Migraine
Conditions
Keywords
Migraine, Episodic migraine, Chronic migraine, Headache, erenumab, topiramate, CAMG 334, Calcitonin Gene-related Peptide, CGRP, CGRP receptor agonist, monoclonal antibody, treatment failure
Brief summary
This study used a single-cohort, 2-treatment arm, parallel-group randomized, double-blind, double-dummy design in adult patients with episodic migraine and chronic migraine, who had to be either naïve or not suitable for or could have failed up to three prophylactic treatments out of: propranolol/metoprolol, amitriptyline, flunarizine. Patients were stratified into groups according to their number of migraine days during the baseline period.
Detailed description
All patients completing the Baseline period and fulfilling baseline eligibility criteria were invited to participate to the Double-blind, double-dummy Treatment Epoch (DBTE, 24 weeks) . Eligible patients were randomized to one of two treatment arms. DBTE started with a titration phase for topiramate of a maximum of 6 weeks to determine the maximal tolerated dose and aimed to reach the recommended treatment dose of 100 mg according to the German SmPC. After the titration phase, maintenance phase started (18 weeks). Topiramate dose had to be maintained until the end of the DBTE. Erenumab dose at beginning of the DBTE was determined patient individually by the investigator based on the guidance provided in the SmPC and was either 70 mg or 140 mg. Dose escalation from 70 mg to 140 mg in case of insufficient response was considered at anytime during the DBTE. Dose reduction of topiramate and erenumab was not allowed during DBTE (Week 0 to Week 24). After Week 24 or if the patient discontinued study drug, a one week double-blind taper off phase followed to ensure proper down titration for topiramate. At the end of the DBTE (24 weeks) the final assessment occurred to address the objectives. A Follow-Up Visit 4 weeks after last study visit (or 8 weeks after last IMP injection for discontinued patients) was required as part of routine safety monitoring. The primary analysis was triggered when all patients had completed their respective last visit of the DBTE. The End of study occurred when the last patient completed last visit (LPLV).
Interventions
BIOLOGICALErenumab
70mg/1mL (70 mg) or 2x70mg/1mL (140 mg) in pre-filled syringe, administered every 4 weeks
DRUGTopiramate
Film-coated tablet taken orally: 25 mg administered once daily (first week of titration phase). After the first week, titration was done according to the summary of product characteristics (SmPC) in 25 mg increments each week and aimed to reach the recommended daily treatment dose of 100 mg (50/75/100 mg). 50/75/100 mg were administered twice daily during titration phase and maintenance phase.
BIOLOGICALErenumab matching placebo
Erenumab matching placebo pre-filled syringue administered every 4 weeks
DRUGTopiramate matching placebo
Topiramate matching placebo administered daily
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
Key Inclusion Criteria: 1. Documented history of migraine in the 12 months prior to screen 2. at least 4 days per month of migraine symptoms 3. \>=80% diary compliance during the Baseline period 4. Patients must be either naïve or not suitable or have failed previous migraine prophylactic treatments Key
Exclusion criteria
1. Older than 50 years of age at migraine onset 2. Pregnant or nursing 3. History of cluster or hemiplegic headache 4. History or evidence of major psychiatric disorder 5. Score of 19 or higher on Beck Depression Inventory (BDI)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Treatment Discontinuation Due to an Adverse Event (AE) During the Double-blind Treatment Epoch/Period (DBTE) | 24 Weeks | The primary objective was to demonstrate the tolerability of 70 mg and 140 mg erenumab compared to topiramate in the highest tolerated dose assessed by the rate of patients discontinuing treatment due to AE during the double-blind epoch of the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With at Least 50% Reduction From Baseline in Monthly Migraine Days (MMD) Over the Last Three Months (Month 4, 5, and 6) | Baseline, Last three months (month 4, 5, and 6) | The secondary objective of this study was to evaluate the effect of erenumab compared to topiramate on the proportion of patients with at least 50% reduction from baseline in MMDs. The Baseline period was defined as the period between Week -4 and the day prior to first dose. This was analyzed by logistic regression over the last 3 months (months 4, 5, and 6) of treatment. All the subjects' data collected regarding 50% response in MMD was used in the analysis regardless of whether subjects discontinue study treatment or not. Subjects with missing response information on this endpoint were imputed as non-response (non-responder imputation). |
Other
| Measure | Time frame | Description |
|---|---|---|
| EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Reduction in the Headache Impact Test (HIT-6) From Baseline to Week 24 | Baseline, Week 24 | The HIT-6 is a widely used patient-reported outcome measure that assesses the negative effects of headaches on normal activity. Six items assess the frequency of pain severity, headaches limiting daily activity (household, work, school, and social), wanting to lie down when headache is experienced, feeling too tired to work or do daily activities because of headache, feeling fed up or irritated because of headache, and headaches limiting ability to concentrate or work on daily activities. Each of the 6 questions is responded to using 1 of 5 response categories: never, rarely, sometimes, very often, or always. For each HIT-6 item, 6, 8, 10, 11, or 13 points, respectively, are assigned to the response provided. These points are summed to produce a total HIT-6 score that ranges from 36 to 78. HIT-6 scores are categorized into 4 grades: little or no impact (49 or less), some impact (50 - 55), substantial impact (56 - 59), and severe impact (60 - 78) due to headache. |
| EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Increase in the Medical Outcome Short Form Health Survey Version 2 (SF-36) From Baseline to Week 24 | Baseline, Week 24 | The SF-36 is a widely used and extensively studied instrument to measure health-related quality of life (HRQoL) among healthy subjects and patients with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF-36 has proven useful in monitoring general and specific populations, comparing the relative burden of different disease, differentiating the health benefits produced by different treatments, and in screening individual patients. The purpose of the SF-36 in this study was to assess the HRQoL of patients. Given the nature of this disease and the 4-weekly assessment, the SF-36 version 2, with a 4-week recall period, was used in this study. |
Countries
Germany
Participant flow
Recruitment details
82 centers in Germany enrolled patients.
Pre-assignment details
A total of 777 patients were randomized to receive either erenumab (389 patients) or topiramate (388 patients).
Participants by arm
| Arm | Count |
|---|---|
| Erenumab 70 mg and 140 mg Erenumab | 388 |
| Topiramate Topiramate in the highest tolerated dose (50 - 100 mg/day) | 388 |
| Total | 776 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 12 |
| Overall Study | Lost to Follow-up | 4 | 2 |
| Overall Study | New therapy for study indication | 1 | 0 |
| Overall Study | Patient's/guardian's decision | 3 | 5 |
| Overall Study | Protocol Violation | 3 | 2 |
| Overall Study | Withdrawal of informed consent | 2 | 1 |
Baseline characteristics
| Characteristic | Topiramate | Total | Erenumab |
|---|---|---|---|
| Age, Continuous | 40.7 Years STANDARD_DEVIATION 12.4 | 40.7 Years STANDARD_DEVIATION 12.4 | 40.8 Years STANDARD_DEVIATION 12.4 |
| Baseline Monthly Migraine Days (MMDs) categories >= 15 days | 42 Participants | 85 Participants | 43 Participants |
| Baseline Monthly Migraine Days (MMDs) categories < 4 days | 0 Participants | 2 Participants | 2 Participants |
| Baseline Monthly Migraine Days (MMDs) categories 4 to 7 days | 92 Participants | 186 Participants | 94 Participants |
| Baseline Monthly Migraine Days (MMDs) categories 8 to 14 days | 254 Participants | 502 Participants | 248 Participants |
| Baseline Monthly Migraine Days (MMDs) categories Missing | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Caucasian | 387 Participants | 770 Participants | 383 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 4 Participants | 3 Participants |
| Race/Ethnicity, Customized Unknown | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 335 Participants | 666 Participants | 331 Participants |
| Sex: Female, Male Male | 53 Participants | 110 Participants | 57 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 388 | 0 / 388 |
| other Total, other adverse events | 253 / 388 | 331 / 388 |
| serious Total, serious adverse events | 10 / 388 | 19 / 388 |
Outcome results
Primary
Proportion of Patients With Treatment Discontinuation Due to an Adverse Event (AE) During the Double-blind Treatment Epoch/Period (DBTE)
The primary objective was to demonstrate the tolerability of 70 mg and 140 mg erenumab compared to topiramate in the highest tolerated dose assessed by the rate of patients discontinuing treatment due to AE during the double-blind epoch of the study.
Time frame: 24 Weeks
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erenumab | Proportion of Patients With Treatment Discontinuation Due to an Adverse Event (AE) During the Double-blind Treatment Epoch/Period (DBTE) | 41 Participants |
| Topiramate | Proportion of Patients With Treatment Discontinuation Due to an Adverse Event (AE) During the Double-blind Treatment Epoch/Period (DBTE) | 151 Participants |
p-value: <0.00195% CI: [0.13, 0.27]Regression, Logistic
Secondary
Number of Patients With at Least 50% Reduction From Baseline in Monthly Migraine Days (MMD) Over the Last Three Months (Month 4, 5, and 6)
The secondary objective of this study was to evaluate the effect of erenumab compared to topiramate on the proportion of patients with at least 50% reduction from baseline in MMDs. The Baseline period was defined as the period between Week -4 and the day prior to first dose. This was analyzed by logistic regression over the last 3 months (months 4, 5, and 6) of treatment. All the subjects' data collected regarding 50% response in MMD was used in the analysis regardless of whether subjects discontinue study treatment or not. Subjects with missing response information on this endpoint were imputed as non-response (non-responder imputation).
