Amyotrophic Lateral Sclerosis and the Innate Immune System
NCT ID: NCT02869048
Last Updated: 2017-10-06
Study Results
Results pending
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
Get a concise snapshot of the trial, including recruitment status, study phase, enrollment targets, and key timeline milestones.
Recruitment Status
RECRUITING
Total Enrollment
375 participants
Study Classification
OBSERVATIONAL
Study Start Date
2016-06-30
Study Completion Date
2026-06-30
Brief Summary
Review the sponsor-provided synopsis that highlights what the study is about and why it is being conducted.
Amyotrophic Lateral Sclerosis (ALS) is an aggressive, deadly disease. ALS leads to destruction of the neural pathways which control the conscious movements of the muscles. This destruction leads to muscular dystrophy with increasing difficulties in moving, breathing, swallowing, and speaking. In the last phase of an ALS patient's life it is necessary with respiratory therapy in order to breathe. In average an ALS patient lives 3 years from the time he or she gets the diagnose.
The cause of the disease is still unknown and there is currently no treatment which can stop the progression of the disease. Former clinical studies have indicated that the innate immune system and in particular the complement system plays a significant role in the progression of ALS. The complement system, which is activated in cascades, is part of the innate system but participates in the innate as well as the acquired immune system. Former clinical trials have been characterized by limited knowledge about both the complement system as well as to how it is measured.
Today it is possible to measure directly on the different components of the complement system and to understand its contribution to the overall immune response. It is also possible today to detect defects of the complement system. All these progressions are the foundation for this project which is carried out in close cooperation with one of the world's leading researchers in the complement system, professor Peter Garred from Rigshospitalet.
The aim is to make a national research project about ALS in order to investigate the role of the innate immune system, and especially the complement system, in patients with ALS.
In the long term the hope is, that this will lead the way to a targeted and effective medical treatment to the people affected by this grave disease.
The cause of the disease is still unknown and there is currently no treatment which can stop the progression of the disease. Former clinical studies have indicated that the innate immune system and in particular the complement system plays a significant role in the progression of ALS. The complement system, which is activated in cascades, is part of the innate system but participates in the innate as well as the acquired immune system. Former clinical trials have been characterized by limited knowledge about both the complement system as well as to how it is measured.
Today it is possible to measure directly on the different components of the complement system and to understand its contribution to the overall immune response. It is also possible today to detect defects of the complement system. All these progressions are the foundation for this project which is carried out in close cooperation with one of the world's leading researchers in the complement system, professor Peter Garred from Rigshospitalet.
The aim is to make a national research project about ALS in order to investigate the role of the innate immune system, and especially the complement system, in patients with ALS.
In the long term the hope is, that this will lead the way to a targeted and effective medical treatment to the people affected by this grave disease.
Detailed Description
Dive into the extended narrative that explains the scientific background, objectives, and procedures in greater depth.
Amyotrophic lateral sclerosis (ALS) is a progressive, deadly, neurodegenerative disease which affects the upper and lower motor neurons. This leads to profound muscular dystrophy, hyperreflexia, fasciculations and paresis of the bulbar as well as the skeletal musculature. ALS causes increasing physical fatigue and the patients soon become bedridden and respiratory insufficient.The diagnosis ALS is made according to the El Escorial revisited. Often clinical and neurophysiological tests must be repeated (1-4).
In Denmark the incidence of ALS is 1-2/100.000 and the prevalence is 4-6/100.000. The average survival time from the time of the diagnosis is 3 years but with great variance. (5+6)
Today the pathogenesis is still unknown and no treatment can stop the progression of ALS. Treatment with riluzole seems to prolong the median time of survival for 2 or 3 months (7).
Most likely, a future medical treatment requires a better understanding of the pathogenesis as well as the pathophysiology of ALS. This present study aims to do so based on the hypothesis that ALS partially or fully is caused by complement activation.
The complement system is a complex system consisting of proteins in plasma as well as membrane bound proteins which together complement the antibody-based immune system. The complement system is a self-perpetuating cascade system which is activated through different pathways. It works by opsonisation where complement proteins bind to microorganisms to activate and target granulocytes, monocytes and macrophages. The complement system also causes cytolysis of microorganisms via MAC (membrane attack complex) by activation of the mast cells. It also inactivates and eliminates burned out immune complexes as well as performing apoptotic renovation.
A recent pilot study of Neuromyelitis Optica has shown how the complement system play a central part in the pathogenesis of a disease that previously was wrongfully perceived as an early stage of Disseminated Sclerosis. These findings resulted in medical treatment with anticomplement (equlizumab) with promising results (8). It is possible that similar pathogenetic mechanisms could be the molecular basis of ALS.
