Clinical Trials Register

Summary
EudraCT Number:	2015-001343-37
Sponsor's Protocol Code Number:	20140316
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:	2018-02-23
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

2015-001343-37

A.3

Full title of the trial

A Randomized, Actively Controlled, Open-label, Multicenter Study of Efficacy and Safety of Evolocumab Compared With Low Density Lipoprotein Cholesterol (LDL-C) Apheresis, Followed by Single-Arm Evolocumab
Administration in Subjects Receiving LDL-C Apheresis Prior to Study Enrollment

Studio randomizzato, controllato verso trattamento attivo, in aperto, multicentrico volto a confrontare l’efficacia e la sicurezza di evolocumab rispetto all'aferesi di colesterolo legato a lipoproteine a bassa densità (LDL-C), seguito dalla somministrazione a braccio singolo di evolocumab in soggetti sottoposti a LDL-C aferesi prima dell'arruolamento nello studio.

A.3.1

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

Study of Evolocumab in Patients Undergoing Low-Density Lipoprotein Apheresis

Studio con evolocumab in pazienti sottoposti ad aferesi per lipoproteine a bassa densità

A.3.2

Name or abbreviated title of the trial where available

Study of Evolocumab in Patients Undergoing Low-Density Lipoprotein Apheresis

Studio con Evolocumab in pazienti sottoposti ad aferesi per lipoproteine a bassa densità

A.4.1

Sponsor's protocol code number

20140316

A.5.4

Other Identifiers

Name:

Number:

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	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	-
B.5.5	Fax number	-
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 soluzione per iniezione in penna preriempita
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.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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/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	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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Hypercholesterolemia

ipercolesterolemia

E.1.1.1

Medical condition in easily understood language

Elevated LDL-cholesterol

elevati livelli di colesterolo LDL

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	20.0
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 efficacy of subcutaneous (SC) evolocumab, compared to regularly scheduled LDL-C apheresis, on reducing the need for future apheresis.

Confrontare l'efficacia di evolocumab per via sottocutanea (SC) rispetto ai cicli ad intervalli regolari della LDL-C aferesi nel ridurre il ricorso a future aferesi.

E.2.2

Secondary objectives of the trial

To assess the effects of SC evolocumab compared with apheresis on percent change from baseline to week 4 in LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), and total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio

Confrontare gli effetti di evolocumab SC e dell'aferesi sulla variazione percentuale dal basale alla settimana 4 dei valori di LDL-C, colesterolo legato alle lipoproteine non ad alta densità (colesterolo non HDL), e rapporto colesterolo totale/colesterolo legato alle lipoproteine ad alta densità (HDL-C)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male or female, ≥ 18 years of age at signing of informed consent.
- Subject has been receiving regular apheresis for LDL-C lowering for at least 3 months immediately prior to lipid screening (per subject or physician report), has a treatment goal of LDL-C < 100 mg/dL (2.6 mmol/L) according to the physician managing the subject’s hypercholesterolemia, and has been receiving LDL-C apheresis during the last ≥ 4 weeks prior to lipid screening at regular QW or Q2W schedule and with no changes in apheresis type.
- Subject is receiving lipid-lowering pharmacological background therapy which includes a high-intensity statin dose (moderate-intensity statin dose with attestation that a higher dose is not appropriate for the subject) per Appendix D, unless the subject has a history of statin intolerance.
- Pre-apheresis LDL-C is ≥ 100 mg/dL (≥ 2.6 mmol/L) and ≤ 190 mg/dL (≤ 4.9 mmol/L) at screening.
- Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L) at screening.

- maschi o femmine ≥ 18 anni che firmano il consenso
- i soggetti hanno ricevuto aferesi regolare per LDL-C per almeno 3 mesi prima dello screening dei lipidi, hanno un treatment goal di LDL < 100 mg/dL (2.6 mmol/L), hanno ricevuto aferesi LDL-C durante le ultime 4 settimane prima dello screening dei lipidi a schedule QW o Q2W e senza modifiche nel tipo di aferesi.
- i soggetti stanno ricevendo terapia farmacologica di background che include una dose di statine elevata (dose moderata solo con una dichiarazione che una piu alta dose non è indicata per il soggetto) per appendice D, almeno che il paziente non abbia una storia di intolleranza alle statine.
- La pre aferesi per LDL è ≥ 100 mg/dL (≥ 2.6 mmol/L) e ≤ 190 mg/dL (≤ 4.9 mmol/L) allo screening
- trigliceridi ≤ 400 mg/dL (4.5 mmol/L) allo screening.

