Chronic Migraine
Conditions
Keywords
chronic migraine, migraine prevention, chronic headache
Brief summary
The purpose of this study is to compare the reduction in the number of severe headache days at six months in people with chronic migraine treated with topiramate and propranolol versus those treated with topiramate and a placebo.
Detailed description
Chronic migraine affects about 2 percent of all adults. Currently there are no effective preventative treatments to deal with this disabling condition. Three randomized, placebo-controlled trials found that topiramate was an effective, safe and generally well-tolerated drug for treating chronic migraine. As a result of these trials, topiramate is becoming the standard treatment among headache specialists. Experts agree that treatment with combinations of preventive agents is required in the majority of individuals with chronic migraine for maximal headache relief. No randomized trials have assessed the value of frequently used combinations of preventive agents for chronic migraine. The goal of this trial is to determine if adding a second drug to topiramate treatment will further reduce the headache burden for people with this condition. In the study, 250 participants with chronic migraine will be randomized to two groups - treatment with topiramate and propranolol or topiramate and placebo. Participants will be followed for six months.
Interventions
DRUGpropranolol LA
Propranolol LA up to 240 mg/day
DRUGtopiramate
Topiramate is an effective, safe and generally well-tolerated drug used for treating chronic migraine. It is becoming the standard treatment among headache specialists.
DRUGplacebo
an inactive substance
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Ortho-McNeil Janssen Scientific Affairs, LLC
Anne Lindblad
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* History of chronic migraine for at least 6 months * Age ≥ 18 years and age of migraine onset 60 or younger * EKG performed in the last 12 months
Exclusion criteria
* Prior neuro-imaging suggesting secondary structural causes of headache * Beck Depression Inventory FastScreen score of 13 or greater or other severe psychiatric disorder * Contraindication to or prior intolerance of topiramate or propranolol (no history of sinus bradycardia, heart block, heart failure, diabetes prone to hypoglycemia, asthma, kidney stones) * History of kidney failure or nephrolithiasis * A female who is currently pregnant or lactating or planning to become pregnant in the next year, or is of child-bearing potential and not practicing an acceptable form of birth control * Currently requires butalbital or opioid drugs for acute headache treatment 10 or more days a month * Failure of prior trials with at least 50 mg of topiramate combined with at least 80 mg of propranolol * Use of other migraine preventive drugs (Medications graded as groups 1, 2, 3, and 4 in the AAN Evidence-based Guideline: valproate, divalproex sodium, gabapentin, amitriptyline, nortriptyline, protriptyline, beta-blocker, calcium channel blocker, cyproheptadine; and tizanidine) within the last two months or has received botulinum toxin injection in the past 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Number of Moderate to Severe Headache Days Within a 28 Day Average Period in Six Months Compared to Baseline | Baseline (pre-randomization), months 5 and 6 post randomization | (Number of moderate to severe headache days (as defined by the International Headache Society Guidelines (2006)) counted over a 28 day diary period at baseline (before treatment with propranolol or placebo)) minus (the number of moderate to severe headache days counted over a 56 day diary period (weeks 16-24 post treatment) divided by 2). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects Experiencing at Least a 50% Reduction in 28-day Moderate to Severe Headache Days | 6 months | — |
| Change From Baseline in Beck's Depression Inventory FastScreen Score at 6 Months | Baseline and 6 months | Total score from Beck's Depression Inventory FastScreen at 6 months minus total score from Beck's Depression Inventory FastScreen at baseline. Scale scores range from 0 to 21 with higher values indicating worsening depression. the following categories separate participants into groups of depression levels: Minimal (Score 0-3), Mild (Score 4-8),Moderate (Score 9-12),Severe (Score 13-21). |
