Headache, Migraine, Migraine Disorders
Conditions
Keywords
Pediatric, Children, Adolescent, Headache, Migraine
Brief summary
The purpose of this research study is to test two medicines for migraine prevention in children and adolescents.
Detailed description
The purpose of this research study is to test two medicines for migraine prevention in children and adolescents. The investigators want to see if amitriptyline and/or topiramate are better than placebo (sugar pill) in reducing headache frequency in children and adolescents ages 8 to 17 with migraines. At this time, there are no FDA approved medicines approved in the US for the prevention treatment of migraine headaches in children and adolescents.
Interventions
DRUGAmitriptyline
Amitriptyline will be administered twice daily at home during the 8-week titration period followed by a 16 week maintenance phase of the highest tolerated dose. The morning dose is a placebo pill. Dosing of amitriptyline will be weight-based.
DRUGTopiramate
Topiramate will be administered twice daily at home during the 8-week titration period followed by a 16 week maintenance phase of the highest tolerated dose. Dosing of topiramate will be weight-based.
DRUGPlacebo
Placebo will be administered twice daily at home during the 8-week titration period followed by a 16 week maintenance period.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Migraine with or without aura (International Classification of Headache Disorders, 2nd Edition (ICHD-II) or chronic migraine (ICHD-II revised) * Migraine frequency based upon prospective headache diary of 28 days must be ≥ 4. Migraine frequency defined as any migraine during one day in the 28 day baseline period (1) * PedMIDAS Disability Score \> 10, indicating at least mild disruption in daily activities and \< 140, indicating extreme disability that may require more comprehensive, multi-component therapy * Females or males 8-17 years, inclusive 1. Migraine frequency is defined as the period from the onset to the stop time of painful migraine symptoms not to exceed 24 hours with the clock starting at midnight. If painful symptoms last longer than 24 hours, this is considered a new and distinct migraine headache. If painful symptoms recur within 24 hours of initial onset, this is considered part of the initial migraine episode and would be counted as one migraine.
Exclusion criteria
* Continuous migraine defined as an unrelenting headache for a 28 day period * Weight less than 30 kg or greater than 120 kg * Unwilling to avoid taking non-specific acute medication such as NSAIDS (e.g., ibuprofen), more than 3 times per week, or migraine specific acute medications such as triptans more than 6 times per month * Currently taking other prophylactic anti-migraine medication within a period equivalent to 2 weeks of that medication before entering the screening phase, or the use of Botulinum toxin (Botox®) within 3 months of entering the screening phase * Subjects who have previously failed an adequate trial of AMI or TPM for prophylaxis of at least 3 months duration at doses recommended for migraine relief because of lack of efficacy or adverse events(2) * Current use of disallowed medications/products: opioids, antipsychotics, antimanics, barbiturates, benzodiazepines, muscle relaxants, sedatives, tramadol, nutraceuticals, SSRIs, or SSNRIs * Known history of allergic reaction or anaphylaxis to AMI or TPM * Abnormal findings on ECG at baseline, particularly lengthening of the QT interval greater than or equal to 450 msec * Subject is pregnant or has a positive pregnancy test * Subject is sexually active and not using a medically acceptable form of contraception * Diagnosis of epilepsy or other neurological diseases * History of kidney stones * Inability to swallow pills after using behavioral techniques if indicated between screening visit and baseline visit (3) * Present psychiatric disease as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM IV) (e.g. psychosis, bipolar disorder, major depression, generalized anxiety disorder), alcohol or drug dependence, or documented developmental delays or impairments (e.g., autism, cerebral palsy, or mental retardation) that, in the opinion of the site investigator, would interfere with adherence to study requirements or safe participation in the trial * Any and all other diagnoses or conditions which in the opinion of the site investigator, that