Clinical Trials Register

Summary
EudraCT Number:	2012-002499-15
Sponsor's Protocol Code Number:	A536-04
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:	2012-09-28
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

2012-002499-15

A.3

Full title of the trial

A Phase 2, Open-Label, Ascending Dose Study to Evaluate the Effects of ACE-536 in Patients with β-Thalassemia Intermedia

Uno studio di fase 2, in aperto, schema posologico ascendente per valutare gli effetti di ACE-536 in pazienti con β-talassemia intermedia

A.3.1

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

A clinical study of a new drug for the treatment of thalassemia

Uno studio clinico per testare un nuova medicina per il trattamento della talassemia

A.4.1

Sponsor's protocol code number

A536-04

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	ACCELERON PHARMA INC
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	Acceleron Pharma, 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	Acceleron Pharma, Inc
B.5.2	Functional name of contact point	Kenneth Attie
B.5.3	Address:
B.5.3.1	Street Address	128 Sidney Street
B.5.3.2	Town/ city	Cambridge, MA
B.5.3.3	Post code	02139
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 617 6499200
B.5.5	Fax number	+1 617 5760479
B.5.6	E-mail	kattie@acceleronpharma.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	NA
D.3.2	Product code	ACE-536
D.3.4	Pharmaceutical form	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.3.9.1	CAS number	1373715-00-4
D.3.9.2	Current sponsor code	ACE-536
D.3.9.3	Other descriptive name	Modified ActRIIB receptor - IgG1 Fc fusion protein
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	50
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

β-thalassemia intermedia

β-talassemia intermedia

E.1.1.1

Medical condition in easily understood language

The intermediate form of β-thalassemia (Mediterranean anemia)

La forma intermedia di β-thalassemia (anemia mediterranea)

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	15.1
E.1.2	Level	LLT
E.1.2	Classification code	10062923
E.1.2	Term	Thalassemia intermedia
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.1
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

To evaluate the effect of ACE-536 on the proportion of patients who have an erythroid response, defined as a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days (in the absence of transfusion) in patients with β-thalassemia intermedi

Valutare l'effetto di ACE-536 per la proporzione di pazienti che hanno una risposta eritroide, definita come un aumento dell' emoglobina ≥ 1.5 g/dl dal basali per ≥ 14 giorni (in assenza di trasfusione) in pazienti con β-talassemia intermedia

E.2.2

Secondary objectives of the trial

To evaluate i)safety and tolerability of ACE-536,(ii)change in hemoglobin level compared to baseline + time and duration of erythroid response(iii)changes in biomarkers of erythropoiesis(iv)pharmacokinetics profile

Valutare (i)sicurezza e tollerabilità di ACE-536,(ii)variazione livello emoglobina rispetto al basale + tempo e durata della risposta eritroide,(iii)variazioni nei biomarcatori dell'eritropoiesi,(iv)profilo farmacocinetico

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Men or women 18 years of age. 2. Documented diagnosis of β-thalassemia intermedia, with anemia requiring
no more than 6 transfusion events in the last year, with no transfusion events for 56 days prior to Cycle 1 Day 1 3. Prior splenectomy or spleen size < 18 cm in the longest diameter by abdominal ultrasound. 4. Mean hemoglobin concentration < 10.0 g/dL of 2 measurements (one performed within one day prior to Cycle 1 Day 1 and the other performed 7-28 days prior, not influenced by RBC transfusion within 7 days of measurement). 5. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x upper limit of normal (ULN). 6. Serum creatinine ≤ 1.5 x ULN. 7. Females of child bearing potential (defined as sexually mature women who have not undergone hysterectomy or bilateral oophorectomy, or are not naturally postmenopausal ≥ 24 consecutive months) must have negative urine or blood pregnancy test prior to enrollment and use adequate birth control methods (abstinence, oral contraceptives, barrier method with spermicide, or surgical sterilization) during study participation. Males must agree to use a latex condom during any sexual contact with females of child-bearing potential while participating in the study and for 12 weeks following the last dose of ACE-536, even if he has undergone a successful vasectomy. Patients must be counseled concerning measures to be used to prevent pregnancy and potential toxicities prior to the first dose of ACE-536. 8. Patients are able to adhere to the study visit schedule, understand and comply with all protocol requirements. 9. Understand and able to provide written informed consent.

