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

Phase 1

Completed

Conditions: Thrombotic Disease
Acute Ischemic Stroke

Interventions: Drug: Placebo
Drug: DS-1040b

Registration Number: NCT02586233

Lead Sponsor: Daiichi Sankyo

Brief Summary: 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).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 106

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants who will be randomized to receive intravenous (IV) infusion of placebo.
DS-1040b	DS-1040b	Participants who will be randomized to receive intravenous (IV) infusion of DS-1040b ranging from 0.6 mg to 9.6 mg.

Primary Outcome Measures

Name	Time	Method
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	Baseline up to 90 days post last dose, up to 3 years 11 months	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.

Secondary Outcome Measures

Name	Time	Method
Summary of Pharmacokinetic (PK) Parameter Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b Following Ascending Doses in Participants With Acute Ischemic Stroke	Predose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours postdose	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
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	Predose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours postdose	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
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	Baseline and 6 hours postdose	The enzymatic activity of thrombin-activatable fibrinolysis inhibitor was assessed using the Stago Coagulation Analyzer.
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	30 days post dose	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.
Summary of Pharmacokinetic Parameter Terminal Half-life (t1/2) of DS-1040b Following Ascending Doses in Participants With Acute Ischemic Stroke	Pre-dose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours post-dose	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.
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	Day 5 (baseline) and Day 90 post dose	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.

Trial Locations

Locations (55): University of Louisville
🇺🇸
Louisville, Kentucky, United States
Palmetto Health, USC School of Medicine
🇺🇸
Columbia, South Carolina, United States
Chattanooga Center for Neurologic Research
🇺🇸
Chattanooga, Tennessee, United States
Monash Health
🇦🇺
Clayton, Victoria, Australia
Royal Melbourne Hospital
🇦🇺
Parkville, Victoria, Australia
Svet zdravia a.s.,Vseobecna nemocnica Rimavska Sobota
🇸🇰
Rimavská Sobota, Slovakia
NsP Spisska Nova Ves
🇸🇰
Spišská Nová Ves, Slovakia
Chang Gung Memorial Hospital-Linkou Branch
🇨🇳
Taoyuan, Hsien, Taiwan
China Medical University Hospital
🇨🇳
Taichung, Taiwan
Klinikum Altenburger Land
🇩🇪
Altenburg, Germany
Penn State Milton S. Hershey Medical Center
🇺🇸
Hershey, Pennsylvania, United States
CHRU Lille - Hôpital Roger Salengro
🇫🇷
Lille, France
University of Kentucky Chandler Medical Center
🇺🇸
Lexington, Kentucky, United States
Ospedale di Branca Largo Unita d'Italia
🇮🇹
Gubbio, Italy
JFK Neuroscience Institute
🇺🇸
Edison, New Jersey, United States
Samsung Medical Center
🇰🇷
Seoul, Korea, Republic of
Hôpital Pellegrin - CHU Bordeaux
🇫🇷
Bordeaux, France
University of South Alabama USA Health System
🇺🇸
Mobile, Alabama, United States
Azienda Ospedaliero Universitaria
🇮🇹
Pisa, Italy
Ospedale Borgo Trento
🇮🇹
Verona, Italy
UC Health Memorial Hospital
🇺🇸
Colorado Springs, Colorado, United States
Hospital de la santa creu i sant pau C
🇪🇸
Barcelona, Spain
Royal Stoke University Hospital
🇬🇧
Stoke-on-Trent, United Kingdom
Vall d'Hebron Hospital
🇪🇸
Barcelona, Spain
Universittsklinikum Essen AR Klinik fr Neurologie
🇩🇪
Essen, Germany
Pusan National University Hospital
🇰🇷
Busan, Korea, Republic of
National Cheng Kung University Hospital
🇨🇳
Tainan, Taiwan
Ospedale Guglielmo da Saliceto Via Taverna
🇮🇹
Piacenza, Italy
Ospedale di Citta di Castello
🇮🇹
Città di Castello, Italy
St. Annes University Hospital
🇨🇿
Brno, Czechia
Klinikum der Johann Wolfgang Goethe-Universitat
🇩🇪
Frankfurt am Main, Germany
Ospedaliero di Albenga - Pietra Ligure Dept Neurology
🇮🇹
Pietra Ligure, Italy
CHRU Besançon - Hôpital Jean Minjoz
🇫🇷
Besançon, France
Seoul National University Bundang Hospital
🇰🇷
Seongnam-si, Korea, Republic of
Salford Royal Hospital
🇬🇧
Salford, United Kingdom
Royal Adelaide Hospital Neurology Dept.
🇦🇺
Adelaide, South Australia, Australia
Hospital Clinico Universitario Lozano Blesa de Zaragoza
🇪🇸
Zaragoza, Spain
National Taiwan University Hospital
🇨🇳
Taipei, Taiwan
Hospital Clinico Universitario de Valladolid
🇪🇸
Valladolid, Spain
Hospital Universitario Virgen Macarena
🇪🇸
Sevilla, Spain
Queen Elizabeth University Hospital
🇬🇧
Glasgow, Scotland, United Kingdom
UCLA Medical Center Stroke Network
🇺🇸
Los Angeles, California, United States
Rush University Medical Center
🇺🇸
Chicago, Illinois, United States
OSU - Wexner Medical Center
🇺🇸
Columbus, Ohio, United States
Duke University Health System
🇺🇸
Durham, North Carolina, United States
Oregon Health Sciences University Hospital
🇺🇸
Portland, Oregon, United States
Henry Ford Health System
🇺🇸
Detroit, Michigan, United States
Icahn School Medicine at Mount Sinai
🇺🇸
New York, New York, United States
Houston Methodist
🇺🇸
Houston, Texas, United States
Royal North Shore Hospital
🇦🇺
Sydney, New South Wales, Australia
Vitkovicka nemocnice a.s. Zaluzanskeho
🇨🇿
Ostrava Vitkovice, Czechia
University College Hospitals NHS Foundation Trust
🇬🇧
London, England, United Kingdom
Hospital Universitario La Paz
🇪🇸
Madrid, Spain
Hospital Virgen del Rocio
🇪🇸
Sevilla, Spain
Hospital Clínico Universitario de Santiago de Compostela
🇪🇸
Santiago de Compostela, Spain