Clinical Trials Register

Summary
EudraCT Number:	2022-002539-79
Sponsor's Protocol Code Number:	CT-L05-301
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:	2022-09-29
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

2022-002539-79

A.3

Full title of the trial

A Multicentre, Randomized, Double-blind Study to Evaluate and Compare the Efficacy and Safety of 8-week Treatment with Azilsartan Medoxomil and Amlodipine Besylate Combined and Alone in Mild-to-moderate Essential Hypertensive Subjects

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

CT-L05-301

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	Celltrion Inc.
B.1.3.4	Country	Korea, Republic of
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	Celltrion Inc.
B.4.2	Country	Korea, Republic of
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Celltrion Inc.
B.5.2	Functional name of contact point	Global Clinical Development 2 Team
B.5.3	Address:
B.5.3.1	Street Address	23, Academy-Ro, Yeonsu-Gu
B.5.3.2	Town/ city	Incheon
B.5.3.3	Post code	22014
B.5.3.4	Country	Korea, Republic of
B.5.4	Telephone number	82-2-3403-9647
B.5.5	Fax number	82-2-046-5001
B.5.6	E-mail	sanghee.byun@celltrion.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	Edarbi
D.2.1.1.2	Name of the Marketing Authorisation holder	Takeda Ireland Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Azilsartan Medoxomil
D.3.2	Product code	AZM/AR14/TAK-491
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	Azilsartan medoxomil
D.3.9.1	CAS number	863031-21-4
D.3.9.2	Current sponsor code	AZM/AR14/TAK-491
D.3.9.3	Other descriptive name	AZILSARTAN MEDOXOMIL
D.3.9.4	EV Substance Code	SUB31560
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.3.11 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	Norvasc
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer Manufacturing Deutschland GmbH
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	amlodipine besylate
D.3.2	Product code	AMLODIPINE BESILATE
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	AMLODIPINE (AMLODIPINE BESYLATE)
D.3.9.1	CAS number	111470-99-6
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.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	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

Mild-to-moderate Essential Hypertensive

E.1.1.1

Medical condition in easily understood language

Mild-to-moderate Essential 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	24.0
E.1.2	Level	PT
E.1.2	Classification code	10020823
E.1.2	Term	Hypertensive heart disease
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

To evaluate antihypertensive efficacy of a combination of Azilsartan medoxomil and Amlodipine besylate, in mild-to-moderate essential hypertensive subjects not adequately controlled by Azilsartan medoxomil monotherapy or Amlodipine besylate monotherapy

E.2.2

Secondary objectives of the trial

• To evaluate the safety and tolerability of a combination of Azilsartan medoxomil and Amlodipine besylate, in mild-to-moderate essential hypertensive subjects not adequately controlled by Azilsartan medoxomil monotherapy or Amlodipine besylate monotherapy
• To determine the dose-response relationship of Azilsartan medoxomil and Amlodipine besylate monotherapy and Azilsartan medoxomil/ Amlodipine besylate combination therapy in subjects with mild-to-moderate essential hypertension.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subject eligibility is determined according to the following criteria:
At screening:
1. Subjects voluntarily agree to participate in the trial and sign the written ICF, after listening to the purpose, method, and effect of clinical trial
2. Male or female adult subjects below the age of 75 years, inclusive
Note: Legal minimum age of adult requirement is country specific, and requirement of current country specific regulations will be applied. The current legal ages of adult in Korea, Taiwan, and Poland are ≥ 19, ≥18, and ≥18 respectively.
3. Subjects with mild-to-moderate essential hypertension:
a. Previously untreated subjects who have not received any antihypertensive medication in the 28 days prior to Visit 1 with msitSBP ≥140 mmHg and ≤180 mmHg
OR
b. Subjects with msitSBP ≥130 mmHg and ≤180 mmHg who have not been controlled with antihypertensive drugs
4. Subjects who are capable of understanding and complying with protocol requirements
Post-4 week, Azilsartan medoxomil or Amlodipine besylate monotherapy treatment:
5. Subjects who do not achieve target BP (defined as clinic SBP < 140 mmHg as determined by the mean of 3 sitting, trough, measurements; for subjects who have diabetes mellitus with or cardiovascular disease (CVD) or chronic kidney disease (CKD) with albuminuria (or proteinuria) target BP is defined as clinic SBP <130 mmHg) following 4 weeks run-in treatment with azilsartan medoxomil or amlodipine besylate monotherapy, prior to randomization to double-blind treatment.
6. Subjects who are compliant (>70% and <130%) with the study medication during run-in treatment period

