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Issues Impacting Adverse Event Frequency and Severity: Differences Between Randomized Phase 2 and Phase 3 Clinical Trials for Lasmiditan

Authors :
Kudrow, David
Krege, John H.
Hundemer, Hans P.
Berg, Paul H.
Khanna, Rashna
Ossipov, Michael H.
Pozo-Rosich, Patricia
Universitat Autònoma de Barcelona
Source :
Headache, Dipòsit Digital de Documents de la UAB, Universitat Autònoma de Barcelona
Publication Year :
2020
Publisher :
Wiley, 2020.

Abstract

Objective We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials. Background Phase 2 and phase 3 trials showed that the centrally penetrant 5-HT1F agonist, lasmiditan, was effective; higher frequency and severity of adverse events (AEs) were seen in phase 2. Methods 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. Results 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. Conclusions 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.

Details

ISSN :
15264610 and 00178748
Volume :
60
Database :
OpenAIRE
Journal :
Headache: The Journal of Head and Face Pain
Accession number :
edsair.doi.dedup.....957a2b7ec2085c0de6ada55bcec04cc0