Clinical Trials Register

Summary
EudraCT Number:	2017-002370-39
Sponsor's Protocol Code Number:	ALXN1210-PNH-303
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-01-18
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

2017-002370-39

A.3

Full title of the trial

A Phase 3, Randomized, Parallel-Group, Multicenter, Open-Label, Pharmacokinetic, Noninferiority Study of Ravulizumab Administered Subcutaneously Versus Intravenously in Adult Patients With Paroxysmal Nocturnal Hemoglobinuria Currently Treated With Eculizumab.

Studio di fase 3, randomizzato, a gruppi paralleli, multicentrico, di farmacocinetica in aperto, di non inferiorità su ravulizumab somministrato per via sottocutanea comparato alla somministrazione per via endovenosa in pazienti adulti con emoglobinuria parossistica notturna trattati con eculizumab.

A.3.1

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

This study compares the pharmacokinetics (PK) of ravulizumab subcutaneous (SC) administered via an on-body delivery system (OBDS) to ravulizumab intravenous (IV) in patients with paroxysmal nocturnal hemoglobinuria (PNH) currently treated With Eculizumab.

Questo studio confronta la farmacocinetica (PK) di ravulizumab sottocutaneo (SC) somministrato tramite un sistema di rilascio nel corpo (OBDS) con quella di ravulizumab somministrato per via endovenosa (IV) n pazienti con emoglobinuria parossistica notturna (PNH) attualmente in trattamento con eculizumab.

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

ALXN1210-PNH-303

A.5.4

Other Identifiers

Name:

IND

Number:

128367

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	ALEXION PHARMACEUTICALS INCORPORATED
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	Alexion Pharmaceuticals, 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	Alexion Europe SAS
B.5.2	Functional name of contact point	European Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	1-15 Avenue Edouard Belin
B.5.3.2	Town/ city	Rueil-Malmaison
B.5.3.3	Post code	92500
B.5.3.4	Country	France
B.5.4	Telephone number	0033147100615
B.5.5	Fax number	0033147100611
B.5.6	E-mail	clinicaltrials.eu@alexion.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.2.1.1.1	Trade name	NA
D.2.1.1.2	Name of the Marketing Authorisation holder	NA
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/3/16/1661
D.3 Description of the IMP
D.3.1	Product name	Ravulizumab
D.3.2	Product code	[ALXN1210]
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.3.9.2	Current sponsor code	ALXN1210
D.3.9.3	Other descriptive name	Ravulizumab
D.3.9.4	EV Substance Code	SUB172162
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	70
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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.2.1.1.1	Trade name	NA
D.2.1.1.2	Name of the Marketing Authorisation holder	NA
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/3/16/1661
D.3 Description of the IMP
D.3.1	Product name	Ravulizumab
D.3.2	Product code	[ALXN1210]
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
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	ALXN1210
D.3.9.3	Other descriptive name	Ravulizumab
D.3.9.4	EV Substance Code	SUB172162
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	10
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Paroxysmal Nocturnal Hemoglobinuria

Emoglobinuria parossistica notturna

E.1.1.1

Medical condition in easily understood language

Paroxysmal Nocturnal Hemoglobinuria

Emoglobinuria parossistica notturna

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10055629
E.1.2	Term	Paroxysmal nocturnal hemoglobinuria
E.1.2	System Organ Class	100000004857

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 PK noninferiority of ravulizumab SC versus ravulizumab IV in adult patients with PNH.

Valutare la non inferiorità della farmacocinetica di ravulizumab sc contro ravulizumab IV in pazienti adulti con PNH.

E.2.2

Secondary objectives of the trial

- To characterize PK of ravulizumab SC
- To characterize PD of ravulizumab SC
- To characterize immunogenicity of ravulizumab SC
- To evaluate HRQoL and treatment satisfaction on ravulizumab SC
- To evaluate safety of ravulizumab SC and ravulizumab OBDS
- To evaluate efficacy of ravulizumab SC
- To assess performance of ravulizumab OBDS

- Caratterizzare la farmacocinetica di ravulizumab SC
- Caratterizzare la farmacodinamica di ravulizumab SC
- Caratterizzare l'immunogenicità di ravulizumab SC
- Valutare HRQoL e la soddisfazione al trattamento con ravulizumab SC
- Valutare la sicurezza di ravulizumab SC e di ravulizumab OBDS
- Valutare l'efficacia di ravulizumab SC
- Valutare la performance di ravulizumab OBDS

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Age
1. Patients must be at least 18 years of age at the time of signing the
informed consent.

