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Frovatriptan for Menstrual Migraine MAM

A randomized trial of frovatriptan for the intermittent prevention of menstrual migraine

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Year of Publication: 2004

Authors: Stephen D. Silberstein, MD, FACP; Arthur H. Elkind, ..., MD; Charlotte Keywood

Journal: Neurology

Citation: NEUROLOGY 2004;63:261-269

Link: https://www.neurology.org/doi/10.1212/01...134620.30129.D6

PDF: https://www.neurology.org/doi/pdfdirect/...134620.30129.D6

Clinical Question

Was frovatriptan, taken for 6 days beginning 2 days before the expected onset of menstrually associated migraine (MAM), more effective than placebo in preventing MAM headache?

Bottom Line

Frovatriptan given prophylactically for 6 days (starting 2 days before anticipated MAM) was effective in reducing the incidence, severity, and duration of menstrually associated migraine. The 2.5 mg BID regimen prevented MAM in 59% of women and was superior to both the 2.5 mg QD regimen and placebo, with excellent tolerability and no evidence of rebound headache.

Major Points

  • First adequately powered randomized, double-blind, placebo-controlled, three-way crossover study of frovatriptan for MAM miniprophylaxis
  • 546 women (mean age 37.6 years) in safety population; 506 in ITT population
  • Primary endpoint met: Incidence of MAM during 6-day PMP was 67% with placebo, 52% with frovatriptan 2.5 mg QD (p<0.0001), and 41% with frovatriptan 2.5 mg BID (p<0.0001 vs placebo; p<0.001 vs QD)
  • Dose-response relationship established: 2.5 mg BID superior to 2.5 mg QD for primary and most secondary endpoints
  • Both frovatriptan regimens reduced MAM severity, with moderate or severe headache occurring in 51% with placebo vs 37% with QD and 28% with BID (p<0.0001)
  • Mean MAM duration reduced from 31.1 hours (placebo) to 20.3 hours (QD) and 16.6 hours (BID); p<0.0001
  • Rescue medication use reduced: 53% placebo, 44% QD (p<0.01), 34% BID (p<0.0001)
  • Both regimens reduced functional impairment and MAM-associated symptoms in dose-dependent manner
  • Patient satisfaction high: 86% rated BID as fair/good/excellent (vs 66% for placebo)
  • Excellent tolerability: AE incidence similar to placebo (40.2% placebo, 42.9% QD, 44.3% BID); tendency for more nausea and dizziness with frovatriptan but more headache and dysmenorrhea with placebo
  • No rebound headache observed after discontinuation of 6-day treatment
  • First study demonstrating repeated daily triptan use for several days was safe and effective
  • Oral contraceptive use (31% of patients) did not alter efficacy or tolerability
  • Patient compliance excellent: 86.7% took ≥11 of 14 tablets

Design

Study Type: Multicenter, randomized, double-blind, placebo-controlled, three-way crossover trial

Randomization: 1

Blinding: Double-blind; patients and investigators blinded to treatment. Identical packaging for frovatriptan and placebo. Code-break envelopes provided but never opened during study

Enrollment Period: Between 2002 and 2007 (patients recruited and followed up)

Follow-up Duration: Three perimenstrual periods (PMPs), each lasting 6 days, with approximately 28-day intervals between treated PMPs. Follow-up visit 7 days (±2 days) after completion of last PMP

Centers: 36

Countries: United States

Sample Size: 579

Analysis: Primary variable analyzed using logistic regression with terms for patient, period, and dose regimen. Carryover tested if period by treatment interaction significant at 5% level (not observed). Each active regimen compared with placebo at 2.5% significance level (Bonferroni correction for multiple testing, maintaining overall 5% level). Secondary analyses: binary data analyzed as primary variable; ordinal data analyzed using ordinal logistic regression with SAS PROC NLMIXED; numeric data analyzed using SAS PROC MIXED for normally distributed response. Direct comparisons between two active regimens performed without Bonferroni correction. ITT analysis included all randomized patients who took ≥1 dose and provided efficacy data for ≥1 analysis. Last observation carried forward used for incomplete diary data

Inclusion Criteria

  • Women aged ≥18 years
  • ≥1-year history of MAM with migraine headache according to International Headache Society (IHS) criteria
  • Attack frequency of at least 3 of 4 perimenstrual periods (PMPs) in the previous year
  • Regular menstrual cycles (28 ± 4 days)
  • Able to predict the onset of MAM headaches
  • MAM defined as migraine occurring between day -2 and day +4 of onset of menstruation (where first day of menstruation defined as day +1)

Exclusion Criteria

  • ≥3 non-MAM attacks per month
  • ≥15 headache days per month
  • Coronary artery disease
  • Notable cerebrovascular disease
  • Uncontrolled hypertension
  • Severe hepatic or renal insufficiency
  • Any other condition that could interfere with study participation
  • Clinically relevant drug allergy (including frovatriptan and other triptans)
  • Treated with other investigational drugs within 30 days of study entry
  • Pregnant or breast-feeding
  • Patients taking oral contraceptives (OCs) were eligible only if OC dosage stable for ≥2 months before entry and remained unchanged throughout study
  • Patients taking migraine prophylaxis medications were eligible only if dosage stable for ≥2 months before entry and remained unchanged throughout study

