Migraine
Conditions
Brief summary
The reason for this study is to see if the study drug LY3451838 is safe and effective in participants who have migraine that have not responded to other preventive treatments.
Interventions
DRUGLY3451838
Administered IV
DRUGPlacebo
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Must have a diagnosis of migraine with a history of migraine headaches of at least 1 year prior, and migraine onset prior to age 50. * Have completed at least 80% of required daily diary entries during the start of the study. * Have documentation of previous failure of 2 to 4 standard-of-care migraine preventive medication categories in the past 10 years. * Women of child-bearing potential must test negative for pregnancy as indicated by a negative serum pregnancy test and negative urine pregnancy test. * Women of child-bearing potential who are abstinent or in a same sex relationship must agree to either remain abstinent or to avoid sexual relationships with males. * Women of child-bearing potential who are not abstinent, must agree to use one highly effective method of contraception, or a combination of two effective methods of contraception during the study, as well as 5 months following. * Women not of childbearing potential may participate and include those who are: A. Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy or tubal ligation) or congenital anomaly; or B. Post-menopausal - defined as either: * i. a woman at least 40 years of age with an intact uterus, not on hormone therapy, who has cessation of menses for at least 1 year without an alternative medical cause, and a follicle-stimulating hormone greater than (\>) 40 multi-international units per milliliter (mIU/mL); or * ii. a woman 55 or older not on hormone therapy, who has had at least 12 months of spontaneous amenorrhea; or * iii. a woman at least 55 years of age with a diagnosis of menopause prior to starting hormone replacement therapy
Exclusion criteria
* Are currently enrolled in any other clinical study or any other type of medical research judged not to be compatible with this study. * Have participated, within the last 30 days or 5-half-lives (whichever is longer), in a clinical study involving any investigational product. If the half-life of the investigational product is unknown, 6 months should have passed prior. * Known hypersensitivity or intolerance to monoclonal antibodies or other therapeutic proteins, or to common antihistamines, epinephrine, methyl prednisone or other systemic corticosteroids. * Are currently receiving medication or other treatment for prevention of migraine headaches. Participants must have discontinued such medications or treatments at least 2 weeks prior. Botulinum toxin A or B that has been administered in the head or neck area use must be discontinued at least 3 months prior. Nerve blocks or device use (such as transcranial magnetic stimulation or electrical nerve stimulation) in the head or neck area for migraine treatment must be discontinued at least 30 days prior. Anti-calcitonin gene-related peptide (CGRP) antibodies must be discontinued at least 5 half-lives prior. * Have previously failed more than 4 migraine preventive medication categories in the past 10 years due to inadequate efficacy (that is, maximum tolerated dose for at least 2 months) and/or safety / tolerability reasons. * History of cluster headache or migraine subtypes including hemiplegic (sporadic or familial) migraine, ophthalmoplegic migraine, retinal migraine, typical aura without headache, complications of migraine and migraine with brainstem aura (basilar-type migraine). * In the 3 months prior, have other types of headache besides migraine, tension type headache, or medication overuse headache (MOH). (In other words, participants can have migraine, tension type headache, or MOH in the 3 months prior, but they cannot have other types of headache in that time). * History of head or neck injury within last 6 months. * History of traumatic cervical or head injury associated with significant change in the quality or frequency of headaches. * Have reading of electrocardiogram (ECG) showing abnormalities considered incompatible with the study. * Any liver tests outside the normal range. * Evidence of significant active or unstable psychiatric disease. * Women who are pregnant or nursing. * Participants who have used opioids or barbiturate-containing analgesic \>4 days per month for the treatment of pain in each of the past 3 months. * History of drug or alcohol abuse/dependence within 1 year. * Have a positive urine drug screen for illicit drugs. * Are unwilling or unable to comply with the use of data collection devices.