Different research groups have tried to illuminate how the immune system is involved in the progression of ALS (9-35). Several studies support the hypothesis that the complement system is of crucial importance for the onset and progression of ALS. (9-28)
In several clinical trials with ALS plasma it is concluded that ALS plasma is cytotoxic when incubated with healthy red blood cells or healthy nerve tissue. Some research indicates that the cytotoxicity is caused by the complement system. The results cannot, however, be reproduced consequently in all clinical trials. These trials were conducted decades ago where the methods of detecting complement activity were limited. (9-14)
Several animal trials indicate that ALS starts in the neuromuscular junctions (NMJ) and therefore should be considered a distal axonopathy rather than a central neurological disease, which today is the general perception of ALS. (27-31)
The purpose of the project The aim is to increase the knowledge of the pathophysiology of the disease ALS as this possibly may lead us closer to a targeted medical treatment.
The project group wants to investigate if a previously found, unique cytotoxicity in the ALS plasma can be retrieved (9-14). If this is the case, then the modern methods of today make it possible to detect whether the immune system in general, and in particular the complement system, is causing this cytotoxicity.
The establishment of a national research project about ALS and the complement system by making a research biobank with systematically collected blood and spinal liquid from ALS patients from all over the country will ensure the opportunity to find out if the complement system plays a role in the onset and progression of ALS.
Furthermore a pilot study will be conducted with the purpose to investigate if there is complement activity in the NMJ in patients with ALS as it has been shown in a study of ALS mice. (28)
The hypotheses
1. ALS is characterized by an abnormal immune response with cytotoxicity and increased complement activity in plasma which is revealed by the following:
1. Plasma from patients with ALS shows increased haemolytic activity when incubated with red blood cells from healthy subjects.
2. The complement activity is increased in the plasma from ALS patients compared with plasma from neurologically healthy subjects and subjects with other neurological disease.
3. The haemolytic activity in the plasma from ALS patients is correlated with the complement activity.
2. Spinal liquid from ALS patients contains increased complement activity compared with spinal liquid from neurologically healthy subjects and from subjects with other neurological disease.
Patients, materials and methods:
Clinical trial 1(CT1): Haemolytic activity and the complement system in ALS plasma
Number of subjects: 25 patients with ALS, 25 patients with other neurological disease, 25 healthy volunteers
The course of CT1: A blood sample is taken from each patient. The red blood cells and the liquid part of the blood, the plasma, are separated. The red blood cells from different subjects are incubated in an other subjects plasma.The same trial course is repeated after inactivation of the present complement system both by heat and by anti-complement.
Clinical trial 2(CT2): Case-control study aiming to mapping the complement system
Number of subjects:100 patients with ALS, 100 patients with other neurological disease and 100 neurologically healthy patients
The course of CT2:Blood samples and cerebrospinal fluid are prepared and then freezed in a research biobank. Then the samples from the 3 groups of subjects are analysed and compared focusing on the complement system: The complement activation potential is measured in the biological material. A cytokine profile is made as well as mapping the acute phase reactants by multiplex assays. Furthermore the RNA expression profile is made on a cell pellet stabilised with RNA later.
Clinical trial 3(CT3): The complement system of ALS patients over time - a cohort study Number of subjects:20 patients with ALS (subset from CT2)
The course of CT3: Every sixth month the course from the CT2 is repeated. The activity of the complement system in each patient with ALS is analyzed as the disease progresses.
Clinical trial 4(CT4): Searching for complement activity in the NMJ of ALS patients
Number of subjects:10 patients with ALS
The course of CT4: The muscle biopsies are taken and immediately brought to the Dep. of Pathology at Rigshospitalet. Then thin layers of tissue are stained in order to analyze the muscle fibers and the NMJ as well as detecting presence of complement activity.
Conducting the study The project consists of four clinical trials. Inclusion of the subjects is done together with staff in ALS outpatient clinics at hospitals all over the country and subjects for the control groups are included according to the list of inclusion sites below.
