Clinical Trials Register

Summary
EudraCT Number:	2017-000487-15
Sponsor's Protocol Code Number:	CLSYN.1702
National Competent Authority:	Czechia - SUKL
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-11-18
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

Czechia - SUKL

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 myocARdial infarction/SYNERGY Stent Registry –
Organization to Assess Strategies for Ischemic Syndromes 9

CLEAR SYNERGY (OASIS 9)
2x2 faktoriální randomizovaná kontrolovaná studie s CoLchicine a spironolaktonem u pacientů s infarktem myokardu/ SYNERGY Stent Registry -
Organizace pro hodnocení strategií pro ischemické syndromy 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.

Studie kolchicinu a spironolaktonu u pacientů s infarktem.

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 xt. 40513
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.3.9.4	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.3.9.1	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

Myocardial Infarction (MI)

infarktem myokardu

E.1.1.1

Medical condition in easily understood language

heart attack

infarkt

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	10007541 - Cardiac disorders

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	10064347
E.1.2	Term	Non ST segment elevation myocardial infarction
E.1.2	System Organ Class	10007541 - Cardiac 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

In patients with MI 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. Zjistit, zda může kolchicin snížit výskyt kardiovaskulární smrti, infarktu myokardu nebo mozkové mrtvice během trvání následné kontroly
2. Zjistit, zda může spironolakton snížit výskyt kardiovaskulární smrti nebo nového či zhoršujícího se selhání srdce během trvání následné kontroly
3. Zjistit četnost závažných nežádoucích srdečních příhod (MACE) u pacientů, kterým byl implantován stent SYNERGY uvoľnující everolimus ve srovnání s cílem zákroku

E.2.2

Secondary objectives of the trial

Not applicable

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 48 hours of symptom onset, not prospectively enrolled in SYNERGY
STENT registry.
OR
c) Patients with diagnosis of Non STEMI with ischemic symptoms and either Hs Troponin > or = 200x ULN or Troponin > or = 100x ULN who
have undergone PCI with one of the following:

i. LVEF< or =45%
ii. Diabetes
iii. Multivessel CAD defined as 50% stenosis in 2nd major epicardial
vessel
iv. Prior MI
v. Age >60 years

2. Able to be enrolled/randomized within 72 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) Pacienti se STEMI doporučeni k PCI do 12 hodin od projevu příznaků, mají lézi určenou k umístění stentu a naplánovanou implantaci stentu SYNERGY pro registr SYNERGY (prvních 800 pacientů)
NEBO
b) Pacienti se STEMI doporučeni k PCI do 48 hodin od projevu příznaků, u kterých se neplánuje zahrnutí do registru SYNERGY STENT (po prvních 800 pacientech ze SYNERGY STENT)
2. Možnost zapsaný/randomizace do 72 hodin od primární PCI a během první hospitalizce, nicméně, pacienti by měli být randomizovaní co nejdříve po PCI
3. Písemný informovaný souhlas

E.4

Principal exclusion criteria

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

1. Věk ≤18 let
2. Těhotenství, kojení nebo ženy v plodném věku, které neužívají žádnou efektivní antikoncepční metodu
3. Jakýkoli zdravotní, geografický nebo sociální faktor, který účast ve studiu činí nepraktickou nebo znemožňuje potřebné následné kontroly
4. Systolický krevní tlak <90 mm Hg
5. Akutní diarea
6. Kontraindikace nebo známá alergie na everolimus, stent SYNERGY nebo kteroukoli z jeho složek
7. Nemožnost podávání duální protidestičkové (antikoagulační) medikace
8. Jakákoli kontraindikace nebo známá intolerance vůči kolchicinu nebo spironolaktonu
9. Potřeba podávání antagonisty ke kolchicinu nebo mineralokortikoidu z důvodu jiné indikace
10. Historie cirhózy nebo aktuální závažná jaterní nemoc
11. Probíhající nebo plánované užívání kteréhokoli z následujících přípravků: cyklosporin, verapamil, inhibitory proteázy HIV, azolová antimykotika nebo makrolidová antibiotika
12. Clearance kreatininu <30 ml/min/1,73 m2
13. Draslík v séru >5,0 meq/l

E.5 End points

E.5.1

Primary end point(s)

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

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

1. Kolchicin vs. placebo: Čas do první události kardiovaskulárního úmrtí, opakovaného MI, mrtvice nebo neplánované revaskularizace z důvodu ischémie, během doby sledování.
2. Spironolakton vs. placebo: Celkový počet událostí kardiovaskulárního úmrtí nebo srdečního selhání (nového nebo zhoršení stávajícího), během doby sledování.
3. Synergy stent: MACE (definováno jako kombinace kardiovaskulárního úmrtí, opakovaného MI nebo neplánované revaskularizace cílové cévy z důvodu ischémie) pro stent SYNERGY ve srovnání s předchozím cílovým výkonem během 1 roku.

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 5 years (average of 3 years).

Čas-do-události během doby trvání nebo následně. Minimální sledování od 1 roku do 5 let (průměr 3 roky)

E.5.2

Secondary end point(s)

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

1. Kolchicin vs. kolchicin-placebo:
a. Čas do složené události (kardiovaskulární úmrtí, opakovaný infarkt myokardu nebo mrtvice), během doby sledování.
b. Celkový počet složených událostí (kardiovaskulární úmrtí, opakovaný infarkt myokardu, mrtvice nebo neplánované revaskularizace z důvodu ischémie), během doby sledování.
2. Spironolakton vs. spironolactone-placebo:
a. Čas do události kardiovaskulárního úmrtí nebo srdečního selhání (nového nebo zhoršení stávajícího), během doby sledování.
b. Čas do události kardiovaskulárního úmrtí během doby sledování.
c. Čas do složené události (kardiovaskulární úmrtí, srdeční selhání – nové nebo zhoršení stávajícího, nebo významná komorová arytmie), během doby sledování.
3. Kombinovaný kolchicin a spironolakton: Čas do první složené události (kardiovaskulární úmrtí, opakovaný infarkt myokardu, mrtvice, neplánovaná revaskularizace z důvodu ischémie nebo nové či zhoršené srdeční selhání), během doby sledování.
4. SYNERGY stent registr: Incidence jednoznačné trombózy stentu během 1 roku.

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 5 years (average of 3 years).

Čas-do-události během doby trvání nebo následně. Minimální sledování od 1 roku do 5 let (průměr 3 roky)

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

Switzerland

North Macedonia

Australia

Canada

Serbia

United Kingdom

United States

Czechia

France

Hungary

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:

2625

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

4375

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

180

F.4.2

For a multinational trial

F.4.2.1

In the EEA

2000

F.4.2.2

In the whole clinical trial

7000

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.

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

2020-04-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-10-16

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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