E.4

Principal exclusion criteria

At screening:
1. Subjects who have msitSBP >180 mmHg or msitDBP >110 mmHg
2. The differences of msitSBP > 20 mmHg or msitDBP > 10 mmHg between 2 arms
3. A history or any suspected history of secondary hypertension (including but not limited to any of the following): coarctation of the aorta, primary hyperaldosteronism, unilateral or bilateral renal artery stenosis, Cushing’s syndrome, pheochromocytoma, polycystic kidney disease, chronic kidney disease on dialysis, etc.
4. Symptomatic orthostatic hypotension (a sudden fall in standing SBP of at least 20 mmHg or standing DBP of at least 10 mmHg after standing compared with BP from the sitting or supine position)
5. Type 1 or 2 diabetes mellitus with poor glucose control which is defined as history of poorly controlled diabetes mellitus (fasting blood glucose > 11.1 mmol/L [200 mg/dL]); excluding subjects who do not need diabetes medication control during the study period
6. Severe heart disease (congestive heart failure [NYHA Class 3 or 4]); ischemic heart disease (unstable angina, myocardial infarction), peripheral arterial vascular disease/endovascular intervention for peripheral artery disease, history of Percutaneous Transluminal Coronary Angioplasty or coronary artery bypass grafting within the past 6 months
7. Clinically significant ventricular tachycardia, atrial fibrillation, atrial flutter or other clinically significant arrhythmia, or clinically significant QT interval corrected using Fridericia formula (QTcF) for heart rate interval > 450 milliseconds (male) and >470 milliseconds (female), or symptomatic bradycardia
8. Clinically significant electrocardiogram (ECG) abnormalities including third-degree atrioventricular block, sick sinus syndrome, sinus-atrial block
9. Hypertrophic obstructive cardiomyopathy, severe obstructive coronary artery disease, aortic stenosis, hemodynamically relevant stenosis of the aortic or mitral valve
10. Severe cerebrovascular disease (history of stroke, cerebral infarction, or cerebral hemorrhage) within the past 6 months
11. Known moderate or malignant retinopathy (history of retinal signs of hemorrhage, visual impairment, retinal microaneurysm, etc.) within the past 6 months
12. A history of or ongoing: wasting disease, autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.), hepatic impairment defined as Child- Pugh Class A and above or connective tissue disease
13. Subjects who have the following clinically significant laboratory abnormalities: either creatinine clearance < 30 mL/min or serum creatinine > 2 mg/dL or > 200 μmol/L, serum potassium > 5.5mmol/L, alanine aminotransferase or aspartate aminotransferase > 3 × upper limit normal (ULN)
14. Significant thyroid disease (thyroid stimulating hormone > 1.5 × ULN)
15. History of unexplained syncope within the prior 2 years, or a known syncopal disorder
16. Any surgical or medical condition of the gastrointestinal tract that might significantly alter the absorption, distribution, metabolism, or excretion of the drug; current active gastritis, gastrointestinal/rectal bleeding, active inflammatory bowel disease within the last 12 months, etc.
17. Positive for human immunodeficiency virus (HIV), Hepatitis C antibody (HCV Ab), and/or positive for Hepatitis B surface antigen (HBsAg) that requires antiviral treatment
18. History of drug or alcohol abuse within the past 1 year
19. Subjects who are pregnant or lactating women, women suspected of being pregnant, women who wish to be pregnant during the study, or women of child-bearing potential who are not using medically acceptable methods of contraception
20. Any chronic inflammatory condition needing chronic anti-inflammatory therapy
21. A known hypersensitivity to any main excipients and components of the investigational drugs or other drugs in the same class
22. Subjects who have previously experienced symptoms characteristic of angioedema during treatment with angiotensin-converting enzyme inhibitors or angiotensin II subtype 1 receptor blocker
23. Subjects who have received any investigational product within 4 weeks (28 days) prior to screening or is currently participating in another investigational study
Note: Subjects participating in observational studies (per local definition) may enter Screening provided that the last intervention or invasive procedure was > 28 days prior to Visit 1.
24. Subjects who are required to take excluded medications (see Section 6.2) at any point during the study
25. Subjects who are judged unsuitable to participate in the study in the opinion of the investigator
Post 4-week of Azilsartan medoxomil or Amlodipine besylate monotherapy treatment:
26. Subjects who have a clinic msitSBP >180 mmHg and/or msitDBP >110 mmHg

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is:
• Change from baseline in mean sitting systolic BP (msitSBP) after 8 weeks of treatment

E.5.1.1

Timepoint(s) of evaluation of this end point

After 8 weeks of treatment

E.5.2

Secondary end point(s)

1) Key secondary efficacy endpoint:
• Change from baseline in mean sitting diastolic BP (msitDBP) after 8 weeks of treatment
2) Other secondary efficacy endpoints:
• Change from baseline in msitSBP after 4 weeks of treatment
• Change from baseline in msitDBP after 4 weeks of treatment
• Proportion of subjects who achieve below response criteria:
a. Clinic msitSBP <140 mmHg (but, subjects having diabetes mellitus or CVD or CKD with albuminuria (or proteinuria) <130 mmHg) and/or reduction of ≥20 mmHg from baseline after 4 and 8 weeks of treatment.
b. Clinic msitDBP <90 mmHg (but, subjects having diabetes mellitus or CVD or CKD with albuminuria (or proteinuria) <80 mmHg) and/or reduction of ≥10 mmHg from baseline after 4 and 8 weeks of treatment
c. (a) and (b)

E.5.2.1

Timepoint(s) of evaluation of this end point

After 4 and 8 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

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

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

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

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

Taiwan

Korea, Republic of

Poland

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

The end of the study is defined as the date of the last visit of the last subject in the study.

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:

150

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

150

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

Yes

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

450

F.4.2

For a multinational trial

F.4.2.1

In the EEA

450

F.4.2.2

In the whole clinical trial

804

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

2022-11-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-09-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-07-19

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