Phase III Clinical Trial of rhTNK-tPA in Treating Acute Ischemic Stroke With Extended Time Window.

Official title

Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Clinical Trial of Recombinant Human TNK Tissue-Type Plasminogen Activator for Injection (rhTNK-tPA, Mingfule) in Intravenous Thrombolysis for Acute Ischemic Stroke With Extended Time Window (4.5-24 Hours After Onset).

Overview

This is a multicenter, randomized, double-blind, placebo-controlled Phase III clinical study designed to evaluate the efficacy of recombinant human tissue-type plasminogen activator variant (rhTNK-tPA) (0.25 mg/kg, maximum dose 25 mg) compared with placebo in patients with acute large vessel occlusive stroke who present within 4.5 to 24 hours of symptom onset. The study plans to enroll patients with acute large vessel occlusive stroke who present within 4.5 to 24 hours of symptom onset (including wake-up strokes and strokes without witnesses). A centralized 1:1 randomization will be adopted, and eligible participants will be randomly assigned to two groups: the experimental group will receive rhTNK-tPA at a dose of 0.25 mg/kg, while the placebo group will receive rhTNK-tPA placebo.

Detailed description

This multicenter, randomized, double-blind, placebo-controlled Phase III clinical study aims to evaluate the efficacy of recombinant human tissue-type plasminogen activator variant (rhTNK-tPA) (0.25 mg/kg, maximum dose 25 mg) compared with placebo in patients with acute large vessel occlusive stroke who present within 4.5 to 24 hours of symptom onset. The study initially planned to enroll 890 patients, who would be randomly assigned to the experimental group (rhTNK-tPA group) or the control group (placebo group) at a 1:1 ratio. After an unblinded sample size re-estimation during the interim analysis, the maximum sample size could be adjusted to 1,300 patients.

Key characteristics of the primary study population include: age ≥ 18 years; time from symptom onset to treatment ranging from 4.5 hours to 24 hours; occlusion of the internal carotid artery, M1 or M2 segment of the middle cerebral artery confirmed by computed tomography angiography (CTA)/magnetic resonance angiography (MRA), which is the responsible vessel for the signs and symptoms of acute ischemic stroke; modified Rankin Scale (mRS) score ≤ 1 before symptom onset; baseline National Institutes of Health Stroke Scale (NIHSS) score ≥ 6; and presence of target mismatch on computed tomography perfusion (CTP) or magnetic resonance imaging (MRI) combined with magnetic resonance perfusion (MRP) (ischemic core volume \< 70 mL, mismatch ratio ≥ 1.8, and mismatch volume ≥ 15 mL). Patients with a known allergy to rhTNK-tPA and those with contraindications to thrombolysis were excluded.

The entire study duration is approximately 90 days, including the screening period, treatment period, and follow-up period. The primary study endpoint is the proportion of participants with a modified Rankin Scale (mRS) score of 0-1 at the 90-day follow-up.

Interventions

• Drug rhTNK-tPA
  Each vial should be dissolved in 3mL of sterile water for injection to prepare a drug solution with a concentration of 5.33mg/mL. Calculate the total drug amount based on the participant's actual body weight, measure the required volume of the drug solution, and ensure the maximum dose does not exceed 25mg. Administer as a single bolus intravenous injection, completing the injection within 5-10 seconds.
• Drug Placebo
  One vial is dissolved in 3mL of sterile water for injection. Calculate the total drug amount based on the participant's actual body weight, then measure the required volume of the drug solution. Administer as a single bolus intravenous injection, completing the injection within 5-10 seconds.

Primary outcome measures

• The proportion of participants with a score of 0-1 on the modified Rankin Scale (mRS) [Time frame: At Day90.]

Secondary outcome measures (12)

• Incidence of symptomatic intracerebral hemorrhage within 36 hours after randomization [Time frame: 36 Hours after Randomization]
• Overall mortality rate at Day 90. [Time frame: At Day90.]
• Incidence of significant systemic hemorrhage (moderate to severe per GUSTO classification) at Day 90. [Time frame: At Day90.]
• Proportion of adverse events (AEs)/serious adverse events (SAEs) at Day 90. [Time frame: At Day90.]
• Modified Rankin Scale (mRS) score at Day 90 (shift analysis). [Time frame: At Day90.]
• Title: Proportion of participants with mRS score of 0-2 at Day 90. [Time frame: At Day90.]
• Proportion of participants with an NIHSS score of ≤1 or a reduction of ≥8 points from baseline within 72 hours after randomization. [Time frame: 72 Hours after Randomization.]
• Change in NIHSS score from baseline at Day 7. [Time frame: At Day7.]
• Proportion of participants with a Barthel Index (BI) score of ≥95 at Day 90. [Time frame: At Day90.]
• Rate of favorable reperfusion (90% improvement in Tmax >6s compared with prior status) within 24 hours after randomization. [Time frame: 24 Hours after Randomization.]
• Growth of irreversible cerebral infarction volume before treatment and 24 hours after treatment. [Time frame: 72 Hours after Treatment.]
• Proportion of participants with favorable reperfusion (TICI 2b/3 or TICI 3) on angiography before endovascular treatment (limited to participants who received endovascular treatment). [Time frame: Periprocedural]

Eligibility criteria

Inclusion criteria

• Aged ≥ 18 years, regardless of gender;
• Time from symptom onset to treatment is 4.5 - 24 hours(Including the boundary values.), including patients with wake-up stroke or stroke without witnesses; the time of symptom onset is defined as the "last known normal time";
• Modified Rankin Scale (mRS) score ≤ 1 before stroke onset;
• Baseline National Institutes of Health Stroke Scale (NIHSS) score ≥ 6;
• Neuroimaging findings: occlusion of the internal carotid artery (ICA), M1 or M2 segment of the middle cerebral artery (MCA) confirmed by computed tomography angiography (CTA)/magnetic resonance angiography (MRA), which is the responsible vessel for the signs and symptoms of acute ischemic stroke; presence of target mismatch on computed tomography perfusion (CTP) or magnetic resonance imaging (MRI) + magnetic resonance perfusion (MRP) (ischemic core volume < 70 mL, mismatch ratio ≥ 1.8, mismatch volume ≥ 15 mL);
• Voluntary signing of the informed consent form by the participant or their legal guardian.

Exclusion criteria

• Patients with known allergy to recombinant human tissue plasminogen activator (rhTNK-tPA);
• Patients with an expected life expectancy of less than 1 year;
• Patients with rapidly improving symptoms (which may indicate spontaneous recanalization), as determined by the investigator;
• Patients with a score of > 2 on Item 1a (Level of Consciousness) of the National Institutes of Health Stroke Scale (NIHSS), or those who had a seizure at stroke onset, or had hemiplegia after seizure, or had other neurological/psychiatric disorders that rendered them unable or unwilling to cooperate;
• Severe and persistent hypertension uncontrolled by medication ;
• Blood glucose < 2.8 mmol/L or > 22.2 mmol/L;
• Active internal bleeding with a high risk of hemorrhage;
• Any known coagulation disorder;
• Known platelet function defect or platelet count less than 100×10⁹/L;

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

China · 1 center

• Puyang Oilfield General Hospital — Puyang

Identifiers

NCT: NCT07201688 · MK02-003

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