Inclusion sites:
ALS outpatient clinic, Neurological clinic, Rigshospitalet Glostrup (CT1+2+3+4) Contact: Chief physician Elisabeth Elmo Neurological Clinic, Rigshospitalet Glostrup (neurological control group, CT1+2) Contact: Professor, Chief physician, dr.med. Rigmor Højland Jensen Neurosurgical Clinic, Rigshospitalet (neurological control group, CT2) Contact: Professor, chief physician, dr.med. Marianne Juhler ALS outpatient clinic, Neurological Dep., Bispebjerg Hospital (CT2) Contact: Chief physician Merete Karlsborg ALS outpatient clinic, Neurological Dep., Roskilde Hospital (CT2 + 3) Contact: Chief physician Helle Thagesen ALS outpatient clinic, Neurological Dep., Odense University Hospital (CT2) Contact: Chief physician, dr.med. Matthias Bode ALS outpatient clinic, Neurological Dep., Aarhus Hospital, Nørrebrogade (Clinical Trial 2) Contact: Chief Physician, ph.d. Anette Torvin Gildhøj Private Hospital, Brøndby (Neurologically healthy control group, Clinical Trial 2) Contact: Anaesthesiologist Niels Anker Pedersen
Power calculations CT1: Haemolytic activity and the complement system in ALS plasma The study Overgaard et al. (18) found a mean difference of about 0,20 (SE 0,052 in the ALS group, N=20, SD 0,22) in the absorbance (415 nm and 5 hours of incubation) between ALS patients and healthy bioanalysts. With α=0,05 og beta=0,20 corresponding to power 0,80 we need to include 21 subjects. As possible drop outs and technically failed are considered tests the investigators choose to include 25 subjects in each group. (36)
CT2: Case-control study mapping the complement system The number of subjects in each group is in this case-control study calculated with α=0,05 The investigators compare the complement activation potential of 3 groups with same amount of subjects in each. In healthy subjects the complement activation potential is 100 % with a normal area ranging from 50-150 % and where the prevalence of low complement activation potential (under 50 %) is under 10 %. With power =0,80 it is calculated to be necessary to include 100 subjects in each group. Hereby it is possible to find statistically significant differences between the groups corresponding to an odds ratio of 2,3, which would correspond to 20 % of ALS patients having a low complement activation potential caused by increased complement activity. (36)
CT3: The complement system of ALS patients over time - a cohort study This is a hypothesis generating study. It is expected that the included 20 ALS patients in this cohort will be a subset from Clinical Trial 2. As a control group at baseline the neurologically healthy control group from Clinical Trial 2 will be used.
CT4: Searching for complement activity in the NMJ of ALS patients There is no previous studies describing the complement activity in the NMJ in living humans. It is therefore not relevant to make a calculation of power.
Data processing CT1: Haemolytic activity and the complement system in ALS plasma Comparing the degree of haemolysis between the ALS patients and the control groups t-test and one way ANOVA are used. For calculating the cut-off values the investigators use receiver operating characteristic (ROC) curves.
CT2: Case-control study mapping the complement system Comparing the concentration of complement and the complement activation potential between ALS patients and the control groups t-test and one way ANOVA are used. In order to calculate the odds for low complement activation potential in the ALS group compared with the control groups the investigators use logistic regression. For calculating the cut-off values receiver operating characteristic (ROC) curves are used.
CT3: The complement system of ALS patients over time - a cohort study As in Clinical Trial 2. Furthermore, regression analysis of the complement activity as a function of time since the onset of ALS, gender, age, subtype of illness and disease progression are conducted.
CT4: Searching for complement activity in the NMJ of ALS patients As in CT2. The degree of complement deposition and muscle pathology is described qualitatively and a blinded scoring in "normal", "light degree" and "severe degree" of changes is conducted. This will be compared quantitatively with 2 x K tables and non-parametric statistics.
Dissemination of results The results of the project will be published in international peer reviewed, journals. Both positive and negative findings will be published.
Perspectivation With the establishment of a big national ALS research biobank it will be possible to conduct many future research projects. Continuous research in ALS is paramount for ALS patients nationally as well as internationally in order to maintain hope for an efficient medical treatment for this aggressive disease is found in the future.
In Denmark the incidence of ALS is 1-2/100.000 and the prevalence is 4-6/100.000. The average survival time from the time of the diagnosis is 3 years but with great variance. (5+6)
Today the pathogenesis is still unknown and no treatment can stop the progression of ALS. Treatment with riluzole seems to prolong the median time of survival for 2 or 3 months (7).
Most likely, a future medical treatment requires a better understanding of the pathogenesis as well as the pathophysiology of ALS. This present study aims to do so based on the hypothesis that ALS partially or fully is caused by complement activation.
The complement system is a complex system consisting of proteins in plasma as well as membrane bound proteins which together complement the antibody-based immune system. The complement system is a self-perpetuating cascade system which is activated through different pathways. It works by opsonisation where complement proteins bind to microorganisms to activate and target granulocytes, monocytes and macrophages. The complement system also causes cytolysis of microorganisms via MAC (membrane attack complex) by activation of the mast cells. It also inactivates and eliminates burned out immune complexes as well as performing apoptotic renovation.
A recent pilot study of Neuromyelitis Optica has shown how the complement system play a central part in the pathogenesis of a disease that previously was wrongfully perceived as an early stage of Disseminated Sclerosis. These findings resulted in medical treatment with anticomplement (equlizumab) with promising results (8). It is possible that similar pathogenetic mechanisms could be the molecular basis of ALS.
Different research groups have tried to illuminate how the immune system is involved in the progression of ALS (9-35). Several studies support the hypothesis that the complement system is of crucial importance for the onset and progression of ALS. (9-28)
In several clinical trials with ALS plasma it is concluded that ALS plasma is cytotoxic when incubated with healthy red blood cells or healthy nerve tissue. Some research indicates that the cytotoxicity is caused by the complement system. The results cannot, however, be reproduced consequently in all clinical trials. These trials were conducted decades ago where the methods of detecting complement activity were limited. (9-14)
Several animal trials indicate that ALS starts in the neuromuscular junctions (NMJ) and therefore should be considered a distal axonopathy rather than a central neurological disease, which today is the general perception of ALS. (27-31)
The purpose of the project The aim is to increase the knowledge of the pathophysiology of the disease ALS as this possibly may lead us closer to a targeted medical treatment.
