Headache ISSN 0017-8748 © 2020 Eli Lilly and Company. Headache: The Journal of Head and Face Pain  doi: 10.1111/head.13731 published by Wiley Periodicals, Inc. on behalf of American Headache Society Published by Wiley Periodicals, Inc. Research Submission Issues Impacting Adverse Event Frequency and Severity: Differences Between Randomized Phase 2 and Phase 3 Clinical Trials for Lasmiditan David Kudrow, MD; John H. Krege, MD; Hans P. Hundemer, MD; Paul H. Berg, MS; Rashna Khanna, MD; Michael H. Ossipov, PhD; Patricia Pozo-Rosich, MD, PhD 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 supple- mented 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 descrip- tive 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. Key words: episodic migraine, migraine headache, lasmiditan, adverse events, treatment-emergent adverse event Abbreviations: A  E adverse event, BMI body mass index, CI confidence interval, CNS central nervous system, CRF case report form, ICF informed consent form, ph2 phase 2, ph3 phase 3, TEAE treatment-emergent adverse event, UK United Kingdom, US United States (Headache 2020;60:576-588) From the California Medical Clinic for Headache, Santa Monica, CA, USA (D. Kudrow); Neurology, David Geffen UCLA School of Medicine, Los Angeles, CA, USA (D. Kudrow); Eli Lilly and Company, Indianapolis, IN, USA (J.H. Krege and P.H. Berg); Eli Lilly and Company, Bad Homburg, Germany (H.P. Hundemer); Eli Lilly and Company, Erl Wood, UK (R. Khanna); Syneos Health, Clinical Division, Raleigh, NC, USA (M.H. Ossipov); Headache & Craniofacial Pain Unit, Neurology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain (P. Pozo-Rosich); Headache Research Group, VHIR, Universitat Autònoma de Barcelona, Barcelona, Spain (P. Pozo-Rosich). Address all correspondence to J.H. Krege, Eli Lilly and Company, Indianapolis, IN 46285, USA, email: krege_john_henry@lilly.com Accepted for publication November 14, 2019. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modi- fications or adaptations are made. 576 Headache 577 INTRODUCTION consent forms (ICF), data collection forms, and data Lasmiditan (previously known as Col-144) is a collection methodologies between these trials in an high affinity, centrally penetrant, selective 5-HT1F effort to understand what factors may have contributed receptor agonist without significant pharmacologi- to the differences. The ph2 trial (NCT00883051) meth- cal activity at 5-HT1B or 5-HT1D receptors. Evidence odology and results have been previously published.1 The suggests that lasmiditan exerts its therapeutic effects methodologies and results of the ph3 trials SAMURAI in the treatment of migraine by decreasing neuropep- (NCT02439320) and SPARTAN (NCT02605174) have tide release and modulating activity in pain pathways also been published.3,4 IRB approvals were obtained important in migraine, including the trigeminal nerve, for each of the original studies. This work represents without causing vasoconstriction.1,2 Lasmiditan has a hybrid of a review of primary documents and study shown efficacy in aborting migraine attacks in phase 2 reports with additional post hoc analyses; therefore, (ph2)1 and phase 3 (ph3)3,4 randomized clinical trials. additional IRB approval was exempted. Farkkila et al reported a relatively high incidence of In these studies, oral lasmiditan was evaluated for central nervous system (CNS)-related treatment-emer- the acute treatment of migraine. The study protocols gent adverse events (TEAEs) in the ph2 study,1 which were reviewed and approved by the appropriate insti- other authors have stated could affect acceptability of tutional review board for each of the study sites, and the drug.5,6 However, Kuca et al and Goadsby et al have the studies were conducted according to Good Clinical reported a lower incidence and severity of TEAEs in Practice and the Declaration of Helsinki guidelines. the ph3 studies.3,4 In the present manuscript, we review Patients provided written informed consent before un- the TEAEs from these lasmiditan studies. Then, we dergoing study procedures. Investigators at each study examine the different approaches related to informed site evaluated and confirmed eligibility, obtained con- consent, adverse event (AE) collection, language/lin- sent, and enrolled the patients. Doses common to the guistic differences, differences in exclusion criteria and studies were lasmiditan 100 and 200 mg, so those doses baseline characteristics and migraine characteristics, are the focus of this project. and differences between geography that may have con- All authors had access to the data and approved tributed to the difference in TEAEs in the ph2 versus the final version of the manuscript prior to submission. ph3 trials. The goal of this project was to explore how All authors participated in drafting and/or critical revi- various methodological issues might influence the ex- sion of the manuscript. perience and reporting of AEs. To accomplish this, Ph2 Study Design.