Clinical Trials Register

Summary
EudraCT Number:	2017-000487-15
Sponsor's Protocol Code Number:	CLSYN.1702
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-02-02
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

Spain - AEMPS

A.2

EudraCT number

2017-000487-15

A.3

Full title of the trial

CLEAR SYNERGY (OASIS 9)
A 2x2 factorial randomized controlled trial of CoLchicine and spironolactonE in patients with ST elevation myocARdial infarction/SYNERGY Stent Registry –
Organization to Assess Strategies for Ischemic Syndromes 9

CLEAR SYNERGY (OASIS 9)
Un ensayo controlado, aleatorizado, factorial, de 2x2 de Colchicina y Espironolactona en pacientes con infarto de miocardio con elevación del segmento ST/Registro de Estent de SYNERGY – Organización para evaluar estrategias para síndromes isquémicos 9

A.3.1

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

A study of colchicine and spironolactone in patients who have had a heart attack.

Colchicina y espironolactona en pacientes con infarto de miocárdico con elevación del ST

A.3.2

Name or abbreviated title of the trial where available

CLEAR SYNERGY (OASIS 9)

A.4.1

Sponsor's protocol code number

CLSYN.1702

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03048825

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 through its Population Health Research Institute
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	Canadian Institutes of Health Research
B.4.2	Country	Canada
B.4.1	Name of organisation providing support	Boston Scientific Corporation
B.4.2	Country	United States
B.4.1	Name of organisation providing support	Population Health Research Institute
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	CLEAR SYNERGY 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	19055274322 x41079
B.5.6	E-mail	clear@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	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	spironolactone
D.3.4	Pharmaceutical form	Coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SPIRONOLACTONE
D.3.9.1	CAS number	52.01.7
D.3.9.3	Other descriptive name	spironolactone
D.3.9.4	EV Substance Code	SUB10631MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	25
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	colchicine
D.2.1.1.2	Name of the Marketing Authorisation holder	TioFarma, B.V.
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	colchicine
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	colchicine
D.3.9.1	CAS number	64-86-8
D.3.9.3	Other descriptive name	COLCHICINE
D.3.9.4	EV Substance Code	SUB01420MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	0.5
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	Coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

ST segment Elevation Myocardial Infarction (STEMI)

Infarto de miocardio con elevación del segmento ST (STEMI)

E.1.1.1

Medical condition in easily understood language

heart attack

ataque al corazón

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	10064345
E.1.2	Term	ST segment elevation myocardial infarction
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

In patients with STEMI who have undergone PCI, the primary objectives of this study is to determine:

1. If colchicine can reduce the incidence of cardiovascular (CV) death, myocardial infarction (MI), or stroke over duration of follow-up.

2. If spironolactone can reduce the incidence of CV death or new or worsening heart failure over duration of follow-up.

3. The rate of major adverse cardiac events (MACE) in patients who have received a SYNERGY everolimus-eluting stent compared to performance goal.

1. Determinar la tasa de eventos cardíacos adversos mayores (MACE, por
sus siglas en inglés) en pacientes que han recibido un estent de elución
de everolimus SYNERGY comparado con el objetivo de rendimiento
2. Determinar si la colchicina puede reducir la incidencia de muerte
cardiovascular (CV), infarto de miocardio (IM) o accidente
cerebrovascular
3. Determinar si la espironolactona puede reducir la incidencia de
muerte cardiovascular o insuficiencia cardiaca nueva o empeoramiento

E.2.2

Secondary objectives of the trial

1. Colchicine vs. placebo: Time-to-event of the composite of cardiovascular death, recurrent MI, unplanned ischemia driven revascularization, or stroke, over the duration of follow-up.

2. Spironolactone vs. placebo:

a) Time-to-event of cardiovascular death over the duration of follow-up.

b) time-to-event of the composite of cardiovascular death, new or worsening heart failure or significant ventricular arrhythmia over the duration of follow-up.

