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Rizatriptan for the acute treatment of ICHD-II proposedmenstrual migraine: two prospective, randomized,placebo-controlled, double-blind studies LK Mannix1, E Loder2, R Nett3, L Mueller4, A Rodgers5, CM Hustad5, KE Ramsey5 & F Skobieranda5
1Headache Associates and ClinExcel Research, West Chester, OH, 2Headache Management Program, Spaulding Rehabilitation Hospital, Boston,
MA,
3Texas Headache Associates, San Antonio, TX, 4University Headache Center, Stratford, NJ and 5Merck & Co., Inc., West Point, PA,
USA

Mannix LK, Loder E, Nett R, Mueller L, Rodgers A, Hustad CM, Ramsey KE &Skobieranda F. Rizatriptan for the acute treatment of ICHD-II proposed men-strual migraine: two prospective, randomized, placebo-controlled, double-blindstudies. Cephalalgia 2007; 27:414–421. London. ISSN 0333-1024 These are the first prospective studies to use criteria for menstrual migraineproposed in the 2004 revision of the International Classification of HeadacheDisorders (ICHD-II) to examine the efficacy of rizatriptan for treatment of amenstrual attack. Two identical protocols (MM1 and MM2) were randomized,parallel, placebo-controlled, double-blind studies. Adult women with ICHD-IImenstrual migraine were assigned to either rizatriptan 10-mg tablet or placeboin a 2 : 1 ratio. Patients treated a single menstrual migraine attack of moderateor severe pain intensity. The primary end-point was 2-h pain relief and thesecondary end-point was 24-h sustained pain relief. A total of 707 patients (MM1357, MM2 350) treated a menstrual migraine attack. The percentage of patientsreporting 2-h pain relief was significantly greater for rizatriptan than for placebo(MM1 70% vs. 53%, MM2 73% vs. 50%), as was the percentage of patientsreporting 24-h sustained pain relief (MM1 46% vs. 33%; MM2 46% vs. 33%).
Rizatriptan 10 mg was effective for the treatment of ICHD-II menstrual migraine,as measured by 2-h pain relief and 24-h sustained pain relief. 䊐Clinical trial,menstrual migraine, migraine, rizatriptan Lisa K Mannix MD, Headache Associates and ClinExcel Research, 7908Cincinnati-Dayton Road, Suite J, West Chester, OH 45069, USA. Tel. + 1 513 7774999, fax + 1 513 777 4309, e-mail 25 July 2006,accepted 13 December 2006 and up to several days after onset of menses (3). In 2004, the International Headache Society (IHS) Migraine attacks occur as acute, intermittent events revised the International Classification of Headache with many well-recognized trigger factors. Menses is Disorders (ICHD-II) guidelines to include proposed frequently cited as a trigger factor for female research criteria for MM in the Appendix (4). Accord- migraineurs (1, 2) and, in consulting populations, it ing to this definition, MM refers to attacks of is commonly believed that migraine attacks that migraine without aura that occur on day 1 ⫾ 2 (i.e.
occur during the perimenstrual period may be more days -2 to +3) of menstruation in at least two of three refractory to treatment. Until recently, there has been menstrual cycles. Two subtypes are described. In no consistently applied definition of menstrual pure menstrual migraine (PMM), attacks occur migraine (MM) in clinical trials; in previous studies, exclusively with menstruation and at no other times the perimenstrual window ranged from beginning of the cycle. In menstrually related migraine (MRM), within one to several days before the onset of menses attacks may also occur at other times of the cycle.
Blackwell Publishing Ltd Cephalalgia, 2007, 27, 414–421
Rizatriptan for menstrual migraine Few studies have looked specifically at treatment to discontinue using monoamine oxidase inhibitors of menstrual migraine. Previous retrospective and and propranolol 2 weeks before receiving study prospective trials with sumatriptan (5, 6), zolmitrip- medication; any 5-HT1B/1D agonist, ergot-type medi- tan (7) and rizatriptan (8, 9) have studied treatment efficacy in MM subgroups; results of these studies opiates or barbiturates 24 h before receiving study have shown that these triptans were effective at medication; and non-opiate analgesics and anti- treating MM, as measured by pain relief at 2 or 4 h.
emetics 6 h before receiving study medication.
