Have you or your loved ones been diagnosed with dilated cardiomyopathy?
You may be eligible to participate in a dilated cardiomyopathy clinical trial.
Have you or your loved ones been diagnosed with dilated cardiomyopathy? You may be eligible to participate in a dilated cardiomyopathy clinical trial.
What is a clinical trial? Is participating in a clinical trial right for you? Learn more
Dilated Cardiomyopathy Clinical Trial in Berlin
Have you or your loved ones been diagnosed with dilated cardiomyopathy?
You may be eligible to participate in a dilated cardiomyopathy clinical trial.
Have you or your loved ones been diagnosed with dilated cardiomyopathy? You may be eligible to participate in a dilated cardiomyopathy clinical trial.
Recruiting
Male & Female
18 - 70
Years old
The purpose of this study is to investigate the effects of immunoadsorption and subsequent IgG substitution in patients with dilated cardiomyopathy compared to a control group.
Details for the study
Brief Title
Multicenter Study of Immunoadsorption in Dilated Cardiomyopathy
Official Title
Multicentre, Randomized, Double-blind, Prospective Investigation on the Effects of Immunoadsorption on Cardiac Function in Patients With Dilated Cardiomyopathy
Brief Summary
The purpose of this study is to investigate the effects of immunoadsorption and subsequent <br /> IgG substitution in patients with dilated cardiomyopathy compared to a control group.
Detailed Description
Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic
dysfunction with normal LV wall thickness. According to reports heretofore, the incidence of
this disorder in industrialized Western countries lies within the order of magnitude of 5 - 8
new illnesses per year for every 100,000 population. The prevalence, accordingly, is
approximately 36 patients for every 100,000 population. However, recent data suggest higher
actual prevalence of DCM: at present the estimated prevalence of congestive heart failure
ranges from 2% to 6%. According to recently published studies (e.g., the MERIT-HF study and
the COPERNICUS study), about 30% to 35% of patients with congestive heart failure suffer from
non-ischemic myocardial heart disease. DCM was diagnosed, furthermore, in 12% of the patients
of the CIBIS II study. Approximately 26% of the patients with reduced left-ventricular
systolic function from the CHARM-added study suffered from heart failure due to DCM. Based on
these data, assumption is justified that in Germany approximately 500,000 patients suffer
from DCM. Despite advances in medical treatment of heart failure, the general prognosis for
DCM is poor. In many cases, treatment options are surgical e.g., heart transplantation or
implantation of an assist device.
An association between virus myocarditis and DCM has been hypothesized for a subset of
patients with DCM. Both experimental and clinical data indicate that viral infection and
inflammatory processes are involved in the pathogenesis of myocarditis and DCM, and may
represent important factors causing progression of ventricular dysfunction.
Abnormalities of the cellular immune system are present in patients with myocarditis and DCM.
For patients with DCM, immunohistological methods have been introduced for diagnosis of
myocardial inflammation. Infiltration with lymphocytes and mononuclear cells as well as
increased expression of cell adhesion molecules, are frequent phenomena in DCM. These
findings support the hypothesis that the immune process is still active. Furthermore,
activation of the humoral immune system with production of cardiac antibodies plays an
important role in DCM. Several antibodies against cardiac structures have been detected in
DCM patients - including antibodies that act against mitochondrial proteins, alpha- and
beta-cardiac myosin heavy chain isoforms, the cardiac beta-receptor, the muscarinic
acetylcholine receptor-2, and the sarcolemmal Na-K-ATPase. The functional significance of
cardiac autoantibodies is under debate. It is possible that autoantibodies are formed as a
consequence of inflammatory reactions to cellular destruction, in which case they should be
regarded as an epiphenomenon. Cardiac autoantibodies, on the other hand, may likewise play an
active role in the pathogenesis of DCM by triggering the disease process, or by contributing
to development of myocardial contractile dysfunction. For certain antibodies, in-vitro data
indicate a negative effect on cardiac performance. In myocarditis and DCM, heart-reactive
cytotoxic auto-antibodies to the ADP/ATP carrier were found. These antibodies cross-react
with the calcium channel of the cardiomyocytes. Purified antibodies obtained from DCM
patients induce a negative inotropic effect in isolated rat cardiomyocytes by decreasing the
calcium transients. Immunization of rodents against peptides derived from cardiovascular
G-protein receptors induces morphological changes of myocardial tissue resembling DCM.
Furthermore, recent data have provided evidence those antibodies against the beat1-receptor
itself induce DCM: rats immunized against the second extracellular loop of cardiac
beta1-receptors develop progressive left ventricular dilatation and dysfunction.
Interestingly, sera transferred from these immunized animals to unsensitized rats induced the
similar cardiomyopathic phenotype, thus demonstrating the pathogenic potential of a
particular antibody for development of DCM. Further confirmation of the principle that
autoantibodies contribute to induction of the disease process and to progression to DCM has
been provided in a recent study. The authors showed that mice deficient in the programmed
cell death-1 (PD-1) immunoinhibitory co-receptor develop autoimmune DCM with production of
high-titre circulating IgG autoantibodies reactive to a 33-kilodalton protein expressed
specifically on the surface of cardiomyocytes. This antigen was recently identified as
cardiac troponin I.
