Trial document




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  DRKS00000115

Trial Description

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Title

Effect and Safety of preventive Treatment with ACE-Inhibitor and Beta-Blocker on the onset of Left Ventricular Dysfunction in Duchenne Muscular Dystrophy

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Trial Acronym

DMD Kardio

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URL of the Trial

[---]*

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Brief Summary in Lay Language

DMD is a lethal disorder of childhood charakterized by progressive muscle wasting caused by mutations (hereditary X-linked) of the dystrophin gene. The defective gene Dystrophin causes an muscle wasting progresses as the patients geting older untill finally respiratory or cardiac failure develops. Prevalence in Germany amount 100 male newborns / year. Nearly all patients with DMD are diagnosed at preschool age and become wheelchair-bound between 13-15 years. Cardiomyopathy develops in the second decade of life resulting in left ventricular dysfunction. Incidence of dilated cardiomyopathy increases with age, up to 57% of DMD patients older than 18 years are suffering under noticeable cardiac insufficiency.

Due to better medical care and home ventilation therapy the life expectancy of DMD-patients has increased in the last three decades, and cardiac failure due to cardiomyopathy increasingly becomes a reason for mortality and morbidity in these patients.

ACE-Inhibitor und Beta-Blocker are established medication used for treatment at cardiac insufficiency mostly at the adult-Patients. The past clinical trials showed already improvement of cardiac dysfunction as also prolongation of Life of Patient who have been taken this medication. There are also a few small studies witch show the same positiv results by children.
It is still an unresolved question if an early prophylactic treatment with a combined ACE-inhibitor/beta-blocker therapy according to modern guidelines in cardiology can delay the onset of left ventricular dysfunction and contribute to a longer survival and better quality of life of DMD patients. A placebo controlled multi-centre trial will assess the effectiveness of preventive treatment with a combination of ACE-inhibitor and beta-blocker.

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Brief Summary in Scientific Language

ACE-inhibitors and beta-blockers are used as treatment for heart failure in Duchenne muscular dystrophy. So far, there is only evidence for this drug therapy in cardiomyopathy of other etiology such as dilative cardiomyopathy, alcohol-toxic or ischemic heart disease in adults. Only few studies of low evidence exist suggesting that ACE-inhibitors and beta-blockers are effective in Duchenne cardiomyopathy. This project wants to test the hypothesis that prophylactic anticongestive therapy can delay or avoid manifestation of Duchenne cardiomyopathy.
N=130 patients with Duchenne Muscular with normal left ventricular function (LVSF > =30%) aged 10-14 years will be included into the study and followed in half-yearly intervals for max. 6 years until left ventricular dysfunction (defined by fraction shortening < 28%) becomes apparent. Time to left ventricular dysfunction will be analyzed in a proportional hazards regression model with treatment assignment and study centre as covariates.
History including symptoms, side effects, concomitant medication, intercurrent diseases and quality of life will be documented together with vital parameters and a standard-10-channel-ECG. At each visit, medication will be handed out according to weight class. For efficacy assessment, fraction shortening will be measured by echocardiography. Tissue Doppler Imaging will be used where available as secondary outcome measure. A yearly safety-lab and a 24-h-ECG will check on safety and tolerability, neurohumeral mediators (Noradrenalin, Aldosteron, Angiotensin II, Renin, pro-BNP) will be done three times during the study. In case of positive study results, further studies to confirm therapeutic benefit will follow. Tissue Doppler Imaging will be evaluated in comparison to 2D echocardiography.
According to Amendment 01 of 12. Dec. 2012 the number of patients to be randomised was reduced from 130 to 55 patients and the recruitment period was extended until December 2013.
The extended recruitment period ended on 31. Dec. 2013 with 42 randomised patients.

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Organizational Data

  •   DRKS00000115
  •   2009/11/18
  •   [---]*
  •   yes
  •   Approved
  •   08_2009, Ethik-Kommission der Friedrich-Alexander-Universität Erlangen-Nürnberg
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Secondary IDs

  •   U1111-1112-2933 
  •   2009-009871-36 
  •   4035573 
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Health Condition or Problem studied

  •   I50 -  Heart failure
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Interventions/Observational Groups

  •   run-in period with open up titration of beta-blocker and ACE inhibitor (Metoprolol-Succinat and Enalaprilmaleat) over 4x4 weeks with consideration of weight, oral application.

