SID-GBS
(2021)Objective
To evaluate whether a second intravenous immunoglobulin dose (SID) is effective in patients with Guillain-Barré syndrome who have a poor predicted prognosis after standard IVIg treatment
Study Summary
• SID was associated with significantly more serious adverse events (51% vs 23%; P=0.005), including thromboembolic complications
• All 4 deaths occurred in the SID group; no secondary outcomes showed benefit
Intervention
Second IVIg dose (Nanogam 2 g/kg over 5 days) vs placebo (albumin 4%) administered 7-9 days after start of standard IVIg treatment; all patients received standard IVIg (2 g/kg over 5 days) first
Inclusion Criteria
Patients ≥12 years with GBS requiring IVIg treatment; poor prognosis defined as modified Erasmus GBS Outcome Score (mEGOS) ≥6 at day 7-9
Study Design
Arms: Second IVIg dose (2 g/kg over 5 days) vs Placebo (albumin 4%, 8 mL/kg over 5 days)
Patients per Arm: 49 SID, 44 placebo (modified ITT); 93 total with poor prognosis randomized
Outcome
• Serious adverse events significantly higher with SID (51% vs 23%; P=0.005), including thromboembolic events
• All 4 deaths occurred in SID group; no benefit in any secondary endpoint
Bottom Line
A second IVIg course in GBS patients with poor prognosis does not provide clinical benefit and is associated with significantly more serious adverse events, including thromboembolic complications. All 4 deaths occurred in the SID group. This trial provides strong evidence against routine use of a second IVIg course in GBS patients with poor prognosis.
Major Points
- First randomized, placebo-controlled, double-blind trial of second IVIg course in GBS with poor prognosis
- Primary endpoint not met: No significant difference in GBS disability score at 4 weeks (adjusted OR 1.4; 95% CI 0.6-3.3; P=0.45)
- No benefit in any secondary outcomes including disability at weeks 8, 12, 26, MRC sumscore, ONLS, or duration of ventilation
- Serious adverse events significantly higher with SID (51% vs 23%; OR 3.54; P=0.005)
- Thromboembolic events more common with SID: pulmonary embolism (2 vs 0), coronary ischemia (1 vs 1), asystole (2 vs 0)
- All 4 deaths occurred in SID group (at 13-24 weeks post-randomization)
- SID maintained higher serum IgG levels longer (34 vs 17 g/L at 2 weeks) but this did not improve outcomes
- 85% of patients were still deteriorating at day 7-9 despite standard IVIg, indicating severe disease
- Prespecified subgroup analyses showed no benefit in any subgroup including those with highest mEGOS or demyelinating subtype
- Results argue against current practice where ~25% of severe GBS patients receive second IVIg course
Study Design
- Study Type
- Phase 3, randomized, double-blind, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; IVIg bags concealed with aluminum foil, opaque connecting lines; patients, outcome adjudicators, monitors, and steering committee masked
- Sample Size
- 93
- Follow-up
- 26 weeks
- Centers
- 59
- Countries
- Netherlands
Primary Outcome
Definition: GBS disability score at 4 weeks after start of standard IVIg (7-point scale: 0=no symptoms to 6=death)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - (0.6-3.3) | 0.45 |
Limitations & Criticisms
- Relatively small sample size with wide confidence intervals
- Baseline imbalance in prognostic factors (SID group older, more preceding diarrhoea)
- Long enrollment period (>8 years) though treatment standards unchanged
- Selected only poor prognosis patients; results may not apply to all GBS
- 4 patients excluded post-randomization (2 alternative diagnoses, 2 withdrew)
- Cannot exclude very small beneficial effect below detection threshold
- Acute-onset CIDP diagnosed in 4 patients during follow-up (known confounder)
- Pre-existing vascular risk factors were exclusion criterion limiting generalizability
- Single country (Netherlands) study
Citation
Lancet Neurol 2021;20:275-283