Treatment for Prevention of Chronic Migraine
Conditions
Keywords
Chronic Migraine
Brief summary
To evaluate the effect of erenumab compared to placebo on the change from baseline in the number of monthly migraine days in adults with chronic migraine.
Detailed description
This study consisted of the following phases: screening, 4-week baseline phase, 12-week double-blind treatment, and 12-week follow-up. Participants may have elected to participate in the optional pharmacokinetic substudy and the optional, novel patient-reported outcome (PRO) assessment substudy. Participants who completed the 12-week double-blind treatment phase of Study 20120295 were eligible to enroll in an open-label extension study (Study 20130255; NCT02174861).
Interventions
BIOLOGICALErenumab
Administered once a month subcutaneously by authorized investigational site study staff.
DRUGPlacebo
Administered once a month subcutaneously by authorized investigational site study staff.
Sponsors
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* History of at least 5 attacks of migraine without aura and/or migraine with visual sensory, speech and/or language, retinal or brainstem aura. * History of ≥ 15 headache days per month of which ≥ 8 headache days were assessed by the subject as migraine day. * ≥ 4 distinct headache episodes, each lasting ≥ 4 hours OR if shorter, associated with use of a triptan or ergot-derivative on the same calendar day based on the eDiary calculations. * Demonstrated at least 80% compliance with the eDiary.
Exclusion criteria
* History of cluster headache or hemiplegic migraine headache * Unable to differentiate migraine from other headaches * Failed \> 3 medication categories due to lack of efficacy for prophylactic treatment of migraine . * Received botulinum toxinin head or neck region within 4 months prior to screening. * Used a prohibited migraine prophylactic medication, device or procedure within 2 months prior to the start of the baseline phase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Monthly Migraine Days | 4-week baseline phase and the last 4 weeks of the 12-week 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 number of migraine days during the last 4 weeks of the 12-week 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 in Monthly Migraine Days From Baseline | 4-week baseline phase and the last 4 weeks of the 12-week 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. Monthly migraine days were calculated as the number of migraine days in the 4-week baseline phase and during the last 4 weeks of treatment. 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 4 weeks of the 12-week 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 | 4-week baseline phase and the last 4 weeks of the 12-week 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. |
| Change From Baseline in Cumulative Monthly Headache Hours | 4-week baseline phase and the last 4 weeks of the 12-week treatment phase | The cumulative duration of any qualified headache between monthly doses of study drug regardless of acute treatment use. A qualified headache was defined as follows: * a qualified migraine headache (including an aura-only event that is treated with acute migraine-specific medication), or * a qualified non-migraine headache, which is a headache that lasted continuously for ≥ 4 hours and was not a qualified migraine headache, or * a headache of any duration for which acute headache treatment was administered. |
| Number of Participants With Adverse Events | From the first dose of study drug up to 16 weeks after the last dose (24 weeks) | Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4, where: Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; Grade 4 = Life-threatening consequences; urgent intervention indicated Grade 5 = Death related to AE. |
| Number of Participants Who Developed Antibodies to Erenumab | Baseline and weeks 2, 4, 8, 12 and 24 | Blood samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect anti-drug antibodies (ADA) against erenumab. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based bioassay to determine neutralizing activity against erenumab (Neutralizing Antibody Assay). Developing antibody incidence indicates participants with a negative or no result at baseline and a positive result at any time post-baseline. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies. |
Countries
Canada, Czechia, Denmark, Finland, Germany, Norway, Poland, Sweden, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 69 centers in Canada, Czech Republic, Denmark, Germany, Finland, Norway, Poland, Sweden, United Kingdom, and the United States of America (USA). The first participant was enrolled on 05 March 2014 and the last participant enrolled on 05 November 2015.
