TANGO
Safety and efficacy of tocilizumab versus azathioprine in highly relapsing neuromyelitis optica spectrum disorder (TANGO): an open-label, multicentre, randomised, phase 2 trial
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
PDF: 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
| Characteristic | Control | Active |
|---|---|---|
| N | 59 | 59 |
| Age median | ~43 | ~43 |
| Sex female | ~90% | ~90% |
| AQP4+ prop | ~85% | ~85% |
| Prior relapses (median) | 3 | 3 |
Arms
| Field | Control | Tocilizumab |
|---|---|---|
| N | 59 | 59 |
| Intervention | Oral azathioprine 2-3 mg/kg/d | Tocilizumab 8 mg/kg IV every 4 weeks |
| Duration | Median ~60 weeks | Median ~60 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Time to first relapse | Primary | 47% relapsed (azathioprine) | 14% relapsed (tocilizumab) | 0.236 | p=0.0004 |
| Annualized relapse rate | Secondary | Higher with azathioprine | Substantially lower with tocilizumab | Significant favorable | |
| EDSS progression | Secondary | More progression with azathioprine | Less progression with tocilizumab | Favorable | |
| Pain score (Brief Pain Inventory) | Secondary | Baseline pain | Improvement with tocilizumab | Favorable | |
| New or enlarging T2 MRI lesions | Secondary | More with azathioprine | Reduced with tocilizumab | Favorable | |
| Gadolinium-enhancing MRI lesions | Secondary | More with azathioprine | Reduced with tocilizumab | Favorable | |
| Any adverse event | Adverse | Comparable | Comparable | Similar | |
| Serious infection | Adverse | Similar rate | Similar rate | No signal | |
| Upper respiratory infection | Adverse | Moderate | Moderate | Similar | |
| Liver enzyme elevation (ALT/AST) | Adverse | Low | More common with tocilizumab | Expected class effect | |
| Lipid elevations (cholesterol, triglycerides) | Adverse | Low | More common with tocilizumab | Expected class effect | |
| Neutropenia | Adverse | Low | Uncommon | Uncommon | |
| Serious AE | Adverse | Low | Low | No significant imbalance | |
| Death | Adverse | Rare | Rare | No 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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