Creutzfeldt-Jakob SyndromeNCT02480725
The Role of the Coagulation Pathway at the Synapse in Prion Diseases
An observational study of Creutzfeldt-Jakob Syndrome, run by Sheba Medical Center.
Trial summary
The study hypothesis is that that the deleterious effect of prions on the brain may be mediated (at least partially) by activation of serine proteases involved in the coagulation system. Read more about this study
- Who is it for?
- Ages 35 to 90 years
- Conditions the study is for
- Creutzfeldt-Jakob Syndrome
- What is being tested?
- collect CSF (Cerebrospinal fluid) sample
- Type of treatment
- Surgery or procedure
- How many people
- 50 participants
- Where
- No sites listed yet
- Study dates
- Jun 2015to Jul 2025
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 35 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: CJD and non-CJD patients
Who may be able to join
- Patient undergoing lumbar puncture test as part of the investigation of cognitive decline.
Who cannot join
- Patients on anticoagulation or those who have contraindication for undergoing lumbar puncture.
Trial locations and contacts
No sites are listed yet.
About this study
The study hypothesis is that that the deleterious effect of prions on the brain may be mediated (at least partially) by activation of serine proteases involved in the coagulation system. If this is true, then measurement of the activity of the coagulation system may be a marker of disease onset (in at higher risk individuals such as E200K* carriers) and for disease progression or activity in affected individuals. In addition, modulation of the coagulation system activity may be a potential tool for therapeutic intervention.
*E200K- E200K mutation (Glu to Lys substitution) in the prion protein gene
Read the detailed description
We plan to collect Cerebrospinal fluid (CSF) samples for thrombin activity assay in order to test whether there is a difference in thrombin activity in the CSF between CJD (Creutzfeldt-Jakob disease) and non-CJD patients. CSF samples will be obtained from two sources 1. Patients with familial or sporadic CJD and control patients with other neurodegenerative disorders (e.g. SDAT**, NPH) that will be evaluated in Sheba Medical Center 2. From our collaborating group of Prof. Zerr in the German Prion Referral Center at the University of Gottingen which has a collection of thousands of CSF samples from patients with familial and sporadic CJD as well as ideal controls with other degenerative brain disease.
The study has 2 sections:
- Prospective part in which we plan to recruit 25 patients with CJD and 25 patients with other types of dementia from Sheba Medical Center (SMC). Prior to inclusion in the study a senior neurologist will interview the patient and will verify that he fully understands the objectives of the study and he is mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider the participation in the study will be excluded). Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales. No clinical data other than the cognitive assessment and those needed for the clinical work up will be especially collected for this study.
- Retrospective part in which CSF samples from CJD patients and patients with other type of dementia will be shipped to us from our collaborators in Germany ans will be assayed for Thrombin activity. We plan to recruit to this part of the study 100-200 CJD patient CSF samples and a same number of samples from age matched controls.
Thrombin activity (for samples from both parts of the study) will be assayed as follows: CSF sample will be placed in a black 96 well dish (10 per well). Thrombin activity will be measured by a fluorometric assay, quantifying the cleavage of the synthetic peptide substrate Boc-Asp(OBzl)-Pro-Arg-AMC*** (I-1560, Bachem, Switzerland, 13 molar final concentration). Measurements will be performed by the Infinite 2000 microplate reader (Tecan, infinite 200, Switzerland) with excitation and emission filters of 360±35 and 460±35 nm, respectively. CSF testing for thrombin activity will be conducted in Professor Chapman's laboratory in Sheba. This laboratory is actively engaged in research on the role of thrombin and PAR-1 in diseases of the nervous system and is fully equipped to perform the biochemical and protein levels experiments.
The assay has the potential for commercialization as a diagnostic test for CJD. In addition, there is the potential to develop therapeutic agents targeting excessive thrombin activation.
