Clevidipine for Vasospasm After Subarachnoid Hemorrhage (SAH)

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Brief Title

Clevidipine for Vasospasm After Subarachnoid Hemorrhage (SAH)

Official Title

Clevidipine for Vasospasm After Subarachnoid Hemorrhage

Brief Summary

      Vasospasm occurs frequently after aneurysmal subarachnoid hemorrhage and can lead to strokes.
      The investigators will investigate if infusion of a novel drug, clevidipine, will decrease
      vasospasm during the infusion and post infusion period using transcranial doppler monitoring
      of patients with subarachnoid hemorrhage and moderate severity vasospasm
    

Detailed Description

      Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH) is a major cause of
      morbidity and mortality days after securing the aneurysm due to development of cerebral
      ischemia and strokes. Vasospasm is detected by measuring the blood flow velocities in the
      cerebral circulation via daily Transcranial Dopplers (TCD). There is no effective treatment
      except for a per os calcium channel blocker (nimodipine) and for keeping the patient
      hypertensive and with euvolemia or hypervolemia. A recently proposed option is to dilate the
      cerebral vessels by infusing continuously another vasodilatory calcium channel blocker,
      nicardipine, and supporting the systemic blood pressure (BP) with vasopressors which do not
      constrict the cerebral vasculature at the same time. Nicardipine has also been used
      extensively intra-arterially as a bolus or infusion to dilate the vasospastic cerebral
      vessels as a rescue therapy for severe vasospasm.

      Clevidipine is a novel, short-acting calcium channel blocker, which in a small series of
      patients with SAH at Henry Ford Hospital, was able to control the elevated BP very
      efficiently and within a narrow window, without adverse events. It has never been used before
      for ameliorating vasospasm, but theoretically offers advantages compared to nicardipine due
      to its shorter half-life and easier titratability. Except for use of clevidipine for BP
      control in the investigators previous study, there are no data on clevidipine use after SAH
      and no data about effect of the drug on vasospasm.

      In this single-center, open-label, uncontrolled, pilot clinical study, the investigators
      hypothesize that clevidipine low-rate infusion will decrease sonographically-detected
      moderate cerebral vasospasm after aneurysmal SAH. The dose of the drug in this exploratory
      study is 2.5 to 5 times lower than the dose used previously to control BP. The effect of the
      drug will be evaluated in 20 patients by TCD monitoring during 3 periods: 1-hour
      pre-infusion, 4-hour infusion and 4-hour post infusion. The cerebral blood flow velocities,
      which are a surrogate marker of vasospasm, will be compared between the 3 periods. The
      primary efficacy end-point will be the percentage of measurements with at least a 10% or more
      decrease of the velocities during the infusion period. Potential long-term effects after
      discontinuation of the drug will be also evaluated in the post-infusion 4-hour period and
      beyond, until the last follow up. The major safety issue is hypotension induced by the drug
      during a period when vasospasm is present. For that reason, two measures will be taken.
      First, only patients with moderate vasospasm will be evaluated. Second, vasopressors will be
      used as needed during the infusion period to counteract the systemic circulatory effect of
      the drug and maintain a stable systemic Mean Arterial Pressure (MAP) within 10% range
      compared to pre-infusion. Potential effect of cerebral vasodilation on intracranial pressure
      (ICP) will be also evaluated during the infusion and post-infusion periods and any elevation
      > 10 mm Hg will be reported.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Efficacy: Change of cerebral blood flow velocities during infusion of clevidipine compared to baseline pre-infusion by >10% at 15 min after start of infusion and/or at 1, 2,3 and 4 hours (during the infusion).

Secondary Outcome

 Safety and Tolerability: Intracranial pressure (ICP) change during infusion compared to pre-infusion

Condition

Subarachnoid Hemorrhage

Intervention

clevidipine

Study Arms / Comparison Groups

 clevidipine
Description:  Four-hour infusion of low-dose intravenous clevidipine in patients with moderate vasospasm after aneurysmal subarachnoid hemorrhage

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

20

Start Date

March 2014

Completion Date

September 2015

Primary Completion Date

March 2015

Eligibility Criteria

        Inclusion Criteria:

          -  Age 18-80 years

          -  Diagnosis of SAH (as diagnosed per history, neuroimaging or lumbar puncture)

          -  Presence of a secured aneurysm via clipping or coiling

          -  Hunt and Hess grade < 5 (non-sedated or paralyzed patients)

          -  Glasgow Coma scale > 4 (non-sedated or paralyzed patients)

          -  MAP goal set by the treating physicians

          -  Temporal insonation window presence on TCD

          -  Moderate supratentorial vasospasm as per daily TCD (CBFV between 130-180 cm/sec or
             Lindergaard index 3-5 for the Middle Cerebral artery or Internal Cerebral artery or
             Anterior Cerebral artery)

        Exclusion Criteria:

          -  Very young or very old patients (<18 or >80 years old)

          -  Traumatic SAH (no aneurysm identified after initial work-up) or Perimesencephalic SAH
             is also excluded

          -  Hunt and Hess grade 5 (deeply comatose or brain dead patients)

          -  Glasgow Coma scale 3 or 4 (brain dead or deeply comatose patients)

          -  Patients with mild or severe supratentorial vasospasm (CBFV < 120 cm/sec or
             Lindergaard index < 3 or > 200 cm/sec or Lindergaard index > 6, respectively, for the
             Middle Cerebral artery or Internal Cerebral artery or Anterior Cerebral artery)

          -  Patients with vasospasm only in the posterior circulation (CBFV > 80 cm/sec for
             Vertebral or Basilar artery)

          -  Patients with severe tachycardia (heart rate > 110)

          -  Patients with preexisting left bundle branch block or permanent ventricular pacemaker

          -  Patients with known allergy to dihydropyridines including clevidipine or allergic to
             soybeans, soy products, eggs, or egg products

          -  Patients with defective lipid metabolism such as pathologic hyperlipemia or lipoid
             nephrosis

          -  Patients with acute pancreatitis, if it is accompanied by hyperlipidemia

          -  Patients with severe aortic stenosis

          -  Pregnant patients
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Panayiots Varelas, MD, PhD, 3139163528, 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02011321

Organization ID

HFHS-CLEVIDIPINE-PV


Responsible Party

Principal Investigator

Study Sponsor

Henry Ford Health System


Study Sponsor

Panayiots Varelas, MD, PhD, Principal Investigator, Henry Ford Health System


Verification Date

December 2013