Safety and Pharmacokinetic Evaluation of Nitrite for Prevention of Cerebral Vasospasm

Phase 2

Completed

• Conditions: Subarachnoid Hemorrhage
• Interventions: Drug: Saline; Drug: Sodium nitrite

• Registration Number: NCT00873015
• Lead Sponsor: Hope Pharmaceuticals

Brief Summary

The purpose of the study is to examine the safety of a 14 day infusion of sodium nitrite, and to study the pharmacokinetics of nitrite, during a 14 day infusion in patients with ruptured cerebral aneurysms.

Detailed Description

Intravenous sodium nitrite has been shown to prevent and to reverse cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). This was a Phase IIA dose escalation study of sodium nitrite to determine its safety in patients with aneurysmal SAH and to establish its pharmacokinetics during a 14 day infusion.

Sodium nitrite was delivered intravenously for 14 days in 18 patients with SAH from a ruptured cerebral aneurysm using a dose escalation scheme in three cohorts of 6 patients each (3 nitrite, 3 saline), with a maximum dose of 64 nmol/min/kg. Sodium nitrite blood levels were frequently sampled and measured using mass spectroscopy and blood methemoglobin levels were continuously monitored using a pulse oximeter.

Study Timeline

• Study First Submitted: 2009-03-31
• Study First Submitted QC: 2009-03-31
• Study First Posted: 2009-04-01
• Study Start: 2010-04
• Primary Completion: 2010-11
• Study Completion: 2012-08
• Results First Submitted: 2013-01-26
• Results First Submitted QC: 2013-05-06
• Results First Posted: 2013-07-16
• Status Verified: 2020-05
• Last Update Submitted: 2020-05-12
• Last Update Posted: 2020-05-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 19

Inclusion Criteria

• Ruptured cerebral aneurysm

Exclusion Criteria

• Pregnancy, sickle cell disease, G6PD deficiency, anticoagulant therapy

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Vehicle control	Saline	Continuous intravenous infusion of saline
Nitrite	Sodium nitrite	Continuous intravenous infusion of Sodium Nitrite

Primary Outcome Measures

Name	Time	Method
Mean Plasma Nitrite Concentration (Micromol/L)	multiple time points up to the end of day 14	Samples for pharmacokinetic analysis were collected from subjects treated with sodium nitrite at -15, -5, 0, 10, 30, 60, and 90 minutes after starting nitrite infusion and then at 2, 4, 6, 8, 12, 24, and every 24 hours after starting nitrite infusion. The sample at the time of starting the infusion was considered to be the time 0 sample. On study day 14 additional blood samples were collected at 0, 10, 30, 60, and 90 minutes and at 2, 4, 6, 8, and 12 hours after stopping nitrite infusion. Blood samples were analyzed for nitrite levels using mass spectroscopy.

Secondary Outcome Measures

Name	Time	Method
Efficacy of 14 Day Infusion of Sodium Nitrite	14 days	Development of vasospasm as documented by onset of neurologic symptoms and documentation of narrowing of vessel(s) on cerebral angiogram. Potential clinical vasospasm was evaluated as appropriate, based on the development of focal neurological deficits that suggested cerebral ischemia (such as hemiparesis and speech deficit) or global neurological deficit (altered level of consciousness) that could not be attributed to other etiologies (such as metabolic abnormalities, intracerebral hemorrhage, and hydrocephalus).
Safety of a 14 Day Infusion of Sodium Nitrite	14 days	Development of methemoglobin \> 5% or hypotension (systolic arterial blood pressure \< 90 mm Hg for more than 15 minutes or \< 80 mm Hg) during infusion of sodium nitrite

Trial Locations

Locations (1)

University of Virginia Health System Medical Center; 🇺🇸 Charlottesville, Virginia, United States