Clinical Trials Register

Summary
EudraCT Number:	2017-001596-23
Sponsor's Protocol Code Number:	KCT06/2017-PRECIOUS
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-10-02
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2017-001596-23

A.3

Full title of the trial

Fixed-Dose Combination of Perindopril/Amlodipine (Amlessa®) and Fixed-Dose Combination of Perindopril/Indapamide /Amlodipine (Co-Amlessa®) - Contribution to Management in newly diagnosed and uncontrolled hypertensive patients (PRECIOUS study)

A.3.1

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

A.4.1

Sponsor's protocol code number

KCT06/2017-PRECIOUS

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	Krka, d.d., Novo mesto
B.1.3.4	Country	Slovenia
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	Krka, d.d., Novo mesto
B.4.2	Country	Slovenia
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	KRKA-POLSKA SP. Z O.O.
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Równoległa 5
B.5.3.2	Town/ city	Warszawa
B.5.3.3	Post code	02-235
B.5.3.4	Country	Poland
B.5.4	Telephone number	004822 57 37 612
B.5.6	E-mail	magdalena.falandysz-kasperska@krka.biz

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	Amlessa®
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Słowenia
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.3	Other descriptive name	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.4	EV Substance Code	SUB03711MIG
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	4
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AMLODIPINE
D.3.9.3	Other descriptive name	AMLODIPINE BESILATE
D.3.9.4	EV Substance Code	SUB12864MIG
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.3.11 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	Amlessa®
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Słowenia
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.3	Other descriptive name	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.4	EV Substance Code	SUB03711MIG
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	8
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AMLODIPINE
D.3.9.3	Other descriptive name	AMLODIPINE BESILATE
D.3.9.4	EV Substance Code	SUB12864MIG
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.3.11 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	Amlessa®
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Słowenia
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.3	Other descriptive name	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.4	EV Substance Code	SUB03711MIG
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	8
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AMLODIPINE
D.3.9.3	Other descriptive name	AMLODIPINE BESILATE
D.3.9.4	EV Substance Code	SUB12864MIG
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.3.11 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	Co-Amlessa®
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Słowenia
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.3	Other descriptive name	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.4	EV Substance Code	SUB03711MIG
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	4
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INDAPAMIDE
D.3.9.1	CAS number	26807-65-8
D.3.9.3	Other descriptive name	INDAPAMIDE
D.3.9.4	EV Substance Code	SUB08169MIG
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	1.25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AMLODIPINE
D.3.9.3	Other descriptive name	AMLODIPINE BESILATE
D.3.9.4	EV Substance Code	SUB12864MIG
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.3.11 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	Co-Amlessa®
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Słowenia
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.3	Other descriptive name	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.4	EV Substance Code	SUB03711MIG
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	8
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INDAPAMIDE
D.3.9.1	CAS number	26807-65-8
D.3.9.3	Other descriptive name	INDAPAMIDE
D.3.9.4	EV Substance Code	SUB08169MIG
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	AMLODIPINE
D.3.9.3	Other descriptive name	AMLODIPINE BESILATE
D.3.9.4	EV Substance Code	SUB12864MIG
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.3.11 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	Co-Amlessa®
D.2.1.1.2	Name of the Marketing Authorisation holder	KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Słowenia
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.3	Other descriptive name	PERINDOPRIL TERT-BUTYLAMINE
D.3.9.4	EV Substance Code	SUB03711MIG
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	8
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INDAPAMIDE
D.3.9.1	CAS number	26807-65-8
D.3.9.3	Other descriptive name	INDAPAMIDE
D.3.9.4	EV Substance Code	SUB08169MIG
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	AMLODIPINE
D.3.9.3	Other descriptive name	AMLODIPINE BESILATE
D.3.9.4	EV Substance Code	SUB12864MIG
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.3.11 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

Newly diagnosed and uncontrolled patients with essential arterial hypertension.

E.1.1.1

Medical condition in easily understood language

Newly diagnosed and uncontrolled patients with essential arterial hypertension.

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	PT
E.1.2	Classification code	10015488
E.1.2	Term	Essential hypertension
E.1.2	System Organ Class	10047065 - Vascular 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

The purpose of the study is to establish the efficacy and safety of fixed-dose combination (FDC) of perindopril/amlodipine (Amlessa®) and fixed-dose combination of perindopril/indapamide/amlodipine (Co-Amlessa®) in wide populations of uncontrolled patients with arterial hypertension (AH) with special focus on effective continuous 24-hour blood pressure (BP) control. The purpose is also to establish the correlation between 24-hour central and peripheral BP.

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Patients with essential arterial hypertension.*
• Men and women aged ≥ 18 years.
• Written informed consent.
• Ability to adhere to study protocol.

*Additional inclusion criteria for Amlessa®:
• Patients with essential arterial hypertension:

o Naïve patients with systolic blood pressure (SBP) from 150 mmHg or higher AND/OR diastolic blood pressure (DBP) from 95 mmHg or higher (SBP ≥ 150 AND/OR DBP ≥ 90 mmHg for patients with type 2 diabetes mellitus)

o Uncontrolled patients on antihypertensive monotherapy with SBP from 140 mmHg or higher AND/OR DBP from 90 mmHg or higher (SBP ≥ 140 AND/OR DBP ≥ 85 mmHg for patients with type 2 diabetes mellitus).

o Uncontrolled patients on dual antihypertensive therapy (either in monoforms or FDC) with SBP from 140 mmHg or higher AND/OR DBP from 90 mmHg or higher (SBP ≥ 140 AND/OR DBP ≥ 85 mmHg for patients with type 2 diabetes mellitus).

