Issues Impacting Adverse Event Frequency and Severity : Differences Between Randomized Phase 2 and Phase 3 Clinical Trials for Lasmiditan
Kudrow, David (California Medical Clinic for Headache)
Krege, John H. (Eli Lilly and Company, Indianapolis)
Hundemer, Hans P. (Eli Lilly and Company, Bad Homburg)
Berg, Paul H. (Eli Lilly and Company, Indianapolis)
Khanna, Rashna (Eli Lilly and Company, Erl Wood)
Ossipov, Michael H. (Syneos Health, Clinical Division)
Pozo-Rosich, Patricia (Hospital Universitari Vall d'Hebron)
Universitat Autònoma de Barcelona

Date:	2020
Abstract:	We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials. Phase 2 and phase 3 trials showed that the centrally penetrant 5-HT agonist, lasmiditan, was effective; higher frequency and severity of adverse events (AEs) were seen in phase 2. This work represents a hybrid of a review of primary documents and study reports with additional post hoc analyses. Protocols, informed consents, data collection forms, and methodologies were reviewed. This information was supplemented by results from the clinical study reports and post hoc analyses of individual patient data from each trial. For lasmiditan 100 and 200 mg, in phase 2, the incidence of ≥1 AE was 72-86% (26% severe), while in phase 3 was 36-43% (2% severe). The most common AEs in all studies were CNS-related. The phase 2 consent form was more descriptive of AEs than phase 3. In phase 2, patients recorded AEs and severity in a paper diary that warned about drowsiness and dizziness. In phase 3, patients recorded in electronic diaries whether they experienced unusual feelings after dosing with lasmiditan that they had not felt with a migraine before, and were contacted to determine if an AE had occurred. In phase 2, the AE Schwindel was variably translated from German as "vertigo" or "dizziness," while phase 3 vertigo cases were queried to ensure there was a sensation of rotation or movement. History of recurrent dizziness and/or vertigo was exclusionary in phase 3. This work illustrates how informed consent wording, AE collection methods, translation, exclusion criteria, and other factors may be important determinants for reporting of the frequency and severity of AEs in clinical trials.
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Episodic migraine ; Migraine headache ; Lasmiditan ; Adverse events ; Treatment-emergent adverse event
Published in:	Headache, Vol. 60 (january 2020) , p. 576-588, ISSN 1526-4610

DOI: 10.1111/head.13731
PMID: 31943195

13 p, 267.6 KB

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