| Change From Baseline in Migraine Disability Assessment (MIDAS) Score at 6 Months | Baseline and 6 months | MIDAS scoring ranges from 0 to 270. The scores are divided into ranges of disability with higher scores indicating increased disability as follows: 0-5 (Grade I - Minimal or infrequent disability); 6-10 (Grade II - Mild or infrequent disability); 11-20 (Grade III - Moderate disability); and 21+ (Grade IV - Severe disability). |
| Number of Subjects Experiencing at Least a 30% Reduction in 28-day Moderate to Severe Headache Days | 6 months post randomization | — |
| Change From Baseline in Migraine-Specific Quality of Life (MSQ)-Role Preventive at 6 Months | Baseline and 6 months | The MSQ (version 2.1 copyrighted 1992, 1996, 1998 by Glaxo Wellcome Inc., Research Triangle Park, North Carolina) is a 14 item questionnaire. Item responses are summed and scored as a total score and three domains: Role Preventive, Role Restrictive, Emotional Function. Scores within each domain are rescaled to range from 0 to 100. A lower score indicates a poorer quality of life associated with that domain or in total. Because of the observed interaction within a domain, only domain scores were used as outcome measures for this study. |
| Change From Baseline in Migraine-Specific Quality of Life (MSQ) - Emotional Function at 6 Months | Baseline and 6 Months | The MSQ (version 2.1 copyrighted 1992, 1996, 1998 by Glaxo Wellcome Inc., Research Triangle Park, North Carolina) is a 14 item questionnaire. Item responses are summed and scored as a total score and three domains: Role Preventive, Role Restrictive, Emotional Function. Scores within each domain are rescaled to range from 0 to 100. A lower score indicates a poorer quality of life associated with that domain or in total. Because of the observed interaction within a domain, only domain scores were used as outcome measures for this study. |
| Change From Baseline in Migraine Specific Quality of Life (MSQ)-Role Restrictive Score at 6 Months | baseline and 6 months post randomization | The MSQ (version 2.1 copyrighted 1992, 1996, 1998 by Glaxo Wellcome Inc., Research Triangle Park, North Carolina) is a 14 item questionnaire. Item responses are summed and scored as a total score and three domains: Role Preventive, Role Restrictive, Emotional Function. Scores within each domain are rescaled to range from 0 to 100. A lower score indicates a poorer quality of life associated with that domain or in total. Because of the observed interaction within a domain, only domain scores were used as outcome measures for this study. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Topiramate Plus Propranolol Participants will receive propranolol and topiramate. | 96 |
| Topiramate Plus Placebo Participants will receive a placebo and topiramate. | 95 |
| Total | 191 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Early termination of trial | 12 | 10 |
| Overall Study | Lost to Follow-up | 20 | 33 |
Baseline characteristics
| Characteristic | Topiramate Plus Placebo | Topiramate Plus Propranolol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 2 Participants | 3 Participants |
| Age, Categorical >=65 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 92 Participants | 94 Participants | 186 Participants |
| Age Continuous | 41.2 years STANDARD_DEVIATION 1.15 | 39.8 years STANDARD_DEVIATION 1.09 | 40.5 years STANDARD_DEVIATION 0.79 |
| Region of Enrollment United States | 95 participants | 96 participants | 191 participants |
| Sex: Female, Male Female | 88 Participants | 84 Participants | 172 Participants |
| Sex: Female, Male Male | 7 Participants | 12 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 59 / 96 | 50 / 95 |
| serious Total, serious adverse events | 7 / 96 | 5 / 95 |
Outcome results
Primary
Change in the Number of Moderate to Severe Headache Days Within a 28 Day Average Period in Six Months Compared to Baseline
(Number of moderate to severe headache days (as defined by the International Headache Society Guidelines (2006)) counted over a 28 day diary period at baseline (before treatment with propranolol or placebo)) minus (the number of moderate to severe headache days counted over a 56 day diary period (weeks 16-24 post treatment) divided by 2).
