Clinical Trials Register

Summary
EudraCT Number:	2015-003766-85
Sponsor's Protocol Code Number:	DFI14223
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-06-02
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

Spain - AEMPS

A.2

EudraCT number

2015-003766-85

A.3

Full title of the trial

An 8-Week Open-Label, Sequential, Repeated Dose-Finding Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents with Heterozygous Familial Hypercholesterolemia Followed by an Extension Phase

Estudio abierto de ocho semanas de duración, de búsqueda de dosis repetidas, secuencial, para evaluar la eficacia y seguridad de alirocumab en niños y adolescentes con hipercolesterolemia Familiar heterocigótica, seguido de una fase de extensión

A.3.1

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

An 8-Week Dose-Finding Study to Evaluate the Efficacy and Safety of Alirocumab in Children and Adolescents with Heterozygous Familial Hypercholesterolemia

Estudio de ocho semanas de duración, de búsqueda de dosis para evaluar la eficacia y seguridad de alirocumab en niños y adolescentes con hipercolesterolemia Familiar heterocigótica

A.3.2

Name or abbreviated title of the trial where available

ODYSSEY KIDS

A.4.1

Sponsor's protocol code number

DFI14223

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1178-4764

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/297/2013

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	sanofi-aventis recherche&developpement
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	sanofi-aventis recherche & developpement
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	sanofi-aventis, s.a.
B.5.2	Functional name of contact point	Unidad de Estudios Clínicos
B.5.3	Address:
B.5.3.1	Street Address	c/ Josep Pla nº2, 4ª planta
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08019
B.5.3.4	Country	Spain
B.5.4	Telephone number	93 485 94 00
B.5.6	E-mail	ES-unidadestudiosclinicos@sanofi.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	alirocumab
D.3.2	Product code	SAR236553
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	alirocumab
D.3.9.1	CAS number	1245916-14-6
D.3.9.2	Current sponsor code	SAR236553 (RGN727)
D.3.9.3	Other descriptive name	ALIROCUMAB
D.3.9.4	EV Substance Code	SUB170596
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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

Hypercholesterolaemia

Hipercolesterolemia

E.1.1.1

Medical condition in easily understood language

Hypercholesterolaemia

Hipercolesterolemia

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10020603
E.1.2	Term	Hypercholesterolaemia
E.1.2	System Organ Class	10027433 - Metabolism and nutrition 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 evaluate the effect of alirocumab on low-density lipoprotein cholesterol (LDL-C) levels after 8 weeks of treatment in heterozygous familial hypercholesterolemia (heFH) patients age of 8 to 17 years, with LDL-C ≥130 mg/dL (3.37 mmol/L) on optimal stable daily dose of statin therapy +/- other lipid modifying therapies (LMTs) or a stable dose of non-statin LMTs in case of intolerance to statins for at least 4 weeks prior to the screening period.

Evaluar el efecto de alirocumab administrado cada 2 semanas (C2S) o cada 4 semanas (C4S) sobre los niveles de colesterol de lipoproteínas de baja densidad (C LDL) tras 8 semanas de tratamiento en pacientes con hipercolesterolemia familiar heterocigótica (HFhe) con edades comprendidas entre 8 y 17 años, con niveles de C LDL ≥130 mg/dl (3,37 mmol/l) que estén recibiendo una dosis diaria estable óptima de tratamiento con estatinas ± otros tratamientos modificadores de lípidos (TML) o una dosis estable de TML sin estatinas en caso de intolerancia a las estatinas, durante al menos 4 semanas antes del periodo de selección.

E.2.2

Secondary objectives of the trial

-To evaluate the safety and tolerability of alirocumab.
-To evaluate the pharmacokinetics profile of alirocumab.
-To evaluate the effects of alirocumab on other lipid parameters.

-Evaluar la seguridad y la tolerabilidad de alirocumab.
-Evaluar el perfil farmacocinético de alirocumab.
-Evaluar los efectos de alirocumab sobre los niveles de otros parámetros lipídicos

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Children and adolescent male and female patients age of 8 to 17 years at the time of signed informed consent. For Russia only: Male and female patients aged ≥12 and ≤17 years at the time of signed informed consent.
-Patients with diagnosis of heterozygous familial hypercholesterolemia (heFH) through genotyping or clinical criteria.
-Patients treated with optimal dose of statin +/- other LMT(s) or non-statin LMT(s) if statin intolerant at stable dose for at least 4 weeks prior to screening visit (Week -2).
-Patients with calculated LDL-C greater than or equal to 130 mg/dL (≥3.37 mmol/L) at the screening visit (Week -2).
-Patients with body weight greater than or equal to 25kg.
-Patients age of 8 to 9 years to be at Tanner stage 1 and patients age of 10 to 17 years to be at least at Tanner stage 2 in their development.
-A signed informed consent indicating parental permission with or without patient assent.

