Trial document

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Trial Description

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Are there abnormalities in hemostasis in patients with duchenne muscular dystrophy?

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Trial Acronym


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URL of the Trial


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Brief Summary in Lay Language

Duchenne Muscular Dystrophy (DMD) is a genetic disease, which is characterized by a progressive muscle weakness that leads to an early death of affected patients by progressive cardiac and respiratory insufficiency. Due to the X-linked inheritance only boys and young men are affected. To date is no causal therapy is available. References that blood clotting disorders exist are found in the literature. These seem to vary in their manifestation: On the one hand several authors reported a bleeding tendency, on the other vasal occlusions by blood clots appear to occur more often.
The research project includes two parts: in a retrospective questionnaire-based survey patients and/or their parents are asked whether any abnormalities in coagulation have been or are still present (e. g. bleeding-complications in performed operations, thrombosis, heart attack). This survey might not be representative for the collective of all patients with Duchenne Muscular Dystrophy but it should be helpful in estimating the frequency of disorders of coagulation in this rare condition - considering that there are about 1200 registered DMD-patients (december 2015).
In a prospective it is planned to perform additional examinations of coagulation in blood in the yearly performed control visits in hospital - where blood samples are drawn in annual intervals. Target of this part of the study is to find out if specific blood clotting disorders exist in DMD-patients, especially in platelet function which has been examined only rudimentary so far.

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Brief Summary in Scientific Language

1. Background
Duchenne Muscular Dystrophy is a genetic disease with an X-linked inheritance. Due to the typical progressive muscle degeneration patients suffer from a cardiac and respiratory insufficiency which eventually leads to an early death of the patients. DMD is caused by a mutation in the dystrophin gene which is coding for a membrane associated protein (dystrophin, 437kDa) of the cytoskeleton. Important references imply that dystrophin plays an important role in the platelet function and thereby in the blood clotting of patients suffering from DMD.
There are case studies as well as clinical and experimental surveys about this topic. Strikingly patients seem to suffer from different types of blood clotting disorders. On the one hand an increased bleeding tendency is reported for example in scoliosis surgery (Forst et al. 1998; Freson et al. 2007; Turturro et al 2004). On the other hand case studies of pulmonary embolism (Riggs 1990), cerebral infarction (Matsuishi et al. 1982; Biller et al. 1987; Hanajima et al. 1996) or cardiac thrombus formation suppose a higher risk for the development of thromboembolic vessel occlusion.
2. Justification
The hemostasis is a system of high complexity that is for reasons of simplification divided into two part processes: the primary (celluar) hemostasis and the secondary (plasmatic) hemostasis. Primary a new tissue defect is provisory patched by platelets, secondary this patch is intensified through coagulation factors and fibrin. Since the secondary hemostasis has been examined in DMD patients various times and has been found to be unremarkable, this research project focuses on the primary hemostasis. The number of platelets, platelet function and the function of the vonWillebrand Factor determine this process significantly.
Platelets have a special complex of membrane and cytoskeleton which is similar to that of muscle cells. The role of dystrophin in platelet activation and thereby in hemostasis is not completely understood (Jagadeesh et al.; 1998, Maurin et al. 1998). There are different theories why blood coagulation could be affected in patients suffering from DMD: the cardiac insufficiency can secondary activate the hemostasis system, moreover the dilatation and dysfunction of the left ventricle can contribute to the formation of a thrombus, additionally the reactivity of vessels can be restricted by the muscular dystrophy and further theories.
Saito et al. were able to show that Left-ventricular diastolic dysfunction (LVDd) - which serves as marker for cardiac ability to keep blood circulation up - was as expected higher in patients with lower values in left-ventricular ejection fraction (LVEF). On the other hand and more interesting these patients also showed elevated parameters for thrombin-antithrombin-complex (TAT) and prothrombin fragment (F1 + 2). TAT is a sensitive parameter for specific detection of thrombogenesis secondary to acitvation of the hemastaseologic cascade. F1 + 2 also serves as sensitive marker reflecting the production of thrombin. Similar to D-Dimers, both parameters are elevated in case of thromboembolic events (Pelzer et al. 1991; Barber et al 2004), indicating that hemostasis and fibrinolysis are activated. Enlargement and dysfunction of the left ventricle also contribute to thrombogenesis (Yamamoto et al, 1995).