**SDAT=Senile Dementia of Alzheimer Type
***AMC= Amino Methyl Coumarin
- Conditions
- Creutzfeldt-Jakob Syndrome
- Being tested
- collect CSF (Cerebrospinal fluid) sample
- Keywords
- CJD, CSF, prion, thrombin
- Medical subject headings
- Creutzfeldt-Jakob Syndrome, Insomnia, Fatal Familial
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
collect CSF (Cerebrospinal fluid) sampleProcedure or surgery
collecting CSF samples for thrombin activity assay
| Study group | Role | What they receive |
|---|---|---|
| CJD (Creutzfeldt-Jakob disease) patients | Prior to inclusion in the study a senior neurologist will interview the patient and will verify that he fully understands the objectives of the study and he is mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider the participation in the study will be excluded). Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales. No clinical data other than the cognitive assessment and those needed for the clinical work up will be especially collected for this study. We plan to collect CSF samples for thrombin activity assay. | |
| non-CJD patients with a type of dementia | Prior to inclusion in the study a senior neurologist will interview the patient and will verify that he fully understands the objectives of the study and he is mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider the participation in the study will be excluded).
Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales.
No clinical data other than the cognitive assessment and those needed for the clinical work up will be especially collected for this study.
We plan to collect CSF samples for thrombin activity assay. Receives: Procedure: collect CSF (Cerebrospinal fluid) sample | |
| CSF samples of non-CJD patient used as control | CSF samples : Thrombin activity will be assayed. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Thrombin activity assay
Measured: 10 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jun 2015 (estimated)
- Study startJun 2015
- Primary completionJul 2024 (estimated)
- Study completionJul 2025 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (29)Papers the sponsor has linked to this study.
- Other trials for Creutzfeldt-Jakob SyndromeStudies of the same condition, open and under way.
- More trials run by Sheba Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sheba Medical Center
- Sponsor type
- Other government
- Collaborators
- Prof. Zerr , Prion Referral Center , University of Gottingen, Germany
- Responsible party
- Principal investigator, Dr. Oren Cohen, Sheba Medical Center
- Investigators
- Oren Cohen, Dr. (MD), Principal investigator, Cheba Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02480725
- Sponsor's protocol ID
- 1702-14 SMC
- Status last verified
- Jun 2015
- First submitted
- 22 Jun 2015
- Last updated
- 24 Jun 2015
- Results posted
- No
- Data monitoring committee
- No
Publications
Prusiner SB. Molecular biology of prion diseases. Science. 1991 Jun 14;252(5012):1515-22. doi: 10.1126/science.1675487.
PubMed 1675487Harris DA, Lele P, Snider WD. Localization of the mRNA for a chicken prion protein by in situ hybridization. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4309-13. doi: 10.1073/pnas.90.9.4309.
PubMed 8483948Windl O, Dempster M, Estibeiro P, Lathe R. A candidate marsupial PrP gene reveals two domains conserved in mammalian PrP proteins. Gene. 1995 Jul 4;159(2):181-6. doi: 10.1016/0378-1119(95)00064-d.
PubMed 7622046Bueler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C. Mice devoid of PrP are resistant to scrapie. Cell. 1993 Jul 2;73(7):1339-47. doi: 10.1016/0092-8674(93)90360-3.
PubMed 8100741Collinge J, Whittington MA, Sidle KC, Smith CJ, Palmer MS, Clarke AR, Jefferys JG. Prion protein is necessary for normal synaptic function. Nature. 1994 Jul 28;370(6487):295-7. doi: 10.1038/370295a0.
PubMed 8035877Tobler I, Gaus SE, Deboer T, Achermann P, Fischer M, Rulicke T, Moser M, Oesch B, McBride PA, Manson JC. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature. 1996 Apr 18;380(6575):639-42. doi: 10.1038/380639a0.
PubMed 8602267Aucouturier P, Geissmann F, Damotte D, Saborio GP, Meeker HC, Kascsak R, Kascsak R, Carp RI, Wisniewski T. Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest. 2001 Sep;108(5):703-8. doi: 10.1172/JCI13155.
