ACT-GLOBAL

Purpose:  To determine if NoNO-42 is a safe and effective neuroprotective agent in participants with AIS Selected for thrombolysis with or without EVT 

Inclusion Criteria:

1) Acute ischemic stroke (AIS) selected for thrombolysis with or without EVT. 

2) Onset (last-known-well) time to randomization time within 3 hours. 

3) Ages ≥ 45 to ≤ 90 years. 

4) Disabling stroke defined as a baseline National Institutes of Health Stroke Score (NIHSS) > 5. 

5) Confirmed 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, defined as early ischemic changes on NCCT. 

2) Any intracranial hemorrhage on qualifying imaging. 

3) Unlikely to initiate study drug/placebo administration before arterial puncture in those selected for EVT. 

4) Estimated or known weight > 115 kg (253 lbs). 

5) Known/suspected pregnancy and/or lactation. 

6) Systolic blood pressure < 90 mmHg 

7) 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 investigating a drug or medical device or a neurointerventional or surgical procedure that is not considered as standard care in the 30 days preceding trial enrolment. 

ACT-42 NOTES:

• Study medication box is located at CT room 4. Passcode for the box is 042.

• Study medication box includes all supplies for administration. 

Dose:

Usual Adult:

• 2.6 mg/kg IV x 1 dose (reconstituted and added to 100mL 0.9% NaCl minibag) to a maximum dose of 300mg/10mL (for patients weighing 112-115 kg)

• Patients randomized to placebo will receive 0.9% NaCl bolus via minibag 

Administration:

• NoNO-42 should be reconstituted and diluted according to guidelines outlined below (“Dilution for IV Infusion”)

• The study drug should be administered to the participant as soon as is practical, but ideally within 10 minutes of randomization

• Each 100mL bag IV solution will be prepared and administered by the study coordinator (or other delegate who has received appropriate training)

• Entire contents of the 100 mL infusion bag will be administered to the participant through an IV catheter inserted into a vein in the upper or lower extremity using a standard infusion pump

• Dose will be administered over 20 minutes (+1 min)

o An infusion rate of 345mL/h can be used for all dose volumes – this will ensure the dosing time is between 19-21 minutes

• After the dose has been administered, an additional 10 mL 0.9% NaCl (minimum) will be administered using the infusion pump to ensure any medication left within the intravenous tubing is administered to the participant

Reconstitution / Dilution / Stability:

AVAILABLE:

NoNO-42 will be supplied in sterile vials containing lyophilized powder for reconstitution in labelled 20mL syringe vials with flip-off caps. Each vial contains 300mg of NoNO-42 active ingredient. Placebo will be a commercially available 100 mL 0.9% normal saline bag.

DILUTION FOR IV INFUSION:

• Reconstitute the lyophilized powder by injecting 10 mL of 0.9% NaCl (or sterile water) into the 20 mL glass vial to create the drug solution

• Gently swirl until the solution is clear and no visible particulates remain (approximately 60 seconds)

• Withdraw the calculated dose from the vial and inject into the IV port of a 100 mL bag of 0.9% NaCl. Mix well by squeezing and inverting the bag a minimum of 4 times.

STABILITY:

-       NoNO-42 should be stored at room temperature (15 – 25 °C) and protected from light during storage (it is not required to be protected from light during preparation and administration). Vials are labelled with expiry dates.

-       NoNO-42 is stable for 4 hours at room temperature once reconstituted.

Purpose:  To determine the optimal dose strategy with IV TNK in various patient risk groups.

Inclusion Criteria:

1) All patients with disabling AIS presenting within 4.5 hours from stroke symptom onset or last known well who may benefit from IVT with tenecteplase. Patients potentially eligible for IVT with conditions described as relative contraindications in national guidelines where physician discretion is recommended are eligible. Patients who received a DOAC, and those planned for EVT are eligible. 

Exclusion Criteria:

1) Any absolute contraindication for IV thrombolysis per current national guidelines. Examples include those who are actively bleeding, had recent (i.e., <7 days) intracranial surgery, head trauma, intracranial or subarachnoid hemorrhage, or a bleeding diathesis. 

2) Minor stroke patients with non-disabling symptoms are excluded. 

Interventions: 

In all eligible patients: 

1) IVT with tenecteplase at standard-dose: 0.25 mg/kg 

2) IVT with tenecteplase at low-dose: 0.18 mg/kg 

If eligible patients are on DOACs within the last 24 hours or planned for emergency EVT, domain interventions will be: 

1) IVT with tenecteplase at standard-dose: 0.25 mg/kg 

2) IVT with tenecteplase at low-dose: 0.18 mg/kg 

3) No IV thrombolysis 

Dose:

• Subjects will receive a dose of intravenous Tenecteplase 0.25 mg/kg (single bolus) or 0.18 mg/kg (single bolus) over 5-10 seconds

• Max dose 5ml (25 mg) 

Reconstitution / Dilution / Administration:

• 50mg vial – add 10 ml sterile water for injection (do not use bacteriostatic water for injection). Gently swirl to dissolve. DO NOT SHAKE.                                                           

• Keep reconstituted vial at room temperature or in the refrigerator. Final Concentration: 5 mg/ml

• IV PUSH: Undiluted over 5-10 seconds into an infusing line of normal saline

• Flush IV with 10 ml normal saline prior to and following administration to ensure full delivery of drug dosage

Maximum Rate: single bolus over 5 seconds

Final  Concentration: 5 mg/ml

Maximum Dose: 50 mg (10 ml) 

Purpose:  To determine if controlling blood pressure improves functional recovery.

Inclusion Criteria:

1) Use of endovascular therapy (EVT) within 24 hours of symptom onset or last known well according to local guidelines; 

2) Sustained SBP ≥150 mmHg (defined as 2 successive readings <10 mins apart) within 3 hours after EVT; 

Exclusion Criteria:

Any definite contraindications to BP lowering treatment. 

Interventions: 

• Conservative SBP Control (no or minimal treatment; if there is a need to treat a patient with a very-high baseline SBP, then the SBP reduction is 5-10mmHg or a target is 175-180 mmHg) 

• Moderate SBP Control (if the patient has a very high or moderate high baseline SBP, SBP reduction is 10-20mmHg or a target of160±5 mmHg, which is higher; patients with low-high baseline SBP will not be treated) 

• Intensive SBP Control (SBP reduction by 30-50mmHg or a target of 140±5 mmHg, which is higher)