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Tocilizumab vs Azathioprine in Neuromyelitis Optica Spectrum Disorders (TANGO)

Primary Purpose

Neuromyelitis Optica Spectrum Disorders, Neuromyelitis Optica

Status
Completed
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Tocilizumab Injection
Azathioprine
Sponsored by
Tianjin Medical University General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neuromyelitis Optica Spectrum Disorders

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male or female patients ≥ 18 years old
  2. Diagnosis of NMO or NMO spectrum disorder
  3. Clinical evidence of at least 2 relapses in last 12 months or 3 relapses in the last 24 months
  4. Able and willing to give written informed consent and comply with the requirements of the study protocol.
  5. EDSS <= 7.5 (8 in special circumstances)
  6. Men and women of reproductive potential must agree to use a highly effective method of birth control from screening to 6 months after final dose of the investigational product.

Exclusion Criteria:

  1. Current evidence or known history of clinically significant infection (Herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus,human immunodeficiency virus, Hepatitis viruses, Syphilis, etc)
  2. Pregnant, breastfeeding, or child-bearing potential during the course of the study
  3. Patients will not participate in any other clinical therapeutic study or will not have participated in any other experimental treatment study within 30 days of screening
  4. Participation in another interventional trial within the last 3 months
  5. Heart or kidney insufficiency
  6. Tumor disease currently or within last 5 years
  7. Clinically relevant liver, kidney or bone marrow function disorder
  8. Intolerance of azathioprine or previous relapses on azathioprine treatment
  9. Receipt of rituximab or any experimental B-cell depleting agent within 6 months prior screening and B-cells below the lower limit of normal.

Sites / Locations

  • Tianjin Medical University General Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Tocilizumab

Azathioprine

Arm Description

Tocilizumab Injection (ACTEMRA®) , a IL-6 receptor blockade

Imuran

Outcomes

Primary Outcome Measures

Time to first relapse
An acute attack was defined as a new neurological worsening lasting for at least 24 hours and occurring more than 30 days after the previous attack.

Secondary Outcome Measures

Proportion of patients who experience relapse-free
To record whether the patients had no relapses in the follow-ups
Worsening in EDSS
The Expanded Disability Status Scale (EDSS) is a rating system that is frequently used for classifying and standardizing the severity and progression. EDSS ranges from 0 to 10.
Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks
Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks
Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death).
Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks
Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death). Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 24 Weeks
Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death).
Percentage Change in Spectral-domain Optical Coherence Tomography (SD-OCT) Average Retinal Nerve Fiber Layer (RNFL) Thickness at Week 60
Adjusted mean percentage change in thickness of the RNFL at Week 60 for the affected eye from the baseline as determined by SD-OCT.
Percentage change in SD-OCT Average Retinal Ganglion Cell Layer/Inner Plexiform Retinal Layer (RGCL/IPL) at Week 60
Adjusted mean change in thicknesses of the RGCL/IPL at Week 60 for the affected eye from the baseline as determined by segmentation of SD-OCT.
Change in Low-contrast Letter Acuity (LCLA) at Week 60
Adjusted mean change in LCLA at Week 60 from baseline as determined by 2.5% low contrast Sloan letter charts, adjusted for the baseline LCLA value.
Change in High-contrast Letter Acuity (HCLA) at Week 60
Adjusted mean change in HCLA at Week 60 from baseline as determined by 100% high contrast Sloan letter charts, adjusted for the baseline HCLA value.
Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI)
The total number of new and/or enlarging T2 lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 12, 36, and 60
Overall safety and tolerability of tocilizumab or azathioprine
Adverse events related to tocilizumab or azathioprine are recorded.
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Treatment-emergent adverse events, treatment-emergent serious adverse events (TESAEs), including laboratory measurements as well as their changes or shift from baseline over time
Counts of peripheral blood B cell subsets
Compare peripheral blood plasma cells before and one year after initial intervention
Determination of serum immunoglobulins
Compare immunoglobulins before and one year after initial intervention
Determination of serum AQP4 antibodies
Compare serum AQP4-ab titers before and one year after initial intervention
Determination of serum cytokines
Compare serum cytokines before and one year after initial intervention