I 01. Niños y adolescentes de ambos sexos con edades comprendidas entre 8 y 17 años en el momento de la firma del consentimiento informado.
I 02. Pacientes con un diagnóstico de hipercolesterolemia familiar heterocigótica (HFhe) por genotipado o criterios clínicos.
I 03. Pacientes tratados con una dosis óptima de estatinas con o sin otro(s) TML o TML sin estatinas en caso de intolerancia a las estatinas a una dosis estable durante al menos 4 semanas antes de la visita de selección (Semana -2).
I 04. Pacientes con C LDL calculado mayor o igual a 130 mg/dl (≥3,37 mmol/l) en la visita de selección (Semana -2).
I 05. Pacientes con peso corporal superior o igual a 25 kg.
I 06. Pacientes con edades comprendidas entre 8 y 9 años con estadio 1 de Tanner y pacientes con edades comprendidas entre 10 y 17 años al menos con estadio 2 de Tanner en su desarrollo.
I 07. Firma de consentimiento informado indicando el permiso paterno con o sin el asentimiento del paciente, dependiendo de la capacidad de comprensión basada en el grado de madurez.

E.4

Principal exclusion criteria

-Patient with secondary hyperlipidemia.
-Diagnosis of homozygous familial hypercholesterolemia.
-Patient who has received lipid apheresis treatment within 2 months prior to the screening period, or has plans to receive it during the study.
-Known history of type 1 or type 2 diabetes mellitus.
-Known history of thyroid disease.
-Known history of hypertension.
-Fasting triglycerides >350 mg/dL (3.95 mmol/L).
-Severe renal impairment (ie, estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m^2.
-Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2 x upper limit of normal (ULN).
-Creatinine phosphokinase (CPK) >3 x ULN.

• Paciente con hiperlipidemia secundaria.
• Diagnóstico de hipercolesterolemia familiar homocigótica.
• Paciente que ha recibido tratamiento de aféresis de lípidos en los 2 meses previos al periodo de selección, o que tiene previsto recibirlo durante el estudio.
• Antecedentes conocidos de diabetes mellitus tipo 1 o tipo 2.
• Antecedentes conocidos de enfermedad tiroidea.
• Antecedentes conocidos de hipertensión.
• Triglicéridos en ayunas >350 mg/dl (3,95 mmol/l) en la visita de selección (Semana -2).
• Insuficiencia renal grave (es decir, TFGe <30 ml/min/1,73 m2 en la visita de selección [Semana -2]).
• ALT o AST >2 x LSN (se permite 1 repetición de la analítica).

E.5 End points

E.5.1

Primary end point(s)

Percent change in calculated LDL-C

Cambio porcentual en el C LDL calculado

E.5.1.1

Timepoint(s) of evaluation of this end point

From baseline to Week 8

Desde el momento basal hasta la Semana 8.

E.5.2

Secondary end point(s)

a) Absolute change in calculated LDL-C
b) Percentage of participants achieving a calculated LDL-C level lower than 130 mg/dL (3.37 mmol/L)
c) Percentage of participants achieving a calculated LDL-C level lower than 110 mg/dL (2.84 mmol/L)
d) Percent change in Apolipoprotein B (Apo B)
e) Percent change in non-high density lipoprotein cholesterol (non HDL-C)
f) Percent change in Total-C
g) Percent change in Lipoprotein (a) (Lp[a])
h) Percent change in triglycerides (TG)
I) Percent change in HDL-C
l) Percent change in Apo A-1
m) Absolute change in Apo B
n) Absolute change in non-HDL-C
o) Absolute change in Total-C
p) Absolute change in Lp(a)
q) Absolute change in TG
r) Absolute change in HDL-C
s) Absolute change in Apo A-1
t) Absolute change in ratio Apo B/Apo A-1

a) Cambio absoluto en el C-LDL calculado
b) Porcentaje de participantes que alcanzaron un nivel de LDL-C por debajo de 130 mg / dl (3,37 mmol / L)
c) Porcentaje de participantes que alcanzaron un nivel de LDL-C inferior a 110 mg / dl (2,84 mmol / L)
d) El porcentaje de cambio en la apolipoproteína B (Apo B)
e) El porcentaje de cambio en las lipoproteínas de colesterol de no-alta densidad (no HDL-C)
f) Cambio porcentual en el total-C
g) Cambio porcentual en el lipoproteína (a) (Lp [a])
h) El porcentaje de cambio en los triglicéridos (TG)
I) El porcentaje de cambio en el HDL-C

E.5.2.1

Timepoint(s) of evaluation of this end point

a) From baseline to Week 8
b), c) : At week 8
d), e), f), g) h), I), l), m), n), o), p), q), r), s), t) : From baseline to Week 8

a) Desde el inicio hasta la semana 8
b), c): En la semana 8
d), e), f), g), h), I), l), m), n), o), p), q), r), s), t): Desde el inicio hasta la semana 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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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

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

Yes

E.8.1.7.1

Other trial design description

ascending dose

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

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

Australia

Canada

Israel

Norway

Russian Federation

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

Última visita del último paciente

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

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

Yes

F.3.3.7.1

Details of other specific vulnerable populations

children age 8 from 17 years

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

F.4.2.2

In the whole clinical trial

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)

Patients participating in the open label extension period will have the possibility to participate in the paediatric Phase 3 study

Los pacientes que participen en el período de extensión abierta tendrán la posibilidad de participar en el estudio de fase 3 pediátrica

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

2016-07-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-29

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-02-22

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