The project group wants to investigate if a previously found, unique cytotoxicity in the ALS plasma can be retrieved (9-14). If this is the case, then the modern methods of today make it possible to detect whether the immune system in general, and in particular the complement system, is causing this cytotoxicity.
The establishment of a national research project about ALS and the complement system by making a research biobank with systematically collected blood and spinal liquid from ALS patients from all over the country will ensure the opportunity to find out if the complement system plays a role in the onset and progression of ALS.
Furthermore a pilot study will be conducted with the purpose to investigate if there is complement activity in the NMJ in patients with ALS as it has been shown in a study of ALS mice. (28)
The hypotheses
1. ALS is characterized by an abnormal immune response with cytotoxicity and increased complement activity in plasma which is revealed by the following:
1. Plasma from patients with ALS shows increased haemolytic activity when incubated with red blood cells from healthy subjects.
2. The complement activity is increased in the plasma from ALS patients compared with plasma from neurologically healthy subjects and subjects with other neurological disease.
3. The haemolytic activity in the plasma from ALS patients is correlated with the complement activity.
2. Spinal liquid from ALS patients contains increased complement activity compared with spinal liquid from neurologically healthy subjects and from subjects with other neurological disease.
Patients, materials and methods:
Clinical trial 1(CT1): Haemolytic activity and the complement system in ALS plasma
Number of subjects: 25 patients with ALS, 25 patients with other neurological disease, 25 healthy volunteers
The course of CT1: A blood sample is taken from each patient. The red blood cells and the liquid part of the blood, the plasma, are separated. The red blood cells from different subjects are incubated in an other subjects plasma.The same trial course is repeated after inactivation of the present complement system both by heat and by anti-complement.
Clinical trial 2(CT2): Case-control study aiming to mapping the complement system
Number of subjects:100 patients with ALS, 100 patients with other neurological disease and 100 neurologically healthy patients
The course of CT2:Blood samples and cerebrospinal fluid are prepared and then freezed in a research biobank. Then the samples from the 3 groups of subjects are analysed and compared focusing on the complement system: The complement activation potential is measured in the biological material. A cytokine profile is made as well as mapping the acute phase reactants by multiplex assays. Furthermore the RNA expression profile is made on a cell pellet stabilised with RNA later.
Clinical trial 3(CT3): The complement system of ALS patients over time - a cohort study Number of subjects:20 patients with ALS (subset from CT2)
The course of CT3: Every sixth month the course from the CT2 is repeated. The activity of the complement system in each patient with ALS is analyzed as the disease progresses.
Clinical trial 4(CT4): Searching for complement activity in the NMJ of ALS patients
Number of subjects:10 patients with ALS
The course of CT4: The muscle biopsies are taken and immediately brought to the Dep. of Pathology at Rigshospitalet. Then thin layers of tissue are stained in order to analyze the muscle fibers and the NMJ as well as detecting presence of complement activity.
Conducting the study The project consists of four clinical trials. Inclusion of the subjects is done together with staff in ALS outpatient clinics at hospitals all over the country and subjects for the control groups are included according to the list of inclusion sites below.
Inclusion sites:
ALS outpatient clinic, Neurological clinic, Rigshospitalet Glostrup (CT1+2+3+4) Contact: Chief physician Elisabeth Elmo Neurological Clinic, Rigshospitalet Glostrup (neurological control group, CT1+2) Contact: Professor, Chief physician, dr.med. Rigmor Højland Jensen Neurosurgical Clinic, Rigshospitalet (neurological control group, CT2) Contact: Professor, chief physician, dr.med. Marianne Juhler ALS outpatient clinic, Neurological Dep., Bispebjerg Hospital (CT2) Contact: Chief physician Merete Karlsborg ALS outpatient clinic, Neurological Dep., Roskilde Hospital (CT2 + 3) Contact: Chief physician Helle Thagesen ALS outpatient clinic, Neurological Dep., Odense University Hospital (CT2) Contact: Chief physician, dr.med. Matthias Bode ALS outpatient clinic, Neurological Dep., Aarhus Hospital, Nørrebrogade (Clinical Trial 2) Contact: Chief Physician, ph.d. Anette Torvin Gildhøj Private Hospital, Brøndby (Neurologically healthy control group, Clinical Trial 2) Contact: Anaesthesiologist Niels Anker Pedersen
Power calculations CT1: Haemolytic activity and the complement system in ALS plasma The study Overgaard et al. (18) found a mean difference of about 0,20 (SE 0,052 in the ALS group, N=20, SD 0,22) in the absorbance (415 nm and 5 hours of incubation) between ALS patients and healthy bioanalysts. With α=0,05 og beta=0,20 corresponding to power 0,80 we need to include 21 subjects. As possible drop outs and technically failed are considered tests the investigators choose to include 25 subjects in each group. (36)
CT2: Case-control study mapping the complement system The number of subjects in each group is in this case-control study calculated with α=0,05 The investigators compare the complement activation potential of 3 groups with same amount of subjects in each. In healthy subjects the complement activation potential is 100 % with a normal area ranging from 50-150 % and where the prevalence of low complement activation potential (under 50 %) is under 10 %. With power =0,80 it is calculated to be necessary to include 100 subjects in each group. Hereby it is possible to find statistically significant differences between the groups corresponding to an odds ratio of 2,3, which would correspond to 20 % of ALS patients having a low complement activation potential caused by increased complement activity. (36)
CT3: The complement system of ALS patients over time - a cohort study This is a hypothesis generating study. It is expected that the included 20 ALS patients in this cohort will be a subset from Clinical Trial 2. As a control group at baseline the neurologically healthy control group from Clinical Trial 2 will be used.