E.4

Principal exclusion criteria

- Known homozygous familial hypercholesterolemia.
- Missing any apheresis session is medically contraindicated or inappropriate based on the opinion of the investigator.
- Stopping apheresis would be inappropriate in the opinion of the investigator even if LDL-C is controlled to < 100 mg/dL with other therapies (eg, subject with Lp(a) > 60 mg/dL and for whom investigator would continue apheresis for Lp(a) reduction even with LDL-C <100 mg/dL).
- Myocardial infarction, unstable angina, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) or stroke within 3 months prior to randomization.
- Known active infection or major hematologic, renal, metabolic, gastrointestinal or endocrine dysfunction (except diabetes) or receiving renal replacement therapy.
- Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 mmHg or diastolic blood pressure (DBP) > 110 mmHg.
- Subject has taken a cholesterylester transfer protein (CETP) inhibitor such as anacetrapib, dalcetrapib or evacetrapib in the last 12 months, or mipomersen or lomitapide in the last 5 months prior to LDL-C screening.
- Subject has previously received fully human anti-PCSK9 antibody therapy (eg, evolocumab) within < 12 weeks prior to lipid screening or has received any other therapy to inhibit PCSK9 at any time.
- Currently receiving treatment in another investigational device or drug study, or less than 30 days since ending treatment on another investigational device or drug study(s) or planning to receive other investigational procedures while participating in this study.
- Female subject who has (1) not used (an) acceptable method(s) of birth control for at least 1 month prior to screening and/or (2) is not willing to inform her partner of her participation in this clinical study and to use such (an) acceptable method(s) of effective birth control during treatment with IP
(evolocumab) and for an additional 15 weeks after the end of treatment with IP (evolocumab), unless the female subject is permanently sterilized or postmenopausal (see protocol);
- Subject is pregnant or breast feeding, or planning to become pregnant or planning to breastfeed during treatment with IP (evolocumab) and/or within 15 weeks after the end of treatment with IP (evolocumab).
-Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 1 year prior to screening.

- conosciuta ipercolesterolemia famigliare omozigotica
- saltare qualsiasi sessione di aferesi è controindicato o inappropriato a giudizio dello sperimentatore
- Interrompere l’aferesi potrebbe essere inappropriate al giudizio dello sperimentatore anche se LDL-C è mantenuto < 100 mg/dL con altre terapie (es soggetti con Lp(a) > 60 mg/dL e per i quali lo sperimentatore raccomanda di continuare l’aferesi per la riduzione di Lp(a) anche con LDL-C <100 mg/dL).
- Infarto del miocardio, angina instabile, intervento coronarico percutaneo (PCI), bypass graft coronarico (CABG) o infarto nell’arco di 3 mesi prima della randomizzazione.
- Infezione attiva conosciuta o disfunzioni ematologiche, renali, metaboliche, gastrointestinali o endocrine maggiori (eccetto diabete) o che ricevono terapia di replacement renale.
- Ipertensione incontrollata definite come pressione sistolica a riposo (SBP) > 180 mmHg o pressione diastolica (DBP) > 110 mmHg.
- Pazienti che hanno assunto negli ultimi 12 mesi un inibitore della proteina tranferasi del colesteril estere, come ad esempio anacetrapib, dalcetrapib o evacetrapib oppure mipomersen o lomitapide negli ultimi 5 mesi prima dello screening LDL-C
- soggetti che hanno precedentemente ricevuto terapia a base di anticorpi anti-PCSK9 (es. evolocumab) entro 12 settimane dallo screening dei lipidi o hanno ricevuto qualsiasi altra terapia per l’inibizione di PCSK9 in qualsiasi momento.
- pazienti che al momento ricevono trattamento in un altro studio o tramite un altro investigational device, o meno di 30 giorni dalla fine del trattamento con un altro device o in un altro studio o che prevedono di ricevere altre procedure di investigazione durante la loro partecipazione allo studio
- soggetti donne che (1) non hanno usato metodi accettabili di controllo delle nascite almeno 1 mese prima dello screening e/o (2) non vogliono informare il loro partner della loro partecipazione a questo studio clinico e non vogliono utilizzare metodi contracettivi durante l’assunzione di evolocumab e per ulteriori 15 settimane dopo la fine del trattamento, almeno che il soggetto femminile non sia sterile o in menopausa
- il soggetto è incinta o sta allattando al seno, o ha in programma di rimanere incinta o allattare durante il trattamento con evolocumab e/o 15 settimane dopo la fine del trattamento
- Malignità (ad eccezione di tumori della pelle non-melanoma, carcinoma della cervice, carcinoma alla mammella, tumore alla prostata di stadio 1) nell’ultimo anno prima dello screening

E.5 End points

E.5.1

Primary end point(s)

Apheresis avoidance at the end of randomized therapy, defined as no
apheresis at week 5 and week 6

Evitare aferesi alla fine della terapia randomizzata, definita come no aferesi alla settimana 5 e 6

E.5.1.1

Timepoint(s) of evaluation of this end point

Weeks 5 and 6

settimana 5 e settimana 6

E.5.2

Secondary end point(s)

Percent change from baseline to week 4 in the following:
− LDL-C
− non-HDL-C
− total cholesterol/HDL-C ratio

Variazione percentuale dal basale alla settimana 4 nei seguenti:
− LDL-C
− non-HDL-C
− colesterolo totale/tasso HDL-C

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline and week 4

baseline e settimana 4

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

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

Yes

E.8.1.7.1

Other trial design description

aferesi LDL-C

LDL-C apheresis

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

aferesi per LDL-C

LDL-C apheresis

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

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

Australia

Czech Republic

France

Germany

Italy

Spain

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

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

LSLV

Ultima visita dell'ultimo paziente

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

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

Yes

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

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

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

2015-12-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-03-17

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

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