Clinical Trials Register

Summary
EudraCT Number:	2013-003000-39
Sponsor's Protocol Code Number:	CL2-38844-010
National Competent Authority:	Latvia - SAM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-09-11
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

Latvia - SAM

A.2

EudraCT number

2013-003000-39

A.3

Full title of the trial

Evaluation of the pharmacodynamics, pharmacokinetics and
safety of repeated escalating oral doses of S 38844 versus placebo
in patients with chronic heart failure and left ventricular systolic
dysfunction
A phase II, randomised, double-blind, parallel-group, placebo
controlled, international multicentre study

A.3.1

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

Evaluation of the reduction in heart rate, of the quantity of drug in the plasma and of the safety after different ascending oral doses of the active substance or a placebo in heart failure patients with a reduction of left ventricular ejection fraction (i.e. the
quantity of blood the heart is able to eject in the body at each heart beat).

A.4.1

Sponsor's protocol code number

CL2-38844-010

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	Institut de Recherches Internationales Servier
B.1.3.4	Country	France
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	ADIR
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Institut de Recherches Internationales Servier
B.5.2	Functional name of contact point	Clinical Studies Department
B.5.3	Address:
B.5.3.1	Street Address	50, rue Carnot
B.5.3.2	Town/ city	Suresnes Cedex
B.5.3.3	Post code	92284
B.5.3.4	Country	France
B.5.4	Telephone number	+33155 72 43 66
B.5.5	Fax number	+33155 72 54 12
B.5.6	E-mail	clinicaltrials@servier.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	S38844
D.3.2	Product code	S38844
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	NA
D.3.9.2	Current sponsor code	S38844
D.3.9.3	Other descriptive name	S38844
D.3.9.4	EV Substance Code	SUB125829
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	25
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	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	S38844
D.3.2	Product code	S38844
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	NA
D.3.9.3	Other descriptive name	S38844
D.3.9.4	EV Substance Code	SUB125829
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: 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	S38844
D.3.2	Product code	S38844
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	NA
D.3.9.2	Current sponsor code	S38844
D.3.9.3	Other descriptive name	S38844
D.3.9.4	EV Substance Code	SUB125829
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.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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Patients with chronic heart failure and left ventricular systolic
dysfunction

E.1.1.1

Medical condition in easily understood language

Cardiovascular diseases

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10007648
E.1.2	Term	Cardiovascular disease, unspecified
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 evaluate the pharmacodynamics in relation to resting heart rate (HR) of two different schemes of starting doses and two step titration doses of S 38844 versus placebo in patients with moderate to severe chronic heart failure and left ventricular systolic dysfunction treated with optimal background therapy.

E.2.2

Secondary objectives of the trial

- To assess the pharmacokinetics of S 38844 and its main metabolites and the pharmacokinetic/pharmacodynamic (PK/PD) relationship with respect to resting heart rate (HR) for each tested dose of S 38844.
- To evaluate the global and cardiac safety of two different schemes of starting doses and two step titration doses of S 38844 versus placebo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Documented sinus rhythm and mean HR ≥ 75 bpm measured on two consecutive resting 12-leads ECGs recordings one minute registration - performed at least 5 minutes apart (supine position for at least 10 minutes rest). If one of the two HR measurements is 73 or 74 bpm at the inclusion visit, the patient can be included provided that the mean of both HR measurements at the visit is ≥ 75 bpm,
- LVEF ≤ 35% as measured and documented within the previous 6 months (in stable clinical condition). For patient without known diagnosis of LVEF ≤ 35%, a LVEF will be scheduled before inclusion visit,
- Compliant to study treatment during run-in period (70-130%),
- Symptomatic CHF of New York Heart Association (NYHA) class II, III or IV for at least 3 months prior to selection,
- In stable clinical condition with regards to CHF symptoms for at least 4 weeks prior to selection,
- With optimal and unchanged CHF medications or dosages, for at least 4 weeks prior to selection.

E.4

Principal exclusion criteria

- LVEF of 35% or higher on a recently performed measurement (less than 6 months),
- Serum haemoglobin < 110 g/L,
- ALT or AST > 3 times the upper limit of normal values,
- Significant change in cardiovascular condition, since the informed consent signature, change in heart failure background therapy or dosage, or use of intravenous inotropic therapies,
- Recent (less than 3 months) myocardial infarction or coronary revascularization,
- Scheduled coronary revascularization,
- Severe aortic or mitral stenosis, or severe aortic regurgitation, or severe primary mitral regurgitation,
- Scheduled surgery for valvular heart disease,
- Cardiac Resynchronisation Therapy (CRT),
- Pacemaker carrier,
- Documented permanent atrial fibrillation or other cardiac arrhythmia that interfere with the sinus node function, or recent hospitalization for atrial fibrillation or other cardiac arrhythmia that interfere with the sinus node function within the last 3 months
- Positive blood and/or urinary pregnancy test

E.5 End points

E.5.1

Primary end point(s)

HR change from baseline to end of each treatment period is the main endpoint to assess the pharmacodynamics effect of S 38844 (mean HR measured at trough from two 12-lead ECGs).

E.5.1.1

Timepoint(s) of evaluation of this end point

All along the study

E.5.2

Secondary end point(s)

Safety endpoints:
- occurence of adverse events
- 24-hour Holter ECG parameters,
- Physical examination including weight, systolic and diastolic blood pressure change,
- HR on 12-lead ECG,
- Laboratory test parameters (haematology and biochemistry parameters).
Pharmacokinetic endpoints:
- Plasma pharmacokinetics parameters of the parent drug S 38844 and of its main metabolites,
- Pharmacokinetic/pharmacodynamic (PK/PD) relationship with respect to resting heart rate (HR) for each tested dose of S38844.

E.5.2.1

Timepoint(s) of evaluation of this end point

All along the study

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Belgium

Bulgaria

Estonia

Hungary

Korea, Republic of

Latvia

Lithuania

Poland

Russian Federation

Singapore

Slovakia

Ukraine

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

Last visit last participant as stated in the protocol

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:

120

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

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

130

F.4.2.2

In the whole clinical trial

200

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)

Not applicable

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

2014-10-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-09-24

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-06-08

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