Clinical Trials Register

Summary
EudraCT Number:	2014-002277-11
Sponsor's Protocol Code Number:	20120123
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:	2015-06-12
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

2014-002277-11

A.3

Full title of the trial

Double-blind, Randomized, Multicenter, Placebo-Controlled, Parallel Group Study to Characterize the Efficacy, Safety, and Tolerability of 24 Weeks of Evolocumab for Low Density Lipoprotein-Cholesterol (LDL-C) Reduction, as Add-On to Diet and Lipid-Lowering Therapy, in Pediatric Subjects 10 to 17 Years
of Age With Heterozygous Familial Hypercholesterolemia (HeFH)

Studio multicentrico, randomizzato, in doppio cieco, a gruppi paralleli, controllato verso placebo volto a caratterizzare l’efficacia, la sicurezza e la tollerabilità di 24 settimane di trattamento con evolocumab per la riduzione del colesterolo legato alle lipoproteine a bassa densità (C-LDL) in aggiunta alla dieta e alla terapia ipolipemizzante in soggetti pediatrici dai 10 ai 17 anni di età affetti da ipercolesterolemia familiare eterozigote (HeFH)

A.3.1

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

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

Studio volto a caratterizzare l’efficacia, la sicurezza e la tollerabilità a lungo termine in soggetti pediatrici dai 10 ai 17 anni di età affetti da ipercolesterolemia familiare eterozigote (HeFH).

A.4.1

Sponsor's protocol code number

20120123

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

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.5.6	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	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	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.3.9.3	Other descriptive name	AMG145
D.3.9.4	EV Substance Code	SUB32500
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	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	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	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

Heterozygous familial hypercholesterolaemia

Ipercolesterolemia familiare eterozigote

E.1.1.1

Medical condition in easily understood language

Increased cholesterol in the blood

Aumento del colesterolo nel sangue

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10057079
E.1.2	Term	Heterozygous familial hypercholesterolemia
E.1.2	System Organ Class	100000004850

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 24 weeks of subcutaneous (SC) evolocumab compared with placebo, when added to standard of care, on percent change from baseline in low-density lipoprotein cholesterol (LDL-C) in pediatric subjects 10 to 17 years of age with heterozygous familial hypercholesterolemia (HeFH).

valutare l’effetto di 24 settimane di trattamento con evolocumab per via sottocutanea (sc) rispetto al placebo, in aggiunta alla terapia standard, sulla variazione percentuale dal basale dei livelli di colesterolo legato alle lipoproteine a bassa densità (C-LDL) in soggetti pediatrici dai 10 ai 17 anni di età con HeFH.

E.2.2

Secondary objectives of the trial

• to evaluate the safety of SC evolocumab compared with placebo, when added to standard of care, in pediatric subjects 10 to 17 years of age with HeFH
• to assess the effects of SC evolocumab compared with placebo, when added to standard of care, on mean percent change from baseline to weeks 22 and 24 and change from baseline to week 24 in LDL-C, and on percent change from baseline to week 24 in other lipid parameters in
pediatric subjects 10 to 17 years of age with HeFH
• To characterize PK exposure

- valutare la sicurezza di evolocumab sc rispetto al placebo, in aggiunta alla terapia standard, in soggetti pediatrici dai 10 ai 17 anni di età con HeFH
- valutare gli effetti di evolocumab sc rispetto al placebo, in aggiunta alla terapia standard, sulla variazione percentuale media dal basale alle settimane 22 e 24 e sulla variazione dal basale alla settimana 24 dei livelli di C-LDL, nonché sulla variazione percentuale dal basale alla settimana 24 dei livelli di colesterolo legato alle lipoproteine non ad alta densità (C-non HDL), apolipoproteina B (ApoB), rapporto colesterolo
totale/C-HDL, e rapporto apoB/apolipoproteina A-1 (ApoA1), in soggetti pediatrici dai 10 ai 17 anni di età con HeFH
- caratterizzare l’esposizione farmacocinetica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

-Subject has provided informed consent or subject assent prior to initiation of any study-specific activities/procedures.
and/or
- Subject’s legally acceptable representative has provided informed consent when the subject is legally too young to provide informed consent and the subject has provided written subject assent based on local regulations and/or guidelines prior to any study-specific activities/procedures being initiated.
- Male or female, ≥ 10 to ≤ 17 years of age at time of randomization (includes the year after the subject completes the 17th year after birth but not the day of completing the 18th year after birth).
-Diagnosis of heterozygous familial hypercholesterolemia by local applicable diagnostic criteria for HeFH (ie, criteria outlined by the Simon Broome Register Group [Scientific Steering Committee, 1991] or the Dutch Lipid Clinic Network [World Health Organization, 1999]) or by genetic testing.
- On an approved statin with stable dose for ≥ 4 weeks before LDL-C screening and, in the opinion of the investigator, not requiring up-titration.