Time frame: Baseline, Last three months (month 4, 5, and 6)
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erenumab | Number of Patients With at Least 50% Reduction From Baseline in Monthly Migraine Days (MMD) Over the Last Three Months (Month 4, 5, and 6) | 215 Participants |
| Topiramate | Number of Patients With at Least 50% Reduction From Baseline in Monthly Migraine Days (MMD) Over the Last Three Months (Month 4, 5, and 6) | 121 Participants |
p-value: <0.00195% CI: [2.06, 3.71]Regression, Logistic
Other Pre-specified
EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Increase in the Medical Outcome Short Form Health Survey Version 2 (SF-36) From Baseline to Week 24
The SF-36 is a widely used and extensively studied instrument to measure health-related quality of life (HRQoL) among healthy subjects and patients with acute and chronic conditions. It consists of eight subscales that can be scored individually: Physical Functioning, Role-Physical, Bodily Pain, General Health, Vitality, Social Functioning, Role-Emotional, and Mental Health. Two overall summary scores, the Physical Component Summary (PCS) and the Mental Component Summary (MCS) also can be computed. The SF-36 has proven useful in monitoring general and specific populations, comparing the relative burden of different disease, differentiating the health benefits produced by different treatments, and in screening individual patients. The purpose of the SF-36 in this study was to assess the HRQoL of patients. Given the nature of this disease and the 4-weekly assessment, the SF-36 version 2, with a 4-week recall period, was used in this study.
Time frame: Baseline, Week 24
Population: Full Analysis Set (FAS)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Erenumab | EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Increase in the Medical Outcome Short Form Health Survey Version 2 (SF-36) From Baseline to Week 24 | Physical Component Summary (PCS) | 185 Participants |
| Erenumab | EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Increase in the Medical Outcome Short Form Health Survey Version 2 (SF-36) From Baseline to Week 24 | Mental Component Summary (MCS) | 98 Participants |
| Topiramate | EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Increase in the Medical Outcome Short Form Health Survey Version 2 (SF-36) From Baseline to Week 24 | Physical Component Summary (PCS) | 145 Participants |
| Topiramate | EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Increase in the Medical Outcome Short Form Health Survey Version 2 (SF-36) From Baseline to Week 24 | Mental Component Summary (MCS) | 65 Participants |
Comparison: Physical Component Summary (PCS)p-value: <0.00195% CI: [1.26, 2.43]Regression, Logistic
Comparison: Mental Component Summary (MCS)p-value: 0.00595% CI: [1.29, 2.69]Regression, Logistic
Other Pre-specified
EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Reduction in the Headache Impact Test (HIT-6) From Baseline to Week 24
The HIT-6 is a widely used patient-reported outcome measure that assesses the negative effects of headaches on normal activity. Six items assess the frequency of pain severity, headaches limiting daily activity (household, work, school, and social), wanting to lie down when headache is experienced, feeling too tired to work or do daily activities because of headache, feeling fed up or irritated because of headache, and headaches limiting ability to concentrate or work on daily activities. Each of the 6 questions is responded to using 1 of 5 response categories: never, rarely, sometimes, very often, or always. For each HIT-6 item, 6, 8, 10, 11, or 13 points, respectively, are assigned to the response provided. These points are summed to produce a total HIT-6 score that ranges from 36 to 78. HIT-6 scores are categorized into 4 grades: little or no impact (49 or less), some impact (50 - 55), substantial impact (56 - 59), and severe impact (60 - 78) due to headache.
Time frame: Baseline, Week 24
Population: Full Analysis Set (FAS)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Erenumab | EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Reduction in the Headache Impact Test (HIT-6) From Baseline to Week 24 | 280 Participants |
| Topiramate | EXPLORATORY ENDPOINT: Proportion of Patients Achieving at Least a 5 Points Reduction in the Headache Impact Test (HIT-6) From Baseline to Week 24 | 209 Participants |
p-value: <0.00195% CI: [1.7, 3.12]Regression, Logistic