Clinical Trials Register

Summary
EudraCT Number:	2017-002671-26
Sponsor's Protocol Code Number:	9113
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:	2017-07-17
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

2017-002671-26

A.3

Full title of the trial

The effect of Opioids on P2Y12 Receptor Inhibition in patients with ST-Elevation Myocardial Infarction who are pre-treated with crushed Ticagrelor

Het effect van opioïden op P2Y12 receptor remming bij patiënten met ST-Elevatie Myocard Infarct die vooraf worden behandeld met gemalen Ticagrelor

A.3.1

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

The effect of Opioids on P2Y12 Receptor Inhibition in patients with ST-Elevation Myocardial Infarction who are pre-treated with crushed Ticagrelor

Het effect van morfine preparaten op de bloedstolling (bloedplaatjes) bij patiënten met een hartinfarct die vooraf worden behandeld met gemalen Ticagrelor

A.3.2

Name or abbreviated title of the trial where available

ON-TIME-3

A.4.1

Sponsor's protocol code number

9113

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	Isala
B.1.3.4	Country	Netherlands
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	Astra Zeneca
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Diagram BV
B.5.2	Functional name of contact point	H. van de Wetering
B.5.3	Address:
B.5.3.1	Street Address	Dokter Stolteweg 96
B.5.3.2	Town/ city	Zwolle
B.5.3.3	Post code	8025 AZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	0031384262999
B.5.5	Fax number	0031384262990
B.5.6	E-mail	H.vd.wetering@diagram-zwolle.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	Fentanyl Bipharma
D.2.1.1.2	Name of the Marketing Authorisation holder	Hameln Pharmaceuticals
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	Fentanyl
D.3.4	Pharmaceutical form	Solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	Comparator
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	Paracetamol B. Braun 10mg/ml solution for infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	B. Braun
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	Paracetamol
D.3.2	Product code	RVG
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous drip use (Noncurrent)
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: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Ticagrelor
D.2.1.1.2	Name of the Marketing Authorisation holder	AstraZeneca
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	Ticagrelor
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute Coronary syndrome

Acuur coronair syndroom

E.1.1.1

Medical condition in easily understood language

Heart attack

Hartinfarct

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	10064346
E.1.2	Term	STEMI
E.1.2	System Organ Class	100000011652

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The aim of the study is to show that STEMI patients who are pre-treated with crushed ticagrelor and paracetamol have a higher level of platelet inhibition after primary PCI than patients pre-treated with crushed ticagrelor who are treated with fentanyl

De doelstelling van de studie is om te laten zien dat STEMI-patiënten die zijn voor behandeld met gemalen ticagrelor en paracetamol een hoger niveau van plaatjes remming na primaire PCI hebben dan patiënten die zijn behandeld met gemalen ticagrelor en die zijn behandeld met fentanyl

E.2.2

Secondary objectives of the trial

-To demonstrate that paracetamol is non-inferior to fentanyl in pain reduction in STEMI patients.
- To show that patients with STEMI who are pre-treated in the ambulance with crushed ticagrelor 180 mg and paracetamol have a higher level of platelet inhibition than patients pre-treated with crushed ticagrelor 180 mg and fentanyl at other time points (T1, T3, T4).
- To show that patients with STEMI who are pre-treated in the ambulance with crushed ticagrelor 180 mg and paracetamol have a higher active metabolite of ticagrelor and AR-C124910XX measured in plasma than patients pre-treated with crushed ticagrelor 180 mg and fentanyl at the four time points (T1, T2, T3, T4).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

In order to be eligible to participate in this study, a subject must meet all of the following criteria:
1.age ≥18 years
2.referred by ambulance paramedics to Isala (Zwolle) or Zuyderland
Hospital (Heerlen)
3.diagnosed in the ambulance with STEMI defined as:
- ongoing chest pain >30 minutes and <12 hours duration and
- ST-segment elevation >0.1 mV in at least 2 contiguous leads
4.ongoing chest pain with a pain score (NRS) ≥4
5.the patient has been informed of the nature of the study, agrees
to its provisions and has provided verbal informed consent in the
pre-hospital phase followed by written informed consent in hospital

