Clinical Trials Register

Summary
EudraCT Number:	2015-003266-87
Sponsor's Protocol Code Number:	CLCZ696B2401
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-05-27
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-003266-87

A.3

Full title of the trial

A multicenter, randomized, open label, parallel group study comparing predischarge
and posT-discharge tReatment initiation with LCZ696 in heArt
failure patieNtS with reduced ejectIon-fracTion hospItalized for an acute
decOmpensation eveNt (ADHF)

Studio multicentrico, randomizzato, in aperto, a gruppi paralleli, per confrontare l¿inizio del trattamento con LCZ696 in pre-dimissione e post-dimissione in pazienti con insufficienza cardiaca con frazione di eiezione depressa, ospedalizzati per un evento di scompenso acuto
(studio TRANSITION)

A.3.1

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

Study to compare Pre-discharge and Post-discharge treatment initiation
with LCZ696 therapy in heart failure patients with reduced ejection fraction
(HF-rEF) after an acute decompensation event

Studio per confrontare l¿inizio del trattamento con LCZ696 in pre-dimissione e post-dimissione in pazienti con insufficienza cardiaca con frazione di eiezione depressa,

A.3.2

Name or abbreviated title of the trial where available

TRANSITION study

studio TRANSITION

A.4.1

Sponsor's protocol code number

CLCZ696B2401

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN12345678

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT12345678

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1234-1234-1234

A.5.4

Other Identifiers

Name:

CLCZ696B2401

Number:

CLCZ696B2401

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 Farma SpA
B.5.2	Functional name of contact point	Drug Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1
B.5.3.2	Town/ city	Origgio (VA)
B.5.3.3	Post code	21040
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390296541
B.5.5	Fax number	0039029659066
B.5.6	E-mail	info.studiclinici@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	No
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.3.9.2	Current sponsor code	LCZ696
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	No
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.3.9.2	Current sponsor code	LCZ696
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	No
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.3.9.2	Current sponsor code	LCZ696
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Heart Failure with reduced ejection fraction (HF-rEF) stabilized after hospitalization due to acute decompensated heart failure episode.

Insufficienza cardiaca con frazione di eiezione depressa (HF-rEF) in stabilizzata dopo ospedalizzazione per episodio di insufficienza cardiaca acuta decompensata.

E.1.1.1

Medical condition in easily understood language

Heart Failure

Insufficienza cardiaca

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	10007554
E.1.2	Term	Cardiac failure
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

the primary objective of this study is to evaluate the proportion of patients in the Pre- and Post-discharge treatment initiation groups achieving the target dose of 200 mg LCZ696 twice daily at the end of the
week-10 after randomization (Treatment Epoch), regardless of previous temporary dose interruption or down-titration.

Studiare la proporzione di pazienti nel gruppo d¿inizio del trattamento pre-dimissione e post-dimissione che raggiungono la dose target di 200 mg di LCZ696 due volte al giorno alla fine delle 10 settimane dopo la randomizzazione (Fase di Trattamento), indipendentemente da una precedente interruzione del trattamento o riduzione della dose.

E.2.2

Secondary objectives of the trial

- To assess the proportion of patients that, regardless of previous dose interruption or downtitration during the Treatment Epoch, achieved and maintained either the dose of 100 mg
and/or 200 mg LCZ696 bid.
- To asssess the proportion of patients that, regardless of previous dose interruption or downtitration during the Treatment Epoch, achieved and maintained any dose of LCZ696.
- To assess the proportion of patients permanently discontinued from study drug, due to Adverse Events during the 10-week Treatment Epoch.

1. Valutare la proporzione di pazienti che, indipendentemente da una precedente interruzione del trattamento o riduzione della dose durante la Fase di Trattamento, raggiunge e mantiene entrambi i dosaggi pi¿ alti di LCZ696 (100 mg e/o 200 mg due volte al giorno) per almeno 2 settimane fino alla decima settimana dopo la randomizzazione.
2. Valutare la proporzione di pazienti che, indipendentemente da una precedente interruzione del trattamento o riduzione della dose durante la Fase di Trattamento, raggiunge e mantiene qualsiasi dosaggio di LCZ696 per almeno 2 settimane fino alla decima settimana dopo la randomizzazione.
3. Valutare la proporzione di pazienti che interrompono permanentemente il trattamento col farmaco in studio, a causa di Eventi Avversi (AE), durante le 10 settimane della Fase di Trattamento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Patients hospitalized due to acute decompensated HF episode (ADHF)
- Diagnosis of HF New York Heart Association class II-to-IV and reduced
ejection fraction
- Patients did not receive any IV vasodilators (except nitrates), and/or
any IV inotropic therapy from the time of presentation for ADHF to
randomization
- Stabilized (while in the hospital) for at least 24 hours leading to
randomization
- Other protocol-defined inclusion criteria may apply.

