Clinical Trials Register

Summary
EudraCT Number:	2016-003085-32
Sponsor's Protocol Code Number:	CLCZ696B3301
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2017-02-10
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

France - ANSM

A.2

EudraCT number

2016-003085-32

A.3

Full title of the trial

A multi-center, prospective, randomized, double-blind study to assess the impact of sacubitril/valsartan vs. enalapril on daily physical activity using a wrist worn actigraphy device in adult chronic heart failure patients

Etude multicentrique, prospective, randomisée, en double aveugle, destinée à évaluer l'impact du sacubitril/valsartan versus énalapril sur l'activité physique quotidienne à l'aide d'un accéléromètre porté au poignet chez les patients adultes insuffisants cardiaques chroniques

A.3.1

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

randOmized stUdy using acceleromeTry to compare Sacubitril/valsarTan and Enalapril in Patients with Heart Failure (OUTSTEP-HF)

Etude randomisée utilisant un accéléromètre pour comparer le sacubitril/valsartan et l'énalapril chez les patients adultes insuffisants cardiaques (OUTSTEP-HF)

A.3.2

Name or abbreviated title of the trial where available

OUTSTEP-HF

A.4.1

Sponsor's protocol code number

CLCZ696B3301

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	Novartis Pharma Services AG
B.1.3.4	Country	Switzerland
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma S.A.S
B.5.2	Functional name of contact point	Information&Communication Médicales
B.5.3	Address:
B.5.3.1	Street Address	2 et 4 rue Lionel Terray
B.5.3.2	Town/ city	Rueil-Malmaison
B.5.3.3	Post code	92500
B.5.3.4	Country	France
B.5.4	Telephone number	+33 1 5547 6600
B.5.5	Fax number	+33 1 5547 6100
B.5.6	E-mail	icm.phfr@novartis.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	Entresto
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	LCZ696 50 mg
D.3.2	Product code	LCZ696
D.3.4	Pharmaceutical form	Film-coated 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	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	Entresto
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	LCZ696 100 mg
D.3.2	Product code	LCZ696
D.3.4	Pharmaceutical form	Film-coated 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	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	Entresto
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited
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	LCZ696 200 mg
D.3.2	Product code	LCZ696
D.3.4	Pharmaceutical form	Film-coated 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.IMP: 4
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	Enalapril
D.2.1.1.2	Name of the Marketing Authorisation holder	Lek Pharmaceuticals d.d.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Enalapril 2.5 mg
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	enalapril
D.3.9.3	Other descriptive name	ENALAPRIL MALEATE
D.3.9.4	EV Substance Code	SUB01884MIG
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.3.11 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	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	EnaHEXAL
D.2.1.1.2	Name of the Marketing Authorisation holder	Hexal AG
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.3.1	Product name	Enalapril 5 mg
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	enalapril
D.3.9.3	Other descriptive name	ENALAPRIL MALEATE
D.3.9.4	EV Substance Code	SUB01884MIG
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	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	EnaHEXAL
D.2.1.1.2	Name of the Marketing Authorisation holder	Hexal AG
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.3.1	Product name	Enalapril 10 mg
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	enalapril
D.3.9.3	Other descriptive name	ENALAPRIL MALEATE
D.3.9.4	EV Substance Code	SUB01884MIG
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated 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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 4
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: 5
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: 6
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

Heart Failure with reduced ejection fraction (HFrEF)

Insuffisance cardiaque avec fraction d'éjection réduite (HFrEF)

E.1.1.1

Medical condition in easily understood language

Heart failure

Insuffisance cardiaque

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	19.1
E.1.2	Level	LLT
E.1.2	Classification code	10019279
E.1.2	Term	Heart failure
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 assess changes in daily non-sedentary daytime activity between baseline and after 12 weeks of treatment in sacubitril/valsartan vs. enalapril treated patients.

Évaluer la variation de l'activité quotidienne non sédentaire diurne entre l'état de base et après 12 semaines de traitement chez les patients traités par sacubitril/valsartan versus énalapril.

E.2.2

Secondary objectives of the trial

-To compare the effects of sacubitril/valsartan vs. enalapril on patients’ symptom progression by means of the Patient Global Assessment (PGA) questionnaire
-To assess dynamics of changes from baseline in daily non-sedentary daytime physical activity in sacubitril/valsartan vs. enalapril treated patients in weekly and two-weekly intervals.
-To assess changes from baseline in mean daily non-sedentary daytime physical activity classified by its intensity for sacubitril/valsartan vs. enalapril treated patients
-To assess the difference in non-sedentary daytime physical activity between sacubitril/valsartan vs. enalapril treated patients during the treatment period
- To assess changes on M6min (an actigraphy-based measure of the peak six minutes of daytime physical activity) in sacubitril/valsartan vs. enalapril treated patients
- To assess changes from baseline in exercise capacity assessed by means of the 6-minute walking test

- Comparer les effets du sacubitril/valsartan versus énalapril sur la progression des symptômes par le questionnaire PGA (Patient Global Assessment)
- Évaluer la dynamique de la variation de l'activité physique quotidienne non sédentaire diurne chez les patients traités par sacubitril/valsartan versus énalapril à des intervalles de 1 et 2 semaines
- Évaluer la variation de l'activité physique quotidienne non sédentaire diurne classée selon son intensité chez les patients sous sacubitril/valsartan versus énalapril
- Évaluer la différence dans l'activité physique quotidienne non sédentaire diurne chez les patients sous sacubitril/valsartan versus énalapril
- Évaluer la variation par rapport à l'état de base notée sur le test M6min (mesure basée sur l'actigraphie des six minutes de pic d'activité physique diurne) chez les patients sous sacubitril/valsartan versus énalapril
- Évaluer la variation de la capacité à l'effort évaluée au moyen du test de marche de 6 minutes

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Written informed consent obtained before any study assessment is performed.
- Ambulatory ≥ 18 years of age with a diagnosis of chronic symptomatic HF (NYHA class ≥ II) with reduced ejection fraction, defined as known LVEF ≤ 40% AND one of the following two criteria:
- Plasma NT-proBNP level of ≥ 300 pg/mL or BNP ≥ 100 pg/mL (measurement may be recorded no longer than past 12 months) OR
- Confirmation of a heart failure hospitalization last 12 months.
- Patients must be on stable HF medication for at least 4 weeks prior to Week - 2, where the minimal daily dose of current evidence based therapies is equivalent to at least 2.5 mg/d enalapril
- Willingness to wear the accelerometer wristband continuously for the duration of the trial.
- Patients must be living in a setting, allowing them to move about freely and where they are primarily self responsible for scheduling their sleep and daily activities.

- Consentement éclairé par écrit obtenu avant réalisation de toute évaluation liée à l'étude.
- Patient ambulatoire ≥ 18 ans avec un diagnostic d'insuffisance cardiaque chronique symptomatique (NYHA classe ≥ II) avec fraction d'éjection réduite, définie comme FEVG ≤ 40 % connue ET un des deux critères suivants:
- Taux de NT-proBNP plasmatique ≥ 300 pg/mL ou de BNP ≥ 100 pg/mL (la mesure ne peut être consignée qu'à condition de ne pas dépasser les 12 derniers mois) OU
- Confirmation d'une hospitalisation pour insuffisance cardiaque dans les 12 derniers mois
- Les patients doivent être sous traitement stable de l'insuffissance cardiaque pendant au moins 4 semaines avant la visite 2, où la dose quotidienne minimale est équivalente à au moins 2,5 mg d'énalapril
- Volonté de porter le bracelet de l'accéléromètre en permanence pendant toute la durée de l'essai.
- Les patients doivent vivre dans un cadre qui leur permet de se déplacer librement et où ils sont en principe personnellement responsables de l'organisation de leur sommeil et de leurs activités quotidiennes

E.4

Principal exclusion criteria

- History of hypersensitivity to any of the study drugs or their excipients or to drugs of similar chemical classes
- Use of sacubitril/valsartan prior to week - 2.
- Bedridden patients, or patients with significantly impaired/limited physical activity and/or fatigue due to medical conditions other than HF, such as, but not limited to angina (chest pain at exertion), arthritis, gout, peripheral artery occlusive disease, obstructive or restrictive lung disease, malignant disease, neurological disorders (e.g. Parkinson’s or Alzheimer’s disease, central and peripheral neuroinflammatory and degenerative disorders or functional central nervous lesions due to hemodynamic or traumatic incidents), injuries (incl. diabetic foot ulcers) or missing limbs
- Patients with palsy, tremor or rigor affecting the nondominant arm.
- Patients with any skin or other condition of the nondominant arm that would limit the ability to wear the actigraphy device continuously (24h/day) over 14 weeks.
- Patients fully depending on a mobility support system, e.g. wheelchair, scooter or walker. Patients are allowed to use a cane as long as this is not used with the non- dominant arm.

- Antécédent d’hypersensibilité à l'un des médicaments de l’étude ou leurs excipients, ou aux médicaments de classes chimiques similaires.
- Utilisation du sacubitril/valsartan avant la visite 1.
- Patients alités, ou patients dont l'activité physique est significativement altérée/limitée et/ou fatigués en raison de pathologies autres que l'IC, telles que, mais sans s'y limiter angine de poitrine (douleur à la poitrine à l'effort), arthrite, goutte, maladie artérielle périphérique occlusive, maladie pulmonaire obstructive ou restrictive, affection maligne, troubles neurologiques (par ex. maladie de Parkinson ou d'Alzheimer, affections neuro-inflammatoires et neuro-dégénératives centrales et périphériques ou lésions nerveuses centrales fonctionnelles dues à des incidents hémodynamiques ou traumatiques), blessures (y compris ulcères du pied diabétique) ou membres manquants
- Patients atteints de paralysie, de tremblements ou de raideur affectant le bras non dominant
- Patients atteints d'une affection cutanée ou autre du bras non dominant qui limiterait leur capacité à porter l'actimètre en permanence (24h/jour) pendant 14 semaines
- Patients entièrement dépendants d'un système d'aide à la mobilité, par ex. fauteuil roulant, scooter pour handicapés ou déambulateur. Les patients sont autorisés à se servir d'une canne aussi longtemps qu'elle n'est pas utilisée avec le bras non-dominant

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in mean daily non-sedentary daytime activity between baseline and end of study

Évaluer la variation de l'activité quotidienne non sédentaire diurne entre l'état de base et la fin de l'étude.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline (week -2 to Week 0), last 14 days of treatment (week 10 to week 12)

Etat de base (semaine -2 à semaine 0), 14 derniers jours de traitement (semaine 10 à semaine 12).

E.5.2

Secondary end point(s)

1) Percentage of patients with improved symptoms of heart failure as assessed by patient's Global Assessment
2) Change from baseline in mean daily non sedentary daytime activity in weekly and two-weekly intervals
3) Change from baseline in mean daily nonsedentary daytime physical activity classified by its intensity
4) Total weekly time spent in nonsedentary daytime physical activity
5) Total weekly time spent in light nonsedentary daytime physical activity
6) Total weekly time spent in moderate-tovigorous nonsedentary daytime physical activity
7) Change from baseline in peak six minutes of daytime physical activity
8) Change from baseline in means of 6-minute walking test
9) Percentage of patients who show increased levels of nonsedentary daytime

1) Pourcentage de patients présentant une amélioration des symptômes d'insuffisance cardiaque au moyen du questionnaire PGA (Patient Global Assessment)
2) Changement par rapport à l'état de base de l'activité physique quotidienne non sédentaire diurne à des intervalles hebdomadaires et à deux semaines d'intervalle
3) Changement par rapport à l'état de base de l'activité physique quotidienne non sédentaire diurne classée selon son intensité
4) Temps hebdomadaire total occupé par l'activité physique quotidienne non sédentaire diurne
5) Temps hebdomadaire total occupé par l'activité physique quotidienne non sédentaire diurne extérieure
6) Temps hebdomadaire total occupé par l'activité physique quotidienne non sédentaire diurne modérée à intense
7) Changement par rapport à l'état de base de l'acitivé physique diurne des six minutes de pic d'activité physique
8) Changement par rapport à l'état de base de la moyenne du test de marche de 6 minutes
9) Pourcentage de patients montrant une augmentation de l'acitivé physique diurne

E.5.2.1

Timepoint(s) of evaluation of this end point

1) Week 4, Week 8, Week 12
2) Week - 1 to Week 0, Week - 2 to Week 0, from week 0 to Week 12
3) Baseline (week - 2 to week 0), week 2 to week 4, week 6 to week 8, week 10 to week 12
4) week 0 to week 12 in weekly intervals
5)week 0 to week 12 in weekly intervals
6) week 0 to week 12 in weekly intervals
7) week -2 to week 0, week 2 to week 4, week 6 to week 8, week 10 to week 12
8) week 0, week 4, week 8, week 12
9) Baseline (week -2 to week 0), Week 12

1) Semaine 4, semaine 8, semaine 12
2) Semaine - 1 à semaine 0, semaine - 2 à semaine 0, de la semaine 0 à semaine 12
3) Etat de base (semaine - 2 à semaine 0), semaine 2 à semaine 4, semaine 6 à semaine 8, semaine 10 à semaine 12
4) semaine 0 à semaine 12, intervalle hebdomadaire
5) semaine 0 à semaine 12, intervalle hebdomadaire
6) semaine 0 à semaine 12, intervalle hebdomadaire
7) semaine -2 à semaine 0, semaine 2 à semaine 4, semaine 6 à semaine 8, semaine 10 à semaine 12
8) semaine 0, semaine 4, semaine 8, semaine 12
9) Etat de base (semaine -2 à semaine 0), semaine 12

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

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

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

100

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

Dernière visite du dernier patient participant à l'étude

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:

300

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

300

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

600

F.4.2.2

In the whole clinical trial

600

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)

Continuation of treatment with commercially available LCZ696 treatment or switching patients to ACEI/ARBs in addition to other guidelines recommended HF medications.

Continuation du traitement avec le LCZ696 disponible sur le marché ou changement de traitement pour un IECA/ARA en complément des médicaments recommendés pour l'insuffisance cardiaque.

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

2017-03-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-03-15

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-04-11

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