Migraine
Conditions
Keywords
Migraine, Headache, Prevention, Prophylaxis
Brief summary
The primary objective of the study was to evaluate the effect of erenumab compared to placebo on the change from baseline in monthly migraine days.
Detailed description
This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. The trial consisted of four phases: screening (≤ 3 weeks of initial screening and a 4-week baseline phase); the double-blind treatment phase (24 weeks) in which participants received placebo or erenumab 70 mg or 140 mg daily; the active-treatment phase, in which participants underwent repeat randomization and were assigned to receive 70 mg or 140 mg of erenumab (28 weeks); and a safety follow-up phase (12 weeks).
Interventions
DRUGErenumab
Administered by subcutaneous injection once a month
DRUGPlacebo
Administered by subcutaneous injection once a month
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* History of migraine (with or without aura) for ≥ 12 months prior to screening according to the International Headache Society (IHS) International Classification of Headache Disorders (ICHD-3) classification * Migraine frequency: ≥ 4 and \< 15 migraine days per month on average across the 3 months prior to screening and during baseline * Headache frequency: \< 15 headache days per month on average across the 3 months prior to screening and baseline * Demonstrated at least 80% compliance with the eDiary.
Exclusion criteria
* Older than 50 years of age at migraine onset * History of cluster headache or hemiplegic migraine headache * Unable to differentiate migraine from other headache * No therapeutic response with \> 2 medication categories for prophylactic treatment of migraine after an adequate therapeutic trial * Used a prohibited medication, device, or procedure within 2 months prior to the start of the baseline phase or during the baseline phase * Concomitant use of 2 or more medications with possible migraine prophylactic effects within 2 months prior to the start of the baseline phase or during the baseline phase. If only 1 prophylactic medication is used, the dose must be stable within 2 months prior to the start of the baseline phase and throughout the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Monthly Migraine Days to the Last 3 Months of the Double-blind Treatment Period | 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase | A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine with or without aura. The change from baseline in monthly migraine days was calculated as the average number of migraine days per month during the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase - the number of migraine days during the 4-week baseline phase. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days in the Last 3 Months of the Double-blind Treatment Phase | 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase | A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine without aura or a migraine with aura. At least a 50% reduction from baseline in monthly migraine days was determined if the change in monthly migraine days from the 4-week baseline phase to the last 3 months (mean of months 4, 5 and 6) of the 24-week double-blind treatment phase \* 100 / baseline monthly migraine days was less than or equal to -50%. |
| Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days to the Last 3 Months of the Double-blind Treatment Period | 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase | Monthly acute migraine-specific medication treatment days is the number of days on which migraine specific medications were used between monthly doses of study drug. Migraine-specific medications includes two categories of medications: triptan-based migraine medications and ergotamine-based migraine medications. The change from baseline in monthly acute migraine-specific treatment days was calculated as the average number of migraine-specific treatment days per month during the last 3 months of the 24-week double-blind treatment phase - the number of migraine-specific treatment days during the 4-week baseline phase. |
| Change From Baseline in Mean Monthly Average Physical Impairment Domain Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase | 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase | The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from Without any difficulty (1) to Unable to do (5) and frequency items ranging from None of the time (1) to All of the time (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Change from baseline was calculated as (mean monthly average physical impairment scores as measured by the MPFID over the last 3 months of the double-blind treatment period) - (baseline monthly average physical impairment scores as measured by the MPFID). |
| Change From Baseline in Mean Monthly Average Impact on Everyday Activities Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase | 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase | The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from Without any difficulty (1) to Unable to do (5) and frequency items ranging from None of the time (1) to All of the time (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Change from baseline was calculated as (mean monthly impact on everyday activities scores as measured by the MPFID over the last 3 months of the double-blind treatment period) - (baseline monthly impact on everyday activities scores as measured by the MPFID). |
Countries
Austria, Belgium, Canada, Czechia, Finland, Germany, Netherlands, Poland, Slovakia, Sweden, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 121 centers in Canada, Austria, Belgium, Czech Republic, Finland, Germany, Poland, Slovakia, Sweden, the United Kingdom, Turkey, the Netherlands and USA. The study consisted of a 24-week double-blind treatment phase and a 28-week active treatment phase.
