Clinical Trials Register

Summary
EudraCT Number:	2021-005077-10
Sponsor's Protocol Code Number:	MEIN/21/AmNe-Hyp/001
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2022-03-16
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

Bulgarian Drug Agency

A.2

EudraCT number

2021-005077-10

A.3

Full title of the trial

Open-label, multicenter, multinational, interventional clinical trial to assess efficacy and safety of the extemporaneous combination of nebivolol and amlodipine in grade 1-2 hypertensive patients versus each monotherapy

A.3.1

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

Study on the effectiveness and safety of combined treatment with nebivolol and amlodipine in mild to moderate hypertensive patients.

A.3.2

Name or abbreviated title of the trial where available

BOTTICELLI

A.4.1

Sponsor's protocol code number

MEIN/21/AmNe-Hyp/001

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	Menarini International Operations Luxembourg SA
B.1.3.4	Country	Luxembourg
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	Menarini International Operations Luxembourg SA
B.4.2	Country	Luxembourg
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Menarini
B.5.2	Functional name of contact point	Clinical Operation Director
B.5.3	Address:
B.5.3.1	Street Address	Via Sette Santi 1-3
B.5.3.2	Town/ city	Firenze
B.5.3.3	Post code	50131
B.5.3.4	Country	Italy
B.5.4	Telephone number	+39 055 5680459
B.5.6	E-mail	pfabrizzi@menarini.it

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	LOBIVON 5 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	A. Menarini Industrie Farmaceutiche Riunite srl
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	Nebivolol
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	NEBIVOLOL
D.3.9.1	CAS number	99200-09-6
D.3.9.4	EV Substance Code	SUB09175MIG
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	AMLODIPINE EUROGENERIC 5 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	EG S.p.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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
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
D.3.9.1	CAS number	88150-42-9
D.3.9.4	EV Substance Code	SUB05467MIG
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	AMLODIPINE EUROGENERIC 10 mg tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	EG S.p.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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
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
D.3.9.1	CAS number	88150-42-9
D.3.9.4	EV Substance Code	SUB05467MIG
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

Grade 1-2 hypertension

E.1.1.1

Medical condition in easily understood language

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	10020772
E.1.2	Term	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

To assess the antihypertensive efficacy of the extemporaneous combination of nebivolol (NEB) 5 mg with amlodipine (AML) 5 mg or AML 10 mg in lowering the sitting diastolic blood pressure (DBP) between Visit 2 (Week 0) and Visit 4 (Week 8) in patients with uncontrolled BP, previously treated with NEB 5 mg or AML 5 mg monotherapies for at least 4 weeks.

E.2.2

Secondary objectives of the trial

1.To assess the antihypertensive efficacy of the extemporaneous combination of NEB 5mg with AML 5mg or AML 10mg in lowering SBP between Visit 2 and 4 in patients with uncontrolled BP previously treated with NEB 5mg or AML 5mg monotherapies for at least 4 weeks.
2.To assess the antihypertensive efficacy of the extemporaneous combination of NEB/AML 5/10mg versus extemporaneous combination NEB/AML 5/5mg, in lowering sitting DBP and SBP between Visit 3 and 4 in patients with uncontrolled BP previously treated with NEB 5mg or AML 5mg monotherapies for at least 4 weeks.
3.To assess the antihypertensive efficacy of the extemporaneous combination of NEB 5mg with AML 5mg or AML 10mg by evaluating the patients who achieve BP goal at Visit 2, 3, and 4.
4.To assess the compliance to the treatment at Visit 2, 3, and 4.
5.To evaluate the safety and tolerability of the monotherapies (NEB 5mg and AML 5mg) and of the extemporaneous combinations (NEB 5mg and AML 5/10mg) after 8 weeks of treatment.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients with Grade 1 - 2 hypertension with mean sitting SBP ≥140 mmHg and ≤179 mmHg and/or mean sitting DBP ≥90 mmHg and ≤109 mmHg at screening (in accordance with the 2018 ESC/ESH guidelines definition), ≥18 and <65 years of age, on monotherapy treatment either with BBs or CCBs for at least 4 weeks before Visit 1 (screening).
2. Patients are able to understand and have freely given written informed consent at Screening Visit.
3. Patients who are able to comply with all study procedures and who are available for the duration of the study.
4. Ability to take oral medication and willing to adhere to the drug regimen.
5. Female patients are eligible to participate if not pregnant, or not breastfeeding and if they refrain from donating or storing eggs. For females of reproductive potential: use of highly effective contraception (eg. method of birth control throughout the study period and for 4 weeks after study completion defined as a method which results in a failure rate of <1% per year) such as:
- Combined hormonal contraception (estrogen- and progestogen-containing) associated with inhibition of ovulation (oral, intravaginal, and transdermal).
- Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, and implantable).
- Intrauterine device.
- Intrauterine hormone-releasing system.
- Bilateral tubal occlusion.
- Vasectomized partner (procedure conducted at least 2 months before the screening), (provided the partner is the sole sexual partner of the trial patient and that the vasectomized partner has received medical assessment of the surgical success).
6. A male patient must agree to use contraception during the whole study period and for at least 1 week after the last dose of study treatment and refrain from donating sperms during this period.

