Clinical Trials Register

Summary
EudraCT Number:	2015-003943-20
Sponsor's Protocol Code Number:	DX-2930-03
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:	2018-04-20
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

2015-003943-20

A.3

Full title of the trial

HELP Study™: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Efficacy and Safety Study to Evaluate DX 2930 For Long-Term Prophylaxis Against Acute Attacks of Hereditary Angioedema (HAE)

HELP StudyTM: Studio di efficacia e sicurezza multicentrico, randomizzato, in doppio cieco, controllato verso placebo, per la valutazione di DX 2930 nella profilassi a lungo termine contro gli attacchi acuti di angioedema ereditario (AEE)

A.3.1

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

Efficacy and safety study to evaluate DX-2930 in preventing agioedema attacks in patients with Type I and Type II heriditary angioedema (HAE)

Studio di efficacia e sicurezza per la valutazione di DX-2930 nella profilassi degli attacchi acuti di angioedema ereditario in pazienti affetti da AEE di tipo I e II.

A.3.2

Name or abbreviated title of the trial where available

DX-2930-03

A.4.1

Sponsor's protocol code number

DX-2930-03

A.5.4

Other Identifiers

Name:

IND

Number:

116647

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	DYAX CORP.
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	Dyax Corp.
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	Voisin Consulting
B.5.2	Functional name of contact point	Clinical Trial Operations
B.5.3	Address:
B.5.3.1	Street Address	3 rue des Longs Prés
B.5.3.2	Town/ city	Boulogne-Billancourt
B.5.3.3	Post code	92100
B.5.3.4	Country	France
B.5.4	Telephone number	+ 33 1 41 31 83 00
B.5.5	Fax number	+33 1 46 20 53 38
B.5.6	E-mail	clinicaltrialinformation@voisinconsulting.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/15/1551
D.3 Description of the IMP
D.3.1	Product name	DX-2930
D.3.2	Product code	DX-2930
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.3.9.1	CAS number	1426055-14-2
D.3.9.2	Current sponsor code	DX-2930
D.3.9.4	EV Substance Code	SUB130835
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	100
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	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
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

Hereditary angioedema (HAE)

Angioedema ereditario (AAE)

E.1.1.1

Medical condition in easily understood language

Long-term, debilitating and life-threatening disease that manifests clinically as unpredictable, intermittent attacks of edema of the face, larynx, gastrointestinal tract, limbs and/or genitalia

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10075280
E.1.2	Term	Hereditary angioedema attack
E.1.2	System Organ Class	100000004850

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 evaluate the efficacy of DX-2930 in preventing HAE attacks

Valutare l'efficacia di DX-2930 nella prevenzione degli attacchi di AEE

E.2.2

Secondary objectives of the trial

To evaluate the safety of repeated subcutaneous administrations of DX-2930

Valutare la sicurezza di somministrazioni sottocutanee ripetute di DX-2930

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Males and females 12 years of age or older at the time of screening
2. Documented diagnosis of HAE (Type I or II) based upon all of the following :
- Documented clinical history consistent with HAE (subcutaneous or mucosal nonpruritic swelling episodes without accompanying urticaria)
- Diagnostic testing results obtained during screening (or a prior DX-2930 study) that confirm HAE Type I or II :
C1 inhibitor (C1-INH) functional level < 40% of the normal level.
Subjects with functional C1-INH level 40-50% of the normal level may be enrolled if they also have a C4 level below the normal range.
Subjects may begin participating in the run-in period before these diagnostic results are available.
Subjects may be retested if results are incongruent with clinical history or believed by the Investigator to be confounded by recent LTP use.
- At least one of the following : age at reported onset of first angioedema symptoms ≤ 30 years, a family history consistent with HAE Type I or II, or C1q within normal range.
3. Experiencing a baseline rate of at least 1 Investigator-confirmed HAE attack per 4 weeks as confirmed during the run-in period.
4. Adult subjects and caregivers of subjects under the age of 18 are willing and able to read, understand, and sign an informed consent form. Subjects age to 12 to 17, whose caregiver provides informed consent, are willing and able to read, understand and sign an assent form.
5. Males and females who are fertile and sexually active must adhere to contraception requirements for the duration of the study as follows:
- Females of childbearing potential must agree to be abstinent or else use any two of the following medically acceptable forms of contraception from screening through 30 days after the final study visit : progestin-only oral contraceptive, condom with or without spermicidal jelly, diaphragm or cevical cap with spermicidal jelly, or intra-uterine device (IUD, all types). A female whose male partner has had a vasectomy must agree to use one additionnal form of medically acceptable contraception.
- Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months do not require contraception during the study.
- Males, including males who are surgically sterile (post vasectomy), with female partners of childbearing potential must agree to be abstinent or else use a medically acceptable form of contraception from screening through 60 days after the final study visit.

