Clinical Trials Register

Summary
EudraCT Number:	2011-003998-28
Sponsor's Protocol Code Number:	CER-001-CLIN-003
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:	2012-03-08
Trial 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

2011-003998-28

A.3

Full title of the trial

Modifying Orphan Disease Evaluation (MODE) Study: A Multicenter, Open-Label Study of the Effects of CER-001 on Plaque Volume in Subjects with Homozygous Familial Hypercholesterolemia (HoFH)

Studio sulla modifica della valutazione di malattia rara (MODE): Studio multicentrico, in aperto sugli effetti di CER-001 sul volume delle placche in pazienti affetti da Ipercolesterolemia familiare omozigote (HoFH)

A.3.1

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

Effect of CER-001 on blockage of arteries (plaque) in subjects with homozygous familial hypercholesterolemia

Effetto di CER-001 sul blocco di arterie (placca) in soggetti affetti da Ipercolesterolemia familiare omozigote

A.3.2

Name or abbreviated title of the trial where available

MODE

A.4.1

Sponsor's protocol code number

CER-001-CLIN-003

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01412034

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	CERENIS THERAPEUTICS SA
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	Cerenis Therapeutics
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	Cerenis Therapeutics
B.5.2	Functional name of contact point	Christopher Prue
B.5.3	Address:
B.5.3.1	Street Address	BP87519-265 rue de la Decouverte
B.5.3.2	Town/ city	Labege
B.5.3.3	Post code	31675
B.5.3.4	Country	France
B.5.4	Telephone number	+33 (0)6 74 91 55 36
B.5.5	Fax number	+33 (0)5 62 19 04 17
B.5.6	E-mail	prue@cerenis.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	Recombinant Human Apolipoprotein
D.3.2	Product code	CER-001
D.3.4	Pharmaceutical form	Sterile concentrate
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	CER-001
D.3.9.3	Other descriptive name	Recombinant Human Apolipoprotein A-I
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	8
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	Sfingomielina
D.3.9.3	Other descriptive name	Sfingomielina
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	20.95
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	NA1,2-Dihexadecanoyl-sn-Glycero-3-Phospho-(1-raac-glycerol)
D.3.9.3	Other descriptive name	1,2-Dihexadecanoyl-sn-Glycero-3-Phospho-(1-raac-glycerol)
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	.65
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

Homozygous familial hypercholesterolemia

Ipercolesterolemia familiare omozigote

E.1.1.1

Medical condition in easily understood language

Genetic defect for high cholesterol in blood

Difetto genetico per alto colesterolo nel sangue

E.1.1.2

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.1
E.1.2	Level	SOC
E.1.2	Classification code	10027433
E.1.2	Term	Metabolism and nutrition disorders
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 assess the impact of 12 intravenous infusions of 8 mg/kg CER-001 given at 2-week intervals on descending thoracic aorta and carotid plaque volume, determined from vessel wall volume of diseased arterial segments using 3T magnetic resonance imaging (3TMRI).

Valutare l'impatto di 12 infusioni intravenose di 8 mg/kg di CER-001 somministrate a intervalli di 2 settimane (ovvero, ogni 10 - 18 giorni) sul volume delle placche dell'aorta toracica discendente e delle placche carotidee, determinato dal volume della parete dei vasi dei segmenti arteriosi interessati con l'impiego della risonanza magnetica per immagini 3T (3TMRI).

E.2.2

Secondary objectives of the trial

Absolute change from baseline in carotid plaque volume. Absolute change in baseline in descending thoracid aorta plaque volume. Percent change from baseline in carotid plaque lipid rich necrotic core volume, carotid plauqe calcium volume and coratid intraplaque hemorrhage.

