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

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

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.

Study Overview

• Status: Completed
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: DS1040b; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Japan
  • Hiroshima, Japan, 730-8518
    • Hiroshima City Hiroshima Citizens Hospital
  • Nagasaki, Japan, 852-8521
    • Nagasaki University Hospital
  • Niigata, Japan, 950-1197
    • Niigata City General Hospital
  • Wakayama, Japan, 641-8509
    • Wakayama Medical University Hospital
  • Aomori
    • Hirosaki, Aomori, Japan, 036-8563
      • Hirosaki University Hospital
  • Chiba
    • Funabashi, Chiba, Japan, 273-8588
      • Funabashi Municipal Medical Center
  • Fukuota
    • Kitakyushu, Fukuota, Japan, 802-8555
      • Kokura Memorial Hospital
  • Gunma
    • Isesaki, Gunma, Japan, 372-0006
      • Mihara Memorial Hospital
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8570
      • Nakamura Memorial Hospital
  • Hyogo
    • Amagasaki, Hyogo, Japan, 660-8511
      • Japan Organization of Occupational Health and Safety Kansai Rosai Hospital
    • Kobe, Hyogo, Japan, 650-0046
      • Kobe City Medical Center General Hospital
    • Nishinomiya, Hyogo, Japan, 663-8501
      • Hyogo College of Medicine College Hospital
  • Ibaraki
    • Tsukuba, Ibaraki, Japan, 305-8576
      • University of tsukuba hospital
  • Iwate
    • Morioka, Iwate, Japan, 020-0066
      • Iwate Prefectural Central Hospital
  • Kanagawa
    • Odawara, Kanagawa, Japan, 250-0001
      • Seisho Hospital
    • Yokohama, Kanagawa, Japan, 240-8555
      • Yokohama Municipal Citizen's Hospital
  • Mie
    • Tsu, Mie, Japan, 514-8507
      • Mie University Hospital
  • Osaka
    • Suita, Osaka, Japan, 565-8565
      • National Cerebral and Cardiovascular Center
  • Saitama
    • Hidaka, Saitama, Japan, 350-1298
      • Saitama Medical University International Medical Center
  • Yamaguchi
    • Ube, Yamaguchi, Japan, 755-8505
      • Yamaguchi University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 89 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. safety or well-being of the participant or their offspring
  2. safety of the study staff
  3. analysis of results

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Daiichi Sankyo Co., Ltd.

Publications and helpful links

General Publications

• Sakai N, Takeuchi M, Imamura H, Shimamura N, Yoshimura S, Naito H, Kimura N, Masuo O, Hirotsune N, Morita K, Toyoda K, Yamagami H, Ishihara H, Nakatsu T, Miyoshi N, Suda M, Fujimoto S. Safety, Pharmacokinetics and Pharmacodynamics of DS-1040, in Combination with Thrombectomy, in Japanese Patients with Acute Ischemic Stroke. Clin Drug Investig. 2022 Feb;42(2):137-149. doi: 10.1007/s40261-021-01112-8. Epub 2022 Jan 21.

Study record dates

Study Major Dates

• Study Start (Actual): July 30, 2017
• Primary Completion (Actual): January 19, 2020
• Study Completion (Actual): January 19, 2020

Study Registration Dates

• First Submitted: June 19, 2017
• First Submitted That Met QC Criteria: June 22, 2017
• First Posted (Actual): June 26, 2017

Study Record Updates

• Last Update Posted (Actual): January 28, 2021
• Last Update Submitted That Met QC Criteria: January 7, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Developmental Phase I; Fibrinolysis enhancer; TAFIa inhibitor
• Additional Relevant MeSH Terms: Pathologic Processes; Necrosis; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Brain Ischemia; Infarction; Brain Infarction; Stroke; Ischemic Stroke; Ischemia; Cerebral Infarction
• Other Study ID Numbers: DS1040-A-J110; 173612 (Registry Identifier: JAPIC CTI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No