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Efficacy and Safety of Mitoxantrone in Patients With Refractory Neuromyelitis Optica and Spectrum Disorders

Primary Purpose

Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorders

Status
Unknown status
Phase
Phase 4
Locations
China
Study Type
Interventional
Intervention
Mitoxantrone
Sponsored by
Xuanwu Hospital, Beijing
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuromyelitis Optica focused on measuring mitoxantrone, neuromyelitis optica, relapse

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Recurrent longitudinal myelitis (>3 segments of spinal cord involvement by MRI) with or without recurrent ON (unilateral or bilateral) but with normal brain MRI and positive serological NMO IgG antibody.
  • Recurrent longitudinal myelitis (>3 segments of spinal cord involvement by MRI) with or without spatially limited brain lesion and positive serological NMO IgG antibody.
  • NMO, fulfilled Wingerchuk 2006 Criteria for NMO.
  • Patient presented at least 2 relapses during the 12 months preceding the start of mitoxantrone therapy, despite immunotherapies using corticosteroid, interferon beta, azathioprine, cyclophosphamide, Cyclosporin A, Mycophenolate Mofetil or a combination of these drugs
  • Extended Disability Status Score 3-8.
  • Normal range for white-blood-cell count (more than 4×109/L), neutrophil count (more than 2×109/L), and platelet count (more than 100×109/L).

Exclusion Criteria:

  • Cardiac risk factors (e.g history of congestive heart failure and left ventricular ejection fraction (LVEF) < 50%
  • Systemic diseases such as lupus, Sjogren's syndrome, anti-phospholipid antibody syndrome, sarcoidosis, rheumatoid arthritis, or vitamin B12 deficiency
  • Previous treatment with mitoxantrone or anthracyclines
  • Pregnant or planning to be pregnant
  • Patients with severe liver disorders (WHO grade 4)

Sites / Locations

  • Department of Neurology, Xuanwu Hospital, Capital Medical UniversityRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

MITO, annual relapse rate, safety

Arm Description

For refractory NMO patients aged 18-55, the initial dose 12 mg/m2 mitoxantrone was administered over a five day course every 3 months for 2 years (a total of eight courses). The initial dose was reduced to 9 mg/m2 if the preinfusion white-blood-cell count was 3.0-3.99 ×109/L,and to 6 mg/m2 if the white-blood-cell count was 2.0-2.99 ×109/L. No infusion if the white-blood-cell count was less than 2.0×109/L. The initial dose was reduced to 10 mg/m2 for nonhaematological toxic effects of WHO grade 2-3. Subsequent dose after 3 month was reduced to 10 mg/m2 for infections that occurred within 3 weeks of a previous infusion accompanied by a white-blood-cell count below 2×109/L, or to 8 mg/m2 for infections accompanied by white-blood-cell count of less than 1×109/L.

Outcomes

Primary Outcome Measures

annual relapse rate (ARR)
ARR is defined as the number of confirmed relapses in a year. The number of annual relapse rate was used as parameters of effectiveness and was compared between premitoxantrone and postmitoxantrone treatment during the follow-up period.
EDSS
Expanded Disability Status Scale (EDSS) scores was used as parameters of effectiveness and was compared between premitoxantrone and postmitoxantrone treatment during the follow-up period.

Secondary Outcome Measures

Changes in LVEF
- Assessment of cardiac function: Changes in LVEF by transthoracic echocardiography and determination of cardiac side effects by ECG and by measurement of CK-MB, Troponin and BNP.
blood cell count
- Assessment of hematological system: Monitoring blood cell count regularly. Considering marrow puncture if necessary.
Flow cytometric analysis
Immunofluorescent staining of wholeblood samples were performed of blood drawing using antibodies against CD3/CD4/CD8/CD19/CD20/CD56 with isotype controls, followed by lysis of red blood cells and immediate acquisition and analysis by flow cytometry.

Full Information

First Posted
September 3, 2013
Last Updated
December 19, 2013
Sponsor
Xuanwu Hospital, Beijing
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1. Study Identification

Unique Protocol Identification Number
NCT02021825
Brief Title
Efficacy and Safety of Mitoxantrone in Patients With Refractory Neuromyelitis Optica and Spectrum Disorders
Official Title
Efficacy and Safety of Mitoxantrone in Patients With Refractory Neuromyelitis Optica and Spectrum Disorders
Study Type
Interventional

2. Study Status

Record Verification Date
December 2013
Overall Recruitment Status
Unknown status
Study Start Date
March 2009 (undefined)
Primary Completion Date
December 2014 (Anticipated)
Study Completion Date
December 2015 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Xuanwu Hospital, Beijing

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The treatment protocol consisted of 12 mg/m2 MITO intravenous infusions every 3 months for 2 years. Dosage was adjusted according to side effects. Neurological assessment including the determination of the Expanded Disability Status Scale (EDSS) score and ophthalmologic evaluations were performed every 3 months and during relapses. Flow cytometric analysis, brain and spinal cord MRI was performed at baseline, 6, 12, 18, and 24 months.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuromyelitis Optica, Neuromyelitis Optica Spectrum Disorders
Keywords
mitoxantrone, neuromyelitis optica, relapse

