Efficacy of Tacrolimus and I.V.-Immunoglobulins in Rasmussen Encephalitis
Information source: University Hospital, Bonn
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Rasmussen Encephalitis
Intervention: Tacrolimus (Drug); i.v. immunoglobulins (Drug)
Phase: Phase 2/Phase 3
Status: Active, not recruiting
Sponsored by: University Hospital, Bonn
Official(s) and/or principal investigator(s):
Christian G Bien, M.D., Principal Investigator, Affiliation: University Hospital Bonn, Bonn, Germany
Rasmussen encephalitis (RE) is a rare but severe chronic inflammatory brain disease of
unknown origin affecting one brain hemisphere. It is usually accompanied by intractable
epilepsy. In addition, it often leads to severe disability due to functional deficits caused
by atrophy of one brain hemisphere. Hemispherectomy is an effective means of surgical
treatment of the epilepsy. It renders the patient, however, hemiplegic, hemianopic and (if
the language dominant hemisphere is affected) aphasic. To slow down or even stop the
progressive inflammatory damage to the affected brain hemisphere, immunotherapies may be
beneficial. According to a literature survey, tacrolimus (twice daily intake of capsules)
and intravenous immunoglobulins (monthly infusions) are the most promising compounds for
this. In the investigators' study, these two types of treatment are randomly assigned to
patients with disease onset within the last year and not too far advanced disability or
hemispheric brain injury. The patients are followed to assess prospectively the functional
and brain MRI course of the disease.
Official title: Efficacy of Tacrolimus and i.v.-Immunoglobulins in Rasmussen Encephalitis With Start of Treatment in the Acute Disease Stage. Prospective, Randomised, Open Parallel Group Study
Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Time to exit, criteria: Deterioration of motor function of the affected side by 15 % (>11 yrs of age: 8%) measured by the "Motricity Index" (scale 0-100) or deterioration of the "Hemispheric ratio" assessed by regular MRI scans by 15% (>11 yrs: 8%).
Secondary outcome: seizure frequency, "Burden of disease" scale, neuropsychological performance, quality of life, T cell receptor studies (H Wiendl, Würzburg)
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.
3. Inclusion/exclusion criteria See appropriate section
4. 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).
5. Outcome measures See appropriate section.
6. 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.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
Minimum age: N/A.
Maximum age: N/A.
- Patients meeting at least two of the following three criteria:
1. Clinical: Epilepsia partialis continua or progressive* hemiparesis
2. MRI: Progressive* cerebral hemiatrophy
3. Histopathology: T cell dominated encephalitis with activated microglial cells
(typically, but not necessarily forming nodules) and reactive astrogliosis.
Numerous macrophages, B cells or plasma cells or positive signs of viral
infections (viral inclusion bodies or immunohistochemical demonstration of viral
protein) exclude the diagnosis of RE.
- "Progressive" means that at least two sequential clinical examinations or
MRI studies documenting increasing deficits or tissue loss are required to
meet the respective criteria.
- Neuroradiological signs of a bihemispheric encephalitis.
- Wave-like course with history of repeated remissions.
- Infectious disease as a contraindication to an immunosuppressive therapy.
- Paraneoplastic encephalitis.
- Previous treatment with > 3 weeks of corticosteroids or tacrolimus or > 1,2 g/kg IVIG
or > 5 PEX/PAI within the last three months.
- Onset of acute disease stage more than 12 months ago.
- Patient already in residual stage, i. e., stable neurological deficit since >6 months.
- Hemispheric Ratio < 80% (< 90% in patients > 11 years)
- Histopathological evidence of cerebral inclusion bodies indicating a viral infection
Locations and Contacts
University of Bonn, Dept. of Epileptology, Bonn 53115, Germany
Homepage of institution performing the trial
Bien CG, Gleissner U, Sassen R, Widman G, Urbach H, Elger CE. An open study of tacrolimus therapy in Rasmussen encephalitis. Neurology. 2004 Jun 8;62(11):2106-9.
Bien CG, Granata T, Antozzi C, Cross JH, Dulac O, Kurthen M, Lassmann H, Mantegazza R, Villemure JG, Spreafico R, Elger CE. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain. 2005 Mar;128(Pt 3):454-71. Epub 2005 Feb 2. Review.
Granata T, Fusco L, Gobbi G, Freri E, Ragona F, Broggi G, Mantegazza R, Giordano L, Villani F, Capovilla G, Vigevano F, Bernardina BD, Spreafico R, Antozzi C. Experience with immunomodulatory treatments in Rasmussen's encephalitis. Neurology. 2003 Dec 23;61(12):1807-10.
Hart YM, Cortez M, Andermann F, Hwang P, Fish DR, Dulac O, Silver K, Fejerman N, Cross H, Sherwin A, et al. Medical treatment of Rasmussen's syndrome (chronic encephalitis and epilepsy): effect of high-dose steroids or immunoglobulins in 19 patients. Neurology. 1994 Jun;44(6):1030-6.
Starting date: November 2002
Last updated: April 9, 2009