Clinical Trials Register

Summary
EudraCT Number:	2018-000539-29
Sponsor's Protocol Code Number:	2018.02.08
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-08-13
Trial 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

Netherlands - Competent Authority

A.2

EudraCT number

2018-000539-29

A.3

Full title of the trial

PeriOperative ISchemic Evaluation-3 (POISE-3) Trial

A.3.1

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

PeriOperative ISchemic Evaluation-3 (POISE-3) Trial

A.3.2

Name or abbreviated title of the trial where available

PeriOperative ISchemic Evaluation-3 (POISE-3) Trial

A.4.1

Sponsor's protocol code number

2018.02.08

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03505723

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	Hamilton Health Sciences Corporation
B.1.3.4	Country	Canada
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Hamilton Health Sciences Corporation
B.4.2	Country	Canada
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Population Health Research Institute
B.5.2	Functional name of contact point	POISE-3 Project Office
B.5.3	Address:
B.5.3.1	Street Address	237 Barton Street East
B.5.3.2	Town/ city	Hamilton
B.5.3.3	Post code	L8L 2X2
B.5.3.4	Country	Canada
B.5.4	Telephone number	001905521-21004063
B.5.6	E-mail	poise3@phri.ca

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	Yes
D.2.1.1.1	Trade name	Cyklokapron oplossing voor injectie 100 mg/ml (Tranexamic Acid)
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer bv Rivium Westlaan 142 2909 LD Capelle a/d IJssel
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Tranexamic acid
D.3.4	Pharmaceutical form	Injection
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	TRANEXAMIC ACID
D.3.9.1	CAS number	1197-18-8
D.3.9.3	Other descriptive name	TRANEXAMIC ACID
D.3.9.4	EV Substance Code	SUB11214MIG
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	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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.IMP: 2
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	Yes
D.2.1.1.1	Trade name	Cyklokapron, oplossing voor injectie 100 mg/ml (Tranexamic Acid)
D.2.1.1.2	Name of the Marketing Authorisation holder	Eureco-Pharma B.V. Boelewerf 2 2987 VD Ridderkerk
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Tranexamic acid
D.3.4	Pharmaceutical form	Injection
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	TRANEXAMIC ACID
D.3.9.1	CAS number	1197-18-8
D.3.9.3	Other descriptive name	TRANEXAMIC ACID
D.3.9.4	EV Substance Code	SUB11214MIG
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	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	Solution for injection/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

The occurrence of life-threatening, major, and critical organ bleeding, and, major arterial and venous thrombosis in patients undergoing noncardiac surgery. And for patients in the blood pressure management factorial, the occurrence of vascular death and major vascular events.

E.1.1.1

Medical condition in easily understood language

Bleeding events or complications related to the heart or blood vessels in patients undergoing non-heart surgery

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	LLT
E.1.2	Classification code	10043611
E.1.2	Term	Thrombosis arterial
E.1.2	System Organ Class	100000004866

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10043640
E.1.2	Term	Thrombosis venous
E.1.2	System Organ Class	100000004866

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10051014
E.1.2	Term	Post procedural bleeding
E.1.2	System Organ Class	100000004863

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To determine if TXA is superior to placebo for the occurrence of life-threatening, major, and critical organ bleeding, and non-inferior to placebo for the occurrence of major arterial and venous thrombotic events; and to determine the impact of a hypotension-avoidance strategy versus a hypertension-avoidance strategy on the risk of vascular death and major vascular events in patients who are followed for 30 days after noncardiac surgery.

