Clinical Trials Register

Summary
EudraCT Number:	2015-002276-25
Sponsor's Protocol Code Number:	20120124
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:	2016-08-05
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

2015-002276-25

A.3

Full title of the trial

Open-label, Single-arm, Multicenter Study to Evaluate the Safety, Tolerability and Efficacy of Evolocumab for LDL-C Reduction, as Add-on to Diet and Lipid-lowering Therapy, in Pediatric Subjects From 10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH) or Homozygous Familial Hypercholesterolemia (HoFH)

Estudio abierto, multicéntrico y de un solo grupo para evaluar la seguridad, tolerabilidad y eficacia de evolocumab, como tratamiento adyuvante de la dieta y del tratamiento hipolipemiante, en la reducción del C-LDL en sujetos pediátricos de 10 a 17 años de edad con hipercolesterolemia familiar heterocigótica (HFHe) o hipercolesterolemia familiar homocigótica (HFHo)

A.3.1

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

Study to assess the safety and efficacy of evolocumab in children aged 10 to 17 years with Heterozygous Familial Hypercholesterolemia or Homozygous Familial Hypercholesterolemia

Estudio para evaluar la seguridad y eficacia de evolocumab en sujetos pediátricos de 10 a 17 años de edad con hipercolesterolemia familiar heterocigótica o hipercolesterolemia familiar homocigótica

A.3.2

Name or abbreviated title of the trial where available

HAUSER-OLE

A.4.1

Sponsor's protocol code number

20120124

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/235/2016

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Amgen Inc
B.1.3.4	Country	United States
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	Amgen Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amgen (EUROPE) GmbH
B.5.2	Functional name of contact point	IHQ Medical Info - Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Dammstrasse 23, P.O. Box 1557
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	(CH-)6300
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+34900850153
B.5.6	E-mail	MedinfoInternational@amgen.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	Repatha 140 mg Solution for Injection in Pre-filled Pen
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
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	Evolocumab
D.3.2	Product code	AMG 145
D.3.4	Pharmaceutical form	Solution for injection in pre-filled pen
D.3.4.1	Specific paediatric formulation	No
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	EVOLOCUMAB
D.3.9.2	Current sponsor code	AMG 145
D.3.9.4	EV Substance Code	SUB128552
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	140
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	Yes
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for injection in pre-filled pen
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hypercholesterolemia

Hipercolesterolemia

E.1.1.1

Medical condition in easily understood language

Elevated levels of 'bad' cholesterol

Elevados niveles de colesterol "malo"

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	LLT
E.1.2	Classification code	10057100
E.1.2	Term	Homozygous familial hypercholesterolaemia
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10057099
E.1.2	Term	Heterozygous familial hypercholesterolaemia
E.1.2	System Organ Class	100000004850

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To describe the safety and tolerability of 80 weeks of SC evolocumab when added to standard of care in pediatric subjects 10 to 17 years of age with HeFH or HoFH.

Describir la seguridad y la tolerabilidad de añadir durante 80 semanas evolocumab SC al tratamiento estándar en sujetos pediátricos de 10 a 17 años de edad con HFHe o HFHo.

E.2.2

Secondary objectives of the trial

To describe percent change and change from baseline in LDL-C, and on
percent change from baseline in non-high-density lipoprotein cholesterol (non-
HDL-C), apolipoprotein B (ApoB), total cholesterol/HDL-C ratio, and ApoB/Apolipoprotein A-1(ApoA1) ratio.

Describir el cambio porcentual y el cambio respecto al valor basal en el C-LDL, así como el cambio porcentual respecto al valor basal en el colesterol no ligado a lipoproteínas de alta densidad (C-no-HDL), la apolipoproteína B (ApoB), la relación colesterol total/C-HDL y la relación ApoB/apolipoproteína A1 (ApoA1)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects with HeFH:
-Completed Study 20120123 while still on assigned investigational
product.
Subjects with HoFH:
-Male or female, ≥ 10 to ≤ 17 years of age at time of enrollment
-Diagnosis of HoFH by genetic confirmation or a clinical diagnosis based
on a
history of an untreated LDL cholesterol concentration > 500 mg/dL (13
mmol/L)
together with either xanthoma before 10 years of age or evidence of heterozygous familial hypercholesterolemia in both parents.
All subjects:
- Subject must be on a low-fat diet and receiving background lipidlowering
therapy
-Lipid-lowering therapy, including statin dose, must be unchanged for ≥
4 weeks
prior to LDL-C screening; fibrates must be stable for at least 6 weeks prior to screening.

Sujetos con HFHe:
-Haber completado el estudio 20120123 y seguir recibiendo el producto en investigación asignado.
Sujetos con HFHo:
-Hombre o mujer de ≥ 10 a ≤ 17 años de edad en el momento de la inclusión.
-Diagnóstico de HFHo por confirmación genética o un diagnóstico clínico basado en una historia clínica de concentración de colesterol LDL no tratada > 500 mg/dL (13 mmol/L) y un xantoma antes de los 10 años de edad o evidencia de hipercolesterolemia familiar heterocigótica en ambos padres.
Todos los sujetos:
-El sujeto debe seguir una dieta baja en grasa y recibir tratamiento hipolipemiante de base (como estatinas, inhibidores de la absorción de colesterol, secuestradores de ácidos biliares, ácido nicotínico o combinaciones de estos).
-El tratamiento hipolipemiante, incluida la dosis de estatina, no debe modificarse durante ≥ 4 semanas antes de la determinación del C-LDL de selección; los fibratos deben permanecer estables durante al menos 6 semanas antes de la selección.

