Trial document





This trial has been registered retrospectively.
drksid header

  DRKS00000445

Trial Description

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Title

Treatment of Duchenne Muscular Dystrophy with Cyclosporine A

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Trial Acronym

DMD-CsA

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Duchenne Muscular Dystrophy (DMD; Online Mendelian Inheritance in Man OMIM # 310200) is an x-linked progressive disease affecting about 1 in 3,500 male live births. Although motor milestones can be mildly delayed, the diagnosis is often made around four years of age when proximal muscle weakness becomes more evident. The progressive nature of the disease leads to loss of ambulation in early teens followed by the occurrence of respiratory insufficiency and dilative cardiomyopathy in the second decade. Without intervention mean age of death is around 19 years. The only pharmacological intervention that has been shown to slow the progression of muscle weakness is the use of glucocorticoids (0.75 mg/kg daily prednisone).Further uncontrolled studies report also beneficial effects of glucocorticoids on the development of respiratory insufficiency, cardiomyopathy and scoliosis. The precise mechanism by which glucocorticoids increase strength in DMD is still not known but there is increasing evidence that the anti-inflammatory and immunosuppressive effect might play a central role. While the short term use of glucocorticoids has proven efficacy in DMD their long-term use is limited through their well-known side effects including weight gain, osteoporosis, and behavioural changes. Therefore alternative regimes such as alternating 10 days on with 10 days off 0.75 mg/kg prednisone have been used but seem to be less effective. The main focus of this trial was to explore the possible role of cyclosporine A (CSA) as a steroid sparing drug in DMD, thus reducing side-effects without loosing efficacy. CSA is a lipophilic cyclic undecapeptide and one of the essential immunosuppressive drugs used in numerous immune and non-immune diseases in childhood. CSA was chosen among other immunosuppressive drugs because two open trials reported increase of voluntary and tetanic force in humans with DMD after daily treatment with 5 mg/kg CSA.More recently a positive treatment effect of low dose CSA was also confirmed in the mdx mouse model of DMD.

Therefore the aim of the study presented here was to assess the short-term effect of CSA as monotherapy and its combination with intermittent prednisone for the treatment of ambulant patients with DMD.


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Brief Summary in Scientific Language

After the screening procedure patients will be randomized in a 1:1 ratio to receive CSA or placebo. A stratified block randomization with a randomly varying length of 4 or 6 participants and stratification for trial site will be used. Allocation is based on computer generated random numbers and is performed centrally via facsimile. A number is communicated to identify each randomized patient’s study medication which is identically prepacked to maintain blinding of patient and investigator. In order to keep the study statistician blinded, reading permission is withdrawn from the computer directory containing randomization information and is reassigned after data base lock.

CSA will be applied in a daily dose of 3.5-4 mg per kilogram body weight and applied as capsules or oral solution twice daily. For capsules and liquid solution placebo preparations identical in appearance, weight, and taste are used. After three months of monotherapy with CSA or placebo intermittent prednisone will be added for all patients (0.75 mg per kilogram bodyweight daily, 10 days on alternating with 10 days off medication) and the combined treatment will be continued for another 12 months. All study medication will be prepared and packed by Novartis Pharma AG (Basel, Switzerland) according to the Good Manufacturing Practice.


Outcomes
Primary outcome will be manual muscle testing using an extended 11-point version of the Medical Research Council (MRC) score. MRC is a validated instrument to assess muscle strength in DMD patients in 28 different muscle groups including neck, shoulder, elbow, wrist, hip, knee, and ankle in defined positions using an ordinal 11-point scale. It has been used as primary outcome measure in various controlled trials for DMD. The MRC score is calculated as a percentage of a possible total score (%MRC) and the change of %MRC between baseline (M0) and month 3 (M3) was used to assess CSA monotherapy. Respectively, change between month 3 (M3) and month 15 (M15) was used to assess the combination of CSA with intermittent prednisone. In addition, quantitative muscle testing using the Citec© hand-held dynamometry (C.I.T. Techniques, Haren, The Netherlands) is used as secondary outcome measure. The Citec© dynamometer is a small hand-held device that is used to measure maximal isometric force in Newton (N). In this study shoulder abduction, elbow flexion, hip flexion, knee extension, and ankle dorsiflexion were assessed on the patient’s dominant site. According to a published protocol, defined positions and locations for each muscle group will be tested and the best of three consecutive measurements will be used for each muscle group. The total score for dynamometry measurement is calculated as the sum of the best value of each muscle group. For MRC and dynamometry scores, missing single items will be replaced by mean values of the remaining items. The time to walk 10 m independently and the time to stand up from supine position are used as functional outcome measures. Muscle strength assessment and timed tests will be performed by experienced physiotherapists at each site. A detailed manual and training material illustrating assessment of different muscle groups as well as central training sessions for all evaluators before and during the trial on an annual basis will be used to ensure inter- and intrarater reliability. The revised German KINDL© questionnaire will be used as a generic quality of life measure for children. Primary and secondary outcome assessments will be done at baseline and months 3, 9, and 15.

