Clinical Trials Register

Summary
EudraCT Number:	2011-000987-92
Sponsor's Protocol Code Number:	C11209
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:	2011-12-27
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

2011-000987-92

A.3

Full title of the trial

Open-label, phase II, single arm study to evaluate the safety, immunogenicity, pharmacokinetics and efficacy of recombinant human C1 inhibitor for the treatment of acute attacks in pediatric patients with hereditary angioedema, from 2 up to and including 13 years of age

Studio di frase II in aperto, a singolo braccio per valutare la sicurezza, l`™immunogenicita', la farmacocinetica e l`™efficacia del Inibitore del C1-inibitore umano ricombinante per il trattamento di attacchi acuti di angioedema in pazienti pediatrici da 2 a 13 anni, affetti da angioedema ereditario

A.3.1

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

Open-label study to evaluate the safety, and efficacy of recombinant human C1 inhibitor for the treatment of acute attacks in pediatric patients with hereditary angioedema, from 2 up to and including 13 years of age

Studio pediatrico in aperto con C1-inibitore umano ricombinante in pazienti da 2 a 13 anni con Angioedema ereditario per valutare la sicurezza e l'efficacia.

A.4.1

Sponsor's protocol code number

C11209

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/103/2011

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	PHARMING TECHNOLOGIES B.V.
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	PHARMING TECHNOLOGIES B.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Pharming Technologies B.V.
B.5.2	Functional name of contact point	Wim Vermeulen
B.5.3	Address:
B.5.3.1	Street Address	Darwinweg 24
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 CR
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+31 71 524 7466
B.5.5	Fax number	+31 71 524 7445
B.5.6	E-mail	w.vermeulen@pharming.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	Ruconest
D.2.1.1.2	Name of the Marketing Authorisation holder	Pharming Technologies
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Powder for solution for injection
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.3.8	INN - Proposed INN	conestat alfa
D.3.9.2	Current sponsor code	rhC1INH
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2100
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

Hereditary angioedema (HAE). Hereditary angioedema is characterized by angioedema localized and recurrent caused by by uncontrolled activation of the Complement systems due to congenital deficiency of Functional C1 inhibitor (C1INH). Reports in Medical the literature suggests that C1INH replacement therapy with human plasma-derived represents a safe and effective acute attacks of HA

Angioedema Ereditario (HAE). L'angioedema ereditario e' caratterizzato da angioedema localizzato a carattere ricorrente causato da attivazione incontrollata dei sistemi del complemento dovuta a carenza congenita del C1-inibitore funzionale (C1INH). Rapporti nella letteratura medica suggeriscono che la terapia sostitutiva con C1INH umano plasma-derivato rappresenta un trattamento sicuro ed efficace degli attacchi acuti di HAE

E.1.1.1

Medical condition in easily understood language

This disease causes repeated attacks, sometimes serious to arms, legs, abdominal cavity and / or uro-genital region swelling.

Questa malattia causa attacchi ripetuti, a volte seri, di gonfiori a braccia, gambe, cavità addominale e/o regione uro-genitale.

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	PT
E.1.2	Classification code	10019860
E.1.2	Term	Hereditary angioedema
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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 assess the clinical safety, immunogenicity and tolerability of Ruconest in the treatment of acute angioedema attacks in 2-13 year old HAE patients

Valutare la sicurezza , l’immunogenicità e la tollerabilità del Ruconest usato per il trattamento di attacchi acuti di angioedema in pazienti dai 2 ai 13 anni affetti da HAE.

