Migraine Headache
Conditions
Keywords
Migraine Headache, Preventive Therapy, Beta Blocker Medication, Behavior Therapy, Clinical Trial
Brief summary
The purpose of this study is to determine if the addition of preventive medication, behavior migraine management or the combination of preventive medication and behavior migraine management improves the outcome of optimal acute therapy for frequent migraines.
Detailed description
During the 5 week Optimal Acute Therapy (OAT) Run in (Month 1) all participants who met initial inclusion criteria received optimal acute therapy (OAT). At the end of the OAT Run-in, participants who continued to meet the migraine severity criteria were stratified by sex and randomized via a computerized randomization procedure to the four added treatments: Beta Blocker Placebo (PL), Beta Blocker (Propranolol LA or Nadolol), Behavioral Migraine Management (BMM) + PL, or BMM + Beta Blocker. Each of the 4 treatment protocols required 4 monthly clinic visits and 3 telephone contacts during the 3 month Treatment/Dose Adjustment Phase (Month 2 to Month 4) where Beta Blocker or PL dose was adjusted and BMM was administered. During the 12 month (Month 5 to Month 16) Evaluation Phase clinic visits were scheduled at Month 5, Month 7, Month 10 (the Primary End Point), Month 13 and Month 16. Treatment conditions were blinded only for the preventive medication (Beta Blocker, Placebo) component, and not for the administration of BMM. Electronic headache diary recordings are obtained for the full 16 months of the trial, including the 12 month evaluation phase, and migraine-related impairments in quality of life are assessed at multiple points over the 16 months of the trial.
Interventions
DRUGPropranolol or nadolol
Treatment initiated with 1 capsule (60 mg long acting propranolol hydrochloride) and increased to 3 capsules (180 mg) at week 12 as tolerated. If subject does not tolerate at least 2 capsules (120 mg) of propranolol hydrochloride-LA, and in treating neurologist's judgment are unimproved, subject switched to second medication (nadolol). Participants initially receive a single 40 mg capsule of nadolol and increased to 2 capsules (80 mg) as tolerated. At week 12 dose stabilized at highest tolerated level. In evaluation phase, an increase to 4 capsules of long acting propranolol hydrochloride (240 mg) or 3 capsules of nadolol (120 mg) permitted.
DRUGPlacebo control
Placebo
BEHAVIORALBehavioral Migraine Management (BMM)
Session 1: Overview of the pathophysiology of migraine; introduce muscle stretching, deep breathing, PMR, imagery; Session 2: Development trigger management strategy; Use early warning signs as a cue to use behavioral migraine management and acute medication; Session 3:(a) continue with basic migraine management skills if these skills have not been mastered;(b) introduce cognitive-behavioral stress-management, if stress is a salient migraine trigger;(c) introduce thermal biofeedback (hand warming) training with a portable home thermal biofeedback device, if stress is not a notable migraine trigger. Session 4: Review problems using various behavioral migraine management skills; Prepare written migraine management plan; Relapse prevention addressed
DRUGOptimal Acute Therapy
This acute therapy protocol emphasized treatment with a 5-HT1B/D-agonist or triptan. Nonsteroidal anti-inflammatory (NSAID; ibuprofen) and anti-emetic (metoclopramide) medication could be added as needed. The choice of triptans (rizatriptan®, sumatriptan®), the route(s) of triptan administration (oral, nasal spray, subcutaneous injection), and the addition of a NSAID, or anti-emetic were tailored to participant preference, treatment history and acute therapy response. Individualized handouts and a phone call (week 3) of the OAT Run-in were used to help participants evaluate and optimize their acute therapy.