3. Combined colchicine and spironolactone: Time to event for the composite of cardiovascular death, recurrent MI, stroke or new or worsening heart failure over follow up.

4. SYNERGY stent: Incidence of Definite Stent Thrombosis within 1 year

1. Colchicina versus placebo: tiempo hasta el evento del compuesto de muerte cardiovascular, infarto de miocardio recurrente, revascularización no planificada provocada por isquemia o accidente cerebrovascular, durante la duración del seguimiento.

2. Espironolactona vs. placebo:

a) Tiempo hasta el evento de muerte cardiovascular durante el seguimiento.

b) tiempo hasta el evento del compuesto de muerte cardiovascular, insuficiencia cardíaca nueva o empeoramiento o arritmia ventricular significativa durante el seguimiento.

3. Combinación de colchicina y espironolactona: tiempo hasta el evento para el compuesto de muerte cardiovascular, infarto de miocardio recurrente, accidente cerebrovascular o insuficiencia cardíaca nueva o empeoramiento durante el seguimiento.

4. Stent SYNERGY: incidencia de trombosis definitiva del stent en 1 año

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. a) Patients with STEMI referred for PCI within 12 hours of symptom onset, have a culprit lesion amenable to stenting, and with planned SYNERGY stent implantation for SYNERGY registry
OR
b) Patients with STEMI referred for PCI within 24 hours of symptom onset, not prospectively enrolled in SYNERGY STENT registry

2. Able to be randomized within 48 hours of index PCI and during initial hospitalization (however patients should be randomized as soon as possible after PCI)

3. Written informed consent

1. a) Los pacientes con STEMI referidos para ICP dentro de las 12 horas luego del inicio de los síntomas, tienen una lesión culpable susceptible de estenting, y con implante de estent SYNERGY planificado para el registro SYNERGY (inicial de 800 pacientes)
O
b) Los pacientes con STEMI referidos para ICP dentro de las 24 horas
luego del inicio de los síntomas, no prospectivamente inscritos en el
registro del ESTENT SYNERGY (después de los primeros 800 pacientes con ESTENT SYNERGY)
2. Aquellos capaces de ser asignados al azar dentro de las 48 horas de
ICP de índice y durante la hospitalización inicial, sin embargo, los pacientes deben ser asignados al azar lo antes posible después de la ICP
3. Consentimiento informado por escrito

E.4

Principal exclusion criteria

- Age ≤18 years
- Pregnancy, breastfeeding, or women of childbaring potential who are not using an effective method of contraception
- Any medical, geographic, or social factor making study participation impractical or precluding required folow-up
- Systolic blood pressure <90 mm Hg
- Active diarrhea
- Known allergy or contraindication to everolimus, the Synergy stent or any of its components
- Unable to receive dual antiplatelet therapy
- Any contraindication or known intolerance to colchicine or spironolactone
- Requirement of cholchicine or mineralocorticoid antagonist for another indication
- History of cirrhosis or current severe hepatic disease
- Current or planned use of any of: cyclosporine, verapamil, HIV protease inbibitors, azole antifungals, or macrolide antibiotics
- Creatinine clearance <30 ml/min/1.73m2
- Serum Potassium >5.0 mew/L

1. Edad ≤18 años
2. Embarazo, lactancia materna o mujeres en edad fértil que no estén
utilizando un método anticonceptivo eficaz
3. Cualquier factor médico, geográfico o social que impida la
participación en el estudio o impida el seguimiento requerido
4. Presión arterial sistólica <90 mm Hg
5. Diarrea activa
6. Alergia conocida o contraindicación al everolimus, al estent SYNERGY o a cualquiera de sus componentes
7. Incapaz de recibir terapia antiplaquetaria dual
8. Cualquier contraindicación o intolerancia conocida a la colchicina o a la espironolactona
9. Requerimiento de colchicina o antagonista mineralocorticoide para
otra indicación
10. Antecedentes de cirrosis o enfermedad hepática grave actual
11. Uso actual o planeado de cualquiera de éstos: ciclosporina,
verapamilo, inhibidores de la proteasa del VIH, antifúngicos azólicos o antibióticos macrólidos
12. Depuración de creatinina <30 ml / min / 1,73 m2
13. Potasio sérico> 5,0 meq / L

