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Philadelphia – according to research presented at the annual meeting of the American Headache Society. This impairment coincides with the time of peak drug concentration and is resolved by 8 hours after dosing.
Lasmiditan, a 5-HT1F receptor agonist, is under regulatory review as an acute treatment of migraine in adults. In two phase 3 trials, a significant proportion of participants who received the treatment were pain-free at 2 hours and free of their most bothersome symptom at 2 hours, compared with controls. The most common treatment-emergent adverse events (dizziness, paresthesia, somnolence, fatigue, and hypoaesthesia) reflected the drug’s penetration of the CNS. Because CNS-related adverse events could affect a patient’s ability to drive, the effects of lasmiditan on simulated driving were studied, consistent with regulatory guidance.
Two studies in healthy participants
Eric Pearlman, MD, PhD, senior medical director for neuroscience, U.S. Medical Affairs, at Eli Lilly, and colleagues conducted two simulated driving studies with crossover designs. In the first study, the researchers randomized 90 healthy subjects (mean age, 34.9 years) to 50 mg, 100 mg, or 200 mg of lasmiditan; 1 mg of alprazolam (an active control); or placebo. After appropriate washout periods, participants received each treatment in random order. At 1.5 hours after each treatment, participants underwent a driving assessment using a driving simulator.
In the second study, Dr. Pearlman and colleagues randomized 68 healthy subjects (mean age, 32.8 years) to 100 mg or 200 mg of lasmiditan, 50 mg of diphenhydramine (an active control), or placebo. Participants underwent driving assessments at 8, 12, and 24 hours after baseline. Participants randomized to lasmiditan received treatment at baseline, but participants randomized to diphenhydramine received treatment 2 hours before each driving assessment. The diphenhydramine arm was intended to test the sensitivity of the driving assessment to impairment, as was the alprazolam arm in the first study.
During the driving assessments, participants were asked to maintain a speed of 100 km/h and to stay in the middle of the lane. The simulated road included gentle curves and hills, and oncoming traffic appeared occasionally. Participants also completed a secondary attention task, mimicking real-world conditions. Each assessment took about 1 hour. The primary endpoint was the standard deviation of lateral position (SDLP), which is known colloquially as weaving. The investigators defined noninferiority to placebo as an SDLP of 4.4 cm or less.
Participants reported that they could drive safely
In the first study, Dr. Pearlman and colleagues reported a dose-related increase in SDLP at 1.5 hours post treatment. All three doses of lasmiditan were inferior to placebo, in terms of their effect on SDLP. In the second study, both doses of lasmiditan were noninferior to placebo at 8 hours, 12 hours, and 24 hours. In both studies, the positive control confirmed the assay’s sensitivity to driving impairment. Secondary endpoints in the second study did not indicate an association between lasmiditan and clinically meaningful driving impairment at 8, 12, and 24 hours after dosing.
Single oral doses of lasmiditan were absorbed rapidly. The median time to peak concentration was approximately 2 hours, and the mean elimination half-life was about 4.25 hours. Exposure to lasmiditan was approximately dose proportional.
Before each driving assessment, investigators asked participants, “Do you feel safe to drive?” Depending on the dose, 55%-80% of participants responded affirmatively, but the majority of participants had clinically meaningful changes in SDLP. “This [result] is consistent with the FDA guidance in the literature that subject perception of safety to drive is faulty and supports the need for formal driving assessments,” said Dr. Pearlman.
Dizziness, somnolence, and headache were the most common adverse events in the study, and this result was similar to those of the phase 3 trials. Most of the adverse events were of mild to moderate severity.
Questions for further study
Among the questions that future research could address is whether the lasmiditan-related effects seen in these studies in healthy subjects are similar to those in patients with migraine when lasmiditan is taken to treat a migraine attack, said Dr. Pearlman. Another open question is whether migraine has ictal and interictal effects on driving performance.
Eli Lilly, which has developed lasmiditan, sponsored the studies. Dr. Pearlman and several of coinvestigators are employees of the company.
SOURCE: Pearlman E et al. AHS 2019, Abstract IOR06.
