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30th January 2009
Telcagepant 300mg improved relief of migraine pain and related symptoms two hours after a single dose as compared to placebo. The trial data suggests that the drug has a similar efficacy to zolmitriptan 5mg, but the study was not powered to detect a difference between the two drugs. The incidence of adverse effects was less with telcagepant than with zolmitriptan.
Action
There has been considerable interest in telcagepant due to its novel mode of action and comparable efficacy to zolmitriptan, with possibly less adverse effects. Therefore, it may be of value in patients for whom triptans are contra-indicated. Additional data on efficacy and safety, as compared to established treatments, are required before its exact role in therapy can be defined. Prescribing committees may wish to consider the role of this drug as the manufacturer, Merck Sharp and Dohme, may apply for a marketing authorisation in 2009.
What is the background to this?
Telcagepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist which is in development for the treatment of migraine. Background information on the management of migraine can be found at Clinical Knowledge Summaries or the pain management section of NPC. Further information is available from the British Association for the Study of Headache and the Scottish Intercollegiate Guidelines Network.
What does this study claim?
Telcagepant 300mg improved relief of migraine pain and migraine-associated symptoms two hours after dosing as compared to placebo. Overall treatment effect was assessed by analysing five primary endpoints. Freedom from pain was achieved in 26.9% of patients taking telcagepant 300mg vs. 9.6% of those taking placebo (P<0.0001) whilst pain relief occurred in 55.0% vs. 27.7% (P<0.0001); an absence of phonophobia was demonstrated in 57.8% vs. 36.8% (P<0.0001) and an absence of photophobia was recorded in 51.0% vs. 28.9% (P<0.0001). Absence of nausea was experienced in 65.1% vs. 55.3% of patients (P=0.0061), respectively. However, the study was not powered to show a difference over zolmitriptan.
How does this relate to other studies?
A proof of concept study demonstrated that the intravenous (IV) CGRP receptor antagonist olcegepant (BIBN4096BS) was as effective as triptans in the management of acute migraine. However, as IV formulations are not first-line treatment in the management of migraine, studies with oral telcagepant have been pursued. Some are awaiting publication and other trials are in progress.
So what?
Oral triptans are used when patients have failed on simple analgesics. Limited statistical data from this study suggests that telcagepant 300mg may have comparable efficacy to zolmitriptan 5mg. Triptans are associated with adverse events such as dizziness, paraesthesia, throat tightness and chest discomfort. Due to their vasoconstrictor effects, they are contra-indicated in patients with substantial underlying cardiovascular disease or uncontrolled hypertension. A potential benefit of the CGRP receptor antagonists may be their lack of vasconstrictive effect. However patients with a history, or clinical evidence, of uncontrolled hypertension or cardiovascular disease were excluded from the trial, so further studies are necessary to determine the safety of telcagepant in these patients.
Study participants had the option of taking a blinded second dose of study medication if the headache recurred within 48 hours, or if moderate or severe migraine was still present two hours after initial dosing. However due to small sample sizes no data for the follow-up doses were reported in this paper.
Design: Phase III double-blind, parallel-treatment triple-dummy trial in which participants were randomised to placebo, telcagepant or zolmitriptan.
Patients: 1,854 adults with a history of 1–8 moderate to severe migraine attacks per month were randomly assigned, but 474 patients did not receive a study dose. The patients (mean age 42 years, 84% women) were instructed to take study medication when they had a moderate or severe migraine attack. An optional second dose of study drug was available if the migraine was still moderate or severe at 2 hours, or for headache recurrence within 48 hours.
Intervention: telcagepant 150mg (n=333) or telcagepant 300mg (n=354).
Comparison: placebo (n=348) or zolmitriptan (n=345).
Outcomes: five co-primary endpoints were measured by the percentage of patients reporting pain freedom, pain relief, absence of photophobia, absence of phonophobia, or absence of nausea at 2 hours post-dose, in comparison with placebo.
Results: for the initial dose: telcagepant 300mg was significantly more effective than placebo. Pain freedom occurred in 26.9% (95%CI 22.4–31.9) of telcagepant 300mg patients vs. 9.6% (6.7–13.2) of placebo patients (P<0.0001); pain relief 55.0% (49.6–60.2) vs. 27.7% ( 23.0–32.8) (P<0.0001); no phonophobia 57.8% (52.4–63.0) vs. 36.8% (31.7–42.2) (P<0.0001); no photophobia 51.0% (45.6–56.3) vs. 28.9% (24.2–34.1) (P<0.0001) and no nausea 65.1% (59.8–70.0) vs. 55.3% (49.8–60.6) (P=0.0061), respectively.
Secondary endpoints: 20.2% of telcagepant 300mg patients vs. 5.0% of placebo patients (P<0.0001) had sustained pain freedom over 2 to 24 hours. 22.9% of telcagepant 300mg patients vs. 8.7% of placebo patients (P<0.0001) were totally free of migraine at two hours.
The efficacy of the second dose was not published due to the small sample size.
Adverse events: occurred in 34.1% of telcagepant 300mg patients, 30.7% of placebo and 50.4% of zolmitriptan patients within 48 hours. The most common adverse effects occurring in patients treated with telcagepant 300mg were dry mouth (6.0%), dizziness (5.1%), somnolence (5.1%), nausea (4.5%) and fatigue (4.3%).
Sponsorship: Merck Research Laboratories.
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