E.5 End points

E.5.1

Primary end point(s)

In patients with STEMI who have undergone PCI, the primary objectives of this study is to determine:
1. Colchicine vs. placebo: time to event of the composite of CV death, recurrent MI, or stroke over duration of follow-up.
2. Spironolactone vs. placebo: time to event of the composite of CV death or new or worsening heart failure over duration of follow-up.
3. SYNERGY stent: MACE (defined as the composite of CV death, recurrent MI, or unplanned ischemia driven target vessel revascularization) for SYNERGY stent compared to a historical performance goal within 1 year

En pacientes con STEMI que se han sometido a ICP, los objetivos principales de este estudio es determinar:
1. Colchicina versus placebo: tiempo hasta el evento del compuesto de muerte CV, MI recurrente o accidente cerebrovascular durante la duración del seguimiento.
2. Espironolactona versus placebo: tiempo hasta el evento del compuesto de muerte CV o insuficiencia cardíaca nueva o empeoramiento durante la duración del seguimiento.
3. Stent SYNERGY: MACE (definido como el compuesto de muerte CV, infarto de miocardio recurrente o revascularización de vasos diana impulsada por isquemia no planificada) para el stent SYNERGY en comparación con un objetivo de rendimiento histórico dentro de 1 año

E.5.1.1

Timepoint(s) of evaluation of this end point

Time-to-event over duration of follow-up. Minimum follow-up of 1 year to maximum of 3 years (average of 2 years).

Tiempo hasta el evento durante la duración del seguimiento. Seguimiento mínimo de 1 año a un máximo de 3 años (promedio de 2 años).

E.5.2

Secondary end point(s)

1. COLCHINE VS. COLCHICINE-PLACEBO: Time-to-event of the composite of cardiovascular death, recurrent MI, unplanned ischemia driven revascularization, or stroke, over the duration of follow-up.
2. SPIRONOLACTONE VS. SPIRONOLACTONE-PLACEBO:
a) Time-to-event of cardiovascular death over the duration of follow-up.
b) Time-to-event of the composite of cardiovascular death, new or worsening heart failure or significant ventricular arrhythmia over the duration of follow-up.
3. COMBINED COLCHICINE AND SPIRONOLACTONE: Time to event for the composite of cardiovascular death, recurrent MI, stroke or new or worsening heart failure over follow up
4. SYNERGY STENT REGISTRY: Incidence of Definite Stent Thrombosis within 1 year.

E.5.2.1

Timepoint(s) of evaluation of this end point

Time-to-event over duration of follow-up. Minimum follow-up of 1 year to maximum of 3 years (average of 2 years).

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)

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

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

factorial

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

Finland

France

Macedonia, the former Yugoslav Republic of

Serbia

Spain

Switzerland

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

LVLS

última visita último paciente

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:

1500

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

2500

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

556

F.4.2

For a multinational trial

F.4.2.1

In the EEA

1650

F.4.2.2

In the whole clinical trial

4000

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)

Patients that require further treatment following the completion of the trial will be provided with the necessary treatment through the hospitals normal practice. At no point during or after the project will patients be declined treatment. Colchicine and spironolactone are both generic drugs that are available by physician prescription outside of this research study.

Los pacientes que requieren tratamiento adicional después de la finalización del ensayo recibirán el tratamiento necesario a través de la práctica habitual del hospital. En ningún momento durante o después del proyecto se rechazará el tratamiento de los pacientes. La colchicina y la espironolactona son medicamentos genéricos que están disponibles por prescripción médica fuera de este estudio de investigación.

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

2018-12-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-22

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

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