Clinical trial NCT02586233: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of DS-1040b in Subjects With Acute Ischemic Stroke
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Acute Ischemic Stroke
Thrombotic Disease
Keywords: Acute Ischemic Stroke
Thrombotic disease
DS-1040b
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
First posted: 2015-10-26
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: 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
timeFrame: Baseline up to 90 days post last dose, up to 3 years 11 months
Secondary outcomes:
measure: Summary of Pharmacokinetic (PK) Parameter Maximum (Peak) Observed Plasma Concentration (Cmax) of DS-1040b Following Ascending Doses in Participants With Acute Ischemic Stroke
timeFrame: Predose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours postdose
measure: 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
timeFrame: Predose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours postdose
measure: Summary of Pharmacokinetic Parameter Terminal Half-life (t1/2) of DS-1040b Following Ascending Doses in Participants With Acute Ischemic Stroke
timeFrame: Pre-dose, 0.5, 3, 6, 9, 12, 24, 48, 72, and 96 hours post-dose
measure: 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
timeFrame: Baseline and 6 hours postdose
measure: 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
timeFrame: 30 days post dose
measure: 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
timeFrame: Day 5 (baseline) and Day 90 post dose
Other outcomes:
Locations:
city: Mobile
country: United States
facility: University of South Alabama USA Health System
state: Alabama
city: Los Angeles
country: United States
facility: UCLA Medical Center Stroke Network
state: California
city: Colorado Springs
country: United States
facility: UC Health Memorial Hospital
state: Colorado
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Lexington
country: United States
facility: University of Kentucky Chandler Medical Center
state: Kentucky
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Edison
country: United States
facility: JFK Neuroscience Institute
state: New Jersey
city: New York
country: United States
facility: Icahn School Medicine at Mount Sinai
state: New York
city: Durham
country: United States
facility: Duke University Health System
state: North Carolina
city: Columbus
country: United States
facility: OSU - Wexner Medical Center
state: Ohio
city: Portland
country: United States
facility: Oregon Health Sciences University Hospital
state: Oregon
city: Hershey
country: United States
facility: Penn State Milton S. Hershey Medical Center
state: Pennsylvania
city: Columbia
country: United States
facility: Palmetto Health, USC School of Medicine
state: South Carolina
city: Chattanooga
country: United States
facility: Chattanooga Center for Neurologic Research
state: Tennessee
city: Houston
country: United States
facility: Houston Methodist
state: Texas
city: Sydney
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital Neurology Dept.
state: South Australia
city: Clayton
country: Australia
facility: Monash Health
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Brno
country: Czechia
facility: St. Annes University Hospital
city: Ostrava Vitkovice
country: Czechia
facility: Vitkovicka nemocnice a.s. Zaluzanskeho
city: Besançon
country: France
facility: CHRU Besançon - Hôpital Jean Minjoz
city: Bordeaux
country: France
facility: Hôpital Pellegrin - CHU Bordeaux
city: Lille
country: France
facility: CHRU Lille - Hôpital Roger Salengro
city: Altenburg
country: Germany
facility: Klinikum Altenburger Land
city: Essen
country: Germany
facility: Universittsklinikum Essen AR Klinik fr Neurologie
city: Frankfurt am Main
country: Germany
facility: Klinikum der Johann Wolfgang Goethe-Universitat
city: Città di Castello
country: Italy
facility: Ospedale di Citta di Castello
city: Gubbio
country: Italy
facility: Ospedale di Branca Largo Unita d'Italia
city: Piacenza
country: Italy
facility: Ospedale Guglielmo da Saliceto Via Taverna
city: Pietra Ligure
country: Italy
facility: Ospedaliero di Albenga - Pietra Ligure Dept Neurology
city: Pisa
country: Italy
facility: Azienda Ospedaliero Universitaria
city: Verona
country: Italy
facility: Ospedale Borgo Trento
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Seongnam-si
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Rimavská Sobota
country: Slovakia
facility: Svet zdravia a.s.,Vseobecna nemocnica Rimavska Sobota
city: Spišská Nová Ves
country: Slovakia
facility: NsP Spisska Nova Ves
city: Barcelona
country: Spain
facility: Hospital de la santa creu i sant pau C
city: Barcelona
country: Spain
facility: Vall d'Hebron Hospital
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Santiago de Compostela
country: Spain
facility: Hospital Clínico Universitario de Santiago de Compostela
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen Macarena
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocio
city: Valladolid
country: Spain
facility: Hospital Clinico Universitario de Valladolid
city: Zaragoza
country: Spain
facility: Hospital Clinico Universitario Lozano Blesa de Zaragoza
city: Taoyuan
country: Taiwan
facility: Chang Gung Memorial Hospital-Linkou Branch
state: Hsien
city: Taichung
country: Taiwan
facility: China Medical University Hospital
city: Tainan
country: Taiwan
facility: National Cheng Kung University Hospital
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: London
country: United Kingdom
facility: University College Hospitals NHS Foundation Trust
state: England
city: Glasgow
country: United Kingdom
facility: Queen Elizabeth University Hospital
state: Scotland
city: Salford
country: United Kingdom
facility: Salford Royal Hospital
city: Stoke-on-Trent
country: United Kingdom
facility: Royal Stoke University Hospital
Study officials:
affiliation: Daiichi Sankyo
name: Global Clinical Leader
role: STUDY_DIRECTOR
References: