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TANGO

Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial

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Year of Publication: 2020

Authors: Zhang C, Zhang M, Qiu W, ..., Shi FD; TANGO Study Investigators

Journal: Lancet Neurology

Citation: Lancet Neurol 2020;19(5):391-401

Link: https://doi.org/10.1016/S1474-4422(20)30070-3

PDF: https://www.thelancet.com/action/showPdf...4422(20)30070-3

Clinical Question

Does monthly IV tocilizumab reduce relapse risk compared to daily oral azathioprine in highly relapsing neuromyelitis optica spectrum disorder?

Bottom Line

In adults with highly relapsing NMOSD, monthly IV tocilizumab 8 mg/kg reduced time to first relapse by 76% compared with oral azathioprine (2-3 mg/kg/d) over a median 60-week follow-up (HR 0.236; 95% CI 0.107-0.522; p=0.0004), with 14% vs 47% relapse rates. Established tocilizumab as an effective alternative to azathioprine in highly relapsing NMOSD.

Major Points

  • Phase 2 open-label multicenter randomized trial at 6 hospitals in China
  • 118 adults with highly relapsing NMOSD (≥2 relapses in preceding 12 months) randomized 1:1
  • Enrollment November 2017 to August 2018
  • Tocilizumab 8 mg/kg IV every 4 weeks vs oral azathioprine 2-3 mg/kg/d
  • Primary endpoint: time to first relapse
  • Secondary: relapse rates, EDSS progression, pain (short-form Brief Pain Inventory), MRI activity
  • Median follow-up ~60 weeks
  • Time to first relapse: HR 0.236 (95% CI 0.107-0.522); p=0.0004 favoring tocilizumab
  • Relapse rates: 14% (tocilizumab) vs 47% (azathioprine)
  • Annualized relapse rate significantly lower with tocilizumab
  • EDSS progression and pain scores favored tocilizumab
  • MRI activity (new/enlarging T2 lesions, gadolinium-enhancing lesions) reduced with tocilizumab
  • Serious infections: similar rates between arms
  • Transaminitis and lipid elevations more common with tocilizumab (expected)
  • Demonstrated IL-6 blockade as effective alternative to azathioprine in highly relapsing NMOSD
  • Bridged the therapeutic landscape to approved agents (eculizumab 2019, inebilizumab 2020, satralizumab 2020)

Design

Study Type: Phase 2 open-label multicenter randomized active-controlled trial

Randomization: 1

Blinding: Open-label

Enrollment Period: November 1, 2017 - August 3, 2018

Follow-up Duration: Median ~60 weeks

Centers: 6

Countries: China

Sample Size: 118

Analyzed: 118

Analysis: Intention-to-treat; Kaplan-Meier; log-rank

Inclusion Criteria

  • Adults ≥18 years
  • NMOSD per 2015 international consensus criteria
  • Seropositive (AQP4-IgG+) or seronegative
  • Highly relapsing: ≥2 relapses in preceding 12 months
  • EDSS ≤7.5

Exclusion Criteria

  • Prior use of monoclonal antibodies within 6 months
  • Active infection
  • Severe hepatic or renal dysfunction
  • Pregnancy or breastfeeding
  • Other significant comorbidities

Baseline Characteristics

CharacteristicControlActive
N5959
Age median~43~43
Sex female~90%~90%
AQP4+ prop~85%~85%
Prior relapses (median)33

Arms

FieldControlTocilizumab
N5959
InterventionOral azathioprine 2-3 mg/kg/dTocilizumab 8 mg/kg IV every 4 weeks
DurationMedian ~60 weeksMedian ~60 weeks

Outcomes

OutcomeTypeControlInterventionHR / OR / RRP-value
Time to first relapsePrimary47% relapsed (azathioprine)14% relapsed (tocilizumab)0.236p=0.0004
Annualized relapse rateSecondaryHigher with azathioprineSubstantially lower with tocilizumabSignificant favorable
EDSS progressionSecondaryMore progression with azathioprineLess progression with tocilizumabFavorable
Pain score (Brief Pain Inventory)SecondaryBaseline painImprovement with tocilizumabFavorable
New or enlarging T2 MRI lesionsSecondaryMore with azathioprineReduced with tocilizumabFavorable
Gadolinium-enhancing MRI lesionsSecondaryMore with azathioprineReduced with tocilizumabFavorable
Any adverse eventAdverseComparableComparableSimilar
Serious infectionAdverseSimilar rateSimilar rateNo signal
Upper respiratory infectionAdverseModerateModerateSimilar
Liver enzyme elevation (ALT/AST)AdverseLowMore common with tocilizumabExpected class effect
Lipid elevations (cholesterol, triglycerides)AdverseLowMore common with tocilizumabExpected class effect
NeutropeniaAdverseLowUncommonUncommon
Serious AEAdverseLowLowNo significant imbalance
DeathAdverseRareRareNo deaths attributed to study drug

Subgroup Analysis

Benefit of tocilizumab over azathioprine was consistent across AQP4+ and AQP4- subgroups — notable because the later approved NMOSD drugs (eculizumab, inebilizumab, satralizumab) are restricted to AQP4+ disease. Tocilizumab's efficacy in seronegative patients is a practical advantage in settings where these newer agents are cost-restricted or unavailable.

Criticisms

  • Open-label design (blinding not feasible due to oral vs IV administration)
  • Single-country (China) enrollment limits external generalizability
  • Phase 2 scale (N=118) and median ~60-week follow-up
  • Active comparator (azathioprine) has known inadequacy in highly relapsing NMOSD
  • Did not directly compare with approved monoclonal antibodies (eculizumab, inebilizumab, satralizumab)
  • Cost and biosimilar availability may limit uptake in resource-limited settings

Funding

National Natural Science Foundation of China

Based on: TANGO (Lancet Neurology, 2020)

Authors: Zhang C, Zhang M, Qiu W, ..., Shi FD; TANGO Study Investigators

Citation: Lancet Neurol 2020;19(5):391-401

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