Abstract
Data from seven randomized, placebo-controlled, double-blind phase III clinical trials were analysed to further evaluate the efficacy of rizatriptan 10 mg (n = 2068) in comparison with placebo (n = 1260) and rizatriptan 5 mg (n = 1486) for the acute treatment of a migraine attack. Migraine was diagnosed according to International Headache Society criteria. Headache severity, associated migraine symptoms and functional disability were measured immediately before dosing and at 0.5, 1, 1.5 and 2 h. Headache recurrence (return of moderate or severe headache after an initial response) was also recorded. In addition to conventional pain relief (reduction of moderate or severe headache to mild or none) and pain free measures, the analysis looked at the elimination of associated migraine symptoms and disability in patients who had symptoms or disability at baseline. Maintenance of pain relief or pain-free status over 24 h was also analysed. At 2 h, rizatriptan 10 mg was significantly more effective than placebo for pain relief (71% vs. 38%, P < 0.001), and for elimination of pain, nausea, photophobia, phonophobia and functional disability. The benefit was maintained over 24 h; 37% of patients on rizatriptan 10 mg had sustained pain relief vs. 18% for placebo (P < 0.001). Rizatriptan 10 mg was also more effective than rizatriptan 5 mg, with a significant superiority at 2 h on all measures except for elimination of nausea. The benefit was maintained over 24 h; 38% of patients on rizatriptan 10 mg had sustained pain relief vs. 32% for rizatriptan 5 mg (P = 0.001).
Keywords
Introduction
Rizatriptan is a selective 5-HT1B/1D receptor agonist for the acute treatment of migraine which was launched in the United States of America (USA) and other markets throughout the world in 1998. Rizatriptan is available in two oral dosage strengths of 10 mg and 5 mg, with the 10 mg dose recommended as the primary dose in most countries. In addition to conventional tablets, rizatriptan is available in a wafer formulation which dissolves within a few seconds of contact with the tongue and can be taken without liquids.
Up to the end of 1998 Merck & Co. Inc. had completed a total of seven phase III randomized, double-blind, placebo-controlled clinical trials in which 2068 patients received rizatriptan 10 mg for the treatment of at least one migraine attack. Six of the studies also included rizatriptan 5 mg. A consistent approach to inclusion criteria, efficacy parameters and study procedures was utilized throughout the development programme, thereby facilitating comparison of results across studies.
In this article we report the results of a meta-analysis based on data from the seven phase III studies of rizatriptan 10 mg. The purpose of the analysis was to provide an overall perspective on the efficacy of rizatriptan 10 mg vs. placebo and vs. rizatriptan 5 mg, based on a large dataset. In addition to reporting on standard efficacy measures such as pain relief and pain free status (1), we also wanted to look at supplementary measures which were not evaluated in the original studies. These include measures of sustained efficacy, which take into account maintenance of pain relief or pain-free status over 24 h (2, 3), and elimination of associated migraine symptoms and functional disability in the subset of patients who had the symptom or disability at baseline; in previous reports absolute incidences of associated symptoms and functional disability were typically given, regardless of whether or not the patient had the symptom or disability at baseline.
Methods
Studies included in the analysis
All phase III efficacy/safety studies on rizatriptan 10 mg in adults conducted by Merck & Co. Inc. and completed by the end of 1998 were included in the analysis (see Table 1). The seven studies included five studies with conventional tablets and two studies with the wafer formulation. The 5 mg dose was also evaluated in six of the studies. Five of the studies have been published as full manuscripts in peer-reviewed journals (4–8), one (Merck Research Laboratories Clinical Study 039) is briefly described in the 1999 USA product label (9), and one has not yet been published (Merck Research Laboratories Clinical Study 052).
Studies included in the meta-analysis
R10, rizatriptan 10 mg p.o.; R5, rizatriptan 5 mg p.o.; P, placebo.
Also included sumatriptan 100 mg p.o.
Also included sumatriptan 50 mg p.o. and 25 mg p.o.
Limited data in product label.
Only data from the first attack included in the meta-analysis.
Study designs
All studies employed randomized, double-blind, placebo-controlled designs. Four of the studies employed single attack, parallel group designs, while three used crossover designs (Table 1). Studies were performed in countries throughout the world, but particularly in the USA and Western Europe. All studies were conducted according to good clinical practice guidelines (10).
Patients
Patients included in the studies were outpatients who had at least a 6-month history of migraine according to the criteria of the International Headache Society (11), were at least 18 years of age, and typically experienced 1–8 migraine attacks per month. Patients with coronary artery disease were excluded. All patients gave written informed consent.
Study procedures
In all studies patients were instructed to ingest the test medication when they developed a moderate or severe migraine headache that was not resolving spontaneously. The patients rated headache severity and functional disability on a diary card, and noted the presence of associated symptoms of nausea, photophobia, phonophobia and vomiting at the following time points: pre-dose, 0.5 h, 1 h, 1.5 h and 2 h (also at 3 and 4 h in some studies). Headache severity and functional disability were rated using 4-grade anchored scales (headache severity: 0 = no headache, 1=mild headache, 2=moderate headache, and 3=severe headache; functional disability: 0=normal, 1=daily activities mildly impaired, 2=daily activities severely impaired, and 3=unable to do activities, requires bed-rest).
Any patient who was still suffering from a moderate or severe headache at 2 h after taking the initial dose of study medication was allowed to take optional ‘escape’ medications consisting of standard analgesics (opiates, acetaminophen (paracetamol), NSAIDs) and antiemetics. Analgesic and antiemetic medications were prohibited from 6 h before to 2 h after dosing, and patients were prohibited from taking ergotamine or other 5-HT1B/1D agonists from 24 h before and after dosing.
Headache recurrence, defined as the return of headache to moderate or severe within 24 h of dosing in patients who initially experienced pain relief at 2 h after dosing, was also noted. Re-dosing with the test drug for treatment of recurrence was allowed in some studies.
Efficacy measures
Headache-related measures
Pain relief: the percentage of patients with a reduction of headache severity from moderate or severe at baseline to mild or none at 0.5, 1, 1.5 and 2 h.
Pain free: the percentage of patients with a reduction of headache severity from moderate or severe at baseline to none (i.e. complete abolition of headache) at 0.5, 1, 1.5 and 2 h.
Sustained pain relief: the percentage of patients who had pain relief at 2 h (see definition above), who did not have a recurrence within 2–24 h (return of headache to moderate or severe), and who did not take any additional migraine medications, including a second dose of rizatriptan in studies where that was an option, within 2–24 h.
Sustained pain free: the percentage of patients who were pain free at 2 h (see definition above), who did not have a recurrence within 2–24 h (return of headache to moderate or severe), and who did not take any additional migraine medications within 2–24 h.
Other measures
Elimination of associated symptoms: the percentage of patients with no nausea, no photophobia or no phonophobia at 0.5, 1, 1.5 and 2 h in the subgroup of patients who had each symptom at baseline. Few patients experienced vomiting at baseline and these data are not reported.
Elimination of functional disability: the percentage of patients with no functional disability (grade 0 on the 4-grade scale) at 0.5, 1, 1.5 and 2 h in the subgroup of patients who had some level of functional disability at baseline (grade 1, 2 or 3 on the 4-grade scale).
Statistical analysis
The statistical analysis was based on attack 1 data only and therefore the data can be regarded as originating from parallel group studies. The analysis included all patients who took study treatment and provided a baseline efficacy evaluation and data for at least one time-point within 2 h after dosing. A last observation carried forward approach was used for missing data, with the proviso that no imputations were made using baseline data.
The statistical analysis compared the efficacy of rizatriptan 10 mg vs. rizatriptan 5 mg, and rizatriptan 10 mg vs. placebo, using a logistic regression model for the pairwise comparisons. The logistic regression model for each measure included terms for treatment, study and baseline headache severity. The homogoneity of the studies (‘poolability’) was tested by including a term for the treatment-by-study interaction. This term was removed from the model if it was not significant (P-value > 0.05). The treatment-by-baseline-severity interaction was also tested in this manner.