3. Target of the research project
Target of the research project is to gather in a retrospective as well as in a prospective part information on the dimension of blood clotting disorders existing in patients suffering from DMD. Furthermore we hope to identify whether possibly present disoreders lead to clinical symptoms and if conclusions for prophylactic anticoagulation of DMD-patients can be drawn.
The retrospective part of the research project consists of a questionnaire-based survey in which patients and/or their parents are asked whether blood clotting disorders or symptoms of them exist.The survey is distributed by the German DMD patient registry. In patients identified additional analysis on the basis of physician’s letters and laboratory results are supposed to follow if patients agree.
In a prospective survey blood samples are drawn from approximately 50 patients suffering from DMD and are examined in additional coagulation diagnostics. The target of this survey is to detect if specific blood clotting disorders exist, especially in platelet function.

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Organizational Data

  •   DRKS00011646
  •   2017/02/08
  •   [---]*
  •   yes
  •   Approved
  •   469/16, Ethik-Kommission der Albert-Ludwigs-Universität Freiburg
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Secondary IDs

  • [---]*
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Health Condition or Problem studied

  •   G71.0 -  Muscular dystrophy
  •   D69.1 -  Qualitative platelet defects
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Interventions/Observational Groups

  •   RETROSPECTIVE PART: recording of concurrent medication, status of ambulation, occurence of thromboembolic events, occurence of bleeding tendencies

    PROSPECTIVE PART: determination of FVIII-activity, hemogram, D-dimer, prothrombin fragment F1+2, c-reactive protein, marker of thrombosis, documentation of clinical trial and medication
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  •   Non-interventional
  •   Other
  •   Single arm study
  •   Open (masking not used)
  •   [---]*
  •   Uncontrolled/Single arm
  •   Screening
  •   Single (group)
  •   N/A
  •   N/A
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Primary Outcome

Primary Outcome:
Documentation of clinically relevant thromboembolic events in patients registered in the DMD-Registry.

Primary Outcome:
Comprehensive examination of platelet function in DMD-patients via exmination of
- vWF-Antigen
- vWF-Collagenbindingcapacity (vWF:CB)
- Multimer structural analysis
- aggregation of thrombocytes
- flow cytometry of thrombocytes

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Secondary Outcome

Secondary Outcome:
Documentation of general medication and ambulatory status in DMD-patients.

Secondary Outcome
Examination of
- Factor VIII-activity
- haemogramm
- D-Dimers
- Prothrombinfragments 1+2
- C-reactive Protein
- Markers of Thrombosis
Documentation of clinical course and medicaments
- Echocardiography (when planned in routine-visit).

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
  • University Medical Center 
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  •   Actual
  •   2017/02/20
  •   50
  •   Multicenter trial
  •   National
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Inclusion Criteria

  •   Male
  •   6   Years
  •   no maximum age
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Additional Inclusion Criteria

Inclusion criteria:
-registration in the DMD patient registry of the TREAT-NMD-network
Inclusion criteria:
-male patients, aged 6 and above
-assured DMD diagnosis, confirmed by genetic results or muscle biopsy
-written approval of the person having the custody of the child
-written approval of the patient as far as he is by age and stage of development able to understand the character, significance and bearing of the research project and is able to declare hereafter his intention
-sufficient ability for cooperation in echocardiographic examination (during routine examination)

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Exclusion Criteria

Exclusion criteria:
Exclusion criteria:
-overweight with Body Mass Index > 30 body weight/m²
-anamnesis or any hint of an intracranial and/or malignant tumor
-known or persistent medical drug abuse, illegal drug abuse or alcohol abuse

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  • start of 1:1-Block address primary-sponsor
    • Universitätsklinikum Freiburg- Zentrum für Kinder- und JugendmedizinKlinik für Neuropädiatrie und Muskelerkrankungen
    • Mr.  Prof.  Jan  Kirschner 
    • Mathildenstraße 1
    • 79106  Freiburg
    • Germany
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    • Zentrum für Kinder- und Jugendmedizin - Klinik für Neuropädiatrie und Muskelerkrankungen.
    • Mr.  Dr.  David  Schorling 
    • Mathildenstraße 1
    • 79106  Freiburg
    • Germany
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    • Zentrum für Kinder- und Jugendmedizin - Klinik für Neuropädiatrie und Muskelerkrankungen.
    • Mr.  Dr.  David  Schorling 
    • Mathildenstraße 1
    • 79106  Freiburg
    • Germany
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Sources of Monetary or Material Support

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    • Deutsche Duchenne Stiftung der Aktion Benni & Co e.V.
    • Huestraße 20
    • 44787  Bochum
    • Germany
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  •   Recruiting ongoing
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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.