Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of DS-1040b in Subjects With Acute Ischemic Stroke (ASSENT)

A Phase 1b/2, Multi-Center, Double-Blind (Principal Investigators and Study Subjects Blinded, Sponsor Unblinded), Placebo-Controlled, Randomized, Single-Ascending Dose Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of DS-1040b in Subjects With Acute Ischemic Stroke

This is a Phase 1b/2, double-blind (study participants and Investigators), placebo-controlled, randomized, single-ascending dose, multi-center study to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of DS-1040b in participants with Acute Ischemic Stroke (AIS).

Study Overview

• Status: Completed
• Conditions: Acute Ischemic Stroke; Thrombotic Disease
• Intervention / Treatment: Drug: DS-1040b; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 106
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2065
      • Royal North Shore Hospital
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Royal Adelaide Hospital Neurology Dept.
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Health
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital
• Czechia
  • Brno, Czechia
    • St. Annes University Hospital
  • Ostrava Vitkovice, Czechia
    • Vitkovicka nemocnice a.s. Zaluzanskeho
• France
  • Besançon, France, 25000
    • CHRU BESANCON - Hopital Jean Minjoz
  • Bordeaux, France, 33000
    • Hôpital Pellegrin - CHU BORDEAUX
  • Lille, France, 59037
    • CHRU Lille - Hôpital Roger Salengro
• Germany
  • Altenburg, Germany, 04600
    • Klinikum Altenburger Land
  • Essen, Germany
    • Universittsklinikum Essen AR Klinik fr Neurologie
  • Frankfurt am Main, Germany
    • Klinikum der Johann Wolfgang Goethe-Universität
• Italy
  • Città di Castello, Italy, 06018
    • Ospedale di Citta di Castello
  • Gubbio, Italy, 06024
    • Ospedale di Branca Largo Unita d'Italia
  • Piacenza, Italy, 29121
    • Ospedale Guglielmo da Saliceto Via Taverna
  • Pietra Ligure, Italy, 17027
    • Ospedaliero di Albenga - Pietra Ligure Dept Neurology
  • Pisa, Italy, 56126
    • Azienda Ospedaliero Universitaria
  • Verona, Italy, 37121
    • Ospedale Borgo Trento
• Korea, Republic of
  • Busan, Korea, Republic of
    • Pusan National University Hospital
  • Seongnam-si, Korea, Republic of
    • Seoul National University Bundang Hospital
  • Seoul, Korea, Republic of
    • Samsung Medical Center
• Slovakia
  • Rimavská Sobota, Slovakia
    • Svet zdravia a.s.,Vseobecna nemocnica Rimavska Sobota
  • Spišská Nová Ves, Slovakia
    • NsP Spisska Nova Ves
• Spain
  • Barcelona, Spain
    • Vall d'Hebron Hospital
  • Barcelona, Spain
    • Hospital de la santa creu i sant pau C
  • Madrid, Spain
    • Hospital Universitario La Paz
  • Santiago de Compostela, Spain
    • Hospital Clínico Universitario de Santiago de Compostela
  • Sevilla, Spain
    • Hospital Virgen del Rocío
  • Sevilla, Spain
    • Hospital Universitario Virgen Macarena
  • Valladolid, Spain
    • Hospital Clínico Universitario de Valladolid
  • Zaragoza, Spain
    • Hospital Clinico Universitario Lozano Blesa de Zaragoza
• Taiwan
  • Taichung, Taiwan
    • China Medical University Hospital
  • Tainan, Taiwan
    • National Cheng Kung University Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
  • Hsien
    • Taoyuan, Hsien, Taiwan
      • Chang Gung Memorial Hospital-Linkou Branch
• United Kingdom
  • Salford, United Kingdom
    • Salford Royal Hospital
  • Stoke-on-Trent, United Kingdom
    • Royal Stoke University Hospital
  • England
    • London, England, United Kingdom
      • University College Hospitals NHS Foundation Trust
  • Scotland
    • Glasgow, Scotland, United Kingdom
      • Queen Elizabeth University Hospital
• United States
  • Alabama
    • Mobile, Alabama, United States, 36604
      • University of South Alabama USA Health System
  • California
    • Los Angeles, California, United States, 90024
      • UCLA Medical Center Stroke Network
  • Colorado
    • Colorado Springs, Colorado, United States, 80909
      • UC Health Memorial Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
  • New Jersey
    • Edison, New Jersey, United States, 08820
      • JFK Neuroscience Institute
  • New York
    • New York, New York, United States, 10029
      • Icahn School Medicine at Mount Sinai
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Health System
  • Ohio
    • Columbus, Ohio, United States, 43210
      • OSU - Wexner Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University Hospital
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • Palmetto Health, USC School of Medicine
  • Tennessee
    • Chattanooga, Tennessee, United States, 37403
      • Chattanooga Center for Neurologic Research
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Has a clinical diagnosis of acute ischemic stroke (including lacunar stroke/infarct) supported by computed topography or magnetic resonance imaging to rule out alternative cause for presenting symptoms
• Has onset of stroke symptoms within 4.5 to 12 hours before initiation of study drug administration - for subjects with a stroke upon waking, time of symptom onset is the last time the subject was known to be well
• Has a NIHSS score of ≥ 2 (for Cohorts 1-5) and ≥ 5 (for Cohort 6)
• Has Low dose heparin or low molecular weight heparin at a preventive dose are allowed from 24 hours after treatment start completion and after confirmation of no intracranial bleeding on the 24-hours repeat brain imaging.
• Is a Cohort 6 participant who is treated or anticipated to be treated with intra-arterial therapy (IAT) for ischemic stroke at the time of randomization (for enrollment in the IAT subgroup)
• Has given written informed consent to participate in the study prior to participating in any study-related procedures - depending on country-specific practice, written informed consent may be acceptable from legally authorized representative
• Has given a separate written informed consent for collecting a blood sample for genotyping