—Briefly, the ph2 study was con- data from lasmiditan studies were used, although the ducted at 43 headache centers in 5 European coun- general principals may apply to other clinical develop- tries (Belgium, Finland, France, Germany, and Spain) ment programs in migraine or other therapeutic areas. from July 2009 to February 2010. Eligible patients were male or female, between the ages of 18 and 65 METHODS years, and had at least a 1-year history of episodic mi- During lasmiditan development, 1 placebo-con- graine with or without aura and 1-8 migraine attacks trolled oral ph2 and 2 placebo-controlled ph3 trials per month. were conducted; therefore, this review includes all ph2 Patients were randomized in a ratio of 1:1:1:1:1 and ph3 placebo-controlled trials of oral lasmiditan as to receive lasmiditan 50, 100, 200, or 400 mg, or pla- an acute treatment for migraine. Because TEAEs were cebo. The patients were instructed to treat their next more frequent and more severe in the ph2 study than moderate to severe migraine attack occurring within in the ph3 trials, we reviewed the protocols, informed 8 weeks with study drug within 4 hours of onset. Rescue Conflict of Interest: JHK, HPH, PHB, and RK are employees of Eli Lilly and Company and own stock in the company. PP-R has received honoraria for medical education programs and consultancy from Allergan, Almirall, Chiesi Spain, Eli Lilly, Novartis, and Teva. DK Advisory Board: Alder, Eli Lilly, Amgen, Novartis, Biohaven, Promius. Research Investigator: Alder, Eli Lilly, Amgen, Novartis, Teva, Biohaven, Roche-Genentech, VM Biopharma, UCB, Allergan. Speaker’s Bureau: Amgen/Novartis, Eli Lilly. Funding: These trials were funded by Eli Lilly and Company. 578 March 2020 medications, excluding triptans or ergotamine, were incidence of any TEAE and of the most common indi- permitted after 2 hours of study drug intake. Further vidual TEAEs in each trial are presented for placebo, study details, including the CONSORT diagram and lasmiditan 100 mg, and lasmiditan 200 mg to facilitate the exclusion criteria, have been published.1 identification of findings with non-overlapping CIs. Phase 3 (SAMURAI and SPARTAN) Study For baseline and migraine characteristics that dif- Designs.—Both the SAMURAI and SPARTAN clinical fered between the ph2 and the ph3 studies, post hoc trials were prospective, randomized, double-blind, and logistic regression analyses were conducted to assess placebo-controlled studies. The SAMURAI study was the potential impact of these factors on the incidence conducted from April 2015 to August 2016 at 99 sites of any TEAE. Separate models using 2 predictor vari- in the United States (US), and the SPARTAN study ables were constructed to explore the impact of ph2 was conducted from May 2016 to June 2017 at 125 versus ph3 and of each individual factor that appeared sites, with 97 sites in the United States, 16 in Germa- to differ between phase 2 and phase 3; these factors ny, and 12 in the United Kingdom (UK). were average migraines per month, baseline migraine For both studies, eligible patients were males severity (severe = Y), body mass index (BMI), nau- and females at least 18 years of age with an onset sea as a baseline symptom (Y/N), and time to dose of migraine with or without aura prior to the age of from migraine pain onset (hours). Wald chi-square 50 years. In addition, patients were required to have statistics and odds ratios with 95% CIs are reported. at least moderately disabling migraine, indicated by a Additionally, a post hoc analysis of TEAEs by geog- total Migraine Disability Assessment Score (MIDAS) raphy was performed to enable a comparison of the ≥11, and a history of 3-8 migraine attacks per month. results for German patients who participated in the Further study details, including the CONSORT dia- ph2 study versus the SPARTAN study. Analyses were gram and the exclusion criteria, have been published conducted using SAS Version 9.1 or higher. Results recently.3,4 Patients were randomized equally to receive were considered statistically significant if the 2-sided a first dose of lasmiditan 50 mg (SPARTAN only), 100 P value was <.05. or 200 mg. Patients were also randomized to a second dose of lasmiditan or placebo for rescue or recurrence RESULTS of migraine. The patients were instructed to treat their Patient Demographics and Clinical Characteris- next migraine attack within 4 hours of onset, provided tics.—The patient demographics, clinical characteris- that the headache severity was either moderate or tics, and migraine characteristics for the safety popu- severe and not improving. Patients were requested to lations of the trials are shown in Table 1. Patients were avoid using any other medication until at least 2 hours predominantly Caucasian females and had a mean after intake of study drug. If the migraine did not age ranging from 40 to 43 years. Patients in the ph3 respond (defined as pain freedom) at 2 hours, or if there studies had a higher BMI (30 kg/m2) than those in the was a response and then a recurrence after 2 hours but ph2 study (24 kg/m2). The average years of history of before 24 hours, then an optional second dose of study migraine and the percentage of patients with histo- drug could be taken if no other acute migraine medi- ry of aura were similar among the 3 studies, but the cation had been used. Alternatively, patients could take average number of migraine attacks per month was other migraine medications excluding triptans, ergota- lower in the ph2 study (3.2) than in the ph3 studies mines, opioids, and barbiturates. (5.1 and 5.3). Patients in the ph2 study had a longer Statistics.