E.4

Principal exclusion criteria

A potential subject will be excluded from participation in this study when any of the following criteria is met:
1.presenting with cardiogenic shock; defined as:
-systolic blood pressure <90 mmHg and
-heart rate >100/min and
-peripheral oxygen saturation <90% (without oxygen
administration)
2.patients with a nasogastric tube in situ or requiring a nasogastric
tube
3.patients who already received fentanyl or paracetamol <2 hours
prior to randomization
4.patients on current treatment with P2Y12 inhibitors
(ticagrelor, clopidogrel or prasugrel)
5.patients with recent major bleeding complications or
contraindication to dual antiplatelet therapy:
-hypersensitivity to aspirin or ticagrelor
-current use of (new) oral anticoagulation
-history of bleeding diathesis or known coagulopathy
-refusal of blood transfusions
-history of intracerebral mass, aneurysm, arteriovenous
malformation, or hemorrhagic stroke
-known severe liver dysfunction
6.received any organ transplant or is on a waiting list for any organ
transplant
7.patients undergoing dialysis
8.pregnant or lactating female
9.patients currently participating in another investigational drug or
device study

E.5 End points

E.5.1

Primary end point(s)

The priamry endpoint to show that patients with STEMI who are pre-treated in the ambulance with crushed ticagrelor 180 mg and paracetamol have a higher level of platelet inhibition directly after primary PCI (T2) than patients pre-treated with crushed ticagrelor 180 mg and fentanyl.

E.5.1.1

Timepoint(s) of evaluation of this end point

Blood sample measurements for platelet function testing and level of active metabolite of ticagrelor, using Verify Now P2Y12 assay (Accumetrics, San Diego, California), will be done at four time points:

T1: when arriving at the cathlab
T2: directly post-primary PCI or 1 hour after coronary angiography
when no PCI was performed
T3: one hour post-primary PCI including electrocardiogram (ECG) or
2 hours post-coronary angiography
T4: six hours post-primary PCI of 7 hours post-coronary angiography

E.5.2

Secondary end point(s)

Secondary endpoints:
-To demonstrate that paracetamol is non-inferior to fentanyl in pain
reduction in STEMI patients, measured by the level of pain using
numeric rating score.
-The level of platelet inhibition (PRU) at T1, T3 and T4.
-The percentage of High on treatment Platelet Reactivity (HPR) as
defined as a PRU >208 at T1, T3 and T4.
-The level of the active metabolite of a higher active metabolite of
ticagrelor and AR-C124910XX measured in plasma, at T1, T2, T3
and T4.
-Extent of ST-segment deviation (≥70% ST-segment resolution) pre-
PCI and 1 hour post-PCI.
-TIMI flow grade 3 in the culprit vessel at initial angiography.
-Requiring of fentanyl in patients randomized to paracetamol.
-MACE and stent thrombosis at 30 days of follow-up.

E.5.2.1

Timepoint(s) of evaluation of this end point

Blood sample measurements for platelet function testing and level of active metabolite of ticagrelor, using Verify Now P2Y12 assay (Accumetrics, San Diego, California), will be done at the following time points:

1: when arriving at the cathlab
2: directly post-primary PCI or 1 hour after coronary angiography
when no PCI was performed
3: one hour post-primary PCI including electrocardiogram (ECG) or
2 hours post-coronary angiography
4: six hours post-primary PCI of 7 hours post-coronary angiography

- Hospital Discgarge
- 30 days after Hospital Discharge

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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 last follow-up visit of the last patient

De laatste follow-up visite van de laatste patient

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

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

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

190

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

Geen

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

2017-07-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-12-19

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

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