Differences in Adverse Events in Phase 2 and Phase 3 Studies: The Case of Lasmiditan

Differences in treatment-emergent adverse events (TEAEs) between studies may be related to methodological differences between clinical studies, as shown by the case of lasmiditan. Phase 2 clinical trials investigating lasmiditan reported higher incidence and severity of TEAEs, compared with the phase 3 studies, according to results published in Headache.

Lasmiditan, a selective 5-hydroxytryptamine 1F receptor agonist, has been shown to be effective for migraine attacks in phase 2 and phase 3 randomized clinical trials. In the phase 2 study the incidence of central nervous system TEAEs was relatively high, but in the phase 3 studies the researchers reported lower incidence and severity of TEAEs.

The researchers used the data from 1 placebo-controlled phase 2 and 2 placebo-controlled phase 3 (SAMURAI and SPARTAN) clinical studies on lasmiditan to investigate the impact of various methodological issues on the frequency and severity of TEAEs, under the assumption that the findings will apply to other clinical development programs. The study protocols, informed consent forms (ICFs), data collection forms, and data collection methodologies were investigated, to assess whether these had an impact on the differences between studies.

In each of the 3 studies, TEAEs were more frequent in the group of patients treated with lasmiditan, compared with the placebo group, and the proportion of patients with TEAEs tended to increase with increasing doses of lasmiditan. Dizziness, paresthesia, and somnolence were the most commonly reported TEAEs.

In the phase 2 study, the rate of TEAEs was 72% (59 of 82) of patients treated with lasmiditan 100 mg and 86% (61 of 71) of those receiving lasmiditan 200 mg. The respective proportions of TEAEs were 36% (229 of 630) and 43% (260 of 609) in the SAMURAI trial and 36% (229 of 635) and 39% (253 of 649) in the SPARTAN study.

Severe TEAEs were also reported more frequently in the phase 2 study (102 of 391 patients, 26%), compared with SAMURAI (44 of 1865 patients, 2.4%) or SPARTAN (43 of 2583 patients, 1.7%) studies.

The researchers assessed the methodological differences between clinical studies and revealed that the ICF provided in the phase 2 trial was more detailed and included information about potential TEAEs. Furthermore, the patients recorded TEAEs and severity in a paper diary that warned about drowsiness and dizziness. However, in the phase 3 trials, patients were presented with open-ended questions about unusual symptoms, and they recorded in electronic diaries whether they experienced unusual feelings after dosing with lasmiditan.

Of note, in the phase 2 study, site personnel were instructed to both transcribe TEAEs recorded by patients and determine whether TEAEs had occurred. At the German-speaking sites that participated in the phase 2 study, the word “Schwindel” was variably translated into English as “vertigo” or “dizziness,” while in the phase 3 studies, vertigo cases were queried to ensure there was a sensation of rotation or movement.

Other factors that may have contributed to the differences include an exclusion of patients with history of disorders that result in recurrent dizziness and/or vertigo.

“Differences in the methods of conducting clinical trials of an acute treatment for migraine along with some differences in patient population and behavior influenced the frequency and severity of the observed TEAEs,” concluded the researchers. They also add that “these considerations are relevant to the design and conduct of clinical trials of acute treatments for migraine, and the general principles may apply to clinical trials in other therapeutic areas.”

Reference

Kudrow D, Krege JH, Hundemer HP, et al. Issues impacting adverse event frequency and severity: differences between randomized phase 2 and phase 3 clinical trials for lasmiditan [published online ahead of print, January 13, 2020]. Headache. doi: 10.1111/head.13731