Migraine Headache
Conditions
Keywords
Chronic Migraine, Medication Overuse Headache
Brief summary
Study 20170703 is a phase 4, randomized, double-blind, parallel-group, placebo-controlled study to evaluate the efficacy and safety of erenumab against placebo in participants with chronic migraine (CM) who have a history of at least 1 preventive treatment failure and are diagnosed with medication overuse headache (MOH).
Detailed description
Study 20170703 is a phase 4, randomized, double-blind, double-dummy, parallel-group, placebo-controlled study to evaluate the safety and efficacy of erenumab against placebo in a CM population with MOH and prior history of treatment failure. Participants will be enrolled based on fulfilment of the International Classification of Headache Disorders, 3rd Edition (ICHD-3) CM and MOH criteria and will not be advised to early discontinue acute medication. Participants who successfully complete the 24-week double-blind treatment period (DBTP) of the study will be offered an opportunity to continue in an open-label treatment period (OLTP) of 28-weeks duration. Participants who received erenumab treatment during the DBTP will continue to receive the same erenumab dose during the OLTP. Participants who received placebo during the DBTP will be allocated in a 1:1 ratio to receive either erenumab 70 mg or 140 mg SC QM during the OLTP. All participants will remain blinded to their original DBTP treatment assignment.
Interventions
DRUGErenumab 70 mg
Erenumab once every 4 weeks. Subcutaneous injection.
DRUGErenumab 140 mg
Erenumab once every 4 weeks. Subcutaneous injection.
DRUGPlacebo
Placebo once every 4 weeks. Subcutaneous injection.
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 99 Years
Healthy volunteers
No
Inclusion criteria
Eligibility criteria will be evaluated during the up to 3-week screening period (part 1) and a 4-week baseline period (part 2). At the end of baseline period, participants who successfully met eligibility criteria will be randomized on study. Key Inclusion Criteria Part 1: To be assessed during the 3-week screening period, prior to the baseline period. Participants are eligible to be included in the study only if all of the following criteria apply: * Participant has provided informed consent prior to initiation of any study-specific activities/procedures * Age ≥ 18 years on entry into the study * Documented history of migraine without aura and/or migraine with aura according to the ICHD-3 classification for ≥ 12 months at screening * Documented history of CM for a minimal duration of 6 months before screening * Current diagnosis of MOH * History of treatment failure with at least 1 preventive treatment as defined as treatment discontinuation due to lack of efficacy, adverse event or general poor tolerability Key
Exclusion criteria
Part 1 Participants are excluded from the study if any of the following criteria apply: Disease Related * Age \> 50 years at migraine onset or \> 65 years at CM onset * History of hemiplegic migraine, cluster headache or other trigeminal autonomic cephalalgia * Current concomitant diagnosis of a secondary type of headache other than MOH * No therapeutic response in prevention of migraine after an adequate therapeutic trial of \> 3 preventive treatment categories * Changes in drug regimen (ie, changes in dose or frequency of use) of an allowed migraine preventive medication within 2 months prior to start of baseline * Received botulinum toxin in the head and/or neck region within 4 months prior to screening * Documented history of treatment with an anti-calcitonin gene-related peptide product preventive treatment * Anticipated to require any excluded medication/device or procedure during the study Other Medical Conditions * History or evidence of unstable or clinically significant medical condition that, in the opinion of the investigator or Amgen's physician, if consulted, would pose a risk to participant safety or interfere with the study evaluation, procedures or completion * Evidence of recreational use of illicit drugs within 12 months prior to screening, based on medical records, self-report, or a positive drug test performed during screening. Key Inclusion Criteria Part 2. To be assessed at the end of the baseline period and prior to enrollment into DBTP. Based on information collected through the electronic diary (eDiary) during the baseline period, the following requirements must be met: -≥ 14 headache days during the 28-day baseline period out of which ≥ 8 headache days meet criteria as migraine days * Observation of acute migraine medication overuse during the baseline period. Medication overuse at baseline is defined as: * ≥ 10 days of combination treatment OR * ≥ 10 days of short-acting opioids/opioid-containing medication OR * ≥ 10 days of triptans, ergots, OR * ≥ 15 days of nonsteroidal anti-inflammatory drugs or simple analgesics intake * At least 2 acute headache medication days per week for each week with at least 5 diary days * Demonstrated at least 80% compliance with the eDiary (eg, must complete eDiary items on at least 23 out of 28 days during the baseline period) Key