Pre-assignment details
Participants were randomized in a 3:2:2 ratio to receive placebo, erenumab 70 mg, or erenumab 140 mg. Randomization was stratified by region (North America vs Other) and medication overuse status at baseline (Yes vs No).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received placebo on day 1 and at weeks 4 and 8 by subcutaneous injection. | 286 |
| Erenumab 70 mg Participants received 70 mg erenumab on day 1 and at weeks 4 and 8 by subcutaneous injection. | 191 |
| Erenumab 140 mg Participants received 140 mg erenumab on day 1 and at weeks 4 and 8 by subcutaneous injection. | 190 |
| Total | 667 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Decision by Sponsor | 5 | 4 | 2 |
| Overall Study | Lost to Follow-up | 7 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 9 | 1 | 4 |
Baseline characteristics
| Characteristic | Placebo | Erenumab 70 mg | Erenumab 140 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 42.1 years STANDARD_DEVIATION 11.3 | 41.4 years STANDARD_DEVIATION 11.3 | 42.9 years STANDARD_DEVIATION 11.1 | 42.1 years STANDARD_DEVIATION 11.3 |
| Age, Customized 18 to 64 years | 285 Participants | 191 Participants | 190 Participants | 666 Participants |
| Age, Customized 65 to 74 years | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Disease Duration of Migraine With or Without Aura | 22.21 years STANDARD_DEVIATION 12.63 | 20.71 years STANDARD_DEVIATION 12.83 | 21.92 years STANDARD_DEVIATION 11.8 | 21.70 years STANDARD_DEVIATION 12.46 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 7 Participants | 10 Participants | 26 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 277 Participants | 184 Participants | 180 Participants | 641 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Medication Overuse Status No | 169 Participants | 112 Participants | 112 Participants | 393 Participants |
| Medication Overuse Status Yes | 117 Participants | 79 Participants | 78 Participants | 274 Participants |
| Monthly Migraine Days | 18.22 days STANDARD_DEVIATION 4.73 | 17.85 days STANDARD_DEVIATION 4.39 | 17.78 days STANDARD_DEVIATION 4.72 | 17.99 days STANDARD_DEVIATION 4.63 |
| Prior Migraine Prophylactic Medication No | 68 Participants | 53 Participants | 54 Participants | 175 Participants |
| Prior Migraine Prophylactic Medication Yes | 218 Participants | 138 Participants | 136 Participants | 492 Participants |
| Prior Migraine Prophylactic Treatment Failure No | 86 Participants | 64 Participants | 64 Participants | 214 Participants |
| Prior Migraine Prophylactic Treatment Failure Yes | 200 Participants | 127 Participants | 126 Participants | 453 Participants |
| Race/Ethnicity, Customized Asian | 4 Participants | 4 Participants | 0 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 11 Participants | 10 Participants | 6 Participants | 27 Participants |
| Race/Ethnicity, Customized Other | 3 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized White | 268 Participants | 176 Participants | 184 Participants | 628 Participants |
| Region North America | 135 Participants | 91 Participants | 89 Participants | 315 Participants |
| Region Other | 151 Participants | 100 Participants | 101 Participants | 352 Participants |
| Sex: Female, Male Female | 226 Participants | 166 Participants | 160 Participants | 552 Participants |
| Sex: Female, Male Male | 60 Participants | 25 Participants | 30 Participants | 115 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 16 / 282 | 6 / 190 | 3 / 188 |
| serious Total, serious adverse events | 7 / 282 | 6 / 190 | 2 / 188 |
Outcome results
Primary
Change From Baseline in Monthly Migraine Days
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 number of migraine days during the last 4 weeks of the 12-week treatment phase - the number of migraine days during the 4-week baseline phase.
Time frame: 4-week baseline phase and the last 4 weeks of the 12-week treatment phase
Population: The efficacy analysis set included participants who received at least 1 dose of study drug and completed at least 1 post-baseline monthly eDiary measurement. The number of participants analyzed includes those with observed data at week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Monthly Migraine Days | -4.18 migraine days / month |
| Erenumab 70 mg | Change From Baseline in Monthly Migraine Days | -6.64 migraine days / month |
| Erenumab 140 mg | Change From Baseline in Monthly Migraine Days | -6.63 migraine days / month |
Comparison: The primary endpoint was analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and medication overuse status), scheduled visit, and the interaction of treatment group with scheduled visit.p-value: <0.00195% CI: [-3.52, -1.39]Generalized linear mixed model
Comparison: The primary endpoint was analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and medication overuse status), scheduled visit, and the interaction of treatment group with scheduled visit.p-value: <0.00195% CI: [-3.51, -1.38]Generalized linear mixed model
Secondary
Change From Baseline in Cumulative Monthly Headache Hours
The cumulative duration of any qualified headache between monthly doses of study drug regardless of acute treatment use. A qualified headache was defined as follows: * a qualified migraine headache (including an aura-only event that is treated with acute migraine-specific medication), or * a qualified non-migraine headache, which is a headache that lasted continuously for ≥ 4 hours and was not a qualified migraine headache, or * a headache of any duration for which acute headache treatment was administered.
Time frame: 4-week baseline phase and the last 4 weeks of the 12-week treatment phase
Population: The efficacy analysis set included participants who received at least 1 dose of study drug and completed at least 1 post-baseline monthly eDiary measurement.~The number of participants analyzed includes those with observed data at week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Cumulative Monthly Headache Hours | -55.22 hours / month |
| Erenumab 70 mg | Change From Baseline in Cumulative Monthly Headache Hours | -64.76 hours / month |
| Erenumab 140 mg | Change From Baseline in Cumulative Monthly Headache Hours | -74.53 hours / month |
Comparison: Analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and medication overuse status), scheduled visit, and the interaction of treatment group with scheduled visit.p-value: 0.2895% CI: [-26.98, 7.9]Generalized linear mixed model
Comparison: Analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and medication overuse status), scheduled visit, and the interaction of treatment group with scheduled visit.p-value: 0.0395% CI: [-36.71, -1.92]Generalized linear mixed model
Secondary
Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days
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.
Time frame: 4-week baseline phase and the last 4 weeks of the 12-week treatment phase
Population: The efficacy analysis set included participants who received at least 1 dose of study drug and completed at least 1 post-baseline monthly eDiary measurement.~The number of participants analyzed includes those with observed data at week 12.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo | Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days | -1.58 acute migraine treatment days / month |
| Erenumab 70 mg | Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days | -3.45 acute migraine treatment days / month |
| Erenumab 140 mg | Change From Baseline in Monthly Acute Migraine-specific Medication Treatment Days | -4.13 acute migraine treatment days / month |
Comparison: Analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and medication overuse status), scheduled visit, and the interaction of treatment group with scheduled visit.p-value: <0.00195% CI: [-2.6, -1.13]Generalized linear mixed model
Comparison: Analyzed using a linear mixed effects model including treatment group, baseline value, stratification factors (region and medication overuse status), scheduled visit, and the interaction of treatment group with scheduled visit.p-value: <0.00195% CI: [-3.28, -1.82]Generalized linear mixed model
Secondary
Number of Participants Who Developed Antibodies to Erenumab
Blood samples were first tested in an electrochemiluminescence (ECL)-based bridging immunoassay to detect anti-drug antibodies (ADA) against erenumab. Samples confirmed to be positive for binding antibodies were subsequently tested in a cell-based bioassay to determine neutralizing activity against erenumab (Neutralizing Antibody Assay). Developing antibody incidence indicates participants with a negative or no result at baseline and a positive result at any time post-baseline. If a sample was positive for binding antibodies and demonstrated neutralizing activity at the same time point, the sample was defined as positive for neutralizing antibodies.
Time frame: Baseline and weeks 2, 4, 8, 12 and 24
Population: Randomized participants who received at least one dose of study drug and with available post-baseline antibody data. This endpoint was analyzed in the erenumab treatment groups only.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Erenumab 70 mg | Number of Participants Who Developed Antibodies to Erenumab | Binding antibody positive | 11 Participants |
| Erenumab 70 mg | Number of Participants Who Developed Antibodies to Erenumab | Neutralizing antibody positive | 0 Participants |
| Erenumab 140 mg | Number of Participants Who Developed Antibodies to Erenumab | Binding antibody positive | 3 Participants |
| Erenumab 140 mg | Number of Participants Who Developed Antibodies to Erenumab | Neutralizing antibody positive | 0 Participants |
Secondary
Number of Participants With Adverse Events
Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4, where: Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL); Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self care ADL; Grade 4 = Life-threatening consequences; urgent intervention indicated Grade 5 = Death related to AE.
