A Phase 2 interventional study of Sodium nitrite and Saline in Subarachnoid Hemorrhage, sponsored by Hope Pharmaceuticals. Completed at 1 site in United States. Open to participants aged 18 Years to 80 Years. Per ClinicalTrials.gov, last updated 2020-05-21.
Sponsored by Hope Pharmaceuticals · Phase 2, Interventional, and Treatment
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.
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.
Exclusion Criteria:
Continuous intravenous infusion of Sodium Nitrite
Drug: Sodium nitrite
Continuous intravenous infusion of saline
Drug: Saline
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
Also known as: Sodium Nitrite Injection NDC 60267-311-10
14 day continuous infusion of a vehicle control infusion
Also known as: Sterile saline
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
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
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
Patients admitted to University of Virginia Medical Center for the treatment of subarachnoid hemorrhage were screened for possible recruitment into this study.
| Milestone | Vehicle Control | Nitrite 32 Nmol/Min/kg | Nitrite 48 Nmol/Min/kg | Nitrite 64 Nmol/Min/kg |
|---|---|---|---|---|
| Started | 9 | 4 | 3 | 3 |
| Completed | 9 | 3 | 3 | 3 |
| Not completed | 0 | 1 | 0 | 0 |
| Withdrew: Withdrawal by subject | 0 | 1 | 0 | 0 |
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.
| micromol/L | 64 Nmol/Min/kg | 48 Nmol/Min/kg | 32 Nmol/Min/kg |
|---|---|---|---|
| Mean Plasma Nitrite Concentration (Micromol/L) | 4.2 ± 0.3 | 4.3 ± 0.4 | 2.6 ± 0.3 |
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
| Participants | 64 Nmol/Min/kg | 48 Nmol/Min/kg | 32 Nmol/Min/kg | Placebo |
|---|---|---|---|---|
| Safety of a 14 Day Infusion of Sodium Nitrite | 0 | 0 | 0 | 0 |
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).
| Participants | 64 Nmol/Min/kg | 48 Nmol/Min/kg | 32 Nmol/Min/kg | Placebo |
|---|---|---|---|---|
| Efficacy of 14 Day Infusion of Sodium Nitrite | 1 | 1 | 0 | 3 |
Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Nitrite | — | 0/9 (0%) | 0/9 (0%) |
| Vehicle Control | — | 2/9 (22.2%) | 0/9 (0%) |
| Event | Nitrite | Vehicle Control |
|---|---|---|
| AbscessInfections and infestations | 0/9 | 1/9 |
| DeathNervous system disorders | 0/9 | 1/9 |
| Age, Categorical(Participants) | 32 Nmol/Min/kg | Vehicle Control | 48 Nmol/Min/kg | 64 Nmol/Min/kg | Total |
|---|---|---|---|---|---|
| <=18 years | 0 | 0 | 0 | 0 | 0 |
| Between 18 and 65 years | 4 | 8 | 3 | 3 | 18 |
| >=65 years | 0 | 1 | 0 | 0 | 1 |
| Age, Continuous(years) | 32 Nmol/Min/kg | Vehicle Control | 48 Nmol/Min/kg | 64 Nmol/Min/kg | Total |
|---|---|---|---|---|---|
| Mean | 50 ± 10 | 52 ± 18.3 | 50 ± 5 | 58 ± 7 | 51 ± 9.9 |
| Sex: Female, Male(Participants) | 32 Nmol/Min/kg | Vehicle Control | 48 Nmol/Min/kg | 64 Nmol/Min/kg | Total |
|---|---|---|---|---|---|
| Female | 3 | 6 | 2 | 2 | 13 |
| Male | 1 | 3 | 1 | 1 | 6 |
| Region of Enrollment(participants) | 32 Nmol/Min/kg | Vehicle Control | 48 Nmol/Min/kg | 64 Nmol/Min/kg | Total |
|---|---|---|---|---|---|
| United States | 4 | 9 | 3 | 3 | 19 |
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Hope Pharmaceuticals