Efficacy of Tacrolimus and I.V.-Immunoglobulins in Rasmussen Encephalitis

1. Trial design/2. Trial interventions Patients are screened in epileptological, neuropediatric, and neurological centers all over Germany. The study design was approved on a meeting in Bonn on April 20, 2002 by several external participants and by the ethical committee of the University of Bonn. Patients with the suspected diagnosis of RE are transferred to the Department of Epileptology of the University of Bonn. If the diagnosis "RE in the acute stage" is confirmed and the patient or (in children) the parents give informed consent, the patients are randomized to one of the two active treatment arms.

The study was started on 1.10.2002. The first patient was included on 20.11.2002.

1. Inclusion/exclusion criteria See appropriate section
2. Duration Recruitment started on 1.10.2002 and will go on until the proposed number of study participants has been included. A patient remains in the study until he or she reaches one of the predefined exit parameters (see below, #4.5). Every patient will be followed under study conditions for at least 12 months (to obtain true long term results).
3. Outcome measures See appropriate section.
4. Methods against bias The patients will be randomized to one of the treatment arms. To avoid unbalanced group sizes and unequal numbers of adolescents and adults, there are two randomization lists, one for patients < 11 years, one for older patients (stratification). Blinding is not possible because the administration of the two drugs is different and would have necessitated the additional use of placebo capsules in the IVIG group and placebo infusions in the tacrolimus group. Because the production and administration of an adequate "IVIG-placebo" is highly impracticable, no blinded treatment application was planned. The physicians assessing the "Motricity Index" and the "Hemispheric ratio" are unaware of the kind of treatment used.
5. Power calculations It is assumed that 1-2 RE patients are diagnosed at a large epilepsy center per year. The cooperation of the study center with the other specialized centers in Germany is good. Therefore, it is expected that the majority of RE cases are transferred to or department. We estimated that 16 suitable patients can be included within the proposed inclusion period. The disease is too rare to perform power calculations (which are mainly used to limit recruitment figures). RE is an orphan disease, so even if the number of participants will not suffice to detect small to moderated differences between the two treatments, the results will provide invaluable information on the conservative treatment of the condition, e.g. in comparison to historical untreated controls.
6. Number of participants It is intended to include at least 16 patients during the above named period (otherwise, the recruitment period will be prolonged). We will perform an intention to treat analysis and an analysis of the patients treated per protocol.
7. Trial sites Potential study participants are referred to our department (Dept. of Epileptology, University of Bonn) from all over Germany. The study procedures, especially the clinical and neuroradiological follow-up studies including assessment of safety parameters are performed in Bonn (visits every two months within the first year, in the second year every four months, thereafter every six months). In the intervals between the visits in Bonn, the referring centers participate in monitoring of the patients and administration of IVIG. There is continuous contact between the study center Bonn and the external study co-workers.
8. Analyses Primary outcome parameter (time to exit): The two groups will be compared by the log rank test (Kaplan-Meyer-survival curves). Non-parametric tests will be applied for the secondary outcome parameters.
9. Ethical considerations Tacrolimus and IVIG can have side effects. The known tacrolimus side effects are more severe and more frequent than those of IVIG. It must be noted, however, that the known tacrolimus side effects were assessed in organ transplant patients who had severe medical diseases and were usually treated with more than one immunosuppressant. In patients with autoimmune disorders treated with tacrolimus-monotherapy, the side effects were considerably lower. RE itself is a disease with a deleterious natural course so that the possible risks of an immunotherapy are clearly outweighed. It must be assumed that most RE patients worldwide are treated with any kind of immunotherapy in the early disease stage due to the favorable case reports in the literature. Therefore, a placebo control group appears ethically unacceptable. This is why we chose to compare the two most promising substances. The ethics committee of the University of Bonn has approved the study design.