In parallel, safety of CSA will be monitored during and 30 days after discontinuation of study drug by adverse event reports and monthly physical examination, assessment of blood pressure, and central laboratory tests (biochemistry and haematology). As serum creatine level is not a reliable biomarker for renal function in DMD due to the low muscle mass, cystatin C will be measured when the creatine level increase. In the case of increase of blood pressure or cystatin C level above normal range a dose reduction of CSA by one fourth is prescribed in the protocol. Additionally, CSA serum concentrations will be analyzed by an external investigator to detect potentially toxic levels and to cause a dose reduction if appropriate. Random CSA serum level alerts with consecutive dose reduction are created in the placebo group to keep investigators blinded.

Sample size and Statistical methods
The sample size calculation based on the primary endpoint (change in %MRC score). A normal distribution with a standard deviation of 4 points was assumed, justified by previously published data. As two treatment comparisons are performed (one after each treatment section), a Bonferroni correction is applied, i.e. two tests were planned at a two-sided significance level of 0.025 in order to control a Type 1 error not exceeding 0.05. Based on the two-sample t-test, the study is planned to detect a difference between the two treatment groups with a power of 80% if the true difference relates to an effect size of 0.5 (2 points on the %MRC scale). Thus about 150 patients (75 per treatment group) are needed.

The primary analysis are performed according to the intention-to-treat principle, referring to those patients who are randomized and analyzing them in their originally allocated treatment group. Patients will be excluded from the intention to treat (ITT) population if either treatment is not started, or no data on the primary endpoint are obtained, or one of two major objective inclusion criteria are violated (DMD diagnosis, ability to walk). In order to include patients with missing values for the primary endpoint, a last observation carried forward (LOCF) approach was used for %MRC and dynamometry. This corresponds to the assumption of a constant development in muscle strength measures for patients with missing data, whereas deterioration is expected to be realistic in the course of the study. We further assumed that study termination due to missing efficacy in the placebo group has a higher probability than termination due to side effects in the treatment group. Therefore, we considered this approach as conservative as it favours the placebo group.

Change in %MRC and change in dynamometry sum scores will be analyzed with a linear regression model with baseline value, treatment group, age, and trial site as covariates. For analysis of secondary outcome measures no adjustment of alpha-values is used. Kaplan-Meier estimation and logrank tests are used for group comparison of time-to-event endpoints. The outcome variables will be age at time of losing the ability to walk independently and age at time of losing the ability to rise unaided from supine, calculated as time from birth until documentation of loss of walking/rising ability in the study. Patients still able to walk/rise are censored at the date of the last documented observation. For safety analysis rates of adverse events and other safety information (laboratory tests, blood pressure) will becompared between groups.

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Organizational Data

  •   DRKS00000445
  •   2010/06/22
  •   2005/11/18
  •   yes
  •   Approved
  •   148/03, Ethik-Kommission der Albert-Ludwig-Universität Freiburg
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Secondary IDs

  •   UKF000560  (Register Klinische Studien des Universitätsklinikum Freiburg)
  •   4021090 
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Health Condition or Problem studied

  •   G71.0 -  Muscular dystrophy
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Interventions/Observational Groups

  •   CSA will be applied in a daily dose of 3.5-4 mg per kilogram body weight and applied as capsules or oral solution twice daily. For capsules and liquid solution placebo preparations identical in appearance, weight, and taste are used.
  •   Placebo will be applied in a daily dose of 3.5-4 mg per kilogram body weight and applied as capsules or oral solution twice daily. For capsules and liquid solution placebo preparations identical in appearance, weight, and taste are used.
  •   After three months of monotherapy with CSA intermittent prednisone will be added for all patients (0.75 mg per kilogram bodyweight daily, 10 days on alternating with 10 days off medication) and the combined treatment will be continued for another 12 months.
  •   After three months of monotherapy with placebo intermittent prednisone will be added for all patients (0.75 mg per kilogram bodyweight daily, 10 days on alternating with 10 days off medication) and the combined treatment will be continued for another 12 months.
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Characteristics

  •   Interventional
  •   [---]*
  •   Randomized controlled trial
  •   Double or multiple blind
  •   [---]*
  •   Placebo, Active control
  •   Treatment
  •   Other
  •   II-III
  •   [---]*
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Primary Outcome

Primary outcome will be manual muscle testing using an extended 11-point version of the Medical Research Council (MRC) score. MRC is a validated instrument to assess muscle strength in DMD patients in 28 different muscle groups including neck, shoulder, elbow, wrist, hip, knee, and ankle in defined positions using an ordinal 11-point scale. It has been used as primary outcome measure in various controlled trials for DMD. The MRC score is calculated as a percentage of a possible total score (%MRC) and the change of %MRC between baseline (M0) and month 3 (M3) was used to assess CSA monotherapy. Respectively, change between month 3 (M3) and month 15 (M15) was used to assess the combination of CSA with intermittent prednisone.