E.2.2

Secondary objectives of the trial

- to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of Ruconest in the treatment of acute angioedema attacks in 2-13 year old HAE patients to assess the efficacy of Ruconest in the treatment of acute angioedema attacks in 2-13 year old HAE patientsu

- Valutare la farmacocinetica (PK) e la farmacodinamica (PD) del Ruconest usato per il trattamento di attacchi acuti di angioedema in pazienti dai 2 ai 13 anni affetti da HAE. - Valutare l’efficacia del Ruconest usato per il trattamento di attacchi acuti di angioedema in pazienti dai 2 ai 13 anni affetti da HAE.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Screening • From 2 up to and including 13 years of age • Clinical and laboratory confirmed diagnosis of HAE (baseline C1INH activity <50% of normal) • Signed written informed consent (parental permission) signed by the legal guardian(s) Treatment • Clinical symptoms of an acute HAE attack • Onset of eligible symptoms within 5 hours from the moment at which medical evaluation to determine eligibility has occurred • IS score for at least one anatomical location at the time of initial evaluation of at least 3 (moderate severity or greater) without signs of spontaneous regression • 24h or more have passed since the patient’s last study treatment

Allo screening •Pazienti dai 2 ai 13 anni inclusi •Diagnosi clinica e di laboratorio confermata di HAE ( livello di attività al basale di C1INH funzionale < 50% del normale) •Firma del consenso informato scritto (permesso dei genitori) firmato dal legale rappresentante/I Trattatamento •Sintomi clinici di attacco di HAE •Insorgenza dei sintomi a meno di 5 ore dal momento in cui la valutazione medica ha determinato l’idoneità per l’inclusione •Il punteggio su “IS” per almeno una posizione anatomica al momento della valutazione iniziale è di almeno 3 (severità moderata o superiore) senza segni di regressione spontanea. • sono trascorse 24 ore o più dall’ultimo trattamento di studio del paziente

E.4

Principal exclusion criteria

Screening
 A diagnosis of acquired C1INH deficiency (AAE)
 A medical history of allergy to rabbits or rabbit-derived products (including rhC1INH, antisera),
or positive anti-rabbit epithelium (dander) IgE test (cut off>0.35 kU/L in ImmunoCap assay
(Phadia, Sweden) or equivalent)
 Treatment with investigational drug in another clinical study in the last 30 days
 Any clinical significant abnormality in the physical examination and/or the routine laboratory
assessments, that in the opinion of the Investigator makes the patient unsuitable for
participation in the study
 Patient or legal guardian whose decision to participate might be unduly influenced by
perceived expectation of gain or harm by participation, such as patient or legal guardian in
detention due to official or legal order
 Any condition or treatment that in the opinion of the investigator might interfere with the
evaluation of the study objectives
Treatment
 Any changes since screening that would exclude patient based on above exclusion criteria.
 10 HAE attacks were previously treated with study medication.
 Suspicion for an alternate explanation of the symptoms other than an acute HAE attack.
 Use of any disallowed concomitant medication since onset of acute HAE attack (see Section
8.2.1).
 Positive pregnancy test (urine or serum)

Allo Screening
 Diagnosi di deficit di C1INH acquisito (AAE)
 Anamnesi di allergia ai conigli o a prodotti derivati da conigli (incluso rhC1INH antisiero) o esame positivo delle IgE anti-epitelio di coniglio (dander) (cut-off >0,35 kU/l; esame ImmunoCap ; (Phadia, Sweden) o equivalente).
 Trattamento con farmaci sperimentali in altri studi clinici negli ultimi 30 giorni.
 Qualsiasi anomalia clinica significativa derivante dall’esame obiettivo e/0 dall’ematologia e biochimica di routine che, a parere dello sperimentatore, possa rendere il paziente non idoneo alla sperimentazione  Paziente o tutore legale la cui decisione di partecipare possa essere indebitamente influenzata dalla percezione di una aspettativa di guadagno o danno, così come pazienti o tutori legali in regime di detenzione a causa di ordine giuridico
 Qualsiasi condizione o trattamento che, a parere dello sperimentatore, possa interferire con la valutazione degli obiettivi dello studio
Trattamento
Qualsiasi cambiamento dallo screening che escluderebbe il paziente sulla base dei suddetti criteri di esclusione
 10 attacchi di HAE precedentemente trattati con il farmaco in studio.
 Sospetto di una spiegazione alternativa dei sintomi diversa da un attacco acuto di HAE
 Utilizzo di farmaci concomitanti proibiti dall’inizio dell’attacco acuto di HAE

