Migraine
Conditions
Keywords
migraine; ESL; eslicarbazepine acetate
Brief summary
This was a multinational, randomised, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy, safety, and tolerability of multiple doses of ESL as prophylactic treatment in subjects with migraine with or without aura. Subjects were randomised in a 1:1:1 ratio to receive placebo, ESL 800 mg/day once daily (QD), or ESL 1200 mg/day QD.
Detailed description
The study consisted of a Screening Period of 2 to 4 weeks, a 4-week placebo Baseline Period, a 2-week Titration Period, a 12-week Maintenance Period, and a 4-week Follow-up Period. During the entire study the subjects had a diary to document the occurrence, duration, and intensity of headaches, the occurrence or not of aura and its nature, as well as other related symptoms, and the use of study medication and acute medication.
Interventions
DRUGPlacebo
Tablets
DRUGESL 1200 mg
Eslicarbazepine acetate was supplied in 400-mg and 600-mg tablets and was administered with a dose of 800 or 1200 mg QD in the evening by the oral route.
DRUGESL 800 mg
Eslicarbazepine acetate was supplied in 400-mg and 600-mg tablets and was administered with a dose of 800 or 1200 mg QD in the evening by the oral route.
Sponsors
Bial - Portela C S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Women or men, 18 years of age or older (according to Amendment #1 for Czech Republic \[24 Mar 2009\]: 18 to 65 years of age). * Diagnosis (established prior to 50 years of age) of migraine headaches for at least 1 year, and a well-documented history of migraine headaches with or without aura according to the criteria of the IHS (see Section 3.5.6.1) for at least 3 months (according to Amendment #1 for Czech Republic \[24 Mar 2009\]: for at least 3 months with at least 3 migraine attacks per month in each of these 3 months). * At least 2 (according to Amendment #1 for Czech Republic \[24 Mar 2009\]: at least 3) (and no more than 10) well-defined migraine headache attacks per month, with at least 24 h of freedom from headaches and other symptoms of migraine between attacks. * Able to distinguish the migraine headache attacks from other types of common headaches (tension-type headaches, sinus-related headaches, etc.). * Not taking any prophylactic migraine therapies for at least 2 weeks prior to Baseline Visit (V2). Flunarizine had to be discontinued at least 4 weeks prior to V2. * Able and willing to provide written informed consent to participate in the study after having the opportunity to review the Subject Information Sheet and Informed Consent Form (ICF). * Able and willing to comply with all study requirements, in the judgment of the investigator. * Women were surgically sterile (i.e. bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), or at least 2 years postmenopausal or, if of childbearing potential, were sexually abstinent or agreed to use medically acceptable non-hormonal methods of contraception (see Section 3.3.3). (According to Amendment #1 for Czech Republic \[24 Mar 2009\]: Women were sexually abstinent or agreed to use a double-barrier method of contraception. Hormonal contraceptives were not acceptable as a contraceptive method in this study. However, their intake was not forbidden throughout the study.)