—Information from the clinical study time to dosing from onset of migraine and there was reports was supplemented with post hoc analyses of a higher percentage of patients with severe migraine individual patient data from each trial. Patient demo- than in the ph3 studies. Photophobia and phono- graphics and clinical characteristics are from the safety phobia were similar among the 3 studies, but the ph2 populations of the studies. The reported TEAEs are study had more patients with nausea (60%) than the from the clinical study reports. Forest plots showing SAMURAI and SPARTAN studies (39% and 39%, percentages and 95% confidence intervals (CIs) for the respectively). Headache 579 Table 1.—Demographics, Clinical, and Migraine treatment group, were compared separately. Thus, diz- Characteristics ziness, paresthesia, somnolence, fatigue, nausea, and lethargy occurred in similar proportions of patients Ph2 SAMURAI SPARTAN at the same doses in the ph3 studies, but in higher pro- (N = 391) (N = 1856)† (N = 2583)† portions in the ph2 study. The numbers and propor- tions of patients reporting each of these TEAEs are Female, n (%) 342 (87.5) 1552 (83.6) 2174 (84.2) summarized in Table 2, and the percentages of patients, Age, years, mean (SD) 40.3 (10.8) 42.0 (12.0) 42.7 (12.8) with 95% CIs, are depicted in Figure 1. Caucasian, n (%) 387 (99.0) 1400 (75.4) 2071 (80.2) BMI (kg/m2), mean (SD) 24.1 (4.1) 30.4 (7.9) 30.1 (8.9) The ph2 study reported a total of 102/391 (26%) Time to dosing (hours), 2.9 (3.6) 1.9 (4.3) 1.6 (8.1) patients with 1 or more severe TEAEs, whereas the mean (SD) SAMURAI and SPARTAN studies each reported Migraine history, years, 19.9 (12.1) 19.3 (12.9) 18.3 (13.0) mean (SD) 44/1856 (2.4%) and 43/2583 (1.7%) patients with 1 or Migraine attacks/month, 3.2 (1.7) 5.1 (1.9) 5.3 (2.1) more severe TEAEs, respectively. Moreover, there were mean (SD) Severe headache, n (%) 164 (41.9) 466 (25.1) 681 (26.4) higher percentages of patients with severe dizziness, Moderate headache, n (%) 224 (57.3) 1174 (63.3) 1594 (61.7) paresthesia, somnolence, fatigue, nausea, lethargy, and Mild headache†, n (%) 0 31 (1.7) 34 (1.3) Baseline symptoms, n (%) vertigo in the ph2 study than in either the SAMURAI Phonophobia 260 (66.5) 1033 (55.7) 1454 (56.3) or SPARTAN studies (Table 3). Photophobia 297 (76.0) 1291 (69.6) 1768 (68.4) In the forest plots showing percentages and 95% Nausea 234 (59.8) 723 (39.0) 1009 (39.1) Accompanying aura at 33 (8.4) 42 (2.3) 62 (2.4) CIs for all TEAEs and for the most frequent TEAEs first dose, n (%) (Fig. 1), there was no overlap between CIs for the lasmiditan dose groups of the ph2 vs the ph3 studies †Patients were encouraged not to take their dose until the for any TEAE, fatigue, and vertigo, suggesting signif- migraine was either moderate or severe as per the study protocol; however, following US Food and Drug Administration advice, icant differences for these outcomes. However, there mild headache was included as an option to choose in the was some overlap for other TEAEs owing to wide CIs electronic diary – these patients are shown here although they around the ph2 findings. deviated from the protocol. BMI = body mass index; Ph2 = phase 2; SD = standard deviation. Logistic regression analysis was conducted to assess potential impact of baseline characteristics and TEAEs in ph2 and ph3 Clinical Studies.—In each migraine characteristics on TEAE frequency; results study, the proportion of patients reporting TEAEs are shown in Table 4. In particular, the impact of ph2 was higher in the lasmiditan compared to the place- versus ph3 and potential predictors BMI, baseline mi- bo group, and the proportion of patients with TEAEs graine severity (severe = Y), time to dose from migraine tended to increase with increasing dose of lasmidi- pain onset (hours), average migraines per month, and tan. The most frequently reported TEAEs were dizzi- nausea as a baseline symptom (Y/N), for all TEAEs ness, paresthesia and somnolence. The proportion of were analyzed. In each analysis, ph2 versus ph3 was patients reporting TEAEs was similar for the same highly significant with odds ratios ranging from 3.87 doses of lasmiditan in the SAMURAI and the SPAR- to 4.45. The various predictors were also statistically TAN studies. In particular, the proportion of patients significant except for time to dose from migraine pain reporting at least 1 TEAE in the SAMURAI and onset; however, the odds ratios were relatively modest, SPARTAN studies receiving 100 mg of lasmiditan was ranging from 0.74 to 1.15. 229/630 (36%) and 229/635 (36%), respectively, and for TEAEs by country of patient participation are those receiving 200 mg was 260/609 (43%) and 253/649 shown in Table 5 to facilitate a comparison of German (39%). In contrast, the proportion of patients in the ph2 patients from the ph2 study with those from the study reporting TEAEs receiving 100 and 200 mg of SPARTAN trial. Consistent with the overall results, lasmiditan was 59/82 (72%) and 61/71 (86%), respec- there was a numerically higher percentage of German tively. Similar results were seen when the most fre- patients reporting dizziness, paresthesia, somnolence, quent TEAEs, defined as those occurring ≥2% in any fatigue, nausea, lethargy, and vertigo in the ph2 study 580 March 2020 than in the ph3 study. Overall, there was no obvious (N = 645) Placebo 16 (2.5) 13 (2.0) 75 (12) 6 (0.9) 6 (0.9) 8 (1.2) 1 (0.2) 1 (0.2) difference in the pattern of reported rates of TEAEs among patients in the UK, Germany, and the US within the SPARTAN ph3 study. (N = 649) 253 (39) 117 (18) 43 (6.6) 42 (6.5) 31 (4.8) 17 (2.6) 14 (2.2) 200 mg 4 (0.6) Assessment of Methodological Differences Between SPARTAN the ph2 and ph3 Clinical Studies.