Study to Evaluate the Reduction of Cardiac Problems in Multiple Sclerosis Patients With Mitoxantrone and Dexrazoxane in Combination

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Dexrazoxane (DRZ) plus Mitoxantrone (MX)
* Drug: Placebo plus Mitoxantrone (MX)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexrazoxane (DRZ) plus Mitoxantrone (MX)<br>DRZ (600 mg/m2) : MX (12 mg/m2) ratio 50:1 | Drug: Dexrazoxane (DRZ) plus Mitoxantrone (MX)<br>* Dosage: DRZ (600 mg/m2) : MX (12 mg/m2) ratio 50:1 DRZ infusion / MX infusion once every three months over a period of 12 months, i.e. 5 infusions<br>* Other names: Ralenova® (Mitoxantrone);|
| Placebo Comparator: Placebo plus Mitoxantrone (MX)<br>Placebo + MX (12 mg/m2) | Drug: Placebo plus Mitoxantrone (MX)<br>* MX Dosage: 12mg/m2 Placebo infusion / MX infusion once every three months over a period of 12 months, i.e. 5 infusions<br>* Other names: Ralenova ® (Mitoxantrone);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in LVEF in the different treatment arms by cardiac MRI | Assessment of cardiac function by measurement of LVEF in mitoxantrone plus dexrazoxane treatment arm versus mitoxantrone plus placebo treatment arm by cardiac MRI | Baseline to month 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Assessment of cardiac function by measurement of LVEF by transthoracic echocardiography, by determination of cardiac side effects by ECG and by measurement of CK-MB, Troponin and BNP in mitoxantrone plus dexrazoxane treatment arm versus mitoxantrone plus placebo treatment arm | Baseline and month 3,6,9,12, 24 | 
| Determination of EDSS and relapse rate in mitoxantrone plus dexrazoxane treatment arm versus mitoxantrone plus placebo treatment arm | Comparison of clinical efficacy of mitoxantrone plus dexrazoxane treatment versus mitoxantrone plus placebo treatment on neurological outcome parameters by means of EDSS and relapse rate | Baseline and month 3,6,9,12 and 24 | 
| Cumulative number of active lesions by cMRI |  | Day1 and month 12 | 
| LVEF in 3D-echocardiography vs. LVEF in cardiac MRI |  | Baseline and month 12 | 
| Clinical efficacy of DRZ+MX vs. MX monotherapy by MSFC |  | Baseline and month 3,6,9,12 and 24 | 
| Quality of Life by SF-36 questionnaire |  | Baseline and month 3,6,9 and month 12 | 
| Changes in magnetic evoked potentials: prolongation of TMCT+CMCT, potential configuration |  | Baseline and month 3,6,9 and month 12 | 
| Annual brain atrophy rates in cMRI |  | Day 1 and month 12 | 
| Changes in transcranial sonography (abnormal iron deposition AID). AID in cMRI. Comparison of both methods |  | Baseline and month 12 | 
| Analysis of ABD transporter gene polymorphisms as predictor of therapy response and side effect profile via TaqMan PCR |  | Baseline and month 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, MS, Mitoxantrone, Dexrazoxane, Cardioxane, cardiotoxicity, cardiac toxicity, cardiotoxic side effects, cardiac MRI, cranial MRI, LVEF, neurological outcome