REACT
(2025)Objective
To assess the efficacy and safety of clazosentan (endothelin receptor antagonist) in preventing clinical deterioration due to delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage
Study Summary
• Clinically relevant cerebral infarcts were nonsignificantly reduced (7.4% vs 11.3%, RRR 34.1%, p=0.177)
• Rescue therapy was significantly less needed with clazosentan (10.4% vs 18.1%, RRR 42.6%)
• No benefit on 12-week functional outcome; nonsignificant trend toward worse outcome with clazosentan (poor mRS/GOSE 24.8% vs 20.1%)
Intervention
Clazosentan 15 mg/hour continuous IV infusion for up to 14 days vs placebo, both added to standard of care including nimodipine
Inclusion Criteria
Adults aged 18–70 years with angiographically confirmed ruptured saccular aneurysm secured by clipping or coiling within 72 hours, WFNS grade 1–4 post-procedure, thick and diffuse clot on admission CT (>4 mm involving ≥3 basal cisterns)
Study Design
Arms: Clazosentan 15 mg/hour IV vs Placebo
Patients per Arm: 202 clazosentan vs 204 placebo
Outcome
• Rescue therapy significantly reduced with clazosentan (RRR 42.6%, 95% CI 5.4–65.2%)
• Poor 12-week outcome nonsignificantly increased with clazosentan (24.8% vs 20.1%, RRI 25.4%)
Bottom Line
Clazosentan 15 mg/hour IV for up to 14 days did not significantly reduce clinical deterioration due to DCI (15.8% vs 17.2%, p=0.734) in high-risk aSAH patients, despite significantly reducing the need for rescue therapy by 42.6%. There was no benefit on 12-week functional outcome. The placebo DCI rate (17.2%) was much lower than the expected 28%, likely contributing to the negative result. These findings contrast with positive results in Japanese phase 3 trials that used clazosentan without concomitant nimodipine.
Major Points
- Phase 3, double-blind RCT of 406 treated patients across 74 ICUs in 15 countries
- Primary endpoint (clinical deterioration due to DCI up to day 14): 15.8% clazosentan vs 17.2% placebo, RRR 7.2% (95% CI –42.6% to 39.6%, p=0.734)
- Main secondary endpoint (clinically relevant cerebral infarction at day 16): 7.4% vs 11.3%, RRR 34.1% (95% CI –21.3% to 64.2%, p=0.177)
- Rescue therapy significantly less needed with clazosentan: 10.4% vs 18.1%, RRR 42.6% (95% CI 5.4–65.2%), confirming antivasospastic activity
- Sensitivity analysis adding rescue therapy to primary endpoint definition: RRR improved to 26.7% (95% CI –8.5% to 50.5%) but remained nonsignificant
- Poor 12-week outcome (mRS ≥3 or GOSE ≤4) nonsignificantly worse with clazosentan: 24.8% vs 20.1%, RRI 25.4% (95% CI –10.7% to 76.0%)
- After adjustment for baseline imbalances (geography, securing procedure), RRI for poor GOSE decreased to 14.0%
- Placebo DCI rate (17.2%) was much lower than the expected 28% based on CONSCIOUS 2/3 data, reducing statistical power
- Key difference from positive Japanese phase 3 trials: clazosentan was given alongside nimodipine in REACT vs without systemic vasodilators in Japanese studies
- Deaths within 24 weeks: 7/207 (3.4%) clazosentan vs 3/199 (1.5%) placebo; 1 death (brain edema) potentially related to clazosentan
- TEAEs more common with clazosentan included lung complications (25.6% vs 10.6%), edema/fluid retention (19.8% vs 4.0%), hypotension (10.1% vs 4.0%), and pulmonary edema (6.3% vs 1.0%)
- Higher premature treatment discontinuation with clazosentan (13.0% vs 5.5%)
Study Design
- Study Type
- Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind. Patients, investigators, and site personnel blinded to treatment until study closure. Study drug kits similarly packaged. Independent clinical event committee and independent radiology committee adjudicated endpoints blinded.
- Sample Size
- 406
- Follow-up
- 24 weeks post-aSAH (primary endpoint assessed at day 14; main secondary at day 16; clinical outcome at week 12)
- Centers
- 74
- Countries
- Austria, Belgium, Canada, Czechia, Denmark, Finland, France, Germany, Hungary, Israel, Italy, Poland, Spain, Sweden, USA
Primary Outcome
Definition: Occurrence of clinical deterioration due to DCI up to 14 days after study drug initiation, defined as worsening of ≥2 points on modified GCS or abbreviated NIHSS lasting ≥2 hours not entirely attributable to causes other than CVS; also met by death during 14-day period, unevaluable neurological status with rescue therapy for vasospasm, or rehospitalization for symptomatic vasospasm after early discharge
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 35/204 (17.2%) | 32/202 (15.8%) | - (–42.6% to 39.6% (for RRR)) | 0.734 |
Limitations & Criticisms
- Placebo DCI rate (17.2%) was far lower than the assumed 28%, substantially reducing statistical power despite adequate sample size
- Study was powered for 90% at 50% RRR; actual RRR was only 7.2%, suggesting either the drug is ineffective for this endpoint or the endpoint was poorly designed to capture treatment effect
- Clazosentan was given alongside nimodipine (95–99.5%), unlike positive Japanese phase 3 trials where systemic vasodilators were avoided — possible ceiling effect or pharmacological interaction
- Primary endpoint definition differed from positive Japanese studies, which included hemodynamic therapy and inotropes as rescue therapy triggers
- Japanese studies required routine angiography at day 9 for all patients, potentially improving identification of vasospasm-attributable deterioration; REACT relied more on clinical judgment
- Imbalance in surgical clipping between arms (35.6% vs 24.5%) and geographic distribution, potentially confounding outcome analyses
- Higher premature treatment discontinuation with clazosentan (13.0% vs 5.5%) may have limited drug exposure
- Notable adverse event profile: lung complications (25.6% vs 10.6%), edema/fluid retention (19.8% vs 4.0%), and pulmonary edema (6.3% vs 1.0%) without clear efficacy benefit
- Trend toward more deaths with clazosentan (7 vs 3 within 24 weeks) and worse functional outcome (24.8% vs 20.1% poor), raising safety concerns
- Nimodipine co-administration varied (95.5% clazosentan vs 99.5% placebo), introducing potential confounding
- mRS and GOSE may lack sensitivity to detect cognitive improvements relevant to aSAH survivors
- The early treatment group protocol change (discontinued after only 11 patients) introduces design instability
- Study funded by Idorsia Pharmaceuticals (clazosentan manufacturer); multiple authors with financial ties to sponsor
Citation
J Neurosurg 142:98–109, 2025