Clinical Trials Register

Summary
EudraCT Number:	2017-000552-25
Sponsor's Protocol Code Number:	DS9231-A-U201
National Competent Authority:	Hungary - National Institute of Pharmacy
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2017-05-31
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Hungary - National Institute of Pharmacy

A.2

EudraCT number

2017-000552-25

A.3

Full title of the trial

Evaluation of Safety and Thrombolytic Effect of Ascending Doses of DS-9231 (TS23) in Subjects with Intermediate-Risk (sub-massive) Acute Pulmonary Embolism (PE)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study to evaluate the safety and thrombolytic effect of increasing doses of DS9231 in sujbects with severe pulmonary embolism

A.4.1

Sponsor's protocol code number

DS9231-A-U201

A.5.4

Other Identifiers

Name:

IND

Number:

118619

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Daiichi Sankyo Inc.
B.1.3.4	Country	United States
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Daiichi Sankyo Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Daiichi Sankyo Inc.
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	211 Mt Airy Road
B.5.3.2	Town/ city	Basking Ridge
B.5.3.3	Post code	NJ 07920
B.5.3.4	Country	United States
B.5.4	Telephone number	+19089926400
B.5.5	Fax number	+17329066652
B.5.6	E-mail	eu_cta@dsi.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	DS9231
D.3.2	Product code	DS9231
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	DS9231
D.3.9.2	Current sponsor code	DS9231
D.3.9.3	Other descriptive name	DS-9231 (TS23)
D.3.9.4	EV Substance Code	SUB186762
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

DS9231, also known as TS23, is an inhibitor of alpha2-antiplasmin, incrasing plasmin acitivy and enhances fibrinolysis (thrombolysis) and intended to be used for the treatment of patients with Intermediate-Risk (Sub-Massive) Acute Pulmonary Embolism (PE).

E.1.1.1

Medical condition in easily understood language

Blood clot in the lung(s).

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10037379
E.1.2	Term	Pulmonary embolism and thrombosis
E.1.2	System Organ Class	100000004866

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10037377
E.1.2	Term	Pulmonary embolism
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To compare the incidence of adjudicated major or clinically relevant non-major (CRNM) bleeding events
2. To compare the change from baseline (% reduction) in total thrombus volume, assessed by computed tomography pulmonary angiography (CTPA) scan,
3. To compare the % of subjects with various gradations of decrease in total thrombus volume (no decrease, ≥20% decrease, ≥30% decrease, ≥50% decrease or 100% resolution)

E.2.2

Secondary objectives of the trial

1. To compare the change from baseline (% reduction) in total thrombus volume (by CTPA scan)
2. compare the % of subjects with various gradations of decrease in total thrombus volume (no decrease, ≥20% decrease, ≥30% decrease, ≥50% decrease or 100% resolution)
3. compare the change from baseline in right ventricular-to-left ventricular (RV/LV) diameter ratio (by CTPA) scan
4. compare the incidence of major or clinically relevant non-major (CRNM) bleeding events (adjudicated by clinical events committee [CEC])
5. compare the rate of PE related deaths
6. compare the rate of all-cause deaths with ascending doses of DS-9231
7. compare the % of subjects with clinical deterioration requiring additional rescue therapies.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female subjects, age >18 years;
2. PE involving a segmental or more proximal pulmonary artery confirmed by CTPA scan and with an onset of symptoms not more than 5 days prior to diagnosis;
3. Subject is hemodynamically stable with a systolic blood pressure (SBP) >90 mm Hg
4. Subject has evidence of RV dysfunction (at least one of the following):
• Right ventricular-to-left ventricular (RV/LV) diameter ratio > 0.9 on CTPA scan (measuring the minor axis of the right and left ventricle in the transverse plane),
• or myocardial injury as evidenced by an elevated cardiac Troponin T or Troponin I (using the test of the local laboratory of Clinical Chemistry at the participating site). An abnormal value is that above the 99th percentile of the healthy population as a cutoff using an assay with acceptable precision. The 99th percentile cutoff point for cardiac Troponin T (cTnT) is well-known at 0.01 ng/mL as only one cTnT assay exists. In contrast, several different assays are commercially available for cardiac Troponin I (cTnI), so the 99th percentile cut point varies based on the assay being used. Please refer to Appendix 17.3 as guideline for acceptable abnormal Troponin I values.
• or RV/LV ratio > 0.9 on echocardiogram (apical or subcostal 4 - chamber view echocardiogram). A trained cardiac sonographer may not be available during non-business hours (for emergency admissions); however, if feasible, obtain echocardiogram prior to the initiation of study drug administration.
Eligible subjects, who qualify and have executed informed consent, will be randomized as early as possible and every effort will be made to administer the study medication (DS-9231 versus placebo) as soon as possible within the first 6 hours after the randomization

