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

Acute Ischemic Stroke Clinical Trial

— ASSENT  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02586233
• Other study ID #: DS1040-A-U103
• Secondary ID: 2015-001824-43
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: September 2015
• Est. completion date: August 13, 2019

Study information

• Verified date: August 2020
• Source: Daiichi Sankyo, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 106
• Est. completion date: August 13, 2019
• Est. primary completion date: August 13, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Acute Ischemic Stroke
• Cerebral Infarction
• Ischemia
• Stroke
• Thrombotic Disease

Intervention

Drug:
• DS-1040b
DS-1040b for IV infusion (0.6 mg to 9.6 mg) over 6-hour period
• Placebo
0.9% sodium chloride (placebo comparator) for IV infusion over 6-hour period

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Daiichi Sankyo, Inc.

Countries where clinical trial is conducted

United States,  Australia,  Czechia,  France,  Germany,  Italy,  Korea, Republic of,  Slovakia,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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