Episodic Migraine
Conditions
Keywords
Migraine, attack, headache, episodic, aura, AMG 334, CGRP receptor agonist, erenumab, adult
Brief summary
The purpose of this study is to determine if AMG 334 is effective in treating migraines in patients who have failed other preventive migraine treatments.
Detailed description
This study was a double blind, placebo-controlled, randomized trial in adult patients with episodic migraine. There was a screening period of 2 weeks to assess initial eligibility, and a 4-week baseline period. After randomization, participants entered the double-blind treatment epoch (DBTE) and had clinic visits for 12 weeks. All participants who completed the DBTE were eligible to enter the Open-Label Treatment Epoch (OLTE) for up to 156 weeks. All participants had a 12 week Follow-Up Epoch and a a Follow-Up visit 16 weeks after the last dose of AMG334 unless the participant continued on commercially available AMG334. Participants who had demonstrated clinical benefit were eligible to enter a Post Trial Access (PTA-Open Label Treatment Epoch) of flexible duration for approximately 6 months.
Interventions
BIOLOGICALAMG334 (70 mg) Pre-Filled Syringe (PFS)
Two injections of AMG 334 70 mg (equaling 140 mg total dose) will be administered via subcutaneous injection
BIOLOGICALPlacebo Pre-Filled Syringe (PFS)
Subcutaneous injection of matching placebo
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Documented history of migraine in the 12 months prior to screen * 4-14 days per month of migraine symptoms * \>=80% diary compliance during the Baseline period * Failure of previous migraine prophylactic treatments
Exclusion criteria
* \>50 years old at migraine onset * Pregnant or nursing * History of cluster or hemiplegic headache * Evidence of seizure or psychiatric disorder * Score of over 19 on Beck Depression Inventory-2 * Active chronic pain syndrome * Cardiac or hepatic disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With at Least 50% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | Baseline, Month 3 (last 4 weeks of treatment) | A migraine day was defined as any calendar day in which the subject experienced a qualified migraine headache defined as: with/without aura, lasting ≥ 30 minutes with at least 1 criteria: 1. ≥ 2 of following pain features: unilateral, throbbing, moderate to severe or exacerbated with exercise/physical activity, 2. ≥ 1 of the following symptoms: nausea and/or vomiting, photophobia and phonophobia. If a migraine-specific medication (ie, triptan or ergotamine) was taken during aura, or a headache, it was counted as a migraine day regardless of duration and pain features/associated symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Physical Impairment and Everyday Activities as Measured by the Migraine Physical Function Impact Diary (MPFID) at Month 3 | Baseline, Month 3 (last 4 weeks of treatment) | MPFID has 2 domains: Everyday Activities, which consisted of 7 items and Physical Impairment with 5 items using a 5-point scale. Scores were summed across each domain and were then transformed and used for analyses. Transforming MPFID domain scores ranged from 0-100, where higher scores were indicative of greater migraine impact (ie, higher burden) |
| Change in the Number of Monthly Acute Migraine-specific Medication Treatment Days at Month 3 | Baseline, Month 3 (last 4 weeks of treatment) | Number of days on which acute migraine-specific medications were used were recorded in eDiary between each monthly IP dose. Migraine-Specific medications included two categories of medications: triptan-based migraine medications and ergotamine-based migraine medications. Monthly migraine-specific medication use at baseline was the number of migraine-specific medication treatment days in the baseline period. |
| Change From Baseline in Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | Baseline, Month 3 (last 4 weeks of treatment) | A migraine day was defined as any calendar day in which the subject experienced a qualified migraine headache defined as: with/without aura, lasting ≥ 30 minutes with at least 1 criteria: 1. ≥ 2 of following pain features: unilateral, throbbing, moderate to severe or exacerbated with exercise/physical activity, 2. ≥ 1 of the following symptoms: nausea and/or vomiting, photophobia and phonophobia. If a migraine-specific medication (ie, triptan or ergotamine) was taken during aura, or a headache, it was counted as a migraine day regardless of duration and pain features/associated symptoms. |
| Percentage of Participants With a 100% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | Baseline, Month 3 (last 4 weeks of treatment) | A migraine day was defined as any calendar day in which the subject experienced a qualified migraine headache defined as: with/without aura, lasting ≥ 30 minutes with at least 1 criteria: 1. ≥ 2 of following pain features: unilateral, throbbing, moderate to severe or exacerbated with exercise/physical activity, 2. ≥ 1 of the following symptoms: nausea and/or vomiting, photophobia and phonophobia. If a migraine-specific medication (ie, triptan or ergotamine) was taken during aura, or a headache, it was counted as a migraine day regardless of duration and pain features/associated symptoms. |
| Number of Participants Who Developed Anti-AMG334 Antibodies | Baseline up to approximately 180 weeks | Blood samples for immunogenicity testing were collected for the measurement of anti-AMG334 binding antibodies. |
| Percentage of Participants With a 75% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | Baseline, Month 3 (last 4 weeks of treatment) | A migraine day was defined as any calendar day in which the subject experienced a qualified migraine headache defined as: with/without aura, lasting ≥ 30 minutes with at least 1 criteria: 1. ≥ 2 of following pain features: unilateral, throbbing, moderate to severe or exacerbated with exercise/physical activity, 2. ≥ 1 of the following symptoms: nausea and/or vomiting, photophobia and phonophobia. If a migraine-specific medication (ie, triptan or ergotamine) was taken during aura, or a headache, it was counted as a migraine day regardless of duration and pain features/associated symptoms. |
Countries
Australia, Austria, Belgium, Czechia, Denmark, Finland, France, Germany, Greece, Italy, Netherlands, Norway, Spain, Sweden, Switzerland, United Kingdom
Participant flow
Pre-assignment details
333 participants were screened for the trial
Participants by arm
| Arm | Count |
|---|---|
| AMG334 140 mg DB AMG334 140 mg subcutaneous injections administered every 4 weeks during Double-Blind Epoch | 121 |
| Placebo DB Matching placebo subcutaneous injections administered every 4 weeks during Double-Blind Epoch | 125 |
| Total | 246 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Double-Blind Treatment Epoch | Pregnancy | 0 | 1 | 0 | 0 |
| Double-Blind Treatment Epoch | Protocol deviation | 2 | 1 | 0 | 0 |
| Double-Blind Treatment Epoch | Subject/guardian decision | 1 | 1 | 0 | 0 |
| Open-Label Treatment Epoch | Adverse Event | 0 | 0 | 5 | 6 |
| Open-Label Treatment Epoch | Lack of Efficacy | 0 | 0 | 15 | 15 |
| Open-Label Treatment Epoch | New therapy for study indication | 0 | 0 | 1 | 1 |
| Open-Label Treatment Epoch | Physician Decision | 0 | 0 | 1 | 0 |
| Open-Label Treatment Epoch | Pregnancy | 0 | 0 | 1 | 0 |
| Open-Label Treatment Epoch | Subject/guardian decision | 0 | 0 | 9 | 17 |
| Safety Follow-Up Epoch | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Safety Follow-Up Epoch | New therapy for study indication | 0 | 0 | 0 | 1 |
| Safety Follow-Up Epoch | Protocol deviation | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | AMG334 140 mg DB | Placebo DB | Total |
|---|---|---|---|
| Age, Customized Between 18 and 65 years | 121 Participants | 125 Participants | 246 Participants |
| Monthly Migraine Days at Baseline | 9.2 Migraine days/month STANDARD_DEVIATION 2.56 | 9.3 Migraine days/month STANDARD_DEVIATION 2.72 | 9.3 Migraine days/month STANDARD_DEVIATION 2.63 |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 112 Participants | 115 Participants | 227 Participants |
| Race/Ethnicity, Customized Other | 9 Participants | 8 Participants | 17 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 97 Participants | 103 Participants | 200 Participants |
| Sex: Female, Male Male | 24 Participants | 22 Participants | 46 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 / 119 | 0 / 124 | 0 / 118 | 0 / 122 |
| other Total, other adverse events | 44 / 119 | 43 / 124 | 94 / 118 | 101 / 122 |
| serious Total, serious adverse events | 2 / 119 | 1 / 124 | 16 / 118 | 18 / 122 |
Outcome results
Primary
Percentage of Participants With at Least 50% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment)