sono eleggibili per questo studio soggetti di sesso maschile e femminile, di età compresa tra i 10 e i 17 anni, con diagnosi di HeFH e in trattamento con terapia ipolipemizzante standard ottimizzata conformemente alle linee guida applicabili a livello locale.
I soggetti dovranno avere firmato il consenso informato o l’assenso per lo studio e dovrà essere disponibile l’apposito modulo di consenso dei genitori/del tutore. I soggetti devono seguire una dieta a basso contenuto di grassi e devono essere in trattamento con una terapia ipolipemizzante di base ottimizzata, che comprenda una statina alla dose ottimale determinata dal medico curante. La terapia ipolipemizzante deve essere stabile da ≥4 settimane prima dello screening. I livelli di C-LDL a digiuno devono essere ≥130 mg/dL (3,4 mmol/L) e i trigliceridi a digiuno ≤400 mg/dL (4,5 mmol/L) come determinato dal laboratorio centrale allo screening.

E.4

Principal exclusion criteria

- Type 1 diabetes or newly diagnosed (within 3 months of randomization) type 2 diabetes, or poorly controlled type 2 diabetes (HbA1c > 8.5%) or newly diagnosed impaired glucose tolerance (within 3 months of randomization).
- Untreated or inadequately treated hyperthyroidism or hypothyroidism as defined by thyroid stimulating hormone (TSH) < lower limit of normal (LLN) or > 1.5 times the upper limit of normal (ULN), respectively, and free thyroxine (T4) levels that are outside normal range at screening.
- Moderate to severe renal dysfunction, defined as an estimated glomerular filtration rate (eGFR) < 30 ml/min/1.73m2 at screening, confirmed by a repeat measurement at least 1 week apart.
- Persistent active liver disease or hepatic dysfunction, defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the ULN as determined by central laboratory analysis at screening, confirmed by a repeat measurement at least 1 week apart.

E.4 Criteri di esclusione principali(elencare i più importanti):
diabete di tipo 1 o diabete di tipo 2 diagnosticato di recente (nei 3 mesi precedenti la randomizzazione) o scarsamente controllato (HbA1c >8,5%) o alterata tolleranza al glucosio di nuova diagnosi; livelli di ormone tireostimolante (TSH) < il limite inferiore della norma (LLN) o TSH >1,5 volte il limite superiore della norma (ULN) e livelli di tiroxina (T4) libera al di fuori dell’intervallo normale, tasso di filtrazione glomerulare stimato (eGFR) <30 mL/min/1,73 m2, aspartato aminotransferasi (AST) o alanina
aminotransferasi (ALT) >2x ULN, creatininchinasi (CK) >3x ULN (tutte le valutazioni di screening sono eseguite dal laboratorio centrale); infezione in atto nota o disfunzione maggiore di natura ematologica, renale, metabolica, gastrointestinale o endocrina. Sono esclusi i soggetti che hanno assunto inibitori della proteina di trasferimento degli esteri del colesterolo (CEPT) negli ultimi 12 mesi, mipomersen o lomitapide negli ultimi 5 mesi, o precedentemente sottoposti al trattamento con evolocumab o con qualsiasi altra terapia sperimentale volta a inibire la proproteina convertasi subtilisina/kexina di tipo 9 (PCSK9). I soggetti non potranno essere arruolati in studi su altri dispositivi o farmaci sperimentali, sottoporsi a trattamento con altri farmaci o procedure sperimentali, o aver concluso uno studio su altri farmaci o dispositivi sperimentali da meno di 30 giorni. I soggetti di sesso femminile potenzialmente fertili non potranno essere in stato di gravidanza, pianificare una gravidanza, essere in allattamento o pianificare di allattare e devono essere disposte a utilizzare uno o più metodi efficaci di contraccezione giudicati accettabili durante il trattamento con il prodotto sperimentale
(evolocumab o placebo) e per altre 15 settimane dopo il termine del trattamento con il prodotto sperimentale (evolocumab o placebo).

E.5 End points

E.5.1

Primary end point(s)

Percent change from baseline to week 24 in LDL-C

variazione percentuale dei livelli di C-LDL dal basale alla settimana 24

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline and week 24

Al basale ed alla settimana 24

E.5.2

Secondary end point(s)

-Mean percent change from baseline to weeks 22 and 24 in LDL-C
-Change from baseline to week 24 in LDL-C
-Percent change from baseline to week 24 in the following:
− non-HDL-C
− ApoB
− total cholesterol/HDL-C ratio
− ApoB/ApoA1 ratio

• variazione percentuale media dei livelli di C-LDL dal basale alle settimane 22 e 24
• variazione dei livelli di C-LDL dal basale alla settimana 24
• variazione percentuale dal basale alla settimana 24 di:
– colesterolo non HDL
– ApoB
– rapporto colesterolo totale/C-HDL
– rapporto ApoB/ApoA1

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline, week 22 and week 24

Al basale, alla settimana 22 ed alla settimana 24

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

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

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

Australia

Brazil

Canada

New Zealand

South Africa

Turkey

United States

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

LVS

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:

150

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:

135

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

150

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

nessuno

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

2015-06-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-01-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-11-25

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