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

Information source: Ruhr University of Bochum
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Multiple Sclerosis

Intervention: Dexrazoxane (DRZ) plus Mitoxantrone (MX) (Drug); Placebo plus Mitoxantrone (MX) (Drug)

Phase: Phase 2

Status: Active, not recruiting

Sponsored by: PD Dr. Andrew Chan

Official(s) and/or principal investigator(s):
Andrew Chan, PD Dr., Principal Investigator, Affiliation: Department of Neurology, St. Josef-Hospital Bochum, Ruhr-University Bochum

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.

Clinical Details

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 design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Primary outcome: Changes in LVEF in the different treatment arms by cardiac MRI

Secondary outcome:

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

Determination of EDSS and relapse rate in mitoxantrone plus dexrazoxane treatment arm versus mitoxantrone plus placebo treatment arm

Cumulative number of active lesions by cMRI

LVEF in 3D-echocardiography vs. LVEF in cardiac MRI

Clinical efficacy of DRZ+MX vs. MX monotherapy by MSFC

Quality of Life by SF-36 questionnaire

Changes in magnetic evoked potentials: prolongation of TMCT+CMCT, potential configuration

Annual brain atrophy rates in cMRI

Changes in transcranial sonography (abnormal iron deposition AID). AID in cMRI. Comparison of both methods

Analysis of ABD transporter gene polymorphisms as predictor of therapy response and side effect profile via TaqMan PCR

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

Minimum age: 18 Years. Maximum age: 55 Years. Gender(s): Both.

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 Ôëą1 point over last 18 months or 2 relapses

- non-response or non-tolerability of pre-treatment

- Ôëą 48 mg/m┬▓ 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

Locations and Contacts

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum 44791, Germany
Additional Information

Related publications:

Flachenecker P, Meissner H. Fatigue in multiple sclerosis presenting as acute relapse: subjective and objective assessment. Mult Scler. 2008 Mar;14(2):274-7. doi: 10.1177/1352458507082480.

Morrissey SP, Le Page E, Edan G. Mitoxantrone in the treatment of multiple sclerosis. Int MS J. 2005 Nov;12(3):74-87. Review.

Rieckmann P, Toyka KV, Bassetti C, Beer K, Beer S, Buettner U, Chofflon M, G├Âtschi-Fuchs M, Hess K, Kappos L, Kesselring J, Goebels N, Ludin HP, Mattle H, Schluep M, Vaney C, Baumhackl U, Berger T, Deisenhammer F, Fazekas F, Freim├╝ller M, Kollegger H, Kristoferitsch W, Lassmann H, Markut H, Strasser-Fuchs S, Vass K, Altenkirch H, Bamborschke S, Baum K, Benecke R, Br├╝ck W, Dommasch D, Elias WG, Gass A, Gehlen W, Haas J, Haferkamp G, Hanefeld F, Hartung HP, Heesen C, Heidenreich F, Heitmann R, Hemmer B, Hense T, Hohlfeld R, Janzen RW, Japp G, Jung S, J├╝gelt E, Koehler J, K├Âlmel W, K├Ânig N, Lowitzsch K, Manegold U, Melms A, Mertin J, Oschmann P, Petereit HF, Pette M, P├Âhlau D, Pohl D, Poser S, Sailer M, Schmidt S, Schock G, Schulz M, Schwarz S, Seidel D, Sommer N, Stangel M, Stark E, Steinbrecher A, Tumani H, Voltz R, Weber F, Weinrich W, Weissert R, Wiendl H, Wieth├Âlter H, Wildemann U, Zettl UK, Zipp F, Zschenderlein R, Izquierdo G, Kirjazovas A, Packauskas L, Miller D, Koncan Vracko B, Millers A, Orologas A, Panellus M, Sindic CJ, Bratic M, Svraka A, Vella NR, Stelmasiak Z, Selmaj K, Bartosik-Psujik H, Mitosek-Szewczyk K, Belniak E, Mochecka A, Bayas A, Chan A, Flachenecker P, Gold R, Kallmann B, Leussink V, M├Ąurer M, Ruprecht K, Stoll G, Weilbach FX; Multiple Sclerosis Therapy Consensus Group. Escalating immunotherapy of multiple sclerosis--new aspects and practical application. J Neurol. 2004 Nov;251(11):1329-39. Review.

Spindler M, Weilbach F, Beer M, Sandstede J, K├Âstler H, Strotmann J, Voelker W, Hahn D, Ertl G, Gold R. Non-invasive functional and biochemical assessment of mitoxantrone cardiotoxicity in patients with multiple sclerosis. J Cardiovasc Pharmacol. 2003 Nov;42(5):680-7.

Weilbach FX, Chan A, Toyka KV, Gold R. The cardioprotector dexrazoxane augments therapeutic efficacy of mitoxantrone in experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2004 Jan;135(1):49-55.

Bernitsas E, Wei W, Mikol DD. Suppression of mitoxantrone cardiotoxicity in multiple sclerosis patients by dexrazoxane. Ann Neurol. 2006 Jan;59(1):206-9.

Cotte S, von Ahsen N, Kruse N, Huber B, Winkelmann A, Zettl UK, Starck M, K├Ânig N, Tellez N, D├Ârr J, Paul F, Zipp F, L├╝hder F, Koepsell H, Pannek H, Montalban X, Gold R, Chan A. ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis. Brain. 2009 Sep;132(Pt 9):2517-30. doi: 10.1093/brain/awp164. Epub 2009 Jul 15.

D├Ârr J, Bitsch A, Schmailzl KJ, Chan A, von Ahsen N, Hummel M, Varon R, Lill CM, Vogel HP, Zipp F, Paul F. Severe cardiac failure in a patient with multiple sclerosis following low-dose mitoxantrone treatment. Neurology. 2009 Sep 22;73(12):991-3. doi: 10.1212/WNL.0b013e3181b878f6.

Hartung HP, Gonsette R, K├Ânig N, Kwiecinski H, Guseo A, Morrissey SP, Krapf H, Zwingers T; Mitoxantrone in Multiple Sclerosis Study Group (MIMS). Mitoxantrone in progressive multiple sclerosis: a placebo-controlled, double-blind, randomised, multicentre trial. Lancet. 2002 Dec 21-28;360(9350):2018-25.

Starting date: April 2012
Last updated: November 4, 2014

Page last updated: August 23, 2015

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