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Number of Monthly Migraine Headache Days During 1-Month | Baseline, Month 1 | Migraine Headache Day is a calendar day on which a migraine or probable migraine headache occurs. Per International Headache Society \[IHS\] International Classification of Headache Disorders version 3 \[ICHD-3\], migraine is defined as a headache, with or without aura, of \>=30 minutes duration with both of the following required features (A) At least 2 of the following headache characteristics: Unilateral location; Pulsatile quality; Moderate or severe pain intensity; Aggravation by or causing avoidance of routine physical activity (B) During headache at least 1 of the following: Nausea and/or vomiting; Photophobia and phonophobia. Least square mean was assessed using Bayesian Mixed Model Analysis with baseline number of monthly migraine headache days as a covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥50% Reduction From Baseline in Monthly Migraine Headache Days | Month 1 | Percentage of Participants with ≥50% Reduction from Baseline in Monthly Migraine Headache Days are reported. |
| Number of Participants With at Least One Treatment-emergent Adverse Events (TEAEs) | Baseline up to 5 Months | Number of Participants with at least one TEAEs are reported. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. |
| Change From Baseline in the Number of Monthly Headache Days During 3-Month | Baseline, Month 3 | Migraine Headache Day is a calendar day on which a migraine or probable migraine headache occurs. Per International Headache Society \[IHS\] International Classification of Headache Disorders version 3 \[ICHD-3\], migraine is defined as a headache, with or without aura, of \>=30 minutes duration with both of the following required features (A) At least 2 of the following headache characteristics: Unilateral location; Pulsatile quality; Moderate or severe pain intensity; Aggravation by or causing avoidance of routine physical activity (B) During headache at least 1 of the following: Nausea and/or vomiting; Photophobia and phonophobia. Least square mean was assessed using Bayesian Mixed Model Analysis with baseline number of monthly migraine headache days as a covariate. |
| Pharmacokinetics (PK): Area Under the Serum Concentration-time Curve From Time 0 to the Last Measurable Serum Concentration (AUC 0-t) of LY3451838 | Pre-infusion, end of infusion, 3hours(h), 365h, 730h, 1095h, 1460h, 1825h, 2190h, 2920h, 3650h post-infusion | PK: AUC(0-t) of LY3451838 |
| PK: Maximum Observed Serum Concentration (Cmax) of LY3451838 | Pre-infusion, end of infusion, 3hours(h), 365h, 730h, 1095h, 1460h, 1825h, 2190h, 2920h, 3650h post-infusion | PK: Cmax of LY3451838 |
| Number of Participants With at Least One Serious Adverse Events (SAEs) | Baseline up to 5 Months | Number of Participants with at least one SAEs are reported. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 1500 mg LY3451838 Participants received a single IV dose of 1500 mg LY3451838. | 19 |
| Placebo Participants received a single IV dose of placebo. | 19 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 |
Baseline characteristics
| Characteristic | 1500 mg LY3451838 | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 48.6 years STANDARD_DEVIATION 10.84 | 48.0 years STANDARD_DEVIATION 12.59 | 48.3 years STANDARD_DEVIATION 11.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 17 Participants | 19 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Monthly Number of Migraine Headache Days | 14.0 migraine days per month STANDARD_DEVIATION 6.21 | 13.0 migraine days per month STANDARD_DEVIATION 7.71 | 13.5 migraine days per month STANDARD_DEVIATION 6.92 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 16 Participants | 35 Participants |
| Region of Enrollment United States | 19 Participants | 19 Participants | 38 Participants |
| Sex: Female, Male Female | 18 Participants | 18 Participants | 36 Participants |
| Sex: Female, Male Male | 1 Participants | 1 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 14 / 19 | 15 / 19 |
| serious Total, serious adverse events | 1 / 19 | 0 / 19 |
Outcome results
Primary
Change From Baseline in the Number of Monthly Migraine Headache Days During 1-Month
Migraine Headache Day is a calendar day on which a migraine or probable migraine headache occurs. Per International Headache Society \[IHS\] International Classification of Headache Disorders version 3 \[ICHD-3\], migraine is defined as a headache, with or without aura, of \>=30 minutes duration with both of the following required features (A) At least 2 of the following headache characteristics: Unilateral location; Pulsatile quality; Moderate or severe pain intensity; Aggravation by or causing avoidance of routine physical activity (B) During headache at least 1 of the following: Nausea and/or vomiting; Photophobia and phonophobia. Least square mean was assessed using Bayesian Mixed Model Analysis with baseline number of monthly migraine headache days as a covariate.