Baseline Characteristics

Safety Population (n=546):

  • Age, mean (range), years: 37.6 (18-56)
  • Ethnic origin - White: 81%
  • Ethnic origin - Black: 11%
  • Ethnic origin - Hispanic: 5%
  • Ethnic origin - Other: 3%
  • Weight, mean (range), lb: 156.6 (91-300)
  • Onset of MAM at day -2: 47%
  • Onset of MAM at day -1: 25%
  • Onset of MAM at day +1: 13%
  • Onset of MAM at day +2: 8%
  • Onset of MAM at day +3 or +4: 5%
  • MAM onset between day -2 and day +1: 85%
  • Non-MAM per month, mean (range): 1.0 (0-3)
  • Mean duration of MAM history, years: 12
  • Average MAM frequency previous 12 months, mean: 11.4 attacks/year
  • True menstrual migraine (TMM) patients: 34%
  • Oral contraceptive users: 31%
  • Previous triptan use: 71%

ITT Population (n=506):

  • Note: Demographics similar to safety population

ITT2 Population (n=445):

  • Note: Demographics similar to safety population; completed all 3 PMPs with efficacy data

Arms

FieldControlFrovatriptan 2.5 mg QDFrovatriptan 2.5 mg BID
InterventionPlacebo tablets taken twice daily at 12-hour intervals for 6 days, starting 2 days before anticipated onset of MAM. Double-loading dose on day 1: 2 placebo tablets every 12 hours (4 tablets total on day 1). Delivered from identical blister packs as active treatmentFrovatriptan 2.5 mg once daily plus matching placebo as second daily dose, taken at 12-hour intervals for 6 days, starting 2 days before anticipated onset of MAM. Double-loading dose on day 1: 2 frovatriptan 2.5 mg tablets in morning plus 2 matching placebo tablets in evening (total 5 mg frovatriptan on day 1). Days 2-6: one 2.5 mg tablet morning, one placebo tablet evening. Total dose per PMP: 17.5 mg frovatriptanFrovatriptan 2.5 mg twice daily at 12-hour intervals for 6 days, starting 2 days before anticipated onset of MAM. Double-loading dose on day 1: 2 frovatriptan 2.5 mg tablets every 12 hours (10 mg total on day 1). Days 2-6: one 2.5 mg tablet every 12 hours. Total dose per PMP: 35 mg frovatriptan
Duration6 days per perimenstrual period (PMP); 3 PMPs treated6 days per perimenstrual period (PMP); 3 PMPs treated6 days per perimenstrual period (PMP); 3 PMPs treated

