NoNO-42 Trial in Acute Ischemic Stroke Patients Selected for Thrombolysis With or Without Endovascular Thrombectomy

A Multicentre, Prospective, Randomized, Open Label, Blinded-Endpoint, Placebo-controlled, Single-dose Trial to Determine the Efficacy and Safety of NoNO-42 in Participants With Acute Ischemic Stroke Selected for Thrombolysis With or Without Endovascular Thrombectomy (ACT-42 Trial)

ACT-42 is a domain of the ACT-GLOBAL platform (NCT06352632).

This trial is a Phase 2b, multicenter, prospective, randomized, open label, blinded-endpoint (PROBE) controlled single-dose adaptive trial.

A total of up to 600 male and female participants aged ≥ 18 to ≤ 90 years harboring an acute ischemic stroke who are eligible for an intravenous thrombolytic with or without endovascular thrombectomy therapy will be enrolled within 4.5 hours of stroke onset/last known well.

Study Overview

• Status: Recruiting
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: NoNO-42

Detailed Description

Because AIS is a medical emergency, the trial is designed to enable the administration of standard-of-care treatments in order to save the life of the person concerned, restore good health and alleviate suffering.

A total of up to 600 male and female participants aged ≥ 18 to ≤ 90 years harboring an acute ischemic stroke who are eligible for an intravenous thrombolytic with or without endovascular thrombectomy therapy will be enrolled within 4.5 hours of stroke onset/last known well. Randomization will be 1:1 drug/placebo. Randomization will be stratified by large vessel occlusion (LVO) (yes/no) and a minimization algorithm to minimize the contribution of imbalances in baseline factors (age, sex, baseline NIHSS score). The design is adaptive with prospective rules for adaptive enrichment, in which enrollment may be restricted to participants without an LVO. LVO is defined as an occlusion of the intracranial ICA, M1 or proximal M2.

Randomized participants will receive/received an intravenous thrombolytic and be allocated to:

• the investigational group, a single, 2.6 mg/kg (up to a maximum of 300 mg) 20-minute intravenous dose of NoNO-42, with a target start time of less than 10 minutes from randomization or
• the control group, no trial specific intervention.

Day 90: All participants will be followed for 90 days (or until death if prior to 90 days) for efficacy and 30 days for safety. The end of the trial is defined as the date that all participants have completed their Day 90 contact.

1-Year follow Up: participants who completed the trial to Day 90 may be followed at 1 year for long-term efficacy.

One database lock and corresponding report for the trial to Day 90 and a separate database lock and analysis for the 1-year follow up are planned.

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Tymianski, MD PhD; Phone Number: 416-583-1687; Email: mtymianski@nonoinc.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 2T9
      • Recruiting
      • University of Calgary - Foothills Medical Centre
      • Contact: Michael Hill, MD; Phone Number: 403-210-7786; Email: michael.hill@ucalgary.ca
      • Principal Investigator: Michael Hill, MD
    • Edmonton, Alberta, Canada, T6G 2B7
      • Recruiting
      • University of Alberta Hospital
      • Principal Investigator: Brian Buck, MD
      • Contact: Brian Buck, MD; Phone Number: 780-248-1927; Email: bbuck@ualberta.ca
  • British Columbia
    • Vancouver, British Columbia, Canada, V5M 1Z9
      • Recruiting
      • Vancouver General Hospital
      • Principal Investigator: Thalia Field, MD
      • Contact: Thalia Field, MD; Phone Number: 604 875-4554; Email: thalia.field@ubc.ca
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 3P5
      • Recruiting
      • University of Manitoba
      • Contact: Nishita Singh, MD; Phone Number: 204-789-3725; Email: nishita.singh@umanitoba.ca
      • Principal Investigator: Nishita Singh, MD
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Recruiting
      • Hamilton General Hospital
      • Principal Investigator: Luciana Catanese, MD
      • Contact: Luciana Catanese, MD; Phone Number: 905-902-9142; Email: luciana.catanese@phri.ca
    • Ottawa, Ontario, Canada, K1H 8L6
      • Recruiting
      • Ottawa Hospital Research Institute
      • Principal Investigator: DARIUSH DOWLATSHAHI, MD
      • Contact: DARIUSH DOWLATSHAHI, MD; Phone Number: 613-798-5555; Email: ddowlat@toh.ca
    • Toronto, Ontario, Canada, M4N 3M5
      • Recruiting
      • Sunnybrook Health Sciences Centre
      • Principal Investigator: Richard Swartz, MD
      • Contact: Richard Swartz, MD; Phone Number: 416-480-4866; Email: rick.swartz@sunnybrook.ca
    • Toronto, Ontario, Canada, M5B 1W8
      • Recruiting
      • Unity Health Toronto, St. Michael's Hospital
      • Contact: Alexandra Muccilli, MD; Phone Number: 416-864-5377; Email: alexandra.muccilli@unityhealth.to
      • Principal Investigator: Alexandra Muccilli, MD
  • Saskatchewan
    • Saskatoon, Saskatchewan, Canada, S7N 0W8
      • Recruiting
      • Royal University Hospital
      • Principal Investigator: Gary Hunter, MD
      • Contact: Gary Hunter, MD; Phone Number: 306-881-9701; Email: grwhunter@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Confirmed or suspected acute ischemic stroke (AIS) selected for intravenous thrombolysis.
2. Onset (last-known-well) time to randomization time within 4.5 hours.
3. Ages ≥ 18 to ≤ 90 years.
4. Disabling stroke defined as a baseline National Institutes of Health Stroke Score (NIHSS) >5.
5. Confirmed or suspected symptomatic anterior circulation intracranial occlusion. Tandem extracranial carotid and intracranial occlusions are permitted.
6. Pre-stroke independent functional status in activities of daily living as judged by the enrolling physician. Patient must be living without requiring nursing care.
7. Consent process completed as per national laws and regulation and the applicable ethics committee requirements.

