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Preventing Vasospasm Improves Outcome After Aneurysmal Subarachnoid Hemorrhage: Rationale and Design of CONSCIOUS-2 and CONSCIOUS-3 Trials

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Abstract

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here, we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18–75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I–IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5, 15 mg/h, or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively.

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Acknowledgments

The authors would like to thank Dr Jo Oswald, Dr Charlotte Mulcare, and Dr Catherine Jones of Watermeadow Medical for medical writing (JO, CM) and editorial assistance (CJ), which was supported by Actelion Pharmaceuticals Ltd.

Conflict of interest

R.L. Macdonald receives grant support from the Physicians Services Incorporated Foundation, is a stock holder of Edge Therapeutics, Inc., and a consultant for Actelion Pharmaceuticals Ltd; N. Kassell is a consultant for Actelion Pharmaceuticals Ltd and Edge Therapeutics; S. Mayer is a consultant for Actelion Pharmaceuticals Ltd and Edge Therapeutics; E. Keller is a consultant for Actelion Pharmaceuticals Ltd, Roche Diagnostics, Philips, and stockholder in NeMoDevices; A. Raabe is a consultant for Actelion Pharmaceuticals Ltd, BrainLAB, and Carl Zeiss; R. Higashida is a consultant for Actelion Pharmaceuticals Ltd; P. Vajkoczy is a consultant for Aesculap, Actelion Pharmaceuticals Ltd, Roche, Essex, and ELANA; A. Molyneux is a consultant for Actelion Pharmaceuticals Ltd. He is also a consultant for and stockholder in Micrus Endovascular, Inc. (and has also received presentation support); I. Wanke is a consultant for Actelion Pharmaceuticals Ltd, Boston Scientific, ev3, and BALT, and receives a departmental grant from Boston; A. Frey, A. Marr, and S. Roux are employees and stock holders of Actelion Pharmaceuticals Ltd.

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Authors and Affiliations

  1. Division of Neurosurgery, St. Michael’s Hospital, University of Toronto, 30 Bond Street, Toronto, Ontario, M5B 1W8, Canada

    R. Loch Macdonald

  2. Division of Neurointerventional Radiology, University of California, San Francisco Medical Center, San Francisco, CA, USA

    Randall T. Higashida

  3. Universitätsspital Zürich, Neurochirurgische Klinik, Zürich, Switzerland

    Emanuela Keller

  4. Department of Neurology, Columbia University, New York, NY, USA

    Stephan A. Mayer

  5. Nuffield Department of Surgery, John Radcliffe Hospital, University of Oxford, Oxford, UK

    Andy Molyneux

  6. Inselspital Bern, Universitätsklinik für Neurochirurgie, Bern, Switzerland

    Andreas Raabe

  7. Department of Neurosurgery, Charite Universitätsmedizin Berlin, Berlin, Germany

    Peter Vajkoczy

  8. Clinic Hirslanden, Zürich, Switzerland

    Isabel Wanke

  9. Actelion Pharmaceuticals Ltd, Allschwil, Switzerland

    Aline Frey, Angelina Marr & Sébastien Roux

  10. Department of Neurosurgery, University of Virginia, Charlottesville, VA, USA

    Neal F. Kassell

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  1. R. Loch Macdonald
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  2. Randall T. Higashida
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Correspondence to R. Loch Macdonald.

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Macdonald, R.L., Higashida, R.T., Keller, E. et al. Preventing Vasospasm Improves Outcome After Aneurysmal Subarachnoid Hemorrhage: Rationale and Design of CONSCIOUS-2 and CONSCIOUS-3 Trials. Neurocrit Care 13, 416–424 (2010). https://doi.org/10.1007/s12028-010-9433-3

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  • DOI: https://doi.org/10.1007/s12028-010-9433-3

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