The primary objective of the trial is to study the efficacccy of sirolimus in paraneoplastisch neurological syndromes associated with anti-Hu antibodies (Hu-PNS)Secondary objectives are to correlate clinical improvement with anti-Hu antibody titers…
ID
Source
Brief title
Condition
- Autoimmune disorders
- Central nervous system infections and inflammations
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint of the study is the functional and neurological
improvement after 8 wees of sirolimus. Functional improvement is defined as a
decrease of one point or more on the Rankin scale after the 8th week of
sirolimus as compared to the baseline evaluation. Improvement of neurological
impairment is defined as a positive score (>0) in the EFIT overall evaluation
after the 8th week of sirolimus as compared to the baseline evaluation.
Secondary outcome
The secondary research variables are anti-Hu antibody titers in serum and CSF,
antigen specific T cells in blood and CSF, oculomotor function, sirolimus
concentration in serum and CSF and MDR1 polymorphisms and improvement in the
Barthel Index, AMC Linear Disability Score and the PNS Neurological scale.
Background summary
Paraneoplastic neurological syndromes (PNS) are devastating neurological
syndromes that are not directly caused by the tumor or its metastases nor by
vascular, metabolic, infectious or treatment related causes. The detection of
antineuronal auto-antibodies directed against antigens that are expressed in
the underlying tumor and in the nervous system has let to the autoimmune
hypothesis of PNS and has facilitated diagnosis of PNS. The most common
paraneoplastic antibody is directed against the Hu-antigens (anti-Hu). Hu-PNS
is probably caused by an auto-immune reaction directed at the Hu-antigens in
the tumor that subsequently reacts with the same or similar antigens in the
nervous system. Recent studies indicate that T-cells are a major cause of the
neuronal damage. Sirolimus is a powerful inhibitor of activated T-cells.
Therefore, this study investigates the hypothesis that sirolimus can
effectively treat Hu-PNS by inhibiting activated T-cells.
Study objective
The primary objective of the trial is to study the efficacccy of sirolimus in
paraneoplastisch neurological syndromes associated with anti-Hu antibodies
(Hu-PNS)
Secondary objectives are to correlate clinical improvement with anti-Hu
antibody titers in serum and cerebrospinal fluid (CSF), HuD specific T cells in
blood and CSF, sirolimus levels in blood and CSF and with MDR1 polymorphisms.
Study design
Prospective, open-label, single center, phase II, 'prove of concept' study
Intervention
Treatment will be initiated with an oral loading dose of 6 mg sirolimus per day
for three consecutive days followed by oral maintenance dosing of 3 mg/day. The
dosing will be adjusted weekly to maintain through concentrations of 8-12
ng/ml.
Study burden and risks
The prognosis of paraneoplastic neurological syndromes associated with anti-Hu
antibodies (Hu-PNS) is dismal. At present no treatment is available. The side
effects of sirolimus can be relatively easily managed when weekly levels are
determined. In addition, patients are treated for only 8 weeks with sirolimus
in this study. Moreover, we do not expect adverse effects of sirolimus on tumor
growth; on the contrary, an oncolytic effect is more likely.
's-Gravendijkwal 230
3015 CE Rotterdam
NL
's-Gravendijkwal 230
3015 CE Rotterdam
NL
Listed location countries
Age
Inclusion criteria
i) PEM/PSN associated with high (>=1:400 by IIF) titer anti-Hu antibodies.
ii) IIF (indirect immunofluorescence) has been confirmed by Western blotting using purified HuD fusion protein as substrate.
iii) The neurological symptoms must still be progressing defined as neurological deterioration over the last 4 weeks.
iv) Patients aged >=18 years.
v) Patients who receive or will receive concomitant anti-tumor therapy are allowed to participate.
vi) Patients who have given written informed consent.
Exclusion criteria
i) Patients who have reached a neurological plateau phase more than 4 weeks before inclusion date (*damage is done*).
ii) Patients who are unwilling to undergo lumbar puncture.
iii) Liver enzyme elevations of more than 5-fold normal values
iv) Renal failure (GFR < 30 ml/min)
v) Extreme hypertriglyceridemia (> 10 mmol/L) and extreme hypercholesterolemia (> 10 mmol/L)
vi) Active infection
vii) Women of childbearing potential who are pregnant or lactating, seeking pregnancy or failing to take adequate contraceptive precautions.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2008-000793-20-NL |
| CCMO | NL21957.078.08 |