Full Information

First Posted
November 10, 2017
Last Updated
October 22, 2019
Sponsor
Tianjin Medical University General Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT03350633
Brief Title
Tocilizumab vs Azathioprine in Neuromyelitis Optica Spectrum Disorders
Acronym
TANGO
Official Title
Safety and Efficacy of Tocilizumab Versus Azathioprine in Neuromyelitis Optica Spectrum Disorders: a Randomized, Controlled, Open-label, Phase 2 Trial
Study Type
Interventional

2. Study Status

Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
November 1, 2017 (Actual)
Primary Completion Date
September 1, 2019 (Actual)
Study Completion Date
September 1, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Tianjin Medical University General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
In neuromyelitis optica spectrum disorder (NMOSD),interleukin-6 (IL-6) may play an important role in facilitating plasma cells to produce pathological aquaporin 4 (AQP4) autoantibody. Inhibition of IL-6 signaling pathway by Tocilizumab (ACTEMRA®), a humanized monoclonal antibody may have shown beneficial clinical effects in a few patients with NMOSD. Larger scale clincial trials may be needed to observe its efficacy and safety. Here, by choosing azathioprine, one of the most frequently used medication in case of relapses, the investigators compare the safety and efficacy of tocilizumab in preventing NMOSD attacks.
Detailed Description
The investigators primarily aim to observe the time to first relapse from initiation of tocilizumab or azathioprine treatment. The proportion of participants who experience relapse-free in one year follow-up will be compared. The secondary outcomes are to determine: The safety profile of tocilizumab and azathioprine in participants with NMO and whether tocilizumab improves visual function, Expanded Disability Status Scale (EDSS), et al.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Neuromyelitis Optica Spectrum Disorders, Neuromyelitis Optica

