Clinical Trials Register

Summary
EudraCT Number:	2018-004882-15
Sponsor's Protocol Code Number:	EntREG-SILICOFCM
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-03-21
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2018-004882-15

A.3

Full title of the trial

Effect of angiotensin receptor neprilysin inhibitor sacubitril/valsartan on cardiopulmonary exercise tolerance in patients with hypertrophic cardiomyopathy – a randomized controlled clinical Phase II trial (EntREG – SILICOFCM)

Effekt des Angiotensin-Rezeptor-Neprilysin-Inhibitors Sacubitril/Valsartan auf die kardiopulmonale Leistungsfähigkeit bei Patienten mit hypertropher Kardiomyopathie – eine randomisierte kontrollierte klinische Phase II Studie (EntREG – SILICOFCM)

A.3.1

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

Effect of the drug sacubitril/valsartan on physical performance in patients with hypertrophic cardiomyopathy

Effekt des Medikaments Sacubitril/Valsartan auf die körperliche Leistungsfähigkeit bei Patienten mit hypertropher Kardiomyopathie

A.3.2

Name or abbreviated title of the trial where available

EntREG-SILICOFCM

A.4.1

Sponsor's protocol code number

EntREG-SILICOFCM

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	University Hospital Regensburg
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement no. 777204
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Regensburg, Department of Internal Medicine II
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Franz-Josef-Strauss-Allee 11
B.5.3.2	Town/ city	Regensburg
B.5.3.3	Post code	93053
B.5.3.4	Country	Germany
B.5.4	Telephone number	00499419447337

D. IMP Identification
D.IMP: 1
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	Entresto 50 mg (24 mg/26 mg)
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	sacubitril/valsartan
D.3.9.3	Other descriptive name	SACUBITRIL VALSARTAN
D.3.9.4	EV Substance Code	SUB171905
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	50
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	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	Entresto 100 mg (49 mg/51 mg)
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	sacubitril/valsartan
D.3.9.3	Other descriptive name	SACUBITRIL VALSARTAN
D.3.9.4	EV Substance Code	SUB171905
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	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	Entresto 200 mg (97 mg/103 mg)
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	sacubitril/valsartan
D.3.9.3	Other descriptive name	SACUBITRIL VALSARTAN
D.3.9.4	EV Substance Code	SUB171905
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	200
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

hypertrophic cardiomyopathy

Hypertrophe Kardiomyopathie

E.1.1.1

Medical condition in easily understood language

Heart disease, that is characterized by an abnormal thickness of the heartmuscle

Herzerkrankung, die durch eine Verdickung des Herzmuskels gekennzeichnet ist

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Compare peak oxygen consumption by cardiopulmonary exercise testing before and after administration of ARNI (Sacubitril/Valsartan)

E.2.2

Secondary objectives of the trial

- Quantitatively determine effects of the intervention on the magnitude or distribution of cardiac hypertrophy or left ventricular chamber dimensions, degree of left ventricular outflow obstruction, systolic or diastolic function, left ventricular wall motion, and fibrosis using echocardiography and cardiac magnetic resonance imaging
- Compare injury and stretch activation markers (i.e. Creatine kinase, Creatine kinase – MB, and NT-proBNP) before and after administration of ARNI (Sacubitril/Valsartan)
- Administer quality of life questionnaires before and after the intervention

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Adults ≥18 years of age
2) Confirmed diagnosis of hypertrophic cardiomyopathy
3) Agreement to be a participant in the study protocol and willing/able to return for follow-up
4) Able to provide written informed consent
5) In women of childbearing age: Willingness to use a highly effective contraceptive method (failure rate per year < 1%)