Pre-assignment details
At the end of the baseline phase, participants were randomized 1:1:1 to receive placebo, erenumab 70 mg, or erenumab 140 mg monthly for 24 weeks. Randomization was stratified by region and treatment status with migraine prophylactic medication. Participants were re-randomized at week 24 to erenumab 70 mg or 140 mg for 28 weeks.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo once a month (QM) by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase. | 319 |
| Erenumab 70 mg QM Participants received erenumab 70 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase. | 317 |
| Erenumab 140 mg QM Participants received erenumab 140 mg QM by subcutaneous injection on day 1 and weeks 4, 8, 12, 16, and 20 in the 24-week double-blind treatment phase. | 319 |
| Total | 955 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Active Treatment Phase (Weeks 24 - 52) | Death | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Active Treatment Phase (Weeks 24 - 52) | Lost to Follow-up | 0 | 0 | 0 | 3 | 2 | 4 | 1 | 3 | 4 |
| Active Treatment Phase (Weeks 24 - 52) | Protocol Specified Criteria | 0 | 0 | 0 | 1 | 4 | 0 | 0 | 0 | 5 |
| Active Treatment Phase (Weeks 24 - 52) | Withdrawal by Subject | 0 | 0 | 0 | 10 | 11 | 9 | 8 | 8 | 9 |
| Double-blind Treatment Phase (24 Weeks) | Decision by Sponsor | 1 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double-blind Treatment Phase (24 Weeks) | Lost to Follow-up | 9 | 4 | 5 | 0 | 0 | 0 | 0 | 0 | 0 |
| Double-blind Treatment Phase (24 Weeks) | Withdrawal by Subject | 27 | 28 | 21 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Erenumab 140 mg QM | Placebo | Erenumab 70 mg QM |
|---|---|---|---|---|
| Age, Continuous | 40.9 years STANDARD_DEVIATION 11.2 | 40.4 years STANDARD_DEVIATION 11.1 | 41.3 years STANDARD_DEVIATION 11.2 | 41.1 years STANDARD_DEVIATION 11.3 |
| Age, Customized 18 - 64 years | 951 Participants | 317 Participants | 317 Participants | 317 Participants |
| Age, Customized 65 - 74 years | 4 Participants | 2 Participants | 2 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 80 Participants | 22 Participants | 32 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 875 Participants | 297 Participants | 287 Participants | 291 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Monthly Migraine Days | 8.29 migraine days/month STANDARD_DEVIATION 2.48 | 8.34 migraine days/month STANDARD_DEVIATION 2.48 | 8.23 migraine days/month STANDARD_DEVIATION 2.51 | 8.29 migraine days/month STANDARD_DEVIATION 2.47 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 17 Participants | 4 Participants | 8 Participants | 5 Participants |
| Race/Ethnicity, Customized Black or African American | 66 Participants | 18 Participants | 24 Participants | 24 Participants |
| Race/Ethnicity, Customized Multiple | 3 Participants | 0 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 14 Participants | 2 Participants | 6 Participants | 6 Participants |
| Race/Ethnicity, Customized White | 851 Participants | 293 Participants | 277 Participants | 281 Participants |
| Region North America | 477 Participants | 160 Participants | 158 Participants | 159 Participants |
| Region Other | 478 Participants | 159 Participants | 161 Participants | 158 Participants |
| Sex: Female, Male Female | 814 Participants | 272 Participants | 274 Participants | 268 Participants |
| Sex: Female, Male Male | 141 Participants | 47 Participants | 45 Participants | 49 Participants |
| Treatment Status with Migraine Prophylactic Medication Current migraine prophylactic treatment | 21 Participants | 7 Participants | 8 Participants | 6 Participants |
| Treatment Status with Migraine Prophylactic Medication No prior / current migraine prophylactic treatment | 576 Participants | 192 Participants | 192 Participants | 192 Participants |
| Treatment Status with Migraine Prophylactic Medication Prior migraine prophylactic treatment only | 358 Participants | 120 Participants | 119 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 53 / 319 | 53 / 314 | 54 / 319 | 83 / 421 | 63 / 424 |
| serious Total, serious adverse events | 7 / 319 | 8 / 314 | 8 / 319 | 14 / 421 | 14 / 424 |
Outcome results
Primary
Change From Baseline in Mean Monthly Migraine Days to the Last 3 Months of the Double-blind Treatment Period
A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine with or without aura. The change from baseline in monthly migraine days was calculated as the average number of migraine days per month during the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase - the number of migraine days during the 4-week baseline phase.