    Tablets with following dose:
    Metoprolol-Succinat: 23,75 g (mini), 47,5mg (medium) and 95 mg (forte); Enalaprilmaleat: 5 mg (medium) and 10 mg (forte).
    3 classes of weight: 20<45 kg , 45-60 kg, >60 kg;
    Starting dose: Metoprolol-Succinat : ½ Tablette mini, Enalaprilmaleat 1/ 2 Tablette medium for all classes of weight.
    Metoprolol-Succinat :1 Tablette medium, Enalaprilmaleat: 2x 1 Tablette medium for class 20<45 kg;
    Metoprolol-Succinat: 1 Tablette mini and 1 medium, Enalaprilmaleat:
    2x 1 Tablette medium for class 45-60 kg;
    Metoprolol-Succinat:1 Tablette forte, Enalaprilmaleat:2x 1 Tablette forte for class >60 kg ;

    experimental intervention: combined therapy with beta-blocker+ ACE-inhibitor versus placebo,double-blinded,
    duration of intervention per patient: max. 6 years
  •   Placebo
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Blinded
  •   patient/subject, investigator/therapist
  •   Placebo
  •   Treatment
  •   Parallel
  •   II-III
  •   [---]*
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Primary Outcome

To evaluate the effect and safety of a preventive treatment with ACE-Inhibitor and a Beta-Blocker on the onset of Left Ventricular Dysfunction in Duchenne Muscular Dystrophy .
Time to first diagnosis of left ventricular dysfunction defined as fraction shortening < 28% in standard echocardiography.

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Secondary Outcome

Overall survival (time from randomization to death)
Quality of life (noted by Kindl-questionnaire) in both groups (baseline; once a year; end of study for individual patient or end of follow-up)
Mean drop of frequency and heart rate variability in 24h-ECG
Tissue-Doppler data: systolic and diastolic strain, strain rate and wall velocities in left and right ventricle
Laboratory parameters (pro-BNP, Angiotensin II, Noradrenalin)
assessment of safety: safety -laboratory (esp.Creatinine, Electrolytes,lowest blood pressure measurements, 24h ECG (heart rate, arrhythmias), Adverse Events

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • [---]*
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Recruitment

  •   Actual
  •   2010/03/01
  •   55
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Male
  •   10   Years
  •   14   Years
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Additional Inclusion Criteria

1. Male patients aged 10 - 14 years
2. Normal left ventricular function (LVSF >=30%)
3. DMD confirmed by genetic analysis (muscle biopsy facultative)
4. Normal renal function (GFR >30 ml/min/1,73 m2)
5. Informed Consent of both parents, assent of patient

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Exclusion Criteria

1. Contraindications for ACE-Inhibitors/Beta-Blocker.
2. Previous therapy with ACE-Inhibitors, AT II Antagonists, Beta-Blockers in the past 3 Months.
3. Participation in another one clinical Trial parallel to this clinical trial
4.Dilated left ventricle ( > 97 percentile) or reduced LVSF < 30%

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Addresses

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    • Friedrich- Alexander- Universität Erlangen Nürnberg, Universitätsklinikum , Dekan
    • Mr.  Prof. Dr. med. Dr. h.c.  Jürgen  Schüttler 
    • Maximiliansplatz
    • 91054  Erlangen
    • Germany
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    •   +49(0)913185-0
    •   +49(0)913185-39191
    •   [---]*
    •   [---]*
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    • Kinderkardiologische Abteilung in der Kinder und Jugendklinik
    • Mr.  Prof. Dr.  Sven  Dittrich 
    • Loschgestrasse 15
    • 91054  Erlangen
    • Germany
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    • Kinderkardiologische Abteilung in der Kinder und Jugendklinik Erlangen
    • Ms.  Verena  Greim 
    • Loschgestrasse 15
    • 91054  Erlangen
    • Germany
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Sources of Monetary or Material Support

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    • Bundesministerium für Bildung und Forschung
    • Heinemannstr. 2
    • 53175  Bonn
    • Germany
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    •   +49 (0)228/ 9957-0
    •   +49 (0)228/ 9957-83601
    •   [---]*
    •   http://www.bmbf.de
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Status

  •   Recruiting complete, follow-up complete
  •   2015/12/11
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.