E.4

Principal exclusion criteria

1) Less than 3 months post septal reduction therapy (surgery or catheter-based intervention)
2) Clinical cardiac decompensation in the previous 3 months, defined as New York Heart Association class IV congestive heart failure symptoms.
3) Resting blood pressure > 180/100 mm Hg or systolic blood pressure < 100 mmHg
4) Hypotensive response to exercise testing (≥20 mmHg decrease of systolic blood pressure from baseline blood pressure or an initial increase in systolic blood pressure followed by a decrease of systolic blood pressure ≥20 mmHg).
5) Concomitant use of angiotensin converting inhibitors or angiotensin receptor blockers; patients previously receiving angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy will require a 36-hour washout period before initiation of ARNI (Sacubitril/Valsartan)
6) Resting left ventricular outflow tract gradient > 50 mmHg.
7) Left ventricular ejection fraction < 50% by echocardiography.
8) Implanted pacemaker or cardio-defibrillator in the last 3 months or scheduled.
9) History of hyperkalaemia (serum potassium >5.2 mmol/l).
10) Renal insufficiency with a glomerular filtration rate < 30 mL/min per 1.73m2.
11) Present or planned pregnancy.
12) Life expectancy less than 12 months.
13) Patients with severe adipositas (adipositas permagna, body mass index >40 kg/m2).
14) History of exercise induced syncope or sustained ventricular arrhythmias.
15) Inability to exercise due to orthopaedic or other non-cardiovascular limitations.
16) Use of other investigational drugs at the time of enrolment.
17) Concomitant treatment with aliskiren-containing drugs; discontinuation of treatment with aliskiren-containing drugs is required before initiation of ARNI (Sacubitril/Valsartan)
18) History of angiotensin converting inhibitors- or angiotensin receptor blockers-induced angioedema or history of hereditary or idiopathic angioedema.
19) Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 2x ULN, severe hepatic insuffucuency (classification Child Pugh C), biliary cirrhosis, cholestasis (current or anamnesic evidence), history of hepatic encephalopathy, history of esophageal varices, or history of portocaval shunt
20) Any surgical or medical condition that in the opinion of the investigator may place the patient at higher risk from his/her participation in the study or is likely to prevent the patient from complying with the requirements of the study or completing the study.
21) History of noncompliance to medical regimens and patients who are considered potentially unreliable.
22) History or evidence of drug or alcohol abuse within the past 12 months.
23) History of malignancy of any organ system (other than localized basal or squamous cell carcinoma of the skin or localized prostate cancer), treated or untreated, within the past 2 years, regardless of whether there is evidence of local recurrence or metastases.
24) Life-threatening or uncontrolled dysrhythmia, including symptomatic or sustained ventricular tachycardia and AF or atrial flutter with a resting ventricular rate >110 beats per minute.

E.5 End points

E.5.1

Primary end point(s)

Change in exercise tolerance (i.e. peak oxygen consumption) in cardiopulmonary exercise testing

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline, after 4 months and after 7 months (follow-up)

E.5.2

Secondary end point(s)

(1) Magnitude or distribution of cardiac hypertrophy or left ventricular chamber dimensions
(2) Degree of left ventricular outflow obstruction
(3) Systolic or diastolic function
(4) Left ventricular wall motion
(5) Injury and stretch activation markers (i.e. Creatine kinase, Creatine kinase – MB, and NT-proBNP)
(6) Quality of life indicators (SF12-v2-, Minnesota Living with Heart Failure-, and Hospital Anxiety and Depression-questionnaires)

E.5.2.1

Timepoint(s) of evaluation of this end point

baseline, after 4 months and after 7 months (follow-up)

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

E.6.5

Efficacy

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

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

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

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)

After the discontinuation of Sacubitril/Valsartan at Research Visit 4 approximately four months after randomization, the medication regime of the patients in the Sacubitril/Valsartan-group will be adjusted adequately. After the last study visit, all study patients are offered to continue attending our outpatient clinic for regular check-ups, in order to review the progression of their hypertrophic cardiomyopathy.

Nach Beendigung der Sacubitril/Valsartan-Einnahme beim Studienbesuch 4 wird das Arzneimittelregime der Patienten in der Sacubitril/Valsartan-Gruppe angepasst. Nach dem letzten Studienbesuch wird allen Studienpatienten angeboten, weiterhin unsere kardiologische Hochschulambulanz zu Verlaufskontrollen zu besuchen, um ein Fortschreiten der hypertrophen Kardiomyopathie zu überprüfen.

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

2019-05-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-11-28

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