1.Soggetti di entrambi i sessi di età ≥ 18 anni. 2.Diagnosi documentata di β -talassemia intermedia, con anemia necessitante non più di 6 episodi trasfusionali nell’ultimo anno, in assenza di episodi trasfusionali nei 56 giorni precedenti il Giorno 1 del Ciclo 1 3.Splenectomia pregressa o dimensioni della milza < 18 cm di diametro longitudinale all'ecografia addominale. 4.Concentrazione media di emoglobina < 10,0 g/dl di 2 misurazioni (una eseguita il giorno precedente il Giorno 1 del Ciclo 1 e la seconda nei 7-28 giorni precedenti, non influenzata da trasfusioni di emazie entro 7 giorni dalla misurazione). 5.Aspartato aminotransferasi (AST) o alanina aminotransferasi (ALT) < 3 volte il limite superiore della norma (LSN). 6.Creatinina sierica ≤ 1,5 volte il LSN 7.I soggetti femminili in età fertile (definite come donne sessualmente mature non sottoposte a isterectomia od ovariectomia bilaterale, o non naturalmente in menopausa per un periodo ≥ 24 mesi consecutivi) devono presentare un test ematico o urinario di gravidanza negativo prima dell'arruolamento e far uso di metodi contraccettivi adeguati (astinenza, contraccettivi orali, metodo di barriera con spermicida, o sterilizzazione chirurgica) durante la partecipazione allo studio. I soggetti maschili devono acconsentire di far uso di un profilattico in lattice durante qualsiasi contatto sessuale con donne in età fertile durante la partecipazione allo studio e per le 12 settimane successive alla somministrazione dell'ultima dose di ACE 536, anche se sottoposti con successo a vasectomia. Prima della somministrazione della prima dose di ACE-536, i pazienti devono essere informati in merito alle misure da adottare per evitare la gravidanza e potenziali tossicità. 8.Pazienti in grado di rispettare il programma delle visite dello studio, di capire tutti i requisiti del protocollo e di aderire a tali requisiti. 9.Pazienti in grado di intendere e di volere e di accordare il consenso informato scritto.

E.4

Principal exclusion criteria

1. Any clinically significant pulmonary (including pulmonary hypertension), cardiovascular, endocrine, neurologic, hepatic, gastrointestinal, infectious or genitourinary disease considered by the investigator as not adequately controlled prior to Cycle 1 Day 1. 2. Folate deficiency. 3. Known positive for human immunodeficiency virus (HIV), active infectious hepatitis B(HBV) or active infectious hepatitis C (HCV). 4. Known history of thromboembolic events ≥ grade 3 according to the National Cancer Institute-Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0 (current active minor version). 5. Ejection fraction < 50% by echocardiogram, MUGA or cardiac MRI. 6. Uncontrolled hypertension defined as systolic blood pressure (BP) ≥ 150 mm Hg or diastolic BP ≥ 95 mm Hg. 7. Heart failure class 3 or higher (New York Heart Association, NYHA, Appendix 1). 8. QTc > 450 msec on screening ECG. 9. Platelet count < 100 x109/L or > 1,000,000 x109/L. 10. Proteinuria ≥ Grade 2. 11. Any active infection requiring parenteral antibiotic therapy within 28 days prior to Cycle 1 Day 1 or oral antibiotics within 14 days of Cycle 1 Day 1. 12. Treatment with another investigational drug or device, or approved therapy for investigational use ≤ 28 days prior to Cycle 1 Day 1, or if the half-life of the previous investigational product is known, within 5 times the half-life prior to Cycle 1 Day 1, whichever is longer. 13. Patients receiving or planning to receive hydroxyurea treatment. Patients must not have had hydroxyurea within 56 days of Cycle 1 Day 1. 14. Splenectomy with 56 days prior to Cycle 1 Day 1. 15. Major surgery (except splenectomy) within 28 days prior to Cycle 1 Day 1. Patients must have completely recovered from any previous surgery prior to Cycle 1 Day 1. 16. Iron chelation therapy if initiated within 56 days prior to Cycle 1 Day 1 17. Cytotoxic agents, systemic corticosteroids, immunosuppressants, or anticoagulant therapy such as warfarin or heparin within 28 days priorto Cycle 1 Day 1 (prophylactic aspirin up to 100 mg/d is permitted). 18. Pregnant or lactating females. 19. History of severe allergic or anaphylactic reactions or hypersensitivity to recombinant proteins or excipients in the investigational drug.

