Episodic Migraine
Conditions
Keywords
Erenumab, AMG334, Migraine, Episodic, Headache, CGRP
Brief summary
The purpose of this study is to compare the sustained long-term benefit between two treatment paradigms of migraine prophylactic agents (erenumab versus a control arm of oral prophylactics) in episodic migraine patients who have previously failed 1 to 2 prophylactic migraine treatments.
Interventions
DRUGAMG334
Subcutaneous Injection
DRUGOral Prophylactic
SOC Oral Tablet/Capsule
Sponsors
Novartis
Amgen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent must be obtained before any assessment is performed. * Adults greater than or equal to 18 years of age upon entry into screening. * Documented history of migraine (with or without aura) greater than or equal to 12 months prior to screening according to the International Classification of Headache Disorders-3rd Edition (ICHD-3). * Greater than or equal to 4 and less than 15 days per month of migraine symptoms (based on ICHD-3 criteria) on average across 3 months prior to screening based on retrospective reporting. * Less than 15 days per month of headache symptoms (i.e., migraine and non-migraine). * Subjects in need for switching by documented failure of 1 or 2 prophylactic treatments in the last 6 months due to either lack of efficacy or poor tolerability. For subjects with 1 prior treatment failure, the failure should have occurred in the last 6 months. For subjects with 2 prior treatment failures, the second treatment failure should have occurred in the last 6 months. * During baseline: Confirmed migraine frequency of 4 to 14 migraine days and less than 15 days of headache symptoms. * During baseline: greater than or equal to 80% compliance with the headache diary.
Exclusion criteria
* Subjects meeting any of the following criteria are not eligible for inclusion in this study. * Older than 50 years of age at migraine onset. * History of cluster headache or hemiplegic migraine headache. * Unable to differentiate migraine from other headaches. * Lack of efficacy or poor tolerability with greater than 2 treatments from the 7 medication categories for prophylactic treatment of migraine after an adequate therapeutic trial. * Efficacy failure is defined as no meaningful reduction in headache frequency, duration, and/or severity after administration of the medication for at least 6 weeks at the generally accepted therapeutic dose(s) based on the investigator's assessment. * Tolerability failure is defined as documented discontinuation due to adverse events of the respective medication during the last 6 months prior to screening. * The following scenarios do not constitute lack of therapeutic response: * Lack of sustained response to a medication. * Patient decision to halt treatment due to improvement. * Used a prohibited medication from the 7 categories of prior prophylactic medications within 3 months prior to the start of and during baseline for a non-migraine indication if dose is not stable * Exposure to botulinum toxin in the head and/or neck region within 4 months. * Taken the following for any indication in any month during the 2 months prior to the start of the baseline period: * Ergotamines or triptans on greater than or equal to 10 days per month, or Simple analgesics (non-steroidal anti-inflammatory drugs \[NSAIDs\], acetaminophen) on greater than or equal to 15 days per month, or * Opioid- or butalbital-containing analgesics on greater than or equal to 4 days per month. * Device, or procedure that potentially may interfere with the intensity or number of migraine days within 2 months prior to the start of or during baseline. * History of major psychiatric disorders (such as schizophrenia or bipolar disorder) or current evidence of depression. Subjects with anxiety disorder and/or major depressive disorders are permitted in the study if they are considered by the investigator to be stable and are taking no more than 1 medication for each disorder. Subjects must have been on a stable dose within the 3 months prior to the start of the baseline period. * History of seizure disorder or other significant neurological conditions other than migraine. Note: a single childhood febrile seizure is not exclusionary. * History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. * Human immunodeficiency virus (HIV) infection by history. * History or evidence of any other unstable or clinically significant medical condition or clinically significant vital sign, laboratory, or electrocardiogram (ECG) abnormality during that could pose a risk to subject safety or interfere with the study evaluation. * Myocardial infarction, stroke, transient ischemic attack, unstable angina, or coronary artery bypass surgery or other re-vascularization