Multicenter Study of Immunoadsorption in Dilated Cardiomyopathy

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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
      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.
    


Study Type

Interventional


Primary Outcome

Left ventricular ejection fraction (LVEF) at rest, as determined by contrast echocardiography

Secondary Outcome

 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)

Condition

Dilated Cardiomyopathy

Intervention

protein A immunoadsorption

Study Arms / Comparison Groups

 IA/IgG group
Description:  immunoadsorption using IA columns and subsequent IgG substitution

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

200

Start Date

December 2007

Completion Date

December 2020

Primary Completion Date

December 2019

Eligibility 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]
      

Gender

All

Ages

18 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

Stephan B Felix, MD, + 49 3834 8680500, [email protected]

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT00558584

Organization ID

IA-2006-001


Responsible Party

Sponsor

Study Sponsor

University Medicine Greifswald

Collaborators

 Krupp von Bohlen und Halbach-Foundation, Essen, Germany

Study Sponsor

Stephan B Felix, MD, Principal Investigator, Ernst-Moritz-Arndt University


Verification Date

June 2018