—Ph2 Study.—The ICF provided in the ph2 study informed patients of Lasmiditan (N = 635) 229 (36) 115 (18) 37 (5.8) 29 (4.6) 26 (4.1) 21 (3.3) 100 mg 8 (1.3) 5 (0.8) previous intravenous infusion and oral administration studies and that no serious AEs had occurred. Howev- er, the ICF for the ph2 study included the following text: (N = 654) 166 (25) 56 (8.6) 16 (2.4) 35 (5.4) 18 (2.8) 18 (2.8) 8 (1.2) 2 (0.3) 50 mg The following adverse events were observed in participants after administration of COL-144: Table 2.—Most Commonly Reported Treatment-Emergent Adverse Events (n = 617) feeling of dizziness (46x), drowsiness and fa- 101 (16) Placebo 21 (3.4) 13 (2.1) 14 (2.3) 12 (1.9) 2 (0.3) 2 (0.3) tigue (43x), paresthesias (abnormal sensation 0 on the skin, 41x), hot flashes (14x), feeling of SAMURAI heaviness (9x), nausea (6x), feeling of tension (n = 609) 260 (43) 48 (7.9) 33 (5.4) 19 (3.1) 32 (5.3) 15 (2.5) 200 mg 99 (16) 2 (0.3) (5x), vertigo (4x), blurry vision (4x), scotoma Lasmiditan (partial visual field loss, 3x), headaches (3x), asthenia (weakness, 2x), abdominal pain (2x), (n = 630) 229 (36) 36 (5.7) 36 (5.7) 26 (4.1) 19 (3.0) 12 (1.9) 100 mg 79 (13) 6 (1.0) vomiting (2x), shortness of breath (2x), diar- rhea (1x), sluggishness (1x), impaired alert- ness (1x), itching (1x), hypotension (low blood (n = 86) Placebo 19 (22) 2 (2.3) 2 (2.3) 2 (2.3) 1 (1.2) 1 (1.2) pressure, 1x), slow heart rate (1x) and collapse 0 0 (1x). (n = 70) 400 mg 59 (84) 14 (20) 26 (37) 17 (24) 17 (24) 5 (7.1) 5 (7.1) 8 (11) There was also a description of another study with ad- ditional AEs: (n = 71) 200 mg 61 (86) 12 (17) 27 (38) 15 (21) 12 (17) In the most recent study on healthy volunteers 2 (2.8) 8 (11) 9 (13) Ph2 who were given COL-144 as an oral liquid for- Lasmiditan mulation, 14 volunteers received the highest dose (n = 82) of 400 mg COL-144. They experienced drowsi- 100 mg 59 (72) 10 (12) 21 (26) 17 (21) 12 (15) 4 (4.9) 9 (11) 8 (10) ness and fatigue (7x), feelings of dizziness (3x), paresthesias (3x), nausea, headaches, nasophar- †Lethargy includes sensation of heaviness. yngitis, tonsillitis and blurred vision (1x each). (n = 82) 53 (65) 19 (23) 10 (12) 2 (2.4) 8 (9.8) 4 (4.9) 4 (4.9) 8 (9.8) 50 mg Patients used a paper diary to record information Patients with ≥1 TEAE, n (%) about the migraine attack prior to and at 0.5, 1, 1.5, 2, 3, 4, and 24 hours after taking the investigational product. At the top of the paper diary, the following Somnolence, n (%) Paresthesia, n (%) text was in large white font within a black background: Lethargy†, n (%) Dizziness, n (%) Preferred Term Nausea, n (%) Fatigue, n (%) Vertigo, n (%) Due to the possible known adverse effects such as drowsiness and dizziness in the 12 hours after administration of the study drug, …. Headache 581 Fig. 1.—The proportion of patients (as %) and the 95% confidence intervals are shown in a forest plot for the most commonly reported treatment-emergent adverse events (TEAEs). The AE page of the paper diary asked the patient to The patient diary included space to record details about take these actions: 4 symptoms. Patients were to record the start date and time and the stop date and time of their symptoms and “Please tell us about any unusual symptoms rate them as mild, moderate, or severe, but these de- you experienced” with directions: “Did you scriptors were not defined. have any unusual symptoms at any time after The protocol stated that when the patient re- taking the study medication? If so, please re- turned to the site, the investigator would determine cord symptoms below until you return to the whether any AEs had occurred, and that patients clinic.” would be questioned generally and specific symptoms 582 March 2020 would not be suggested. However, the protocol also (N = 649) (N = 645) Placebo 4 (0.6) 1 (0.2) 1 (0.2) specified that the AE information from the patient 0 0 0 0 0 diary would be transcribed into the case report form (CRF) by the investigator. Investigators were to 19 (2.9) 11 (1.7) 200 mg 2 (0.3) 1 (0.2) 1 (0.2) 3 (0.5) record AEs and their severity (mild – the AE is eas- 0 0 SPARTAN ily tolerated and does not interfere with normal daily activities, moderate – the AE causes some interfer- Lasmiditan (N = 635) 10 (1.6) 100 mg 1 (0.2) 2 (0.3) 2 (0.3) 4 (0.6) 1 (0.2) 1 (0.2) ence with daily activities, and severe – the AE causes 0 all normal daily activities to be completely halted). The CRF for AEs included a space for a description (N = 654) of each AE, start date and time, stop date and time, 10 (1.5) 1 (0.2) 2 (0.3) 1 (0.2) 2 (0.3) 50 mg 0 0 0 severity, relationship to study medication, action taken, outcome, and whether the AE was serious. Notably, at the German-speaking ph2 study sites, the (n = 617) Placebo 1 (0.2) 7 (1.1) 1 (0.2) word “Schwindel” was variably translated to English 0 0 0 0 0 Table 3.—Severe Treatment-Emergent Adverse Events (TEAEs) as “vertigo” or “dizziness,” and translations to ver- tigo were apparently not assessed for presence of a SAMURAI (n = 609) 21 (3.4) 200 mg movement or rotational component. 4 (0.7) 6 (1.0) 2 (0.3) 0 0 0 0 Ph3 Studies SAMURAI and SPARTAN.