Clinical Trials Register

Summary
EudraCT Number:	2017-002343-14
Sponsor's Protocol Code Number:	FMD-TRI-2017-01
National Competent Authority:	Portugal - INFARMED
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2018-01-10
Trial results	View 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

Portugal - INFARMED

A.2

EudraCT number

2017-002343-14

A.3

Full title of the trial

A multicentre, randomised, open-label, parallel-group trial to study the safety and efficacy of a new therapeutic strategy (Trinomia®) versus usual care on LDLc and blood pressure levels in patients with atherothrombotic cardiovascular disease: The APOLO trial.

A.3.1

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

A trial to study a new therapeutic strategy (Trinomia®) versus usual care on LDLc and blood pressure levels in patients with atherothrombotic cardiovascular disease: The APOLO trial.

A.3.2

Name or abbreviated title of the trial where available

APOLO

A.4.1

Sponsor's protocol code number

FMD-TRI-2017-01

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	Ferrer Internacional, S.A.
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Ferrer Internacional, S.A.
B.4.2	Country	Spain
B.4.1	Name of organisation providing support	Ferrer Internacional, S.A.
B.4.2	Country	Portugal
B.4.1	Name of organisation providing support	Ferrer Internacional, S.A.
B.4.2	Country	Ireland
B.4.1	Name of organisation providing support	Ferrer Internacional, S.A.
B.4.2	Country	Mexico
B.4.1	Name of organisation providing support	Ferrer Internacional, S.A.
B.4.2	Country	Ukraine
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dynamic Science S.L.
B.5.2	Functional name of contact point	Departamento de Ensayos Clínicos
B.5.3	Address:
B.5.3.1	Street Address	C/ Azcona, 31
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28028
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034914561105
B.5.5	Fax number	0034914561126
B.5.6	E-mail	ensayosclinicos@dynasolutions.com

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	Trinomia 100 mg/20 mg/10 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Ferrer Internacional SA
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Capsule, hard
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	RAMIPRIL
D.3.9.1	CAS number	87333-19-5
D.3.9.3	Other descriptive name	RAMIPRIL
D.3.9.4	EV Substance Code	SUB10248MIG
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	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATORVASTATIN
D.3.9.1	CAS number	134523-00-5
D.3.9.4	EV Substance Code	SUB05600MIG
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	20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.4	EV Substance Code	SUB12730MIG
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	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	Trinomia 100 mg/20 mg/5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Ferrer Internacional, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Capsule, hard
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	RAMIPRIL
D.3.9.1	CAS number	87333-19-5
D.3.9.3	Other descriptive name	RAMIPRIL
D.3.9.4	EV Substance Code	SUB10248MIG
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	5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATORVASTATIN
D.3.9.1	CAS number	134523-00-5
D.3.9.4	EV Substance Code	SUB05600MIG
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	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.4	EV Substance Code	SUB12730MIG
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	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: 3
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	Trinomia 100 mg/20 mg/2,5 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Ferrer Internacional, S.A.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Capsule, hard
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	RAMIPRIL
D.3.9.1	CAS number	87333-19-5
D.3.9.3	Other descriptive name	RAMIPRIL
D.3.9.4	EV Substance Code	SUB10248MIG
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	2.5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATORVASTATIN
D.3.9.1	CAS number	134523-00-5
D.3.9.4	EV Substance Code	SUB05600MIG
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	20
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.4	EV Substance Code	SUB12730MIG
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	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: 4
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	Trinomia
D.2.1.1.2	Name of the Marketing Authorisation holder	Ferrer Internacional SA
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Trinomia 100 mg/40 mg/10 mg
D.3.4	Pharmaceutical form	Capsule, hard
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	RAMIPRIL
D.3.9.1	CAS number	87333-19-5
D.3.9.3	Other descriptive name	RAMIPRIL
D.3.9.4	EV Substance Code	SUB10248MIG
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	10
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATORVASTATIN
D.3.9.1	CAS number	134523-00-5
D.3.9.4	EV Substance Code	SUB05600MIG
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	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.4	EV Substance Code	SUB12730MIG
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	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: 5
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	Trinomia
D.2.1.1.2	Name of the Marketing Authorisation holder	Ferrer Internacional SA
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Trinomia 100 mg/40 mg/5 mg
D.3.4	Pharmaceutical form	Capsule, hard
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	RAMIPRIL
D.3.9.1	CAS number	87333-19-5
D.3.9.3	Other descriptive name	RAMIPRIL
D.3.9.4	EV Substance Code	SUB10248MIG
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	5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATORVASTATIN
D.3.9.1	CAS number	134523-00-5
D.3.9.4	EV Substance Code	SUB05600MIG
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	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.4	EV Substance Code	SUB12730MIG
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	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: 6
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	Trinomia
D.2.1.1.2	Name of the Marketing Authorisation holder	Ferrer Internacional SA
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Trinomia 100 mg/40 mg/2.5 mg
D.3.4	Pharmaceutical form	Capsule, hard
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	RAMIPRIL
D.3.9.1	CAS number	87333-19-5
D.3.9.3	Other descriptive name	RAMIPRIL
D.3.9.4	EV Substance Code	SUB10248MIG
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	2.5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ATORVASTATIN
D.3.9.1	CAS number	134523-00-5
D.3.9.4	EV Substance Code	SUB05600MIG
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	40
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ACETYLSALICYLIC ACID
D.3.9.1	CAS number	50-78-2
D.3.9.4	EV Substance Code	SUB12730MIG
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	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: 7
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	Usual care - treatment for cardiovascular prevention: Antiplatelet, lipid-lowering and blocking agents of the renin-angiotensinaldosterone system.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	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