1. Soggetti di entrambi i sessi di età pari o superiore ai 12 anni.
2. Diagnosi documentata di AEE (tipo I o II), basata su tutti i seguenti fattori:
- anamnesi clinica documentata coerente con AEE (episodi di gonfiore non pruriginoso, sottocutaneo o mucosale, con assenza di orticaria concomitante);
- risultati dei test diagnostici acquisiti durante lo screening (o un precedente studio DX-2930) che confermano la presenza di AEE di tipo I o II: livello funzionale dell’inibitore della C1 esterasi (C1 INH) < 40% del livello normale. I soggetti con livello funzionale di C1 INH pari al 40 50% del livello normale possono essere arruolati se presentano anche un livello C4 inferiore ai limiti della norma. I soggetti possono iniziare la partecipazione al periodo di run in prima che questi risultati diagnostici siano disponibili. I test possono essere ripetuti nei soggetti se i risultati sono incoerenti con l’anamnesi clinica o se lo Sperimentatore ritiene che sia presente un certo grado di confondimento dovuto all’uso recente della LTP;
- almeno uno dei seguenti fattori: età ≤ 30 anni al momento della segnalazione dell’esordio dei primi sintomi di angioedema, anamnesi familiare coerente con AEE di tipo I o II o C1q entro i limiti della norma.
3. Soggetti che presentano un tasso basale di almeno un attacco di AEE confermato dallo Sperimentatore in 4 settimane, come attestato durante il periodo di run in.
4. Soggetti adulti e caregiver dei soggetti di età inferiore a 18 anni disposti e in grado di leggere, comprendere e firmare una dichiarazione di consenso informato. Soggetti di età compresa tra 12 e 17 anni, i cui caregiver accordano il consenso informato, disposti e in grado di firmare una dichiarazione di consenso informato.
5. I soggetti maschi e femmine fertili e sessualmente attivi devono rispettare i requisiti di contraccezione per l’intera durata dello studio come indicato di seguito:
- le donne in età fertile devono accettare di astenersi dai rapporti sessuali, oppure di far uso di due dei seguenti metodi anticoncezionali, accettabili sotto il profilo medico, a partire dallo screening fino a 30 giorni dopo la visita finale dello studio: contraccettivo orale a base di solo progestinico, profilattico con o senza gel spermicida, diaframma o cappuccio cervicale con gel spermicida o dispositivo intrauterino (IUD di qualsiasi tipo); una donna il cui partner è stato sottoposto a vasectomia deve accettare di far uso di un metodo contraccettivo addizionale, accettabile sotto il profilo medico;
- le donne non potenzialmente fertili, definite come chirurgicamente sterili (status post-isterectomia, ooforectomia bilaterale o legatura tubarica bilaterale) o in postmenopausa da almeno 12 mesi non necessitano di contraccezione durante lo studio;
- gli uomini, compresi i soggetti chirurgicamente sterili (vasectomizzati) con partner femmine potenzialmente fertili, devono accettare di astenersi dai rapporti sessuali, oppure di far uso di un metodo anticoncezionale, accettabile sotto il profilo medico, a partire dallo screening fino a 60 giorni dopo la visita finale.

E.4

Principal exclusion criteria

1. Concomitant diagnosis of another form of chronic, recurrent angioedema, such as acquired angioedema (AAE), HAE with normal C1-INH (also known as HAE Type III), idiopathic angioedema, or recurrent angioedema associated with urticaria.
2. Dosing with an investigational drug or exposure to an investigational device within 4 weeks prior to screening.
3. Exposure to angiotensin-converting enzyme (ACE) inhibitors or any estrogen-containing medications with systemic absorption (such as oral contraceptives or hormonal replacement therapy) within 4 weeks prior to screening.
4. Exposure to androgens (e.g. stanozolol, danazol, oxandrolone, methyltestosterone, testosterone) within 2 weeks prior to entering the run-in period.
5. Use of long-term prophylaxis for HAE (C1-INH, attenuated androgens, anti-fibrinolytics) within 2 weeks prior to entering the run-in period.
6. Use of short-term prophylaxis for HAE within 7 days prior to entering the run-in period. Short-term prophylaxis is defined as C1-INH, attenuated androgens, or anti-fibrinolytics used to avoid angioedema complications from medically indicated procedures.
7. Any of the following liver function test abnormalities : alanine aminotransferase (ALT) > 3x upper limit of normal, or aspartate aminotransferase (AST) >3x upper limit of normal, or total bilirubin > 2x upper limit of normal (unless the bilirubin elevation is a result of Gilbert's Syndrome).
8. Pregnancy or breastfeeding.
9. Subject has any condition that, in the opinion of the Investigator or Sponsor, may compromise their safety or compliance, preclude successful conduct of the study, or interfere with interpretation of the results (e.g. history of substance abuse or dependence, significant pre-existing illness or other major comorbidity that the Investigator considers may confound the interpretation of study results).