Exclusion criteria
* A known hypersensitivity to ESL or to other carboxamide derivatives (e.g. oxcarbazepine, carbamazepine), or to any of the excipients. * Suspected or confirmed medication-overuse headache. * More than 14 headache days (migraine or other headache types) per month in either of the 2 months prior to screening. * Consistent or recurrent frequent headaches (i.e. ≥6 headache days a month) other than migraine headaches. * Unable to discontinue medications primarily used for migraine prophylaxis that have been commonly used for other indications (tricyclic agents, divalproic acid, topiramate, etc.). A subject who received beta blockers or calcium channel blocker therapy for reasons other than migraine prophylaxis was eligible for inclusion, provided his/her dosing regimen had been stable for ≥2 months and was not expected to change during the course of the study. * Using prohibited concomitant medication (see Section 3.5.5.2). * A white blood cell (WBC) count \<2.5 \* 109/L, neutrophil count \<1.5 \* 109/L, sodium \<125 mmol/L, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥2 times the upper limit of normal at V1 (Screening Visit), or any other clinically relevant laboratory abnormality that, in the investigator's opinion, could compromise the subject's safety. * A creatinine clearance lower than 60 mL/min at screening. * A second- or third-degree atrioventricular blockade not corrected with a pacemaker or any other clinically significant abnormality in the 12-lead electrocardiogram (ECG) as determined by the investigator. * Pregnant or nursing women. * A history of chronic alcohol or drug abuse or addiction within the last 2 years. * A severe hepatic, renal, respiratory, haematological, or immunologic illness, unstable cardiovascular disease, or any other medical or psychiatric condition that, in the judgment of the investigator, made the subject inappropriate for entry into this study. * Received an investigational drug (or a medical device) within 3 months of screening or was currently participating in another study of an investigational drug (or medical device). * An employee of the investigator or study centre, with direct involvement in the proposed study or other studies under the direction of that investigator or study centre, or was a family member of the employees or the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change From Baseline in the Frequency of Migraine Attacks | 4 weeks | The primary efficacy variable was the absolute change from baseline in the frequency of migraine attacks standardised to 4 weeks in the Maintenance Period, as recorded in the subject diary. If there were less than 24 h between the end of 1 migraine event and the start of the next event, these 2 events were considered to belong to 1 migraine attack. There had to be a minimum of 24 h of freedom from headache, pain, and symptoms of migraine between attacks recorded in the subject diary to be considered as more than 1 attack of migraine for statistical analysis. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo tablets
Placebo : Tablets | 136 |
| ESL 800 mg eslicarbazepine acetate 800 mg
ESL 800 mg : | 135 |
| ESL 1200 mg eslicarbazepine acetate 1200 mg
ESL 1200 mg : | 139 |
| Total | 410 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 | 13 |
| Overall Study | At sponsor request | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 3 | 2 | 3 |
| Overall Study | Lost to Follow-up | 3 | 2 | 2 |
| Overall Study | Protocol Violation | 2 | 1 | 3 |
| Overall Study | Subject's non-compliance | 1 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 2 | 5 |
Baseline characteristics
| Characteristic | Total | Placebo | ESL 800 mg | ESL 1200 mg |
|---|---|---|---|---|
| Age, Customized <=65 years | 406 participants | 135 participants | 135 participants | 136 participants |
| Age, Customized >65 years | 4 participants | 1 participants | 0 participants | 3 participants |
| Sex: Female, Male Female | 346 Participants | 121 Participants | 114 Participants | 111 Participants |
| Sex: Female, Male Male | 64 Participants | 15 Participants | 21 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 46 / 136 | 67 / 135 | 74 / 139 |
| serious Total, serious adverse events | 1 / 136 | 1 / 135 | 4 / 139 |
Outcome results
Primary
Absolute Change From Baseline in the Frequency of Migraine Attacks
The primary efficacy variable was the absolute change from baseline in the frequency of migraine attacks standardised to 4 weeks in the Maintenance Period, as recorded in the subject diary. If there were less than 24 h between the end of 1 migraine event and the start of the next event, these 2 events were considered to belong to 1 migraine attack. There had to be a minimum of 24 h of freedom from headache, pain, and symptoms of migraine between attacks recorded in the subject diary to be considered as more than 1 attack of migraine for statistical analysis.
Time frame: 4 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Absolute Change From Baseline in the Frequency of Migraine Attacks | -0.8 number of migraine attacks/participant | Standard Error 0.1429 |
| ESL 800 mg | Absolute Change From Baseline in the Frequency of Migraine Attacks | -1.0 number of migraine attacks/participant | Standard Error 0.1428 |
| ESL 1200 mg | Absolute Change From Baseline in the Frequency of Migraine Attacks | -1.0 number of migraine attacks/participant | Standard Error 0.1416 |