Time frame: Baseline, Month 1
Population: All randomized participants who received at least one dose of study drug and had baseline and at least one post baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 1500 mg LY3451838 | Change From Baseline in the Number of Monthly Migraine Headache Days During 1-Month | -3.8 migraine days per month |
| Placebo | Change From Baseline in the Number of Monthly Migraine Headache Days During 1-Month | -2.7 migraine days per month |
95% CI: [-3.6, 1.2]Bayesian Mixed Model Analysis
Secondary
Change From Baseline in the Number of Monthly Headache Days During 3-Month
Migraine Headache Day is a calendar day on which a migraine or probable migraine headache occurs. Per International Headache Society \[IHS\] International Classification of Headache Disorders version 3 \[ICHD-3\], migraine is defined as a headache, with or without aura, of \>=30 minutes duration with both of the following required features (A) At least 2 of the following headache characteristics: Unilateral location; Pulsatile quality; Moderate or severe pain intensity; Aggravation by or causing avoidance of routine physical activity (B) During headache at least 1 of the following: Nausea and/or vomiting; Photophobia and phonophobia. Least square mean was assessed using Bayesian Mixed Model Analysis with baseline number of monthly migraine headache days as a covariate.
Time frame: Baseline, Month 3
Population: All randomized participants who received at least one dose of study drug and had baseline and at least one post baseline value.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| 1500 mg LY3451838 | Change From Baseline in the Number of Monthly Headache Days During 3-Month | -3.6 migraine days per month |
| Placebo | Change From Baseline in the Number of Monthly Headache Days During 3-Month | -2.2 migraine days per month |
95% CI: [-4.2, 1]Bayesian Mixed Model Analysis
Secondary
Number of Participants With at Least One Serious Adverse Events (SAEs)
Number of Participants with at least one SAEs are reported. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
Time frame: Baseline up to 5 Months
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1500 mg LY3451838 | Number of Participants With at Least One Serious Adverse Events (SAEs) | 1 Participants |
| Placebo | Number of Participants With at Least One Serious Adverse Events (SAEs) | 0 Participants |
Secondary
Number of Participants With at Least One Treatment-emergent Adverse Events (TEAEs)
Number of Participants with at least one TEAEs are reported. A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section.
Time frame: Baseline up to 5 Months
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 1500 mg LY3451838 | Number of Participants With at Least One Treatment-emergent Adverse Events (TEAEs) | 11 Participants |
| Placebo | Number of Participants With at Least One Treatment-emergent Adverse Events (TEAEs) | 13 Participants |
Secondary
Percentage of Participants With ≥50% Reduction From Baseline in Monthly Migraine Headache Days
Percentage of Participants with ≥50% Reduction from Baseline in Monthly Migraine Headache Days are reported.
Time frame: Month 1
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 1500 mg LY3451838 | Percentage of Participants With ≥50% Reduction From Baseline in Monthly Migraine Headache Days | 21.1 Percentage of participants |
| Placebo | Percentage of Participants With ≥50% Reduction From Baseline in Monthly Migraine Headache Days | 26.3 Percentage of participants |
Secondary
Pharmacokinetics (PK): Area Under the Serum Concentration-time Curve From Time 0 to the Last Measurable Serum Concentration (AUC 0-t) of LY3451838
PK: AUC(0-t) of LY3451838
Time frame: Pre-infusion, end of infusion, 3hours(h), 365h, 730h, 1095h, 1460h, 1825h, 2190h, 2920h, 3650h post-infusion
Population: All randomized participants who received at least one dose of LY3451838 and had evaluable serum concentrations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1500 mg LY3451838 | Pharmacokinetics (PK): Area Under the Serum Concentration-time Curve From Time 0 to the Last Measurable Serum Concentration (AUC 0-t) of LY3451838 | 176000 microgram*hour per milliliter (μg*h/mL) | Geometric Coefficient of Variation 26.5 |
Secondary
PK: Maximum Observed Serum Concentration (Cmax) of LY3451838
PK: Cmax of LY3451838
Time frame: Pre-infusion, end of infusion, 3hours(h), 365h, 730h, 1095h, 1460h, 1825h, 2190h, 2920h, 3650h post-infusion
Population: All randomized participants who received at least one dose of LY3451838 and had evaluable serum concentrations.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 1500 mg LY3451838 | PK: Maximum Observed Serum Concentration (Cmax) of LY3451838 | 613 microgram per milliliter (µg/ml) | Geometric Coefficient of Variation 32.6 |