed or powered to show significance in subgroups; no adjustment for multiple comparisons.
Citation
Dodick DW, Doty EG, Aurora SK, Ruff DD, Stauffer VL, Jedynak J, Dong Y, Pearlman EM. Medication overuse in a subgroup analysis of phase 3 placebo-controlled studies of galcanezumab in the prevention of episodic and chronic migraine. Cephalalgia. 2021;41(3):340-352. doi:10.1177/0333102420966658.