The retrospective studies, however, examined MM Patients using agents for perimenstrual migraine attacks that were merely coincidental to the men- prophylaxis were excluded. In addition, daily anal- strual period; the antecedent history of migraine gesics taken for any reason were not permitted attacks as a prevalent feature of the menstrual (except for aspirin ⱕ325 mg/day for cardioprotec- period, as suggested in the 2004 ICHD-II research tion). Patients were not eligible to participate in criteria, was not reported. Recent prospective both studies.
studies of sumatriptan (10, 11), zolmitriptan (7) andnaratriptan (12) for the treatment of MM (using Study design different definitions of the perimenstrual period)have also demonstrated efficacy. A prospective sub- A Scientific Advisory Committee comprising head- group analysis of the rizatriptan Treat A Migraine ache medicine physicians and Merck & Co., Inc.
Early (TAME) studies, in which patients were clinical research professionals developed the proto- instructed to treat a migraine attack within 1 h of cols, formulated the statistical analysis plan, analy- onset, while the pain was still mild, demonstrated sed and interpreted the data and authored this efficacy in the subgroup of patients who (i) had a report. Protocols 071 (MM1) and 072 (MM2) were history of ICHD-II MM and (ii) elected to treat a identical, randomized, parallel, placebo-controlled, menstrual attack as the study attack (13, 14). The double-blind studies. MM1 was conducted at 22 studies reported here—the first prospective studies centres in the USA from June 2005 to February 2006.
to use the 2004 ICHD-II diagnostic criteria for MM2 was conducted at 28 centres in the USA from MM—were performed to compare the efficacy of June 2005 to March 2006. The protocols were rizatriptan 10 mg with placebo in the treatment of approved by a central Institutional Review Board MM, as defined by the newly proposed ICHD-II and all patients gave written informed consent to criteria. The results of each trial are presented sepa- participate. Patients were randomly assigned to rately; the data were not pooled for these analyses.
either rizatriptan 10-mg tablet or matching placeboin a 2 : 1 ratio using a computer-generated alloca-tion schedule with a block size of six that was supplied by the sponsor. Patients were instructed totake the study medication to treat a single MM attack when the pain was moderate (Grade 2) or Women aged ⱖ18 years who had both a ⱖ6-month severe (Grade 3). Patients were allowed three men- history of ICHD-II migraine and a ⱖ6-month strual cycles after randomization to treat a qualify- history of MM as proposed in the 2004 update of ing MM attack. Rescue medication was allowed for ICHD-II guidelines were eligible for the studies.
a non-responsive headache or a headache recur- Additionally, a history of monthly menses and a rence 2 h postdose.
recent history of MM occurrence in at least two ofthe most recent three menstrual periods were Efficacy and safety end-points required. If MM typically preceded menstrual flow,the patient attested to her ability to predict the Patients rated baseline headache severity and func- onset of menstrual flow within 1 day. Patients had tional disability immediately before taking study to agree to use adequate contraception during the medication and at 30, 45, 60 and 90 min and at 2 study. Patients with other headache disorders were and 4 h postdose and recorded that information in required to be able to distinguish clearly migraine a diary. Headache severity was rated on a scale from 0 to 3: 0, no headache; 1, mild pain; 2, mod- ischaemic heart disease, uncontrolled hypertension, erate pain; 3, severe pain. Functional disability was coronary artery vasospasm (including Prinzmetal's also rated on a scale from 0 to 3 (0, able to perform variant angina) or other significant underlying car- daily activities; 1, daily activities mildly impaired; diovascular disease were excluded. Patients agreed 2, daily activities severely impaired; 3, unable to Blackwell Publishing Ltd Cephalalgia, 2007, 27, 414–421
LK Mannix et al. carry out daily activities, requires bed rest). Patients rizatriptan 10 mg compared with placebo with recorded the presence of migraine-associated symp- respect to 2-h pain relief and 92% power to dem- toms (photophobia, phonophobia, nausea and vom- onstrate superiority of rizatriptan with respect to iting) at baseline and at all post-baseline time 24-h sustained pain relief, based on a two-sided a intervals. For the analysis of 24-h sustained pain level of 0.05.
