ACT-GLOBAL

Randomization eTMS Link: https://platform.actglobaltrial.com/

ACT-GLOBAL Inclusion Criteria:

1. Age ≥18 years 

2. Clinical diagnosis of stroke 

*There are no platform level exclusion criteria, please see below for domain specific inclusion/exclusion criteria*

*THIS STUDY IS APPROVED FOR DEFERRAL OF CONSENT. Patient/SDM are invited to give or decline rapid verbal consent to participate in the trial. The verbal consent form is in the study binder along with a physician script.

*Study binders are located in the filing cabinet in front of green zone bed 14. 

*For any study related questions call Dr. Swartz or Kiran (647-997-3492).

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. 

Administration:

• 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 delegated staff

• 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

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:

1. Reconstitute the lyophilized powder by injecting 10 mL of 0.9% NaCl into the 20 mL glass vial to create the drug solution

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

3. 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.

4. Dose will be administered over 20 minutes (+1 min) - An infusion rate of 345mL/h can be used for all dose volumes – this will ensure the dosing time is between 19-21 minutes

5. 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

Sunnycare note- Discussion with [patient name/SDM] regarding TNK and ACT-GLOBAL/ACT-42 trial enrollment.  Briefly, using lay language, explained the overall platform trial, and explained the ACT-42 neuroprotection trial, including 1:1 randomization, potential risks and possible effects of NAoNO-42, prior experience/safety from NA-1 trials and follow-ups. Discussed alternatives (including not enrolling) and that patient can withdraw consent for follow-ups later if they wish. No questions asked and verbal consent provided. Verbal consent provided/no concerns raised. [Patient/SDM] understood the research coordinators will follow-up and provide written consent and copies for them tomorrow. Enrolled and randomized at [date and time].  Randomized to [NoNO treatment or placebo] arm.  Vial # [enter number].  Subject ID # [enter ID number].  Study drug mixed in 10cc NS as per directions. [Drug Dose] was injected into a 100cc NS minibag and the contents infused over 20 mins ([IV start time and IV stop time]) with a NS flush of the IV line afterwards.   BP at beginning of infusion was [BP measurement] at [time] and  BP at end of infusion was [BP measurement] at [time]. BP 60 minutes post-dose was [BP measurement] at [time]. Patient was observed throughout the infusion. [note any flushing, any adverse reactions].

Key notes:

-       Ask nurses to note down BP at beginning of infusion, end of infusion, and one hour post dose.

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) 

Sunnycare note: Discussion with [patient name/SDM] regarding TNK and ACT-GLOBAL/ACT-WHEN trial enrollment. Briefly, using lay language, explained the overall platform trial, and explained the ACT-WHEN TNK doses interventions, potential risks, and follow-ups. Discussed alternatives (including not enrolling) and that patient can withdraw consent for follow-ups later if they wish. Verbal consent provided/no concerns raised. [patient/SDM] understood the research coordinators will follow-up and provide written consent and copies for them tomorrow. Enrolled and randomized at [date and time].  Randomized to receive [TNK dose - 0.25mg/kg, 0.18mg/kg, no TNK] given at [time]. Subject ID # [enter ID number].

Key notes:

-      If patient is on a DOAC, note date and time last taken if known

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 if very-high baseline SBP [≥180mmHg]) 

• 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) 

Sunnycare note: Discussion with [patient name/SDM] regarding ACT-GLOBAL/ACT-ENCHANTED  trial enrollment.  Briefly, using lay language, explained the overall platform trial, and explained the ACT-ENCHANTED blood pressure targets, potential risks and benefits, and follow-ups. Verbal consent provided/no concerns raised.

This trial is randomizing people who undergo EVT and have sustained post-operative hypertension (sBP > 150) to one of 3 blood pressure targets. Patient has been randomized to:  [Conservative/ Moderate/Intensive  sustained BP control]. This is defined as a sBP reduction by [5-10mmHg or /10-20mmHg/30-50mmHg]. Pre-randomization sBP was [XmmHg], so the target BP is sBP [X-XmmHg].  This target should be achieved within 1 hour and maintained for 24 hours. Locally available and approved IV BP lowering agents should be used. If his sBP drops below target, pressors are not required to increase BP for the trial - only if clinically indicated based on his circumstances and medical need.

Order note: patient enrolled in ACT-GLOBAL BP domain [Conservative/ Moderate/Intensive  sustained BP control]. BP target goal is X-X mmHg continuous for 24 hours to be achieved within 1 hour. Do not use pressors if becomes less than target. Use standard of care meds. Please see note in sunnycare or call for any questions.

Key notes:

-      Ask nurse to start recording BP on Metavision at 15 min intervals starting from randomization (BP recordings required post randomization at 0mins, 15min, 30mins, 45mins, and at every hour)