Philadelphia – according to research presented at the annual meeting of the American Headache Society. This impairment coincides with the time of peak drug concentration and is resolved by 8 hours after dosing.
Lasmiditan, a 5-HT1F receptor agonist, is under regulatory review as an acute treatment of migraine in adults. In two phase 3 trials, a significant proportion of participants who received the treatment were pain-free at 2 hours and free of their most bothersome symptom at 2 hours, compared with controls. The most common treatment-emergent adverse events (dizziness, paresthesia, somnolence, fatigue, and hypoaesthesia) reflected the drug’s penetration of the CNS. Because CNS-related adverse events could affect a patient’s ability to drive, the effects of lasmiditan on simulated driving were studied, consistent with regulatory guidance.
Two studies in healthy participants
Eric Pearlman, MD, PhD, senior medical director for neuroscience, U.S. Medical Affairs, at Eli Lilly, and colleagues conducted two simulated driving studies with crossover designs. In the first study, the researchers randomized 90 healthy subjects (mean age, 34.9 years) to 50 mg, 100 mg, or 200 mg of lasmiditan; 1 mg of alprazolam (an active control); or placebo. After appropriate washout periods, participants received each treatment in random order. At 1.5 hours after each treatment, participants underwent a driving assessment using a driving simulator.
In the second study, Dr. Pearlman and colleagues randomized 68 healthy subjects (mean age, 32.8 years) to 100 mg or 200 mg of lasmiditan, 50 mg of diphenhydramine (an active control), or placebo. Participants underwent driving assessments at 8, 12, and 24 hours after baseline. Participants randomized to lasmiditan received treatment at baseline, but participants randomized to diphenhydramine received treatment 2 hours before each driving assessment. The diphenhydramine arm was intended to test the sensitivity of the driving assessment to impairment, as was the alprazolam arm in the first study.
During the driving assessments, participants were asked to maintain a speed of 100 km/h and to stay in the middle of the lane. The simulated road included gentle curves and hills, and oncoming traffic appeared occasionally. Participants also completed a secondary attention task, mimicking real-world conditions. Each assessment took about 1 hour. The primary endpoint was the standard deviation of lateral position (SDLP), which is known colloquially as weaving. The investigators defined noninferiority to placebo as an SDLP of 4.4 cm or less.
Participants reported that they could drive safely
In the first study, Dr. Pearlman and colleagues reported a dose-related increase in SDLP at 1.5 hours post treatment. All three doses of lasmiditan were inferior to placebo, in terms of their effect on SDLP. In the second study, both doses of lasmiditan were noninferior to placebo at 8 hours, 12 hours, and 24 hours. In both studies, the positive control confirmed the assay’s sensitivity to driving impairment. Secondary endpoints in the second study did not indicate an association between lasmiditan and clinically meaningful driving impairment at 8, 12, and 24 hours after dosing.
Single oral doses of lasmiditan were absorbed rapidly. The median time to peak concentration was approximately 2 hours, and the mean elimination half-life was about 4.25 hours. Exposure to lasmiditan was approximately dose proportional.
Before each driving assessment, investigators asked participants, “Do you feel safe to drive?” Depending on the dose, 55%-80% of participants responded affirmatively, but the majority of participants had clinically meaningful changes in SDLP. “This [result] is consistent with the FDA guidance in the literature that subject perception of safety to drive is faulty and supports the need for formal driving assessments,” said Dr. Pearlman.
Dizziness, somnolence, and headache were the most common adverse events in the study, and this result was similar to those of the phase 3 trials. Most of the adverse events were of mild to moderate severity.
Questions for further study
Among the questions that future research could address is whether the lasmiditan-related effects seen in these studies in healthy subjects are similar to those in patients with migraine when lasmiditan is taken to treat a migraine attack, said Dr. Pearlman. Another open question is whether migraine has ictal and interictal effects on driving performance.
Eli Lilly, which has developed lasmiditan, sponsored the studies. Dr. Pearlman and several of coinvestigators are employees of the company.
SOURCE: Pearlman E et al. AHS 2019, Abstract IOR06.