E.4

Principal exclusion criteria

Subjects with HoFH:
- estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2; CK >
3x ULN; AST or ALT > 3x ULN; (all screening by central laboratory);
- known active infection or major hematologic, renal, metabolic,
gastrointestinal or endocrine dysfunction;
- subject has taken a cholesterylester transfer protein (CETP) inhibitor in
the last 12 months, or mipomersen or lomitapide in the last 5 months
prior to LDL-C screening, or has received any therapy to inhibit
proprotein convertase subtilisin/kexin type 9 (PCSK9) within 12 weeks
prior to screening;
- subject has a history or evidence of any other clinically significant
disorder, condition or disease, or planned or expected procedure that, in
the opinion of the Investigator or Amgen physician, would pose a risk to
subject safety or interfere with the study evaluation, procedures or
completion.
The following are major exclusion criteria for all subjects:
- subjects cannot be receiving treatment in another investigational
device or drug study, or less than 30 days since ending treatment on
another investigational device or drug study;
- female subjects of childbearing potential cannot be pregnant or breast
feeding or planning to become pregnant or planning to breast feed and
must be willing to use acceptable method(s) of effective birth control
(may include true sexual abstinence) during treatment with evolocumab
and for an additional 15 weeks after the end of treatment with
evolocumab.

Sujetos con HFHo:
-Insuficiencia renal grave o moderada, definida como una tasa de filtración glomerular estimada (TFGe) < 30 mL/min/1,73 m2 en la selección, confirmada mediante mediciones repetidas con 1 semana de diferencia como mínimo. Nota: la TFGe se calculará en el laboratorio central y se facilitará al centro para determinar la elegibilidad.
-Enfermedad hepática activa persistente o disfunción hepática, definida por aspartato aminotransferasa (AST) o alanina aminotransferasa (ALT) > 2 veces el límite superior de la normalidad, determinadas mediante análisis en el laboratorio central en la selección y confirmadas mediante mediciones repetidas con 1 semana de separación como mínimo.
-CK > 3 veces el LSN en la selección, confirmada mediante mediciones repetidas con 1 semana de separación como mínimo.
-Infección activa conocida o disfunción importante hematológica, renal, metabólica, gastrointestinal o endocrina a criterio del investigador.
-El sujeto ha sido tratado con inhibidores de la proteína de transferencia de ésteres de colesterol (CETP) como anacetrapib, dalcetrapib, evacetrapib en los últimos 12 meses, o con mipomersen o lomitapida en los últimos 5 meses previos a la determinación del C-LDL de selección.
-El sujeto ha recibido evolocumab o cualquier otro tratamiento para inhibir la PCSK9 durante las 12 semanas de selección.
-Antecedentes o evidencia de cualquier otro trastorno, afección o enfermedad clínicamente significativos, o procedimiento previsto o esperado que, en opinión del investigador o del médico de Amgen, si se consultan, puedan suponer un riesgo para la seguridad del sujeto o interferir en la evaluación, los procedimientos o la finalización del estudio.
Todos los sujetos:
-Estar recibiendo actualmente tratamiento en otro estudio de un fármaco o dispositivo en investigación o haber transcurrido menos de 30 días desde el fin del tratamiento en otro estudio de un fármaco o dispositivo en investigación. Están excluidos otros procedimientos o tratamientos experimentales durante la participación en este estudio.
-Mujer que ha experimentado la menarquia y no está dispuesta a utilizar métodos anticonceptivos aceptables y eficaces durante el tratamiento con evolocumab y durante 15 semanas más después del fin del tratamiento con evolocumab. Una mujer que ha experimentado la menarquia se considera en edad fértil

E.5 End points

E.5.1

Primary end point(s)

Subject incidence of treatment emergent adverse events.

Incidencia en los sujetos de acontecimientos adversos que aparecen durante el tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

Screening, day 1, weeks 4, 12, 24, 36, 48, 60, 72 and 80.

See further details in the protocol.

Screening, día 1, semanas 4, 12, 24, 36, 48, 60, 72 y 80.

Ver más detalles en el protocolo.

E.5.2

Secondary end point(s)

Percent change from baseline at week 80 in:
− LDL-C
− non-HDL-C
− ApoB
− total cholesterol/HDL-C ratio
− ApoB/ApoA1 ratio

Change from baseline in LDL-C at week 80.

Cambio porcentual respecto al valor basal en la semana 80 en los parámetros siguientes:
- C-LDL
- C-no-HDL
- ApoB
- Relación colesterol total/C-HDL
- Relación ApoB/ApoA1

Cambio en el C-LDL respecto al valor basal en la semana 80.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline and week 80.

Valor basal y en la semana 80.

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

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

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)

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

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

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.8.3

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

Brazil

Canada

Colombia

New Zealand

South Africa

Turkey

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

The end of the study (primary completion) is defined as the last day on which an enrolled subject in this study completes the end-of-study visit (week 80) or terminates the study early.

El fin del estudio (finalización principal) se define como el último día en que un sujeto incluido en este estudio completa la visita de fin del estudio (semana 80) o termina el estudio prematuramente.

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

Yes

F.1.1

Number of subjects for this age range:

115

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

104

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

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

115

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)

None

Ninguno

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

2017-02-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2021-06-01

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