Clinical Trials Register

Summary
EudraCT Number:	2019-000208-13
Sponsor's Protocol Code Number:	ACE-536-B-THAL-004
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Restarted
Date on which this record was first entered in the EudraCT database:	2020-10-07
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

2019-000208-13

A.3

Full title of the trial

A phase 2a study to evaluate the safety and pharmacokinetics of Luspatercept (ACE-536) in paediatric subjects who require regular red blood cell transfusions due to beta thalassemia

Studio di fase 2A per valutare la sicurezza e la farmacocinetica di Luspatercept (ACE-536) in soggetti pediatrici che richiedono regolari trasfusioni di globuli rossi a causa della beta (ß) talassemia.

A.3.1

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

A phase 2a study to evaluate the safety and pharmacokinetics of Luspatercept (ACE-536) in paediatric subjects who required regular red blood cell transfusions due to beta thalassemia

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

ACE-536-B-THAL-004

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/130/2019

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	CELGENE CORPORATION
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	Celgene corporation
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	PPD
B.5.2	Functional name of contact point	PPD Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Rua Leopoldo, Couto de Magalhaes jr, 758 6°
B.5.3.2	Town/ city	Sao Paulo
B.5.3.3	Post code	04542-000
B.5.3.4	Country	Brazil
B.5.4	Telephone number	00551145044700
B.5.5	Fax number	00551145044000
B.5.6	E-mail	Claudia.Mazara@ppdi.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/3/14/1300
D.3 Description of the IMP
D.3.1	Product name	Luspatercept
D.3.2	Product code	[ACE-536]
D.3.4	Pharmaceutical form	Lyophilisate for 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.3.8	INN - Proposed INN	LUSPATERCEPT
D.3.9.1	CAS number	1373715-00-4
D.3.9.2	Current sponsor code	ACE-536
D.3.9.3	Other descriptive name	Luspatercept
D.3.9.4	EV Substance Code	SUB189400
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	87
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.IMP: 2
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/3/14/1300
D.3 Description of the IMP
D.3.1	Product name	Luspatercept
D.3.2	Product code	[ACE-536]
D.3.4	Pharmaceutical form	Lyophilisate for 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.3.8	INN - Proposed INN	LUSPATERCEPT
D.3.9.1	CAS number	1373715-00-4
D.3.9.2	Current sponsor code	ACE-536
D.3.9.3	Other descriptive name	Luspatercept
D.3.9.4	EV Substance Code	SUB189400
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	37
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

Beta-Thalassemia

Beta-Talassemia

E.1.1.1

Medical condition in easily understood language

Beta thalassemia is a blood disorder that reduces the production of hemoglobin (iron-containing protein in red blood cells that carries oxygen to cells throughout the body).

Beta thalassemia è na malattia del sangue che riduce la produzione di emoglobina (proteina contenente ferro nei globuli rossi che trasporta ossigeno alle cellule attraverso il corpo)

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	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10054660
E.1.2	Term	Thalassemia beta
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10054660
E.1.2	Term	Thalassemia beta
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

The primary objective of the study is:
- To determine the recommended dose (RD) of luspatercept that is safe and tolerable in pediatric subjects with transfusion-dependent (TD) ß-thalassemia
- To examine the pharmacokinetic (PK) profile of luspatercept in pediatric subjects with TD ß-thalassemia

Obiettivi primari:
- Determinare la dose raccomandata (recommended dose, RD) di luspatercept che sia sicura e tollerabile in soggetti pediatrici affetti da ß-talassemia trasfusione dipendente (TD)
- Esaminare il profilo di farmacocinetica (PK) di luspatercept in soggetti pediatrici affetti da ß-talassemia TD

E.2.2

Secondary objectives of the trial

The secondary objectives are to evaluate:
- The mean change in red blood cell (RBC) transfusion burden
- The hemoglobin levels over the course of the study
- The immunogenicity of luspatercept
- Safety of luspatercept in pediatric subjects

Valutare:
- La variazione media nel carico da trasfusione di RBC
- I livelli di emoglobina nel corso dello studio
- L’immunogenicità di luspatercept
-La sicurezza di luspatercept in soggetti pediatrici
Un elenco completo degli obiettivi e degli endpoint è disponibile nella Sezione 2 del protocollo.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