relief, defined as pain relief at 2 h with no recur-rence between 2 and 24 h and no use of any addi- Tolerability and adverse events tional abortive migraine medications during thatperiod, patients recorded the presence of headache All patients treated in the studies were included in between 2 and 24 h postdose and any medication the tolerability analysis. Tolerability was assessed taken for migraine headache up to 24 h after initial by statistical and clinical review of the incidence of treatment. Patients recorded any adverse experi- adverse events (AEs) and vital signs. The primary ences occurring between enrolling in the study and tolerability measurement was the incidence of AEs the end-of-study visit.
(overall, drug-related, serious and those causingdiscontinuation) reported by patients before takingany rescue medication. Pairwise comparisons of the incidence of AEs were conducted using Fisher's exact test. No multiplicity adjustment was used for The primary hypothesis of these studies was that, the tolerability analysis.
in patients with MM, rizatriptan 10 mg would besuperior to placebo, as measured by the percentage of patients with 2-h pain relief. A secondaryhypothesis was that, in patients with MM, rizatrip- tan 10 mg would be superior to placebo, as mea-sured by the percentage of patients with 24-h In MM1, 417 patients were screened, 403 patients sustained pain relief.
were randomly assigned to treatment and 357patients (89%) treated a qualifying migraine (Fig. 1a). In MM2, 413 patients were screened, 399 The primary end-point for efficacy analysis was patients were randomly assigned to treatment and pain relief, defined as a reduction in headache 350 (88%) treated a qualifying migraine (Fig. 1b).
severity from moderate or severe pain (Grade 2 or The most common reason cited for not treating was 3) at baseline to no pain or mild pain (Grade 0 or 1) the lack of a qualifying migraine during the treat- at 2 h. The primary efficacy analysis used a modi- ment period. All but two randomized patients who fied intention-to-treat (mITT) approach, which treated a migraine had at least one post-treatment included all randomized patients who had at least diary headache severity assessment and were one pain severity rating within 2 h after taking the included in the primary efficacy analysis of 2-h pain study medication. Missing values in the treatment relief (MM1 357 patients; MM2 348 patients).
phase were imputed by carrying forward the pre-ceding on-treatment values, except that no imputa- Demographics and baseline characteristics tions were made to missing values at baseline or at30 min. A logistic regression model with factors for The treatment groups were generally similar with treatment group and baseline pain severity (mod- respect to demographic characteristics (Table 1).
erate or severe) was used to compare treatment The majority of patients were White. The median groups with respect to 2-h pain relief, as well as all age was 37 years in both studies and ages ranged other binary efficacy outcome measures. All treat- from 18 to 54 years.
ment group comparison P-values based on thelogistic regression model were summarized with the corresponding odds ratio (OR) and associated95% confidence interval (CI).
The results of both studies are presented sepa- With a projected 315 patients (210 for rizatriptan rately; the data were not pooled for these analyses.