Exclusion Criteria:

• Is a Cohort 1-5 participant who has been treated or is going to be treated with tissue plasminogen activator (tPA) and/or endovascular thrombectomy during current stroke
• Is a Cohort 6 participant treated or anticipated to be treated with tPA during current stroke
• Has evidence of intracranial hemorrhage on non-contrast computed tomography (CT/CAT) scan or magnetic resonance imaging (MRI)
• Has symptoms of subarachnoid hemorrhage, even with normal imaging
• Has an Alberta Stroke Program Early CT Score (ASPECTS) <6
• Has prior non-traumatic intracranial hemorrhage (excluding microhemorrhages observed in imaging)
• Has known arteriovenous malformation or aneurysm
• Has evidence of active bleeding
• Has platelet count less than 100,000
• Has International Normalized Ratio greater than 1.7
• Has used unfractionated heparin within 24 hours prior to treatment and has an elevated partial thromboplastin time
• Has used a non-vitamin K antagonist oral anticoagulant such as dabigatran, rivaroxaban, apixaban, or other factor Xa inhibitors within 24 hours before treatment
• Has used fondaparinux or low molecular weight heparin at an anticoagulation dose within 24 hours prior to treatment
• Has anticipated use of an anticoagulation dose of heparin, or fondaparinux or low molecular weight heparin, or nonvitamin K antagonist oral anticoagulant such as dabigatran, rivaroxaban, apixaban, or other factor Xa inhibitors within 48 hours after completion of study drug treatment (low dose heparin or low molecular weight heparin at a preventive dose are allowed from 24 hours after treatment completion and after confirmation of no intracranial bleeding on the 24 hours repeat brain imaging. In Cohort 6, heparin treatment associated with IAT is allowed.)
• Has blood pressure > 185/110 mmHg, or requires aggressive medication to maintain blood pressure below this limit (routine medical treatment including IV drug treatment is allowed to lower the blood pressure below this limit)
• Has had intracranial surgery, clinically significant head trauma (in the opinion of Principal Investigator), Alteplase treatment, or a previous stroke within 1 month
• Has had major surgery within 14 days
• Has had gastrointestinal or genitourinary bleeding in the last 21 days
• Has had a lumbar puncture (or epidural steroid injection) within 14 days
• Has had a preexisting disability classified by modified Rankin Scale (mRS) > 2
• Has an estimated glomerular filtration rate < 60 mL/min/1.73 m^2
• Has baseline hemoglobin < 10.5 g/dL
• Has a positive pregnancy test
• Is currently participating in another investigational study or has participated in an investigational drug study within 30 days or 5 half-lives of that investigational drug prior to administration of the study drug
• Is an employee or an immediate family member of an employee of the Sponsor, the Contract Research Organization (CRO), or the Site
• Has any other condition the investigator determines would preclude participation in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: SINGLE_GROUP
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: DS-1040b; Participants who will be randomized to receive intravenous (IV) infusion of DS-1040b ranging from 0.6 mg to 9.6 mg.	Drug: DS-1040b; DS-1040b for IV infusion (0.6 mg to 9.6 mg) over 6-hour period; Other Names: Experimental product
PLACEBO_COMPARATOR: Placebo; Participants who will be randomized to receive intravenous (IV) infusion of placebo.	Drug: Placebo; 0.9% sodium chloride (placebo comparator) for IV infusion over 6-hour period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Treatment-Emergent Adverse Event Reported by >10% of Participants Following Ascending Doses of DS-1040b and a Placebo in Participants With Acute Ischemic Stroke	Treatment-emergent adverse event (TEAE) is defined as an adverse event that emerges during the treatment period (from first dose date until 30 days after the last dosing date), having been absent at predose; or reemerges during treatment, having been present at baseline but stopped prior to treatment; or worsens in severity after starting treatment relative to the pre-dose state, when the adverse event is continuous.	Baseline up to 90 days post last dose, up to 3 years 11 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Summary of Pharmacokinetic (PK) Parameter Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b Following Ascending Doses in Participants With Acute Ischemic Stroke	The PK parameter of Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b was calculated from the plasma concentrations of DS-1040b using non-compartmental analysis	Predose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours postdose