It should be noted that the pairwise comparisons were based only on data from studies which included both the treatments being compared. Rizatriptan 10 mg was directly compared with placebo in seven studies, and with rizatriptan 5 mg in six studies. The efficacy figures given for rizatriptan 10 mg therefore differ depending on whether it is being compared with placebo or rizatriptan 5 mg.
The primary efficacy endpoint for the comparison of rizatriptan 10 mg with placebo in the individual studies was pain relief at 2 h; each study was powered to detect a difference for rizatriptan 10 mg over placebo on this measure.
Results
Patient characteristics and sample sizes
Patient characteristics and sample sizes are summarized in Table 2. A total of 4814 migraineurs received treatment with rizatriptan 10 mg (n = 2068), rizatriptan 5 mg (n = 1486) or placebo (n = 1260). Patients included in the studies were predominantly white, middle-aged (mean age = 40), females. The distribution of demographic parameters and baseline headache severity (approximately 60% moderate, 40% severe) was similar across treatment groups.
Patient characteristics and sample sizes
Homogeneity of the studies
As anticipated on the basis of the very similar study designs, inclusion criteria and procedures, there were no significant treatment-by-study interactions (P-values > 0.05), indicating that the studies were homogenous with respect to treatment effects and that the meta-analysis was valid.
Baseline headache severity
There were no significant treatment-by-baseline-severity interactions (P-values > 0.05), indicating that conclusions regarding treatment effects were equally applicable to moderate and severe headaches. For some measures (pain relief, pain free, elimination of photophobia, elimination of phonophobia) there was a significant main effect of baseline headache severity (P-values < 0.05). This reflects the fact that, in general, patients with moderate headaches at baseline tended to have higher efficacy rates than those with severe headaches. The effect of baseline headache severity was not significant (P-values > 0.05) for elimination of nausea and elimination of functional disability.
Efficacy of rizatriptan 10 mg vs. placebo
Rizatriptan 10 mg was effective in eliminating migraine symptoms from 0.5 h after dosing in some patients, and in eliminating functional disability from 1 h after dosing (Table 3). At 2 h, 71% of patients had pain relief vs. 38% for placebo, and 41% were pain free vs. 10% for placebo. The percentage of patients on rizatriptan 10 mg with sustained pain relief over 24 h was 37% vs. 18% for placebo, and 25% had sustained pain-free status vs. 7% for placebo.
Efficacy of rizatriptan 10 mg vs. placebo
n=number of evaluable patients at 2 h; R10=rizatriptan 10 mg; P=placebo.
To illustrate the pattern of findings across individual studies, the placebo-subtracted mean efficacy rates (‘therapeutic gains’) for the pain relief and pain free measures at 2 h are shown in Fig. 1. Pain relief placebo-subtracted rates ranged from 19% to 46%, with a mean for the combined studies of 33%, while pain free placebo-subtracted rates ranged from 20% to 37%, with a mean for the combined studies of 31%.
Mean placebo-subtracted pain relief and pain free efficacy rates at 2 h, with 95% confidence intervals, for rizatriptan 10 mg in individual studies and all studies combined.
Efficacy of rizatriptan 10 mg vs. rizatriptan 5 mg
Rizatriptan 10 mg was generally more effective than rizatriptan 5 mg (Table 4). Significantly more patients had pain relief on rizatriptan 10 mg from 0.5 h after dosing. At 2 h, statistically significant differences were observed on all measures except elimination of nausea. Rizatriptan 10 mg was also superior to 5 mg with regard to the percentage of patients with sustained pain relief over 24 h and the percentage who had sustained pain free status.
Efficacy of rizatriptan 10 mg vs. rizatriptan 5 mg
n, number of evaluable patients at 2 h; R10, rizatriptan 10 mg; R5, rizatriptan 5 mg.
Headache recurrence
Headache recurrence rates were 39% for rizatriptan 10 mg, 40% for rizatriptan 5 mg, and 32% for placebo. The median time to recurrence was 12 h for rizatriptan 10 mg, 9 h for rizatriptan 5 mg, and 6 h for placebo.
