PDF: CONSCIOUS-1
(2008)Objective
To assess efficacy and safety of clazosentan (endothelin receptor antagonist) at three doses in preventing vasospasm after aneurysmal subarachnoid hemorrhage
Study Summary
• No significant difference in morbidity/mortality based on local investigator assessment
• Post-hoc central review showed trend toward reduced vasospasm-related morbidity/mortality
Intervention
Intravenous clazosentan at 1, 5, or 15 mg/h versus placebo, started within 56 hours of SAH and continued up to 14 days
Inclusion Criteria
Age 18-70 years, aneurysmal SAH confirmed by DSA, diffuse or thick localized clot on CT within 48 hours, WFNS Grade 1-4
Study Design
Arms: Four arms: Placebo, Clazosentan 1 mg/h, Clazosentan 5 mg/h, Clazosentan 15 mg/h
Patients per Arm: Placebo n=96, 1 mg/h n=108, 5 mg/h n=111, 15 mg/h n=98
Outcome
• Secondary: No significant effect on locally-assessed morbidity/mortality
• Adverse events: Increased pulmonary complications, hypotension, and anemia with clazosentan
Bottom Line
Clazosentan significantly reduced moderate and severe angiographic vasospasm in a dose-dependent manner (65% relative risk reduction with 15 mg/h), with a trend toward reduction in vasospasm-related morbidity and mortality on central review. The drug increased pulmonary complications, hypotension, and anemia, but adverse effects were generally manageable.
Major Points
- This was the largest trial to date using angiographic vasospasm as primary endpoint and the first to show significant reduction
- All three doses (1, 5, and 15 mg/h) significantly reduced moderate/severe vasospasm compared to placebo
- The 15 mg/h dose achieved 65% relative risk reduction (vasospasm rate: 23% vs 66% placebo, P<0.0001)
- No significant effect on locally-assessed morbidity/mortality endpoint
- Post-hoc central review showed trend toward reduced vasospasm-related morbidity/mortality (29% with 15 mg/h vs 39% placebo)
- Discrepancy between local and central assessment emphasized need for consistent evaluation of vasospasm-related complications
- Adverse events included increased pulmonary complications, hypotension, and anemia in clazosentan groups
- Results support endothelin's role in vasospasm pathogenesis and justified Phase 3 trial (CONSCIOUS-2)
Study Design
- Study Type
- Phase 2b randomized, double-blind, placebo-controlled, dose-finding trial
- Randomization
- Yes
- Blinding
- Double-blind - all investigators, patients, and individuals responsible for conduct, monitoring, and analysis were blinded except pharmacist and independent pharmacy monitor
- Sample Size
- 413
- Follow-up
- 12 weeks post-aneurysm rupture
- Centers
- 52
- Countries
- Austria, Canada, Finland, France, Germany, Israel, Italy, Sweden, Switzerland, United Kingdom, United States
Primary Outcome
Definition: Moderate or severe angiographic vasospasm within 14 days of SAH based on centrally read, blinded evaluation of DSA at baseline and day 7-11 post-SAH. Moderate defined as 34-66% arterial diameter reduction, severe as 67-100% reduction
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 56/85 (66%, 95% CI 55-76%) | 1 mg/h: 41/95 (43%, 95% CI 33-54%); 5 mg/h: 37/95 (39%, 95% CI 29-50%); 15 mg/h: 18/79 (23%, 95% CI 14-34%) | - (1 mg/h RRR 34% (95% CI 14-50%); 5 mg/h RRR 41% (95% CI 21-56%); 15 mg/h RRR 65% (95% CI 47-78%)) | 1 mg/h: P=0.0027; 5 mg/h: P=0.0003; 15 mg/h: P<0.0001 |
Limitations & Criticisms
- No significant effect on locally-assessed morbidity/mortality endpoint despite marked reduction in vasospasm
- Discrepancy between local and central assessment of vasospasm-related complications
- Study not powered to detect treatment effect on functional outcome measures like Glasgow Outcome Scale
- Increased adverse events including pulmonary complications, hypotension, and anemia in clazosentan groups
- Higher mortality in clazosentan groups (4-8%) versus placebo (4%), with preponderance of intraoperative complications
- Three patients discontinued study drug due to hypotension (all on clazosentan)
- Phase 2b trial, not definitive for clinical outcomes - required Phase 3 trial for confirmation
- Potential fluid retention as class effect of endothelin receptor antagonists may have contributed to pulmonary complications
- Only 35% of screened patients were recruited, potential selection bias
- Some patients excluded from per-protocol analysis due to protocol violations
Citation
Stroke. 2008;39:3015-3021