Clinical Trials Register

Summary
EudraCT Number:	2012-002471-34
Sponsor's Protocol Code Number:	AZA-MDS-003
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:	2012-12-13
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

2012-002471-34

A.3

Full title of the trial

A Phase 3, Multicenter, Randomized, Double-Blind Study to Compare the Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Placebo Plus Best Supportive Care in Subjects With Red Blood Cell Transfusion-Dependent Anemia And Thrombocytopenia due to IPSS Lower- Risk Myelodysplastic Syndromes.

STUDIO DI FASE 3, MULTICENTRICO, RANDOMIZZATO, IN DOPPIA CECITÀ, CHE SI PROPONE DI CONFRONTARE L’EFFICACIA E LA SICUREZZA DELL’AZACITIDINA ORALE SOMMINISTRATA INSIEME ALLA MIGLIOR TERAPIA DI SUPPORTO CON IL PLACEBO SOMMINISTRATO INSIEME ALLA MIGLIORE TERAPIA DI SUPPORTO A SOGGETTI CON ANEMIA TRASFUSIONE-DIPENDENTE E TROMBOCITOPENIA CAUSATE DA SINDROMI MIELODISPLASTICHE A PIÙ BASSO RISCHIO SECONDO L’IPSS

A.3.1

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

The Efficacy and Safety of Oral Azacitidine Plus Best Supportive Care Versus Placebo and Best Supportive Care in Subjects With lack of normal Red Blood Cells requiring Transfusion and low platelets in the blood Due to Lower Risk Myelodysplastic Syndrome (MDS)

Studio per valutare la efficacia e la sicurezza di azacitidina orale più la migliore terapia di supporto vs. placebo più la migliore terapia di supporto in soggetti senza un numero sufficiente di globuli rossi aventi bisogno di trasfusioni di sangue e un numero basso di piastrine causato da sindromi mielodisplastiche a più basso rischio secondo l'IPSS.

A.3.2

Name or abbreviated title of the trial where available

QUAZAR lower-risk MDS

QUAZAR sindrome mielodisplastica a basso rischio

A.4.1

Sponsor's protocol code number

AZA-MDS-003

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01566695

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	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	Celgene Corporation
B.5.2	Functional name of contact point	ClinicalTrialDisclosure
B.5.3	Address:
B.5.3.1	Street Address	9900 W. 109th Street, Suite 300, Building 70, Overland Park
B.5.3.2	Town/ city	Kansas
B.5.3.3	Post code	66210
B.5.3.4	Country	United States
B.5.4	Telephone number	+1 888 2601599
B.5.5	Fax number	+1 913 4513459
B.5.6	E-mail	ClinicalTrialDisclosure@celgene.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/3/01/084
D.3 Description of the IMP
D.3.1	Product name	Oral Azacitidine
D.3.2	Product code	CC-486
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AZACITIDINE
D.3.9.1	CAS number	320-67-2
D.3.9.4	EV Substance Code	SUB05624MIG
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	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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/3/01/084
D.3 Description of the IMP
D.3.1	Product name	Oral Azacitidine
D.3.2	Product code	CC-486
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AZACITIDINE
D.3.9.1	CAS number	320-67-2
D.3.9.4	EV Substance Code	SUB05624MIG
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	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	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	No
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Subjects with Red Blood Cell Transfusion-Dependent Anemia and Thrombocytopenia due to IPSS Lower-Risk Myelodysplastic Syndromes

Soggetti con anemia trasfusione dipendenti e trombocitopenia dovuta a sindromi mielodisplastiche a basso rischio secondo l'IPSS

E.1.1.1

Medical condition in easily understood language

Subjects with a lack of normal red blood cells requiring a transfusion and low platelets in the blood caused by lower risk myelodysplastic syndrome

Soggetti con un numero basso di globuli rossi e piastrine, che richiedono trasfusioni, dovuto asindrom mielodisplastica a basso rischio.