Efficacy of tablet formulation vs. wafer formulation
The tablet and wafer formulations showed similar efficacy in the meta-analysis. On the pain relief measure, both formulations of rizatriptan 10 mg were significantly (P < 0.05) effective vs. placebo at all time-points from 0.5 to 2 h. The percentages of patients with pain relief for each formulation of the 10 mg dose (n = 1758 for tablet, n = 298 for wafer) were: 0.5 h: tablet=19%, wafer=20%; 1 h: tablet=45%, wafer=44%; 1.5 h: tablet=61%, wafer=62%; 2 h: tablet=71%, wafer=71%.
Tolerability of rizatriptan 10 mg, rizatriptan 5 mg and placebo
Although efficacy was the main focus of this paper, the total number of adverse events was also calculated. The analysis included adverse events occurring after a single dose of rizatriptan. Adverse events occurring after a second dose of rizatriptan in studies where repeat dosing was allowed (for treatment of recurrence, from 2 h onwards) were not included. The analysis was descriptive only and no formal statistical testing was undertaken. There was a dose-related increase in the incidence of patients with one or more adverse events, drug-related adverse events, and common adverse events (Table 5). Most adverse events were short lasting and of mild or moderate intensity. The incidence of patients with one or more adverse events was similar for the tablet and wafer formulations: 10 mg tablet=43% (34% drug related), 10 mg wafer=39% (35% drug related). Chest pain was noted as an adverse event in 3% of patients on rizatriptan 10 mg, 2% of patients on rizatriptan 5 mg, and 1% of patients on placebo.
Percentage of patients with adverse events following rizatriptan and placebo
The table shows adverse events occurring after a single dose of study medication and prior to a second dose in patients who took more than one dose (this was permitted from 2 h in some studies for the treatment of recurrence). Drug-related adverse events are those rated by the investigator as definitely, probably, or possibly drug related.
Discussion
This meta-analysis was based on data from all the phase III randomized, controlled, clinical trials on rizatriptan 10 mg completed by Merck & Co. Inc. up to the end of 1998, the year in which the drug was launched. There are no reports in the literature of controlled clinical trials on rizatriptan performed by other groups, and it is therefore reasonable to assume that the analysis covers all the existing data on the drug as of the end of 1998. Data from two phase IIB dose-finding studies (12, 13) were not included in the analysis since the drug supplies were encapsulated for blinding purposes, and the study designs differed in some respects from the phase III studies. However, in the phase IIB studies rizatriptan 10 mg showed a similar advantage over placebo to that described here. For example, in the combined phase IIB studies the placebo-subtracted pain relief rate at 2 h was 31% for rizatriptan 10 mg, vs. 33% reported here. Two additional post-marketing studies were completed by Merck & Co. Inc. at the beginning of 1999, after this analysis had been performed (14, 15); rizatriptan 10 mg showed similar efficacy to that reported here, with a placebo-subtracted pain relief rate at 2 h of 43% for the two studies combined.
The present results confirm that oral rizatriptan 10 mg is a rapidly effective acute treatment for migraine. During treatment of a single migraine attack, rizatriptan 10 mg eliminated headache pain and other migraine symptoms from 30 min after dosing in some patients. At 2 h after dosing, rizatriptan 10 mg was superior to placebo on all efficacy measures, including pain free status which is a recommended efficacy endpoint of the International Headache Society Committee on Clinical Trials in Migraine (16). The analysis of associated symptoms and functional disability looked at patients who actually had the symptom or disability at baseline. Previous analyses of associated symptoms and functional disability following treatment have often included all patients, regardless of whether or not they had the symptom or disability at baseline. The present analysis of single attack data demonstrates that rizatriptan 10 mg is more effective than placebo in eliminating associated symptoms and functional disability. The efficacy advantage for rizatriptan 10 mg vs. placebo was also maintained over multiple attacks in a double-blind, placebo-controlled, crossover study which showed that rizatriptan 10 mg was more effective than placebo at relieving headache pain during each of four consecutive migraine attacks (5).
