iNO: Inhaled Nitric Oxide in Acute Ischemic Stroke Patients Undergoing Mechanical Thrombectomy

Sponsor

Wake Forest University Health Sciences (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05871606

Collaborator

Mallinckrodt (Industry)

Enrollment

Locations

Arms

Anticipated Duration (Months)

13.5

Patients Per Site

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and feasibility of using inhaled nitric oxide (iNO) in patients undergoing intra-arterial mechanical thrombectomy (blood clot extraction or IAMT) for treatment of acute ischemic (non-bleeding) stroke (AIS).

Condition or Disease	Intervention/Treatment	Phase
Cerebrovascular Disorders Acute Cerebrovascular Disease	Drug: iNO	Phase 1

Detailed Description

This dose escalation phase I study is to evaluate the safety and feasibility of iNO as adjunctive therapy in the treatment of AIS in adult patients with clinically significant strokes.

iNO will act as a selective vasodilator to ischemic tissues in the brain, increasing perfusion to the area of the brain most at risk (penumbra) in AIS patients. This therapy will help to increase collateral circulation and perfusion to the penumbra, salvaging this tissue and limiting the volume of core infarct while mitigating reperfusion injury to the salvaged tissue.

Protection of ischemic penumbra is paramount in IAMT stroke patients. IAMT to re-establish blood flow during AIS from a large vessel occlusion (LVO) reduces death and disability. Initially this intervention was recommended up until 6 hours after symptom onset, but more recently has proven safe and effective up to 16 and 24 hours after stroke onset in select patients. These studies have confirmed the long believed thought that supporting ischemic penumbra during AIS helps limit the size of the ultimate core infarct and therefore reduces disability and death from stroke. Treatment aimed at protecting ischemic penumbra is thus paramount to treatment and research endeavors in AIS patients.

iNO protects ischemic penumbra. Nitric oxide is an endothelial-derived vasodilator and has been shown to mediate cytoprotection after ischemic reperfusion injury and appears to aid in ischemic preconditioning signaling pathways. iNO has been shown to cause selective dilation of arterioles in the ischemic penumbra of stroke and subarachnoid hemorrhage animal models, helping augment the cerebral microcirculation and improve penumbral blood flow. This has been shown to reduce ischemic brain damage, limit core infarct, and consistently improve neurological outcome in a middle cerebral artery AIS mouse model

Study Design

Study Type:

Interventional

Anticipated Enrollment :

27 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

The study has been designed to follow a standard 3+3 cohort expansion design, assessing 5 doses. Specifically, 3 individuals will begin at dose 1. If none of these individuals experience a dose limiting toxicity (DLT), then the dose will be escalated to dose 2. DLT is defined as a patient experiencing sICH, our primary outcome measure, or any other listed ASE. Dose escalation will continue after each set of 3 individuals until at least one person experiences DLT. If only 1 of the 3 experience a DLT, the cohort will be expanded to 6 (an additional 3). If 2 of the 6 experience DLTs, then dose escalation is stopped and the previous dose level (one level below) is declared the maximum tolerated dose. If 2 of the initial 3 experience DLT, the previous dose level (one level below) is declared the maximum tolerated dose. However, if only 1 of 6 experience DLT, the dose will escalate.The study has been designed to follow a standard 3+3 cohort expansion design, assessing 5 doses. Specifically, 3 individuals will begin at dose 1. If none of these individuals experience a dose limiting toxicity (DLT), then the dose will be escalated to dose 2. DLT is defined as a patient experiencing sICH, our primary outcome measure, or any other listed ASE. Dose escalation will continue after each set of 3 individuals until at least one person experiences DLT. If only 1 of the 3 experience a DLT, the cohort will be expanded to 6 (an additional 3). If 2 of the 6 experience DLTs, then dose escalation is stopped and the previous dose level (one level below) is declared the maximum tolerated dose. If 2 of the initial 3 experience DLT, the previous dose level (one level below) is declared the maximum tolerated dose. However, if only 1 of 6 experience DLT, the dose will escalate.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Inhaled Nitric Oxide in Acute Ischemic Stroke Patients Undergoing Mechanical Thrombectomy: A Phase I Drug Pilot Research Plan

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

Jan 1, 2024

Anticipated Study Completion Date :

