Clinical Trials Register

Summary
EudraCT Number:	2011-001480-42
Sponsor's Protocol Code Number:	MIPO3801011
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:	2012-02-22
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

2011-001480-42

A.3

Full title of the trial

A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients with Familial Hypercholesterolemia and Inadequately Controlled Low-Density-Lipoprotein Cholesterol

Studio di fase 3, randomizzato, in doppio cieco, con controllo placebo, a gruppi paralleli per valutare la sicurezza e l'efficacia di due diversi regimi posologici di Mipomersen in pazienti affetti da ipercolesterolemia familiare e colesterolo delle lipoproteine a bassa densita' non controllato adeguatamente

A.3.1

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

A Study of the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol

Studio di fase 3, randomizzato, in doppio cieco, con controllo placebo, a gruppi paralleli per valutare la sicurezza e l’efficacia di due diversi regimi posologici di Mipomersen in pazienti affetti da ipercolesterolemia familiare e colesterolo delle lipoproteine a bassa densita' non controllato adeguatamente

A.3.2

Name or abbreviated title of the trial where available

FOCUS FH

A.4.1

Sponsor's protocol code number

MIPO3801011

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	GENZYME EUROPE BV
B.1.3.4	Country	Netherlands
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	GENZYME
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	Genzyme Europe B.V.
B.5.2	Functional name of contact point	Medical Information Genzyme Europe
B.5.3	Address:
B.5.3.1	Street Address	Gooimer 10
B.5.3.2	Town/ city	Naarden
B.5.3.3	Post code	1411 DD
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	NA
B.5.5	Fax number	NA
B.5.6	E-mail	eumedinfo@genzyme.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	Mipomersen
D.3.2	Product code	ISIS 301012
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	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mipomersen
D.3.9.1	CAS number	629167-92-6
D.3.9.2	Current sponsor code	ISIS 301012
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
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	200
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	Mipomersen
D.3.2	Product code	ISIS 301012
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	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mipomersen
D.3.9.1	CAS number	629167-92-6
D.3.9.2	Current sponsor code	ISIS 301012
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	NA
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	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	Solution for injection
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 hypercholesterolemia

ipercolesterolemia eterozigote familiare

E.1.1.1

Medical condition in easily understood language

Heterozygous familial hypercholesterolemia

ipercolesterolemia eterozigote familiare

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10057079
E.1.2	Term	Heterozygous familial hypercholesterolemia
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic 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

Determine whether mipomersen (ISIS 301012) significantly reduces atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (severe HeFH), defined as low-density lipoprotein cholesterol (LDL-C) levels ≥200 mg/dL plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ≥300 mg/dL regardless of the presence of CHD/risk equivalents (referred to as Cohort 1) compared to placebo. Two different mipomersen dosing regimens will be studied: subcutaneous (SC) mipomersen 200 mg once weekly versus placebo, and SC mipomersen 70 mg thrice weekly versus placebo.

L’obiettivo primario del presente studio consiste nello stabilire se mipomersen (ISIS 301012) è in grado di abbassare in maniera significativa i livelli dei lipidi aterogenici nei pazienti affetti da ipercolesterolemia familiare eterozigota grave (HeFH grave), consistente in livelli di colesterolo delle lipoproteine a bassa densità (LDL-C) ≥200 mg/dL oltre alla presenza di cardiopatie coronariche (CHD)/equivalenti di rischio o in livelli di LDL-C ≥300 mg/dL a prescindere dalla presenza di CHD/equivalenti di rischio (denominati Coorte 1) rispetto al placebo. Si esamineranno due diversi regimi posologici di mipomersen: mipomersen 200 mg sottocutaneo (SC) una volta a settimana rispetto al placebo e mipomersen 70 mg SC tre volte a settimana rispetto al placebo.

E.2.2

Secondary objectives of the trial

Determine whether there are qualitative differences between the safety profiles of the 2 dosing regimens and placebo in Cohort 1, patients with HeFH with LDL-C levels ≥160 mg/dL and <200 mg/dL plus the presence of CHD/risk equivalents (referred to as Cohort 2), and the overall study population (comprising patients in both Cohort 1 and Cohort 2) - Determine whether there are qualitative differences between the tolerability of the 2 dosing regimens and placebo in Cohort 1, Cohort 2, and the overall study population -Further characterize the pharmacokinetics (PK) of the 2 dosing regimens in Cohort 1, Cohort 2, and the overall study population - Determine whether the 2 mipomersen dosing regimens significantly reduce atherogenic lipid levels in Cohort 2 compared to placebo

- Stabilire se vi sono differenze qualitative tra i profili di sicurezza dei 2 regimi posologici e il placebo nella Coorte 1, tra i pazienti affetti da HeFH con livelli di LDL-C ≥160 mg/dL e <200 mg/dL oltre alla presenza di CHD/ equivalenti di rischio (denominati Coorte 2) e la popolazione di studio complessiva (comprendente sia i pazienti della Coorte 1 che della Coorte 2) - Stabilire se vi sono differenze qualitative in termini di tollerabilità tra 2 regimi posologici e il placebo nella Coorte 1, nella Coorte 2 e nella popolazione di studio complessiva - Caratterizzare ulteriormente la farmacocinetica (PK) dei 2 regimi posologici nella Coorte 1, nella Coorte 2 e nella popolazione di studio complessiva - Stabilire se i 2 regimi posologici di mipomersen abbassano in maniera significativa i livelli dei lipidi aterogenici nella Coorte 2 rispetto al placebo