—In the Lasmiditan ph3 clinical studies, responses to the first dose and, if taken, to the second dose of study drug were record- (n = 630) 15 (2.4) 100 mg 1 (0.2) 6 (1.0) 3 (0.5) 3 (0.5) ed by the patient in an electronic diary at baseline and 0 0 0 0.5, 1, 1.5, 2, 3, 4, 24, and 48 hours after dosing. At each time point, the electronic diary included a ques- (n = 86) Placebo 1 (1.2) 5 (5.8) 1 (1.2) 1 (1.2) tion: “Do you feel anything unusual since you took the 0 0 0 0 Study Medication that you have not felt with a migraine before?” A “yes” response to this question triggered an email alert to the site to contact the subject and (n = 70) 400 mg 31 (44) 12 (17) 3 (4.3) 5 (7.1) 2 (2.9) 8 (11) 8 (11) 0 assess the AE in terms of what the subject was experiencing, how long the symptoms lasted and how much the symptom(s) impacted them. Severity of AEs (n = 71) 200 mg 28 (39) 11 (16) 11 (16) 2 (2.8) 2 (2.8) 3 (4.2) 4 (5.6) 2 (2.8) Ph2 were assessed as mild (awareness of sign or symptom, Lasmiditan but easily tolerated), moderate (discomfort enough to cause interference with usual activity), severe (incapac- (n = 82) 100 mg 22 (27) 1 (1.2) 3 (3.7) 8 (9.8) 2 (2.4) 2 (2.4) 7 (8.5) itating with inability to work or perform usual activ- 0 †Lethargy includes sensation of heaviness. ity), or life threatening (no life threatening AEs were reported). All AEs reported from the time of dosing up (n = 82) 16 (20) 3 (3.7) 1 (1.2) 1 (1.2) 1 (1.2) 3 (3.7) 5 (6.1) 2 (2.4) 50 mg to 48 hours afterward were considered to be TEAEs. Pa- tients were provided with an instruction sheet for their electronic diary with some white space where they were Patients with ≥1 Severe advised to write down, in their own words, what was Somnolence, n (%) happening during an AE in order to facilitate discus- Paresthesia, n (%) Lethargy†, n (%) Dizziness, n (%) TEAE, n (%) Preferred Term sion, and were to be called within 48 hours by the site, so Nausea, n (%) Fatigue, n (%) Vertigo, n (%) that any potential recall bias might be minimized. Dif- ferences in collection of TEAEs between the ph2 and ph3 studies are summarized in Table 6. Headache 583 Table 4.—Logistic Regression Analyses for Baseline and Migraine Characteristics on Incidence of Any TEAE Phase 2 vs Phase 3 Factor Odds Ratio Odds Ratio Event Factor P Value (95% CI) P Value (95% CI) Any TEAE Body mass index <.001 3.87 (3.10, 4.84) <.001 0.99 (0.98, 0.99) Severe migraine <.001 4.45 (3.57, 5.55) <.001 0.74 (0.64, 0.86) Time to dose from migraine pain onset (hours) <.001 4.26 (3.43, 5.31) .869 1.00 (0.99, 1.02) Average migraines per month <.001 3.98 (3.18, 4.99) .021 0.96 (0.93, 0.99) Nausea as a baseline symptom <.001 4.17 (3.36, 5.19) .027 1.15 (1.02, 1.31) CI = confidence interval; TEAE = treatment-emergent adverse event. In the ph3 studies, the ICF informed patients as fol- and found that the best explanation for the difference lows: “You may experience some or none of these side in the rates of TEAEs may have been related to dif- effects: dizziness, fatigue, sleepiness, tingling sensation ferences in ICF documents and the methods used to in hands and feet, generalized weakness, unsteadiness, record and code data. Other factors that may have con- orthostatic hypotension (drop in blood pressure when tributed to the differences include an exclusion related you stand up) with or without dizziness. This is very tran- to recurrent dizziness or vertigo and baseline charac- sient and resolves quickly. Because lasmiditan (the study teristics of patients and their behavior. Geography did drug) may cause dizziness or sleepiness, do not drive a not appear to explain the differences. car, use machinery or do anything where you need to be Regarding the ICF, patients participating in the ph2 alert until you know how you will react to lasmiditan.” study received information about potential AEs such as For all studies, AEs were entered into the CRF. The “feeling of dizziness (46x).” The meaning of “46x” was English translations of the reported TEAEs were then not defined, so patients may have interpreted this vari- coded using classifications and preferred terms from the ably (eg, instances of the event or fold increase in risk). Medical Dictionary for Regulatory Activities, version In addition, the patients in the ph2 were warned about 18.0. In the ph3 studies, if a case of vertigo was reported, drowsiness and dizziness in the paper diary, while those the site was queried about whether there was a movement in the ph3 studies who used the electronic diaries were or rotational component; if not, the site was asked if they asked open-ended questions about unusual symptoms. thought the AE should be changed to dizziness. Although it might be supposed that the repeated warn- ings regarding side effects in ph2 might lead to higher DISCUSSION expectations of efficacy, review of the efficacy data Previous studies established that lasmiditan was from the ph2 study does not show increased efficacy superior to placebo in relieving migraine headache relative to the ph3 studies (data not shown). pain and associated symptoms.1,3,4 However, published Several reviews provide evidence that the wording of reviews discussing the ph2 study of oral lasmiditan ICFs can influence patients’ reported AEs.7-10 Notably, expressed some concern about the relatively high in- nonspecific symptoms, such as drowsiness, nausea, diz- cidence of CNS-related TEAEs (especially dizziness, ziness, and fatigue, which