German Clinical Trials Register

Acronym/abbreviation of the study

CJK - Zerr

URL of the study

http://www.cjd-goettingen.de/

Brief summary in lay language

The clinical trial intends to evaluate the efficacy of orally administered doxycyclin compared to a placebo in regard to the total survival time of the patients. The control-group receiving the placebo represent the natural course of the disease. Further goals are to measure the effects of doxycyclin on disease progression, especially the decline of the neurologic and cognitive status, the degree of disability and the level of consciousness (measured by scores and functional scales).

Brief summary in scientific language

Creutzfeldt-Jakob disease is a subacute encephalopathy with an incidence of 1- 1.5 cases per million inhabitants per year. The mean age at onset is 65 years (range 14-92); both genders are equally affected by the disease. Like other human prion diseases (Kuru, Gerstmann-Sträussler-Scheinker-Syndrom, Fatal Familial Insomnia), as well as Scrapie affecting sheep and goat and bovine spongiform encephalopathy (BSE), CJD belongs to the group of transmissible spongiform encephalopathies (TSE), also called prion diseases. The pathogenic mechanism of this disease lies within a conformational change of the physiologic cellular prion protein (PrPc) into the pathological, disease-specific form call PrPsc (sc=scrapie), which yields abnormal physicochemical features like insolubility and protease-resistance and therefore accumulates in the brain in form of aggregates and amyloid-fibrills. There is evidence that PrPsc is responsible for neuropathological processes (neuronal degeneration and glia-activation) and is essential for the transmissibility of the disease. In 85% of the cases CJD occurs sporadically without known cause (sCJD); 15% of all cases are familial prion diseases caused by a mutation in the prion protein gene (PRNP), less than 1% of all cases are iatrogenic. In 1996 a new clinical-pathological variant of the disease (vCJD) was observed in Great Britain which could be linked to the consumption of BSE-infected meat. Clinically CJD is characterized by rapid progressive dementia, and additional symptoms such as visual and cerebellar perturbances, extrapyramidal signs and myoclonus. Periodic sharp-wave-complexes in the EEG, abnormally high concentrations of neuronal proteins (14-3-3 and TAU-protein) in the cerebro-spinal fluid, as well as signal abnormalities in the basal ganglia, the putamen and the neocortex in the MRI can be observed. Usually the disease progresses rapidly to the state of acinetic mutism and leads to death within less than a year, the median survival time being 5-7 months. However, recent improvement of diagnostic investigations allows clinicians to identify previously unidentified atypical cases showing a longer survival time , which account for 10% of all CJD cases. The heterogeneity in the phenotype can be explained by the following two factors: First, the genotype at the Codon 129 of the PRNP shows a polymorphism for either methionine or valine. Second, the variant of the tertiary structure of the PrPsc displaying two types (Type 1 and Type 2), which show different conformation with different physico-chemical and pathogenetic characteristics. In addition survival time is influenced by sex and age; disease duration tends to be significantly longer in women and young people. At the moment no effective treatment for CJD is available. Although several substances (i.e. Pentosan-Polysulfate, Polyen-antibiotics, Tetrapyrols, polyamines, Anthracyclines and Quinacrine) seem to have an anti-prion effect in animal- or cell-culture models of prion diseases, these substances are only of little use in humans, mainly because they fail to pass the blood-brain barrier, because of toxicity or ineffective when administered after clinical disease onset. In clinical trials, none of these substances had a significant effect on the survival time of the patients, however patients receiving Flupiritin demonstrated to have a slower cognitive decline than patients of the control-group. Clinical studies with Quinacrine are currently carried out in the USA and Great Britain, however preliminary data could not show a significant effect on the disease course. Another substance currently being investigated is Pentosan-Polysulfate, which has to be administered intraventricularly, since it cannot surpass the blood-brain barrier. It seems to prolong disease progression, but it should be mentioned that the form of administration is very invasive and is certainly not lacking complications. In contrast to the mentioned findings, investigations carried out by the group around F. Tagliavini from Mailand, showed an effect of Tetracyclines in clinical apparent CJD. In a series of cell-culture and animal experiments the effect seemed to be due to a direct binding of Doxycycline to the PrPsc inhibiting the conformational change. Because of these observations a small number of CJD patients in Italy received a dose of 100 mg Doxycyclin administered by oral route from the time of diagnosis until death. Doxycycline was favored because unlike the other tetracyclic substances it shows a better kinetic, passes the blood-brain barrier and is less toxic with little side effects. In fact none of the patients receiving Doxycyline reported side effects. The retrospective analysis showed that those patients who had received Doxycline (n=21) had survived notably longer (13 ± 4 months) than those patients who did not receive treatment (n=78, 6 ± 7 months). This result is based on an open monitoring trial, therefore the efficacy of Doxycycline in CJD patients has to be confirmed in a randomized, placebo-controlled, double-blind clinical trial. If the study leads to a positive outcome, other studies for similar diseases caused by the misfolding of proteins will follow, since the effect of Doxycycline seems to result rather from a direct interaction with abnormally folded proteins that display beta-sheet structures than with specific aminoacid sequences. The primary investigator of this clinical trial and all other investigators will keep themselves updated throughout the duration of the clinical trial about new findings regarding CJD and Doxycycline and any potential new side effects reported.