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We have read the comments of Overwater and colleagues regarding our recent paper and thank them for their thoughtful input and kind words. Our trial was designed as a pilot study and is the first prospective human clinical trial of a mammalian target of rapamycin (mTOR) inhibitor with a primary outcome measure of reduction in seizure frequency.[1] As noted, we found a beneficial effect from everolimus treatment that was statistically significant. We agree with Overwater and colleagues that a single open-label study with 20 patients does not “prove” that either everolimus, or mTOR inhibition generally, is effective for epilepsy, either in tuberous sclerosis or in other conditions. There is no dispute that a placebo-controlled, double-blind, randomized trial generally provides more powerful information than open-label studies, case series, or anecdotal reports. Such an open-label placebo-controlled trial (EXIST 3) is currently ongoing and actively enrolling patients.[2]

We do, however, take issue with the assertion that use of mTOR inhibition for epileptic seizures is “not yet evidence-based.” Although not having the power of a double-blind, placebo-controlled, randomized trial such as EXIST 1,[3] open-label trials do constitute evidence that can be used for the planning of further research, as well as to guide clinical practice. Consider our initial report of sirolimus for the treatment of subependymal giant cell astrocytomas (SEGAs),[4] also published in this journal. We found the likelihood of 4 consecutive patients showing reduction in astrocytoma volume after the same treatment by random chance to be <0.0039 (ie, 0.4%), even allowing for a 25% incidence of spontaneous regression. This did not “prove” that sirolimus should always be used for SEGAs, but it did constitute evidence that it could be an effective treatment. Similarly, our subsequent open-label single-site trial of everolimus for SEGA in 28 patients[5] was judged to be sufficiently “evidential” by the US Food and Drug Administration for it to grant approval of the drug for this indication.

It is also unclear to us why Overwater and colleagues feel that the observed decrease in seizure frequency with everolimus treatment could reflect a spontaneous improvement. Patients experienced a 70% reduction in seizures during the evaluation phase of our study as compared to baseline, for a probability value of 0.007, suggesting that this result would be expected to occur randomly 7 times out of 1,000. Overwater and colleagues state, “The chance of a seizure frequency improving after this period is not unlikely.” What is the specific statistical calculation or literature reference that this assertion is based upon? What is meant by “not unlikely”? Ten percent? Five percent? Presumably, some value greater than the observed 0.7%. In a recent report by Wiegand et al,[6] patients with medically intractable epilepsy also showed beneficial effects on their epilepsy after everolimus treatment. These patients have been followed for many years, using a standardized program (Epivista®) at a single site in Germany. This program allows for rigorous assessment of seizure frequency as well as any spontaneous variation. Even against this background, significant improvement in seizure frequency was noted with the addition of everolimus treatment, which was not explainable by spontaneous remission.

Finally, as far as the caution urged by Overwater et al against off-label use of everolimus or other mTOR inhibitors for tuberous sclerosis, we appreciate and respect their opinion. Certainly, further clinical trials are critical for both confirmation and more exact definition of the appropriate use of mTOR inhibition for epilepsy and other indications in tuberous sclerosis. Off-label use of medications can certainly impact the conduct of clinical research into these same off-label usages. Nonetheless, we believe that individual therapeutic decisions must be made in the context of specific patients and their treating physicians, not dictated by persons unfamiliar with the specific case or situation. Despite use of everolimus for intractable epilepsy not being a “proven” treatment, patients, families, and physicians deserve to know the results of clinical and basic science research, and to determine for themselves the best course of action.

Potential Conflicts of Interest

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  2. Potential Conflicts of Interest
  3. References

D.A.K.: consultancy Novartis, Lundbeck; grants/grants pending, Novartis, NINDS, Tuberous Sclerosis Alliance; speaking fees, travel expenses, Novartis. A.A.W.: consultancy, Lundbeck, Supernus, Cyberonics; grants/grants pending, Novartis, NINDS, Moody Foundation, UCB, Pfizer, Upsher-Smith, Impax, GSK; speaking fees, travel expenses, Cyberonics; royalites, Up to Date. D.N.F.: consultancy, grants/grants pending, Novartis.

References

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  2. Potential Conflicts of Interest
  3. References
  • 1
    Krueger D, Wilfong A, Holland-Bouley K, et al. Everolimus treatment of refractory epilepsy in tuberous sclerosis complex. Ann Neurol 2013 Jun 24. doi: 10.1002/ana.23960. [Epub ahead of print].
  • 2
    ClinicalTrials.gov. A placebo-controlled study of efficacy & safety of 2 trough-ranges of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) & refractory partial-onset seizures (EXIST-3). 2013. Available at: clinicaltrials.gov/ct2/show/NCT01713946. Accessed on November 15, 2013.
  • 3
    Franz D, Belousova E, Sparagana S, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2012;381:125132.
  • 4
    Franz DN, Leonard J, Tudor C, et al. Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 2006;59:490498.
  • 5
    Krueger D, Care M, Holland-Bouley K, et al. Everolimus for supependymal giant-cell astrocytomas in tuberous sclerosis complex. N Engl J Med 2010;363:18011811.
  • 6
    Wiegand G, May T, Ostertag P, et al. Everolimus in tuberous sclerosis patients with intractable epilepsy: a treatment option? Eur J Paediatr Neurol 2013 Nov;17(6):631638. doi: 10.1016/j.ejpn.2013.06.002. Epub 2013 Jul 8.