CT4: Searching for complement activity in the NMJ of ALS patients There is no previous studies describing the complement activity in the NMJ in living humans. It is therefore not relevant to make a calculation of power.
Data processing CT1: Haemolytic activity and the complement system in ALS plasma Comparing the degree of haemolysis between the ALS patients and the control groups t-test and one way ANOVA are used. For calculating the cut-off values the investigators use receiver operating characteristic (ROC) curves.
CT2: Case-control study mapping the complement system Comparing the concentration of complement and the complement activation potential between ALS patients and the control groups t-test and one way ANOVA are used. In order to calculate the odds for low complement activation potential in the ALS group compared with the control groups the investigators use logistic regression. For calculating the cut-off values receiver operating characteristic (ROC) curves are used.
CT3: The complement system of ALS patients over time - a cohort study As in Clinical Trial 2. Furthermore, regression analysis of the complement activity as a function of time since the onset of ALS, gender, age, subtype of illness and disease progression are conducted.
CT4: Searching for complement activity in the NMJ of ALS patients As in CT2. The degree of complement deposition and muscle pathology is described qualitatively and a blinded scoring in "normal", "light degree" and "severe degree" of changes is conducted. This will be compared quantitatively with 2 x K tables and non-parametric statistics.
Dissemination of results The results of the project will be published in international peer reviewed, journals. Both positive and negative findings will be published.
Perspectivation With the establishment of a big national ALS research biobank it will be possible to conduct many future research projects. Continuous research in ALS is paramount for ALS patients nationally as well as internationally in order to maintain hope for an efficient medical treatment for this aggressive disease is found in the future.
Conditions
See the medical conditions and disease areas that this research is targeting or investigating.
Amyotrophic Lateral Sclerosis
Neurodegenerative Disease
Motor Neuron Disease
Study Design
Understand how the trial is structured, including allocation methods, masking strategies, primary purpose, and other design elements.
Observational Model Type
CASE_CONTROL
Study Time Perspective
PROSPECTIVE
Study Groups
Review each arm or cohort in the study, along with the interventions and objectives associated with them.
ALS patients
Patients diagnosed with ALS will be included in this group. Blood and spinal fluid samples will be stored in biobank and later analyzed. A subset of this group (20 ALS patients) will give blood and spinal fluid every 6 months during progression of the disease. A subset of 10 will donate a muscle biopsy.
No interventions assigned to this group
Control group with patients with other neurological disease
Patients referred to hospital with symptoms of acute or chronic headache.
No interventions assigned to this group
Neurologically healthy control group
Patients having orthopaedic surgery performed in spinal anaesthesia.
No interventions assigned to this group
Eligibility Criteria
Check the participation requirements, including inclusion and exclusion rules, age limits, and whether healthy volunteers are accepted.
Inclusion Criteria
* For ALS group:Diagnosed with the diagnose category "certain ALS" or "likely ALS according to the El Escorial rev. diagnose criteria
* For Neurological control group: Referred to neurological department to be examined for acute or chronic headache or referred to get a lumbar perfusion test performed.
* For Neurological control group: Referred to neurological department to be examined for acute or chronic headache or referred to get a lumbar perfusion test performed.
Exclusion Criteria
* For all groups (Clinical study 2-3): permanent contraindication for having a lumbar puncture performed
* For Neurological control group: Known with chronic inflammatory disease or autoimmune disease.
* For healthy control group (clinical study 1): Known with any disease
* For healthy control group (clinical study 1): Taking daily medication
* For Neurologically healthy control group (Clinical study 2): Known with neurological disease
* For Neurologically healthy control group (Clinical study 2): Known with chronic inflammatory disease or autoimmune disease.
* For Neurological control group: Known with chronic inflammatory disease or autoimmune disease.