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	14.1
E.1.2	Level	SOC
E.1.2	Classification code	10029104
E.1.2	Term	Neoplasms benign, malignant and unspecified (incl cysts and polyps)
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 RBC transfusion independence in the 2 treatment arms (oral azacitidine plus best supportive care versus placebo plus best supportive care) in subjects with RBC transfusion-dependent anemia and thrombocytopenia (platelet count ≤ 50 x 109/L) due to IPSS lower-risk MDS.To evaluate RBC transfusion independence in the 2 treatment arms (oral azacitidine plus best supportive care versus placebo plus best supportive care) in subjects with RBC transfusion-dependent anemia and thrombocytopenia (platelet count ≤ 50 x 109/L) due to IPSS lower-risk MDS.

• Valutare l'indipendenza da trasfusioni di globuli rossi nei 2 bracci di trattamento (azacitidina orale associata alla migliore terapia di supporto rispetto a placebo associato alla migliore terapia di supporto) in soggetti con anemia dipendente da trasfusioni di globuli rossi e trombocitopenia (numero di piastrine ≤ 50 x 109/l) a causa della SMD a più basso rischio secondo l’IPSS.

E.2.2

Secondary objectives of the trial

To evaluate in both treatment arms: - overall survival (OS); - hematologic improvement-platelet response (HI-P); - duration of RBC transfusion independence and time to RBC transfusion independence; - progression to acute myeloid leukemia (AML), and time to AML progression; - hematologic improvement-erythroid response (HI-E); - platelet-transfusion independence, duration of platelet transfusion independence, and time to platelet transfusion independence; - hematologic response; - clinically significant bleeding events; - safety; - health-related quality-of-life (HRQoL); and - healthcare resource utilization.

• Valutare in entrambi i bracci di trattamento
- la sopravvivenza globale (OS);
- la risposta ematologica con miglioramento della conta piastrinica (HI-P);
- la durata dell'indipendenza da trasfusioni di globuli rossi e il tempo trascorso fino al raggiungimento dell'indipendenza da trasfusioni di globuli rossi;
- la progressione a Leucemia Mieloide Acuta (LAM) e il tempo trascorso prima della comparsa di tale progressione;
- la risposta ematologica con miglioramento eritroide (HI-E);
- l'indipendenza dalle trasfusioni di piastrine, la durata dell'indipendenza dalle trasfusioni di piastrine e il tempo trascorso prima del raggiungimento dell'indipendenza dalle trasfusioni di piastrine;
- la risposta ematologica;
- eventi di sanguinamento clinicamente significativi;
- la sicurezza;
- la qualità della vita relativa allo stato di salute (HRQoL); e
- l'utilizzo di risorse mediche.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 years at the time of signing the informed consent document 2. Have a documented diagnosis of MDS according to WHO 2008 classification 3. Be RBC transfusion-dependent as defined by: - Average transfusion requirement of ≥ 2 units** per 28 days of RBCs confirmed for a minimum of 84 days immediately preceding randomization *Hemoglobin levels at the time of or within 7 days prior to administration of an RBC transfusion must have been ≤ 9.0 g/dL in order for the transfusion to be counted towards RBC transfusion-dependent status. Red blood cell transfusions administered when Hgb levels were > 9.0 g/dL and/or RBC transfusions administered for elective surgery will not qualify as a required transfusion for the purpose of providing evidence of RBC transfusiondependent status * No consecutive 42 days that are RBC-transfusion-free during the 84 days immediately preceding randomization 4. Have thrombocytopenia as defined by two platelet counts that are ≤ 50 x 109/L and ≥ 21 days apart. The second confirmatory platelet count must be obtained ≤ 14 days prior to randomization - If additional platelet counts were obtained during the interim period, these must also have been ≤ 50 x 109/L. Platelet counts > 50 x 109/L within the interim period are acceptable only if directly associated with a platelet transfusion administered within 7 days prior to the date of the platelet count 5. Have an ECOG performance status of 0, 1, or 2 6. Females of childbearing potential (FCBP) may participate, providing they meet the following conditions: - Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intrauterine device; barrier contraceptive with spermicide; or vasectomized partner) throughout the study, and for 3 months following the last dose of study drug; and - Have a negative serum or urine pregnancy test (investigator's discretion; sensitivity of at least 25 mIU/mL) at screening; and - Have a negative serum or urine pregnancy test (investigator's discretion) within 72 hours prior to starting study therapy in the treatment phase (note that the screening serum pregnancy test can be used as the test prior to starting study therapy in the treatment phase if it is performed within the 72-hour timeframe). 7. Male subjects with a female partner of childbearing potential must agree to the use of at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study and for 3 months following the last dose of study drug

