Healthy
Conditions
Brief summary
This study will assess the effects on heart rate and blood pressure when a single dose of lasmiditan is administered with a daily dose of propranolol. This study will also measure how much lasmiditan gets into the bloodstream after taking lasmiditan alone and after taking it together with propranolol. The study will also look at how well both drugs are tolerated. Information about any side effects that may occur will be collected. This study will last approximately 45 days including screening. This study will require 13 days/12 nights in a Clinical Research Unit (CRU) followed by 1 follow-up appointment approximately 7 days after the last dose. Screening is required within 28 days prior to the start of the study. This study is for research purposes only and is not intended to treat any medical condition.
Interventions
DRUGLasmiditan
Administered orally
DRUGPropranolol
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy males or females, as determined by medical history and physical examination * Have a body mass index (BMI) of 19 to 35 kilograms per meter squared (kg/m²) inclusive, at the time of screening
Exclusion criteria
* Have known allergies to lasmiditan, propranolol, related compounds or any components of the formulation of lasmiditan or propranolol * Have a history of, or electrocardiogram (ECG) findings of, clinically significant bradycardia, heart block, tachy or brady arrhythmias, sick sinus syndrome/sinoatrial block, or second or third-degree heart block, or have any other abnormality in the 12-lead ECG that, in the opinion of the investigator, increases the risks associated with participating in the study * Have an abnormal supine blood pressure, defined as systolic blood pressure less than (\<) 95 or greater than (\>) 140 millimeters of mercury (mmHg) or diastolic blood pressure \<65 or \>90 mmHg at screening * Have a supine pulse rate of \<50 or \>90 beats per minute (bpm) at screening * Have an estimated glomerular filtration rate (eGFR) of \<60 milliliter per minute (mL/min) per 1.73 meter squared (m2) * Show evidence of significant active neuropsychiatric disease (for example, manic depressive illness, schizophrenia, depression) * Show a history of central nervous system (CNS) conditions such as strokes, transient ischaemic attacks, significant head trauma, CNS infections, migraines, brain surgery or any other neurological conditions that, in the opinion of the investigator, increases the risk of participating in the study * Are women with a positive pregnancy test or women who are lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (Day 8) in Mean Hourly Heart Rate Following Propranolol Administered Alone and When Coadministered With Lasmiditan | Baseline (Day 8), Day 9 | Change from baseline in mean hourly heart rate recorded as beats per minute and collected by Holter ambulatory monitoring in response to propranolol administered alone and in combination with lasmiditan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Propranolol Alone and When Coadministered With Lasmiditan | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose | Maximum concentration of propranolol when administered alone on Day 8 and when coadministered with lasmiditan on Day 9. |
| Pharmacokinetic: Area Under the Concentration Versus Time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-tlast)] of Lasmiditan Alone and When Administered With Propranolol | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose. | AUC versus time curve (AUC 0-tlast) of lasmiditan when administered alone on Day 1 and when coadministered with propranolol on Day 9. |
| Pharmacokinetic: Area Under the Concentration Versus Time Curve (AUC) of Propranolol During One Dosing Interval Alone and When Administered With Lasmiditan | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose | AUC versus time curve of propranolol during one dosing interval when administered alone on Day 8 and when administered with lasmiditan on Day 9. |
| Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Lasmiditan Alone and When Coadministered With Propranolol | Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose. | Maximum concentration of lasmiditan when administered alone on Day 1 and when coadministered with propranolol on Day 9. |
| Change From Baseline (Day 8) in Systolic Blood Pressure Following Propranolol Administered Alone and When Coadministered With Lasmiditan | Baseline (Day 8), Day 9 | Change from baseline in systolic blood pressure was measured in supine position. |
| Change From Baseline (Day 8) in Diastolic Blood Pressure Following Propranolol Administered Alone and When Coadministered With Lasmiditan | Baseline (Day 8), Day 9 | Change from baseline in diastolic blood pressure was measured in supine position. |
| Change From Baseline (Day 8) in PR Interval Following Propranolol Administered Alone and When Coadministered With Lasmiditan | Baseline (Day 8), Day 9 | Change from baseline in PR interval, the interval between the P wave and the QRS complex calculated from electrocardiogram (ECG) data. |
Countries
United States
Participant flow
Pre-assignment details
Open-label fixed-sequence study in which participants received a single oral dose of lasmiditan 200 mg on Day (D) 1 Reference Treatment (R), then propranolol 80 mg administered orally twice daily from Day 4 through Day 10 Reference Treatment, with one single oral dose of lasmiditan 200 mg on Day 9 Test Treatment (T).