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Merck Sharp & Dohme LLC
GlaxoSmithKline
Ohio University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 18 to 65 years * Diagnosis of migraine with or without aura (International Classification of Headache Disorders) * 3 or more migraine episodes/month with disability for the past 6 months * Less than 20 total headache days/month for the past 6 months
Exclusion criteria
* Medication overuse headaches * Currently taking medications contraindicated by study protocol and unable or unwilling to withdraw * Concurrently undergoing counseling/psychotherapy treatment * Unable to read, understand or record information in study diaries, questionnaires, and migraine management manual. * Unable/unwilling to give written informed consent * History of exclusionary medical condition such as, but not limited to, epilepsy, heart disease, kidney disease, liver disease, hepatic or renal impairment, stroke, ischemic abdominal syndromes, peripheral vascular disease. * Uncontrolled hypertension at screening (sitting systolic pressure \> 160 mmHg, diastolic pressure \> 95 mmHg) * Fertile female who is breastfeeding, pregnant planning a pregnancy within the next year or is unwilling to use adequate contraception. * Has exclusionary medical condition such as but not limited to diabetes (insulin dependent), tuberculosis, bronchospastic disease (asthma), heart disease (or multiple risk factors for heart disease), angina pectoris, documented silent ischemia, or cardiac arrythmias requiring medication, or a clinically significant EKG abnormality. * Other pain diagnosis is primary presenting problem (e.g., fibromyalgia) * Has a substance abuse problem or a psychological disorder that prevents participation in study (e.g., unmanaged severe depression that requires immediate treatment or limits participation in home-based treatment) * Hypersensitivity, intolerance or contraindication to use of Propranolol, Nadolol, Sumatriptan, or Rizatriptan
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Number of Migraine Episodes Per 30 Days at Month 10. | Change from Month 1 to Month 10 | Change in number of migraine episodes(with 24 hours pain free period required between episodes)per 30 days from OAT run-in (Month 1) to Month 10.Obtained from daily electronic diary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in the Number of Migraine Days Per 30 Days at Month 10 | Change from Month 1 to Month 10 | Change in the number of days with migraine per 30 days at Month 10 relative to the OAT Run-in (Month 1). Obtained from daily electronic diary. |
| Change in Quality of Life at Month 10 | Change from Month 1 to Month 10 | Change in Migraine Specific Quality of Life Questionnaire (MSQL; Martin, et al., 2000: v 2.1) scores at Month 10 relative to OAT run-in (Month 1). The MSQL is a 14-item self-report measure that assesses the impact of migraine. The total score ranges from 14 to 84 with higher scores reflecting greater impairment. |
| Change in Number of Migraine Episodes Per 30 Days at Month 16. | Change from Month 1 to Month 16 | Change in number of migraine episodes (with 24 hours pain free period required between episodes) per 30 days from OAT run-in (Month 1) to Month 16. Assessed by participant daily electronic diary. |
| Change in the Number of Migraine Days Per 30 Days at Month 16 | Change form Month 1 to Month 16 | Change in the number of migraine days per 30 days at Month 16 relative to the OAT run-in (Month 1). Assessed by participant electronic diary. |
| Change in Quality of Life at Month 16 | Change from Month 1 to Month 16 | Change in Migraine Specific Quality of Life Questionnaire (MSQL; Martin, et al., 2000: v 2.1) scores relative to OAT run-in. The MSQL is a 14-item self-report measure that assesses the impact of migraine. The total score ranges from 14 to 84 with higher scores reflecting greater impairment. |
Countries
United States
Participant flow
Recruitment details
Outpatient clinics
Pre-assignment details
5 week Optimal Acute Therapy (OAT) Run in (M1) precedes random assignment (see detailed design description).
Participants by arm
| Arm | Count |
|---|---|
| OAT + Placebo (PL) Optimal Acute Therapy plus Beta Blocker Placebo | 55 |
| OAT + Beta Blocker (Beta-B) Optimal Acute Therapy plus Beta Blocker (propranolol or nadolol) | 53 |
| OAT + BMM + PL Optimal Acute Therapy plus Behavioral Migraine Management plus placebo | 55 |
| OAT + BMM + Beta-B Optimal Acute Therapy plus Behavioral Migraine Management plus Beta Blocker (propranolol or nadolol) | 69 |
| Total | 232 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Month 1: Optimal Acute Therapy Run in | No Post OAT Run-in data | 2 | 1 | 5 | 10 |
| Month 2- 4: Treatment Period | Adverse Event | 2 | 3 | 2 | 0 |
| Month 2- 4: Treatment Period | Lack of Efficacy | 2 | 1 | 0 | 0 |
| Month 2- 4: Treatment Period | Lost to Follow-up | 3 | 4 | 1 | 3 |
| Month 2- 4: Treatment Period | Perceived Improvement | 0 | 0 | 1 | 0 |
| Month 2- 4: Treatment Period | Pregnancy | 0 | 2 | 0 | 0 |
| Month 2- 4: Treatment Period | Protocol Violation | 1 | 0 | 0 | 0 |
| Month 2- 4: Treatment Period | Time Demands | 1 | 0 | 4 | 8 |