procedures within 6 months prior to screening. * Score yes on item 4 or item 5 of the Suicidal Ideation section of the C-SSRS, if this ideation occurred in the past 6 months, or yes on any item of the Suicidal Behavior section, except for the Non-Suicidal Self-Injurious Behavior (item also included in the Suicidal Behavior section), if this behavior occurred in the past 2 years. * Evidence of drug or alcohol abuse or dependence, based on Investigator discretion within 12 months. * Pregnant or nursing (lactating) women. * Women of child-bearing potential must use contraception during dosing with study treatment. * Use of other investigational drugs within 5 half-lives of enrollment, or until the expected pharmacodynamic effect has returned to baseline, whichever is longer. * History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar chemical classes. * Previous exposure to AMG334 or exposure to any other prophylactic CGRP-targeted therapy (prior to the study).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Completed Initially Assigned Treatment and Achieved at Least a 50% Reduction From Baseline in Monthly Migraine Days at Month 12 | Baseline and Month 12 | A migraine day was defined as 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 as a migraine with or without aura, lasting for ≥ 30 minutes, and meeting at least one of the following criteria: 1. ≥2 of the following pain features: * Unilateral * Throbbing * Moderate to severe * Exacerbated with exercise/physical activity 2. ≥1 of the following associated symptoms: * Nausea and/or vomiting * Photophobia and phonophobia If the participant took a migraine-specific medication (ie, triptan or ergotamine) during aura, or to treat a headache on a calendar day, then it was counted as a migraine day regardless of the duration and pain features/associated symptoms. In addition to achieving at least a 50% reduction from baseline in monthly migraine days, participants must have also completed their initially assigned treatment through Month 12. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Completed Initially Assigned Treatment at Month 12 | Month 12 | — |
| Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Baseline and Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52 | A migraine day was defined as any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). The mean of monthly migraine days was obtained cumulatively every 4 weeks across 52 weeks (for example, at Week 8 the mean will be based on data from Week 1 to Week 8; and at Week 12 the mean will be based on data from Week 1 to Week 12). The cumulative mean change from baseline in monthly migraine days was derived using difference between cumulative average of each month and baseline monthly migraine days. |
| Number of Responders as Measured by the Patient's Global Impression of Change (PGIC) Scale at Week 52 | Baseline and Week 52 | The PGIC scale consists of one item which measures the participants' perception of change in their condition relative to the beginning of the study. Responses are rated on a 7-item response scale ranging from very much improved (7) to no change or worsened condition (1). A responder was defined as a participant with a PGIC score of at least 5 (5=moderately better, 6=better, 7=a great deal better), at Week 52 for participants who completed the treatment period at Week 52 on the initially assigned treatment. |
Countries
Argentina, Austria, Belgium, Czechia, Finland, France, Germany, Greece, Ireland, Israel, Italy, Netherlands, Poland, Portugal, Slovakia, Spain, United Kingdom, United States
Participant flow
Recruitment details
621 participants were enrolled at 84 centers in Argentina, Austria, Belgium, Czechia, Finland, France, Germany, Greece, Israel, Italy, the Netherlands, Poland, Portugal, Slovakia, Spain, the United Kingdom and the United States. The primary completion date based on the Core Phase was 01-Oct-2021. The study completion date was 30-Sep-2022.
Pre-assignment details
Participants were randomized 2:1 \[AMG334 70/140 mg: oral prophylactic\]. Randomization was stratified by prior prophylactic migraine medication treatment failure (due to insufficient efficacy or poor tolerability) reported during Screening/Baseline Period: 1 treatment failure (TF1) vs 2 treatment failures (TF2). A 30% cap of randomized participants to the TF2 strata was implemented. The stratification and 30% cap were implemented within Interactive Response Technology.
Participants by arm
| Arm | Count |
|---|---|
| AMG334 70 mg/140 mg Participants received 70 mg or 140 mg of AMG334 as a subcutaneous injection once per month for 52 weeks in the Core Phase.
Participants were permitted to switch to an approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion.
