Migraine
Conditions
Keywords
Migraine headache, menstrual, oral contraceptive, Menstrually-Related Migraine Headache
Brief summary
This study is being conducted to evaluate the efficacy of a 91-day extended cycle oral contraceptive compared to placebo for decreasing the frequency and severity of menstrually-related migraine headaches.
Interventions
91-day treatment consisting of 84 blue combination tablets containing 150 µg LNG/30 µg EE and 7 yellow tablets containing 10 µg EE.
DRUGPlacebo
1 tablet daily to match experimental arm
Sponsors
Duramed Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 34 Years
Healthy volunteers
No
Inclusion criteria
* Premenopausal, non-pregnant, non-lactating * History of migraine headaches without aura for at least 6 months * History of migraine headaches associated with menstruation * Others as directed by FDA-approved protocol
Exclusion criteria
* History of migraine headaches with aura or focal neurological symptoms * Any contraindication to the use of oral contraceptives * Others as dictated by FDA-approved protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the Treatment Period | Baseline (25-35 days before Day 1) and Days 1-91 | The number of participants with at least 50% reduction in migraine frequency (average weekly number of migraine episodes) through the end of the 91-day treatment period compared with Baseline (the 25- to 35-day baseline qualification period). Participants recorded the incidence, timing and intensity of migraines in a migraine diary during the prequalification period and throughout the 91-day treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Average Migraine Severity | Baseline and Month 1, Month 2 and Month 3 | Migraine severity was recorded by participants in the Baseline qualification diary and study migraine diary during the treatment period. Participants could report a severity of none (score = 0), mild (1), moderate (2), or severe (3). In general, if a headache was mild, daily activities could be resumed and little to no medication was taken. Moderate headaches required medication and effected daily activities. Severe headaches were debilitating and required medication. Average migraine severity is defined as the sum of the severity ratings divided by the total number of migraine episodes reported during the observation period (for example, Baseline, First Month, Second Month, Third Month, and 91-Day Treatment Period). A negative change from Baseline score indicates improvement in severity. |
| Percentage of Participants Who Required Rescue Medications During the Study Period | Baseline, Month 1, Month 2 and Month 3 | Participants recorded use of rescue medications for migraines in the migraine diary during the course of study treatment. |
| Change From Baseline in Migraine Disability Assessment | Baseline and Week 15 | The migraine disability assessment (MIDAS) test is used to determine how severely migraines affect a patient's life. Participants were asked five questions about how often their headaches limited their ability to go to work or school, to do household work or to do family or leisure activities in the past 3 months. The MIDAS score equals the sum of the days answered for each question and ranges from 0 (no disability) to approximately 270 (severe disability; the upper bound is dependent on the number of days a participant would plan to work or participate in other activities). The MIDAS score is classified into four grades of severity: * 0 to 5: MIDAS Grade I, Little or no disability * 6 to 10: MIDAS Grade II, Mild disability * 11 to 20: MIDAS Grade III, Moderate disability * 21+: MIDAS Grade IV, Severe disability |
| Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the First, Second and Third Months | Baseline, Month1, Month 2 and Month 3 | The percentage of participants with at least 50% reduction in migraine frequency (average weekly number of migraine episodes) compared to Baseline at each month of the treatment period. |
| Number of Participants With Adverse Events (AEs) | Up to 15 weeks | An AE is any untoward medical occurrence in a clinical investigation participant and which does not necessarily have to have a causal relationship with this treatment or clinical study. The following definitions were used to assess AE severity: Mild: Awareness of signs or symptoms, but they are easily tolerated; Moderate: Enough discomfort to cause interference with usual activity; Severe: Incapacitating, with inability to perform usual activity. Relationship to study drug was assessed as either: None: Causal relationship can be ruled out; Possibly: Causal relationship at least reasonably possible, i.e. relationship cannot be ruled out; Definitely: Causal relationship is certain. A serious adverse event (SAE) is one that met any one of the following criteria: * Fatal or life threatening * Requires or prolongs in patient hospitalization * Results in persistent or significant disability/incapacity * Congenital anomaly / birth defect * Important medical event. |
| Mean Number of Days of Bleeding or Spotting | 91-day treatment period | Bleeding and spotting were recorded by participants in the migraine diary during the 91-day treatment period. |
| Change From Baseline in Headache Impact Test | Baseline and Week 15 | The Headache Impact Test (HIT) is a tool used to measure the impact headaches have on patients' ability to function on the job, at school, at home and in social situations. HIT-6 consists of 6 questions each scored on a scale from Never (6 points) to Always (13 points). The total score ranges from 36 to 78 with higher scores indicating greater impact on life. There was an error in administration of the HIT-6 in this study. Question 6 was not administered, and question 3 from the MIDAS was included instead. Therefore, the total score of the HIT-6 could not be calculated. |
Countries
United States
Participant flow
Recruitment details
A total of 304 women with menstrually related migraine were screened for enrollment at 37 study centers in the United States. Of the 304 screened, 109 women at 23 centers met entry criteria and were considered eligible for enrollment into the study.
