Clinical trial NCT01627938: Study to Evaluate the Reduction of Cardiac Problems in Multiple Sclerosis Patients With Mitoxantrone and Dexrazoxane in Combination
Official title: A Phase II Proof of Concept Study Evaluating the Reduction of Mitoxantrone-induced Cardiotoxicity and Neurological Outcome in the Combined Use of Mitoxantrone and Dexrazoxane (Cardioxane®) in Multiple Sclerosis (MSCardioPro)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Multiple Sclerosis
Keywords: Multiple Sclerosis
MS
Mitoxantrone
Dexrazoxane
Cardioxane
cardiotoxicity
cardiac toxicity
cardiotoxic side effects
cardiac MRI
cranial MRI
LVEF
neurological outcome
Lead sponsor: Ruhr University of Bochum
Sponsor class: OTHER
First posted: 2012-06-26
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will primarily address the question whether the combination of Mitoxantrone therapy with dexrazoxane can reduce cardiotoxic side effects in the treatment of Multiple Sclerosis patients in comparison to Mitoxantrone monotherapy.

Detailed description: It is designed to provide clinical and paraclinical efficacy and safety data for dexrazoxane in Mitoxantrone treatment of Multiple Sclerosis in order to investigate the possible positive influence of dexrazoxane on cardiac function of Mitoxantrone-affected myocardial tissue and on the possible augmented clinical efficacy of Mitoxantrone in combination with dexrazoxane on neurological outcome parameters. The incidence of cardiotoxicity during combined Mitoxantrone/dexrazoxane treatment will be investigated and compared to the standard Mitoxantrone-treatment without dexrazoxane.

Eligibility criteria: Inclusion Criteria:

* Written informed consent to participate in the study
* Male or female subject is 18 years of age to 55 years of age
* Subject must have one of the below mentioned confirmed diagnoses of Multiple Sclerosis: RRMS or CPMS according to rev. McDonald Criteria (2005)
* If female of childbearing potential: Will to practice reliable birth control measures during study treatment and for at least 6 months after completion of study medication; not lactating or pregnant; and has a documented negative pregnancy test result within 72 hours prior to study medication administration. Male study participants: Will to practice reliable birth control measures during study treatment and for at least 6 months after completion of study medication
* Subject is willing to participate in the study, follow protocol study treatment regimen, and comply with all planned assessments
* Mitoxantrone treatment indication is given according to current guidelines:

  * Relapsing progressive or secondary progressive MS with/without superimposed relapses
  * EDSS 3-6; EDSS deterioration ≥1 point over last 18 months or 2 relapses
  * non-response or non-tolerability of pre-treatment
* ≥ 48 mg/m² BSA MX dose received up to baseline visit as lifetime dosage before study entry. If the patient is under regular ongoing MX treatment, the infusion interval of 3 months must be obtained (see exclusion criteria)

Exclusion Criteria:

* Concomitant clinically suspected or confirmed neurologic disorder at study entry that may interfere with the evaluation in this protocol \[i.e. EDSS, MSFC, MEP or MRI measurements\]
* Pre-Treatment with DRZ or immunosuppressive drugs of the anthracycline family with cardiotoxic potential other than MX prior to study enrollment
* Last Treatment with MX within the past 84 days prior to study enrollment (regular 3-monthly intervals must be obtained)
* History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures
* Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive HCG laboratory test (\>5 mIU/ml)
* Unwillingness to perform adequate contraception
* Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer
* Subjects unable or unwilling to adhere to the study-designated procedures and restrictions
* Patients not able to perform cardiac/neurological investigations including MRI, e.g. hypersensitivity to MRI contrast agent
* Other known contraindication for DRZ or MX according to current labelling
* Subject has a pre-existing cardiac disease interfering with left ventricular ejection fraction, i.e. cardiac insufficience for different reasons (resulting from prior cardial conditions such as myocardial infarction, myocarditis)
* Routine co-administration of cortisone-pulse therapy (other than for treatment of relapses), intrathecal triamcinolone-therapy or other off-label/ investigational agents (e.g. fampridine, aminopyridine)
* History of malignancy in the past 5 years (excluding localized basal cell carcinoma of the skin)
* Pre-Treatment with other immunosuppressive drugs (azathioprine, methotrexate, mycophenolate, cyclophosphamide) within the past 3 months
* Pre-Treatment with monoclonal antibodies (natalizumab, rituximab) within the past 6 months

Primary outcomes:
measure: Changes in LVEF in the different treatment arms by cardiac MRI
timeFrame: Baseline to month 12
Secondary outcomes:
measure: Changes in LVEF by transthoracic echocardiography and determination of cardiac side effects by ECG and by measurement of CK-MB, Troponin and BNP in mitoxantrone plus dexrazoxane versus mitoxantrone plus placebo treatment arms
timeFrame: Baseline and month 3,6,9,12, 24
measure: Determination of EDSS and relapse rate in mitoxantrone plus dexrazoxane treatment arm versus mitoxantrone plus placebo treatment arm
timeFrame: Baseline and month 3,6,9,12 and 24
measure: Cumulative number of active lesions by cMRI
timeFrame: Day1 and month 12
measure: LVEF in 3D-echocardiography vs. LVEF in cardiac MRI
timeFrame: Baseline and month 12
measure: Clinical efficacy of DRZ+MX vs. MX monotherapy by MSFC
timeFrame: Baseline and month 3,6,9,12 and 24
measure: Quality of Life by SF-36 questionnaire
timeFrame: Baseline and month 3,6,9 and month 12
measure: Changes in magnetic evoked potentials: prolongation of TMCT+CMCT, potential configuration
timeFrame: Baseline and month 3,6,9 and month 12
measure: Annual brain atrophy rates in cMRI
timeFrame: Day 1 and month 12
measure: Changes in transcranial sonography (abnormal iron deposition AID). AID in cMRI. Comparison of both methods
timeFrame: Baseline and month 12
measure: Analysis of ABD transporter gene polymorphisms as predictor of therapy response and side effect profile via TaqMan PCR
timeFrame: Baseline and month 12
Other outcomes:
Locations:
city: Bochum
country: Germany
facility: Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum
Study officials:
affiliation: Department of Neurology, St. Josef-Hospital Bochum, Ruhr-University Bochum
name: Andrew Chan, PD Dr.
role: PRINCIPAL_INVESTIGATOR
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