Patient and Disease Characteristics
2. Treated with eculizumab according to the labeled dosing
recommendation for PNH (900 mg every 14 days ± 2 days) for at least 6
months prior to study entry with no missed doses within 2 months prior
to study entry and no more than 2 doses outside of the visit window.
3. Lactate dehydrogenase levels = 1.5 × ULN (upper limit of normal),
according to central laboratory, at Screening. Sample must be obtained
within 24 hours of or immediately prior to a scheduled eculizumab dose
administration (ie, at trough eculizumab level).
4. Documented diagnosis of PNH confirmed by high-sensitivity flow
cytometry evaluation (Borowitz, Craig et al. 2010).
5. Vaccinated against meningococcal infections within 3 years prior to,
or at the time of, initiating study drug to reduce the risk of
meningococcal infection (N meningitidis).

Età
1. I pazienti devono avere minimo 18 anni al momento della firma del consenso informato.

Pazienti e caratteristiche della malattia
2. Trattati con eculizumab secondo il dosaggio previsto sull'etichetta per pazienti con PNH (900 mg ogni 14 giorni ± 2 giorni) per almeno 6 mesi prima dell'entrata nello studio e che non abbiano saltato alcuna dose entro i 2 mesi prima dell'inizio dello studio e che non abbiano ricevuto più di 2 dosial di fuori della finiestra delle visite.
3. Livelli di lattatodeidrogenasi = 1.5 × ULN (upper limit of normal), secondo il laboratorio centrale, allo screening. I campioni devono essere ottenuti entro 24 ore oppure immediatamente prima di un trattamento programmato con eculizumab (i.e. con il livello pià basso di eculizumab)
4. Diagnosi documentata di PNH confermata da citometria a flusso ad alta sensibilità (Borowitz, Craig et al. 2010).
5. Vaccinati contro infezione meningococcica entro 3 anni dall'inizio dello studio, oppure all'inizio dello studio, per ridurre il rischio di infezione meningococcica (N meningitidis).

E.4

Principal exclusion criteria

Medical Conditions
1. More than 1 LDH value > 2 × ULN within the 6 months prior to study
entry.
2. Major adverse vascular event (MAVE) in the 6 months prior to study
entry.
3. Platelet count < 30,000/mm3 (30 × 109/L) at Screening.
4. Absolute neutrophil count < 500/µL (0.5 × 109/L) at Screening.
5. History of bone marrow transplantation.
6. History of N meningitidis infection.

Condizione medica
1. Più di 1 valore di LDH > 2 × ULN entro 6 mesi dall'ingresso nello studio.
2. Evento vascolare avverso importante (MAVE) entro 6 mesi priam dell'ingresso nello studio.
3. Conta delle piastrine < 30,000/mm3 (30 × 109/L) allo screening
4. Conta assoluta dei neutrofili < 500/µL (0.5 × 109/L) allo screening
5. Anamnesi di trapianto di midollo
6. Anamnesi di infezione da N meningitidis

E.5 End points

E.5.1

Primary end point(s)

Day 71 serum ravulizumab Ctrough

Cthrough di ravulizumab nel siero al giorno 71

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 71

Giorno 71

E.5.2

Secondary end point(s)

- PK Endpoint: Ctrough over time
- PD Endpoint: Free serum C5 concentrations over time
- Immunogenicity
- HRQoL and Treatment Satisfaction Endpoints
- Safety Endpoints
- Efficacy Endpoints

- Cthrough e PK nel tempo
- PD: concentrazione diC5 nel siero nel tempo
- Immunogenicità
- HRQoL e soddisfazione al trattamento
- Sicurezza
- Efficacia

E.5.2.1

Timepoint(s) of evaluation of this end point

Throughout the study

Durante lo 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)

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

I pazienti nel gruppo ravulizimab IV passeranno a ravulizumab SC 490 mg durante il periodo di estens

Patients in the ravulizumab IV group will switch to 490 mg of ravulizumab SC in the extension period

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

Stesso farmaco, forma farmaceutica differente.

Same drug, different pharmaceutical form.

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

Brazil

Canada

Korea, Republic of

Russian Federation

Turkey

United States

Austria

Belgium

Czechia

Finland

France

Germany

Italy

Netherlands

Spain

Sweden

United Kingdom

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

The end of the study is defined as the date of the last patient visit or safety follow up, whichever occurs later.

La fine dello studio è definita come la data dell'ultima visita dell'ultimo paziente oppure del follow-up di sicurezza, a seconda di quale evento occorra prima.

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.1.1.1

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:

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

F.4.2.2

In the whole clinical trial

105

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)

Upon completion of the last study visit, patients will return to the care of their treating physician.

Dopo il completamento dell'ultima visita dello studio, i pazienti torneranno in cura presso i rispettivi medici.

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

2019-02-21

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-18

P. End of Trial
P.	End of Trial Status	Ongoing

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