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2, Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
118 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tocilizumab
Arm Type
Experimental
Arm Description
Tocilizumab Injection (ACTEMRA®) , a IL-6 receptor blockade
Arm Title
Azathioprine
Arm Type
Active Comparator
Arm Description
Imuran
Intervention Type
Drug
Intervention Name(s)
Tocilizumab Injection
Other Intervention Name(s)
ACTEMRA®
Intervention Description
Tocilizumab Injection will be intravenously administered with a dose of 8 mg/kg every 4 weeks.
Intervention Type
Drug
Intervention Name(s)
Azathioprine
Other Intervention Name(s)
Imuran
Intervention Description
Azathioprine will be orally given at a dose of 2-3 mg/kg/d
Primary Outcome Measure Information:
Title
Time to first relapse
Description
An acute attack was defined as a new neurological worsening lasting for at least 24 hours and occurring more than 30 days after the previous attack.
Time Frame
From baseline to one year after
Secondary Outcome Measure Information:
Title
Proportion of patients who experience relapse-free
Description
To record whether the patients had no relapses in the follow-ups
Time Frame
From baseline to 60 weeks
Title
Worsening in EDSS
Description
The Expanded Disability Status Scale (EDSS) is a rating system that is frequently used for classifying and standardizing the severity and progression. EDSS ranges from 0 to 10.
Time Frame
Worsening from baseline in EDSS to 60 weeks
Title
Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks
Description
Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death due to multiple sclerosis). Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 12 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Time Frame
From baseline to 60 weeks
Title
Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks
Description
Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death).
Time Frame
From baseline to 60 weeks
Title
Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks
Description
Disability progression was defined as an increase in the Expanded Disability Status Scale (EDSS) score of: A) >=1.0 point from the baseline EDSS score when the baseline score was less than or equal to (<=) 5.5 B) >=0.5 point from the baseline EDSS score when the baseline score was >5.5 The EDSS scale ranges from 0 (normal neurological exam) to 10 (death). Disability progression was considered confirmed when the increase in the EDSS was confirmed at a regularly scheduled visit at least 24 weeks after the initial documentation of neurological worsening. Participants who had initial disability progression with no confirmatory EDSS assessment and who were on treatment at time of clinical cut-off date were censored at the date of their last EDSS assessment.
Time Frame
From baseline to 60 weeks
Title
Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 24 Weeks
Description
Disability improvement was assessed only for the subgroup of participants with a baseline EDSS score of >= 2.0. It was defined as a reduction in EDSS score of: A) >=1.0 from the baseline EDSS score when the baseline score was >=2 and <=5.5 B) >= 0.5 when the baseline EDSS score > 5.5. The EDSS scale ranges from 0 (normal neurological exam) to 10 (death).
Time Frame
From baseline to 60 weeks
Title
Percentage Change in Spectral-domain Optical Coherence Tomography (SD-OCT) Average Retinal Nerve Fiber Layer (RNFL) Thickness at Week 60
Description
Adjusted mean percentage change in thickness of the RNFL at Week 60 for the affected eye from the baseline as determined by SD-OCT.
Time Frame
From baseline to 60 weeks
Title
Percentage change in SD-OCT Average Retinal Ganglion Cell Layer/Inner Plexiform Retinal Layer (RGCL/IPL) at Week 60
Description
Adjusted mean change in thicknesses of the RGCL/IPL at Week 60 for the affected eye from the baseline as determined by segmentation of SD-OCT.
Time Frame
From baseline to 60 weeks
Title
Change in Low-contrast Letter Acuity (LCLA) at Week 60
Description
Adjusted mean change in LCLA at Week 60 from baseline as determined by 2.5% low contrast Sloan letter charts, adjusted for the baseline LCLA value.
Time Frame
From baseline to 60 weeks
Title
Change in High-contrast Letter Acuity (HCLA) at Week 60
Description
Adjusted mean change in HCLA at Week 60 from baseline as determined by 100% high contrast Sloan letter charts, adjusted for the baseline HCLA value.
Time Frame
From baseline to 60 weeks
Title
Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI)
Description
The total number of new and/or enlarging T2 lesions for all participants in the treatment group was calculated as the sum of the individual number of lesions at Weeks 12, 36, and 60
Time Frame
From baseline to 60 weeks
Title
Overall safety and tolerability of tocilizumab or azathioprine
Description
Adverse events related to tocilizumab or azathioprine are recorded.
Time Frame
From baseline to 60 weeks
Title
Number of Participants with Adverse Events as a Measure of Safety and Tolerability
Description
Treatment-emergent adverse events, treatment-emergent serious adverse events (TESAEs), including laboratory measurements as well as their changes or shift from baseline over time
Time Frame
From baseline to 60 weeks
Title
Counts of peripheral blood B cell subsets
Description
Compare peripheral blood plasma cells before and one year after initial intervention
Time Frame
From baseline to 60 weeks
Title
Determination of serum immunoglobulins
Description
Compare immunoglobulins before and one year after initial intervention
Time Frame
From baseline to 60 weeks
Title
Determination of serum AQP4 antibodies
Description
Compare serum AQP4-ab titers before and one year after initial intervention
Time Frame
From baseline to 60 weeks
Title
Determination of serum cytokines
Description
Compare serum cytokines before and one year after initial intervention
Time Frame
From baseline to 60 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female patients ≥ 18 years old Diagnosis of NMO or NMO spectrum disorder Clinical evidence of at least 2 relapses in last 12 months or 3 relapses in the last 24 months Able and willing to give written informed consent and comply with the requirements of the study protocol. EDSS <= 7.5 (8 in special circumstances) Men and women of reproductive potential must agree to use a highly effective method of birth control from screening to 6 months after final dose of the investigational product. Exclusion Criteria: Current evidence or known history of clinically significant infection (Herpes simplex virus, varicella-zoster virus, cytomegalovirus, Epstein-Barr virus,human immunodeficiency virus, Hepatitis viruses, Syphilis, etc) Pregnant, breastfeeding, or child-bearing potential during the course of the study Patients will not participate in any other clinical therapeutic study or will not have participated in any other experimental treatment study within 30 days of screening Participation in another interventional trial within the last 3 months Heart or kidney insufficiency Tumor disease currently or within last 5 years Clinically relevant liver, kidney or bone marrow function disorder Intolerance of azathioprine or previous relapses on azathioprine treatment Receipt of rituximab or any experimental B-cell depleting agent within 6 months prior screening and B-cells below the lower limit of normal.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Fu-Dong Shi, MD,PhD
Organizational Affiliation
Tianjin Medical University General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Tianjin Medical University General Hospital
City
Tianjin
State/Province
Tianjin
ZIP/Postal Code
300052
Country
China

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32333897
Citation
Zhang C, Zhang M, Qiu W, Ma H, Zhang X, Zhu Z, Yang CS, Jia D, Zhang TX, Yuan M, Feng Y, Yang L, Lu W, Yu C, Bennett JL, Shi FD; TANGO Study Investigators. Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial. Lancet Neurol. 2020 May;19(5):391-401. doi: 10.1016/S1474-4422(20)30070-3.
Results Reference
derived

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Tocilizumab vs Azathioprine in Neuromyelitis Optica Spectrum Disorders

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