E.4

Principal exclusion criteria

1. Subjects for whom thrombolytic therapy or thrombectomy is planned; or subjects with history of administration of thrombolytic agents within the previous 4 days;
2. Subjects receiving ≥ 48 hours of therapeutic doses of heparin or LMWH or other anticoagulant therapy immediately prior to randomization;
3. Subjects with contraindications to SOC therapies such as unfractionated heparin or LMWH or oral anticoagulant, or any of the excipients (including study drug excipients);
4. Subjects who are considered at very high risk of bleeding:
a. Known coagulation disorder with history of pathologic bleeding tendencies
b. Subjects with prior intracranial hemorrhage, known arteriovenous malformation or aneurysm of the
brain, or evidence of active bleeding;
c. Subjects with a history of major surgery, clinically significant head trauma (in the opinion of the
Principal Investigator), or stroke in the past 3 months prior to randomization;
d. Subjects with uncontrolled hypertension defined as SBP ≥180 mm Hg and/or diastolic BP
(DBP) ≥110 mm Hg at randomization
e. Subjects requiring concomitant dual antiplatelet therapy
5. Subjects with Creatinine Clearance (CrCL) < 30 mL/min or serum creatinine ≥ 2.5 mg/dL;
6. Subjects with hemoglobin < 8.0 g/dL;
7. Subjects with a platelet count < 100,000/µL;
8. Subjects with acute or persistent hepatitis or diagnosed active liver disease or with elevation of liver enzymes: Alanine transaminase (ALT) or aspartate transaminase (AST) ≥ 3 x upper limit of normal (ULN);
9. Subjects with known history of testing positive for Hepatitis B antigen or Hepatitis C antibody;
10. Subjects with known history of testing positive for the human immunodeficiency virus (HIV);
11. Subjects with life-expectancy < 6 months;
12. Female subjects of child bearing potential with a positive pregnancy test or who are lactating, or unwilling to use highly effective methods of contraception. Highly effective methods of birth control include combination hormonal therapy (estrogen and progresterone), contraceptives administered orally, intravaginally or transdermally, progesterone-only contraceptives administered orally, by injection or implantation, use of an intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, partner vasectomy or sexual abstinence;
13. Subjects currently participating in another investigational study or who have participated in an investigational drug study within 30 days (or longer depending on the half-life of the investigational drug; should allow at least five half-life of the investigational drug) prior to randomization.

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoints:
• % reduction in total thrombus volume at 48-96 hours after completion of study drug administration, as assessed by CTPA scan.
• % of subjects with various gradations of decrease in total thrombus volume (no decrease, ≥20% decrease, ≥30% decrease, ≥50% decrease or 100% resolution) at 48-96 hours after the completion of study drug administration

Primary safety endpoints:
• Adjudicated major or clinically relevant non-major bleeding events occurring within the first 7 days after completion of study drug administration

E.5.1.1

Timepoint(s) of evaluation of this end point

Efficacy: 48-96 hours after completion of study drug administration
Safety: Within the first 7 days after completion of study drug administration

E.5.2

Secondary end point(s)

Seconday efficacy enpoints:
1. % reduction in total thrombus volume, as assessed by CTPA scan.
2. % of subjects with various gradations of decrease in total thrombus volume (no decrease, ≥20% decrease, ≥30% decrease, ≥50% decrease or 100% resolution) .
3. % change from baseline in RV/LV diameter ratio (by CTPA scan).
4. PE related deaths .
5. % of subjects with clinical deterioration requiring additional rescue therapy for PE
6. % of subjects with recurrent, objectively documented VTE.
7. Quality of life

Seconday safety endpoints:
a. Adjudicated major or clinically relevant non-major bleeding events
b. All-cause deaths
c. Re-hospitalizations for any reason
d. Non-bleeding AEs
e. Anti-drug antibodies (ADA)

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy:
1, 2 and 3: at Day 30 after completion of study drug administration
4: within the first 7 days, 8-30 days, and overall 1-30 days after completion of study drug administration
5, 6: within the first 7 days, 8-30 days, and overall 1-30 days after completion of study drug administration
7: at baseline and Day 30

Safety:
a. within 8-30 days and overall 1-30 days after completion of study drug administration
b, c and d: within the first 7 days, 8-30 days and overall 1-30 days after completion of study drug administration
e: baseline, Day7, and at Day 30 follow-up visit

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Ascending doses

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Canada

Czech Republic

Denmark

Hungary

United States

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

Yes

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

104

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None- expected normal treatment of that condition.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2017-08-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-31

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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