would prevent the patient from being a suitable candidate for the study or interfere with the medical care needs of the study subject (2)Previously failed an adequate trial of AMI or TPM is defined as: dosage of 1mg/kg/day of AMI or 2 mg/kg/day of TPM; trial of at least 3 months duration; efficacy of having at least a 50% decrease in migraine frequency in response to drug therapy; or unable to tolerate taking the medication due to treatment-related side effects. (3)Subjects who cannot swallow pills at the time of the screening visit will be given a training session using behavioral techniques. Upon return for baseline visit, if the subject continues to be unable to swallow pills, the subject will be excluded from the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number (Percentage) of Participants Reporting a ≥ 50% Reduction in Headache Days | 4 week baseline period and last 4 weeks of the 24-week trial | The primary endpoint was a ≥ 50% reduction in headache frequency from the 28 days (4 weeks) baseline period prior to randomization to the last 28 days (4 weeks) of the trial. Headache frequency was defined as the number of days with headache for a given four week 28 day (4 week) period. A headache day was defined as any day during which any headache occurs within a 24 hour period, starting and ending at midnight. For each participant, the primary endpoint involved a determination of whether a 50% or greater reduction in headache frequency was observed during the last 4 weeks of active treatment as compared with the headache frequency during the 4-week baseline period. Results were compared across the three treatment groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Absolute Headache Disability Score on PedMIDAS | baseline and 24 week endpoint | The PedMIDAS scale which evaluated the impact of headaches in school, home, play, and social activities, is comprised of six items that pertain to days missed in various activities over the past 90 days. Questions were answered by the youth in consultation with their parents and reviewed by study staff. The PedMIDAS scale was administered at baseline (covering the three months prior to enrollment) and at the 24-week endpoint visit (the end of the maintenance period, covering three months of enrollment). A total PedMIDAS score (sum of items 1-6) was used in this trial. Scores range from 0-240; with a score of 0-10 indicating no disability, 11-30 mild disability, 31-50 moderate disability, and more than 50 severe disability in daily activities. The main outcome measure for this comparison will be the difference in the baseline and endpoint (24 week) PedMIDAS total scores for: 1. Amitriptyline vs. Placebo 2. Topiramate vs. Placebo 3. Amitriptyline vs Topiramate |
| Change in Number of Headache Days | 4 week baseline period and last 4 weeks of the 24-week trial | This outcomes measure examines whether the rate of absolute number of headache days, per 28 day period, differs between treatment groups over time. This was assessed longitudinally based on the actual number of headache days from the 28 days prior to randomization to the last 28 days of this 24 week trial. The change in absolute headache days was compared between: 1. Amitriptyline vs. placebo 2. Topiramate vs. placebo 3. Amitriptyline vs. Topiramate |
| Tolerability, as Indicated by the Number (Percentage) of Participants That Completed the 24-week Treatment Phase | 24 weeks | To assess tolerability, the percentage of subjects who complete the entire 24-week treatment period will be estimated in each of the three groups. |
| Occurrence of Treatment Emergent Serious Adverse Events | 24 weeks of the trial | To determine if amitriptyline or topiramate differ from placebo on the occurrence of treatment emergent serious adverse events. |
Countries
United States
Participant flow
Recruitment details
From July 16, 2012 through November 24, 2014, 488 patients were assessed for eligibility from 31 sites in the United States. Of those, 361 patients underwent randomization.
Pre-assignment details
Of the patients assessed for eligibility, 21 (4%) did not undergo randomization owing to early trial closure and 106 (22%) were excluded. Eighty-one (81) were excluded due to not meeting inclusion criteria, 25 declined participation (13 were unwilling, but eligibility was otherwise confirmed and 12 were willing and eligibility was unknown).
