Clinical Trials Register

Summary
EudraCT Number:	2016-001529-15
Sponsor's Protocol Code Number:	RATIOSTUDY
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-09-07
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-001529-15

A.3

Full title of the trial

Randomized Anticoagulation Trial In Opcab HIGH DOSE VERSUS LOW DOSE HEPARINIZATION IN PATIENTS

Randomized Anticoagulation Trial In Opcab HIGH DOSE VERSUS LOW DOSE HEPARINIZATION IN PATIENTS
UNDERGOING OFFPUMP CORONARY ARTERY BYPASS

A.3.1

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

non prevista

Eparinizzazione completa e parziale in pazienti sottoposti a
bypass coronarico senza circolazione extracorporea

A.3.2

Name or abbreviated title of the trial where available

Randomized Anticoagulation Trial In Opcab

RATIO STUDY

A.4.1

Sponsor's protocol code number

RATIOSTUDY

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02812355

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	AZIENDA SOCIO-SANITARIA TERRITORIALE DI LECCO (ASST LECCO)
B.1.3.4	Country	Italy
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	Maquet Italia S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ASST Lecco
B.5.2	Functional name of contact point	S.S. Tecniche Mini-Invasive in Card
B.5.3	Address:
B.5.3.1	Street Address	Via dell'Eremo 9/11
B.5.3.2	Town/ city	Lecco
B.5.3.3	Post code	23900
B.5.3.4	Country	Italy
B.5.4	Telephone number	0341253066
B.5.5	Fax number	0
B.5.6	E-mail	m.triggiani@asst-lecco.it

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	EPSOCLAR - 25.000 U.I./5 ML SOLUZIONE PER INFUSIONE 10 FIALE 5 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	HOSPIRA ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	epsoclar
D.3.2	Product code	030705026
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
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	EPSOCLAR - 25.000 U.I./5 ML SOLUZIONE PER INFUSIONE 10 FIALE 5 ML
D.2.1.1.2	Name of the Marketing Authorisation holder	HOSPIRA ITALIA S.R.L.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	epsoclar
D.3.2	Product code	030705026
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 use
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
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

Off-pump coronary artery bypass grafting (OPCAB) is an established alternative to on-pump coronary artery bypass grafting (CABG),
OPCAB, like any other surgical procedure, determines a pro-coagulant state potentially deleterious on grafts patency, that is not counterbalanced by the adverse effects of cardiopulmonary bypass on coagulation occurring in CABG, and that lasts as long as one month. Therefore systemic heparinization is necessary in OPCAB to prevent thrombotic complications during trans

Pazienti sottoposti a bypass coronarico a cuore battente senza circolazione extracorporea (OPCAB).

E.1.1.1

Medical condition in easily understood language

HIGH DOSE VERSUS LOW DOSE HEPARINIZATION IN PATIENTS
UNDERGOING OFFPUMP CORONARY ARTERY BYPASS

Pazienti sottoposti a bypass coronarico a cuore battente senza circolazione extracorporea.

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	10011098
E.1.2	Term	Coronary bypass
E.1.2	System Organ Class	100000004865

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 test the hypothesis that in OPCAB low dose heparinization is superior to high dose heparinization for the prevention of major perioperative bleeding events, without an higher rate of thrombotic complications.

L’obiettivo dello studio è il confronto tra l’efficacia dell’eparinizzazione intra-operatoria completa (3 mg/kg) e parziale (1.5 mg/kg) nel periodo postoperatorio di pazienti elettivi sottoposti ad intervento di rivascolarizzazione miocardica mediante bypass coronarici multipli eseguiti a cuore battente senza circolazione extracorporea (OPCAB). Nella letteratura internazionale uno studio del genere non è stato mai condotto, i protocolli di eparinizzazione negli OPCAB sono estremamente variabili, e non esistono indicazioni su quale sia il migliore

E.2.2

Secondary objectives of the trial

To reduce the need for red blood cell and platelets transfusions

Gli endpoints secondari saranno rappresentati dall’incidenza di stroke, ischemia intestinale, embolia polmonare, valore di picco del marcatore di necrosi miocardica, trasfusione di 2-3 Unità di emazie concentrate e sanguinamento totale a distanza di 24 ore dall’intervento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

All consecutive patients undergoing elective multivessel OPCAB, aged >18 years, of both sexes

Saranno valutati per l’arruolamento tutti i pazienti consecutivi candidati elettivamente a bypass coronarici multipli senza circolazione extracorporea. Lo studio prevede l’arruolamento di pazienti di entrambi i sessi, di età maggiore o uguale a 18.

E.4

Principal exclusion criteria

Exclusion criteria are represented by the diagnosis of acute coronary syndrome, on-going double anti-platelets treatment (the second antiplatelet drug should be suspended 5 days before surgery), on-going intravenous heparinization or sub-cutaneous low molecular weight heparin (LMWH), known coagulopathy, documented liver disease, chronic renal failure (creatinine = 2 mg/dl) or previous renal transplantation surgery, previous cardiac surgery.

I criteri di esclusione dei pazienti saranno la sindrome coronarica acuta, la doppia terapia antiaggregante in corso, l’infusione di eparina endovena in corso, l’eparina a basso peso molecolare sottocute in corso, una nota coagulopatia od epatopatia documentata, insufficienza renale cronica (creatininemia = 2 mg/dl), pregresso trapianto renale o pregresso intervento cardiochirurgico.

E.5 End points

E.5.1

Primary end point(s)

Composite vascular endpoint (death from vascular causes, perioperative myocardial infarction, stroke), and composite peri-operative major bleeding endpoint (redo for excessive bleeding, cardiac tamponade, transfusion =3 Units of packed red cells or of platelets).

Enpoint composito vascolare (decesso per cause vascolari, infarto miocardico perioperatorio, stroke) ed endpoint composito emorragico (revisione per sanguinamento eccessivo, tamponamento cardiaco, trasfusione di =3 Unità di emazie concentrate e/o piastrine).

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days post-operatives

30 giorni dopo chirurgia

E.5.2

Secondary end point(s)

Post-operative bleeding, transfusion of <3 Units of packed red cells or of platelets, peak value of cardiac biomarker, transient ischemic cerebral attack, bowel ischemia, pulmonary embolus.

Sanguinamento postoperatorio, trasfusione di < 3 Unità di emazie concentrate e/o piastrine, valore di picco dei marcatori di necrosi miocardica, attacchi ischemici cerebrali transitori, ischemia intestinale, embolia polmonare

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days

30 giorni

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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

E.8.1.3

Single blind

Yes

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.8.5.1

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

Last subject undergoing intervention

L'ultimo soggetto arruolato che va contro intervento

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:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

600

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-09-07.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

Yes

F.3.3.4

Nursing women

Yes

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

900

F.4.2

For a multinational trial

F.4.2.1

In the EEA

900

F.4.2.2

In the whole clinical trial

900

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)

Follow-up by phone 1 year later

Follow-up telefonico a un anno

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

2016-10-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-07-21

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

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