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Secondary Outcome

In addition, quantitative muscle testing using the Citec© hand-held dynamometry (C.I.T. Techniques, Haren, The Netherlands) is used as secondary outcome measure. The Citec© dynamometer is a small hand-held device that is used to measure maximal isometric force in Newton (N). In this study shoulder abduction, elbow flexion, hip flexion, knee extension, and ankle dorsiflexion were assessed on the patient’s dominant site. According to a published protocol, defined positions and locations for each muscle group will be tested and the best of three consecutive measurements will be used for each muscle group. The total score for dynamometry measurement is calculated as the sum of the best value of each muscle group. For MRC and dynamometry scores, missing single items will be replaced by mean values of the remaining items. The time to walk 10 m independently and the time to stand up from supine position are used as functional outcome measures. Muscle strength assessment and timed tests will be performed by experienced physiotherapists at each site. A detailed manual and training material illustrating assessment of different muscle groups as well as central training sessions for all evaluators before and during the trial on an annual basis will be used to ensure inter- and intrarater reliability. The revised German KINDL© questionnaire will be used as a generic quality of life measure for children. Primary and secondary outcome assessments will be done at baseline and months 3, 9, and 15.

In parallel, safety of CSA will be monitored during and 30 days after discontinuation of study drug by adverse event reports and monthly physical examination, assessment of blood pressure, and central laboratory tests (biochemistry and haematology). As serum creatine level is not a reliable biomarker for renal function in DMD due to the low muscle mass, cystatin C will be measured when the creatine level increase. In the case of increase of blood pressure or cystatin C level above normal range a dose reduction of CSA by one fourth is prescribed in the protocol. Additionally, CSA serum concentrations will be analyzed by an external investigator to detect potentially toxic levels and to cause a dose reduction if appropriate. Random CSA serum level alerts with consecutive dose reduction are created in the placebo group to keep investigators blinded.

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Countries of Recruitment

  •   Germany
  •   Austria
  •   Switzerland
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Locations of Recruitment

  • [---]*
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Recruitment

  •   Actual
  •   2003/11/24
  •   150
  •   Multicenter trial
  •   International
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Inclusion Criteria

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

- Male patients, minimum age 5
- Ability to walk independently (minimum 50 meters)
- Proven diagnosis of duchenne muscular dystrophy:
clinical symptoms, increase of CK (more than 10-fold), together with at least one of the following criteria:
dystrophine immunofluorescence and/or
immunoblot negative muscle biopsy;
positive gene deletion for duchenne;
positive family history (with proven duchenne dystrophy)
- Cooperation concerning visits
- Able to swallow study medication (capsules)
- Parents´ written informed consent
- Child´s written informed consent if able to understand meaning of the study

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Exclusion Criteria

- Preceding therapy of duchenne with steroids
- Change of a medication or alimentary additive within the last 3 months
- Intake of clenbuterol or other sympathicomimetic drugs within 3 months of study entry
- Participation on another trial within the last 3 months
- Contraindications against intake of csA: functional renal impairment (creatinine above 0.7 mg/dl), uncontrolled hypertension (blood pressure above 97 percentile), known allergy against csA, uncontrolled infectious diseases, malignant tumors, severe liver disease, hyperuricemia, hypo magnesemia, necessity of therapy with drugs interfering pharmacokinetically with csA
- Contraindications against intake of prednisone: known anamnestic gastrointestinal bleeding, cataract, diabetes, uncontrolled hypertension, uncontrolled infectious diseases (tuberculosis, infections with herpes, systemic mycosis), pronounced osteoporosis, 8 weeks before or 2 weeks after vaccination, glaucoma

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Addresses

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    • Universitätsklinikum Freiburg Zentrum für Kinder- und Jugendmedizin
    • Mr.  Prof.Dr.med.  Rudolf  Korinthenberg 
    • Mathildenstr.1
    • 79106  Freiburg
    • Germany
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    start of 1:1-Block address contact primary-sponsor
    end of 1:1-Block address contact primary-sponsor
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    • Universitätsklinikum Freiburg Zentrum für Kinder- und Jugendmedizin
    • Mr.  Dr.med  Janbernd  Kirschner 
    • Mathildenstr.1
    • 79106  Freiburg
    • Germany
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    start of 1:1-Block address contact scientific-contact
    end of 1:1-Block address contact scientific-contact
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    • Universitätsklinikum Freiburg Zentrum für Kinder- und Jugendmedizin
    • Ms.  Ursula  Wein 
    • Mathildenstr.1
    • 79106  Freiburg
    • Germany
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    start of 1:1-Block address contact public-contact
    end of 1:1-Block address contact public-contact
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Sources of Monetary or Material Support

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    • BMBF
    • Hannoversche Straße 30
    • 10115  Berlin
    • Germany
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    end of 1:1-Block address contact materialSupport
  • start of 1:1-Block address otherSupport
    • aktion benni & co e.V.
    • Nikolaistr. 2
    • 44866  Bochum
    • Germany
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Status

  •   Recruiting complete, follow-up complete
  •   2007/12/31
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Trial Publications, Results and other Documents

  •   Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial ;Lancet Neurology 27.August 2010
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* This entry means the parameter is not applicable or has not been set.