Clinical Trials Register

Summary
EudraCT Number:	2020-000761-16
Sponsor's Protocol Code Number:	ALXN1210-TMA-314
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:	2021-05-24
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

2020-000761-16

A.3

Full title of the trial

A Phase 3, Open-label, Single Arm, Multicenter Study of Ravulizumab in Addition to Best Supportive Care in Pediatric Participants (from 1 month to < 18 years of age) with Thrombotic Microangiopathy (TMA) after Hematopoietic Stem Cell Transplantation (HSCT)

Studio multicentrico di fase 3, in aperto, a braccio singolo, per valutare ravulizumab in aggiunta alla migliore terapia di supporto in partecipanti pediatrici (da 1 mese a <18 anni di età) con microangiopatia trombotica (MAT) dopo trapianto di cellule staminali ematopoietiche (HSCT)

A.3.1

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

Study of ravulizumab in pediatric participants with HSCT-TMA

Studio di ravulizumab in partecipanti pediatrici con HSCT-MAT

A.3.2

Name or abbreviated title of the trial where available

Ravulizumab in Pediatric Participants with TMA after HSCT

Ravulizumab in partecipanti pediatrici con MAT dopo HSCT

A.4.1

Sponsor's protocol code number

ALXN1210-TMA-314

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	103-105 Rue Anatole France
B.5.3.2	Town/ city	Levallois-Perret
B.5.3.3	Post code	92300
B.5.3.4	Country	France
B.5.4	Telephone number	+33147100615
B.5.5	Fax number	+33147100611
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.2.5	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	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.3.8	INN - Proposed INN	RAVULIZUMAB
D.3.9.1	CAS number	1803171-55-2
D.3.9.2	Current sponsor code	ALXN1210
D.3.9.4	EV Substance Code	SUB192773
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

hematopoietic stem cell transplant-associated thrombotic microangiopathy

microangiopatia trombotica da trapianto di cellule staminali emopoietiche

E.1.1.1

Medical condition in easily understood language

HSCT-TMA

HSCT-MAT

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10043645
E.1.2	Term	Thrombotic microangiopathy
E.1.2	System Organ Class	10005329 - Blood and lymphatic system 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 efficacy of ravulizumab plus BSC in the treatment of HSCTTMA

Valutare l’efficacia di ravulizumab più MTS nel trattamento dell’HSCT-MAT

E.2.2

Secondary objectives of the trial

Safety and tolerability of ALXN1210 and additional efficacy measures

Sicurezza e tollerabilità di ALXN1210 e misure di efficacia aggiuntive

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. 1 month of age up to < 18 years of age at the time of signing the informed consent
2. Participants who received HSCT within the past 6 months at the time of Screening
3. A TMA diagnosis, based on all of the following criteria occurring simultaneously:
• De novo thrombocytopenia or platelet transfusion refractoriness, where:
• De novo anemia or increase in transfusion requirements
• Either one of the following markers of hemolysis:
-Lactate dehydrogenase > 1.5 × ULN or,
- Presence of schistocytes = 2 high power field (HPF)
• Proteinuria on spot urinalysis
• Presence of hypertension
4. Participants must have HSCT-TMA that persists for at least 72 hours after initial management of
any triggering agent/condition
5.Body weight = 5 kg at Screening
6. Male or female Contraceptive use by men or women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical studies
7. Vaccinated against meningococcal infections if clinically feasible, according to institutional
guidelines for immune reconstitution after HSCT. Participants must be re-vaccinated against
Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae if clinically feasible,
according to institutional guidelines for immune reconstitution after HSCT. All participants should
be administered coverage with prophylactic antibiotics according to institutional posttransplant
infection prophylaxis guidances including coverage against N. meningiditis for at least 2 weeks
after meningococcal vaccination. Participants who cannot receive meningococcal vaccine should
receive antibiotic prophylaxis coverage against N. meningiditis the entire Treatment Period and for
8 months following the final dose of ravulizumab.
8. Participants or their legally authorized representative must be capable of giving signed informed
consent which includes compliance with the requirements and restrictions listed in the informed
consent or assent form and in this protocol