and 105 for placebo) satisfying criteria from both The percentage of patients reporting pain relief at studies and assuming 2-h pain-relief rates of 68% 2 h after taking study drug was significantly and 56% for rizatriptan and placebo, respectively, higher in the rizatriptan group compared with the there was 98% power to demonstrate superiority of placebo group, based on a logistic regression Blackwell Publishing Ltd Cephalalgia, 2007, 27, 414–421
Rizatriptan for menstrual migraine Screened N = 417 Not randomized N = 14 Randomized N = 403 Rizatriptan regimen Discontinued N = 34 Discontinued N = 12 Clinical adverse event=1 Clinical adverse event=0 Protocol deviation=1 Protocol deviation=1 Lack of qualifying migraine=17 Lack of qualifying migraine=5 Lost to follow-up=8 Lost to follow-up=4 Withdrew consent=1 Withdrew consent=1 Included in efficacy Included in efficacy Screened N = 413 Not randomized N = 14 Ineligible = 13 Withdrew consent = 1 Randomized N = 399 Rizatriptan regimen Discontinued N = 23 Discontinued N = 26 Protocol deviation=1 Protocol deviation=2 Lack of qualifying migraine=12 Lack of qualifying migraine=12 Lost to follow-up=9 Lost to follow-up=7 Withdrew consent=0 Withdrew consent=2 Included in efficacy Included in efficacy Figure 1 Patient accounting. (a) MM1. (b) MM2. *One rizatriptan patient and one placebo patient completed the study but
had no diary data.
Blackwell Publishing Ltd Cephalalgia, 2007, 27, 414–421
LK Mannix et al. Table 1 Patient demographics and baseline characteristics
Patient demographics Median age, years Age >45 years, % Prior triptan use, % At any time in the past Pain severity at baseline, % Functional disability, % Severely impaired Unable to perform activities, Associated symptoms, % Rizatriptan 10 mg (N=234, 245) Placebo (N=123, 103) Percentage of patients 2-hour pain relief 24-hour sustained pain relief (primary efficacy end-point) efficac end-point Figure 2 Two-hour pain relief and 24-h sustained pain relief in both MM1 and MM2. Bar graph showing the percentage
of MM patients who reported 2-h pain relief (left) and the percentage of patients who reported 24-h sustained pain relief
(right) after taking rizatriptan 10 mg (䊏) or placebo (䊐). †Rizatriptan 10 mg vs. placebo, P-value based on a logistic
regression model including factors for treatment group and baseline pain severity (moderate or severe).
model including factors for treatment group and pain relief was also significantly higher in the riza- baseline pain severity (moderate or severe; Fig. 2; triptan group than in the placebo group (Fig. 2; OR OR 2.11, 95% CI 1.34, 3.32, P = 0.001 in MM1; OR 1.75, 95% CI 1.11, 2.77, P = 0.016 in MM1; OR 1.74, 2.69, 95% CI 1.66, 4.36, P < 0.001 in MM2). The 95% CI 1.08, 2.82, P = 0.024 in MM2). Other effi- percentage of patients reporting 24-h sustained cacy end-points are shown in Figs 3a,3b and 4.
Blackwell Publishing Ltd Cephalalgia, 2007, 27, 414–421
Rizatriptan for menstrual migraine Rizatriptan 10 mg (N=234, 245) Rizatriptan 10 mg (N=234, 245) Placebo (N=123, 103) =NS† P=NS† Placebo (N=123, 103) 80 P=NS† P=NS† Percentage of patients Percentage of patients cutaneous sensitivity Figure 4 Supportive efficacy end-points at 2 h. Bar graph
showing the percentage of MM patients who reported not Rizatriptan 10 mg needing rescue medication, not having any functional disability, or not having symptoms of cutaneous sensitivity at 2 h after taking rizatriptan (䊏) or placebo (䊐).
†Rizatriptan 10 mg vs. placebo, P-value based on a logistic regression model including factors for treatment group and baseline pain severity (moderate or severe). NS, Percentage of patients 20 patients); MM2: rizatriptan 13.0% (32 patients), placebo 5.8% (six patients)] was greater in the riza- triptan treatment group compared with the placebo (155, 82) (153, 64) group for both studies. There were no serious AEs reported in either study. The most common clinical AEs are listed in Table 2.
