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

Primary Purpose

Cerebrovascular Disorders, Acute Cerebrovascular Disease

Status
Not yet recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
iNO
Sponsored by
Wake Forest University Health Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cerebrovascular Disorders focused on measuring Stroke, blood clot extraction, large vessel occlusion

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Carolinas Medical Center
  • Atrium Health

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose 1 Group

Dose 2 Group

Dose 3 Group

Dose 4 Group

Dose 5 Group

Arm Description

Dose 1- Inhaled Nitrous Oxide (iNO) 40ppm.

Dose 2- Inhaled Nitrous Oxide (iNO) 50ppm.

Dose 3- Inhaled Nitrous Oxide (iNO) 60ppm.

Dose 4- Inhaled Nitrous Oxide (iNO) 70ppm.

Dose 5- Inhaled Nitrous Oxide (iNO) 80ppm.

Outcomes

Primary Outcome Measures

Maximum safe dose of iNO for AIS patients - assessing for reperfusion hemorrhage/symptomatic intracranial hemorrhage (sICH)
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
Core infarct measurement pre/post

Full Information

First Posted
May 12, 2023
Last Updated
October 24, 2023
Sponsor
Wake Forest University Health Sciences
Collaborators
Mallinckrodt
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1. Study Identification

Unique Protocol Identification Number
NCT05871606
Brief Title
Inhaled Nitric Oxide in Acute Ischemic Stroke Patients Undergoing Mechanical Thrombectomy
Acronym
iNO
Official Title
Inhaled Nitric Oxide in Acute Ischemic Stroke Patients Undergoing Mechanical Thrombectomy: A Phase I Drug Pilot Research Plan
Study Type
Interventional

2. Study Status

Record Verification Date
April 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
December 2023 (Anticipated)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Wake Forest University Health Sciences
Collaborators
Mallinckrodt

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. 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).
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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cerebrovascular Disorders, Acute Cerebrovascular Disease
Keywords
Stroke, blood clot extraction, large vessel occlusion

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Sequential Assignment
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.
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
27 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Dose 1 Group
Arm Type
Experimental
Arm Description
Dose 1- Inhaled Nitrous Oxide (iNO) 40ppm.
Arm Title
Dose 2 Group
Arm Type
Experimental
Arm Description
Dose 2- Inhaled Nitrous Oxide (iNO) 50ppm.
Arm Title
Dose 3 Group
Arm Type
Experimental
Arm Description
Dose 3- Inhaled Nitrous Oxide (iNO) 60ppm.
Arm Title
Dose 4 Group
Arm Type
Experimental
Arm Description
Dose 4- Inhaled Nitrous Oxide (iNO) 70ppm.
Arm Title
Dose 5 Group
Arm Type
Experimental
Arm Description
Dose 5- Inhaled Nitrous Oxide (iNO) 80ppm.
Intervention Type
Drug
Intervention Name(s)
iNO
Other Intervention Name(s)
Inhaled Nitrous Oxide
Intervention Description
Inhaled Nitrous Oxide
Primary Outcome Measure Information:
Title
Maximum safe dose of iNO for AIS patients - assessing for reperfusion hemorrhage/symptomatic intracranial hemorrhage (sICH)
Description
To establish a maximum safe dose of iNO for acute ischemic (non-bleeding) stroke (AIS) patients, assessing for reperfusion hemorrhage/symptomatic intracranial hemorrhage (sICH)
Time Frame
Year 2
Secondary Outcome Measure Information:
Title
Change in pre-endovascular mechanical thrombectomy (IAMT) and post-IAMT core infarct volume
Description
Core infarct measurement pre/post
Time Frame
Year 2

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Clara Schommer, CCRP
Phone
704-355-9434
Email
clara.schommer@atriumhealth.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
William R Stetler, MD
Organizational Affiliation
Wake Forest University Health Sciences
Official's Role
Principal Investigator
Facility Information:
Facility Name
Carolinas Medical Center
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28203
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
William Stetler, MD
Facility Name
Atrium Health
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28204
Country
United States
Facility Contact:
First Name & Middle Initial & Last Name & Degree
William Stetler, MD

12. IPD Sharing Statement

Plan to Share IPD
No

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Inhaled Nitric Oxide in Acute Ischemic Stroke Patients Undergoing Mechanical Thrombectomy

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