Time frame: Baseline (pre-randomization), months 5 and 6 post randomization
Population: ITT to the extent diary information was available. Available defined as all subjects with 12 or more diary entries between 16 and 24 weeks. Multiple imputation used on all randomized subjects as a sensitivity analysis on the primary outcome.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate Plus Propranolol | Change in the Number of Moderate to Severe Headache Days Within a 28 Day Average Period in Six Months Compared to Baseline | 4.4 Moderate to severe headache days | Standard Deviation 5.98 |
| Topiramate Plus Placebo | Change in the Number of Moderate to Severe Headache Days Within a 28 Day Average Period in Six Months Compared to Baseline | 4.7 Moderate to severe headache days | Standard Deviation 5.66 |
Comparison: The study was designed to enroll 250 subjects to provide at least 90% power to detect a 3-day difference and 87% power to detect a 2.5-day difference in 28-day moderate-to-severe headache rate reductions at six months, assuming a type I error rate of 0.05, a two-sided test, a 10% loss to follow-up and a standard deviation of within-person change in days with headache of six.p-value: 0.7795% CI: [-1.8, 2.4]ANCOVA
Secondary
Change From Baseline in Beck's Depression Inventory FastScreen Score at 6 Months
Total score from Beck's Depression Inventory FastScreen at 6 months minus total score from Beck's Depression Inventory FastScreen at baseline. Scale scores range from 0 to 21 with higher values indicating worsening depression. the following categories separate participants into groups of depression levels: Minimal (Score 0-3), Mild (Score 4-8),Moderate (Score 9-12),Severe (Score 13-21).
Time frame: Baseline and 6 months
Population: The number who completed the Beck's Depression Inventory at baseline and three months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate Plus Propranolol | Change From Baseline in Beck's Depression Inventory FastScreen Score at 6 Months | 0.3 units on a scale | Standard Deviation 0.25 |
| Topiramate Plus Placebo | Change From Baseline in Beck's Depression Inventory FastScreen Score at 6 Months | 0.6 units on a scale | Standard Deviation 0.3 |
Secondary
Change From Baseline in Migraine Disability Assessment (MIDAS) Score at 6 Months
MIDAS scoring ranges from 0 to 270. The scores are divided into ranges of disability with higher scores indicating increased disability as follows: 0-5 (Grade I - Minimal or infrequent disability); 6-10 (Grade II - Mild or infrequent disability); 11-20 (Grade III - Moderate disability); and 21+ (Grade IV - Severe disability).
Time frame: Baseline and 6 months
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate Plus Propranolol | Change From Baseline in Migraine Disability Assessment (MIDAS) Score at 6 Months | -3.18 units on a scale | Standard Deviation 3.7 |
| Topiramate Plus Placebo | Change From Baseline in Migraine Disability Assessment (MIDAS) Score at 6 Months | -3.46 units on a scale | Standard Deviation 3.82 |
p-value: 0.91ANCOVA
Secondary
Change From Baseline in Migraine-Specific Quality of Life (MSQ) - Emotional Function at 6 Months
The MSQ (version 2.1 copyrighted 1992, 1996, 1998 by Glaxo Wellcome Inc., Research Triangle Park, North Carolina) is a 14 item questionnaire. Item responses are summed and scored as a total score and three domains: Role Preventive, Role Restrictive, Emotional Function. Scores within each domain are rescaled to range from 0 to 100. A lower score indicates a poorer quality of life associated with that domain or in total. Because of the observed interaction within a domain, only domain scores were used as outcome measures for this study.