Figure 3 (a) Associated symptoms at 2 h. Bar graph
showing the percentage of MM patients who reported
having the specified associated symptoms at 2 h aftertaking rizatriptan 10 mg (䊏) or placebo (䊐). †Rizatriptan There is a perception that MM attacks are more 10 mg vs. placebo, P-value based on a logistic regression painful, longer lasting and more difficult to manage model including factors for treatment group and baseline than non-menstrual attacks. Recent studies in pain severity (moderate or severe). NS, P-values >0.05. (b)Elimination of associated symptoms at 2 h. Bar graph treatment-seeking women support this view, but showing the percentage of MM patients who reported this is less clearly true in the general population of having the specified associated symptoms at baseline, but women with migraine (15). In a study of 155 not at 2 h after taking rizatriptan 10 mg (䊏) or placebo women in a specialized migraine clinic, MacGregor (䊐). †Rizatriptan 10 mg vs. placebo, P-value based on a and Hackshaw (16) found that the risk of migraine logistic regression model including factors for treatmentgroup and baseline pain severity (moderate or severe). NS, was greater during the perimenstrual period and that women reported MM as more severe and moreassociated with nausea and vomiting. Granella et al.
(17) studied women with menstrually related migraine who were referred to tertiary care centres Tolerability was evaluated in each treatment group and reported that attacks during the perimenstrual by summarizing the number of AEs reported after period were of longer duration and greater inten- treatment but before use of any rescue medication sity. Martin and colleagues (18) found that abortive (primary approach for safety). The incidence of AEs medication use was greater for treatment of [MM1: rizatriptan 18.8% (44 patients), placebo migraine during the perimenstrual time period 11.4% (14 patients); MM2: rizatriptan 17.5% (43 when compared with other periods of the men- strual cycle. Dowson et al. (19) found a trend for investigator-determined drug-related AEs [MM1: migraine headaches concurrent with menses to be rizatriptan 15.0% (35 patients), placebo 5.7% (seven more disabling than those occurring at other times Blackwell Publishing Ltd Cephalalgia, 2007, 27, 414–421
LK Mannix et al. Table 2 Clinical adverse events ⱖ2% in any treatment group
of the menstrual cycle. Although the findings cited lower response among older (age >45 years) vs.
did not involve all menstrual migraineurs as younger patients in the placebo group; the current defined by the new ICHD-II criteria, it is commonly trials enrolled a substantially smaller proportion believed that, for some women, MM is more severe, (13% in MM1 and 18% in MM2) of older patients disabling and refractory to abortive treatment than (age >45 years) than were enrolled, for example, in the pivotal trials ( 31%). A second explanation may To our knowledge, these are the first studies to be that patients in the current trials treated a greater use the newly proposed ICHD-II MM research cri- proportion of moderate (and smaller proportion of teria. These criteria, by convention, exclude patients severe) headache than that seen in the pivotal trials; with aura. Applying these criteria did not appear to the placebo effect was greater in those patients with affect the recruitment of patients for these trials, moderate (and not severe) headache at baseline.
which was not more difficult than for trials in the A limitation of this study is the perception that general migraine population. The current studies MM is a more severe and/or more difficult-to-treat examined the efficacy of rizatriptan 10 mg for the form of migraine. Though ample evidence sup- treatment of MM and demonstrated that rizatriptan ports this belief in women who consult because of was superior to placebo, as measured by 2-h and such headaches (22), the efficacy of rizatriptan in 24-h pain relief. Other efficacy end-points were these studies of MM is consistent with the efficacy consistent with the hypothesized 2-h and 24-h effi- of rizatriptan in the pivotal trials in migraine, and cacy end-points. Across the two studies, the differ- this finding could support the hypothesis that ence between rizatriptan and placebo reached treatment response of this subtype of migraine is statistical significance for some end-points and not significantly different than that of non-MM revealed a non-significant trend in others.
attacks. Future studies that directly compare men- The efficacy of rizatriptan for the treatment of strual and non-menstrual attacks within the same MM in these studies was similar to that seen for the patient, in both treatment-seeking and general treatment of migraine demonstrated in the rizatrip- population subgroups, would help address this tan pivotal registration trials (20), although it is unresolved issue.
important to note that we did not directly comparemenstrual and non-menstrual efficacy in the currentstudies. These studies are consistent with the exist- ing retrospective data for rizatriptan, in which effi-cacy was unaffected by relationship to menses.