| Months 11- 16: Evaluation Period II | Adverse Event | 2 | 4 | 2 | 2 |
| Months 11- 16: Evaluation Period II | Lack of Efficacy | 2 | 3 | 3 | 1 |
| Months 11- 16: Evaluation Period II | Lost to Follow-up | 3 | 0 | 1 | 2 |
| Months 11- 16: Evaluation Period II | Perceived Improvement | 0 | 0 | 0 | 1 |
| Months 11- 16: Evaluation Period II | Physician Decision | 0 | 2 | 1 | 0 |
| Months 11- 16: Evaluation Period II | Pregnancy | 1 | 0 | 0 | 0 |
| Months 11- 16: Evaluation Period II | Time Demands | 2 | 1 | 0 | 0 |
| Months 5 - 10: Evaluation Period I | Adverse Event | 1 | 0 | 2 | 4 |
| Months 5 - 10: Evaluation Period I | Lack of Efficacy | 0 | 1 | 1 | 1 |
| Months 5 - 10: Evaluation Period I | Lost to Follow-up | 2 | 5 | 1 | 1 |
| Months 5 - 10: Evaluation Period I | Pregnancy | 0 | 0 | 2 | 0 |
| Months 5 - 10: Evaluation Period I | Protocol Violation | 1 | 1 | 0 | 0 |
| Months 5 - 10: Evaluation Period I | Time Demands | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | OAT + Beta Blocker (Beta-B) | OAT + BMM + PL | OAT + Placebo (PL) | OAT + BMM + Beta-B | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 53 Participants | 55 Participants | 55 Participants | 69 Participants | 232 Participants |
| Age, Continuous | 37.7 years STANDARD_DEVIATION 10.1 | 37.1 years STANDARD_DEVIATION 9.4 | 39.5 years STANDARD_DEVIATION 10.2 | 38.3 years STANDARD_DEVIATION 10.9 | 38.2 years STANDARD_DEVIATION 10.2 |
| Region of Enrollment United States | 53 participants | 55 participants | 55 participants | 69 participants | 232 participants |
| Sex: Female, Male Female | 45 Participants | 45 Participants | 45 Participants | 49 Participants | 184 Participants |
| Sex: Female, Male Male | 8 Participants | 10 Participants | 10 Participants | 20 Participants | 48 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / — | 7 / — | 2 / — | 2 / — |
| serious Total, serious adverse events | 0 / 55 | 0 / 53 | 0 / 55 | 0 / 69 |
Outcome results
Primary
Change in Number of Migraine Episodes Per 30 Days at Month 10.
Change in number of migraine episodes(with 24 hours pain free period required between episodes)per 30 days from OAT run-in (Month 1) to Month 10.Obtained from daily electronic diary.
Time frame: Change from Month 1 to Month 10
Population: Efficacy analyses were intent-to-treat analyses that included all randomized (N = 232) participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OAT + Placebo (PL) | Change in Number of Migraine Episodes Per 30 Days at Month 10. | -2.1 Number of Migraine episodes |
| OAT + Beta Blocker (Beta-B) | Change in Number of Migraine Episodes Per 30 Days at Month 10. | -2.1 Number of Migraine episodes |
| OAT + BMM + PL | Change in Number of Migraine Episodes Per 30 Days at Month 10. | -2.2 Number of Migraine episodes |
| OAT + BMM + Beta-B | Change in Number of Migraine Episodes Per 30 Days at Month 10. | -3.3 Number of Migraine episodes |
Comparison: Omnibus Test: A mixed model with fixed effects for treatment,natural time(defined as natural log of months) and treatment-by-time interaction was used to obtain maximum likelihood estimates of missing values and to evaluate treatment effects(using the PROC MIXED procedure in SAS statistical software,version 9;www.sas.com). A significant treatment by time interaction(p \< .05, 2-tailed) was followed by post-tests (see below). Details of significant post tests are reported as separate analyses.p-value: <0.01Mixed Models Analysis
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.25t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.98t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.29t-test, 2 sided
Secondary
Change in Number of Migraine Episodes Per 30 Days at Month 16.
Change in number of migraine episodes (with 24 hours pain free period required between episodes) per 30 days from OAT run-in (Month 1) to Month 16. Assessed by participant daily electronic diary.
Time frame: Change from Month 1 to Month 16
Population: Efficacy analyses were intent-to-treat analyses that included all randomized (N = 232) participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OAT + Placebo (PL) | Change in Number of Migraine Episodes Per 30 Days at Month 16. | -2.5 Number of Migraine Episodes |
| OAT + Beta Blocker (Beta-B) | Change in Number of Migraine Episodes Per 30 Days at Month 16. | -2.5 Number of Migraine Episodes |
| OAT + BMM + PL | Change in Number of Migraine Episodes Per 30 Days at Month 16. | -2.7 Number of Migraine Episodes |
| OAT + BMM + Beta-B | Change in Number of Migraine Episodes Per 30 Days at Month 16. | -3.8 Number of Migraine Episodes |
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.83t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.05t-test, 2 sided
Comparison: Significant post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.2t-test, 2 sided
Secondary
Change in Quality of Life at Month 10
Change in Migraine Specific Quality of Life Questionnaire (MSQL; Martin, et al., 2000: v 2.1) scores at Month 10 relative to OAT run-in (Month 1). The MSQL is a 14-item self-report measure that assesses the impact of migraine. The total score ranges from 14 to 84 with higher scores reflecting greater impairment.