Participants by arm
| Arm | Count |
|---|---|
| Lasmiditan + Propranolol Single 200 mg dose of lasmiditan administered orally on Day 1, then 80mg propranolol twice per day administered orally on Days 4 through 10, and 200 mg lasmiditan coadministered orally with propranolol on Day 9. | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Day 1 Lasmiditan Reference | Physician Decision | 1 |
| Day 4 - 10 Propranolol Reference | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Lasmiditan + Propranolol |
|---|---|
| Age, Continuous | 41.1 years STANDARD_DEVIATION 12.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 24 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Mean Hourly Heart Rate | 59.7 beats per minute (BPM) STANDARD_DEVIATION 7.1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Region of Enrollment United States | 44 Participants |
| Sex: Female, Male Female | 12 Participants |
| Sex: Female, Male Male | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 43 | 0 / 42 |
| other Total, other adverse events | 9 / 44 | 1 / 43 | 7 / 42 |
| serious Total, serious adverse events | 0 / 44 | 1 / 43 | 0 / 42 |
Outcome results
Primary
Change From Baseline (Day 8) in Mean Hourly Heart Rate Following Propranolol Administered Alone and When Coadministered With Lasmiditan
Change from baseline in mean hourly heart rate recorded as beats per minute and collected by Holter ambulatory monitoring in response to propranolol administered alone and in combination with lasmiditan.
Time frame: Baseline (Day 8), Day 9
Population: All participants who had at least one dose of study drug and had baseline and post-baseline cardiovascular measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propranolol (Reference Treatment) | Change From Baseline (Day 8) in Mean Hourly Heart Rate Following Propranolol Administered Alone and When Coadministered With Lasmiditan | 59.7 beats per minute (bpm) | Standard Deviation 7.1 |
| Lasmiditan + Propranolol (Test Treatment) | Change From Baseline (Day 8) in Mean Hourly Heart Rate Following Propranolol Administered Alone and When Coadministered With Lasmiditan | 54.2 beats per minute (bpm) | Standard Deviation 5.8 |
Comparison: Mean hourly HR was evaluated in a linear mixed-effects model with a fixed effect for treatment and a random effect for subject.90% CI: [-7.27, -3.64]
Secondary
Change From Baseline (Day 8) in Diastolic Blood Pressure Following Propranolol Administered Alone and When Coadministered With Lasmiditan
Change from baseline in diastolic blood pressure was measured in supine position.
Time frame: Baseline (Day 8), Day 9
Population: All participants who had at least one dose of study drug and had evaluable baseline and post-baseline cardiovascular measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propranolol (Reference Treatment) | Change From Baseline (Day 8) in Diastolic Blood Pressure Following Propranolol Administered Alone and When Coadministered With Lasmiditan | 64.0 mmHg | Standard Deviation 6.2 |
| Lasmiditan + Propranolol (Test Treatment) | Change From Baseline (Day 8) in Diastolic Blood Pressure Following Propranolol Administered Alone and When Coadministered With Lasmiditan | 67.4 mmHg | Standard Deviation 7.8 |
Comparison: Diastolic blood pressure was evaluated in a linear mixed-effects model with a fixed effect for treatment and a random effect for subject.90% CI: [1.99, 4.95]
Secondary
Change From Baseline (Day 8) in PR Interval Following Propranolol Administered Alone and When Coadministered With Lasmiditan
Change from baseline in PR interval, the interval between the P wave and the QRS complex calculated from electrocardiogram (ECG) data.
Time frame: Baseline (Day 8), Day 9
Population: All participants who had at least one dose of study drug and had evaluable baseline and post-baseline cardiovascular measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propranolol (Reference Treatment) | Change From Baseline (Day 8) in PR Interval Following Propranolol Administered Alone and When Coadministered With Lasmiditan | 165.6 millisecond (msec) | Standard Deviation 20.5 |
| Lasmiditan + Propranolol (Test Treatment) | Change From Baseline (Day 8) in PR Interval Following Propranolol Administered Alone and When Coadministered With Lasmiditan | 161.9 millisecond (msec) | Standard Deviation 20.3 |
Comparison: PR interval was evaluated in a linear mixed-effects model with a fixed effect for treatment and a random effect for subject.90% CI: [-6.39, -0.64]
Secondary
Change From Baseline (Day 8) in Systolic Blood Pressure Following Propranolol Administered Alone and When Coadministered With Lasmiditan
Change from baseline in systolic blood pressure was measured in supine position.