Philadelphia – according to research presented at the annual meeting of the American Headache Society. This impairment coincides with the time of peak drug concentration and is resolved by 8 hours after dosing.
Lasmiditan, a 5-HT1F receptor agonist, is under regulatory review as an acute treatment of migraine in adults. In two phase 3 trials, a significant proportion of participants who received the treatment were pain-free at 2 hours and free of their most bothersome symptom at 2 hours, compared with controls. The most common treatment-emergent adverse events (dizziness, paresthesia, somnolence, fatigue, and hypoaesthesia) reflected the drug’s penetration of the CNS. Because CNS-related adverse events could affect a patient’s ability to drive, the effects of lasmiditan on simulated driving were studied, consistent with regulatory guidance.
Two studies in healthy participants
Eric Pearlman, MD, PhD, senior medical director for neuroscience, U.S. Medical Affairs, at Eli Lilly, and colleagues conducted two simulated driving studies with crossover designs. In the first study, the researchers randomized 90 healthy subjects (mean age, 34.9 years) to 50 mg, 100 mg, or 200 mg of lasmiditan; 1 mg of alprazolam (an active control); or placebo. After appropriate washout periods, participants received each treatment in random order. At 1.5 hours after each treatment, participants underwent a driving assessment using a driving simulator.
In the second study, Dr. Pearlman and colleagues randomized 68 healthy subjects (mean age, 32.8 years) to 100 mg or 200 mg of lasmiditan, 50 mg of diphenhydramine (an active control), or placebo. Participants underwent driving assessments at 8, 12, and 24 hours after baseline. Participants randomized to lasmiditan received treatment at baseline, but participants randomized to diphenhydramine received treatment 2 hours before each driving assessment. The diphenhydramine arm was intended to test the sensitivity of the driving assessment to impairment, as was the alprazolam arm in the first study.
During the driving assessments, participants were asked to maintain a speed of 100 km/h and to stay in the middle of the lane. The simulated road included gentle curves and hills, and oncoming traffic appeared occasionally. Participants also completed a secondary attention task, mimicking real-world conditions. Each assessment took about 1 hour. The primary endpoint was the standard deviation of lateral position (SDLP), which is known colloquially as weaving. The investigators defined noninferiority to placebo as an SDLP of 4.4 cm or less.
Participants reported that they could drive safely
In the first study, Dr. Pearlman and colleagues reported a dose-related increase in SDLP at 1.5 hours post treatment. All three doses of lasmiditan were inferior to placebo, in terms of their effect on SDLP. In the second study, both doses of lasmiditan were noninferior to placebo at 8 hours, 12 hours, and 24 hours. In both studies, the positive control confirmed the assay’s sensitivity to driving impairment. Secondary endpoints in the second study did not indicate an association between lasmiditan and clinically meaningful driving impairment at 8, 12, and 24 hours after dosing.
Single oral doses of lasmiditan were absorbed rapidly. The median time to peak concentration was approximately 2 hours, and the mean elimination half-life was about 4.25 hours. Exposure to lasmiditan was approximately dose proportional.
Before each driving assessment, investigators asked participants, “Do you feel safe to drive?” Depending on the dose, 55%-80% of participants responded affirmatively, but the majority of participants had clinically meaningful changes in SDLP. “This [result] is consistent with the FDA guidance in the literature that subject perception of safety to drive is faulty and supports the need for formal driving assessments,” said Dr. Pearlman.
Dizziness, somnolence, and headache were the most common adverse events in the study, and this result was similar to those of the phase 3 trials. Most of the adverse events were of mild to moderate severity.
Questions for further study
Among the questions that future research could address is whether the lasmiditan-related effects seen in these studies in healthy subjects are similar to those in patients with migraine when lasmiditan is taken to treat a migraine attack, said Dr. Pearlman. Another open question is whether migraine has ictal and interictal effects on driving performance.
Eli Lilly, which has developed lasmiditan, sponsored the studies. Dr. Pearlman and several of coinvestigators are employees of the company.
SOURCE: Pearlman E et al. AHS 2019, Abstract IOR06.
REPORTING FROM AHS 2019