were among the most common vertigo, and fatigue).5,6 However, the results of 2 ph3 TEAEs observed in the studies, are most susceptible to studies have now been reported with the incidence and a possible nocebo response.10 An example of how ICFs severity of these TEAEs being relatively lower.3,4 We can influence outcomes is provided by a placebo-con- explored various factors which may have contributed trolled trial of aspirin, where the ICF used at 2 centers to this difference between ph2 and ph3 TEAE reporting included a statement that “side effects are not anticipated 584 March 2020 beyond occasional gastrointestinal irritation and, rarely, US (n = 2154) skin rash.”11 This statement was not included in the 112 (5.2) 233 (11) 77 (3.6) 58 (2.7) 45 (2.1) 21 (1.0) 4 (0.2) n (%) ICF at the third study center. Patients at the centers informing versus those at centers not informing about UK (n = 174) gastrointestinal irritation reported significantly higher gastrointestinal symptoms and 6 times higher withdraw- 29 (16.7) 13 (7.5) 3 (1.7) 8 (4.6) 3 (1.7) 5 (2.9) n (%) als from the study because of gastrointestinal distress.11 SPARTAN 0 That ICFs may themselves influence patients’ experi- ences during clinical trials is a concern, and strategies to mitigate this influence have been discussed in the liter- Germany (n = 255) ature.7,10 Suggestions include informing patients of the 42 (16.5) 12 (4.7) 15 (5.9) 16 (6.3) 4 (1.6) 5 (2.0) 8 (3.1) n (%) percentage who do not report certain side effects (“pos- itive” communication) rather than the percentage of those who do (“negative” communication).7 In addition, the concept of “contextualized informed consent” has been proposed, where the possible side effects, the char- Belgium (n = 27) acteristics of the patient, and the disease involved are 5 (18.5) 6 (22.2) 5 (18.5) 2 (7.4) 1 (3.7) n (%) considered when formulating the informed consent.10 0 0 Table 5.—Adverse Effects by Country One suggestion is for the patient to contact the study site if they experience “any new or unusual symptoms,” so that the site can then evaluate the patient and determine Spain (n = 31) if the patient’s event is related to the study drug.9 This 4 (12.9) 5 (16.1) 2 (6.5) 1 (3.2) n (%) 0 0 0 strategy differs from what was employed in ph3 stud- ies described here, where patients were asked at 8 post- baseline time points whether they were feeling anything France (n = 36) unusual, and if they recorded yes in the electronic diary, 13 (36.1) 8 (22.2) then the site contacted the patient. While this approach 2 (5.6) 1 (2.8) 2 (5.6) n (%) 0 0 might detect clinically relevant TEAEs, it might also Ph2 result in underreporting, as some patients might be reluctant to call the investigative site. Finland (n = 124) A possible factor that may have influenced the AE 22 (17.7) 33 (26.6) reporting from these clinical trials is the nocebo (“I will 11 (8.9) 11 (8.9) 5 (4.0) 8 (6.5) 4 (3.2) n (%) harm”) effect.7,8,12 Although it has not been as well studied as the placebo (“I will please”) response in clin- ical trials, evidence suggests that its impact may be as UK = United Kingdom; US = United States. †Lethargy includes sensation of heaviness. important.7,8 Nocebo effect has been demonstrated in Germany (n = 173) several studies,8-10 including one where an innocuous 35 (20.2) 34 (19.7) 48 (27.7) 19 (11.0) 14 (8.1) 16 (9.2) stimulus produced a perception of pain,13 and another 9 (5.2) n (%) where a potent analgesic (ie, remifentanil) was rendered ineffective,14 due to the subjects’ negative expectations. Supportive of a possible nocebo effect, the placebo group in the ph2 study showed an incidence of ≥1 TEAE Preferred Term in 22% of patients (5.8% severe) while SAMURAI Somnolence Paresthesia showed 16% (1.1% severe) and SPARTAN showed 12% Lethargy† Dizziness Nausea Fatigue Vertigo (0.6% severe). However, the rates of TEAEs were con- siderably lower in the placebo than lasmiditan groups Headache 585 Table 6.—Differences† in Phase 2 vs Phase 3 Collection of Adverse Events Ph2 SAMURAI, SPARTAN History consideration Diagnoses, not symptoms Diagnoses, symptoms Ascertainment of AEs Patient could write down on an AE Daily question “How are you feeling today” and page questions during migraine Prompting Patient AE form instructions warned No specific warnings about particular AEs, sites patients about drowsiness, dizziness, asked open-ended question and restricted driving or operating heavy machinery Diary Paper Electronic with alarms Site participation or discussion Site instructed to both transcribe infor- Site determined if there was a new issue or previous with patient about each event mation from patient journal as well issues had worsened or changed as determine whether AEs occurred Vertigo Not managed with German word Cases of vertigo were queried regarding whether Schwindel sometimes translated there was a movement or rotational component; to “vertigo” and sometimes to if not the site was asked whether dizziness might “dizziness” be more appropriate †Patients with a history of recurrent dizziness and/or vertigo including benign paroxysmal positional vertigo (BPPV), Meniere’s disease, vestibular migraine, and other vestibular disorders were excluded from the SAMURAI and SPARTAN studies. AE = adverse event; Ph2 = phase 2. in all studies, indicating that a drug effect is present time after taking the study medication?” and