E.5 End points

E.5.1

Primary end point(s)

The primary objective is Safety Tolllerability and immunogenicity. Safety and tolerability by standard criteria (vital signs, ECG, adverse events, routine laboratory safety parameters and immunogenicity (anti-host related impurities (HRI) and anti C1INH antibodies)

L'obiettivo primario è la sicurezza e la tollerabilità e l'immunogenicità. La sicurezza e la tollerabilità verranno valutate in base a criteri standard (segni vitali, ECG, eventi avversi, parametri di laboratorio di routine e l'immunogenicità (impurità anti-host (HRI) e anticorpi anti C1INH)

E.5.1.1

Timepoint(s) of evaluation of this end point

AEs will be recorded throughout the study. For safety evaluation, prior to and at Day 28 after study medication administration, a blood sample will be drawn for routine laboratory parameters. In addition to monitoring of vital signs (prior to and 30 min, 1, 2 and 4 hours after study medication administration), an ECG will be recorded prior to and between 30 minutes and 2 hours after study medication administration.

Gli eventi avversi saranno registrati per tutta la durata dello studio Per la valutazione di sicurezza verrà prelevato un campione di sangue per i parametri di laboratorio di routine prima della somministrazione del farmaco e al giorno 28 °. Oltre al monitoraggio dei segni vitali (pre-dose, 30 min, 1, 2 e 4 ore dopo la somministrazione di farmaco in studio), verrà eseguito un ECG prima e tra i 30 minuti e le 2 ore dalla somministrazione del farmaco in studio.

E.5.2

Secondary end point(s)

To assess the pharmacokinetics (PK) and pharmacodynamics (PD) of Ruconest in the treatment of acute angioedema attacks in 2-13 year old HAE patients. To assess the efficacy of Ruconest in the treatment of acute angioedema attacks in 2-13 year old HAE patients.

• Valutare la farmacocinetica (PK) e la farmacodinamica (PD) del Ruconest usato per il trattamento di attacchi acuti di angioedema in pazienti dai 2 ai 13 anni affetti da HAE. • Valutare l’efficacia del Ruconest usato per il trattamento di attacchi acuti di angioedema in pazienti dai 2 ai 13 anni affetti da HAE.

E.5.2.1

Timepoint(s) of evaluation of this end point

For PK/PD evaluation, blood samples will be collected prior to the first treated attack, and at 5 minutes and between 2 and 4 hours following the first study medication administration. For Efficacy evaluation: The evolution of the acute angioedema attack will be monitored by the administration of patient questionnaires (Visual Analog Scale (VAS) and Treatment Effect Questionnaire (TEQ)) at 30 min, 1, 2, 4, 8, and 24 hours, and the Investigator Score (IS) at 30 min, 1, 2 and 4 hours post study medication administration.

Per la valutazione della PK / PD, verranno raccolti i campioni di sangue prima del primo attacco trattato, a 5 minuti e tra le 2 e le 4 ore dopo la prima somministrazione del farmaco di studio Per la valutazione dell'efficacia: L'evoluzione dell’attacco acuto di angioedema verrà monitorata attraverso la somministrazione ai pazienti di questionari (Visual Analog Scale (VAS) e Questionario sull’effetto del Trattamento (TEQ)) a 30 min, 1, 2, 4, 8, e 24 ore, e dal Punteggio dello sperimentatore (IS) a 30 min, 1, 2 e 4 ore dopo la somministrazione farmaco in studio.

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

Yes

E.6.7

Pharmacodynamic

Yes

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

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)

Information not present in EudraCT

E.8.2.2

Placebo

Information not present in EudraCT

E.8.2.3

Other

Information not present in EudraCT

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

Israel

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)

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:

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

patients 2 up to and including 13 years of age

Pazienti da 2 a 13 anni

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)

according to normal clinical practice

In accordo alla normale pratica clinica

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

2011-12-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-09

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

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