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Diagnosis of severe hypercholesterolemia (LDL-C ≥300 mg/dL (7.77 mmol/L) or LDL-C ≥ 200 mg/dL (5.18 mmol/L) and documented coronary heart disease (CHD) or CHD risk equivalent or diagnosis of Heterozygous Familial Hypercholesterolemia and LDL-C ≥160 mg/dL (4.14 mmol/L) and <200 mg/dL (5.18 mmol/L)) On stable, maximally tolerated, statin therapy for at least 12 weeks or if statin intolerant, on at least 1 medication from another class of hypolipidemic agents (i.e., bile acid sequestrants, niacin/nicotinic acid, cholesterol absorption inhibitors, fibrates). On stable, low fat diet for 12 weeks Body mass index (BMI) ≤40 kg/m2 and stable weight for 6 weeks

-diagnosi di ipercolesterolemia severa (LDL-C>=300mg/dL (7.77 mmol/L)o LDL-C ≥ 200 mg/dL (5.18 mmol/L)e patologia coronarica documentata o rischio di malattia coronarica equivalente o diagnosi di ipercolesterolemia familiare eterozigote e LDL-C ≥160 mg/dL (4.14 mmol/L) and <200 mg/dL (5.18 mmol/L)) Il paziente ha intrapreso un regime stabile, sostanzialmente tollerato con statine almeno 12 settimane prima dello screening o se intollerante alle statine il paziente deve assumere almeno 1 farmaco appartenente a un’altra categoria di agenti ipolipidemici (ad es. sequestranti dell'acido biliare, niacina/acido nicotinico, inibitori dell’assorbimento del colesterolo, fibrati). -Una dieta stabile a basso contenuto di grassi per 12 settimane -indice di massa corporea ≤40 kg/m2 e un peso stabile per 6 settimane

E.4

Principal exclusion criteria

Significant health problems in the recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, hypertension, blood disorders, liver disease, cancer, digestive disorders, Type I diabetes, or uncontrolled Type II diabetes Apheresis within 3 months prior to Screening or expected to start apheresis during the treatment phase

- significativi problemi di salute nel recente passato come attacco cardiaco, stroke, sindrome coronarica, angina instabile, insufficienza cardiaca, aritmie significative, ipertensione, malattie ematologiche o epatiche, tumori e disturbi digestivi, diabete di tipi I, o diabete non controllato di tipo II, aferesi nei tre mesi precedenti lo screening o programmata durante la fase di trattamento.

E.5 End points

E.5.1

Primary end point(s)

Percent change from Baseline in low-density lipoprotein cholesterol in Cohort 1

-variazione percentuale dal basale del colesterolo LDL nella coorte 1

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline to Week 60

dal basale alla settimana 60

E.5.2

Secondary end point(s)

Percent change from Baseline in Apolipoprotein Percent change from Baseline in Lipoprotein a Percent change from Baseline in low-density lipoprotein cholesterol in Cohort 2 Number of Participants with Adverse Events Number of Participants with injection site reactions Blood plasma concentration of Mipomersen

la variazione percentuale dal basale di: -apolipoproteine -lipoproteine a -colesterolo LDL nella coorte 2 - n. di partecipanti con eventi avvesi - n. di partecipanti con reazioni nel sito d'iniezione -concentrazione plasmatiche di Mipomersen

E.5.2.1

Timepoint(s) of evaluation of this end point

Percent change from Baseline in Apolipoprotein : Baseline to Week 60 Percent change from Baseline in Lipoprotein a : Baseline to Week 60 Percent change from Baseline in low-density lipoprotein cholesterol in Cohort 2 : Baseline to Week 60 Number of Participants with Adverse Events : 60 weeks Number of Participants with injection site reactions : 60 weeks Blood plasma concentration of Mipomersen : Pre-dose and at 2, 4, 6, 24, 48 and 72 hours post-dose at Weeks 1,13, 30, 38, 50 and 60.

dal basale alla settimana 60 per tutti, tranne per le concentrazioni plasmatiche di Mipomersen che vengono misurate: plasma prima e dopo la somministrazione (a 2, 4, 6 24,48 e 72 ore) alle settimane 1,13, 30, 38, 50 e 60.

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

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

Yes

E.8.2.3.1

Comparator description

- Stesso farmaco ad altro dosaggio

- same IMP used at different dosage

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

Argentina

Australia

Brazil

Canada

Hong Kong

India

Israel

Malaysia

New Zealand

Russian Federation

South Africa

Taiwan

Turkey

Ukraine

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

lvls

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

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:

460

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

260

F.4.2.2

In the whole clinical trial

480

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

2012-06-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-18

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

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