Multicenter Study of Immunoadsorption in Dilated Cardiomyopathy

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT00558584
Recruitment Status : Recruiting
First Posted : November 15, 2007
Last Update Posted : July 2, 2018
Krupp von Bohlen und Halbach-Foundation, Essen, Germany
ENDI-Foundation, Bad Homburg, Germany
Bristol-Myers Squibb
Information provided by (Responsible Party):
University Medicine Greifswald

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Dilated Cardiomyopathy Device: protein A immunoadsorption Device: pseudo-immunoadsorption Not Applicable

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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.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Multicentre, Randomized, Double-blind, Prospective Investigation on the Effects of Immunoadsorption on Cardiac Function in Patients With Dilated Cardiomyopathy
Study Start Date : December 2007
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020

Arm Intervention/treatment
Active Comparator: IA/IgG group
immunoadsorption using IA columns and subsequent IgG substitution
Device: protein A immunoadsorption
protein-A immunoadsorption and i.v. IgG substitution

Placebo Comparator: control group
pseudo-immunoadsorption followed by an intravenous infusion without IgG
Device: pseudo-immunoadsorption
pseudo-immunoadsorption followed by an intravenous infusion without IgG

Primary Outcome Measures :
  1. Left ventricular ejection fraction (LVEF) at rest, as determined by contrast echocardiography [ Time Frame: six months ]

Secondary Outcome Measures :
  1. Clinical outcome (non-cardiovascular death, cardiovascular death, sudden death, hospitalization for cardiovascular cause/heart failure, acute myocardial infarction, unstable angina, stroke, cardiac interventions/procedures, clinical deterioration) [ Time Frame: 24 months ]
  2. LVEF at rest, as determined by contrast echocardiography [ Time Frame: 12 and 24 months ]
  3. Reduction of brain natriuretic peptides (BNP and/or NT pro-BNP) [ Time Frame: 6, 12, and 24 months ]
  4. Cardiopulmonary exercise capacity [ Time Frame: 6, 12, and 24 months ]
  5. LVEF at rest, as determined by magnetic resonance imaging (optional) [ Time Frame: 6, 12, and 24 months ]
  6. Serious clinical adverse events [ Time Frame: day 7, 1 month, and 6 months ]
  7. Quality of life (MLHFQ) [ Time Frame: 6, 12, and 24 months ]

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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]

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00558584

Contact: Stephan B Felix, MD + 49 3834 8680500
Contact: Alexander Staudt, MD + 49 385 5202550