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Incidence of MAM headache during the 6-day perimenstrual period (PMP)Primary67% (325/486 evaluable attacks in ITT population); 69% (307/445) in ITT2 populationFrovatriptan 2.5 mg QD: 52% (251/484 evaluable attacks in ITT); 52% (232/445) in ITT2. Frovatriptan 2.5 mg BID: 41% (199/483 evaluable attacks in ITT); 43% (190/445) in ITT215.01%QD vs Placebo: p<0.0001; BID vs Placebo: p<0.0001; BID vs QD: p<0.001 (ITT and ITT2 populations)
Incidence of moderate or severe MAM headacheSecondary51%37% (QD); 28% (BID)QD vs Placebo: p<0.0001; BID vs Placebo: p<0.0001; BID vs QD: p<0.0001
Total duration of MAM headache (all patients)SecondaryMean 31.1 hours (median 14.0 hours)Mean 20.3 hours (median 2.0 hours) for QD; Mean 16.6 hours (median 0 hours) for BIDBoth frovatriptan regimens vs placebo: p<0.0001; no difference between QD and BID
Duration of MAM headache (in patients who had MAM)SecondaryMean 43.0 hours (median 29.2 hours) in n=325Mean 35.8 hours (median 23.0 hours) for QD in n=251; Mean 37.2 hours (median 24.0 hours) for BID in n=199Tendency toward reduction but not formally significant
Maximum headache severity score (0=absent, 1=mild, 2=moderate, 3=severe)SecondaryMean 1.53Mean 1.13 (QD); Mean 0.85 (BID)Both frovatriptan regimens vs placebo: p<0.0001
Severe headache in patients with MAMSecondary36% (116/325)29% (73/251) for QD; 23% (46/199) for BIDQD vs Placebo: p<0.001; BID vs Placebo: p<0.001
Use of rescue medication from 15 minutes after treatmentSecondary53%44% (QD); 34% (BID)QD vs Placebo: p<0.01; BID vs Placebo: p<0.0001
Incidence of any MAM-associated symptom (nausea, vomiting, photophobia, phonophobia)Secondary62%51% (QD); 38% (BID)QD vs Placebo: p<0.001; BID vs Placebo: p<0.0001; BID vs QD: p<0.0001
Moderate or severe functional impairmentSecondary38%29% (QD); 18% (BID)QD vs Placebo: p<0.01; BID vs Placebo: p<0.0001
Maximum functional impairment scoreSecondaryMean 1.17Mean 0.88 (QD); Mean 0.62 (BID)BID vs QD: p<0.001
Patient rating of effectiveness as 'fair,' 'good,' or 'excellent'Secondary66%80% (QD); 86% (BID)Both frovatriptan regimens vs placebo: p<0.0001; BID vs QD: p<0.0001
Patient rating of effectiveness as 'excellent'Secondary16%24% (QD); 32% (BID)Not specified
Any adverse eventAdverse40.2% (n=505)42.9% for QD (n=501); 44.3% for BID (n=501)QD vs Placebo: p=0.281; BID vs Placebo: p=0.185
HeadacheAdverse6.3%4.6% (QD); 4.2% (BID)QD vs Placebo: p=0.185; BID vs Placebo: p=0.011
NauseaAdverse3.4%4.8% (QD); 6.8% (BID)QD vs Placebo: p=0.091; BID vs Placebo: p=0.028
DizzinessAdverse2.6%3.6% (QD); 4.8% (BID)QD vs Placebo: p=0.371; BID vs Placebo: p=0.188
NasopharyngitisAdverse2.4%3.2% (QD); 3.4% (BID)QD vs Placebo: p=0.315; BID vs Placebo: p=0.609
DysmenorrheaAdverse3.0%2.2% (QD); 1.8% (BID)QD vs Placebo: p=0.564; BID vs Placebo: p=0.981
Withdrawals due to adverse eventsAdverse0.8% (n=4)1.6% (n=8) for QD; 1.8% (n=9) for BIDMost common AEs leading to withdrawal: nausea (n=6 for BID; n=1 for QD) and dizziness (n=3 for BID; n=2 for QD). During placebo, most common was abnormal EKG (n=2)

Subgroup Analysis

Oral contraceptive (OC) use (31% of patients) did not alter the results of the study. Frovatriptan was as effective and well tolerated in patients taking OCs as in those who were not. No significant differences in treatment effect were observed based on sex, cluster headache type, or attack order in the logistic regression model

Criticisms

  • Most commonly reported protocol violation was not taking first dose exactly 2 days before anticipated MAM onset (31% of patients in each treatment period), due to natural menstrual cycle variation causing predetermined dates at screening to become inconsistent with actual cycles during study
  • Post hoc analysis showed most patients (69.3%) took medication 1-3 days before anticipated MAM; only 36.4% dosed exactly 2 days before; 11.6% dosed on or after day of anticipated MAM. However, post hoc analysis suggested this did not compromise results
  • High attrition rate: only 109/334 screened patients (33%) were randomized; only 76/109 (70%) completed study; reasons included prior oxygen use exclusion becoming problematic as study progressed, patients unwilling to take placebo when clinically established treatment available, and episodic cluster headache patients coming out of bout
  • Second most common protocol violation was not performing safety assessment on dosing day 5 (17-19% of patients per treatment period)
  • Some patients did not complete full diaries for all attacks; 9 patients (8% of randomized, 12% of completers) provided only primary endpoint data via telephone/email/follow-up rather than full diaries
  • Missing secondary endpoint data from periods after rescue medication taken (excluded from analysis as uncertain whether effects due to trial treatment or rescue medication)
  • First time frovatriptan given repeatedly for several days in clinical trial; no prior repeated-dose safety data available at study initiation
  • Some patients took treatment when attack already underway rather than at commencement as specified in protocol
  • Crossover design introduces complexity as observations from same patient not strictly independent (addressed through multilevel multivariate analysis)
  • Relatively short follow-up limited to 3 menstrual cycles; long-term efficacy and safety beyond 3 months not established
  • Timing of dosing relies on patients' ability to predict MAM onset; may not be practical for all patients with less regular cycles
  • Study population self-selecting (as in all clinical trials); may not fully represent all MAM patients
  • No active comparator arm (e.g., NSAIDs, other triptans); only placebo-controlled
  • Study does not establish optimal timing of treatment initiation or optimal duration of prophylactic treatment

Funding

Supported by Vernalis, Ltd, Winnersh, Wokingham, UK. Drs. Silberstein and Elkind received honoraria from UCB Pharma/Elan Pharmaceuticals, the comarketers of frovatriptan. Dr. Keywood is a paid consultant for UCB Pharma

Based on: Frovatriptan for Menstrual Migraine MAM (Neurology, 2004)

Authors: Stephen D. Silberstein, MD, FACP; Arthur H. Elkind, ..., MD; Charlotte Keywood

Citation: NEUROLOGY 2004;63:261-269

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