Time frame: Baseline (Day 8), Day 9
Population: All participants who had at least one dose of study drug and had evaluable baseline and post-baseline cardiovascular measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Propranolol (Reference Treatment) | Change From Baseline (Day 8) in Systolic Blood Pressure Following Propranolol Administered Alone and When Coadministered With Lasmiditan | 106.9 millimeters of mercury (mmHg) | Standard Deviation 6.6 |
| Lasmiditan + Propranolol (Test Treatment) | Change From Baseline (Day 8) in Systolic Blood Pressure Following Propranolol Administered Alone and When Coadministered With Lasmiditan | 112.4 millimeters of mercury (mmHg) | Standard Deviation 10.9 |
Comparison: Systolic blood pressure was evaluated in a linear mixed-effects model with a fixed effect for treatment and a random effect for subject.90% CI: [3.57, 7.57]
Secondary
Pharmacokinetic: Area Under the Concentration Versus Time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-tlast)] of Lasmiditan Alone and When Administered With Propranolol
AUC versus time curve (AUC 0-tlast) of lasmiditan when administered alone on Day 1 and when coadministered with propranolol on Day 9.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
Population: All participants who received at least one dose of study drug and have evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Propranolol (Reference Treatment) | Pharmacokinetic: Area Under the Concentration Versus Time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-tlast)] of Lasmiditan Alone and When Administered With Propranolol | 2100 nanograms * hour/mL (ng*h/mL) | Geometric Coefficient of Variation 39 |
| Lasmiditan + Propranolol (Test Treatment) | Pharmacokinetic: Area Under the Concentration Versus Time Curve (AUC) From Time Zero to Last Measurable Concentration [AUC(0-tlast)] of Lasmiditan Alone and When Administered With Propranolol | 2160 nanograms * hour/mL (ng*h/mL) | Geometric Coefficient of Variation 30 |
Comparison: Log-transformed PK parameters were evaluated in a linear mixed-effects model with a fixed effect for treatment and a random effect for subject.90% CI: [0.967, 1.04]
Secondary
Pharmacokinetic: Area Under the Concentration Versus Time Curve (AUC) of Propranolol During One Dosing Interval Alone and When Administered With Lasmiditan
AUC versus time curve of propranolol during one dosing interval when administered alone on Day 8 and when administered with lasmiditan on Day 9.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose
Population: All participants who received at least one dose of study drug and have evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Propranolol (Reference Treatment) | Pharmacokinetic: Area Under the Concentration Versus Time Curve (AUC) of Propranolol During One Dosing Interval Alone and When Administered With Lasmiditan | 910 ng*hr/mL | Geometric Coefficient of Variation 50 |
| Lasmiditan + Propranolol (Test Treatment) | Pharmacokinetic: Area Under the Concentration Versus Time Curve (AUC) of Propranolol During One Dosing Interval Alone and When Administered With Lasmiditan | 910 ng*hr/mL | Geometric Coefficient of Variation 43 |
Comparison: Log-transformed PK parameters were evaluated in a linear mixed-effects model with a fixed effect for treatment and a random effect for subject.90% CI: [0.967, 1.03]
Secondary
Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Propranolol Alone and When Coadministered With Lasmiditan
Maximum concentration of propranolol when administered alone on Day 8 and when coadministered with lasmiditan on Day 9.
Time frame: Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 12 hours post-dose
Population: All participants who received at least one dose of study drug and have evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Propranolol (Reference Treatment) | Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Propranolol Alone and When Coadministered With Lasmiditan | 133 ng/mL | Geometric Coefficient of Variation 52 |
| Lasmiditan + Propranolol (Test Treatment) | Pharmacokinetic: Maximum Observed Drug Concentration (Cmax) of Propranolol Alone and When Coadministered With Lasmiditan | 127 ng/mL | Geometric Coefficient of Variation 43 |
Comparison: Ratio of geometric LSMeans of Cmax used a mixed-effects repeated measures model adjusted for fixed effects for treatment, time point, time point by treatment, and random effect for subjects.90% CI: [0.917, 1]
Secondary
Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Lasmiditan Alone and When Coadministered With Propranolol
Maximum concentration of lasmiditan when administered alone on Day 1 and when coadministered with propranolol on Day 9.
Time frame: Predose, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, 36 and 48 hours post-dose.
Population: All participants who received at least one dose of study drug and have evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Propranolol (Reference Treatment) | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Lasmiditan Alone and When Coadministered With Propranolol | 323 nanogram per mililiter (ng/mL) | Geometric Coefficient of Variation 43 |
| Lasmiditan + Propranolol (Test Treatment) | Pharmacokinetics (PK): Maximum Observed Drug Concentration (Cmax) of Lasmiditan Alone and When Coadministered With Propranolol | 290 nanogram per mililiter (ng/mL) | Geometric Coefficient of Variation 31 |
Comparison: Log-transformed PK parameters were evaluated in a linear mixed-effects model with a fixed effect for treatment and a random effect for subject.90% CI: [0.832, 0.939]