The meta-analysis clearly demonstrates that rizatriptan 10 mg is more effective than rizatriptan 5 mg. On the pain relief measure, rizatriptan 10 mg was better than rizatriptan 5 mg from 30 min after dosing. At 2 h, a significant superiority was observed on all measures except for elimination of nausea, where the two doses appeared to be equally effective. Superior efficacy of rizatriptan 10 mg vs. 5 mg over multiple attacks was also observed in a previous pooled analysis of three long-term extension studies, where 1438 patients took rizatriptan to treat an average of 18 migraine attacks occurring over periods of up to 1 year (17). Although these studies were not double-blind or placebo-controlled, the majority of patients were blinded to the dose of rizatriptan that they received. Overall, 73% of the 825 patients on rizatriptan 10 mg reported pain relief at 2 h in at least three-quarters of their treated attacks vs. 56% of the 613 patients who treated with 5 mg (17).
Recurrence of headache following initial pain relief at 2 h is a common problem for all acute migraine treatments, and occurs in approximately a third of attacks (18). The average time to recurrence following treatment with rizatriptan 10 mg in the present studies was 12 h. It has been suggested that there may be differences in the recurrence rates associated with individual ‘triptan’ drugs (19, 20). However, recurrence rates need to be assessed within the context of initial efficacy rates (2). As an extreme example, a drug which was completely ineffective at 2 h would have a superficially impressive recurrence rate of 0%, since recurrence by definition can only occur in patients who initially respond. Recurrence rates may also be influenced by the use of additional medications, which are typically permitted from 2 h after initial dosing with the test drug in clinical trials.
To take account of initial efficacy and recurrence, as well as use of additional medications over 24 h, ‘sustained pain relief’ and ‘sustained pain free’ measures have been proposed (2, 3). In the present analysis, a patient with sustained pain relief was defined as one who had pain relief at 2 h, no recurrence (return of moderate or severe headache) within 2–24 h, and no use of any additional migraine medications, including repeat doses of study drug, within 2–24 h. The definition of sustained pain free was the same except that the criteria for initial efficacy was pain free at 2 h, rather than pain relief. In the analysis, 37% of patients on rizatriptan 10 mg had sustained pain relief and 25% had sustained pain-free status. The superior efficacy of rizatriptan 10 mg vs. placebo and rizatriptan 5 mg at 2 h was maintained over 24 h on these measures.
Sustained efficacy measures may provide a clearer assessment of single dose drug efficacy over 24 h and may be useful for comparing the efficacy of different drugs in direct head-to-head studies. However, it should be noted that in clinical practice re-dosing with rizatriptan (up to a maximum of 30 mg per day) is allowed for the treatment of recurrence. A previous study established that rizatriptan 10 mg was an effective treatment for recurrence, with 82% of patients who experienced a recurrence having pain relief 2 h after taking a second dose (4).
Both doses of rizatriptan were generally well tolerated. The most common adverse events in the meta-analysis consisted of asthenia/fatigue, dizziness, nausea and somnolence. There was a small increase in the number of patients reporting adverse events with rizatriptan 10 mg compared with rizatriptan 5 mg. However, most adverse events were of mild or moderate severity and short lasting. The 10 mg dose of rizatriptan has the more favourable benefit:risk profile since it is more effective than the 5 mg dose yet well tolerated. The present results thus support the selection of 10 mg as the recommended dose in most countries. The 5 mg dose is recommended for patients taking propranolol, because plasma concentrations of rizatriptan are increased by up to 70% on average following coadministration with propranolol, but not with other β-blockers (9, 21). It should be noted that patients with coronary artery disease were excluded from the rizatriptan clinical trials; all 5-HT1B/1D receptor agonists are contraindicated in patients with coronary artery disease and uncontrolled hypertension because of their potential to cause vasoconstriction (9, 22–24).
In conclusion, this meta-analysis supports and extends findings from previous studies in demonstrating that rizatriptan 10 mg is an effective treatment for migraine with onset of action from 30 min in some patients. Rizatriptan 10 mg is more effective than rizatriptan 5 mg.
Footnotes
Acknowledgements
This analysis was supported by funding from Merck & Co. Inc., the manufacturers of rizatriptan. Dr Ferrari and Dr Loder have acted as paid consultants for Merck and have received funding from Merck to perform studies. Dr McCarroll and Dr Lines are employees of Merck.