1. Da 1 mese fino a <18 anni di età al momento della firma del consenso informato
2. Partecipanti che si sono sottoposti a un HSCT negli ultimi 6 mesi al momento dello screening
3. Diagnosi di MAT in base al soddisfacimento di tutti i seguenti criteri contemporaneamente:
• Trombocitopenia de novo o refrattarietà alla trasfusione di piastrine dove:
• Anemia de novo o aumento della necessità di trasfusioni
• Uno dei seguenti marcatori di emolisi:
- lattato deidrogenasi >1,5 × ULN o,
- presenza di schistociti =2 per campo ad alto ingrandimento (HPF)
• Proteinuria rilevata all’analisi di un campione estemporaneo di urine
• Presenza di ipertensione
4. I partecipanti devono presentare HSCT-MAT che persiste da almeno 72 ore dopo la gestione
iniziale di qualsiasi agente/condizione scatenante
5. Peso corporeo =5 kg allo screening
6. L’uso di contraccettivi maschili o femminili da parte di uomini o donne deve essere coerente con
le normative locali riguardanti i metodi contraccettivi per coloro che partecipano a studi clinici
7. Vaccinati contro infezioni da meningococco se clinicamente fattibile, secondo le linee guida
istituzionali per la ricostituzione immunitaria dopo HSCT. I partecipanti devono essere ri-vaccinati
contro Haemophilus influenzae di tipo b (Hib) e Streptococcus pneumoniae se clinicamente
fattibile, secondo le linee guida istituzionali per la ricostituzione immunitaria dopo HSCT. A tutti i
partecipanti deve essere somministrata una copertura con antibiotici profilattici secondo le linee
guida istituzionali per la profilassi delle infezioni post-trapianto, compresa la copertura contro la N.
meningiditis per almeno 2 settimane dopo la vaccinazione anti-meningococco.
I partecipanti che non possono ricevere un vaccino anti-meningococco devono ricevere una
copertura profilattica antibiotica contro N. meningiditis per l’intera durata del periodo di trattamento
e per 8 mesi dopo la dose finale di ravulizumab.
8. I partecipanti o il loro rappresentante legalmente autorizzato devono essere in grado di fornire il
consenso informato firmato, che include la conformità con i requisiti e le restrizioni elencati nel
modulo di consenso informato o assenso e in questo protocollo

E.4

Principal exclusion criteria

1. Known familial or acquired 'a disintegrin and metalloproteinase with a thrombospondin type 1
motif, member 13' (ADAMTS13) deficiency (activity < 5%)
2. Known Shiga toxin-related hemolytic uremic syndrome (ST-HUS)
3. Positive direct Coombs test
4. Diagnosis or suspicion of disseminated intravascular coagulation (DIC)
5. Known bone marrow/graft failure
6. Diagnosis of veno-occlusive disease (VOD)
7. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titer,
8. Unresolved meningococcal disease
9. Presence or suspicion of sepsis (treated or untreated) within 7 days prior to Screening
10. Pregnancy or breastfeeding
11. Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab
12. Previously or currently treated with a complement inhibitor

1. Deficit noto, congenito o acquisito, di ADAMTS13 (13° membro della famiglia di disintegrina e
metalloproteinasi con motivo di tipo 1 della trombospondina) (attività <5%)
2. Sindrome emolitico uremica correlata alla tossina Shiga (ST-HUS) nota
3. Test di Coombs diretto positivo
4. Diagnosi o sospetto di coagulazione intravascolare disseminata (CID)
5. Fallimento di trapianto di midollo osseo noto
6. Diagnosi di malattia veno-occlusiva (VOD)
7. Infezione da virus dell’immunodeficienza umana (HIV) (come evidenziato dal titolo anticorpale
anti-HIV-1 o anti-HIV-2,
8. Malattia meningococcica non risolta
9. Presenza o sospetto di sepsi (trattata o non trattata) nei 7 giorni precedenti lo screening
10. Gravidanza o allattamento
11. Ipersensibilità a proteine murine o a 1 degli eccipienti di ravulizumab
12. Trattamento attuale o precedente con un inibitore del complemento

E.5 End points

E.5.1

Primary end point(s)

TMA response

Risposta della MAT

E.5.1.1

Timepoint(s) of evaluation of this end point

Throughout 26 Weeks

Nel corso di 26 settimane

E.5.2

Secondary end point(s)

1. Time to TMA response
2. Change from baseline in TMA-associated organ dysfunctiond in renal system,
cardiovascular system, pulmonary system, CNS, and GI system at 6 months and 1 year
3. TMA relapse during the study
4. Overall survival at 6 months and 1 year
5. Non-relapse mortality (
6. Platelet response
7. Hematologic response

1. Tempo alla risposta della MAT
2. Variazione dal basale nella disfunzione d’organo associata alla MAT nel sistema renale,
cardiovascolare, polmonare, SNC e GI a 6 mesi e a 1 anno
3. Recidiva della MAT durante lo studio
4. Sopravvivenza complessiva a 6 mesi e a 1 anno
5. Mortalità non correlata alla recidiva
6. Risposta piastrinica
7. Risposta ematologica

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 26 and Week 52

Settimana 26 e Settimana 52

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

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity, biomarker, characterization

Immunogenicità, caratterizzazione dei biomarcatori

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

E.8.1.1

Randomised

E.8.1.2

Open

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

Yes

E.8.1.7.1

Other trial design description

In aperto

Open-label

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

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

Canada

Japan

Korea, Republic of

United States

France

Germany

Italy

Spain

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

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.1.1.1

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

pediatric participants

partecipanti pediatrici

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)

Participants will not receive any additional treatment with ravulizumab as part of the protocol after completion of the study or withdrawal from the study. Upon completion of a participant's last study visit (ie, EoS or ED Visit), the participant will return to the care of their treating physician

I partecipanti non riceveranno alcun trattamento aggiuntivo con ravulizumab nell’ambito del protocollo dopo il completamento dello studio o il ritiro dallo studio. Al completamento dell’ultima visita dello studio di un partecipante (ossia, visita EoS o ED), quest’ultimo riprenderà le cure del proprio medico curante

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

2021-01-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-12-16

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

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