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Absence of Medication Overuse Headaches (MOH) at Month 6 | Months 4, 5, and 6 (weeks 13 through 24) of the DBTP | Absence of MOH at month 6 was defined as mean monthly acute headache medication days (AHMD) \< 10 days over months 4, 5, and 6 (weeks 13 through 24) or mean monthly headache days \< 14 days over months 4, 5, and 6 (weeks 13 through 24) of the DBTP where an AHMD was defined as a calendar day in which the participant took at least 1 acute headache medication. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Monthly AHMDs Over Months 4, 5, and 6 | Baseline and months 4, 5, and 6 (weeks 13 through 24) of the DBTP | An AHMD was defined as a calendar day in which the participant takes at least 1 acute headache medication. Acute headache medications included triptan-based, ergotamine-based and ditan-based migraine medications, non-opioid and opioid-containing acute headache medications, non-opioid butalbital and opioid-containing butalbital containing medications. |
| Number of Participants With Sustained MOH Remission at Month 6 | Month 3 (week 12) to month 6 (week 24) of the DBTP | Sustained MOH remission was defined as the absence of MOH at month 3 (week 12) and month 6 (week 24) of the DBTP. Absence of MOH was achieved when mean monthly AHMD \< 10 days or mean monthly headache days \< 14 days over the 3-month period (weeks 12 to 24). |
| Change From Baseline in Mean Monthly Average Physical Impairment Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) | Baseline and months 4, 5, and 6 (weeks 13 through 24) of the DBTP | The MPFID is a self-administered 13-item instrument measuring physical functioning, completed daily using the eDiary. The physical impairment domain includes 5 items. Participants respond to items using a 5-point scale, with difficulty items ranging from Without any difficulty to Unable to do, and frequency items ranging from None of the time to All of the time. Each item is assigned a score from 1 to 5, with 5 representing the greatest burden. For each domain, the scores are calculated as the sum of the item responses and the sum is rescaled to a 0 to 100 scale, with higher scores representing greater impact of migraine, i.e., higher burden. |
| Change From Baseline in Mean Monthly Average Impact on Everyday Activities Domain Scores as Measured by the MPFID | Baseline and months 4, 5, and 6 (weeks 13 through 24) of the DBTP | The MPFID is a self-administered 13-item instrument measuring physical functioning, completed daily using the eDiary. The impact on everyday activities domain includes 7 items. Participants respond to items using a 5-point scale, with difficulty items ranging from Without any difficulty to Unable to do, and frequency items ranging from None of the time to All of the time. Each item is assigned a score from 1 to 5, with 5 representing the greatest burden. For each domain, the scores are calculated as the sum of the item responses and the sum is rescaled to a 0 to 100 scale, with higher scores representing greater impact of migraine, i.e., higher burden. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | Day 1 to Week 24 (DBTP) and Week 25 to 52 weeks (OLTP) | TEAEs were defined as any adverse event (AE) that started on or after first dose of IP, and up to the end of the study (52 weeks). Any clinically significant changes in vital signs were included as TEAEs. |
Countries
Australia, Austria, Czechia, Finland, France, Hungary, Italy, Poland, Portugal, Spain, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 67 study centers in North America, Europe, and Australia, and participated from 07 October 2019 to 13 June 2023.
Pre-assignment details
Adult participants with a history of chronic migraine and medication overuse headaches according to the International Classification of Headache Disorders 3rd Edition (ICHD-3) criteria were randomized 1:1:1 to receive erenumab 70 mg or 140 mg subcutaneously (SC) once every 4 weeks (QM) or matching placebo. Prior to randomization, participants completed a 4-week baseline period to evaluate eligibility.
