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Tocilizumab vs Azathioprine in Neuromyelitis Optica Spectrum Disorders (TANGO)

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ClinicalTrials.gov Identifier: NCT03350633
Recruitment Status : Active, not recruiting
First Posted : November 22, 2017
Last Update Posted : October 16, 2018
Sponsor:
Information provided by (Responsible Party):
Fu-Dong Shi, Tianjin Medical University General Hospital

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.


Condition or disease Intervention/treatment Phase
Neuromyelitis Optica Spectrum Disorders Neuromyelitis Optica Drug: Tocilizumab Injection Drug: Azathioprine Phase 2 Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 118 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Safety and Efficacy of Tocilizumab Versus Azathioprine in Neuromyelitis Optica Spectrum Disorders: a Randomized, Controlled, Open-label, Phase 2 Trial
Actual Study Start Date : October 15, 2017
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : June 2019


Arm Intervention/treatment
Experimental: Tocilizumab
Tocilizumab Injection (ACTEMRA®) , a IL-6 receptor blockade
Drug: Tocilizumab Injection
Tocilizumab Injection will be intravenously administered with a dose of 8 mg/kg every 4 weeks.
Other Name: ACTEMRA®

Active Comparator: Azathioprine
Imuran
Drug: Azathioprine
Azathioprine will be orally given at a dose of 2-3 mg/kg/d
Other Name: Imuran




Primary Outcome Measures :
  1. Time to first relapse [ Time Frame: From baseline to one year after ]
    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 :
  1. Proportion of patients who experience relapse-free [ Time Frame: From baseline to 60 weeks ]
    To record whether the patients had no relapses in the follow-ups

  2. Worsening in EDSS [ Time Frame: Worsening from baseline in EDSS to 60 weeks ]
    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.

  3. Time to Onset of Confirmed Disability Progression (CDP) for at Least 12 Weeks [ Time Frame: From baseline to 60 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.

  4. Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 12 Weeks [ Time Frame: From baseline to 60 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).

  5. Time to Onset of Confirmed Disability Progression (CDP) for at Least 24 Weeks [ Time Frame: From baseline to 60 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.

  6. Percentage of Participants With Confirmed Disability Improvement (CDI) for at Least 24 Weeks [ Time Frame: From baseline to 60 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).

  7. Percentage Change in Spectral-domain Optical Coherence Tomography (SD-OCT) Average Retinal Nerve Fiber Layer (RNFL) Thickness at Week 60 [ Time Frame: From baseline to 60 weeks ]
    Adjusted mean percentage change in thickness of the RNFL at Week 60 for the affected eye from the baseline as determined by SD-OCT.

  8. Percentage change in SD-OCT Average Retinal Ganglion Cell Layer/Inner Plexiform Retinal Layer (RGCL/IPL) at Week 60 [ Time Frame: From baseline to 60 weeks ]
    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.

  9. Change in Low-contrast Letter Acuity (LCLA) at Week 60 [ Time Frame: From baseline to 60 weeks ]
    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.

  10. Change in High-contrast Letter Acuity (HCLA) at Week 60 [ Time Frame: From baseline to 60 weeks ]
    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.

  11. Number of New, and/or Enlarging T2 Hyperintense Lesions as Detected by Brain Magnetic Resonance Imaging (MRI) [ Time Frame: From baseline to 60 weeks ]
    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

  12. Overall safety and tolerability of tocilizumab or azathioprine [ Time Frame: From baseline to 60 weeks ]
    Adverse events related to tocilizumab or azathioprine are recorded.

  13. Number of Participants with Adverse Events as a Measure of Safety and Tolerability [ Time Frame: From baseline to 60 weeks ]
    Treatment-emergent adverse events, treatment-emergent serious adverse events (TESAEs), including laboratory measurements as well as their changes or shift from baseline over time

  14. Counts of peripheral blood B cell subsets [ Time Frame: From baseline to 60 weeks ]
    Compare peripheral blood plasma cells before and one year after initial intervention

  15. Determination of serum immunoglobulins [ Time Frame: From baseline to 60 weeks ]
    Compare immunoglobulins before and one year after initial intervention

  16. Determination of serum AQP4 antibodies [ Time Frame: From baseline to 60 weeks ]
    Compare serum AQP4-ab titers before and one year after initial intervention

  17. Determination of serum cytokines [ Time Frame: From baseline to 60 weeks ]
    Compare serum cytokines before and one year after initial intervention



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. Receipt of rituximab or any experimental B-cell depleting agent within 6 months prior screening and B-cells below the lower limit of normal.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03350633


Locations
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China, Tianjin
Tianjin Medical University General Hospital
Tianjin, Tianjin, China, 300052
Sponsors and Collaborators
Tianjin Medical University General Hospital
Investigators
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Principal Investigator: Fu-Dong Shi, MD,PhD Tianjin Medical University General Hospital

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Responsible Party: Fu-Dong Shi, Director of Neurology Department, Tianjin Medical University General Hospital
ClinicalTrials.gov Identifier: NCT03350633     History of Changes
Other Study ID Numbers: IRB2017-YX-009
First Posted: November 22, 2017    Key Record Dates
Last Update Posted: October 16, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Neuromyelitis Optica
Disease
Pathologic Processes
Myelitis, Transverse
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Optic Neuritis
Optic Nerve Diseases
Cranial Nerve Diseases
Demyelinating Diseases
Eye Diseases
Autoimmune Diseases
Immune System Diseases
Azathioprine
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents