Efficacy and Safety of SP-8203 (Otaplimastat) in Patients With Acute Ischemic Stroke Receiving Thrombolytic Standard of Care

Official title

A Multi-Center, Randomized, Double-Blind, Parallel, Placebo-Controlled, Phase III Clinical Study to Evaluate Efficacy and Safety of SP-8203 (Otaplimastat) in Patients With Acute Ischemic Stroke Requiring Thrombolytic Therapy as Standard of Care

Overview

This clinical study is designed to evaluate the efficacy and safety of the combination therapy of SP-8203 (otaplimastat) and thrombolytic standard of care in acute ischemic stroke patient. As a standard of care, thrombolytic therapy (for instance, recombinant tissue plasminogen activator) will be administered. When reperfusion is not achieved in spite of thrombolytic therapy, endovascular therapy can be performed.

Detailed description

Intravenous administration of SP-8203 (otaplimastat), a multipotent neuroprotectant inhibiting matrix metalloprotease activity, significantly reduced infarct volume and recombinant tissue plasminogen activator (rtPA)/ ischemic-induced damage in animal models.

This clinical study is designed to evaluate the efficacy and safety of the combination therapy of SP-8203 (otaplimastat) and thrombolytic standard of care in acute ischemic stroke patient.

As a standard of care, thrombolytic therapy (for instance, recombinant tissue plasminogen activator) will be administered. When reperfusion is not achieved in spite of thrombolytic therapy, endovascular therapy can be performed.

A total of 852 participants will be enrolled in double-blind, randomized and parallel design with 426 participants assigned to 80 mg/day SP-8203 arm or placebo arm, respectively.

Eligible participants are the patients with neurologic deficit of ≥8 point on National Institute of Health Stroke Scale (NIHSS) score. The participant will receive the study intervention a total of 6 times, with 12 hours intervals. Imaging test will be performed using validated machine and method. The participant will have initial brain Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA) performed within 6 hours before or after the administration of study intervention, and brain Computed Tomography (CT) will be performed at 24±3 hours after completion of the first administration of study intervention.

Brain Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA) will be followed-up on Day 5, and additionally the participant will undergo additional functional and neurological evaluations for up to 90 days.

When unexpected serious adverse reaction occurs during the clinical study, Data Safety Monitoring Board (DSMB) will be convened to validation safety.

Interventions

• Drug SP-8203
  SP-8203 80 mg will be intravenously administered as 40 mg/dose twice daily (intervals of 12 hours)
• Drug Placebo
  Placebo will be intravenously administered twice daily (intervals of 12 hours)

Primary outcome measures

• Proportion of participants with modified Rankin Scale (mRS) 0-1 [Time frame: Day 90]

Secondary outcome measures (10)

• Incidence of parenchymal hematoma observed on brain Computed Tomography (CT) scan [Time frame: Day 1]
• Proportion of participants with modified Rankin Scale (mRS) 0-1 [Time frame: Day 30]
• Proportion of participants with modified Rankin Scale (mRS) 0-2 [Time frame: Day 30 and Day 90]
• Change from Baseline in National Institute of Health Stroke Scale (NIHSS) scores [Time frame: Day 0 (baseline), Day 3, Day 5, Day 30 and Day 90]
• Fold change in infarct growth classified by modified treatment in cerebral ischemia (mTICI) grade within 5 days [Time frame: Day 5]
• The incidence of serious adverse events [Time frame: follow-up to 90 days after the first study intervention administration]
• The rate of death [Time frame: follow-up to 90 days after the first study intervention administration]
• The incidence rate of adverse events, and adverse drug reaction [Time frame: follow-up to 90 days after the first study intervention administration]
• The incidence of symptomatic Intracranial Hemorrhage (sICH) [Time frame: within 5 days from the first study intervention administration]
• The Incidence of major systemic bleeding [Time frame: within 5 days after the first study intervention administration]

Eligibility criteria

Inclusion criteria

• Patients with neurologic deficit of ≥ 8 points by National Institute of Health Stroke Scale (NIHSS) score
• Patients with pre-stroke modified Rankin Scale (mRS) must be 0 or 1, which means they were able to carry out all usual duties and activities
• Adults aged ≥19 years and ≤85 years
• Patients who can receive thrombolytic standard of care within 4.5 hours after the onset of early symptoms of acute ischemic stroke
• Patients available for brain Magnetic Resonance Imaging (MRI) scanning
• Patients who consent to participate in this study

Exclusion criteria

• Patients with systemic allergic diseases or hypersensitivity to specific drugs.
• Patients who were diagnosed with myocardial infarction (MI) within the last 6 months.
• Patients who had arrhythmia causing clinical symptoms such as dyspnea or palpitation within the last 6 months.
• Patients showing the following abnormal ECG findings in stable condition at Emergency Room:

• The range of pulse rate - under 55/min or exceed 120/min
• 2nd or 3rd degree Atrioventricular (AV) block indicated in ECG
• Congenital or acquired QT syndrome indicated in ECG
• Pre-excitation syndrome indicated in ECG
• Patients with severe heart failure of New York Heart Association (NYHA) Class III or Class IV.
• Patients with fever (≥ 38℃) or infection signs which require antibiotic therapy at screening.
• Patients with pulmonary diseases (asthma, Chronic Obstruction Pulmonary disease, and active tuberculosis etc.) who have being recently been treated more than 1 month at screening.
• Patients with decreased hemoglobin (Hb< 10g/dL), decreased platelet count (PLT< 100,000/mm3) or hematocrit of <25% in complete blood count.
• Patients who have undergone hemodialysis and/or treatments due to nephropathies, acute or chronic renal failure at screening.
• Patients with a cancer in following conditions: diagnosed within 6 months before the screening time, or any treatment for cancer within the previous 6 months, or with recurrent/ metastatic cancer.
• Pregnant and lactating women. However, Women of Childbearing Potential (WOCBP) can participate in the study only when non-pregnancy is confirmed. Women of Childbearing Potential (WOCBP) is defined as woman who is not definitely menopause and did not receive a surgical contraception.
• Patients who do not consent to use double barrier contraception until 90 days from the first study intervention administration.
• Patients who have participated in other clinical trials of other drugs within the past 3 months. However, if they participated in observational studies and did not take drugs, they can participate in this trial.
• Patients who cannot participate in the study at the discretion of investigators
• Patients who are unable to receive thrombolytic standard of care, rtPA

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

South Korea · 2 centers

• Dong-A University Hospital — Busan
• Ulsan University Hospital — Ulsan

Identifiers

NCT: NCT06660719 · SP-8203-3001

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