* For healthy control group (clinical study 1): Known with any disease
* For healthy control group (clinical study 1): Taking daily medication
* For Neurologically healthy control group (Clinical study 2): Known with neurological disease
* For Neurologically healthy control group (Clinical study 2): Known with chronic inflammatory disease or autoimmune disease.
Minimum Eligible Age
18 Years
Eligible Sex
ALL
Accepts Healthy Volunteers
Yes
Sponsors
Meet the organizations funding or collaborating on the study and learn about their roles.
Zealand University Hospital
OTHER
Sponsor Role
collaborator
Bispebjerg Hospital
OTHER
Sponsor Role
collaborator
Aarhus University Hospital
OTHER
Sponsor Role
collaborator
Odense University Hospital
OTHER
Sponsor Role
collaborator
Rigshospitalet, Denmark
OTHER
Sponsor Role
lead
Responsible Party
Identify the individual or organization who holds primary responsibility for the study information submitted to regulators.
Anne-Lene Kjældgaard
Ph.d.-student, MD
Responsibility Role
PRINCIPAL_INVESTIGATOR
Principal Investigators
Learn about the lead researchers overseeing the trial and their institutional affiliations.
Kirsten Møller, Prof., MD
Role: STUDY_CHAIR
Clinic of Neuroanestesiology, Rigshospitalet, Denmark
Peter Garred, Prof., MD
Role: STUDY_CHAIR
Department of Clinical Immunology
Stephen Wørlich Pedersen, dr.med
Role: STUDY_CHAIR
Dept. of Neurology, Rigshospitalet Glostrup
Karsten Skovgaard Olsen, Dr.med.
Role: STUDY_CHAIR
Clinic of Neuroanaestesiology, Rigshospitalet Glostrup
Anne Øberg Lauritsen, MD
Role: STUDY_CHAIR
Clinic of Neuroanaestesiology, Rigshospitalet Glostrup
Eva Løbner Lund, MD, PhD
Role: STUDY_CHAIR
Dept. of Pathology, Rigshospitalet
Anne-Lene Kjældgaard, MD
Role: PRINCIPAL_INVESTIGATOR
Clinic of Neuroanaestesiology, Rigshospitalet Glostrup
Locations
Explore where the study is taking place and check the recruitment status at each participating site.
Dept. of Neurology Aarhus Hospital, Nørrebrogade
Aarhus, , Denmark
Site Status
RECRUITING
Gildhøj Private Hospital
Brøndby, , Denmark
Site Status
COMPLETED
Clinic of neuroanestesiology, Rigshospitalet Glostrup
Copenhagen, , Denmark
Site Status
RECRUITING
Dept. of Neurology, Bisbebjerg Hospital
Copenhagen NV, , Denmark
Site Status
RECRUITING
Clinic of Neurosurgery, Rigshospitalet
Copenhagen Ø, , Denmark
Site Status
NOT_YET_RECRUITING
The Dept. og Neurology, Rigshospitalet Glostrup
Glostrup Municipality, , Denmark
Site Status
RECRUITING
Dept. of Neurology, Odense Hospital
Odense C, , Denmark
Site Status
RECRUITING
The dept. of Neurology, Roskilde Hospital
Roskilde, , Denmark
Site Status
RECRUITING
Countries
Review the countries where the study has at least one active or historical site.
Denmark
Central Contacts
Reach out to these primary contacts for questions about participation or study logistics.
Facility Contacts
Find local site contact details for specific facilities participating in the trial.
Anette Torvin Møller, MD, PhD
Role: primary
Anne-Lene Kjældgaard, MD
Role: primary
Merete Karlsborg, MD
Role: primary
Marianne Juhler, dr.med, prof
Role: primary
Elisabeth Elmo, MD
Role: primary
Matthias Bode, MD
Role: primary
Helle Thagesen, MD
Role: primary
References
Explore related publications, articles, or registry entries linked to this study.
Andersen PM, Al-Chalabi A. Clinical genetics of amyotrophic lateral sclerosis: what do we really know? Nat Rev Neurol. 2011 Oct 11;7(11):603-15. doi: 10.1038/nrneurol.2011.150.
Reference Type
BACKGROUND
Tumer Z, Bertelsen B, Gredal O, Magyari M, Nielsen KC, Lucamp, Gronskov K, Brondum-Nielsen K. Novel heterozygous nonsense mutation of the OPTN gene segregating in a Danish family with ALS. Neurobiol Aging. 2012 Jan;33(1):208.e1-5. doi: 10.1016/j.neurobiolaging.2011.07.001. Epub 2011 Aug 26.
Reference Type
BACKGROUND
Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 2007 Nov;6(11):994-1003. doi: 10.1016/S1474-4422(07)70265-X.
Reference Type
BACKGROUND
Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9. doi: 10.1080/146608200300079536. No abstract available.