These studies were sponsored by Merck & Co., Inc., WestPoint, PA, USA. The lead author had free access to all data Although not intended as a validation study for the and analyses. Statistical analysis was provided by Merck & proposed MM criteria, this study may serve as a Co., Inc. The following investigators participated in the frame of reference for future studies of ICHD-II MAXALT Protocol 071 (MM1) and Protocol 072 (MM2) studies: JU Adelman, Greensboro, NC; SK Aurora, Seattle, It is interesting to note that a large placebo effect WA; GD Berman, Plymouth, MN; JL Brandes, Nashville, rate was seen in both of these trials. There are TN; R Cady, Springfield, MO; AH Calhoun, Chapel Hill, several possible explanations. One explanation, NC; JR Couch, Oklahoma City, OK; JW Dean, Tulsa, OK;SE DeRossett, Decatur, GA; ML Diamond, Chicago, IL; which has been seen in other triptan trials (21), may CA Foster, Phoenix, AZ; BM Frishberg, Oceanside, CA; be a higher placebo response rate with younger J Goldstein, San Francisco, CA; G Ishkanian, Mt Vernon, age. A posthoc exploratory analysis revealed a NY; RG Kaniecki, Pittsburgh, PA; LC Kirby, II, Peoria, AZ; treatment-by-age interaction driven primarily by a SF Knox, Sacramento, CA; DB Kudrow, Santa Monica, CA; Blackwell Publishing Ltd Cephalalgia, 2007, 27, 414–421
Rizatriptan for menstrual migraine RS Kunkel, Cleveland, OH; HA Leonard, Portland, OR; SM retrospective analysis of long-term data. Headache 2002; Lucas, Seatlle, WA; LK Mannix, West Chester, OH; DA Marcus, Pittsburgh, PA; VT Martin, Cincinnati, OH; NT 10 Landy S, Savani N, Shackelford S, Loftus J, Jones M.
Mathew, Houston, TX; A Mauskop, New York, NY; L Efficacy and tolerability of sumatriptan tablets adminis- Mueller, Stratford, NJ; P Nikpey, Charlottesville, VA; CP tered during the mild-pain phase of menstrually associ- O'Carroll, Newport Beach, CA; FJ O'Donnell, Westerville, ated migraine. Int J Clin Pract 2004; 58:913–9.
OH; N Ramadan, North Chicago, IL; AM Rapoport, Stam- 11 Nett R, Landy S, Shackelford S, Richardson MS, Ames M, ford, CT; LD Robbins, Northbrook, IL; JF Rothrock, Mobile, Lener M. Pain-free efficacy after treatment with sumatrip- AL; GE Ruoff, Kalamazoo, MI; JR Saper, Ann Arbor, MI; tan in the mild pain phase of menstrually associated TR Smith, Chesterfield, MO; ELH Spierings, Wellesley migraine. Obstet Gynecol 2003; 102:835–42.
Hills, MA; SR Stark, Alexandria, VA; RM Stewart, Dallas, 12 Massiou H, Jamin C, Hinzelinc G, Bidaut-Mazel C and TX; CB Strout, Mt Pleasant, SC; FR Taylor, Minneapolis, the French Naramig Collaborative Study Group. Efficacy MN; GE Tietjen, Toledo, OH; JJ Tomasovic, San Antonio, of oral naratriptan in the treatment of menstrually related TX; MM Tuchman, Palm Beach Gardens, FL; RD Verson, migraine. Eur J Neurol 2005; 12:774–81.
Columbus, GA; TN Ward, Lebanon, NH; SD Wheeler, 13 Cady R, Martin V, Mauskop A, Rodgers A, Hustad CM, Hialeah, FL; M-C. Wilson, Tampa, FL; WB Young, Phila- Ramsey KE, Skobieranda F. Efficacy of rizatriptan 10 mg delphia, PA. The authors thank Susan Macera for assistance administered early in a migraine attack. Headache 2006; with the execution of the study.
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