Participants by arm
| Arm | Count |
|---|---|
| 91-day Levonorgestrel Oral Contraceptive Participants received 12 weeks (84 consecutive days) of active combination tablets containing 150 µg levonorgestrel (LNG)/30 µg ethinyl estradiol (EE), followed by 7 days of 10 µg EE monotherapy, for a total of 13 weeks. | 54 |
| Placebo Participants received placebo, 12 weeks (84 consecutive days) of inactive tablets, followed by an additional 7 days of inactive tablets, for a total of 13 weeks. | 45 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 3 |
| Overall Study | Lost to Follow-up | 10 | 5 |
| Overall Study | Noncompliance With Protocol | 1 | 1 |
| Overall Study | Other Reason, Unknown | 0 | 1 |
| Overall Study | Protocol Violation | 4 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 5 |
Baseline characteristics
| Characteristic | 91-day Levonorgestrel Oral Contraceptive | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 26.7 years STANDARD_DEVIATION 4.7 | 27.4 years STANDARD_DEVIATION 3.83 | 27.1 years STANDARD_DEVIATION 4.32 |
| Gender Female | 54 Participants | 45 Participants | 99 Participants |
| Gender Male | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Black | 11 participants | 9 participants | 20 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 14 participants | 10 participants | 24 participants |
| Race/Ethnicity, Customized Other | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized White | 28 participants | 23 participants | 51 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 57 | 11 / 49 |
| serious Total, serious adverse events | 0 / 57 | 0 / 49 |
Outcome results
Primary
Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the Treatment Period
The number of participants with at least 50% reduction in migraine frequency (average weekly number of migraine episodes) through the end of the 91-day treatment period compared with Baseline (the 25- to 35-day baseline qualification period). Participants recorded the incidence, timing and intensity of migraines in a migraine diary during the prequalification period and throughout the 91-day treatment period.
Time frame: Baseline (25-35 days before Day 1) and Days 1-91
Population: Intent-to-treat population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 91-day Levonorgestrel Oral Contraceptive | Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the Treatment Period | 48.1 percentage of participants |
| Placebo | Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the Treatment Period | 48.9 percentage of participants |
p-value: 0.95495% CI: [-0.82, 0.87]Regression, Logistic
Secondary
Change From Baseline in Average Migraine Severity
Migraine severity was recorded by participants in the Baseline qualification diary and study migraine diary during the treatment period. Participants could report a severity of none (score = 0), mild (1), moderate (2), or severe (3). In general, if a headache was mild, daily activities could be resumed and little to no medication was taken. Moderate headaches required medication and effected daily activities. Severe headaches were debilitating and required medication. Average migraine severity is defined as the sum of the severity ratings divided by the total number of migraine episodes reported during the observation period (for example, Baseline, First Month, Second Month, Third Month, and 91-Day Treatment Period). A negative change from Baseline score indicates improvement in severity.