6 months to < 18 years of age at the time of signing the informed consent form (ICF)/informed assent form (IAF).
Documented diagnosis of ß-thalassemia or Hemoglobin E/ß-thalassemia
Regularly transfused, defined as: >= 4 RBC transfusions in the 24 weeks prior to enrollment with no transfusion-free period >= 42 days during that period.
Note: For the purpose of the study, transfusions administered over 2 or 3 consecutive days are considered as part of a single transfusion event.
Karnofsky (age >=16 years) or Lansky (age < 16 years) performance status score >= 50 at screening

Il soggetto deve avere da 6 mesi a < 18 anni di età al momento della firma del modulo di consenso informato (ICF)/modulo di assenso informato(IAF)
Il soggetto deve presentare una diagnosi documentata di ß-talassemia o emoglobina E/ß-talassemia.
Il soggetto deve essere sottoposto a trasfusioni regolari, definite come: >= 4 trasfusioni di RBC nelle 24 settimane precedenti l’arruolamento e nessun periodo libero da trasfusione >= 42 giorni in quell’arco di tempo.
Nota: per l'obiettivo dello studio, le trasfusioni somministrate nell'arco di 2 o 3 giorni consecutivi sono considerate come parte di un singolo evento di trasfusione.
Il soggetto ha un punteggio dello stato di validità di Karnofsky (età >= 16 anni) o di Lansky (età < 16 anni) >= 50 allo screening.

E.4

Principal exclusion criteria

Subject has a diagnosis of Hemoglobin S/ß-thalassemia or alpha (a)-thalassemia (eg, Hemoglobin H); ß-thalassemia combined with a-thalassemia is allowed.
Subject has chronic anticoagulant therapy <= 28 days prior to enrollment
Subject has used an erythropoiesis-stimulating agent (ESA) <= 24 weeks prior to enrollment.
Subject use of iron chelation therapy, if initiated <= 8 weeks prior to enrollment (allowed if initiated > 8 weeks before or during treatment).
Subject use of hydroxyurea treatment <= 24 weeks prior to enrollment.
Subject use of chronic systemic glucocorticoids <= 12 weeks prior to enrollment
Subject use of cytotoxic agents, immunosuppressants <= 28 days prior to enrollment
Subject has treatment with another investigational drug or device <= 28 days prior to enrollment

Il soggetto presenta una diagnosi di emoglobina S/ß-talassemia o alfa (a)-talassemia (ad es. emoglobina H); è consentita la diagnosi di ß-talassemia combinata con a-talassemia.
Il soggetto è in trattamento con una terapia anticoagulante cronica da <= 28 giorni prima dell'arruolamento (le terapie anticoagulanti utilizzate per la profilassi per interventi chirurgici o procedure ad alto rischio, nonché l’eparina a basso peso molecolare [LMW] per trombosi venosa superficiale [TVS] e l’aspirina cronica sono concesse).
Il soggetto ha utilizzato un agente stimolante l'eritropoiesi (ESA) <= 24 settimane prima dell'arruolamento.
Il soggetto è in trattamento con terapia ferrochelante (iron chelation therapy, ICT), se avviata <= 8 settimane prima dell’arruolamento (consentita se avviata > 8 settimane prima, o durante il trattamento).
Il soggetto è in trattamento con idrossiurea da <= 24 settimane prima dell'arruolamento.
Il soggetto fa uso di glucocorticoidi per via sistemica cronica da <= 12 settimane prima dell'arruolamento (è consentita la terapia sostitutiva fisiologica per insufficienza surrenale). È consentito un trattamento di un solo giorno con glucocorticoidi (ad es., per la prevenzione o il trattamento di reazioni alla trasfusione).
Il soggetto fa uso di agenti citotossici, immunosoppressivi da <= 28 giorni prima dell'arruolamento (ovvero, globulina anti-timociti [ATG] o ciclosporina).
Il soggetto è in trattamento con un altro farmaco o dispositivo sperimentale da <= 28 giorni prima dell’arruolamento.