1. Pazienti ospedalizzati per un episodio di insufficienza cardiaca acuta (ADHF) come prima diagnosi, con segni e sintomi coerenti
2. Diagnosi di HF NYHF II-IV e frazione di eiezione depressa: frazione di eiezione del ventricolo sinistro (LVHF) = 40% allo screening
3. Pazienti che non hanno ricevuto vasodilatatori IV (ad eccezione dei nitrati), e/o qualsiasi inotropo IV dal momento della presentazione in ospedale per ADHF alla randomizzazione
4. Pazienti stabilizzati (ancora in ospedale) per almeno 24 ore prima della randomizzazione, definiti come:
• Nessuna necessità di terapia diuretica IV nelle ultime 24 ore
• Pressione arteriosa sistolica (SBP) = 110 mm HG almeno 6 ore prima della randomizzazione
5. Almeno uno dei seguenti criteri:
• Pazienti in terapia con qualsiasi dosaggio di ACEi o ARB allo screening
• Pazienti naïve al trattamento con ACEi/ARB, e pazienti non in trattamento con ACEi o ARB da almeno 4 settimane prima dello screening

E.4

Principal exclusion criteria

- Symptomatic hypotension and/or a SBP < 110 mm Hg or SBP > 180
mm Hg prior to randomization
- End stage renal disease at ccreening; or estimated GFR < 30
mL/min/1.73 m2 as measured by (MDRD) formula at randomization.
- Serum potassium > 5.4 mmol/L at randomization.
- Current hospitalization where patient does not receive treatment for
decompensated HF.
- Known history of hereditary or idiopathic angioedema or angioedema
related to previous ACE inhibitor or ARB therapy
- Severe hepatic impairment, biliary cirrhosis and cholestasis
- Other protocol-defined exclusion criteria may apply.

1. Anamnesi di ipersensibilità al sacubitril, valsartan, o a qualsiasi ARBs, inibitore NEP o a qualsiasi eccipiente di LCZ696
2. Ipotensione sintomatica e/o SBP < 110 mm Hg o SBP > 180 mm Hg prima della randomizzazione
3. Malattia renale all’ultimo stadio allo screening; o GFR stimata < 30 mL/min/1.73 m2 misurata tramite formula semplificata MDRD (Modification of Diet in Renal Disease) alla randomizzazione
4. Potassio sierico > 5.4 mmol/L alla randomizzazione
5. Ospedalizzazione attuale dove il paziente non ha ricevuto alcun trattamento per l’insufficienza cardiaca acuta
6. Anamnesi positiva per angioedema idiopatico o ereditario, o angioedema correlato a precedente terapia con ACEi o ARB
7. Insufficienza epatica grave, cirrosi biliare e colestasi

E.5 End points

E.5.1

Primary end point(s)

The proportion of patients who achieve 10 weeks up-titration success

Proporzione di pazienti che raggiungono la dose target dopo 10 settimane dalla randomizzazione

E.5.1.1

Timepoint(s) of evaluation of this end point

10 weeks after randomization

10 settimane dalla randomizzazione

E.5.2

Secondary end point(s)

- Assess the proportion of patients achieving and maintaining either the dose of 100 mg and/or 200 mg LCZ696 bid for at least 2 weeks leading
to week 10 after randomization.; Assess the proportion of patients achieving and maintaining any dose of LCZ696 for at least 2 weeks leading to week 10 after randomization; Assess the proportion of patients permanently discontinued from study drug, at any time between randomization and week 10

Valutare la proporzione di pazienti che raggiunge e mantiene entrambi i dosaggi pi¿ alti di LCZ696 (100 mg e/o 200 mg due volte al giorno) per almeno 2 settimane fino alla decima settimana dopo la randomizzazione; 2. Valutare la proporzione di pazienti che raggiunge e mantiene qualsiasi dosaggio di LCZ696 per almeno 2 settimane fino alla decima settimana dopo la randomizzazione.; 3. Valutare la proporzione di pazienti che interrompono permanentemente il trattamento col farmaco in studio tra la randomizzazione e la decima settimana.

E.5.2.1

Timepoint(s) of evaluation of this end point

10 weeks after randomization; 10 weeks after randomization; 10 weeks after randomization

10 settimane dalla randomizzazione; 10 settimane dalla randomizzazione; 10 settimane dalla randomizzazione

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

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

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

Yes

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

Yes

E.8.2.3.1

Comparator description

Pazienti che iniziano terapia con LCZ696 in pre-dimissione versus pazienti che iniziano terapia co

Pre-discharge initiation of LCZ696 arm versus the Post-discharge initiation of LCZ696 arm

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

155

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

Information not present in EudraCT

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

Albania

Australia

Canada

Lebanon

Mexico

Russian Federation

Saudi Arabia

Turkey

United Arab Emirates

Belgium

Finland

France

Germany

Hungary

Italy

Norway

Poland

Portugal

Slovakia

Spain

Sweden

Switzerland

United Kingdom

Czechia

Argentina

E.8.7

Trial has a data monitoring committee

Yes

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

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:

255

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1445

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

700

F.4.2.2

In the whole clinical trial

1000

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 or switching patients to ACEI/ARBs in addition to other guidelines recommended HF medications.

I pazienti continueranno il trattamento con LCZ696 del commercio, oppure saranno trattati con ACEI/ARBs in combinazione con altri farmaci raccomandati dalle linee guida per il trattamento dell'insufficienza cardiaca .

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

2016-04-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-04-15

P. End of Trial
P.	End of Trial Status	Completed

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