Time frame: From the first dose of study drug up to 16 weeks after the last dose (24 weeks)
Population: All randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Placebo | Number of Participants With Adverse Events | AEs grade ≥ 2 | 65 Participants |
| Placebo | Number of Participants With Adverse Events | Serious adverse events | 7 Participants |
| Placebo | Number of Participants With Adverse Events | AEs grade ≥ 4 | 0 Participants |
| Placebo | Number of Participants With Adverse Events | Any adverse event | 110 Participants |
| Placebo | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Placebo | Number of Participants With Adverse Events | AEs leading to discontinuation of study drug | 2 Participants |
| Placebo | Number of Participants With Adverse Events | AEs grade ≥ 3 | 13 Participants |
| Erenumab 70 mg | Number of Participants With Adverse Events | AEs grade ≥ 4 | 1 Participants |
| Erenumab 70 mg | Number of Participants With Adverse Events | Any adverse event | 83 Participants |
| Erenumab 70 mg | Number of Participants With Adverse Events | AEs grade ≥ 2 | 45 Participants |
| Erenumab 70 mg | Number of Participants With Adverse Events | AEs grade ≥ 3 | 11 Participants |
| Erenumab 70 mg | Number of Participants With Adverse Events | Serious adverse events | 6 Participants |
| Erenumab 70 mg | Number of Participants With Adverse Events | AEs leading to discontinuation of study drug | 0 Participants |
| Erenumab 70 mg | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Erenumab 140 mg | Number of Participants With Adverse Events | Serious adverse events | 2 Participants |
| Erenumab 140 mg | Number of Participants With Adverse Events | AEs grade ≥ 2 | 42 Participants |
| Erenumab 140 mg | Number of Participants With Adverse Events | Fatal adverse events | 0 Participants |
| Erenumab 140 mg | Number of Participants With Adverse Events | AEs leading to discontinuation of study drug | 2 Participants |
| Erenumab 140 mg | Number of Participants With Adverse Events | AEs grade ≥ 4 | 0 Participants |
| Erenumab 140 mg | Number of Participants With Adverse Events | AEs grade ≥ 3 | 4 Participants |
| Erenumab 140 mg | Number of Participants With Adverse Events | Any adverse event | 88 Participants |
Secondary
Percentage of Participants With at Least a 50% Reduction in Monthly Migraine Days From Baseline
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. Monthly migraine days were calculated as the number of migraine days in the 4-week baseline phase and during the last 4 weeks of treatment. 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 4 weeks of the 12-week treatment phase \* 100 / baseline monthly migraine days was less than or equal to -50%.
Time frame: 4-week baseline phase and the last 4 weeks of the 12-week treatment phase
Population: The efficacy analysis set included participants who received at least 1 dose of study drug and completed at least 1 post-baseline monthly eDiary measurement.~Participants with missing post-baseline data were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With at Least a 50% Reduction in Monthly Migraine Days From Baseline | 23.5 percentage of participants |
| Erenumab 70 mg | Percentage of Participants With at Least a 50% Reduction in Monthly Migraine Days From Baseline | 39.9 percentage of participants |
| Erenumab 140 mg | Percentage of Participants With at Least a 50% Reduction in Monthly Migraine Days From Baseline | 41.2 percentage of participants |
Comparison: Analyzed using a Cochran-Mantel-Haenszel test after the missing data were imputed as non-response, stratified by stratification factors (region and medication overuse status).p-value: <0.00195% CI: [1.46, 3.27]Cochran-Mantel-Haenszel
Comparison: Analyzed using a Cochran-Mantel-Haenszel test after the missing data were imputed as non-response, stratified by stratification factors (region and medication overuse status).p-value: <0.00195% CI: [1.56, 3.51]Cochran-Mantel-Haenszel