PubMed 11544275Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10962-6. doi: 10.1073/pnas.90.23.10962.
PubMed 7902575Ellis V, Daniels M, Misra R, Brown DR. Plasminogen activation is stimulated by prion protein and regulated in a copper-dependent manner. Biochemistry. 2002 Jun 4;41(22):6891-6. doi: 10.1021/bi025676g.
PubMed 12033920Epple G, Schleuning WD, Kettelgerdes G, Kottgen E, Gessner R, Praus M. Prion protein stimulates tissue-type plasminogen activator-mediated plasmin generation via a lysine-binding site on kringle 2. J Thromb Haemost. 2004 Jun;2(6):962-8. doi: 10.1111/j.1538-7836.2004.00675.x.
PubMed 15140132Fischer MB, Roeckl C, Parizek P, Schwarz HP, Aguzzi A. Binding of disease-associated prion protein to plasminogen. Nature. 2000 Nov 23;408(6811):479-83. doi: 10.1038/35044100.
PubMed 11100730Praus M, Kettelgerdes G, Baier M, Holzhutter HG, Jungblut PR, Maissen M, Epple G, Schleuning WD, Kottgen E, Aguzzi A, Gessner R. Stimulation of plasminogen activation by recombinant cellular prion protein is conserved in the NH2-terminal fragment PrP23-110. Thromb Haemost. 2003 May;89(5):812-9.
PubMed 12719777Deininger MH, Trautmann K, Magdolen V, Luther T, Schluesener HJ, Meyermann R. Cortical neurons of Creutzfeldt-Jakob disease patients express the urokinase-type plasminogen activator receptor. Neurosci Lett. 2002 May 10;324(1):80-2. doi: 10.1016/s0304-3940(02)00168-4.
PubMed 11983300Zerr I, Bodemer M, Kaboth U, Kretzschmar H, Oellerich M, Armstrong VW. Plasminogen activities and concentrations in patients with sporadic Creutzfeldt-Jakob disease. Neurosci Lett. 2004 Nov 23;371(2-3):163-6. doi: 10.1016/j.neulet.2004.08.063.
PubMed 15519749Almeida LM, Basu U, Khaniya B, Taniguchi M, Williams JL, Moore SS, Guan LL. Gene expression in the medulla following oral infection of cattle with bovine spongiform encephalopathy. J Toxicol Environ Health A. 2011;74(2-4):110-26. doi: 10.1080/15287394.2011.529061.
PubMed 21218340
Study at a glance
From the registry record, last updated by the sponsor on 24 Jun 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Role of the Coagulation Pathway at the Synapse in Prion Diseases
- ClinicalTrials.gov ID
- NCT02480725
- Acronym / sponsor ID
- 1702-14 SMC
- Conditions
- Creutzfeldt-Jakob Syndrome
- Keywords
- CJD, CSF, prion, thrombin
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- Sheba Medical CenterOther government
- Collaborators
- Prof. Zerr , Prion Referral Center , University of Gottingen, Germany
- Study start
- Jun 2015
- Primary completion
- Jul 2024 (estimated)
- Study completion
- Jul 2025 (estimated)
- First posted
- 24 Jun 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The study hypothesis is that that the deleterious effect of prions on the brain may be mediated (at least partially) by activation of serine proteases involved in the coagulation system. If this is true, then measurement of the activity of the coagulation system may be a marker of disease onset (in at higher risk individuals such as E200K* carriers) and for disease progression or activity in affected individuals. In addition, modulation of the coagulation system activity may be a potential tool for therapeutic intervention.