Participants by arm
| Arm | Count |
|---|---|
| Placebo (DBTP) Participants were randomized to receive matching placebo SC QM for 24 weeks in the DBTP. | 206 |
| Erenumab 70 mg (DBTP) Participants were randomized to receive 1 mL of erenumab 70 mg/mL SC QM for 24 weeks in the DBTP. | 207 |
| Erenumab 140 mg (DBTP) Participants were randomized to receive 1 mL of erenumab 140 mg/mL SC QM for 24 weeks in the DBTP. | 207 |
| Total | 620 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Double-blind Treatment Period (DBTP) | Other | 2 | 2 | 0 | 0 | 0 |
| Double-blind Treatment Period (DBTP) | Sponsor decision | 0 | 1 | 0 | 0 | 0 |
| Double-blind Treatment Period (DBTP) | Withdrawal by Subject | 7 | 11 | 6 | 0 | 0 |
| Open-label Treatment Period | Lost to Follow-up | 0 | 0 | 0 | 0 | 1 |
| Open-label Treatment Period | Sponsor decision | 0 | 0 | 0 | 0 | 1 |
| Open-label Treatment Period | Withdrawal by Subject | 0 | 0 | 0 | 10 | 13 |
Baseline characteristics
| Characteristic | Placebo (DBTP) | Erenumab 70 mg (DBTP) | Erenumab 140 mg (DBTP) | Total |
|---|---|---|---|---|
| Age, Continuous | 44.3 years STANDARD_DEVIATION 12.5 | 43.1 years STANDARD_DEVIATION 11.6 | 43.5 years STANDARD_DEVIATION 12.2 | 43.6 years STANDARD_DEVIATION 12.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 10 Participants | 13 Participants | 32 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 196 Participants | 197 Participants | 194 Participants | 587 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 2 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants | 15 Participants | 17 Participants | 38 Participants |
| Race (NIH/OMB) White | 196 Participants | 187 Participants | 187 Participants | 570 Participants |
| Sex: Female, Male Female | 166 Participants | 170 Participants | 174 Participants | 510 Participants |
| Sex: Female, Male Male | 40 Participants | 37 Participants | 33 Participants | 110 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 | 0 / 206 | 0 / 207 | 0 / 207 | 0 / 291 | 0 / 296 |
| other Total, other adverse events | 29 / 206 | 67 / 206 | 72 / 206 | 65 / 291 | 75 / 296 |
| serious Total, serious adverse events | 8 / 206 | 3 / 206 | 3 / 206 | 6 / 291 | 12 / 296 |
Outcome results
Primary
Number of Participants With Absence of Medication Overuse Headaches (MOH) at Month 6
Absence of MOH at month 6 was defined as mean monthly acute headache medication days (AHMD) \< 10 days over months 4, 5, and 6 (weeks 13 through 24) or mean monthly headache days \< 14 days over months 4, 5, and 6 (weeks 13 through 24) of the DBTP where an AHMD was defined as a calendar day in which the participant took at least 1 acute headache medication.
Time frame: Months 4, 5, and 6 (weeks 13 through 24) of the DBTP
Population: Efficacy analysis set (nonopioid-treated cohort): randomized participants with an opioid medication use of ≤ 4 days per month during the baseline period and who received at least 1 dose of IP during DBTP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (DBTP) | Number of Participants With Absence of Medication Overuse Headaches (MOH) at Month 6 | 102 Participants |
| Erenumab 70 mg (DBTP) | Number of Participants With Absence of Medication Overuse Headaches (MOH) at Month 6 | 117 Participants |
| Erenumab 140 mg (DBTP) | Number of Participants With Absence of Medication Overuse Headaches (MOH) at Month 6 | 134 Participants |
p-value: 0.1395% CI: [0.92, 2.05]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [1.33, 3.05]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Mean Monthly AHMDs Over Months 4, 5, and 6
An AHMD was defined as a calendar day in which the participant takes at least 1 acute headache medication. Acute headache medications included triptan-based, ergotamine-based and ditan-based migraine medications, non-opioid and opioid-containing acute headache medications, non-opioid butalbital and opioid-containing butalbital containing medications.
Time frame: Baseline and months 4, 5, and 6 (weeks 13 through 24) of the DBTP
Population: Efficacy analysis set (nonopioid-treated cohort): randomized participants with an opioid medication use of ≤ 4 days per month during the baseline period and who received at least 1 dose of IP during DBTP. Participants with evaluable data from weeks 13 through 24 are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (DBTP) | Change From Baseline in Mean Monthly AHMDs Over Months 4, 5, and 6 | -6.61 days per month | Standard Error 0.41 |
| Erenumab 70 mg (DBTP) | Change From Baseline in Mean Monthly AHMDs Over Months 4, 5, and 6 | -7.83 days per month | Standard Error 0.41 |
| Erenumab 140 mg (DBTP) | Change From Baseline in Mean Monthly AHMDs Over Months 4, 5, and 6 | -9.35 days per month | Standard Error 0.41 |
p-value: 0.03395% CI: [-2.35, -0.1]Linear Mixed Model
p-value: <0.00195% CI: [-3.87, -1.62]Linear Mixed Model
Secondary
Change From Baseline in Mean Monthly Average Impact on Everyday Activities Domain Scores as Measured by the MPFID
The MPFID is a self-administered 13-item instrument measuring physical functioning, completed daily using the eDiary. The impact on everyday activities domain includes 7 items. Participants respond to items using a 5-point scale, with difficulty items ranging from Without any difficulty to Unable to do, and frequency items ranging from None of the time to All of the time. Each item is assigned a score from 1 to 5, with 5 representing the greatest burden. For each domain, the scores are calculated as the sum of the item responses and the sum is rescaled to a 0 to 100 scale, with higher scores representing greater impact of migraine, i.e., higher burden.