Time frame: Baseline and Month 1, Month 2 and Month 3
Population: Intent-to-treat population with available data. N indicates the number of participants with available data at each time period.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| 91-day Levonorgestrel Oral Contraceptive | Change From Baseline in Average Migraine Severity | 91-Day Treatment Period (N=54, 45) | -0.37 units on a scale | Standard Error 0.097 |
| 91-day Levonorgestrel Oral Contraceptive | Change From Baseline in Average Migraine Severity | First Month (N=54, 45) | -0.55 units on a scale | Standard Error 0.138 |
| 91-day Levonorgestrel Oral Contraceptive | Change From Baseline in Average Migraine Severity | Second Month (N= 51, 44) | -0.98 units on a scale | Standard Error 0.158 |
| 91-day Levonorgestrel Oral Contraceptive | Change From Baseline in Average Migraine Severity | Third Month (N=40, 37) | -1.06 units on a scale | Standard Error 0.19 |
| Placebo | Change From Baseline in Average Migraine Severity | Third Month (N=40, 37) | -0.66 units on a scale | Standard Error 0.197 |
| Placebo | Change From Baseline in Average Migraine Severity | 91-Day Treatment Period (N=54, 45) | -0.18 units on a scale | Standard Error 0.109 |
| Placebo | Change From Baseline in Average Migraine Severity | Second Month (N= 51, 44) | -0.72 units on a scale | Standard Error 0.173 |
| Placebo | Change From Baseline in Average Migraine Severity | First Month (N=54, 45) | -0.52 units on a scale | Standard Error 0.154 |
Comparison: Comparison of change from Baseline in migraine severity during the 91-day treatment period.p-value: 0.18295% CI: [-0.47, 0.09]ANCOVA
Comparison: Comparison of change from Baseline in migraine severity during the first month of treatmentp-value: 0.85395% CI: [-0.71, 0.19]ANCOVA
Comparison: Comparison of change from Baseline in migraine severity during the second month of treatmentp-value: 0.24995% CI: [-0.71, 0.19]ANCOVA
Comparison: Comparison of change from Baseline in migraine severity during the third month of treatmentp-value: 0.11995% CI: [-0.9, 0.1]ANCOVA
Secondary
Change From Baseline in Headache Impact Test
The Headache Impact Test (HIT) is a tool used to measure the impact headaches have on patients' ability to function on the job, at school, at home and in social situations. HIT-6 consists of 6 questions each scored on a scale from Never (6 points) to Always (13 points). The total score ranges from 36 to 78 with higher scores indicating greater impact on life. There was an error in administration of the HIT-6 in this study. Question 6 was not administered, and question 3 from the MIDAS was included instead. Therefore, the total score of the HIT-6 could not be calculated.
Time frame: Baseline and Week 15
Population: Analysis was not performed due to an error in the administration of the test.
Secondary
Change From Baseline in Migraine Disability Assessment
The migraine disability assessment (MIDAS) test is used to determine how severely migraines affect a patient's life. Participants were asked five questions about how often their headaches limited their ability to go to work or school, to do household work or to do family or leisure activities in the past 3 months. The MIDAS score equals the sum of the days answered for each question and ranges from 0 (no disability) to approximately 270 (severe disability; the upper bound is dependent on the number of days a participant would plan to work or participate in other activities). The MIDAS score is classified into four grades of severity: * 0 to 5: MIDAS Grade I, Little or no disability * 6 to 10: MIDAS Grade II, Mild disability * 11 to 20: MIDAS Grade III, Moderate disability * 21+: MIDAS Grade IV, Severe disability
Time frame: Baseline and Week 15
Population: Intent-to-treat population with available data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 91-day Levonorgestrel Oral Contraceptive | Change From Baseline in Migraine Disability Assessment | -7.8 units on a scale | Standard Deviation 16.26 |
| Placebo | Change From Baseline in Migraine Disability Assessment | -8.5 units on a scale | Standard Deviation 10.65 |
Secondary
Mean Number of Days of Bleeding or Spotting
Bleeding and spotting were recorded by participants in the migraine diary during the 91-day treatment period.
Time frame: 91-day treatment period
Population: Safety population with available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 91-day Levonorgestrel Oral Contraceptive | Mean Number of Days of Bleeding or Spotting | 21.2 days | Standard Deviation 19.58 |
| Placebo | Mean Number of Days of Bleeding or Spotting | 15.5 days | Standard Deviation 7.73 |
Secondary
Number of Participants With Adverse Events (AEs)
An AE is any untoward medical occurrence in a clinical investigation participant and which does not necessarily have to have a causal relationship with this treatment or clinical study. The following definitions were used to assess AE severity: Mild: Awareness of signs or symptoms, but they are easily tolerated; Moderate: Enough discomfort to cause interference with usual activity; Severe: Incapacitating, with inability to perform usual activity. Relationship to study drug was assessed as either: None: Causal relationship can be ruled out; Possibly: Causal relationship at least reasonably possible, i.e. relationship cannot be ruled out; Definitely: Causal relationship is certain. A serious adverse event (SAE) is one that met any one of the following criteria: * Fatal or life threatening * Requires or prolongs in patient hospitalization * Results in persistent or significant disability/incapacity * Congenital anomaly / birth defect * Important medical event.
Time frame: Up to 15 weeks
Population: Safety population, consisting of all participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Any adverse event | 32 participants |
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Mild adverse event | 11 participants |
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Moderate adverse event | 17 participants |
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Severe adverse event | 4 participants |
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Adverse event not related to study drug | 11 participants |
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Adverse event possibly related to study drug | 20 participants |
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Adverse event related to study drug | 1 participants |
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Deaths | 0 participants |
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Other serious adverse event | 0 participants |
| 91-day Levonorgestrel Oral Contraceptive | Number of Participants With Adverse Events (AEs) | Withdrawn due to adverse event | 3 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Deaths | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Any adverse event | 17 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Adverse event possibly related to study drug | 11 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Mild adverse event | 2 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Withdrawn due to adverse event | 3 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Moderate adverse event | 10 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Adverse event related to study drug | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Severe adverse event | 5 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Other serious adverse event | 0 participants |
| Placebo | Number of Participants With Adverse Events (AEs) | Adverse event not related to study drug | 6 participants |
Secondary
Percentage of Participants Who Required Rescue Medications During the Study Period
Participants recorded use of rescue medications for migraines in the migraine diary during the course of study treatment.