E.4

Principal exclusion criteria

1. Significant history of hypersensitivity to nebivolol, amlodipine, other BBs or other dihydropyridines, or any related products (including excipients of the formulations)as outlined in the relevant Investigators Brochures, summary of product characteristics (SmPC) or local package inserts for NEB and AML.
2. Patients with serious disorders (in the opinion of the Investigator) which may limit the ability to evaluate the efficacy or safety of the tested medications, including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine/or metabolic, hematological, or oncological, neurological, and psychiatric diseases. The same applies for immunocompromised and/or neutropenic patients.
3. Patients having a history of the following conditions within the last 6 months: myocardial infarction, unstable angina pectoris, percutaneous coronary intervention, bypass surgery, heart failure, hypertensive encephalopathy, valve replacement (transcatheter aortic valve implantation, mitraclip), cerebrovascular accident (stroke), or transient ischemic attack.
4. Patients with condition of hypotension with SBP <90 mmHg and/or DBP <60mmHg.
5. Acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring intravenous inotropic therapy.
6. Patients with secondary hypertension of any etiology including renal diseases, pheochromocytoma, Cushing’s syndrome, hyperaldosteronism, renovascular disease, thyroid disorders.
7. Patients with a narrowing of the aortic or bicuspid valve, an obstruction of cardiac outflow (obstructive, hypertrophic cardiomyopathy), obstruction of the outflow tract of the left ventricle (eg. high grade aortic stenosis) or symptomatic coronary disease.
8. Patients with severe renal impairment or renal transplant.
9. Patients with clinically relevant hepatic impairment.
10. Patients with sick sinus syndrome, including sino-atrial block.
11. Patients with second- or third-degree heart block (without a pacemaker).
12. Patients with history of bronchospasm and bronchial asthma.
13. Patients with untreated pheochromocytoma.
14. Patients with bradycardia (heart rate <60 bpm; <50 bpm in patients already on BBs treatment).
15. Patient with metabolic acidosis.
16. Patients with severe peripheral circulatory disturbances.
17. Participation in another interventional study within the last 4 weeks before screening (Visit 1).
18. Patients with diseases that, in the opinion of the Investigator, prevent a careful adherence to the protocol.
19. Patients using and not suitable for withdrawing the prohibited medications prior to the administration of study treatment.

E.5 End points

E.5.1

Primary end point(s)

Change in mean sitting DBP between Visit 2 (Week 0) and Visit 4 (Week 8).

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 2 (Week 0) and Visit 4 (Week 8)

E.5.2

Secondary end point(s)

1. Change in mean sitting SBP between Visit 2 (Week 0) and Visit 4 (Week 8).
2. Change in mean sitting DBP and SBP between Visit 3 (Week 4) and 4 (Week 8) in patients receiving extemporaneous combination of NEB/AML 5/5 mg versus patients uptitrated to the extemporaneous combination of NEB/AML 5/10 mg.
3. Number and proportion of patients achieving the BP goal (sitting SBP/DBP <130/80 mmHg) at Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8).
4. Adherence to the treatments (% of doses taken/doses to be taken) at Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8).
5. Safety and tolerability of the monotherapies (NEB 5 mg and AML 5 mg) and of the extemporaneous combinations (NEB 5 mg and AML 5mg or AML 10 mg) will be measured by incidence, intensity (severity), seriousness of Adverse Events (AEs) during the study period, (screening, run-in period and assessment period), relationship to the study treatments, clinically significant abnormal change in vital signs, electrocardiogram (ECG) (only at Visit 1 and Visit 4), laboratory parameters (if applicable) at Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8).

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Visit 2 (Week 0) and Visit 4 (Week 8)
2. Visit 3 (Week 4) and 4 (Week 8)
3. Visit 2 (Week 0), Visit 3 (Week 4) and Visit 4 (Week 8)
4. Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8)
5. Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8)

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

E.8.6.2

Trial being conducted completely outside of the EEA

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 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:

216

F.1.3

Elderly (>=65 years)

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

231

F.4.2

For a multinational trial

F.4.2.1

In the EEA

302

F.4.2.2

In the whole clinical trial

302

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)

Standard of care as per local practice.

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

2022-04-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-04-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-11-15

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