Participants by arm
| Arm | Count |
|---|---|
| Topiramate Topiramate enclosed in capsules to maintain the blind was administered orally in a divided dose of 1 capsule twice daily. A target dose was 2 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved. | 145 |
| Placebo Placebo enclosed in capsules to maintain the blind was administered orally twice daily during an 8 week titration period followed by a 16 week maintenance phase (mirroring the other two treatment arms). | 72 |
| Amitriptyline Amitriptyline enclosed in capsules to maintain the blind was administered orally in dose of 1 capsule twice daily (AM capsule did not contain medication. A target dose was 1 mg per kilogram per day. Dose escalation occurred every two weeks over a period of 8 weeks, with dose modification based on side effects. A 16 week constant-dose (maintenance) phase followed at the highest dosage achieved. | 144 |
| Total | 361 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Early Study Closure | 15 | 6 | 12 |
Baseline characteristics
| Characteristic | Placebo | Amitriptyline | Topiramate | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 72 Participants | 144 Participants | 145 Participants | 361 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 14.2 years STANDARD_DEVIATION 2.2 | 14.2 years STANDARD_DEVIATION 2.4 | 14.2 years STANDARD_DEVIATION 2.5 | 14.2 years STANDARD_DEVIATION 2.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 6 Participants | 8 Participants | 14 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 65 Participants | 128 Participants | 123 Participants | 316 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 8 Participants | 8 Participants | 17 Participants |
| Headache Days | 11.0 days STANDARD_DEVIATION 6.3 | 11.5 days STANDARD_DEVIATION 6.2 | 11.5 days STANDARD_DEVIATION 6.1 | 11.4 days STANDARD_DEVIATION 6.1 |
| Pediatric Migriane Disability Assessment Score (PedMIDAS) | 42.9 units on a scale STANDARD_DEVIATION 26.7 | 40.6 units on a scale STANDARD_DEVIATION 26.4 | 42.6 units on a scale STANDARD_DEVIATION 27.4 | 41.9 units on a scale STANDARD_DEVIATION 26.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 5 Participants | 8 Participants | 14 Participants | 27 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 6 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 26 Participants | 24 Participants | 67 Participants |
| Race (NIH/OMB) More than one race | NA Participants | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 3 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) White | 48 Participants | 107 Participants | 98 Participants | 253 Participants |
| Region of Enrollment United States | 72 Participants | 144 Participants | 145 Participants | 361 Participants |
| Sex: Female, Male Female | 49 Participants | 97 Participants | 101 Participants | 247 Participants |
| Sex: Female, Male Male | 23 Participants | 47 Participants | 44 Participants | 114 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 | 111 / 145 | 51 / 72 | 106 / 144 |
| serious Total, serious adverse events | 4 / 145 | 2 / 72 | 6 / 144 |
Outcome results
Primary
Number (Percentage) of Participants Reporting a ≥ 50% Reduction in Headache Days
The primary endpoint was a ≥ 50% reduction in headache frequency from the 28 days (4 weeks) baseline period prior to randomization to the last 28 days (4 weeks) of the trial. Headache frequency was defined as the number of days with headache for a given four week 28 day (4 week) period. A headache day was defined as any day during which any headache occurs within a 24 hour period, starting and ending at midnight. For each participant, the primary endpoint involved a determination of whether a 50% or greater reduction in headache frequency was observed during the last 4 weeks of active treatment as compared with the headache frequency during the 4-week baseline period. Results were compared across the three treatment groups.
Time frame: 4 week baseline period and last 4 weeks of the 24-week trial
Population: The primary endpoint involved a determination of whether a 50% or greater reduction in headache frequency was observed during the last 4 weeks of active treatment as compared with the headache frequency during the 4-week baseline period between the participants receiving amitriptyline and participants receiving placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Topiramate | Number (Percentage) of Participants Reporting a ≥ 50% Reduction in Headache Days | 72 Participants |
| Placebo | Number (Percentage) of Participants Reporting a ≥ 50% Reduction in Headache Days | 40 Participants |
| Amitriptyline | Number (Percentage) of Participants Reporting a ≥ 50% Reduction in Headache Days | 69 Participants |
Comparison: Logistic regression models were used to estimate the odds of successful primary endpoint for amitriptyline relative to placebo. The analyses followed the intention to treat principle, imputing an outcome of failure for any participant who withdrew early for any reason or did not provide week 24 headache diary data (endpoint data). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).p-value: 0.263698.3% CI: [0.34, 1.48]Regression, Logistic
Comparison: Logistic regression models were used to estimate the odds of successful primary endpoint for topiramate relative to placebo. The analyses followed the intention to treat principle, imputing an outcome of failure for any participant who withdrew early for any reason or did not provide week 24 headache diary data (endpoint data). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).p-value: 0.482198.3% CI: [0.39, 1.68]Regression, Logistic
