Subarachnoid Hemorrhage
Conditions
Keywords
Cerebral aneurysm, Subarachnoid hemorrhage, Nitrite
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.
Interventions
DRUGSodium nitrite
14 day continuous infusion of one of 3 escalating doses of sodium nitrite: 32 nmol/min/kg, 48 nmol/min/kg, or 64 nmol/min/kg
DRUGSaline
14 day continuous infusion of a vehicle control infusion
Sponsors
National Institute of Neurological Disorders and Stroke (NINDS)
Hope Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Ruptured cerebral aneurysm
Exclusion criteria
* Pregnancy, sickle cell disease, G6PD deficiency, anticoagulant therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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). |
Countries
United States
Participant flow
Recruitment details
Patients admitted to University of Virginia Medical Center for the treatment of subarachnoid hemorrhage were screened for possible recruitment into this study.
Pre-assignment details
Patients underwent neurosurgical repair of their subarachnoid hemorrhage prior to study recruitment and assignment.
Participants by arm
| Arm | Count |
|---|---|
| 32 Nmol/Min/kg Sodium nitrite : 14 day continuous infusion 32 nmol/min/kg | 4 |
| Vehicle Control Nitrite : 14 day continuous infusion of a vehicle control infusion | 9 |
| 48 Nmol/Min/kg Sodium nitrite: 14 day continuous infusion 48 nmol/min/kg | 3 |
| 64 Nmol/Min/kg Sodium nitrite: 14 day continuous infusion 64 nmol/min/kg | 3 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Vehicle Control | 48 Nmol/Min/kg | 32 Nmol/Min/kg | 64 Nmol/Min/kg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 3 Participants | 4 Participants | 3 Participants | 18 Participants |
| Age, Continuous | 52 years STANDARD_DEVIATION 18.3 | 50 years STANDARD_DEVIATION 5 | 50 years STANDARD_DEVIATION 10 | 58 years STANDARD_DEVIATION 7 | 51 years STANDARD_DEVIATION 9.9 |
| Region of Enrollment United States | 9 participants | 3 participants | 4 participants | 3 participants | 19 participants |
| Sex: Female, Male Female | 6 Participants | 2 Participants | 3 Participants | 2 Participants | 13 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 1 Participants | 1 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 9 | 2 / 9 |
Outcome results
Primary
Mean Plasma Nitrite Concentration (Micromol/L)
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.
Time frame: multiple time points up to the end of day 14
Population: Per protocol
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 64 Nmol/Min/kg | Mean Plasma Nitrite Concentration (Micromol/L) | 4.2 micromol/L | Standard Deviation 0.3 |
| 48 Nmol/Min/kg | Mean Plasma Nitrite Concentration (Micromol/L) | 4.3 micromol/L | Standard Deviation 0.4 |
| 32 Nmol/Min/kg | Mean Plasma Nitrite Concentration (Micromol/L) | 2.6 micromol/L | Standard Deviation 0.3 |
Secondary
Efficacy of 14 Day Infusion of Sodium Nitrite
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).
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 64 Nmol/Min/kg | Efficacy of 14 Day Infusion of Sodium Nitrite | 1 Participants |
| 48 Nmol/Min/kg | Efficacy of 14 Day Infusion of Sodium Nitrite | 1 Participants |
| 32 Nmol/Min/kg | Efficacy of 14 Day Infusion of Sodium Nitrite | 0 Participants |
| Placebo | Efficacy of 14 Day Infusion of Sodium Nitrite | 3 Participants |
Secondary
Safety of a 14 Day Infusion of Sodium Nitrite
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
Time frame: 14 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 64 Nmol/Min/kg | Safety of a 14 Day Infusion of Sodium Nitrite | 0 Participants |
| 48 Nmol/Min/kg | Safety of a 14 Day Infusion of Sodium Nitrite | 0 Participants |
| 32 Nmol/Min/kg | Safety of a 14 Day Infusion of Sodium Nitrite | 0 Participants |
| Placebo | Safety of a 14 Day Infusion of Sodium Nitrite | 0 Participants |