Patients with atherothrombotic cardiovascular disease

E.1.1.1

Medical condition in easily understood language

Patients with atherothrombotic cardiovascular disease

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10007648
E.1.2	Term	Cardiovascular disease, unspecified
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

To determine whether the treatment with a new therapeutic strategy (Trinomia®) is at least non-inferior to usual care in terms of low-density lipoprotein cholesterol (LDLc) and systolic blood pressure reductions in subjects with atherothrombotic cardiovascular disease after 6 months of treatment.

E.2.2

Secondary objectives of the trial

- To assess whether the treatment with the cardiovascular polypill is at least non-inferior to usual care in terms of LDLc and blood pressure in subgroups of patients with coronary artery disease, stroke and peripheral artery disease of patients.
- To compare the percentage of patients with LDLc and blood pressure under control according to 2016 European Guidelines on cardiovascular disease prevention, between both groups of treatment.
- To compare the changes versus baseline values in total cholesterol, LDLc, high-density lipoprotein cholesterol (HDLc), non-HDLc, triglycerides and blood pressure after 6 months of treatment, for each group and between both groups of treatement.
- To evaluate satisfaction with medication and patients' preferences in preventive treatment of secondary cardiovascular events with a cardiovascular polypill.
- To evaluate the safety of the cardiovascular polypill.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age ≥18; both genders.
2) Subjects with atherothrombotic cardiovascular disease, with at least one of the following clinical events, the last one having occurred within the required time frame:
2.a) Previous acute myocardial infarction (>6 months after the event).
2.b) Cardiac revascularization with coronary stent (>6 months after the surgery) or coronary artery bypass grafting (3 months after the surgery).
2.c) Diagnosis of stable angina (patients to be submitted to a coronary interventional procedure or functional (ischemic test) and/or anatomic (coronary stenosis assessed by coronary angiography or computed tomography).
2.d) Previous ischemic stroke with atherothrombotic background, including lacunar infarction (>6 months after the event).
2.e) Peripheral artery disease, including patients with stable claudication (>6 months) or operated patients (revascularization or amputation) (2 weeks after the surgery).
3) Subjects treated with an ACE inhibitor or ARB, statin and acetylsalicylic acid for secondary cardiovascular prevention.
4) Subjects who are clinically stable, with no changes in medication for LDLc and blood pressure control within the last 3 months, and in whom it is not planned to change their medication for LDLc and blood pressure in the following 6 months after randomisation.
5) Written informed consent form.

