From Cologne in Germany comes news that the trial of frovatriptan for prophylactic treatment of cluster headache has flamed out. The sponsor has pulled the plug! Dr. Pageler’s paper discusses why.
Most people are familiar with Imitrex, a.k.a. sumatriptan, which is a member of a class of medications known as “serotonin 1B/1D agonists”. This means that they activate the serotonin receptor subtypes 1B and 1D, which are found in the walls of arteries and veins in the head and decrease cerebral inflammation. Some triptans also activate serotonin 1F receptors also, which are also found on blood vessels but work in a different way. Triptans are generally used to treat cluster attacks.
Frovatriptan, however, is unique among the triptans in that its half-life is 26 hours, meaning that in theory you could take one shot a day and always have enough frovatriptan in your system to prevent a headache. That is—if frovatriptan works to prevent cluster attacks as well as to treat them, which is what this study was intended to demonstrate.
It was a horrorshow from the beginning.”Recruitment was very slow and all of the 11 patients enrolled conducted major protocol violations,” writes Dr. Pagler somewhat mournfully. What were these protocol violations? For one thing, patients were forbidden to use sumatriptan (Imitex) to treat their cluster attacks, because that would mean “doubling up” on triptans. As most patients with cluster headache will tell you, to not reach for that syringe when you know that’s all it takes to end your attack is all but impossible. Six patients—more than half—did this. There were eight other violations of inclusion and exclusion criteria, three violations of the time window for follow-up visit, three patients didn’t take the frovatriptan, one signed the informed consent form after the study had already started, one became lost to follow-up, and one had other missing documentation. Finally, after thirteen months, the sponsor of the study (Berlin-Chemie/Menarini) pulled the plug, with only 11 subjects out of a target 80 enrolled.
Why the difficulty recruiting? Partly, as I am fond of complaining to people at length, it is because it is just plain difficult to recruit patients for cluster headache trials. There aren’t many cluster headache patients around (compared to migraine), they’re usually not in cycle, and they’re in more distress when they are. Dr. Pagler notes several other problems:
1. The study forbade patients from using triptans to end their attacks, instructing them to use oxygen instead. However, oxygen is seldom provided to cluster headache patients in Germany (or in the US either, I have to note), and even patients who do have oxygen inhalation equipment at home seldom have portable equipment to take with them. This caused a lot of potential subjects to refuse to participate.
2. Other prophylactic treatments (other than frovatriptan) were not allowed; patients who used them within the last month were barred from entry. However, corticosteroids are a prophylactic medication, and are often given at the beginning of a cluster period. Anyone that happened to was automatically excluded.
3. Often patients who are prescribed prophylactic medications will stop taking them between cluster periods (when they are not necessary) without consulting their doctors, then when a cluster period starts will start taking them again, also without consulting their doctors. Because this is a recent medication change, these patients were also excluded.
4. Guidelines for cluster headache trials recommend that only patients who have already been in their cluster period for a week should be enrolled, and also that patents should not be enrolled unless their cluster period is expected to continue for another six weeks. That means that any cluster headache patients with a typical cluster period of less than seven weeks is automatically excluded from ANY cluster headache trial, not just this one—and that’s a lot of patients!
For these reasons, most of the cluster headache patients who might have benefited from frovatriptan weren’t allowed in the study to begin with, and lack of recruitment eventually killed it. So how did frovatriptan fare in the few patients who were enrolled? In the four subjects who received frovatriptan, mean attack frequency declined slightly from 14.8 a week to 14.1 a week. However, that’s so few people that the true value (which the experiment would converge on if it enrolled every cluster headache patient on the planet) could be anywhere from 3.4 to 24.9 (95% chance). Meanwhile, the six people in the placebo group declined from 16.2 attacks a week to 10.1 a week, meaning that frovatriptan did substantially worse than placebo. There is only one other study that looks at frovatriptan for cluster headache. Seven years ago, Drs. Siow and Silberstein in Philadelphia reported on 17 patients in their practice whom they had treated protectively with frovatriptan. Apparently, it worked for them! So the jury’s still out on frovatriptan as a preventative.