*E200K- E200K mutation (Glu to Lys substitution) in the prion protein gene
Detailed description
We plan to collect Cerebrospinal fluid (CSF) samples for thrombin activity assay in order to test whether there is a difference in thrombin activity in the CSF between CJD (Creutzfeldt-Jakob disease) and non-CJD patients. CSF samples will be obtained from two sources 1. Patients with familial or sporadic CJD and control patients with other neurodegenerative disorders (e.g. SDAT**, NPH) that will be evaluated in Sheba Medical Center 2. From our collaborating group of Prof. Zerr in the German Prion Referral Center at the University of Gottingen which has a collection of thousands of CSF samples from patients with familial and sporadic CJD as well as ideal controls with other degenerative brain disease.
The study has 2 sections:
- Prospective part in which we plan to recruit 25 patients with CJD and 25 patients with other types of dementia from Sheba Medical Center (SMC). Prior to inclusion in the study a senior neurologist will interview the patient and will verify that he fully understands the objectives of the study and he is mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider the participation in the study will be excluded). Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales. No clinical data other than the cognitive assessment and those needed for the clinical work up will be especially collected for this study.
- Retrospective part in which CSF samples from CJD patients and patients with other type of dementia will be shipped to us from our collaborators in Germany ans will be assayed for Thrombin activity. We plan to recruit to this part of the study 100-200 CJD patient CSF samples and a same number of samples from age matched controls.
Thrombin activity (for samples from both parts of the study) will be assayed as follows: CSF sample will be placed in a black 96 well dish (10 per well). Thrombin activity will be measured by a fluorometric assay, quantifying the cleavage of the synthetic peptide substrate Boc-Asp(OBzl)-Pro-Arg-AMC*** (I-1560, Bachem, Switzerland, 13 molar final concentration). Measurements will be performed by the Infinite 2000 microplate reader (Tecan, infinite 200, Switzerland) with excitation and emission filters of 360±35 and 460±35 nm, respectively. CSF testing for thrombin activity will be conducted in Professor Chapman's laboratory in Sheba. This laboratory is actively engaged in research on the role of thrombin and PAR-1 in diseases of the nervous system and is fully equipped to perform the biochemical and protein levels experiments.
The assay has the potential for commercialization as a diagnostic test for CJD. In addition, there is the potential to develop therapeutic agents targeting excessive thrombin activation.
**SDAT=Senile Dementia of Alzheimer Type
***AMC= Amino Methyl Coumarin
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| CJD (Creutzfeldt-Jakob disease) patients | – | –Prior to inclusion in the study a senior neurologist will interview the patient and will verify that he fully understands the objectives of the study and he is mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider the participation in the study will be excluded). Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales. No clinical data other than the cognitive assessment and those needed for the clinical work up will be especially collected for this study. We plan to collect CSF samples for thrombin activity assay. |
| non-CJD patients with a type of dementia | – | Procedure: collect CSF (Cerebrospinal fluid) samplePrior to inclusion in the study a senior neurologist will interview the patient and will verify that he fully understands the objectives of the study and he is mentally qualified to sign the informed consent form (severely demented patients who will not be able to adequately consider the participation in the study will be excluded). Cognitive performance will be evaluated using the Mini-mental Status Examination and Frontal Assessment Battery scales. No clinical data other than the cognitive assessment and those needed for the clinical work up will be especially collected for this study. We plan to collect CSF samples for thrombin activity assay. |
| CSF samples of non-CJD patient used as control | – | –CSF samples : Thrombin activity will be assayed. |
Who may qualify
- Ages
- 35 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- CJD and non-CJD patients
Key inclusion criteria (1 listed)
- Patient undergoing lumbar puncture test as part of the investigation of cognitive decline.
Key exclusion criteria (1 listed)
- Patients on anticoagulation or those who have contraindication for undergoing lumbar puncture.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| collect CSF (Cerebrospinal fluid) samplecollecting CSF samples for thrombin activity assay | Procedure or surgery | non-CJD patients with a type of dementia |
Primary outcome
Thrombin activity assay
Time frame: 10 years
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Jun 2015.
- Background: PubMed 1675487Prusiner SB. Molecular biology of prion diseases. Science. 1991 Jun 14;252(5012):1515-22. doi: 10.1126/science.1675487.