Exclusion Criteria:

1. Large extent early ischemic changes/infarct in the ischemic territory on qualifying imaging.
2. Any intracranial hemorrhage on qualifying imaging.
3. Unlikely to initiate study drug administration before arterial puncture in those selected for EVT.
4. Known/suspected pregnancy and/or lactation.
5. Systolic blood pressure < 90 mmHg
6. Known prior receipt of NoNO-42 for any reason, including prior enrolment in this trial.

8) Severe comorbid illness with life expectancy less than 90 days, or likely to prevent completing 90-day follow-up.

9) Long term care facility resident or prisoner 10) Participation in another clinical trial outside of the ACT-GLOBAL platform investigating a drug or medical device or a neuro-interventional or surgical procedure that is not considered as standard care in the 30 days preceding trial enrolment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control
Active Comparator: NoNO-42; Randomized participants will be given a single, 2.6 mg/kg 20-minute intravenous dose of NoNO-42 with a target start time of less than 10 minutes from randomization.	Drug: NoNO-42; a single dose sterile 20 ml vial containing lyophilized powder for reconstitution containing 300 mg of NoNO-42 active ingredient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reducing global disability in participants with acute ischemic stroke (AIS)	The primary outcome is the mRS at Day 90. The primary analysis of the primary outcome will be a "shift" analysis, which is an ordinal analysis across the mRS scale. The primary estimand is odds-ratio for a better outcome on the mRS scale for NoNO-42 compared to control.	90 days from intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improving excellent functional outcome	Proportion of participants with a mRS of 0-1 at Day 90	90 days from intervention
Reducing worsening of stroke	Proportion of participants exhibiting a worsening of their index stroke during hospitalization. Worsening of stroke is defined as (A) progression of the index stroke or symptomatic intracranial, or symptomatic intracranial hemorrhagic within the first 7-days after randomization, supported and confirmed by medical imaging that is (a) life-threatening requiring intervention and/or (b) results in increased disability as gauged by a ≥ 4-point increase from lowest NIHSS during initial hospitalization or (B) results in death from the index stroke (i.e., index stroke is judged to be the principal cause of death) within the first 21-days after randomization.	90 days from intervention
Reducing mortality rate	Proportion of participant mortality over the 90-day trial period	90 days from intervention
Improving health-related quality of life	Health-related quality of life, as measured by the EQ-5D-5L at Day 90	90 days from intervention
Improving functional independence	Proportion of participants with a mRS of 0-2 at Day 90.	90 days from intervention

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
1 year Follow-up	Whenever possible, participants will be followed up to 1 year post stroke to determine the efficacy of NoNO-42 at 1 year post stroke in: • Reducing global disability in participants with acute ischemic stroke (AIS).- - proportion of participants with a shift of one or more categories to reduced functional dependence analyzed across the whole distribution of outcomes on the mRS Scale The secondary objectives are to determine the efficacy of NoNO-42 at 1 year post stroke in: Improving excellent functional outcome - Proportion of participants with a mRS of 0-1 at 1-year.; Improving functional independence - Proportion of participants with a mRS of 0-2 at 1-year; Reducing mortality rate - Proportion of participant mortality over 1-year; Improving health-related quality of life - Health-related quality of life, as measured by the EQ-5D-5L at 1-year	1 year post intervention
Safety Outcome	safety of a single 2.6 mg/kg dose of intravenous NoNO- 42 based on: Serious adverse events (SAEs) to Day 30 and; 90-day mortality.	30 and 90 days post intervention

Collaborators and Investigators

• Sponsor: NoNO Inc.
• Collaborators: University of Calgary
• Investigators: Study Chair: Bijoy Menon, MBBS, MD, University of Calgary

Study record dates

Study Major Dates

• Study Start (Actual): October 2, 2024
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: April 26, 2024
• First Submitted That Met QC Criteria: May 6, 2024
• First Posted (Actual): May 7, 2024

Study Record Updates

• Last Update Posted (Actual): July 15, 2025
• Last Update Submitted That Met QC Criteria: July 10, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Neuroprotection; Reperfusion; Neuroprotectant; Thrombolysis, Endovascular thrombectomy
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Brain Infarction; Brain Ischemia; Infarction; Necrosis; Ischemic Stroke; Stroke; Cerebral Infarction; Ischemia
• Other Study ID Numbers: NoNO42-02 (ACT-42)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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.: Yes