Eligible Core Phase completers (completed Week 52 and were benefitting from AMG334 treatment) entered the Extension Phase to continue to receive 70 mg or 140 mg AMG334 for up to 52 weeks. | 413 |
| Oral Prophylactic Participants received a standard of care (SOC) approved oral prophylactic once per day for 52 weeks in the Core Phase, as prescribed per local country labels.
Participants were permitted to switch to a different approved oral prophylactic based on treatment failure status and at the investigator's and participant's discretion.
Eligible Core Phase completers (completed Week 52 and were in need of a treatment switch) entered the Extension Phase to receive 70 mg or 140 mg AMG334 for up to 52 weeks. | 208 |
| Total | 621 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Core Phase | Adverse Event | 9 | 5 |
| Core Phase | Lost to Follow-up | 3 | 2 |
| Core Phase | New Therapy for Study Indication | 0 | 1 |
| Core Phase | No Longer Clinically Benefiting | 4 | 4 |
| Core Phase | Physician Decision | 2 | 8 |
| Core Phase | Protocol Violation | 2 | 2 |
| Core Phase | Withdrawal by Subject | 16 | 40 |
| Extension Phase | Adverse Event | 2 | 1 |
| Extension Phase | No longer clinically benefiting | 4 | 5 |
| Extension Phase | Pregnancy | 1 | 0 |
| Extension Phase | Protocol Violation | 0 | 1 |
| Extension Phase | Withdrawal by Subject | 8 | 3 |
Baseline characteristics
| Characteristic | Oral Prophylactic | Total | AMG334 70 mg/140 mg |
|---|---|---|---|
| Age, Continuous | 41.5 years STANDARD_DEVIATION 10.4 | 41.3 years STANDARD_DEVIATION 11.2 | 41.1 years STANDARD_DEVIATION 11.5 |
| Race/Ethnicity, Customized Hispanic or Latino | 17 Participants | 42 Participants | 25 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 190 Participants | 571 Participants | 381 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 7 Participants | 6 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 206 Participants | 612 Participants | 406 Participants |
| Sex: Female, Male Female | 182 Participants | 545 Participants | 363 Participants |
| Sex: Female, Male Male | 26 Participants | 76 Participants | 50 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 408 | 0 / 206 | 0 / 343 | 0 / 118 |
| other Total, other adverse events | 131 / 408 | 91 / 206 | 106 / 343 | 47 / 118 |
| serious Total, serious adverse events | 15 / 408 | 9 / 206 | 9 / 343 | 4 / 118 |
Outcome results
Primary
Number of Participants Who Completed Initially Assigned Treatment and Achieved at Least a 50% Reduction From Baseline in Monthly Migraine Days at Month 12
A migraine day was defined as 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 as a migraine with or without aura, lasting for ≥ 30 minutes, and meeting at least one of the following criteria: 1. ≥2 of the following pain features: * Unilateral * Throbbing * Moderate to severe * Exacerbated with exercise/physical activity 2. ≥1 of the following associated symptoms: * Nausea and/or vomiting * Photophobia and phonophobia If the participant took a migraine-specific medication (ie, triptan or ergotamine) during aura, or to treat a headache on a calendar day, then it was counted as a migraine day regardless of the duration and pain features/associated symptoms. In addition to achieving at least a 50% reduction from baseline in monthly migraine days, participants must have also completed their initially assigned treatment through Month 12.
Time frame: Baseline and Month 12
Population: FAS: Included all participants to whom study treatment had been assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG334 70 mg/140 mg | Number of Participants Who Completed Initially Assigned Treatment and Achieved at Least a 50% Reduction From Baseline in Monthly Migraine Days at Month 12 | 232 Participants |
| Oral Prophylactic | Number of Participants Who Completed Initially Assigned Treatment and Achieved at Least a 50% Reduction From Baseline in Monthly Migraine Days at Month 12 | 35 Participants |
p-value: <0.000195% CI: [4.28, 9.82]Cochran-Mantel-Haenszel
Secondary
Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52
A migraine day was defined as any calendar day in which the participant experienced a qualified migraine headache (onset, continuation, or recurrence of the migraine headache). The mean of monthly migraine days was obtained cumulatively every 4 weeks across 52 weeks (for example, at Week 8 the mean will be based on data from Week 1 to Week 8; and at Week 12 the mean will be based on data from Week 1 to Week 12). The cumulative mean change from baseline in monthly migraine days was derived using difference between cumulative average of each month and baseline monthly migraine days.
