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

NCT01627938 | Unknown Phase 2 DMC

• 2 other identifiers: RUB001CarMS2010-018508-95
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Sclerosis

Keywords

Multiple Sclerosis; MS; Mitoxantrone; Dexrazoxane; Cardioxane; cardiotoxicity; cardiac toxicity; cardiotoxic side effects; cardiac MRI; cranial MRI; LVEF; neurological outcome

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (10)

• 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

  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

  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

Study Arms (2)

Dexrazoxane (DRZ) plus Mitoxantrone (MX)

EXPERIMENTAL

DRZ (600 mg/m2) : MX (12 mg/m2) ratio 50:1

Drug: Dexrazoxane (DRZ) plus Mitoxantrone (MX)

Placebo plus Mitoxantrone (MX)

PLACEBO COMPARATOR

Placebo + MX (12 mg/m2)

Drug: Placebo plus Mitoxantrone (MX)

Interventions

Dexrazoxane (DRZ) plus Mitoxantrone (MX) DRUG

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

Also known as: Cardioxane® (Dexrazoxane), Ralenova® (Mitoxantrone)

Dexrazoxane (DRZ) plus Mitoxantrone (MX)

Placebo plus Mitoxantrone (MX) DRUG

MX Dosage: 12mg/m2 Placebo infusion / MX infusion once every three months over a period of 12 months, i.e. 5 infusions

Also known as: Ralenova ® (Mitoxantrone)

Placebo plus Mitoxantrone (MX)

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• PD Dr. Andrew Chan: lead

Study Sites (1)

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum

Bochum, 44791, Germany

Location

Related Publications (9)

• 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.

  PMID: 18337428 BACKGROUND

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

  PMID: 16417821 BACKGROUND

• Rieckmann P, Toyka KV, Bassetti C, Beer K, Beer S, Buettner U, Chofflon M, Gotschi-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, Freimuller M, Kollegger H, Kristoferitsch W, Lassmann H, Markut H, Strasser-Fuchs S, Vass K, Altenkirch H, Bamborschke S, Baum K, Benecke R, Bruck 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, Jugelt E, Koehler J, Kolmel W, Konig N, Lowitzsch K, Manegold U, Melms A, Mertin J, Oschmann P, Petereit HF, Pette M, Pohlau 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, Wietholter 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, Maurer 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. doi: 10.1007/s00415-004-0537-6.

  PMID: 15592728 BACKGROUND

• Spindler M, Weilbach F, Beer M, Sandstede J, Kostler 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. doi: 10.1097/00005344-200311000-00015.

  PMID: 14576518 BACKGROUND

• 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. doi: 10.1111/j.1365-2249.2004.02344.x.

  PMID: 14678264 BACKGROUND

• Bernitsas E, Wei W, Mikol DD. Suppression of mitoxantrone cardiotoxicity in multiple sclerosis patients by dexrazoxane. Ann Neurol. 2006 Jan;59(1):206-9. doi: 10.1002/ana.20747.

  PMID: 16374818 BACKGROUND

• Cotte S, von Ahsen N, Kruse N, Huber B, Winkelmann A, Zettl UK, Starck M, Konig N, Tellez N, Dorr J, Paul F, Zipp F, Luhder 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.

  PMID: 19605531 BACKGROUND

• Dorr 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. No abstract available.

  PMID: 19770476 BACKGROUND

• Hartung HP, Gonsette R, Konig 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. doi: 10.1016/S0140-6736(02)12023-X.

  PMID: 12504397 BACKGROUND

MeSH Terms

Conditions

Multiple Sclerosis; Cardiotoxicity

Interventions

Dexrazoxane; Mitoxantrone

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Autoimmune Diseases; Immune System Diseases; Heart Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Drug-Related Side Effects and Adverse Reactions; Chemically-Induced Disorders; Radiation Injuries; Wounds and Injuries

Intervention Hierarchy (Ancestors)

Razoxane; Diketopiperazines; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Quinones; Polycyclic Compounds

Study Officials

• Andrew Chan, PD Dr.

  Department of Neurology, St. Josef-Hospital Bochum, Ruhr-University Bochum

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 30, 2012
• First Posted: June 26, 2012
• Study Start: April 1, 2012
• Primary Completion: April 1, 2015
• Study Completion: April 1, 2016
• Last Updated: November 5, 2014

Record last verified: 2014-11

Locations

DE (1)