When cardiac antibodies impair cardiac function, their removal would logically be expected to
lead to an improvement in the patient's haemodynamic situation. Cardiac antibodies belong to
the IgG fraction and can be eliminated by immunoadsorption (IA) therapy. Immunoadsorption has
been introduced as a method for treatment of autoimmune processes e.g., Goodpasture's
syndrome and lupus erythematodes. This form of therapy has already been successfully applied
for treatment of DCM. Several pilot studies have shown that IA improves cardiac function in
patients with DCM. The first uncontrolled pilot study disclosed acute beneficial haemodynamic
effects of IA in patients with severe heart failure due to DCM. A randomized study followed,
to investigate the haemodynamic effects of additional IA therapy for DCM. This study included
patients with DCM (NYHA III-IV, LVEF <30%) who were under stable medication. In the IA group,
IA was conducted on three consecutive days, with one IA session daily. On the grounds of
safety - i.e., to reduce the risk of infection after immunoglobulin depletion -
immunoglobulin G was substituted after the last IA session. Immunoadsorption and subsequent
IgG substitution (IA/IgG) was repeated for 3 courses at monthly intervals until month 3. In
contrast to the control group, patients in the IA/IgG group demonstrated after 3 months a
significant increase in cardiac index (CI), paralleled by a similar increase in stroke volume
index. A recent study demonstrated that IA/IgG therapy likewise mitigates the inflammatory
process in the myocardium of DCM patients. A case-controlled study, performed by others,
conducted IA in one course of 5 consecutive days without IgG substitution subsequent to
immunoglobulin depletion. This study did not repeat IA during follow-up. In this study, LVEF
increased from 22 to 40% one year after IA: a significant gain in contrast to the control
group without IA therapy.
Recent data indicate that the beneficial haemodynamic effects of IA are related to removal of
negative inotropic cardiac antibodies. Detection of cardio-depressant antibodies in the
plasma of DCM patients, before IA, effectively predicts acute and prolonged haemodynamic
improvement during IA. A further study clearly disclosed that the cardio depressant
antibodies belong to the IG-3 subclass [38]. The removal of antibodies of the IgG-3 subclass
accordingly represents an essential mechanism in IA therapy of DCM.
Protein-A and anti-IgG columns are licensed for IA. Anti-IgG sepharose effectively eliminates
all IgG subclasses, including IgG-3. Protein A binds to the Fc part of human IgG-1, -2, -4.
However, the affinity of protein A to IgG-3 is low. IgG-3 removal can be markedly increased
by protein-A, through the use of an optimized treatment regime, by prolonging the IA course
to 4 - 5 sessions, and by reducing the loading volume of the protein columns with plasma. In
use of this adsorption regime for IgG-3 elimination, protein-A IA induces significant acute
and prolonged haemodynamic improvement of DCM patients. Furthermore, IA treatment with
protein A adsorption performed in 1 course on 5 consecutive days induces improvement of the
left ventricular function of DCM patients over a period of 6 months, with results comparable
to those received by IA treatment repeated in 4 courses at monthly intervals. Despite
optimized medical treatment, the prognosis of DCM is still poor. For most patients, heart
transplantation will represent the only palliative treatment option. Alternative therapeutic
strategies for treatment of DCM are consequently of essential interest.
This randomized multicentre study will investigate for the first time by means of a
double-blind study design whether a specific causal intervention - i.e., the removal of
autoantibodies - will influence the disease process and improve the cardiac function of
patients suffering from heart failure due to DCM.
Treatments and/or Procedures
Protein A immunoadsorption
protein-A immunoadsorption and i.v. IgG substitution
pseudo immunoadsorption
pseudo-immunoadsorption followed by an intravenous infusion without IgG
Study Criteria
Inclusion Criteria: - Dilated cardiomyopathy - LVEF <= 40% determined by contrast echocardiography - NYHA class II - IV - Age 18 - 70 - Disease duration: symptomatic heart failure ≥ 6 months and <7 years prior to screening date - Treatment with ACE inhibitors or angiotensin II receptor blockers (ARB), beta-blockers, and aldosterone antagonists (the latter at the discretion of the attending physician), for at least 6 months and at stable doses for at least 2 months prior to screening date. - The patient's informed consent Exclusion Criteria: - NYHA class IV patients who are bed-ridden and dependent upon parenteral medication - Cardiac insufficiency resulting from another basic disease (e.g. coronary artery disease, ≥50% stenosis of major vessel as ascertained by coronary angiography performed more recent than three years before screening date, hypertensive heart disease, or valvular defects >second degree - History of myocardial infarction - Acute myocarditis according to Dallas criteria - Endocrine disorder excluding insulin-dependent diabetes mellitus - Implanted cardiac defibrillator (ICD) <1 month before screening date - Cardiac resynchronization therapy (CRT) <6 months before screening date - I.v. medication with inotropic drugs, vasodilators or repeated (>1/day) i.v. administration of diuretics. - Active infectious disease, or signs of ongoing infection with CRP >10mmol/L - Impaired renal function (serum creatinine >220 µmol/L) - Any disease requiring immunosuppressive drugs - Anaemia (haemoglobin below 90 g/L) due to other causes than CHF - Pregnancy or lactation, or childbearing potential without appropriate contraception - Alcohol or drug abuse - Presence of a malignant tumour, or remission of malignancy < 5 years - Refusal of the patient to provide consent - Suspected poor capability to follow instructions and cooperate - Another life-threatening disease with poor prognosis (survival less than 2 years) - Participation in any other clinical study within less than 30 days prior to screening date - Previous treatments with IA or immunoglobulin - Contraindications for application of the echocardiography contrast agent used (in accordance to the product specification). [Amendment 8]