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 compared with oral azathioprine (2-3 mg/kg/d) over a minimum planned 60-week treatment period (HR 0.236; 95% CI 0.107-0.518; p<0.0001), with 14% (8/59) vs 47% (28/59) 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, or 3 relapses in preceding 24 months with ≥1 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
- Minimum planned treatment duration: 60 weeks
- Time to first relapse (FAS): HR 0.236 (95% CI 0.107-0.518); p<0.0001 favoring tocilizumab
- Relapse rates: 14% (8/59, tocilizumab) vs 47% (28/59, azathioprine)
- Median time to first relapse: 78.9 weeks (tocilizumab) vs 56.7 weeks (azathioprine); p=0.0026
- Per-protocol analysis: HR 0.188 (95% CI 0.076-0.463); p<0.0001
- 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 (central review committee, EDSS raters, laboratory personnel, and radiologists masked)
Enrollment Period: November 1, 2017 - August 3, 2018
Follow-up Duration: Minimum planned 60 weeks
Centers: 6
Countries: China
Sample Size: 118
Analyzed: 118
Analysis: Full analysis set (n=118); per-protocol (n=108); 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, or 3 relapses in preceding 24 months with ≥1 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 | Minimum planned 60 weeks | Minimum planned 60 weeks |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Time to first relapse (full analysis set) | Primary | 47% (28/59) relapsed (azathioprine); median time to first relapse 56.7 weeks | 14% (8/59) relapsed (tocilizumab); median time to first relapse 78.9 weeks | 0.236 | p<0.0001 |
| Time to first relapse (per-protocol) | Secondary | 29/52 relapse-free (56%) | 50/56 relapse-free (89%) | HR 0.188 (95% CI 0.076-0.463) | p<0.0001 |
| 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 | 56/59 (95%) | 57/59 (97%) | Similar | |
| Treatment-associated adverse events | Adverse | 49/59 (83%) | 36/59 (61%) | Lower with tocilizumab | |
| 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 | 1/59 (not treatment-related) | 1/59 (not treatment-related) | No deaths attributed to study drug |
Subgroup Analysis
Prespecified subgroups by concomitant autoimmune disease status. Among patients without concomitant autoimmune diseases: 3/34 (9%) tocilizumab vs 13/37 (35%) azathioprine relapsed. Among patients with concomitant autoimmune diseases: 5/25 (20%) tocilizumab vs 15/22 (68%) azathioprine relapsed (HR 0.192, 95% CI 0.070-0.531; p=0.0004). Benefit was consistent across subgroups.
Criticisms
- Open-label design (blinding not feasible due to oral vs IV administration; central adjudicators/EDSS raters/radiologists were masked)
- Single-country (China) enrollment limits external generalizability
- Phase 2 scale (N=118) and minimum planned 60-week treatment
- 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
Tianjin Medical University; Advanced Innovation Center for Human Brain Protection; National Key Research and Development Program of China; National 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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