Migraine
Conditions
Brief summary
The purpose of this study was to assess the efficacy and safety of erenumab for prevention of migraine in Japanese adults with episodic migraine (EM) and chronic migraine (CM).
Detailed description
Migraine prevention is an area of a large unmet medical need, with existing therapies often having modest efficacy and poor tolerability. Calcitonin gene-related peptide (CGRP) receptor antagonism is a novel approach to migraine preventive therapy. Erenumab is a human monoclonal antibody against canonical CGRP receptor. The present study is a phase 3 trial intended to assess the efficacy and safety of erenumab for prevention of migraine in Japanese adults with episodic migraine (EM) and chronic migraine (CM). The study consists of a screening period (up to 7 weeks, including a 4-week baseline period), a 24-week double-blind treatment period (DBTP), a 28-week open-label treatment period (OLTP), and an 8-week safety follow-up period (12 weeks after the last dose of investigational product).
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
20 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subject has provided informed consent/assent prior to initiation of any study specific activities/procedures. * Japanese subjects greater than or equal to 20 to less than or equal to 65 years of age upon entry into screening. * History of migraine (with or without aura) for greater than or equal to 12 months before screening according to the International Headache Society Classification ICHD-3 (Headache Classification Committee of the International Headache Society, 2018) based on medical records and/or patient self-report * Migraine frequency: Chronic Migraine (CM) or Episodic Migraine (EM) over the 3 months before screening based on the following criteria: 1. CM is defined as greater than or equal to 15 headache days per month of which greater than or equal to 8 headache days on average across the 3 months meet criteria as migraine days 2. EM is defined as less than 15 headache days per month of which at least 4 or more headache days on average across the 3 months meet criteria as migraine days
Exclusion criteria
* Subjects greater than 50 years of age at migraine onset. * History of cluster headache or hemiplegic migraine headache. * Unable to differentiate migraine from other headaches. * Migraine with continuous pain, in which the subject does not experience any pain-free periods (of any duration) during the 1 month before the screening period. * Malignancy, except non-melanoma skin cancers, cervical or breast ductal carcinoma in situ within the last 5 years. Other
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Monthly Migraine Days (MMD) Over Months 4, 5, and 6 of the Double-blind Treatment Period | 4-week baseline period and the last 3 months (months 4, 5, and 6) of the 24-week 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, lasting for ≥ 4 hours, and meeting at least 1 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 * vomiting * photophobia and phonophobia 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 period minus the number of migraine days during the 4-week baseline period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least a 50% Reduction From Baseline in Mean Monthly Migraine Days Over Months 4, 5, and 6 of the DBTP | 4-week baseline period and the last 3 months (months 4, 5, and 6) of the 24-week 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, lasting for ≥ 4 hours, and meeting at least 1 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 * vomiting * photophobia and phonophobia |
| Change From Baseline in Mean Monthly Acute Migraine-specific Medication Treatment Days Over Months 4, 5, and 6 of the DBTP | 4-week baseline period and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment period | An acute migraine-specific medication treatment day is any calendar day during which a participant took a migraine-specific medication (e.g., triptan or ergotamine). 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 period minus the number of migraine-specific treatment days during the 4-week baseline period. |
Countries
Japan
Participant flow
Recruitment details
This study was conducted at 41 centers in Japan. The study consisted of a 24-week double-blind treatment period (DBTP), a 28-week open-label treatment period (OLTP), followed by an 8-week safety follow-up (12 weeks after the last dose of investigational product).
Pre-assignment details
Eligible participants were randomized 1:1 to erenumab 70 mg or placebo. Randomization was stratified by migraine type (episodic migraine \[EM\] / chronic migraine \[CM\]) and migraine preventive treatment status (ever used \[prior and/or current\] or never used).
Participants by arm
| Arm | Count |
|---|---|
| Placebo QM Participants randomized to receive placebo once a month (QM) for 24 weeks during the double-blind treatment period followed by erenumab 70 mg once a month for 28 weeks during the open-label treatment period. | 131 |
| Erenumab 70 mg QM Participants randomized to receive erenumab 70 mg once a month for 24 weeks during the double-blind treatment period followed by erenumab 70 mg once a month for 28 weeks during the open-label treatment period. | 130 |
| Total | 261 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind Treatment Period | Decision by Sponsor | 0 | 1 |
| Double-blind Treatment Period | Withdrawal by Subject | 4 | 2 |
| Open-label Treatment Period | Decision by Sponsor | 0 | 1 |
| Open-label Treatment Period | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Placebo QM | Erenumab 70 mg QM | Total |
|---|---|---|---|
| Age, Continuous | 44.6 years STANDARD_DEVIATION 9.3 | 44.2 years STANDARD_DEVIATION 8.5 | 44.4 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 131 Participants | 130 Participants | 261 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Migraine Type Chronic migraine | 51 Participants | 51 Participants | 102 Participants |
| Migraine Type Episodic migraine | 80 Participants | 79 Participants | 159 Participants |
| Monthly Migraine Days | 11.84 days / month STANDARD_DEVIATION 5.7 | 12.40 days / month STANDARD_DEVIATION 5.99 | 12.12 days / month STANDARD_DEVIATION 5.84 |
| Prior Migraine Preventive Treatment Status Ever used (including prior and/or current users) | 100 Participants | 100 Participants | 200 Participants |
| Prior Migraine Preventive Treatment Status Never used | 31 Participants | 30 Participants | 61 Participants |
| Race/Ethnicity, Customized Asian | 131 Participants | 130 Participants | 261 Participants |
| Sex: Female, Male Female | 116 Participants | 111 Participants | 227 Participants |
| Sex: Female, Male Male | 15 Participants | 19 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 131 | 0 / 130 | 0 / 254 |
| other Total, other adverse events | 40 / 131 | 44 / 130 | 62 / 254 |
| serious Total, serious adverse events | 2 / 131 | 2 / 130 | 7 / 254 |
Outcome results
Primary
Change From Baseline in Mean Monthly Migraine Days (MMD) Over Months 4, 5, and 6 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, lasting for ≥ 4 hours, and meeting at least 1 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 * vomiting * photophobia and phonophobia 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 period minus the number of migraine days during the 4-week baseline period.
Time frame: 4-week baseline period and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment period
Population: The efficacy analysis set included randomized participants who received at least 1 dose of investigational product and had at least 1 change from baseline measurement in MMD during the DBTP. Observed data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo QM | Change From Baseline in Mean Monthly Migraine Days (MMD) Over Months 4, 5, and 6 of the Double-blind Treatment Period | -1.98 migraine days / month |
| Erenumab 70 mg QM | Change From Baseline in Mean Monthly Migraine Days (MMD) Over Months 4, 5, and 6 of the Double-blind Treatment Period | -3.60 migraine days / month |
Comparison: The primary endpoint was analyzed using a generalized linear mixed model which includes treatment, visit, treatment-by-visit interaction, stratification factors of migraine type and prior migraine preventive treatment status, and baseline value as covariates and assumes a first-order auto regression covariance structure.p-value: <0.00195% CI: [-2.52, -0.73]Generalized Linear Mixed Model
Secondary
Change From Baseline in Mean Monthly Acute Migraine-specific Medication Treatment Days Over Months 4, 5, and 6 of the DBTP
An acute migraine-specific medication treatment day is any calendar day during which a participant took a migraine-specific medication (e.g., triptan or ergotamine). 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 period minus the number of migraine-specific treatment days during the 4-week baseline period.
Time frame: 4-week baseline period and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment period
Population: Efficacy analysis set; observed data
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Placebo QM | Change From Baseline in Mean Monthly Acute Migraine-specific Medication Treatment Days Over Months 4, 5, and 6 of the DBTP | -1.10 days / month |
| Erenumab 70 mg QM | Change From Baseline in Mean Monthly Acute Migraine-specific Medication Treatment Days Over Months 4, 5, and 6 of the DBTP | -2.57 days / month |
Comparison: Analysis utilizes a generalized linear mixed model which includes treatment, visit, treatment-by-visit interaction, stratification factors of migraine type (episodic migraine or chronic migraine) and prior migraine preventive treatment status (ever used or never used), and baseline value as covariates and assumes a first-order auto regression covariance structure.p-value: <0.00195% CI: [-2.24, -0.71]Generalized Linear Mixed Model
Secondary
Percentage of Participants With at Least a 50% Reduction From Baseline in Mean Monthly Migraine Days Over Months 4, 5, and 6 of the DBTP
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, lasting for ≥ 4 hours, and meeting at least 1 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 * vomiting * photophobia and phonophobia
Time frame: 4-week baseline period and the last 3 months (months 4, 5, and 6) of the 24-week double-blind treatment period
Population: Efficacy analysis set; participants with missing data were counted as non-responders.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo QM | Percentage of Participants With at Least a 50% Reduction From Baseline in Mean Monthly Migraine Days Over Months 4, 5, and 6 of the DBTP | 16.8 percentage of participants |
| Erenumab 70 mg QM | Percentage of Participants With at Least a 50% Reduction From Baseline in Mean Monthly Migraine Days Over Months 4, 5, and 6 of the DBTP | 31.5 percentage of participants |
p-value: 0.00595% CI: [1.29, 4.23]Cochran-Mantel-Haenszel