Deutsches Herzzentrum München Recruiting
München, Bayern, Germany, 80636
Contact: Schunkert Heribert, MD    +49 89 21184019   
Principal Investigator: Schunkert Heribert, MD         
Medizinische Klinik und Poliklinik I (Campus Großhadern u. Campus Innenstadt) Recruiting
München, Bayern, Germany, 81377
Contact: Dirk Sibbing, MD    +49 89 440073028   
Principal Investigator: Dirk Sibbing, MD         
Zentralklinik Bad Berka GmbH, Klinik für Kardiologie Withdrawn
Bad Berka, Germany, 99437
Kerckhoff-Klinik Forschungsgesellschaft mbH Recruiting
Bad Nauheim, Germany, 61231
Contact: Veselin Mitrovic, MD    +49 6032-996-2347   
Principal Investigator: Veselin Mitrovic, MD         
Herz- und Diabeteszentrum NRW, Klinik für Thorax- und Kardiovaskularchirurgie Terminated
Bad Oeynhausen, Germany, 32545
Herz- und Diabeteszentrums NRW Terminated
Bad Oeynhausen, Germany, 32545
Medizinische Klinik und Poliklinik, Kardiologie, Angiologie, Pneumologie , Charité, Universitätsmedizin Berlin, Campus Mitte Recruiting
Berlin, Germany, 10117
Contact: Fabian Knebel    +49 30-450 613 216   
Principal Investigator: Fabian Knebel, MD         
Kardiologie (CC11), Campus Virchow, Charité, Universitätsmedizin Berlin Recruiting
Berlin, Germany, 13353
Contact: Uwe Kühl, MD, PhD    +49 30 - 450-553741   
Principal Investigator: Uwe Kühl, MD, PhD         
Deutsches Herzzentrum Berlin Recruiting
Berlin, Germany
Contact: Christoph Knosalla, MD    +49 30 4593 2087   
Principal Investigator: Christoph Knosalla, MD         
Medizinische Klinik und Poliklinik II, Universitätsklinkum Bonn Recruiting
Bonn, Germany, 53105
Contact: Nikos Werner, MD    +49 228 - 287-16670   
Principal Investigator: Nikos Werner, MD         
Klinik für Kardiologie, Westdeutsches Herzzentrum Essen, Universität Duisburg-Essen Terminated
Essen, Germany, 45122
Klinik für Innere Medizin B, Universität Greifswald Recruiting
Greifswald, Germany, 17487
Contact: Marcus Dörr, MD    +49 3834 86-80510   
Contact: Daniel Beug, MD    +49 3834 86-80858   
Principal Investigator: Marcus Dörr, MD         
Abteilung Kardiologie und Pneumologie, Universität Göttingen - Bereich Humanmedizin Recruiting
Göttingen, Germany, 37075
Contact: Rolf Wachter, MD    +49 551-39-22624   
Principal Investigator: Rolf Wachter, MD         
Klinik für Innere Medizin III, Medizinische Universitätsklinik Heidelberg Recruiting
Heidelberg, Germany, 69120
Contact: Andreas Dösch, MD    +49 6221-5639936   
Principal Investigator: Andreas Dösch, MD         
Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinik Homburg/Saar Recruiting
Homburg (Saar), Germany, 66421
Contact: Andreas Link, MD    +49 6841 162 1202   
Principal Investigator: Andreas Link, MD         
Klinik für Innere Medizin I, Universitätsklinikum Jena Recruiting
Jena, Germany, 07747
Contact: Michel Noutsias, MD    +49 3641-9324527   
Principal Investigator: Michel Noutsias, MD         
Universitätsklinikum Magdeburg, Universitätsklinik für Kardiologie Recruiting
Magdeburg, Germany, 39120
Contact: Rüdiger C Braun-Dullaeus, MD    +49 391-67-13203   
Principal Investigator: Rüdiger Braun-Dullaeus, MD         
Abteilung Kardiologie und Pulmologie, Robert-Bosch-Krankenhaus Terminated
Stuttgart, Germany, 70376
Medizinische Klinik und Poliklinik, Abteilung Innere Medizin III, Medizinische Univ.-Klinik Tübingen Terminated
Tübingen, Germany, 72076
Medizinische Klinik und Poliklinik I, Klinikum der Bayrischen Julius-Maximilians-Universität Recruiting
Würzburg, Germany, 97080
Contact: Bettina Kraus, MD    +49 931 201-46252   
Principal Investigator: Bettina Kraus, MD         
Internal Medicine - Cardiology, Belgrade University School of Medicine Recruiting
Belgrade, Serbia
Contact: Dragan Simic, MD    +38 111 361 4738   
Principal Investigator: Dragan Simic, MD         
Department of Cardiology, Sahlgrenska University Hospital Terminated
Göteborg, Sweden, S-41345
Sponsors and Collaborators
University Medicine Greifswald
Krupp von Bohlen und Halbach-Foundation, Essen, Germany
ENDI-Foundation, Bad Homburg, Germany
Bristol-Myers Squibb
Principal Investigator: Stephan B Felix, MD Ernst-Moritz-Arndt University

Additional Information:
Responsible Party: University Medicine Greifswald Identifier: NCT00558584     History of Changes
Other Study ID Numbers: IA-2006-001
First Posted: November 15, 2007    Key Record Dates
Last Update Posted: July 2, 2018
Last Verified: June 2018

Keywords provided by University Medicine Greifswald:
dilated cardiomyopathy
immunoglobulin G

Additional relevant MeSH terms:
Cardiomyopathy, Dilated
Heart Diseases
Cardiovascular Diseases