臨床研究等提出・公開システム

A phase 1, single blind, placebo-controlled, randomized study to assess the safety of DS-1040b in subjects with thombectomy-treated acute ischemic stroke.

Safety study of DS-1040b in acute ischemic stroke patients with thrombectomy

42

There were no major differences in background factors between the treatment groups.

Forty-two subjects were randomized; only 1 subject in DS-1040b 2.4 mg group did not receive the study drug. Forty-one subjects who received study drug (9 subjects in the pooled placebo group and 32 subjects in the pooled DS-1040b group) were included in the full analysis set and the safety analysis set. Of the 9 subjects who were randomized to the pooled placebo group, 2 subjects discontinued from the study. Of the 33 subjects who were randomized to the DS-1040b groups, 3 subjects discontinued from the study.

A TEAE is defined as an AE that is not present prior to the study and occurs after the start of study drug administration but before Visit 5 (Day 30), or an AE that worsens in severity after the start of study drug administration but before Visit 5 (Day 30). TEAEs were reported in 8 (88.9%) subjects in the pooled placebo group and 27 (84.4%) subjects in the pooled DS-1040b group. Drug-related TEAE was reported in only 1 (16.7%) subject (PT: subarachnoid haemorrhage) in the DS-1040b 0.6 mg group. Serious TEAEs were reported in 1 (11.1%) subject in the pooled placebo group and 4 (12.5%) subjects in the pooled DS-1040b group. None of these serious TEAEs were considered to be related to the study drug.

There were no subjects who had symptomatic ICH and non-intracranial (TIMI) major bleeding. Asymptomatic ICH occurred in 1 (11.1%) subject in the pooled placebo group and 12 (37.5%) subjects in the pooled DS-1040b group.

- An approximately dose-dependent increase in DS-1040a exposure (based on AUC) was observed over the dose range evaluated in this study. The mean t1/2 of DS-1040a ranged between 4.61 hours and 29.7 hours. - The mean baseline TAFIa activity (%NPP) was comparable between placebo and DS-1040b treated subjects: 88.7 for the pooled placebo subjects and 91.9 for the pooled DS-1040b subjects. At 6 hours post-dose, TAFIa activity decreased in DS-1040b treated subjects, while placebo treated subjects had a very slight increase in TAFIa activity. At 24 and 48 hours post-dose, TAFIa activity remained low in DS-1040b treated subjects while placebo treated subjects had practically no changes from baseline - The mean baseline D-dimer levels (micro g/mL FEU) were 3.096 in the pooled placebo group and 1.349 in the pooled DS-1040b group. D-dimer levels did not appear to change from baseline in both groups. - NIHSS: The mean baseline NIHSS total score was 20.0 in the pooled placebo group and 20.6 in the pooled DS-1040b group. The mean changes from baseline to 24 hours post-dose were similar between the pooled placebo group and the pooled DS-1040b group (-10.1 versus -11.8). - mRS: The proportion of subjects with good prognosis ( mRS score of 0 to 2) on Day 90 was 33.1% in the pooled placebo group and 20.6 % in the pooled DS-1040b group. There was no clinically noteworthy difference between the pooled placebo group and the pooled DS-1040b group. Additionally, there was no apparent dose response among the DS-1040b subjects on Day 90.

The objective of this study was to confirm the safety and tolerability of DS-1040b in patients with acute ischemic stroke in whom a thrombectomy device was indicated. There were no subjects who had symptomatic ICH and non-intracranial (TIMI) major bleeding. DS-1040b was safe and well tolerated with an overall safety profile similar to placebo.

Yes

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/ Supporting Documents: - Study Protocol - Statistical Analysis Plan - Clinical Study Report 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. 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. URL: https://vivli.org/ourmember/daiichi-sankyo/

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

DAIICHI SANKYO Co.,Ltd.

dsclinicaltrial@daiichisankyo.co.jp

completed

July. 30, 2017

Interventional

Multi center, placebo controlled, randomized, single blinded study

treatment purpose

1

1. Female and male from 20 to 89 years old
2. Acute ischemic stroke patients with CTA or MRA evidence of intracranial vascular occlusion (ICA, MCA M1 division)
3. In principle within 8 hours of symptom onset
4. Treatment with stent retriever is planned
5. NIHSS >= 6, ASPECTS >= 6

1. Treated with fibrinolysis or fibrinolysis is planned
2. Intracranial hemorrhage or subarachnoid hemorrhage is identified by CT or MRI
3. Subjects have active bleeding like gastrointestinal hemorrhage
4. Subjects with cerebral bleeding risk; intracranial tumor, brain aneurysm, cerebral arteriovenous malformation, or history of intracranial bleeding
5. Subjects with aortic dissection
6. Subjects have had head trauma, spinal cord trauma, or intracranial surgery within 3 months
7. Subjects have had gastrointestinal or genitourinary bleeding in the last 21 days
8. Subjects have had major surgery within 14 days or trauma
9. Subjects with an elevated APTT or PTT more than twice of normal range
10. INR > 1.7
11. Platelet < 100,000/mm3
12. Uncontrolled hypertension (SBP > 185 mmHg, DBP > 110 mmHg)
13. Blood glucose > 400 mg/dL
14. Subjects with more than two major artery occluded
15. Inadequate for treatment with stent retrievers, for example, carotid dissection, totally occluded carotid artery, or allergy for contrast agent
16. Severe hepatic impairment (fulminant hepatitis, cirrhosis, hepatophyma, TB >= 3.0 mg/dL, AST >= 2.5x ULN, ALT >= 2.5x ULN, ALP >= 2.5x ULN)
17. Severe renal impairment patients with chronic dialysis, nephrotic syndrome, acute renal failure, chronic renal failure, uremia, hydronephrosis, or serum creatinine >= 2.0 mg/dL
18. History of ischemic stroke within 30 days prior to treatment
19. Participant in other clinical trial within 30 days prior to treatment
20. Subject with pregnant, during lactation, planning on becoming pregnant during treatment period
21. Any other reason, in the opinion of the Investigator, which precludes subjects participation in the study

Both

Acute ischemic stroke

investigational material(s)
Generic name etc : DS-1040b
INN of investigational material : -
Therapeutic category code : 333 Anticoagulants
Dosage and Administration for Investigational material : 4 cohorts of 0.6 mg, 1.2 mg, 2.4 mg, and 4.8 mg will be administrated intravenously for 6 hours in dose ascending manner.

control material(s)
Generic name etc : -
INN of investigational material : -
Therapeutic category code :
Dosage and Administration for Investigational material : -

safety
- The rate of Symptomatic ICH (definition of European Cooperative Acute Stroke Study[ECASS])
- The rate of Asymptomatic ICH
- The rate of non-ICH major bleeding [definition of TIMI]

efficacy
pharmacokinetics
pharmacodynamics
- Pharmacokinetics parameters of plasma and urine
- Biomarker related to the fibrinolysis activity (TAFIa activity, D-dimer, TAFI antigen volume)
- Change of NIHSS from baseline to 24 after administration of DS-1040b
- The rate of good clinical outcome (mRS 0-2) at Day 90

May. 19, 2017