E.2.2

Secondary objectives of the trial

To determine the impact of TXA on the following outcomes at 30 days after randomization: a net risk-benefit outcome as a composite of vascular death, and nonfatal life-threatening bleeding, and nonfatal major bleeding, critical organ bleeding, myocardial infarction, stroke, peripheral arterial thrombosis, and symptomatic venous thromboembolism; International Society on Thrombosis and Haemostasis (ISTH) major bleeding; bleeding impacting mortality after noncardiac surgery (BIMS); myocardial injury after noncardiac surgery (MINS); and myocardial infarction.
To determine the impact of a perioperative hypotension-avoidance strategy on all-cause mortality; MINS; and myocardial infarction at 30 days after randomization.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients are eligible if they fulfill all of the following criteria: 1. ≥45 years of age; 2. expected to require at least an overnight hospital admission after noncardiac surgery; 3. provide written informed consent to participate in POISE-3; AND 4. have a preoperative NT-pro-BNP measurement ≥200 ng/L; OR 5. if a preoperative NT-pro-BNP measurement is not available, then the patient must fulfill ≥1 of the following 5 criteria: A. history of coronary artery disease; B. history of peripheral arterial disease; C. history of stroke; D. undergoing major vascular surgery; E. any 3 of the following 9 criteria: undergoing major surgery (i.e. intraperitoneal, intrathoracic, retroperitoneal, or major orthopedic surgery), history of congestive heart failure, transient ischemic attack, diabetic and currently taking an oral hypoglycemic agent or insulin, age >70 years, hypertension, serum creatinine >175 µmol/L (>2.0 mg/dl), history of smoking within 2 years of surgery, undergoing urgent/emergent surgery.
Additionally, patients will be considered eligible for the BP partial factorial if they have been chronically receiving ≥1 antihypertensive medication.

E.4

Principal exclusion criteria

We will exclude patients meeting any of the following criteria:
1. Patients undergoing cardiac surgery
2. Patients undergoing cranial neurosurgery
3. Planned use of systemic TXA during surgery
4. Hypersensitivity or known allergy to TXA
5. Creatinine clearance <30 mL/min (Cockcroft-Gault equation) or on chronic dialysis
6. History of seizure disorder
7. Patients with recent stroke, myocardial infarction, acute arterial thrombosis or venous thromboembolism (<3 months)
8. Patients with fibrinolytic conditions following consumption coagulopathy
9. Patients with subarachnoid hemorrhage within the past 30 days
10. Women of childbearing potential who are not taking effective contraception, pregnant or breast-feeding
11. Previously enrolled in POISE-3 Trial
Additionally, patients will be excluded for the BP partial factorial if:
1. Patients with advanced congestive heart failure (New York Heart Association functional class III or IV or left ventricular ejection fraction ≤30%),
2. Patients with untreated brain aneurysm,
3. Patients with previous history of hypertensive related cerebral hemorrhage,
4. Patients undergoing surgery for pheochromocytoma or history of untreated pheochromocytoma,
5. Patients who are hemodynamically unstable or requiring vasopressors or inotropic support before undergoing surgery.
6. Patients with thyrotoxicosis (i.e., severe hyperthyroidism) requiring perioperative beta-blocker therapy.

E.5 End points

E.5.1

Primary end point(s)

The co-primary efficacy outcome for TXA trial is a composite of life-threatening bleeding, major bleeding, and critical organ bleeding at 30 days after randomization.
The co-primary safety outcome for TXA trial is a composite of myocardial infarction, non-hemorrhagic stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism at 30 days after randomization.
The primary outcome for the BP management trial is a composite of vascular death, and non-fatal myocardial infarction, stroke, and cardiac arrest at 30 days after randomization.

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days and 1 year after randomization

E.5.2

Secondary end point(s)

The secondary outcomes for TXA trial are: 1) a net risk-benefit outcome as a composite of vascular death, and non-fatal life-threatening, major or critical organ bleeding, myocardial infarction, stroke, peripheral arterial thrombosis, and symptomatic proximal venous thromboembolism at 30 days after randomization; 2) International Society on Thrombosis and Haemostasis (ISTH) major bleeding; 3) BIMS; 4) MINS; and 5) myocardial infarction at 30 days after randomization.

The secondary outcomes for the BP management factorial are: 1) all-cause mortality at 30 days after randomization; 2) MINS; and 3) myocardial infarction at 30 days after randomization.

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days and 1 year after randomization

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

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)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

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

Partial factorial design evaluating perioperative hypotension-avoidance versus hypertension-avoid

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

Yes

E.8.4

The trial involves multiple sites in the 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

Argentina

Australia

Austria

Belgium

Brazil

Canada

Chile

China

Colombia

Denmark

France

Germany

Hong Kong

India

Ireland

Italy

New Zealand

Poland

Romania

Saudi Arabia

South Africa

Spain

Switzerland

Uganda

United Kingdom

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

The trial will end when all the recruited patients are actively followed for 1 year, including patients enrolled at the end of the recruitment phase.

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

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:

3000

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

7000

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

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

300

F.4.2

For a multinational trial

F.4.2.1

In the EEA

3000

F.4.2.2

In the whole clinical trial

10000

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

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-08-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-04

P. End of Trial
P.	End of Trial Status	Ongoing

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