E.4

Principal exclusion criteria

1) Any contraindication to the polypill, such as:
1.a) Patients on haemodialysis or with severe renal impairment (defined by glomerular filtration rate (calculated by CKD-EPI formula) <30 ml/min).
1.b) Patients with moderate hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevation >3 times the upper limit of normal (ULN) or severe hepatic impairment (defined by the Child-Pugh criteria for patients with ALT/AST >5 times the ULN).
1.c) Patients with hypersensitivity to any of the components of the polypill (atorvastatin, ramipril or acetylsalicylic acid), soy, peanuts, or to any ACE inhibitors or salicylates other than acetylsalicylic acid or ramipril.
1.d) Patients with a history of asthma episodes or nasal polyps associated with asthma, or other allergic reactions due to acetylsalicylic acid or other non-steroidal anti-inflammatory drugs.
1.e) Patients with active recurrent peptic ulcer, history and/or active gastric or intestinal bleeding, cerebrovascular haemorrhage, or regular history of dyspepsia.
1.f) Patients with anaemia (haemoglobin <10 g/dl) or worsening of haemoglobin, suggesting the presence of active bleeding, according to investigator’s criteria, which may contraindicate the use of acetylsalicylic acid.
1.g) Patients with haemophilia or other disorders of coagulation.
1.h) Patients with myopathy, myalgia, myositis or a history of rhabdomyolysis, or those that have creatine kinase (CK) tested and whose result is > 5 LSN (it is recommended not to measure CK after intense exercise).
1.i) Patients with a history of angioedema or cough due to ACE inhibitors.
1.j) Patients with bilateral renal artery stenosis or renal artery stenosis with a single functioning kidney.
2) Patients in whom, at the discretion of the investigator, it is not clinically appropriate to use the polypill (including atorvastatin 20 or 40 mg and ramipril 2.5 to 10 mg) as treatment for the control of LDLc cholesterol and blood pressure.
3) Subjects with suspected familiar hypercholesterolemia or triglycerides >400 mg/dl.
4) Patients with hypotensive or haemodynamically unstable states.
5) Subjects with diagnosed of congestive heart failure (New York Heart Association [NYHA] class III-IV).
6) Patients diagnosed with atrial fibrillation.
7) Patients with haemorrhagic stroke, cardioembolic stroke or stroke of undetermined aetiology.
8) Patients taking any of the following medication:
- Treatment with a fixed dose combination of 3 antihypertensives.
- Chronic treatment with non-steroidal anti-inflammatory drugs; its occasional use is allowed. It will be considered occasional use when ibuprofen (maximal dose 1200 mg/day), or other non-steroidal anti-inflammatory drugs at equivalent dose, is used for a maximum of 3 days in a period of one month.
- Potent inhibitor of CYP3A4 or transport proteins (e.g. ciclosporin, rifampicin, telitromicin, claritromicin, delavirdin, estiripentol, ketoconazol, voriconazol, itraconazol, posaconazol and HIV protease inhibitors such as ritonavir, lopinavir, atazanavir, indinavir, darunavir, telaprevir, etc).
- Other medications as: Gemfibrozil, Aliskiren, Methotrexate, Fusidic acid (oral) or Sacubitril /Valsartan
9) Women who are pregnant, breastfeeding or planning to become pregnant during the study, as well as fertile women who do not take adequate contraceptive measures such as: combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomised partner or sexual abstinence). In fertile women, additional pregnancy tests should be performed at monthly intervals.
10) Presence of major systemic illnesses that in the investigator’s opinion may interfere with the study procedures and/or assessments.
11) Patients with a mental illness (such as dementia) or living in a nursing home or committed to an institution by an order issued by the judicial or the administrative authorities that may limit their capacity of self-care.
12) Medical history of drug/alcohol abuse.
13) Participants in another clinical trial < 30 days prior to randomisation.
14) Patients treated with the polypill prior to randomisation.
15) Patients with active cancer or with chemotherapy treatment.

E.5 End points

E.5.1

Primary end point(s)

systolic blood pressure and LDLc values

E.5.1.1

Timepoint(s) of evaluation of this end point

at the end of the study treatment period

E.5.2

Secondary end point(s)

- Blood pressure and LDLc levels at the end of the treatment period in subgroups of patients with atherothrombotic cardiovascular disease with coronary artery disease, stroke and/or peripheral artery disease.
- Changes in the SBP / DBP and LDL-c levels from baseline to month 6.
- The percentage of patients with LDLc and blood pressure under control as per the 2016 European Guidelines on Cardiovascular Disease Prevention at month 6; the LDLc and blood pressure control as per these guidelines is defined as:
- LDLc levels:
- In patients at very high cardiovascular risk (including patients in secondary prevention), an LDLc goal <1.8 mmol/l (<70 mg/dl) or a reduction of at least 50% if the baseline is between 1.8 and 3.5 mmol/l (70 and 135 mg/dl).
- Blood pressure:
- General: systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg.
- In patients aged >60 years with systolic blood pressure ≥160 mmHg, target between 150 and 140 mmHg.
- In fit patients aged <80 years, systolic blood pressure <140 mmHg.
- In individuals aged >80 years and with initial systolic blood pressure ≥160 mmHg, systolic blood pressure between 140 and 150 mmHg.
- In diabetic patients: systolic blood pressure <140mmHg and diastolic blood pressure <85mmHg
- Total cholesterol, HDLc, non-HDLc and triglyceride levels at the end of the treatment period.
- Changes in total cholesterol, HDLc, non-HDLc and triglyceride levels from baseline to month 6.
- Patients’ satisfaction with medication according to the abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9; Appendix 2) and patients’ preferences reported in the specific ad-hoc questions on treatment preferences (Appendix 3) at the end of the treatment period.
- The safety of the polypill will be assessed according to the occurrence of adverse events (AEs; e.g. cardiovascular events, other AEs, serious AEs [SAEs] and AEs causing withdrawal) throughout the study.

E.5.2.1

Timepoint(s) of evaluation of this end point

At month 6 and throughout the study.

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

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

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

Ireland

Mexico

Portugal

Spain

Ukraine

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

Folow up visit 28 days after the end of treatment visit

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

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:

100

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

400

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

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

150

F.4.2

For a multinational trial

F.4.2.1

In the EEA

400

F.4.2.2

In the whole clinical trial

500

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

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-05-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-04-23

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-03-09

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