Time frame: 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
Population: The analysis was conducted in the efficacy analysis set which includes participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in monthly migraine days in the double-blind treatment phase.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Monthly Migraine Days to the Last 3 Months of the Double-blind Treatment Period | -1.83 migraine days / month | Standard Error 0.18 |
| Erenumab 70 mg QM | Change From Baseline in Mean Monthly Migraine Days to the Last 3 Months of the Double-blind Treatment Period | -3.23 migraine days / month | Standard Error 0.18 |
| Erenumab 140 mg QM | Change From Baseline in Mean Monthly Migraine Days to the Last 3 Months of the Double-blind Treatment Period | -3.67 migraine days / month | Standard Error 0.18 |
Comparison: The primary endpoint was analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.p-value: <0.00195% CI: [-1.88, -0.92]Generalized Linear Mixed Model
Comparison: The primary endpoint was analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.p-value: <0.00195% CI: [-2.33, -1.37]Generalized Linear Mixed Model
Secondary
Change From Baseline in Mean Monthly Average Impact on Everyday Activities Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase
The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from Without any difficulty (1) to Unable to do (5) and frequency items ranging from None of the time (1) to All of the time (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Change from baseline was calculated as (mean monthly impact on everyday activities scores as measured by the MPFID over the last 3 months of the double-blind treatment period) - (baseline monthly impact on everyday activities scores as measured by the MPFID).
Time frame: 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
Population: The analysis was conducted in the efficacy analysis set including participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in MPFID average impact on everyday activities domain score in the double-blind treatment phase.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Monthly Average Impact on Everyday Activities Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase | -3.30 units on a scale | Standard Error 0.39 |
| Erenumab 70 mg QM | Change From Baseline in Mean Monthly Average Impact on Everyday Activities Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase | -5.52 units on a scale | Standard Error 0.39 |
| Erenumab 140 mg QM | Change From Baseline in Mean Monthly Average Impact on Everyday Activities Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase | -5.86 units on a scale | Standard Error 0.39 |
Comparison: Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.p-value: <0.00195% CI: [-3.62, -1.51]Generalized Linear Mixed Model
Comparison: Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.p-value: <0.00195% CI: [-3.28, -1.16]Generalized Linear Mixed Model
Secondary
Change From Baseline in Mean Monthly Average Physical Impairment Domain Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase
The Migraine Physical Function Impact Diary (MPFID) is a self-administered 13-item instrument measuring physical functioning. It has two domains, Impact on Everyday Activities (7 items) and Physical Impairment (5 items), and one stand-alone global question. Participants completed the MPFID daily in an electronic diary based on the past 24 hours. Participants responded to each item on a 5-point scale, with difficulty items ranging from Without any difficulty (1) to Unable to do (5) and frequency items ranging from None of the time (1) to All of the time (5). For each domain, the scores were calculated as the sum of the responses and rescaled to 0 - 100, with higher scores representing greater impact of migraine. Change from baseline was calculated as (mean monthly average physical impairment scores as measured by the MPFID over the last 3 months of the double-blind treatment period) - (baseline monthly average physical impairment scores as measured by the MPFID).