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
50 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
MITO, annual relapse rate, safety
Arm Type
Other
Arm Description
For refractory NMO patients aged 18-55, the initial dose 12 mg/m2 mitoxantrone was administered over a five day course every 3 months for 2 years (a total of eight courses). The initial dose was reduced to 9 mg/m2 if the preinfusion white-blood-cell count was 3.0-3.99 ×109/L,and to 6 mg/m2 if the white-blood-cell count was 2.0-2.99 ×109/L. No infusion if the white-blood-cell count was less than 2.0×109/L. The initial dose was reduced to 10 mg/m2 for nonhaematological toxic effects of WHO grade 2-3. Subsequent dose after 3 month was reduced to 10 mg/m2 for infections that occurred within 3 weeks of a previous infusion accompanied by a white-blood-cell count below 2×109/L, or to 8 mg/m2 for infections accompanied by white-blood-cell count of less than 1×109/L.
Intervention Type
Drug
Intervention Name(s)
Mitoxantrone
Other Intervention Name(s)
Novantrone
Intervention Description
The treatment protocol consisted of 12 mg/m2 MITO intravenous infusions every 3 months for 2 years. Dosage was adjusted according to side effects.
Primary Outcome Measure Information:
Title
annual relapse rate (ARR)
Description
ARR is defined as the number of confirmed relapses in a year. The number of annual relapse rate was used as parameters of effectiveness and was compared between premitoxantrone and postmitoxantrone treatment during the follow-up period.
Time Frame
one year
Title
EDSS
Description
Expanded Disability Status Scale (EDSS) scores was used as parameters of effectiveness and was compared between premitoxantrone and postmitoxantrone treatment during the follow-up period.
Time Frame
six months
Secondary Outcome Measure Information:
Title
Changes in LVEF
Description
- Assessment of cardiac function: Changes in LVEF by transthoracic echocardiography and determination of cardiac side effects by ECG and by measurement of CK-MB, Troponin and BNP.
Time Frame
six months
Title
blood cell count
Description
- Assessment of hematological system: Monitoring blood cell count regularly. Considering marrow puncture if necessary.
Time Frame
three months
Title
Flow cytometric analysis
Description
Immunofluorescent staining of wholeblood samples were performed of blood drawing using antibodies against CD3/CD4/CD8/CD19/CD20/CD56 with isotype controls, followed by lysis of red blood cells and immediate acquisition and analysis by flow cytometry.
Time Frame
six months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
55 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Recurrent longitudinal myelitis (>3 segments of spinal cord involvement by MRI) with or without recurrent ON (unilateral or bilateral) but with normal brain MRI and positive serological NMO IgG antibody. Recurrent longitudinal myelitis (>3 segments of spinal cord involvement by MRI) with or without spatially limited brain lesion and positive serological NMO IgG antibody. NMO, fulfilled Wingerchuk 2006 Criteria for NMO. Patient presented at least 2 relapses during the 12 months preceding the start of mitoxantrone therapy, despite immunotherapies using corticosteroid, interferon beta, azathioprine, cyclophosphamide, Cyclosporin A, Mycophenolate Mofetil or a combination of these drugs Extended Disability Status Score 3-8. Normal range for white-blood-cell count (more than 4×109/L), neutrophil count (more than 2×109/L), and platelet count (more than 100×109/L). Exclusion Criteria: Cardiac risk factors (e.g history of congestive heart failure and left ventricular ejection fraction (LVEF) < 50% Systemic diseases such as lupus, Sjogren's syndrome, anti-phospholipid antibody syndrome, sarcoidosis, rheumatoid arthritis, or vitamin B12 deficiency Previous treatment with mitoxantrone or anthracyclines Pregnant or planning to be pregnant Patients with severe liver disorders (WHO grade 4)
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Huiqing Dong, Doctor
Phone
+86-18611786966
Email
shshtt@sina.com
First Name & Middle Initial & Last Name or Official Title & Degree
Zheng Liu, Doctor
Phone
+86-13910320552
Email
lzwcy2003@aliyun.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Huiqing Dong, Doctor
Organizational Affiliation
Department of Neurology, Xuanwu Hospital, Capital Medical University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Neurology, Xuanwu Hospital, Capital Medical University
City
Beijing
State/Province
Beijing
ZIP/Postal Code
100053
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Zheng Liu, Doctor
Phone
0086-13910320552
Email
lzwcy2003@aliyun.com
First Name & Middle Initial & Last Name & Degree
Huiqing Dong, Doctor

12. IPD Sharing Statement

Citations:
PubMed Identifier
12504397
Citation
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.
Results Reference
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PubMed Identifier
16095713
Citation
Neuhaus O, Kieseier BC, Hartung HP. Therapeutic role of mitoxantrone in multiple sclerosis. Pharmacol Ther. 2006 Jan;109(1-2):198-209. doi: 10.1016/j.pharmthera.2005.07.002. Epub 2005 Aug 10.
Results Reference
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PubMed Identifier
21149806
Citation
Kim SH, Kim W, Park MS, Sohn EH, Li XF, Kim HJ. Efficacy and safety of mitoxantrone in patients with highly relapsing neuromyelitis optica. Arch Neurol. 2011 Apr;68(4):473-9. doi: 10.1001/archneurol.2010.322. Epub 2010 Dec 13.
Results Reference
background
PubMed Identifier
16831964
Citation
Weinstock-Guttman B, Ramanathan M, Lincoff N, Napoli SQ, Sharma J, Feichter J, Bakshi R. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease). Arch Neurol. 2006 Jul;63(7):957-63. doi: 10.1001/archneur.63.7.957.
Results Reference
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Efficacy and Safety of Mitoxantrone in Patients With Refractory Neuromyelitis Optica and Spectrum Disorders

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