Amyotrophic Lateral Sclerosis Clinical Trial
Official title:
Amyotrophic Lateral Sclerosis and the Innate Immune System
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.
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.
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