E.5 End points

E.5.1

Primary end point(s)

Determination of the Recommended Dose
Development of a PK model that describes the PK exposure data of luspatercept and associated variability

Determinare la dose raccomandata
Sviluppo di un modello PK che descrive i dati di esposizione PK di luspatercept e la varibilità associata

E.5.1.1

Timepoint(s) of evaluation of this end point

Cycle 1 Day 1 through Cycle 1 Day 22
Cycle 1 Day 1 through EOT following the Treatment Period

- Ciclo 1 Giorno 1 fino a Ciclo 1 giorno 22
- ciclo 1 giorno 1 fino alla fine dello studio che segue il periodo di trattamento

E.5.2

Secondary end point(s)

To evaluate the change in RBC transfusion burden
To evaluate the change in hemoglobin levels over the course of the study
Safety
Frequency of antidrug antibodies and its effect on safety
Exposure-response relationships for measures of activities and toxicity

- To evaluate the change in RBC transfusion burden
- To evaluate the change in hemoglobin levels over the course of the study
- Safety
- Frequency of antidrug antibodies and its effect on safety
- Exposure-response relationships for measures of activities and toxicity

E.5.2.1

Timepoint(s) of evaluation of this end point

12 weeks prior to enrollment; 12 weeks of the Treatment Period through to EOT
Cycle 1 Day 1 through 12 weeks post-last dose
Cycle 1 Day 1 through 12 weeks post-last dose; if positive, every 24 weeks for up to 2 years from Cycle 1 Day 1 or until negative or stabilized
Cycle 1 Day 1 through EOT following the Treatment Period

- 12 weeks prior to enrollment; 12 weeks of the Treatment Period through to EOT
- Cycle 1 Day 1 through 12 weeks post-last dose
- Cycle 1 Day 1 through 12 weeks post-last dose; if positive, every 24 weeks for up to 2 years from Cycle 1 Day 1 or until negative or stabilized
- Cycle 1 Day 1 through EOT following the Treatment Period

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

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

Yes

E.6.13.1

Other scope of the trial description

Dose-ascending Design

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

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

aperto

open

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

Thailand

Turkey

United States

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

The End of Trial is defined as either the date of the last visit of the last subject to complete the Long-Term Treatment and Follow-up Period, or the date of receipt of the last data point from the last subject that is required for primary and/or secondary analysis, as prespecified in the protocol, whichever is the later date. Celgene may end the trial when all key endpoints and objectives of the study have been analyzed.

La Fine della sperimentazione è definita come la data dell’ultima visita dell’ultimo soggetto per completare il Periodo di trattamento a lungo termine e follow-up, oppure la data di ricezione degli ultimi dati dell’ultimo soggetto necessari per l’analisi primaria, l’analisi secondaria e/o l’analisi esplorativa, come specificato in precedenza nel protocollo, a seconda di quale si verifichi più tardi.

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

F.3.3.7

Others

Yes

F.3.3.7.1

Details of other specific vulnerable populations

Minors

Minori

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)

Subjects completing Cycle 4 (last dose) of the Treatment Period and benefiting from the study treatment, at the discretion of the Investigator, will be transitioned to the Longterm Treatment Period to continue dosing with luspatercept for up to a maximum of 5 years from their Cycle 1 Day 1 or when the drug is approved for pediatric patients (whichever comes first). After the trial, subjects will be treated according to normal standard of care.

I soggetti che completano il Ciclo 4 (ultima dose) del Periodo di trattamento e traggono beneficio dal trattamento, a discrezione dello sperimentatore, saranno trasferiti al Periodo di trattamento a lungo termine per continuare il dosaggio con luspatercept per un periodo di max 5 anni dal Giorno 1 del Ciclo 1 o fino a quando il farmaco non viene approvato per pazienti pediatrici (a seconda di quale evento si verifichi per primo). A fine studio i soggetti saranno tratti secondo terapia standard.

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

2019-08-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-24

P. End of Trial
P.	End of Trial Status	Restarted

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IMP with orphan designation in the indication
Orphan Designation Number:
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