Comparison: Logistic regression models were used to estimate the odds of successful primary endpoint for topiramate relative to amitriptyline. The analyses followed the intention to treat principle, imputing an outcome of failure for any participant who withdrew early for any reason or did not provide week 24 headache diary data (endpoint data). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).p-value: 0.610798.3% CI: [0.49, 1.59]Regression, Logistic
Secondary
Change in Absolute Headache Disability Score on PedMIDAS
The PedMIDAS scale which evaluated the impact of headaches in school, home, play, and social activities, is comprised of six items that pertain to days missed in various activities over the past 90 days. Questions were answered by the youth in consultation with their parents and reviewed by study staff. The PedMIDAS scale was administered at baseline (covering the three months prior to enrollment) and at the 24-week endpoint visit (the end of the maintenance period, covering three months of enrollment). A total PedMIDAS score (sum of items 1-6) was used in this trial. Scores range from 0-240; with a score of 0-10 indicating no disability, 11-30 mild disability, 31-50 moderate disability, and more than 50 severe disability in daily activities. The main outcome measure for this comparison will be the difference in the baseline and endpoint (24 week) PedMIDAS total scores for: 1. Amitriptyline vs. Placebo 2. Topiramate vs. Placebo 3. Amitriptyline vs Topiramate
Time frame: baseline and 24 week endpoint
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate | Change in Absolute Headache Disability Score on PedMIDAS | -26.8 units on a scale | Standard Deviation 27.5 |
| Placebo | Change in Absolute Headache Disability Score on PedMIDAS | -22.6 units on a scale | Standard Deviation 29.42 |
| Amitriptyline | Change in Absolute Headache Disability Score on PedMIDAS | -22.5 units on a scale | Standard Deviation 26.37 |
Comparison: The mean change from baseline in PedMIDAS score over time for the three groups was assessed using a linear regression model for each of the three pairwise comparisons (Amitriptyline relative to placebo, Topiramate relative to placebo, and Amitriptyline relative to Topiramate), adjusted for the baseline PedMIDAS score. The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).p-value: 0.913795% CI: [-6.64, 5.95]Regression, Linear
Comparison: The mean change from baseline in PedMIDAS score over time for the three groups was assessed using a linear regression model for each of the three pairwise comparisons (Amitriptyline relative to placebo, Topiramate relative to placebo, and Amitriptyline relative to Topiramate), adjusted for the baseline PedMIDAS score. The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).p-value: 0.133195% CI: [-11.16, 1.49]Regression, Linear
Comparison: The mean change from baseline in PedMIDAS score over time for the three groups was assessed using a linear regression model for each of the three pairwise comparisons (Amitriptyline relative to placebo, Topiramate relative to placebo, and Amitriptyline relative to Topiramate), adjusted for the baseline PedMIDAS score. The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).p-value: 0.101195% CI: [-0.88, 9.87]Regression, Linear
Secondary
Change in Number of Headache Days
This outcomes measure examines whether the rate of absolute number of headache days, per 28 day period, differs between treatment groups over time. This was assessed longitudinally based on the actual number of headache days from the 28 days prior to randomization to the last 28 days of this 24 week trial. The change in absolute headache days was compared between: 1. Amitriptyline vs. placebo 2. Topiramate vs. placebo 3. Amitriptyline vs. Topiramate
Time frame: 4 week baseline period and last 4 weeks of the 24-week trial
Population: The analysis population included all participants who had observed end-point data: 101 in the topiramate group, 59 in the placebo group, and104 in the amitriptyline group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate | Change in Number of Headache Days | -6.7 days | Standard Deviation 4.99 |
| Placebo | Change in Number of Headache Days | -5.9 days | Standard Deviation 6.96 |
| Amitriptyline | Change in Number of Headache Days | -6.7 days | Standard Deviation 6.2 |
Comparison: Another major secondary objective was to determine if the change in absolute headache days from baseline to week 24 differed between treatment groups. This objective was assessed using linear regression models, with three pairwise comparisons between treatment groups (Amitriptyline vs. Placebo, Topiramate vs. Placebo, and Amitriptyline vs. Topiramate). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).p-value: 0.355398.3% CI: [-2.59, 1.15]Regression, Linear
Comparison: Another major secondary objective was to determine if the change in absolute headache days from baseline to week 24 differed between treatment groups. This objective was assessed using linear regression models, with three pairwise comparisons between treatment groups (Amitriptyline vs. Placebo, Topiramate vs. Placebo, and Amitriptyline vs. Topiramate). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).p-value: 0.414398.3% CI: [-2.52, 1.24]Regression, Linear
Comparison: Another major secondary objective was to determine if the change in absolute headache days from baseline to week 24 differed between treatment groups. This objective was assessed using linear regression models, with three pairwise comparisons between treatment groups (Amitriptyline vs. Placebo, Topiramate vs. Placebo, and Amitriptyline vs. Topiramate). The models, and corresponding odds ratios, were adjusted for the two stratification variables (age and baseline number of headache days).p-value: 0.903898.3% CI: [-1.68, 1.52]Regression, Linear
Secondary
Occurrence of Treatment Emergent Serious Adverse Events
To determine if amitriptyline or topiramate differ from placebo on the occurrence of treatment emergent serious adverse events.