1. Diagnosi concomitante di un’altra forma di angioedema cronico, recidivante, come angioedema acquisito (AEA), AEE con C1 INH normale (chiamato anche AEE di tipo III), angioedema idiopatico o angioedema recidivante associato a orticaria.
2. Somministrazione di un farmaco sperimentale o esposizione a un dispositivo sperimentale nelle 4 settimane precedenti allo screening.
3. Esposizione agli inibitori dell’enzima di conversione dell’angiotensina (ACE) o a qualsiasi medicinale contenente estrogeni con assorbimento sistemico (come contraccettivi orali o terapia ormonale sostitutiva) nelle 4 settimane precedenti allo screening.
4. Esposizione ad androgeni (ad es. stanozololo, danazolo, oxandrolone, metiltestosterone, testosterone) nelle 2 settimane precedenti all’ammissione nel periodo di run in.
5. Uso di terapia profilattica a lungo termine contro l’AEE (C1 INH, androgeni attenuati o antifibrinolitici) nelle 2 settimane precedenti all’ammissione nel periodo di run in.
6. Uso di profilassi a breve termine contro l’AEE nei 7 giorni precedenti all’ammissione nel periodo di run in. Per profilassi a breve termine si intendono C1 INH, androgeni attenuati o antifibrinolitici utilizzati per evitare le complicanze dell’angioedema provocate dalle procedure clinicamente indicate.
7. Uno qualsiasi dei seguenti risultati anomali dei test di funzionalità epatica: alanina aminotransferasi (ALT) > 3 volte il limite superiore della norma, o aspartato aminotransferasi (AST) > 3 volte il limite superiore della norma, o bilirubina totale > 2 volte il limite superiore della norma (a meno che l’innalzamento dei valori di bilirubina sia una conseguenza della sindrome di Gilbert).
8. Gravidanza o allattamento.
9. Soggetti che presentano una qualsiasi patologia che, a giudizio dello Sperimentatore o del Promotore, possa compromettere la loro sicurezza o compliance, precludere il successo nell’esecuzione dello studio o interferire con l’interpretazione dei risultati (ad es. anamnesi di abuso o dipendenza da sostanze, importante malattia preesistente o altra comorbilità maggiore che lo Sperimentatore ritiene possa essere un fattore confondente nell’interpretazione dei risultati dello studio).

E.5 End points

E.5.1

Primary end point(s)

Number of HAE attacks per week

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 14 (Visit 2) to Day 182 (Visit 14)

E.5.2

Secondary end point(s)

1. Time to first attack, i.e. duration that a subject is attack-free until their first attack
2. Number per week of HAE attacks requiring acute attack therapy use
3. Number per week of moderate or severe HAE attacks
4. Number per week of high-morbidity HAE attacks; a high-morbidity HAE attack is defined as any attack that has at least one of the following characteristics: severe, results in hospitalization (except hospitalization for observation < 24 hours), hemodynamically significant (systolic blood pressure < 90, requires IV hydratation, or associated with syncope or near-syncope) or laryngeal.

1. Tempo al primo attacco, ossia per quanto tempo il soggetto non accusa attacchi fino al primo attacco.
2. Numero di attacchi di AEE per settimana che necessitano l’utilizzo di terapia per l’ attacco acuto.
3. Numero di attacchi di AEE da moderati a severi alla settimana.
4. Numero di attacchi di AEE ad alta morbilità alla settimana. Per attacco di AEE ad alta morbilità si intende qualsiasi attacco che presenta almeno una delle seguenti caratteristiche: severo, necessitante di ricovero in ospedale (con l’eccezione dei ricoveri per osservazione < 24 ore), emodinamicamente importante (pressione sistolica < 90, che necessita di idratazione e.v. o associato a sincope o presincope) o laringeo.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 14 (Visit 2) to Day 182 (Visit 14)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

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

Yes

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

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

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

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

Canada

Germany

Italy

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:

103

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

120

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)

Subjects who complete the treatment period will be offered the option of enrolling in the DX-2930-04 Open Label Extension (OLE) study for continued treatment and safety follow-up. Subjects who do not roll over to the OLE study will be followed for an additional 8 weeks (visits 15 and 16).

Ai soggetti che hanno completato il periodo di trattamento verrà offerta la possibilità di arruolarsi nello studio di estensione in aperto DX-2930-04 (OLE) per la continuazione del trattamento e le valutazioni di sicurezza durante il follow-up. I soggetti che non proseguiranno nello studio OLE saranno seguiti per ulteriori 8 settimane (visite 15 e 16).

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

2016-01-14

Ethics Committee Opinion of the trial application

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-04-13

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