the elec- but that the nocebo effect may have influenced the fre- tronic diary used in the ph3 studies asked patients, “Do quency and severity of reported TEAEs. you feel anything unusual since you took the study medi- Collection methodology can influence the fre- cation that you have not felt with a migraine before?” The quency of AE reporting. For example, a prospective difference between these prompts may be relevant since study of 415 patients with migraine who were on a trip- the ph2 study may have included more reporting of symp- tan for ≥3 months assessed how the means of collecting toms related to migraine than the ph3 study. However, the AEs affected outcome.15 In that study, patients filled ph3 studies included this question at 8 post-baseline time out one part of a questionnaire that asked if they had points, and this frequency of questioning may have facil- any AEs while taking triptans (ie, unprompted), and itated more complete ascertainment of AEs. if yes, to list and grade the severity of the AEs. They Consistent with overall results, German patients then received a second form that listed 49 possible AEs, reported TEAEs at higher frequency in the ph2 study most of which were known side effects of triptans (ie, compared to in the SPARTAN study. Because the German prompted). Most patients (75% in United States, 66% patients in the ph2 study may have been relatively sim- in Italy) reported no AEs on the unprompted form, yet ilar to those in SPARTAN, this finding strengthens the a majority (63% United States, 54% Italy) also reported argument that ICF and diary language may significantly at least 1 AE on the prompted form. Most patients who affect reporting of AE symptoms by patients within a rel- reported unprompted AEs only indicated 1, whereas atively similar cultural and linguistic context. with the prompted form, most patients indicated 2 or There were methodological differences between more AEs. This finding is consistent with the results of the ph2 and the ph3 studies regarding the collection of the present investigation, where the ph2 study, including the TEAE vertigo. Some patients at German speaking some prompting about potential AEs, had higher num- ph2 sites were recorded to have the TEAE Schwindel; bers of reported AEs when compared to the ph3 stud- this German word was translated to English variably ies, where an unprompted collection method was used. as “vertigo” or “dizziness,” apparently without regard The paper patient diary for the ph2 study asked to whether there was a movement or rotational compo- patients, “Did you have any unusual symptoms at any nent suggesting actual vertigo. In contrast, in the ph3 586 March 2020 studies, AEs of vertigo were queried and if there was contributed to vertigo decreasing relatively more than no movement or rotational component, the site was the decrease in any TEAE in the ph3 studies. While asked to consider whether reporting dizziness might be this is possible, other factors, as discussed above, may more appropriate. However, reports of dizziness were also have contributed to the relatively low incidence of not similarly queried, possibly reducing the number of vertigo in ph3 versus ph2, including differences in the cases of vertigo reported during the ph3 study. Thus, question about AEs, site queries, and translation. both translation issues as well as querying sites about particular TEAEs may have markedly influenced the CONCLUSION observed rate of particular TEAEs such as vertigo. Several factors likely contributed to the relatively A previous 5-HT1F agonist, LY334370, underwent higher incidence and severity of TEAEs in the lasmidi- ph2 testing and showed TEAEs, including dizziness in tan ph2 study compared with the ph3 studies. The ph2 35%, asthenia in 27%, somnolence in 23%, and par- study included more description of potential TEAEs in esthesia in 19% in the 200-mg dose group.16 This ph2 the ICF, and the paper diary included warnings about study also included a paper diary and might have served dizziness and somnolence that could have contributed as a model for the conduct of the lasmiditan ph2 study, to a possible nocebo effect. Additional studies could raising the possibility that similar methods may have help to further explore the importance of the nocebo contributed to the relatively high rate of TEAEs in the effect in randomized clinical trials of acute treatments LY33470 and lasmiditan ph2 studies. for migraine. In the ph2 study, sites were instructed In contrast to the lasmiditan development pro- to both transcribe TEAEs recorded by patients and gram, development of other drugs with more similar also to determine whether TEAEs had occurred. methodology in the ph2 and ph3 studies has shown The transcription of TEAEs recorded by patients in more similar results. For example, the ph2 study for the ph2 study may have included some symptoms of galcanezumab for the preventive treatment of episodic migraine rather than drug effects. Recording of TEAEs migraine reported at least 1 TEAE in 72% of patients by trained investigative personnel asking open-ended receiving galcanezumab and 67% patients receiving questions may lead to more consistent reporting of placebo.17 In the EVOLVE-1 ph3 study, between 60% TEAEs across sites and patients. In addition, linguis- and 68% of patients reported at least 1 TEAE,18 and tic and cultural issues may