Time frame: 24 weeks of the trial
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Topiramate | Occurrence of Treatment Emergent Serious Adverse Events | 4 serious adverse events |
| Placebo | Occurrence of Treatment Emergent Serious Adverse Events | 2 serious adverse events |
| Amitriptyline | Occurrence of Treatment Emergent Serious Adverse Events | 6 serious adverse events |
Comparison: The occurrence of treatment-related SAE's was assessed in two ways: 1) percentage of subjects who experience any treatment-related SAE in each of the three groups was compared using Fishers exact test; 2) rates of treatment-emergent SAS's across the three groups were compared using a Poisson regression model. However, due to the small number of SAEs that were deemed treatment-emergent (4 in AMI, 1 in TPM, 0 in PBO), the parameter estimates did not converge for the Poisson regression model.p-value: 0.3038Fisher Exact
Comparison: The occurrence of treatment-related SAE's was assessed in two ways: 1) percentage of subjects who experience any treatment-related SAE in each of the three groups was compared using Fishers exact test; 2) rates of treatment-emergent SAS's across the three groups were compared using a Poisson regression model. However, due to the small number of SAEs that were deemed treatment-emergent (4 in AMI, 1 in TPM, 0 in PBO), the parameter estimates did not converge for the Poisson regression model.p-value: 1Fisher Exact
Comparison: The occurrence of treatment-related SAE's was assessed in two ways: 1) percentage of subjects who experience any treatment-related SAE in each of the three groups was compared using Fishers exact test; 2) rates of treatment-emergent SAS's across the three groups were compared using a Poisson regression model. However, due to the small number of SAEs that were deemed treatment-emergent (4 in AMI, 1 in TPM, 0 in PBO), the parameter estimates did not converge for the Poisson regression model.p-value: 0.2139Fisher Exact
Secondary
Tolerability, as Indicated by the Number (Percentage) of Participants That Completed the 24-week Treatment Phase
To assess tolerability, the percentage of subjects who complete the entire 24-week treatment period will be estimated in each of the three groups.
Time frame: 24 weeks
Population: Tolerability was assessed for all participants included in the primary analysis. Of those randomized, 33 were not included in the primary analysis due to early trial closure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Topiramate | Tolerability, as Indicated by the Number (Percentage) of Participants That Completed the 24-week Treatment Phase | 102 Participants |
| Placebo | Tolerability, as Indicated by the Number (Percentage) of Participants That Completed the 24-week Treatment Phase | 59 Participants |
| Amitriptyline | Tolerability, as Indicated by the Number (Percentage) of Participants That Completed the 24-week Treatment Phase | 106 Participants |
Comparison: Tolerability was assessed by calculating the percent of subjects who completed the entire 24 week treatment period and the corresponding 95% confidence intervals for each treatment group. Concerns regarding tolerability would be raised if the upper bound of a confidence interval was less than 65% or if the percent of subjects who completed the entire 24 week treatment period in either of the active treatment groups was significantly less than the placebo group.p-value: 0.155795% CI: [0.85, 5.05]Fisher Exact
Comparison: Tolerability was assessed by calculating the percent of subjects who completed the entire 24 week treatment period and the corresponding 95% confidence intervals for each treatment group. Concerns regarding tolerability would be raised if the upper bound of a confidence interval was less than 65% or if the percent of subjects who completed the entire 24 week treatment period in either of the active treatment groups was significantly less than the placebo group.p-value: 0.075495% CI: [0.95, 5.62]Fisher Exact
Comparison: Tolerability was assessed by calculating the percent of subjects who completed the entire 24 week treatment period and the corresponding 95% confidence intervals for each treatment group. Concerns regarding tolerability would be raised if the upper bound of a confidence interval was less than 65% or if the percent of subjects who completed the entire 24 week treatment period in either of the active treatment groups was significantly less than the placebo group.p-value: 0.761195% CI: [0.49, 1.62]Fisher Exact