Time frame: Baseline and 6 Months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate Plus Propranolol | Change From Baseline in Migraine-Specific Quality of Life (MSQ) - Emotional Function at 6 Months | 8.9 units on a scale | Standard Deviation 3.43 |
| Topiramate Plus Placebo | Change From Baseline in Migraine-Specific Quality of Life (MSQ) - Emotional Function at 6 Months | 9.8 units on a scale | Standard Deviation 3.8 |
Secondary
Change From Baseline in Migraine-Specific Quality of Life (MSQ)-Role Preventive at 6 Months
The MSQ (version 2.1 copyrighted 1992, 1996, 1998 by Glaxo Wellcome Inc., Research Triangle Park, North Carolina) is a 14 item questionnaire. Item responses are summed and scored as a total score and three domains: Role Preventive, Role Restrictive, Emotional Function. Scores within each domain are rescaled to range from 0 to 100. A lower score indicates a poorer quality of life associated with that domain or in total. Because of the observed interaction within a domain, only domain scores were used as outcome measures for this study.
Time frame: Baseline and 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate Plus Propranolol | Change From Baseline in Migraine-Specific Quality of Life (MSQ)-Role Preventive at 6 Months | 12.9 units on a scale | Standard Deviation 2.88 |
| Topiramate Plus Placebo | Change From Baseline in Migraine-Specific Quality of Life (MSQ)-Role Preventive at 6 Months | 5.9 units on a scale | Standard Deviation 3.1 |
| Topiramate Plus Propranolol, Prior, Stable Topiramate | Change From Baseline in Migraine-Specific Quality of Life (MSQ)-Role Preventive at 6 Months | -11.5 units on a scale | Standard Deviation 5 |
| Topiramate Plus Placebo, Prior, Stable Topiramate | Change From Baseline in Migraine-Specific Quality of Life (MSQ)-Role Preventive at 6 Months | 11.0 units on a scale | Standard Deviation 5.06 |
Secondary
Change From Baseline in Migraine Specific Quality of Life (MSQ)-Role Restrictive Score at 6 Months
The MSQ (version 2.1 copyrighted 1992, 1996, 1998 by Glaxo Wellcome Inc., Research Triangle Park, North Carolina) is a 14 item questionnaire. Item responses are summed and scored as a total score and three domains: Role Preventive, Role Restrictive, Emotional Function. Scores within each domain are rescaled to range from 0 to 100. A lower score indicates a poorer quality of life associated with that domain or in total. Because of the observed interaction within a domain, only domain scores were used as outcome measures for this study.
Time frame: baseline and 6 months post randomization
Population: per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topiramate Plus Propranolol | Change From Baseline in Migraine Specific Quality of Life (MSQ)-Role Restrictive Score at 6 Months | -0.7 units on a scale | Standard Deviation 5.5 |
| Topiramate Plus Placebo | Change From Baseline in Migraine Specific Quality of Life (MSQ)-Role Restrictive Score at 6 Months | -2.2 units on a scale | Standard Deviation 5.71 |
Secondary
Number of Subjects Experiencing at Least a 30% Reduction in 28-day Moderate to Severe Headache Days
Time frame: 6 months post randomization
Population: All subjects randomized with opportunity for 6 month followup. Due to early study termination those who did not have opportunity for 6 month followup at time of study closure were excluded. All lost to followups were counted as failure
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Topiramate Plus Propranolol | Number of Subjects Experiencing at Least a 30% Reduction in 28-day Moderate to Severe Headache Days | 37 participants |
| Topiramate Plus Placebo | Number of Subjects Experiencing at Least a 30% Reduction in 28-day Moderate to Severe Headache Days | 28 participants |
95% CI: [0.75, 2.78]
Secondary
Number of Subjects Experiencing at Least a 50% Reduction in 28-day Moderate to Severe Headache Days
Time frame: 6 months
Population: All participants with the opportunity for 6-month follow-up. Due to early study termination some participants were randomized and did not have the opportunity to be followed for six months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Topiramate Plus Propranolol | Number of Subjects Experiencing at Least a 50% Reduction in 28-day Moderate to Severe Headache Days | 26 participants |
| Topiramate Plus Placebo | Number of Subjects Experiencing at Least a 50% Reduction in 28-day Moderate to Severe Headache Days | 23 participants |
95% CI: [0.5, 2.02]