Summary of Pharmacokinetic Parameter Area Under the Concentration Versus Time Curve From Zero to Last Quantifiable Concentration Sampling Point (AUClast) of DS-1040b Following Ascending Doses in Participants With Acute Ischemic Stroke	The PK parameter of Area Under the Concentration Versus Time Curve from Zero to Last Quantifiable Concentration Sampling Point of DS-1040b was calculated from the plasma concentrations of DS-1040b using non-compartmental analysis	Predose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours postdose
Summary of Pharmacokinetic Parameter Terminal Half-life (t1/2) of DS-1040b Following Ascending Doses in Participants With Acute Ischemic Stroke	The PK parameter of Terminal Half-life of DS-1040b was calculated from the plasma concentrations of DS-1040b using non-compartmental analysis in patients with available sample for the analysis.	Pre-dose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours post-dose
Summary of Activated Form of Thrombin-activatable Fibrinolysis Inhibitor (TAFIa) Following Ascending Doses of DS-1040b and a Placebo in Participants With Acute Ischemic Stroke	The enzymatic activity of thrombin-activatable fibrinolysis inhibitor was assessed using the Stago Coagulation Analyzer.	Baseline and 6 hours postdose
Summary of Changes From Baseline at Day 30 in National Institute of Health Stroke Scale (NIHSS) Score Following Ascending Doses of DS-1040b and a Placebo in Participants With Acute Ischemic Stroke	The National Institute of Health Stroke Scale (NIHSS) quantifies stroke severity based on weighted evaluation findings. The score for each ability is a number between 0 and 4, with 0 being normal functioning and 4 being completely impaired. The patient's NIHSS score is calculated by adding the number for each element of the scale; 42 is the highest score possible. In the NIHSS, the higher the score indicates more impairment (worse outcome) in a stroke patient.	30 days post dose
Percentage of Participants With a Modified Rankin Scale (mRS) Score of 0 to 2 Following Ascending Doses of DS-1040b and a Placebo in Participants With Acute Ischemic Stroke	The modified Rankin scale (mRS) is a commonly used disability scale derived from the Rankin scale that is used to measure the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. The level of disability following a stroke is assessed via a scale from 0 to 6, where 0 is no symptoms at all and 6 indicates death. Higher scores indicate worse outcome. The percentage of participants with an mRS score of 0 to 2 at Day 5 (baseline) and Day 90 is being reported.	Day 5 (baseline) and Day 90 post dose

Collaborators and Investigators

• Sponsor: Daiichi Sankyo, Inc.

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 1, 2015
• Primary Completion (ACTUAL): August 13, 2019
• Study Completion (ACTUAL): August 13, 2019

Study Registration Dates

• First Submitted: October 21, 2015
• First Submitted That Met QC Criteria: October 23, 2015
• First Posted (ESTIMATE): October 26, 2015

Study Record Updates

• Last Update Posted (ACTUAL): September 9, 2020
• Last Update Submitted That Met QC Criteria: August 21, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: Acute Ischemic Stroke; Thrombotic disease; DS-1040b
• 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-U103; 2015-001824-43 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
• IPD Sharing Time Frame: Studies for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
• IPD Sharing Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents from clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

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