Reference Type
BACKGROUND
Seals RM, Hansen J, Gredal O, Weisskopf MG. Age-period-cohort analysis of trends in amyotrophic lateral sclerosis in Denmark, 1970-2009. Am J Epidemiol. 2013 Oct 15;178(8):1265-71. doi: 10.1093/aje/kwt116. Epub 2013 Sep 24.
Reference Type
BACKGROUND
Chio A, Logroscino G, Traynor BJ, Collins J, Simeone JC, Goldstein LA, White LA. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology. 2013;41(2):118-30. doi: 10.1159/000351153. Epub 2013 Jul 11.
Reference Type
BACKGROUND
Annunziata P, Volpi N. High levels of C3c in the cerebrospinal fluid from amyotrophic lateral sclerosis patients. Acta Neurol Scand. 1985 Jul;72(1):61-4. doi: 10.1111/j.1600-0404.1985.tb01548.x.
Reference Type
BACKGROUND
Apostolski S, Nikolic J, Bugarski-Prokopljevic C, Miletic V, Pavlovic S, Filipovic S. Serum and CSF immunological findings in ALS. Acta Neurol Scand. 1991 Feb;83(2):96-8. doi: 10.1111/j.1600-0404.1991.tb04656.x.
Reference Type
BACKGROUND
Conradi S, Ronnevi LO. Cytotoxic activity in the plasma of amyotrophic lateral sclerosis (ALS) patients against normal erythrocytes. Quantitative determinations. J Neurol Sci. 1985 May;68(2-3):135-45. doi: 10.1016/0022-510x(85)90095-4.
Reference Type
BACKGROUND
Conradi S, Ronnevi LO. Immunoglobulin-mediated cytotoxic effect of ALS-plasma towards erythrocytes: reflexion of a pathogenetic mechanism? Adv Exp Med Biol. 1987;209:7-13. doi: 10.1007/978-1-4684-5302-7_2. No abstract available.
Reference Type
BACKGROUND
Digby J, Harrison R, Jehanli A, Lunt GG, Clifford-Rose F. Cultured rat spinal cord neurons: interaction with motor neuron disease immunoglobulins. Muscle Nerve. 1985 Sep;8(7):595-605. doi: 10.1002/mus.880080709.
Reference Type
BACKGROUND
Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, Khan J, Polak MA, Glass JD. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004 Feb;185(2):232-40. doi: 10.1016/j.expneurol.2003.10.004.
Reference Type
BACKGROUND
Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P. Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci. 2000 Apr 1;20(7):2534-42. doi: 10.1523/JNEUROSCI.20-07-02534.2000.
Reference Type
BACKGROUND
Goldknopf IL, Sheta EA, Bryson J, Folsom B, Wilson C, Duty J, Yen AA, Appel SH. Complement C3c and related protein biomarkers in amyotrophic lateral sclerosis and Parkinson's disease. Biochem Biophys Res Commun. 2006 Apr 21;342(4):1034-9. doi: 10.1016/j.bbrc.2006.02.051. Epub 2006 Feb 20.
Reference Type
BACKGROUND
Grewal RP, Morgan TE, Finch CE. C1qB and clusterin mRNA increase in association with neurodegeneration in sporadic amyotrophic lateral sclerosis. Neurosci Lett. 1999 Aug 13;271(1):65-7. doi: 10.1016/s0304-3940(99)00496-6.
Reference Type
BACKGROUND
Heurich B, El Idrissi NB, Donev RM, Petri S, Claus P, Neal J, Morgan BP, Ramaglia V. Complement upregulation and activation on motor neurons and neuromuscular junction in the SOD1 G93A mouse model of familial amyotrophic lateral sclerosis. J Neuroimmunol. 2011 Jun;235(1-2):104-9. doi: 10.1016/j.jneuroim.2011.03.011. Epub 2011 Apr 17.
Reference Type
BACKGROUND
Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992 Mar;140(3):691-707.
Reference Type
BACKGROUND
Kong J, Xu Z. Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1. J Neurosci. 1998 May 1;18(9):3241-50. doi: 10.1523/JNEUROSCI.18-09-03241.1998.
Reference Type
BACKGROUND
Lee JD, Kamaruzaman NA, Fung JN, Taylor SM, Turner BJ, Atkin JD, Woodruff TM, Noakes PG. Dysregulation of the complement cascade in the hSOD1G93A transgenic mouse model of amyotrophic lateral sclerosis. J Neuroinflammation. 2013 Sep 26;10:119. doi: 10.1186/1742-2094-10-119.
Reference Type
BACKGROUND
Liveson J, Frey H, Bornstein MB. The effect of serum from ALS patients on organotypic nerve and muscle tissue cultures. Acta Neuropathol. 1975 Aug 11;32(2):127-31. doi: 10.1007/BF00689566.
