Pattern of Reports of Headache in Phase 3 Clinical Trials of Lemborexant

Abstract: Introduction: Headache is a frequently reported treatment-emergent adverse event (TEAE) in clinical trials of hypnotics. We evaluated the frequency and timing of TEAEs of headache in the Phase 3 clinical program of lemborexant (LEM), a dual orexin receptor antagonist. Methods: Study 304 (NCT02783729) was a 1mo, randomized, double-blind, placebo (PBO)- and active-controlled (zolpidem tartrate extended-release 6.25mg), parallel-group study in age ≥55y insomnia subjects (n=1006). Study 303 (NCT02952820) was a 12mo, randomized, double-blind study in subjects age ≥18y (n=949). PBO-, LEM 5 mg (LEM5)-, and LEM 10 mg (LEM10)-treated subjects were analyzed. Results: In an integrated analysis, the incidence of TEAEs of headache was similar between LEM10 (45/705[6.4%]) and PBO (34/528[6.4%]), despite differences in exposure duration (LEM10 up to 1y, PBO max. 6mo). The incidence with LEM5 was 60/713(8.4%). Most headaches were mild in severity. Across treatments, ≥50% headaches occurred within 30 days of treatment initiation. In the integrated analysis, among 98 subjects who had reported a medical history of migraine, reports of headache were somewhat more common in the LEM groups than PBO (LEM 10 4/38[10.5%]; LEM5 4/42[9.5%]; PBO 0/18) than in subjects without migraine histories (LEM10 41/667[6.1%]; LEM5 56/671[8.3%]; PBO 34/510[6.7% ]). Reports of migraine headaches in subjects with/without migraine histories were low (migraine history: LEM10 1/38[2.6%]; LEM5 2/42[4.8%]; PBO 1/18[5.6% ]; no migraine history: LEM10 1/667[0.1%]; LEM5 1/671[0.1%]; PBO 0/510). Discussion: There was no dose response with TEAEs of headache. TEAEs of migraine were not common, even in those with a medical history of migraine.Short Description: Headache is among the most reported treatment-emergent adverse events (TEAE) in clinical trials of hypnotics. Therefore, we evaluated the frequency and timing of TEAEs of headache in the Phase 3 clinical program of lemborexant (LEM), a dual orexin receptor antagonist. Results show that there was no LEM dose response associated with reports of headache. TEAEs of migraine were not common, even in those with a medical history of migraine.Name of Sponsoring Organization(s): Eisai Inc.