Time frame: Baseline, Month 1, Month 2 and Month 3
Population: Intent-to-treat population with available data. N indicates the number of participants with available data at each time period.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 91-day Levonorgestrel Oral Contraceptive | Percentage of Participants Who Required Rescue Medications During the Study Period | During the 91-day treatment period (N=54, 45) | 72.2 percentage of participants |
| 91-day Levonorgestrel Oral Contraceptive | Percentage of Participants Who Required Rescue Medications During the Study Period | Baseline (N=54, 45) | 85.2 percentage of participants |
| 91-day Levonorgestrel Oral Contraceptive | Percentage of Participants Who Required Rescue Medications During the Study Period | First Month (N=54, 45) | 63.0 percentage of participants |
| 91-day Levonorgestrel Oral Contraceptive | Percentage of Participants Who Required Rescue Medications During the Study Period | Second Month (N=51, 44) | 45.1 percentage of participants |
| 91-day Levonorgestrel Oral Contraceptive | Percentage of Participants Who Required Rescue Medications During the Study Period | Third Month (N=40, 37) | 35.0 percentage of participants |
| Placebo | Percentage of Participants Who Required Rescue Medications During the Study Period | Third Month (N=40, 37) | 62.2 percentage of participants |
| Placebo | Percentage of Participants Who Required Rescue Medications During the Study Period | Second Month (N=51, 44) | 54.5 percentage of participants |
| Placebo | Percentage of Participants Who Required Rescue Medications During the Study Period | Baseline (N=54, 45) | 75.6 percentage of participants |
| Placebo | Percentage of Participants Who Required Rescue Medications During the Study Period | During the 91-day treatment period (N=54, 45) | 75.6 percentage of participants |
| Placebo | Percentage of Participants Who Required Rescue Medications During the Study Period | First Month (N=54, 45) | 55.6 percentage of participants |
Comparison: Comparison of percentage of participants requiring rescue medication during the first month of treatment.p-value: 0.457Cochran-Mantel-Haenszel
Comparison: Comparison of percentage of participants requiring rescue medication during the second month of treatment.p-value: 0.361Cochran-Mantel-Haenszel
Comparison: Comparison of percentage of participants requiring rescue medication during the third month of treatment.p-value: 0.018Cochran-Mantel-Haenszel
Comparison: Comparison of percentage of participants requiring rescue medication during the 91-day treatment period.p-value: 0.709Cochran-Mantel-Haenszel
Secondary
Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the First, Second and Third Months
The percentage of participants with at least 50% reduction in migraine frequency (average weekly number of migraine episodes) compared to Baseline at each month of the treatment period.
Time frame: Baseline, Month1, Month 2 and Month 3
Population: Intent-to-treat population with available data. N indicates the number of participants with available data at each time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 91-day Levonorgestrel Oral Contraceptive | Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the First, Second and Third Months | Third Month (N=40, 37) | 60.0 percentage of participants |
| 91-day Levonorgestrel Oral Contraceptive | Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the First, Second and Third Months | First Month (N=54, 45) | 42.6 percentage of participants |
| 91-day Levonorgestrel Oral Contraceptive | Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the First, Second and Third Months | Second Month (N=51, 44) | 62.7 percentage of participants |
| Placebo | Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the First, Second and Third Months | First Month (N=54, 45) | 37.8 percentage of participants |
| Placebo | Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the First, Second and Third Months | Second Month (N=51, 44) | 52.3 percentage of participants |
| Placebo | Percentage of Participants With ≥ 50% Reduction in Migraine Frequency During the First, Second and Third Months | Third Month (N=40, 37) | 64.9 percentage of participants |
Comparison: Comparison of percentage of participants with a reduction of 50% or more in migraine frequency during the first month of treatment.p-value: 0.47995% CI: [-0.55, 1.17]Regression, Logistic
Comparison: Comparison of percentage of participants with a reduction of 50% or more in migraine frequency during the second month of treatmentp-value: 0.25695% CI: [-0.36, 1.37]Regression, Logistic
Comparison: Comparison of percentage of participants with a reduction of 50% or more in migraine frequency during the third month of treatment.p-value: 0.78895% CI: [-1.16, 0.88]Regression, Logistic