A migraine day was defined as any calendar day in which the subject experienced a qualified migraine headache defined as: with/without aura, lasting ≥ 30 minutes with at least 1 criteria: 1. ≥ 2 of following pain features: unilateral, throbbing, moderate to severe or exacerbated with exercise/physical activity, 2. ≥ 1 of the following symptoms: nausea and/or vomiting, photophobia and phonophobia. If a migraine-specific medication (ie, triptan or ergotamine) was taken during aura, or a headache, it was counted as a migraine day regardless of duration and pain features/associated symptoms.
Time frame: Baseline, Month 3 (last 4 weeks of treatment)
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMG334 140 mg DB | Percentage of Participants With at Least 50% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | 30.3 Percentage of participants |
| Placebo DB | Percentage of Participants With at Least 50% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | 13.7 Percentage of participants |
p-value: 0.00295% CI: [1.43, 5.19]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment)
A migraine day was defined as any calendar day in which the subject experienced a qualified migraine headache defined as: with/without aura, lasting ≥ 30 minutes with at least 1 criteria: 1. ≥ 2 of following pain features: unilateral, throbbing, moderate to severe or exacerbated with exercise/physical activity, 2. ≥ 1 of the following symptoms: nausea and/or vomiting, photophobia and phonophobia. If a migraine-specific medication (ie, triptan or ergotamine) was taken during aura, or a headache, it was counted as a migraine day regardless of duration and pain features/associated symptoms.
Time frame: Baseline, Month 3 (last 4 weeks of treatment)
Population: Number of participants with both baseline and valid post baseline value from the Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG334 140 mg DB | Change From Baseline in Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | -1.75 Monthly migraine days | Standard Error 0.43 |
| Placebo DB | Change From Baseline in Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | -0.16 Monthly migraine days | Standard Error 0.41 |
Comparison: Month 3p-value: 0.00495% CI: [-2.67, -0.51]Mixed Models Analysis
Secondary
Change From Baseline in Physical Impairment and Everyday Activities as Measured by the Migraine Physical Function Impact Diary (MPFID) at Month 3
MPFID has 2 domains: Everyday Activities, which consisted of 7 items and Physical Impairment with 5 items using a 5-point scale. Scores were summed across each domain and were then transformed and used for analyses. Transforming MPFID domain scores ranged from 0-100, where higher scores were indicative of greater migraine impact (ie, higher burden)
Time frame: Baseline, Month 3 (last 4 weeks of treatment)
Population: Number of participants with both baseline and valid post baseline value from the Full Analysis Set
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| AMG334 140 mg DB | Change From Baseline in Physical Impairment and Everyday Activities as Measured by the Migraine Physical Function Impact Diary (MPFID) at Month 3 | Physical impairment domain | -1.85 scores on a scale | Standard Error 0.84 |
| AMG334 140 mg DB | Change From Baseline in Physical Impairment and Everyday Activities as Measured by the Migraine Physical Function Impact Diary (MPFID) at Month 3 | Everyday activities domain | -3.36 scores on a scale | Standard Error 0.83 |
| Placebo DB | Change From Baseline in Physical Impairment and Everyday Activities as Measured by the Migraine Physical Function Impact Diary (MPFID) at Month 3 | Physical impairment domain | 1.61 scores on a scale | Standard Error 0.8 |
| Placebo DB | Change From Baseline in Physical Impairment and Everyday Activities as Measured by the Migraine Physical Function Impact Diary (MPFID) at Month 3 | Everyday activities domain | 0.55 scores on a scale | Standard Error 0.81 |
Comparison: Physical impairment domainp-value: 0.00395% CI: [-5.7, -1.23]Mixed Models Analysis
Comparison: Everyday activities domainp-value: <0.00195% CI: [-6.12, -1.7]Mixed Models Analysis
Secondary
Change in the Number of Monthly Acute Migraine-specific Medication Treatment Days at Month 3
Number of days on which acute migraine-specific medications were used were recorded in eDiary between each monthly IP dose. Migraine-Specific medications included two categories of medications: triptan-based migraine medications and ergotamine-based migraine medications. Monthly migraine-specific medication use at baseline was the number of migraine-specific medication treatment days in the baseline period.
Time frame: Baseline, Month 3 (last 4 weeks of treatment)
Population: Number of participants with both baseline and valid post baseline value from the Full Analysis Set
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AMG334 140 mg DB | Change in the Number of Monthly Acute Migraine-specific Medication Treatment Days at Month 3 | -1.25 Migraine treatment specific days/month | Standard Error 0.24 |
| Placebo DB | Change in the Number of Monthly Acute Migraine-specific Medication Treatment Days at Month 3 | 0.46 Migraine treatment specific days/month | Standard Error 0.28 |
p-value: <0.00195% CI: [-2.43, -0.99]Mixed Models Analysis
Secondary
Number of Participants Who Developed Anti-AMG334 Antibodies
Blood samples for immunogenicity testing were collected for the measurement of anti-AMG334 binding antibodies.
Time frame: Baseline up to approximately 180 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMG334 140 mg DB | Number of Participants Who Developed Anti-AMG334 Antibodies | 0 participants |
Secondary
Percentage of Participants With a 100% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment)
A migraine day was defined as any calendar day in which the subject experienced a qualified migraine headache defined as: with/without aura, lasting ≥ 30 minutes with at least 1 criteria: 1. ≥ 2 of following pain features: unilateral, throbbing, moderate to severe or exacerbated with exercise/physical activity, 2. ≥ 1 of the following symptoms: nausea and/or vomiting, photophobia and phonophobia. If a migraine-specific medication (ie, triptan or ergotamine) was taken during aura, or a headache, it was counted as a migraine day regardless of duration and pain features/associated symptoms.
Time frame: Baseline, Month 3 (last 4 weeks of treatment)
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMG334 140 mg DB | Percentage of Participants With a 100% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | 5.9 Percentage of participants |
| Placebo DB | Percentage of Participants With a 100% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | 0 Percentage of participants |
Secondary
Percentage of Participants With a 75% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment)
A migraine day was defined as any calendar day in which the subject experienced a qualified migraine headache defined as: with/without aura, lasting ≥ 30 minutes with at least 1 criteria: 1. ≥ 2 of following pain features: unilateral, throbbing, moderate to severe or exacerbated with exercise/physical activity, 2. ≥ 1 of the following symptoms: nausea and/or vomiting, photophobia and phonophobia. If a migraine-specific medication (ie, triptan or ergotamine) was taken during aura, or a headache, it was counted as a migraine day regardless of duration and pain features/associated symptoms.
Time frame: Baseline, Month 3 (last 4 weeks of treatment)
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AMG334 140 mg DB | Percentage of Participants With a 75% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | 11.8 Percentage of participants |
| Placebo DB | Percentage of Participants With a 75% Reduction From Baseline of Monthly Migraine Days (MMD) in the Last Month (Last 4 Weeks of Treatment) | 4.0 Percentage of participants |
p-value: 0.02595% CI: [1.11, 9.01]Cochran-Mantel-Haenszel