Time frame: Baseline and Week 4, Week 8, Week 12, Week 16, Week 20, Week 24, Week 28, Week 32, Week 36, Week 40, Week 44, Week 48, and Week 52
Population: Participants in the FAS with data available at each time point. The FAS included all participants to whom study treatment had been assigned. All participants included in the overall number of participants analyzed contributed to the post-baseline data for this endpoint.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 12 | -3.27 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 32 | -3.93 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 20 | -3.63 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 36 | -3.99 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 8 | -3.00 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 40 | -4.05 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 24 | -3.75 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 44 | -4.12 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 16 | -3.45 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 48 | -4.18 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 28 | -3.84 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 52 | -4.24 migraine days per month | Standard Error 0.17 |
| AMG334 70 mg/140 mg | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 4 | -2.55 migraine days per month | Standard Error 0.17 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 52 | -2.11 migraine days per month | Standard Error 0.27 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 4 | -0.55 migraine days per month | Standard Error 0.25 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 8 | -1.01 migraine days per month | Standard Error 0.25 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 12 | -1.05 migraine days per month | Standard Error 0.26 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 16 | -1.22 migraine days per month | Standard Error 0.26 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 20 | -1.35 migraine days per month | Standard Error 0.26 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 24 | -1.56 migraine days per month | Standard Error 0.26 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 28 | -1.73 migraine days per month | Standard Error 0.26 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 32 | -1.91 migraine days per month | Standard Error 0.27 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 36 | -1.99 migraine days per month | Standard Error 0.27 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 40 | -2.06 migraine days per month | Standard Error 0.27 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 44 | -2.11 migraine days per month | Standard Error 0.27 |
| Oral Prophylactic | Cumulative Mean Change From Baseline on the Monthly Migraine Days to Week 52 | Week 48 | -2.07 migraine days per month | Standard Error 0.27 |
Comparison: Comparison of mean change from baseline in monthly migraine days at Week 52p-value: <0.00195% CI: [-2.74, -1.52]Linear mixed effects model
Secondary
Number of Participants Who Completed Initially Assigned Treatment at Month 12
Time frame: Month 12
Population: FAS: Included all participants to whom study treatment has been assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG334 70 mg/140 mg | Number of Participants Who Completed Initially Assigned Treatment at Month 12 | 359 Participants |
| Oral Prophylactic | Number of Participants Who Completed Initially Assigned Treatment at Month 12 | 78 Participants |
p-value: <0.000195% CI: [7.53, 16.87]Cochran-Mantel-Haenszel
Secondary
Number of Responders as Measured by the Patient's Global Impression of Change (PGIC) Scale at Week 52
The PGIC scale consists of one item which measures the participants' perception of change in their condition relative to the beginning of the study. Responses are rated on a 7-item response scale ranging from very much improved (7) to no change or worsened condition (1). A responder was defined as a participant with a PGIC score of at least 5 (5=moderately better, 6=better, 7=a great deal better), at Week 52 for participants who completed the treatment period at Week 52 on the initially assigned treatment.
Time frame: Baseline and Week 52
Population: FAS: Included all participants to whom study treatment had been assigned.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| AMG334 70 mg/140 mg | Number of Responders as Measured by the Patient's Global Impression of Change (PGIC) Scale at Week 52 | 314 Participants |
| Oral Prophylactic | Number of Responders as Measured by the Patient's Global Impression of Change (PGIC) Scale at Week 52 | 39 Participants |
p-value: <0.00195% CI: [9.08, 20.83]Cochran-Mantel-Haenszel