Time frame: Baseline and months 4, 5, and 6 (weeks 13 through 24) of the DBTP
Population: Efficacy analysis set (nonopioid-treated cohort): randomized participants with an opioid medication use of ≤ 4 days per month during the baseline period and who received at least 1 dose of IP during DBTP. Participants with evaluable data from weeks 13 through 24 are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (DBTP) | Change From Baseline in Mean Monthly Average Impact on Everyday Activities Domain Scores as Measured by the MPFID | -10.91 Scores on a scale | Standard Error 0.84 |
| Erenumab 70 mg (DBTP) | Change From Baseline in Mean Monthly Average Impact on Everyday Activities Domain Scores as Measured by the MPFID | -13.52 Scores on a scale | Standard Error 0.85 |
| Erenumab 140 mg (DBTP) | Change From Baseline in Mean Monthly Average Impact on Everyday Activities Domain Scores as Measured by the MPFID | -13.29 Scores on a scale | Standard Error 0.84 |
p-value: 0.02895% CI: [-4.92, -0.29]Linear Mixed Model
p-value: 0.04395% CI: [-4.67, -0.07]Linear Mixed Model
Secondary
Change From Baseline in Mean Monthly Average Physical Impairment Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID)
The MPFID is a self-administered 13-item instrument measuring physical functioning, completed daily using the eDiary. The physical impairment domain includes 5 items. Participants respond to items using a 5-point scale, with difficulty items ranging from Without any difficulty to Unable to do, and frequency items ranging from None of the time to All of the time. Each item is assigned a score from 1 to 5, with 5 representing the greatest burden. For each domain, the scores are calculated as the sum of the item responses and the sum is rescaled to a 0 to 100 scale, with higher scores representing greater impact of migraine, i.e., higher burden.
Time frame: Baseline and months 4, 5, and 6 (weeks 13 through 24) of the DBTP
Population: Efficacy analysis set (nonopioid-treated cohort): randomized participants with an opioid medication use of ≤ 4 days per month during the baseline period and who received at least 1 dose of IP during DBTP. Participants with evaluable data from weeks 13 through 24 are included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo (DBTP) | Change From Baseline in Mean Monthly Average Physical Impairment Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) | -8.50 Scores on a scale | Standard Error 0.86 |
| Erenumab 70 mg (DBTP) | Change From Baseline in Mean Monthly Average Physical Impairment Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) | -11.75 Scores on a scale | Standard Error 0.87 |
| Erenumab 140 mg (DBTP) | Change From Baseline in Mean Monthly Average Physical Impairment Domain Scores as Measured by the Migraine Physical Function Impact Diary (MPFID) | -10.63 Scores on a scale | Standard Error 0.86 |
p-value: 0.00795% CI: [-5.62, -0.88]Linear Mixed Model
p-value: 0.07595% CI: [-4.48, 0.22]Linear Mixed Model
Secondary
Number of Participants With Sustained MOH Remission at Month 6
Sustained MOH remission was defined as the absence of MOH at month 3 (week 12) and month 6 (week 24) of the DBTP. Absence of MOH was achieved when mean monthly AHMD \< 10 days or mean monthly headache days \< 14 days over the 3-month period (weeks 12 to 24).
Time frame: Month 3 (week 12) to month 6 (week 24) of the DBTP
Population: Efficacy analysis set (nonopioid-treated cohort): randomized participants with an opioid medication use of ≤ 4 days per month during the baseline period and who received at least 1 dose of IP during DBTP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (DBTP) | Number of Participants With Sustained MOH Remission at Month 6 | 73 Participants |
| Erenumab 70 mg (DBTP) | Number of Participants With Sustained MOH Remission at Month 6 | 96 Participants |
| Erenumab 140 mg (DBTP) | Number of Participants With Sustained MOH Remission at Month 6 | 119 Participants |
p-value: 0.01995% CI: [1.08, 2.43]Cochran-Mantel-Haenszel
p-value: <0.00195% CI: [1.75, 3.96]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
TEAEs were defined as any adverse event (AE) that started on or after first dose of IP, and up to the end of the study (52 weeks). Any clinically significant changes in vital signs were included as TEAEs.
Time frame: Day 1 to Week 24 (DBTP) and Week 25 to 52 weeks (OLTP)
Population: Safety analysis set: randomized participants who received at least 1 dose of IP.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (DBTP) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 130 Participants |
| Erenumab 70 mg (DBTP) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 139 Participants |
| Erenumab 140 mg (DBTP) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 142 Participants |
| Erenumab 70 mg (OLTP) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 178 Participants |
| Erenumab 140 mg (OLTP) | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 182 Participants |