- Background: PubMed 8483948Harris DA, Lele P, Snider WD. Localization of the mRNA for a chicken prion protein by in situ hybridization. Proc Natl Acad Sci U S A. 1993 May 1;90(9):4309-13. doi: 10.1073/pnas.90.9.4309.
- Background: PubMed 7622046Windl O, Dempster M, Estibeiro P, Lathe R. A candidate marsupial PrP gene reveals two domains conserved in mammalian PrP proteins. Gene. 1995 Jul 4;159(2):181-6. doi: 10.1016/0378-1119(95)00064-d.
- Background: PubMed 8100741Bueler H, Aguzzi A, Sailer A, Greiner RA, Autenried P, Aguet M, Weissmann C. Mice devoid of PrP are resistant to scrapie. Cell. 1993 Jul 2;73(7):1339-47. doi: 10.1016/0092-8674(93)90360-3.
- Background: PubMed 8035877Collinge J, Whittington MA, Sidle KC, Smith CJ, Palmer MS, Clarke AR, Jefferys JG. Prion protein is necessary for normal synaptic function. Nature. 1994 Jul 28;370(6487):295-7. doi: 10.1038/370295a0.
- Background: PubMed 8602267Tobler I, Gaus SE, Deboer T, Achermann P, Fischer M, Rulicke T, Moser M, Oesch B, McBride PA, Manson JC. Altered circadian activity rhythms and sleep in mice devoid of prion protein. Nature. 1996 Apr 18;380(6575):639-42. doi: 10.1038/380639a0.
- Background: PubMed 11544275Aucouturier P, Geissmann F, Damotte D, Saborio GP, Meeker HC, Kascsak R, Kascsak R, Carp RI, Wisniewski T. Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie. J Clin Invest. 2001 Sep;108(5):703-8. doi: 10.1172/JCI13155.
- Background: PubMed 7902575Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, Mehlhorn I, Huang Z, Fletterick RJ, Cohen FE, et al. Conversion of alpha-helices into beta-sheets features in the formation of the scrapie prion proteins. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):10962-6. doi: 10.1073/pnas.90.23.10962.
- Background: PubMed 12033920Ellis V, Daniels M, Misra R, Brown DR. Plasminogen activation is stimulated by prion protein and regulated in a copper-dependent manner. Biochemistry. 2002 Jun 4;41(22):6891-6. doi: 10.1021/bi025676g.
- Background: PubMed 15140132Epple G, Schleuning WD, Kettelgerdes G, Kottgen E, Gessner R, Praus M. Prion protein stimulates tissue-type plasminogen activator-mediated plasmin generation via a lysine-binding site on kringle 2. J Thromb Haemost. 2004 Jun;2(6):962-8. doi: 10.1111/j.1538-7836.2004.00675.x.
- Background: PubMed 11100730Fischer MB, Roeckl C, Parizek P, Schwarz HP, Aguzzi A. Binding of disease-associated prion protein to plasminogen. Nature. 2000 Nov 23;408(6811):479-83. doi: 10.1038/35044100.
- Background: PubMed 12719777Praus M, Kettelgerdes G, Baier M, Holzhutter HG, Jungblut PR, Maissen M, Epple G, Schleuning WD, Kottgen E, Aguzzi A, Gessner R. Stimulation of plasminogen activation by recombinant cellular prion protein is conserved in the NH2-terminal fragment PrP23-110. Thromb Haemost. 2003 May;89(5):812-9.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Oren Cohen, Dr. (MD) principal investigator
Cheba Medical Center
Questions about this trial
What is this clinical trial studying?
An observational study of Creutzfeldt-Jakob Syndrome, run by Sheba Medical Center.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 24 Jun 2015. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Oren Cohen, Dr. (MD) (+972-52-6667584, coheno@asaf.health.gov.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Thrombin activity assay (time frame: 10 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02480725, which also lists 29 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Jun 2015.