Safety of DS-1040b in Acute Ischemic Stroke Patients Treated With Thrombectomy

Study Overview
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Brief Summary
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The aim of this study is to find out if DS-1040b is safe and tolerable in acute ischemic stroke patients with thrombectomy. Four groups will receive different doses of DS-1040b by intravenous infusion for 6 hours. Groups with the lowest dose will start. When it is determined that each dose is safe and tolerable, the next higher dose will be given to the next group.

Official Title
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A Phase I, Single Blind, Placebo-controlled, Randomized Study to Assess the Safety of DS-1040b in Subjects With Thrombectomy Treated Acute Ischemic Stroke.

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: DS1040b
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is an acute ischemic stroke patients with evidence of intracranial vascular occlusion Is enrolled in principle within 8 hours of symptom onset Has treatment plan that includes stent retriever Has protocol-defined scores on several scales Exclusion Criteria: Has treatment plan that includes fibrinolysis or fibinolysis Has identified intracranial hemorrhage or subarachnoid hemorrhage Has active bleeding like gastrointestinal hemorrhage Has cerebral bleeding risk; intracranial tumor, brain aneurysm, cerebral arteriovenous malformation, or history of intracranial bleeding Has severe hepatic or renal impairment Has been a participant in other clinical trial within 30 days prior to treatment Is pregnant, lactating, or planning on becoming pregnant during treatment period Has any condition or history that might, per protocol or in the opinion of the investigator, compromise: safety or well-being of the participant or their offspring safety of the study staff analysis of results

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 89 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: DS-1040b 0.6 mg<br>Participants receive DS-1040b 0.6 mg by intravenous infusion over six hours | Drug: DS1040b<br>* DS-1040b in solution for intravenous infusion<br>* Other names: Investigational product;|
| Experimental: DS-1040b 1.2 mg<br>Participants receive DS-1040b 1.2 mg by intravenous infusion over six hours | Drug: DS1040b<br>* DS-1040b in solution for intravenous infusion<br>* Other names: Investigational product;|
| Experimental: DS-1040b 2.4 mg<br>Participants receive DS-1040b 2.4 mg by intravenous infusion over six hours | Drug: DS1040b<br>* DS-1040b in solution for intravenous infusion<br>* Other names: Investigational product;|
| Experimental: DS-1040b 4.8 mg<br>Participants receive DS-1040b 4.8 mg by intravenous infusion over six hours | Drug: DS1040b<br>* DS-1040b in solution for intravenous infusion<br>* Other names: Investigational product;|
| Placebo Comparator: Placebo<br>Participants receive saline by intravenous infusion over six hours | Drug: Placebo<br>* Saline solution for intravenous infusion<br>* Other names: Saline solution;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Symptomatic or Asymptomatic Intracranial Hemorrhage (ICH) Within 36 Hours From Start of Treatment With DS-1040b in Acute Ischemic Stroke Participants | Symptomatic and asymptomatic intracranial hemorrhage (ICH) confirmed by head imaging (CT or MRI) are reported. Symptomatic ICH was defined as Intracranial hemorrhage with clinical deterioration causing an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥ 4 points (defined by European Cooperative Acute Stroke Study). Asymptomatic ICH included the following: Hemorrhagic infarction type 1: Small petechial hemorrhage along the margins of the infarct, Hemorrhagic infarction type 2: Confluent petechial hemorrhage within the infarcted area, but without a mass effect, Parenchymal hematoma type 1: Hematoma involving ≤ 30% of the infarcted area with a slight mass effect, Parenchymal hematoma type 2: Hematoma involving > 30% of, or outside the infarcted area, with a significant mass effect. | From start of treatment up to 36 hours post single, intravenous dose | 
| Number of Participants With Non-ICH Major Bleeding Within 96 Hours From Start of Treatment With DS-1040b In Acute Ischemic Stroke Participants | Non-ICH was defined as a clinically evident bleeding with a 5 g/dL or greater decrease in hemoglobin. | From start of treatment up to 96 hours post single, intravenous dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic Analysis Area Under The Plasma Concentration Time Curve (AUC) of DS-1040a in Plasma | The pharmacokinetic (PK) parameter of area under the plasma concentration-time curve up to the last quantifiable time was calculated using linear up logarithmic down rule. | Predose, 0.5 hours (h), 3 h, 6 h, 18 h, 24 h, 48 h, and 96 h post single, intravenous dose | 
| Pharmacokinetic Analysis Maximum Concentration (Cmax) of DS-1040a in Plasma | The PK parameter of maximum concentration (Cmax) was observed values. | Predose, 0.5 hours (h), 3 h, 6 h, 18 h, 24 h, 48 h, and 96 h post single, intravenous dose | 
| Pharmacokinetic Analysis Time to Maximum Concentration (Tmax) of DS-1040b in Plasma | The PK parameter of time to maximum concentration (Tmax) was observed values. When there are more than one time point, the time point when the concentration reached the first Cmax will be used as Tmax. | Predose, 0.5 hours (h), 3 h, 6 h, 18 h, 24 h, 48 h, and 96 h post single, intravenous dose | 
| Pharmacokinetic Analysis Terminal Half-Life (T1/2) of DS-1040b in Plasma | The PK parameter of terminal half-life (T1/2) was calculated from the following formula in participants whose Kel could be calculated. T1/2=ln2 / Kel | Predose, 0.5 hours (h), 3 h, 6 h, 18 h, 24 h, 48 h, and 96 h post single, intravenous dose | 
| Pharmacokinetic Analysis Mean Amount of DS-1040a Excreted in Urine in Acute Ischemic Stroke Participants | The pharmacokinetic parameter of amount of drug excreted in urine was calculated from the following formula: urine concentration (ng/mL) /10^6× (urine weight / urinary specific gravity) | From start of treatment up to 24 hours post single, intravenous dose | 
| Pharmacodynamic Analysis Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Antigen Levels in Plasma and Change From Baseline in Acute Ischemic Stroke Participants | The mean thrombin activatable fibrinolysis (TAFI) antigen levels and change from baseline in TAFI levels are reported. Change from baseline is based on the number of participants with baseline and at least one post-baseline laboratory test. | Baseline, 6 hours and 24 hours post single, intravenous dose | 
| Pharmacodynamic Analysis D-dimer Levels in Plasma and Change From Baseline in Acute Ischemic Stroke Participants | Mean D-dimer levels and change from baseline in D-dimer levels are reported.Change from baseline is based on the number of subjects with baseline and at least one post-baseline laboratory test. | Baseline, 6 hours, 24 hours, and 48 hours post single, intravenous dose | 
| Pharmacodynamic Analysis Activated Form of Thrombin-Activatable Fibrinolysis Inhibitor (TAFIa) Activity and Change From Baseline in Acute Ischemic Stroke Participants | Mean activated form of thrombin-activatable fibrinolysis inhibitor (TAFIa) and change from baseline in TAFIa are reported. Change from baseline is based on the number of subjects with baseline and at least one post-baseline laboratory test. | Baseline, 6 hours, 24 hours, and 48 hours post single, intravenous dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Developmental Phase I, Fibrinolysis enhancer, TAFIa inhibitor