Variazione assoluta dal baseline del volume delle placche carotidee.Variazione assoluta dal baseline nel volume della placca dell'aorta toracica discendente.Variazione in percentuale dal baseline del volume del nucleo necrotico ricco di lipidi nelle placche carotidee,del volume del calcio nelle placche carotidee e nell'emorragia interplacca carotidea.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject or Subject guardian must sign the informed consent, and subject must sign assent if applicable, as approved by the EC/IRB prior to performance of any screening procedures 2. Male or female subject 12 years or older 3. Females of childbearing potential that agree and commit to use an acceptable form of birth control from the time of consent through the last follow-up visit required by the protocol or sixty (60) days after the last administration of study drug, whichever comes later. Acceptable forms of birth control for this study are defined as a barrier method plus hormonal therapy (implants, injections, oral contraceptives and IUDs) or abstinence. 4. Males that agree and commit to use an acceptable form of contraception from the time of consent through the last follow-up visit required by the protocol or sixty (60) days after the last administration of study drug, whichever comes later. Acceptable forms of male contraception for this study include use of condom for all sexual intercourse and/or documented vasectomy for all sexually active males, or abstinence. 5. Subject diagnosis of Homozygous FH defined as: • Genetic testing on record classifying the subject as Homozygous FH -or - • Genetic testing on record classifying the subject as Compound Heterozygous FH with accompanying phenotypical criteria of: • a history of LDL-C ≥220 mg/dL (5.69 mmol/L) while receiving maximally tolerated lipid-lowering therapy with <15% respons -and- • LDL-C above the 90th percentile in ≥2 first-degree relatives –and- • the presence of tendinous xanthomas and/or manifestations of premature coronary heart disease or corneal arcus. 6. Subject must be willing to participate in the study and comply with all protocol requirements, including willingness to: • Undergo two baseline contrast-enhanced 3TMRI evaluations separated by about 5-10 days • Return to the clinic every two weeks for a total of twelve IV infusions of study drug • Return to the clinic at the end of the study for a follow-up contrast-enhanced 3TMRI procedure.

1. il paziente o il tutore del paziente deve firmare il consenso informato, ed il paziente deve firmare il consenso del caso, come approvato dalla CE / IRB prima della performance di eventuali procedure di screening 2. Maschio o femmina soggetti a 12 anni o superiore ai 3. Le femmine in età fertile che accettano e si impegnano ad utilizzare una forma accettabile di controllo delle nascite a partire dal momento del consenso attraverso l`ultima visita di follow-up richiesto dal protocollo o 60 (60) giorni dopo l`ultima somministrazione del farmaco in studio, se successiva. Forme accettabili di controllo delle nascite per questo studio sono definiti come un metodo di barriera più terapia ormonale (impianti, iniezioni, contraccettivi orali e IUD) o astinenza. 4. I maschi che accettano e si impegnano ad utilizzare una forma accettabile di contraccezione a partire dal momento del consenso attraverso l`ultima visita di follow-up richiesto dal protocollo o 60 (60) giorni dopo l`ultima somministrazione del farmaco in studio, se successiva. Forme accettabili di contraccezione maschile per questo studio comprendono l`uso del preservativo per tutti i rapporti sessuali e / o vasectomia documentata per tutti i maschi sessualmente attivi, o astinenza.5. Oggetto della diagnosi FH omozigote, definito come: • I test genetici come prova della classificazione del soggetto come HoFH - o - • I test genetici come prova della classificazione del soggetto come FH eterozigote composto con accompagnamento criteri fenotipici di: • una storia di LDL-C ≥ 220 mg / dL (5,69 mmol / L) durante la ricezione al massimo tollerato terapia ipolipemizzante con <respons-e-15% • LDL-C al di sopra del 90 ° percentile in ≥ 2 parenti di primo grado-and- • la presenza di xantomi tendinei e / o manifestazioni di malattia coronarica prematura o Arcus corneali. 6. il soggetto deve essere disposti a partecipare allo studio e rispettare il protocollo requisiti, ivi compresa la disponibilità a: • sottoposti a due basali intensificazione di contrasto 3TMRI valutazioni separate da circa 5-10 giorni • Ritorno alla clinica ogni due settimane per un totale di dodici infusioni di farmaco in studio • Ritorno alla clinica, alla fine dello studio per un follow-up contrast-enhanced procedura 3TMRI.

E.4

Principal exclusion criteria

1. Subjects weighing more than 100 kg at Screening. 2. Subjects with significant health problems in the recent past including blood disorders, cancer, or digestive problems but not cardiovascular disease as manifested in inclusion criteria #5 above. 3. Females who are pregnant, breastfeeding, or plan to become pregnant during the study. 4. Subject has known major hematologic, renal [serum creatinine > 2.0 mg/dL (180 μmol/L)], hepatic (liver enzymes greater than twice the upper limits of normal for the performing laboratory), metabolic, gastrointestinal or endocrine dysfunction in the judgment of the Investigator 5. Any clinically significant medical condition or presence of any laboratory abnormality performed prior to randomization that is considered by the investigator to be clinically important and could interfere with the conduct of the study. 6. Subject is likely to be unreliable as a study participant based on the Investigator`s (or designee’s) knowledge of the subject (e.g., alcohol or other drug abuse, inability or unwillingness to adhere to the protocol, or psychosis) 7. Subject has a contraindication to MRI scanning such as imbedded metal (e.g., schrapnel), implanted metal objects (e.g., pacemaker), claustrophobia, allergy to gadolinium chelate contrast or severe renal insufficiency (e.g., GFR < 30 mL/min/1.73m2) that would preclude the use of contrast-enhanced 3TMRI. 8. Subject has participated in any investigational drug study within 30 days prior to randomization, or expects to participate in any other investigational drug study during his/her planned participation in this study. The last dose of any investigational product must have been taken at least 30 days prior to the first dose of CER-001. 9. Subject has previously participated in this study or another study involving CER-001.