Time frame: 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
Population: The analysis was conducted in the efficacy analysis set including participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in MPFID average physical impairment domain score in the double-blind treatment phase.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Mean Monthly Average Physical Impairment Domain Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase | -2.38 units on a scale | Standard Error 0.4 |
| Erenumab 70 mg QM | Change From Baseline in Mean Monthly Average Physical Impairment Domain Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase | -4.24 units on a scale | Standard Error 0.4 |
| Erenumab 140 mg QM | Change From Baseline in Mean Monthly Average Physical Impairment Domain Score Measured by MPFID in the Last 3 Months of the Double-blind Treatment Phase | -4.81 units on a scale | Standard Error 0.4 |
Comparison: Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.p-value: <0.00195% CI: [-3.51, -1.35]Generalized Linear Mixed Model
Comparison: Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.p-value: <0.00195% CI: [-2.95, -0.77]Generalized Linear Mixed Model
Secondary
Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days to the Last 3 Months of the Double-blind Treatment Period
Monthly acute migraine-specific medication treatment days is the number of days on which migraine specific medications were used between monthly doses of study drug. Migraine-specific medications includes two categories of medications: triptan-based migraine medications and ergotamine-based migraine medications. The change from baseline in monthly acute migraine-specific treatment days was calculated as the average number of migraine-specific treatment days per month during the last 3 months of the 24-week double-blind treatment phase - the number of migraine-specific treatment days during the 4-week baseline phase.
Time frame: 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
Population: The analysis was conducted in the efficacy analysis set which includes participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in monthly acute migraine-specific treatment days in the double-blind treatment phase.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days to the Last 3 Months of the Double-blind Treatment Period | -0.20 Acute migraine-specific med days/mo | Standard Error 0.11 |
| Erenumab 70 mg QM | Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days to the Last 3 Months of the Double-blind Treatment Period | -1.13 Acute migraine-specific med days/mo | Standard Error 0.11 |
| Erenumab 140 mg QM | Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days to the Last 3 Months of the Double-blind Treatment Period | -1.61 Acute migraine-specific med days/mo | Standard Error 0.11 |
Comparison: Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, stratification factors (region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.p-value: <0.00195% CI: [-1.23, -0.64]Generalized Linear Mixed Model
Comparison: Analyzed using a generalized linear mixed model which includes treatment, visit, treatment by visit interaction, (stratification factors region and prior/current treatment with migraine prophylactic medication), and baseline value as covariates.p-value: <0.00195% CI: [-1.71, -1.12]Generalized Linear Mixed Model
Secondary
Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days in the Last 3 Months of the Double-blind Treatment Phase
A migraine day was any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). A qualified migraine headache was defined either as a migraine without aura or a migraine with aura. At least a 50% reduction from baseline in monthly migraine days was determined if the change in monthly migraine days from the 4-week baseline phase to the last 3 months (mean of months 4, 5 and 6) of the 24-week double-blind treatment phase \* 100 / baseline monthly migraine days was less than or equal to -50%.
Time frame: 4-week baseline phase and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment phase
Population: The analysis was conducted in the efficacy analysis set which includes participants who received at least 1 dose of study drug and had at least 1 change from baseline measurement in monthly migraine days in the double-blind treatment phase. Participants with missing data at months 4, 5, and 6 were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days in the Last 3 Months of the Double-blind Treatment Phase | 26.6 percentage of participants |
| Erenumab 70 mg QM | Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days in the Last 3 Months of the Double-blind Treatment Phase | 43.3 percentage of participants |
| Erenumab 140 mg QM | Percentage of Participants With at Least a 50% Reduction From Baseline in Monthly Migraine Days in the Last 3 Months of the Double-blind Treatment Phase | 50.0 percentage of participants |
Comparison: Analyzed using a Cochran-Mantel-Haenszel test, stratified by the randomization stratification factors (region and prior/current treatment with migraine prophylactic medication).p-value: <0.00195% CI: [1.52, 2.98]Cochran-Mantel-Haenszel
Comparison: Analyzed using a Cochran-Mantel-Haenszel test, stratified by the randomization stratification factors (region and prior/current treatment with migraine prophylactic medication).p-value: <0.00195% CI: [2.01, 3.94]Cochran-Mantel-Haenszel