PDF: SAMURAI and SPARTAN Pooled Analysis
(2019)Objective
Lasmiditan - To evaluate the efficacy and safety of lasmiditan for the acute treatment of migraine in patients concurrently using migraine preventive medications.
Study Summary
• Efficacy outcomes (pain-free, MBS-free, sustained pain freedom) were similar regardless of preventive use.
• Adverse event rates were comparable between patients using and not using preventives.
Intervention
Post hoc analysis of two phase 3 randomized, double-blind, placebo-controlled trials (SAMURAI and SPARTAN) of lasmiditan 50 mg (SPARTAN only), 100 mg, or 200 mg vs placebo. Included patients with 3–8 migraine attacks/month. Concomitant preventive use was allowed if stable for ≥3 months prior to screening. Outcomes assessed included pain-free and most bothersome symptom (MBS)-free at 2 hours post-dose.
Inclusion Criteria
Adults ≥18 years with episodic migraine (with or without aura), MIDAS score ≥11, and 3–8 attacks/month. Preventive users had to be on stable doses of guideline-based agents (antiepileptics, beta-blockers, antidepressants, botulinum toxin, candesartan).
Study Design
Arms: Lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, and placebo
Patients per Arm: Total enrolled: 3,981; 698 (17.5%) used preventives
Outcome
• MBS-free at 2 h: 34.4–39.5% (lasmiditan) vs. 23.8% (placebo)
• Sustained pain freedom at 24 h: 11.5–18.0% (lasmiditan) vs. 5.6% (placebo)
• Disability-free at 2 h: 24.9–28.9% (lasmiditan) vs. 16.9% (placebo)
• PGIC “very much” or “much better” at 2 h: 31.9–36.5% (lasmiditan) vs. 18.8% (placebo)
• Adverse events were similar in preventive and non-preventive groups; most common were dizziness, paresthesia, somnolence.
Bottom Line
Lasmiditan was more effective than placebo for acute treatment of migraine in patients concurrently using migraine preventive medications, with efficacy and safety measures similar for patients using and not using preventive medications
Major Points
- Post hoc analysis of pooled data from two phase 3 trials (SAMURAI and SPARTAN) evaluating lasmiditan efficacy in patients using vs not using migraine preventives
- Of 3,981 patients in ITT population, 698 (17.5%) were using migraine preventive treatments
- Primary outcome (pain-free at 2h): all lasmiditan doses significantly superior to placebo in patients using preventives (50mg: 24.0%, 100mg: 25.1%, 200mg: 30.5% vs placebo: 11.7%, all p<0.05)
- Key secondary outcome (MBS-free at 2h): significant benefit with all lasmiditan doses in patients using preventives (50mg: 38.1%, 100mg: 34.4%, 200mg: 39.5% vs placebo: 23.8%)
- No significant interaction between preventive medication use and lasmiditan efficacy for any outcome (all interaction p-values ≥0.1)
- Patients using preventives had lower overall placebo response than those not using preventives, possibly due to greater experience with migraine treatments
- Odds ratios for lasmiditan vs placebo were similar or higher in patients using preventives compared to those not using preventives
- Most common preventives used: anti-epileptics (35%), beta-blockers (32.3%), antidepressants (25.5%), botulinum toxin A (5.7%), candesartan (1.4%)
- Safety profile similar between patients using and not using preventives; no deaths, TEAEs balanced across groups
- Lasmiditan is a selective 5-HT1F receptor agonist distinct from triptans (no vasoconstriction)
Study Design
- Study Type
- Post hoc analysis of pooled data from two phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies
- Randomization
- Yes
- Blinding
- Double-blind; all research participants, clinicians, and research personnel blinded throughout trial duration; assignment concealed; investigational product shipped frozen with protocol-specific labeling
- Sample Size
- 3981
- Follow-up
- Single attack treatment with assessments at baseline and 0.5, 1, 1.5, 2, 3, 4, 24, and 48 hours post-dose using electronic diary
- Centers
- 128
- Countries
- United States, United Kingdom, Germany
Primary Outcome
Definition: Proportion of patients pain-free at 2 hours post-dose (complete absence of headache pain), assessed using electronic diary; migraine day defined per ICHD-3 criteria
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Using preventives: 23/196 (11.7%); Not using preventives: 172/867 (19.8%) | Using preventives - 50mg: 25/104 (24.0%), 100mg: 44/175 (25.1%), 200mg: 51/167 (30.5%); Not using preventives - 50mg: 134/452 (29.6%), 100mg: 265/860 (30.8%), 200mg: 321/879 (36.5%) | - (Using preventives - 50mg: OR 2.2 (1.0-4.7), 100mg: OR 2.5 (1.4-4.4), 200mg: OR 3.3 (1.9-5.7); Not using preventives - 50mg: OR 1.4 (1.0-1.9), 100mg: OR 1.8 (1.4-2.2), 200mg: OR 2.3 (1.9-2.9)) | All lasmiditan doses p<0.05 vs placebo in patients using preventives; interaction p-values all >0.1 (no significant difference between subgroups) |
Limitations & Criticisms
- Post hoc analysis not pre-specified in original trial protocols, though topiramate and propranolol subgroups were pre-specified
- Patients using preventives were older (45.7 vs 41.4 years), had longer migraine duration (21.4 vs 18.1 years), and different demographics than non-users, which may have contributed to lower placebo response
- Lower baseline placebo response in preventive users (11.7% vs 19.8% pain-free at 2h) potentially due to greater treatment experience and reduced placebo susceptibility
- Too few patients using each specific preventive medication to perform individual subgroup analyses for each preventive agent
- Lasmiditan 50 mg included in only one trial (SPARTAN), limiting comparative data
- Single-attack treatment design does not evaluate consistency of response across multiple attacks
- Industry-sponsored study (Eli Lilly) with multiple author conflicts of interest
- Relatively short follow-up (48 hours) does not assess long-term safety of concurrent use
- Excluded patients with significant cardiovascular disease, limiting generalizability
- Open-label regarding preventive medication use (post hoc analysis), though blinded to lasmiditan vs placebo
- Some preventive medications used for non-migraine indications: 10.7% strictly for migraine, 5.4% strictly for non-migraine, 1.5% for both
- No evaluation of potential pharmacokinetic interactions, though separate drug-drug interaction studies were conducted
- Limited to patients with episodic migraine (3-8 attacks/month); not applicable to chronic migraine population
- Patients on preventives had somewhat less severe baseline migraine attacks (24.9% severe vs 29.6% in non-users)
Citation
Loo et al. The Journal of Headache and Pain (2019) 20:84. https://doi.org/10.1186/s10194-019-1032-x