Time frame: Change from Month 1 to Month 10
Population: Efficacy analyses were intent-to-treat analyses that included all randomized (N = 232) participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OAT + Placebo (PL) | Change in Quality of Life at Month 10 | -7.1 Scores on a scale |
| OAT + Beta Blocker (Beta-B) | Change in Quality of Life at Month 10 | -7.1 Scores on a scale |
| OAT + BMM + PL | Change in Quality of Life at Month 10 | -8.6 Scores on a scale |
| OAT + BMM + Beta-B | Change in Quality of Life at Month 10 | -13.0 Scores on a scale |
Comparison: Omnibus test:A mixed model with fixed effects for treatment, time (defined as the natural log of months), and the treatment-by-time interaction and pretreatment Migraine Specific Quality of Life scores as covariate was used to obtain maximum likelihood estimates of missing values and to evaluate treatment effects (using the PROC MIXED procedure in SAS statistical software, version 9; www. sas.com).A significant treatment by time interaction (p \< .05, 2-tailed) was followed by post-testsp-value: <0.005Mixed Models Analysis
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.87t-test, 2 sided
Secondary
Change in Quality of Life at Month 16
Change in Migraine Specific Quality of Life Questionnaire (MSQL; Martin, et al., 2000: v 2.1) scores relative to OAT run-in. The MSQL is a 14-item self-report measure that assesses the impact of migraine. The total score ranges from 14 to 84 with higher scores reflecting greater impairment.
Time frame: Change from Month 1 to Month 16
Population: Efficacy analyses were intent-to-treat analyses that included all randomized (N = 232) participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OAT + Placebo (PL) | Change in Quality of Life at Month 16 | -8.8 Scores on a scale |
| OAT + Beta Blocker (Beta-B) | Change in Quality of Life at Month 16 | -8.5 Scores on a scale |
| OAT + BMM + PL | Change in Quality of Life at Month 16 | -9.6 Scores on a scale |
| OAT + BMM + Beta-B | Change in Quality of Life at Month 16 | -15.2 Scores on a scale |
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.56t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.08t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.03t-test, 2 sided
Secondary
Change in the Number of Migraine Days Per 30 Days at Month 10
Change in the number of days with migraine per 30 days at Month 10 relative to the OAT Run-in (Month 1). Obtained from daily electronic diary.
Time frame: Change from Month 1 to Month 10
Population: Efficacy analyses were intent-to-treat analyses that included all randomized (N = 232) participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OAT + Placebo (PL) | Change in the Number of Migraine Days Per 30 Days at Month 10 | -3.3 Number of days |
| OAT + Beta Blocker (Beta-B) | Change in the Number of Migraine Days Per 30 Days at Month 10 | -3.9 Number of days |
| OAT + BMM + PL | Change in the Number of Migraine Days Per 30 Days at Month 10 | -3.3 Number of days |
| OAT + BMM + Beta-B | Change in the Number of Migraine Days Per 30 Days at Month 10 | -5.4 Number of days |
Comparison: Omnibus test:A mixed model with fixed effects for treatment, time (defined as the natural log of months), and the treatment-by-time interaction was used to obtain maximum likelihood estimates of missing values and to evaluate treatment effects (PROC MIXED, SAS 9).When the treatment by time interaction was significant (p \< .05, 2-tailed)post-tests were conducted (see below).Details of significant post tests are reported as separate analyses.p-value: <0.03Mixed Models Analysis
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.02t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.79t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.02t-test, 2 sided
Secondary
Change in the Number of Migraine Days Per 30 Days at Month 16
Change in the number of migraine days per 30 days at Month 16 relative to the OAT run-in (Month 1). Assessed by participant electronic diary.
Time frame: Change form Month 1 to Month 16
Population: Efficacy analyses were intent-to-treat analyses that included all randomized (N = 232) participants.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OAT + Placebo (PL) | Change in the Number of Migraine Days Per 30 Days at Month 16 | -3.9 Number of Days |
| OAT + Beta Blocker (Beta-B) | Change in the Number of Migraine Days Per 30 Days at Month 16 | -4.5 Number of Days |
| OAT + BMM + PL | Change in the Number of Migraine Days Per 30 Days at Month 16 | -4.1 Number of Days |
| OAT + BMM + Beta-B | Change in the Number of Migraine Days Per 30 Days at Month 16 | -6.1 Number of Days |
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: <0.001t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.04t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.33t-test, 2 sided
Comparison: Post-test contrast. Mean difference in change.p-value: >0.21t-test, 2 sided