1.Qualsiasi patologia polmonare(compresa ipertensione polmonare), cardiovascolare, endocrina,neurologica, epatica, gastrointestinale, infettiva o urogenitale clinicamente significativa, che lo sperimentatone non ritiene adeguatamente controllata prima del Giorno 1 del Ciclo 1. 2.Deficit di acido folico. 3.Nota positività per il virus dell'immunodeficienza umana (HIV), epatite B infettiva attiva (HBV) o epatite C infettiva attiva (HCV). 4.Nota anamnesi di eventi tromboembolici di grado ≥ 3 secondo il Common Terminology Criteria for Adverse Events del National Cancer Institute (NCI-CTCAE) versione 4.0 (attuale versione minore, attiva). 5.Frazione di eiezione < 50% all'ecocardiogramma, MUGA o risonanza magnetica cardiaca. 6.Ipertensione non controllata, definita come pressione sistolica ≥ 150 mm Hg o pressione diastolica ≥ 95 mm Hg. 7.Insufficienza cardiaca di classe 3 o superiore (New York Heart Association, NYHA, Appendice 1). 8.QTc > 450 msec all'ECG di screening. 9.Conta piastrinica < 100 x109/l o > 1.000.000 x109/l. 10.Proteinuria di grado ≥ 2. 11.Qualsiasi infezione attiva necessitante terapia antibiotica per via parenterale nei 28 giorni precedenti il Giorno 1 del Ciclo 1 oppure antibiotici orali nei 14 giorni precedenti il Giorno 1 del Ciclo 1. 12.Trattamento con un altro farmaco o dispositivo sperimentale, oppure terapia approvata per uso sperimentale ≤ 28 giorni precedenti il Giorno 1 del Ciclo 1, oppure, se si conosce l'emivita del precedente prodotto sperimentale, entro un periodo 5 volte superiore al valore dell'emivita precedente al Giorno 1 del Ciclo 1, a seconda di quale periodo di tempo sia quello più lungo. 13.Pazienti in terapia o che prevedono di essere sottoposti a terapia con idrossiurea. I pazienti non devono aver assunto idrossiurea nei 56 giorni precedenti il Giorno 1 del Ciclo 1. 14.Splenectomia nei 56 giorni precedenti il Giorno 1 del Ciclo 1. 15.Chirurgia maggiore (eccetto la splenectomia) nei 28 giorni precedenti il Giorno 1 del Ciclo 1. I pazienti devono essersi ripresi completamente dal precedente intervento chirurgico prima del Giorno 1 del Ciclo 1. 16.Terapia ferrochelante se avviata nei 56 giorni precedenti il Giorno 1 del Ciclo 1. 17.Agenti citotossici, corticosteroidi sistemici, immunosoppressori o terapia anticoagulante, come warfarin o eparina, nei 28 giorni precedenti il Giorno 1 del Ciclo 1 (è ammessa l'aspirina per uso profilattico fino a 100 mg/die). 18.Donne in gravidanza o che allattano. 19.Anamnesi di gravi reazioni allergiche o anafilattiche o ipersensibilità alle proteine ricombinanti o agli eccipienti del farmaco sperimentale.

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is erythroid response, defined as the proportion of patients who have a hemoglobin increase of ≥ 1.5 g/dL from baseline for ≥ 14 days, in the absence of transfusion. The erythroid response will be summarized using both a point estimate and its exact 95% confidence interval based on binomial distribution. The primary efficacy analysis will be performed using the EE population.

L'endpoint primario di efficacia è la risposta eritroide, definita come la proporzione di pazienti che ha manifestato un aumento dell'emoglobina ≥ 1,5 g/dl dal basale per ≥ 14 giorni, in assenza di trasfusione. La risposta eritroide sarà riepilogata utilizzando una stima puntuale e il suo intervallo di confidenza esatto al 95% basato sulla distribuzione binomiale. L’analisi di efficacia primaria verrà condotta sulla popolazione EE.

E.5.1.1

Timepoint(s) of evaluation of this end point

20 weeks following initiation of treatment

20 settimane dopo l'inizio del trattamento

E.5.2

Secondary end point(s)

Secondary efficacy endpoints will be assessed by examining other hematology, erythropoiesis, iron metabolism, and bone metabolism parameters, as well as MRI scan for liver iron content (LIC). - Erythropoiesis parameters include serum erythropoietin levels, hemoglobin analysis (electrophoresis, globin chain RNA), reticulocytes, and nucleated RBCs - Hemolysis parameters include haptoglobin, indirect bilirubin, and lactate dehydrogenase (LDH) - Iron metabolism parameters include serum iron, total iron binding capacity (TIBC), transferrin, soluble transferrin receptor, ferritin, non-transferrin bound iron (NTBI), hepcidin, and liver iron content (LIC) by MRI - Bone metabolism parameters include bone specific alkaline phosphatase (BSAP) and C-telopeptide of type I collagen (CTX) Exploratory endpoints will include evaluation of biomarkers related to the TGF Beta superfamily.

Gli endpoint secondari di efficacia saranno valutati esaminando gli altri parametri ematologici, i parametri eritropoietici, i parametri del metabolismo del ferro e quelli del metabolismo osseo, nonché i referti della risonanza magnetica per rilevare la concentrazione di ferro epatico (LIC). 1. I parametri eritropoietici comprendono i livelli di eritropoietina sierica, l'analisi dell'emoglobina (elettroforesi, RNA catena globinica), dei reticolociti e degli eritrociti nucleati 2.I parametri emolitici comprendono aptoglobina, bilirubina indiretta e lattato deidrogenasi (LDH). 3.)I parametri del metabolismo del ferro comprendono ferro sierico, capacità ferro-legante totale (TIBC), transferrina, recettore solubile della transferrina, ferritina, ferro non legato alla transferrina (NTBI), epcidina e concentrazione di ferro epatico (LIC) alla risonanza magnetica 4. I parametri del metabolismo osseo comprendono fosfatasi alcalina osso-specifica (BSAP) e telopeptide C del collagene di tipo I (CTX) Gli endpoint esploratori comprenderanno la valutazione dei biomarcatori correlati alla superfamiglia del TGFβ.

E.5.2.1

Timepoint(s) of evaluation of this end point

20 weeks following initiation of treatment

20 settimane dopo l'inizio del trattamento

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

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)

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

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

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)

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)

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.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)

Patients will return to standard of care under their treating physician

I pazienti torneranno alla terapia convenzionale presso il loro medico

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

2012-12-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-26

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-11-11

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