Jun 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose 1 Group Dose 1- Inhaled Nitrous Oxide (iNO) 40ppm.	Drug: iNO Inhaled Nitrous Oxide Other Names: Inhaled Nitrous Oxide
Experimental: Dose 2 Group Dose 2- Inhaled Nitrous Oxide (iNO) 50ppm.	Drug: iNO Inhaled Nitrous Oxide Other Names: Inhaled Nitrous Oxide
Experimental: Dose 3 Group Dose 3- Inhaled Nitrous Oxide (iNO) 60ppm.	Drug: iNO Inhaled Nitrous Oxide Other Names: Inhaled Nitrous Oxide
Experimental: Dose 4 Group Dose 4- Inhaled Nitrous Oxide (iNO) 70ppm.	Drug: iNO Inhaled Nitrous Oxide Other Names: Inhaled Nitrous Oxide
Experimental: Dose 5 Group Dose 5- Inhaled Nitrous Oxide (iNO) 80ppm.	Drug: iNO Inhaled Nitrous Oxide Other Names: Inhaled Nitrous Oxide

Outcome Measures

Primary Outcome Measures

Maximum safe dose of iNO for AIS patients - assessing for reperfusion hemorrhage/symptomatic intracranial hemorrhage (sICH) [Year 2]
To establish a maximum safe dose of iNO for acute ischemic (non-bleeding) stroke (AIS) patients, assessing for reperfusion hemorrhage/symptomatic intracranial hemorrhage (sICH)

Secondary Outcome Measures

Change in pre-endovascular mechanical thrombectomy (IAMT) and post-IAMT core infarct volume [Year 2]
Core infarct measurement pre/post

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age 18 and < 80
Clinical evidence of acute ischemic (non-bleeding) stroke (AIS) with NIH Stroke Scale of 6 or higher
Non-contrast Computed tomography (CT) Head with ASPECT (Alberta Stroke Program Early CT) score 6
Symptom onset began < 16 hours from initiation of intra-arterial mechanical thrombectomy (IAMT) procedure
CT Angiogram (CTA) evidence of anterior circulation MCA (Middle Cerebral Artery) M1 segment occlusion.
CT Perfusion (CTP) evidence of core infarct volume of < 70ml and a ratio of ischemic tissue to initial core infarct volume of 1.8 or greater, and an absolute volume of penumbra of 15ml or greater
Patient or patient's representative provides consent
Pre-stroke modified Rankin Scale (mRS) of < =2
General endotracheal anesthesia (GETA) is planned to be used, as standard care, for IAMT
Treatment with iNO requires mechanical ventilation. Because IAMT can be performed using conscious sedation and not GETA, only those patients for which the procedure is planned with GETA will be included. The decision for the type of anesthetic depends on the severity of stroke, region of brain affected by the stroke, and the ability for the patient to cooperate for the procedure.

Exclusion Criteria:

Hypotension at presentation, defined as systolic blood pressure (SBP) < 100 or MAP < 60; profound hypertension with SBP >185 or DBP >110mmHg unable to be controlled with IV medications
Inability to undergo a brain MRI (e.g., implanted pacemaker)
Patients who received IV tPA >4.5hrs after symptom onset
Coaguloapathy, defined as platelet count < 50,000, INR >3.0, PTT > 3x normal, use of novel anticoagulants with eGFR < 30ml/min
Vulnerable Subjects including: mentally ill or incompetent patients, those with diminished decision-making capacity, prisoners, inpatient care for long-term chronic illness, terminally ill, pregnant women, and children
Any form of hemorrhage on non-contrast CT Head or mass lesion
Severe head injury within 90 days
Pre-existing severe neurological/psychiatric disease
Seizure at stroke onset (unable to assess NIHSS)
Blood glucose < 50mg/dL or >400mg/dL
Hemoglobin <7mmol/L
eGFR < 30ml/min
Allergy to contrast media
Presumed septic embolus as source of stroke
Flow limiting intracranial or extracranial carotid stenosis, or complete carotid occlusion

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Carolinas Medical Center	Charlotte	North Carolina	United States	28203
2	Atrium Health	Charlotte	North Carolina	United States	28204

Sponsors and Collaborators

Wake Forest University Health Sciences
Mallinckrodt

Investigators

Principal Investigator: William R Stetler, MD, Wake Forest University Health Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Wake Forest University Health Sciences

ClinicalTrials.gov Identifier:

NCT05871606

Other Study ID Numbers:

IRB00090271

First Posted:

May 23, 2023

Last Update Posted:

May 23, 2023

Last Verified:

Apr 1, 2023

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Keywords provided by Wake Forest University Health Sciences

Stroke

blood clot extraction

large vessel occlusion

Additional relevant MeSH terms:

Ischemic Stroke

Cerebrovascular Disorders

Nitrous Oxide

Study Results

No Results Posted as of May 23, 2023