*Additional inclusion criteria for Co-Amlessa®:
• Patients with essential arterial hypertension (AH):

o Uncontrolled patients on dual antihypertensive therapy (either in monoforms or FDC, including perindopril+amlodipine combination) with SBP from 140 mmHg or higher AND/OR DBP from 90 mmHg or higher (SBP ≥ 140 AND/OR DBP ≥ 85 mmHg for patients with type 2 diabetes mellitus).

o Uncontrolled patients on triple antihypertensive therapy (either in monoforms or FDC) with SBP from 140 mmHg or higher AND/OR DBP from 90 mmHg or higher (SBP ≥ 140 AND/OR DBP ≥ 85 mmHg for patients with type 2 diabetes mellitus).

E.4

Principal exclusion criteria

• History of adverse reactions or hypersensitivity associated with the use of the active substances, or any other components of the Investigational medicinal products (IMPs) used in the trial.
• Hereditary/idiopathic angioedema.
• Known secondary AH (e.g. pheochromocytoma, primary aldosteronism, renal artery stenosis)
• Office measured Systolic blood pressure ≥200 mmHg
• Unstable angina pectoris.
• Acute heart failure and heart failure NYHA IV.
• Antihypertensive drugs used for other indication than AH (e.g. tachyarrhythmia, glaucoma) less than 3 months before the study or in changed dosages less than 3 months before the study
• Severe liver impairment OR biliary cirrhosis OR cholestasis OR hepatic encephalopathy
• Renal dysfunction - GFR <60 ml/min (bilateral renal artery stenosis, renal artery stenosis in a solitary kidney, patients with only 1 kidney, or post-renal transplant patients, dialysis patients
• Any of the following clinically relevant laboratory or ECG findings
- significant anaemia with haemoglobin less than 100 g/l,
- serum AST and/or ALT and/or ALP and/or GammaGT of more than 3 x ULN (upper limit of normal)
- hyperkalaemia (serum potassium of more than 5 mmol/l)
- A-V block grade 2 or 3
- ECG signs of acute ischemia
• Concurrent therapy with:
o aliskiren-containing products (in patients with diabetes mellitus or renal impairment)
o Lithium
o Estramustine
o Any “not allowed” medication(s) listed in Study protocol section 6.2
• Bradycardia with heart rate less than 50/min.
• Female patients who are pregnant, planning to become pregnant.
• Breastfeeding female patients.
• Any significant acute condition (severe infection, exacerbation or uncontrolled phase of a chronic disease, major trauma, major surgery) within 30 days prior to screening visit.
• Pathological clinical states (e.g. malignant diseases, excessive alcohol consumption, drug abuse or drug addiction, psychiatric conditions) or any life-threatening illness.
• Patients currently participating in another clinical trial.
• Patient’s refusal to participate with the investigator.
• Normal average 24-hour SBP and DBP obtained by ABPM (<130/80 mmHg at baseline).
• Severe orthostatic hypotension.
• Patients to whom β-blocker therapy cannot be discountinued in one day.
• Previous or current therapy with perindopril and amlodipine and indapamide taken concomitantly all together as 3 separate tablets or as a fixed-dose combination.
• In Amlessa® arm patients on previous or current therapy with perindopril and amlodipine taken concomitantly all together as 2 separate tablets or as a fixed-dose combination. (this exclusion criterion does not apply to Co-Amlessa® arm).

E.5 End points

E.5.1

Primary end point(s)

Responder rate after 16 weeks (visit 5): proportion of patients reaching normal office blood pressure (NBP)*.
* Normal (office) blood pressure (NBP): SBP < 140 mmHg and DBP < 90 mmHg; patients with type 2 diabetes mellitus: SBP < 140 mmHg and DBP < 85 mmHg)

E.5.1.1

Timepoint(s) of evaluation of this end point

After 16 weeks of treatment

E.5.2

Secondary end point(s)

o Responder rate after 4 (visit 2), 8 (visit 3) and 12 weeks (visit 4): proportion of patients reaching office NBP*.
o Mean absolute and relative change from baseline in office SBP and DBP after 4, 8, 12 and 16 weeks (Visit 2, 3, 4, 5).
o Mean absolute and relative changes from baseline to 16 weeks in average 24-hour SBP and DBP, average awake time SBP and DBP, and average sleep time SBP and DBP, all obtained by ABPM.
o Responder rate after 16 weeks (visit 5) in average 24-hour SBP and DBP, average awake time SBP and DBP, and average sleep time SBP and DBP, all obtained by ABPM: proportion of patients reaching normal average 24h ABPM SBP and DBP (<130/80), normal average awake time SBP and DBP (<135/85) and normal average sleep time SBP and DBP (<120/70).
o Proportion of patients reaching a reduction of office SBP by at least 20 mmHg or DBP by at least 10 mmHg from baseline after 16 weeks.
o Proportion of patients reaching a reduction of central (systolic) blood pressure parameters (in 24-hour measurement) below 120 mmHg from baseline after 16 weeks.
o Proportion of patients reaching a reduction of pulse wave velocity (in 24-hour measurement) for at least 0,5 m/s from baseline after 16 weeks.
o Proportion of patients reaching a reduction of SBP and DBP variability expressed as reduction of day-night standard deviation (SDdn) by at least 0.5 and that of average real variability (ARV) by at least 0.5.

E.5.2.1

Timepoint(s) of evaluation of this end point

After 4, 8, 12 and 16 weeks of treatment

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

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)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

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

Armenia

Croatia

Hungary

Poland

Russian Federation

Serbia

Slovenia

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

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

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:

285

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

285

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

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

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

250

F.4.2.2

In the whole clinical trial

570

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

2017-11-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-10-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-09-27

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