Reference Type
BACKGROUND
Lobsiger CS, Boillee S, Cleveland DW. Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons. Proc Natl Acad Sci U S A. 2007 May 1;104(18):7319-26. doi: 10.1073/pnas.0702230104. Epub 2007 Apr 26.
Reference Type
BACKGROUND
Lobsiger CS, Boillee S, Pozniak C, Khan AM, McAlonis-Downes M, Lewcock JW, Cleveland DW. C1q induction and global complement pathway activation do not contribute to ALS toxicity in mutant SOD1 mice. Proc Natl Acad Sci U S A. 2013 Nov 12;110(46):E4385-92. doi: 10.1073/pnas.1318309110. Epub 2013 Oct 29.
Reference Type
BACKGROUND
Overgaard K, Werdelin L, Sorensen H, Mogensen P, Boysen G. Cytotoxic activity in plasma from patients with amyotrophic lateral sclerosis. Neurology. 1991 Jun;41(6):925-7. doi: 10.1212/wnl.41.6.925.
Reference Type
BACKGROUND
Pinter MJ, Waldeck RF, Wallace N, Cork LC. Motor unit behavior in canine motor neuron disease. J Neurosci. 1995 May;15(5 Pt 1):3447-57. doi: 10.1523/JNEUROSCI.15-05-03447.1995.
Reference Type
BACKGROUND
Roisen FJ, Bartfeld H, Donnenfeld H, Baxter J. Neuron specific in vitro cytotoxicity of sera from patients with amyotrophic lateral sclerosis. Muscle Nerve. 1982 Jan;5(1):48-53. doi: 10.1002/mus.880050109.
Reference Type
BACKGROUND
Conradi, S. Cytotoxic factor in plasma from ALS patients provokes haemolysis of normal erythrocytes. Acta Neurologica Scandinavica, 65: 246-247, 1982
Reference Type
BACKGROUND
Ronnevi LO, Conradi S. Increased fragility of erythrocytes from amyotrophic lateral sclerosis (ALS) patients provoked by mechanical stress. Acta Neurol Scand. 1984 Jan;69(1):20-6. doi: 10.1111/j.1600-0404.1984.tb07775.x.
Reference Type
BACKGROUND
Ronnevi LO, Conradi S, Karlsson E, Sindhupak R. Nature and properties of cytotoxic plasma activity in amyotrophic lateral sclerosis. Muscle Nerve. 1987 Oct;10(8):734-43. doi: 10.1002/mus.880100810.
Reference Type
BACKGROUND
Sta M, Sylva-Steenland RM, Casula M, de Jong JM, Troost D, Aronica E, Baas F. Innate and adaptive immunity in amyotrophic lateral sclerosis: evidence of complement activation. Neurobiol Dis. 2011 Jun;42(3):211-20. doi: 10.1016/j.nbd.2011.01.002. Epub 2011 Jan 8.
Reference Type
BACKGROUND
Tsuboi Y, Yamada T. Increased concentration of C4d complement protein in CSF in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 1994 Jul;57(7):859-61. doi: 10.1136/jnnp.57.7.859.
Reference Type
BACKGROUND
Wolfgram F, Myers L. Amyotrophic lateral sclerosis: effect of serum on anterior horn cells in tissue culture. Science. 1973 Feb 9;179(4073):579-80. doi: 10.1126/science.179.4073.579.
Reference Type
BACKGROUND
Woodruff TM, Costantini KJ, Crane JW, Atkin JD, Monk PN, Taylor SM, Noakes PG. The complement factor C5a contributes to pathology in a rat model of amyotrophic lateral sclerosis. J Immunol. 2008 Dec 15;181(12):8727-34. doi: 10.4049/jimmunol.181.12.8727.
Reference Type
BACKGROUND
Pun S, Santos AF, Saxena S, Xu L, Caroni P. Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF. Nat Neurosci. 2006 Mar;9(3):408-19. doi: 10.1038/nn1653. Epub 2006 Feb 12.
Reference Type
BACKGROUND
Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012 Mar 14;2012(3):CD001447. doi: 10.1002/14651858.CD001447.pub3.
Reference Type
BACKGROUND
Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF, O'Toole O, Wingerchuk DM. Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 2013 Jun;12(6):554-62. doi: 10.1016/S1474-4422(13)70076-0. Epub 2013 Apr 26.
Reference Type
BACKGROUND
Armitage P BG. Statistical Methods for Medical Researchers. Blackwell1994.
Reference Type
BACKGROUND
Kjaeldgaard AL, Pilely K, Olsen KS, Lauritsen AO, Pedersen SW, Moller K, Garred P. Amyotrophic lateral sclerosis and the innate immune system: protocol for establishing a biobank and statistical analysis plan. BMJ Open. 2020 Aug 5;10(8):e037753. doi: 10.1136/bmjopen-2020-037753.
Reference Type
DERIVED
Other Identifiers
Review additional registry numbers or institutional identifiers associated with this trial.
H-16017145
Identifier Type: -
Identifier Source: org_study_id