also influence the reporting in the EVOLVE-2 ph3 study, at least 1 TEAE was of TEAEs. These can be minimized by employing uni- reported by between 62% and 72% of patients.19 form, internally consistent translations and coding that The most marked differences in populations and account for vagaries of culture, language, and dialects. behavior between these studies were examined as Finally, patients had a lower BMI, migraine headache potential factors explaining the differences in report- was more severe, average migraines per month was ing of any TEAE. In those analyses, while ph2 versus lower, and nausea was higher in the ph2 compared to ph3 was highly predictive (odds ratios 3.87 to 4.45), the the ph3 studies, and these factors significantly influ- impact of other factors such as BMI, baseline migraine enced the occurrence of TEAEs. Moreover, the ph3 severity, average migraines per month, and nausea as a study excluded patients with history of disorders that baseline symptom were statistically significant but rela- result in recurrent dizziness and/or vertigo. In conclu- tively less predictive (odds ratios 0.74 to 1.15). sion, although the particular common TEAEs were The exclusion of patients with history of recurrent similar, differences in the methods of conducting clini- dizziness and/or vertigo in the ph3 studies but not in cal trials of an acute treatment for migraine along with the ph2 study may have impacted the observed fre- some differences in patient population and behavior quencies of those events. For dizziness, this exclusion influenced the frequency and severity of the observed does not appear to be a major factor since the propor- TEAEs. These considerations are relevant to the design tions of patients with dizziness and with any TEAE and conduct of clinical trials of acute treatments for decreased approximately similarly in ph3 studies rela- migraine, and the general principals may apply to clini- tive to the ph2 study. However, this exclusion may have cal trials in other therapeutic areas. Headache 587 Acknowledgments: The authors thank the patients who 2. Ferrari MD, Färkkilä M, Reuter U, et al. Acute treat- participated in the studies. The authors also thank Teri ment of migraine with the selective 5-HT1F receptor Tucker, ELS of Syneos Health for her help with writing, agonist lasmiditan – A randomised proof-of-concept editing, and formatting the manuscript and Gina Moore of trial. Cephalalgia. 2010;30:1170-1178. Syneos health for her help with writing the manuscript. Eli 3. Kuca B, Silberstein SD, Wietecha L, Berg PH, Dozier G, Lipton RB. Lasmiditan is an effective acute treat- Lilly and Company contracted Syneos Health for writing and ment for migraine: A phase 3 randomized study. editorial services. Neurology. 2018;91:e2222-e2232. 4. Goadsby PJ, Wietecha LA, Dennehy EB, et al. Phase STATEMENT OF AUTHORSHIP 3 randomized, placebo-controlled, double-blind study Category 1 of lasmiditan for acute treatment of migraine. Brain. 2019;142:1894-1904. (a) Conception and Design 5. Mitsikostas DD, Tfelt-Hansen P. Targeting to 5-HT1F David Kudrow, John H. Krege, Hans P. Hundemer, receptor subtype for migraine treatment: Lessons Paul H. Berg, Rashna Khanna, Michael H. from the past, implications for the future. Cent Nerv OssipovPatricia Pozo-Rosich Syst Agents Med Chem. 2012;12:241-249. (b) Acquisition of Data 6. Tfelt-Hansen PC, Olesen J. The 5-HT1F receptor ag- David Kudrow, John H. Krege, Hans P. Hundemer, onist lasmiditan as a potential treatment of migraine Paul H. Berg, Rashna Khanna, Michael H. attacks: A review of two placebo-controlled phase II trials. J Headache Pain. 2012;13:271-275. OssipovPatricia Pozo-Rosich 7. Benedetti F, Shaibani A. Nocebo effects: More (c) Analysis and Interpretation of Data investigation is needed. Expert Opin Drug Saf. David Kudrow, John H. Krege, Hans P. Hundemer, 2018;17:541-543. Paul H. Berg, Rashna Khanna, Michael H. 8. Glick M. Placebo and its evil twin, nocebo. J Am Dent OssipovPatricia Pozo-Rosich Assoc. 2016;147:227-228. Category 2 9. Barsky AJ, Saintfort R, Rogers MP, Borus JF. Nonspecific medication side effects and the nocebo (a) Drafting the Manuscript phenomenon. JAMA. 2002;287:622-627. John Krege and Michael Ossipov 10. Wells RE, Kaptchuk TJ. To tell the truth, the whole (b) Revising It for Intellectual Content truth, may do patients harm: The problem of the David Kudrow, John H. Krege, Hans P. Hundemer, nocebo effect for informed consent. Am J Bioeth. Paul H. Berg, Rashna Khanna, Michael H. 2012;12:22-29. OssipovPatricia Pozo-Rosich 11. Myers MG, Cairns JA, Singer J. The consent form as a possible cause of side effects. Clin Pharmacol Ther. Category 3 1987;42:250-253. (a) Final Approval of the Completed Manuscript 12. Carlino E, Vase L. Can knowledge of placebo and David Kudrow, John H. Krege, Hans P. Hundemer, nocebo mechanisms help improve randomized clinical trials? Int Rev Neurobiol. 2018;138:329-357. Paul H. Berg, Rashna Khanna, Michael H. 13. Schweiger A, Parducci A. Nocebo: The psycho- OssipovPatricia Pozo-Rosich logic induction of pain. Pavlov J Biol Sci. 1981;16: 140-143. 14. Bingel U, Wanigasekera V, Wiech K, et al. The effect REFERENCES of treatment expectation on drug efficacy: Imaging 1. Färkkilä M, Diener HC, Géraud G, et al. Efficacy and the analgesic benefit of the opioid remifentanil. 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