1.Soggetti di peso superiore a 100 kg allo screening. 2. I soggetti con problemi di salute significativi del recente passato tra cui disturbi del sangue, cancro, o problemi digestivi, tranne le malattie non cardiovascolari che si manifesta nei criteri di inclusione # 5. 3. Le femmine in stato di gravidanza, l`allattamento al seno, o piano di una gravidanza durante lo studio. 4. Il soggetto ha conosciuto importanti disfunzioni ematologiche, renali [creatinina sierica> 2,0 mg / dL (180 micromol / L)], epatiche (enzimi epatici superiore a due volte i limiti superiori della norma per il laboratorio che esegue), disfunzione metabolica, gastrointestinale o endocrina a giudizio dello sperimentatore.5. Qualsiasi condizione clinicamente significativa medica o la presenza di anomalie di laboratorio eseguiti prima della randomizzazione che è considerato dallo sperimentatore essere clinicamente importante e potrebbe interferire con lo svolgimento dello studio. 6. Il soggetto è probabile che sia inaffidabile come partecipante allo studio basato sulla conoscenza dello sperimentatore (o designata dallo sperimetatore) del soggetto (ad esempio, alcool o altre droghe, l`incapacità o la riluttanza ad aderire al protocollo, o psicosi) 7. Soggetto ha una controindicazione alla scansione di risonanza magnetica come il metallo piani integrati (ad esempio, schrapnel), oggetti metallici impiantati (es. pacemaker), claustrofobia, allergia al contrasto chelato di gadolinio o grave insufficienza renale (ad esempio, GFR <30 ml/min/1.73m2) che esclude l`uso di contrast-enhanced 3TMRI. 8. Oggetto ha partecipato a uno studio farmaco sperimentale entro 30 giorni prima della randomizzazione, o si aspetta di partecipare a qualsiasi altro studio farmaco sperimentale durante il suo / la sua prevista partecipazione in questo studio. L`ultima dose di qualsiasi prodotto in sperimentazione devono essere state scattate almeno 30 giorni prima della prima dose di CER-001. 9. Oggetto ha già partecipato a questo studio o in un altro studio che ha coinvolto CER-001.

E.5 End points

E.5.1

Primary end point(s)

Percent change from baseline to follow-up in carotid plaque volume measured as arterial wall volume of diseased portions of the arterial wall using 3TMRI.

Variazione in percentuale dal baseline al controllo nel volume delle placche carotidee misurato come volume della parete arteriosa delle porzioni interessate della parete arteriosa usando la 3TMRI.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline and 1-3 weeks after last infusion.

Baseline e 1-3 settimane dopo l'ultima infusione.

E.5.2

Secondary end point(s)

Absolute change from baseline for carotid plaque volume, descending thoracic aorta plaque volume. Percent change from baseline in carotid plaque lipid rich necrotic core volume, carotid plaque calcium volume and carotid intraplaque hemorrhage.

Variazione assoluta in percentuale dal baseline del volume della placca carotidea, volume della placca dell'aorta toracica discendente. Variazione in percentuale dal baseline del volume del nucleo necrotico ricco di lipidi nelle placche carotidee, del volume del calcio nelle placche carotidee e nell'emorragia interplacca carotidea.

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline and 1-3 weeks after last infusion.

Baseline e 1-3 settimane dopo l'ultima infusione.

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

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

Yes

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

Yes

E.8.2.3.1

Comparator description

Non applicabile

Not applicable

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

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

Canada

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

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)

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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)

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

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)

No immediate plans are outlined in the protocol. It is possible that a follow-up safety extension could be started for these patients.

Programmi immediati non sono previsti nel protocollo. Per questi pazienti e` possibile che possa essere iniziato uno studio `extension` di controllo sulla sicurezza.

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

2012-02-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-01-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-07-08

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IMP with orphan designation in the indication
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