Criteri di inclusione: Per essere arruolati nello studio, i soggetti devono soddisfare i seguenti criteri:
1. Età ≥ a 18 anni al momento della firma del modulo di consenso informato
2. Diagnosi documentata di SMD in base alla classificazione WHO 2008
3. Dipendenza da trasfusioni di globuli rossi , definita come:
• Fabbisogno medio di trasfusioni pari a ≥ 2 unità di globuli rossi nell'arco di 28 giorni confermate per un minimo di 84 giorni prima della randomizzazione
- I livelli di emoglobina al momento della somministrazione della trasfusione di globuli rossi o nei 7 giorni precedenti devono essere ≤ 9,0 g/dl affinché la trasfusione sia conteggiata per definire lo stato di dipendenza da trasfusioni di globuli rossi. Le trasfusioni di globuli rossi somministrate con livelli Hgb > 9,0 g/dl e/o le trasfusioni somministrate nel corso di un intervento di chirurgia elettiva non vengono considerate necessarie e non sono comprovanti dello stato di dipendenza da trasfusioni di globuli rossi
• Nessun periodo di 42 giorni consecutivi senza la somministrazione di trasfusioni di globuli rossi negli 84 giorni immediatamente precedenti la randomizzazione
4. Trombocitopenia definita come valutazione di due conte piastriniche ≤ 50 x 109/l eseguite a ≥ 21 giorni di distanza. La seconda valutazione di conta piastrinica di deve essere confermata ≤ 14 giorni prima della randomizzazione
• Se durante il periodo a interim sono state eseguite delle conte piastriniche aggiuntive, anche queste devono avere un valore ≤ 50 x 109/l. Le conte piastriniche con valori > 50 x 109/l eseguite durante il periodo a interim sono accettabili solo se direttamente associate a una trasfusione di piastrine somministrata nei 7 giorni precedenti la data della conta piastrinica
5. Performance Status secondo ECOG di 0, 1 o 2
6. Le donne potenzialmente fertili (FCBP) possono partecipare allo studio se soddisfano le condizioni seguenti:
• Accettino di usare almeno due metodi contraccettivi efficaci (contraccettivo ormonale orale, iniettabile o impiantabile; legatura delle tube; dispositivo intrauterino; contraccettivo a barriera con spermicida o partner vasectomizzato) per tutta la durata dello studio e per 3 mesi dopo l’assunzione dell'ultima dose di farmaco sperimentale; e
• Abbiano un test di gravidanza sul siero o sulle urine negativo (a discrezione dello Sperimentatore; sensibilità di almeno 25 mIU/ml) allo screening; e
• Abbiano un test di gravidanza sul siero o sulle urine negativo (a discrezione dello Sperimentatore) nelle 72 ore precedenti l'inizio della terapia sperimentale (il test di gravidanza sul siero allo screening può essere usato come test prima dell'inizio della terapia sperimentale se eseguito entro le 72 ore)
7. I soggetti di sesso maschile con partner di sesso femminile potenzialmente fertile devono accettare di usare almeno due metodi contraccettivi approvati dal medico per l'intero corso dello studio ed evitare di concepire un figlio per l'intero corso dello studio e nei 3 mesi successivi l’assunzione dell'ultima dose di farmaco sperimentale
8. Comprensione e sottoscrizione volontaria del modulo di consenso informato prima che venga effettuata qualsiasi valutazione/procedura correlata allo studio
9. Capacità di attenersi al programma di visite dello studio e agli altri requisiti del protocollo.

E.4

Principal exclusion criteria

1. IPSS higher-risk (INT-2 or High risk) MDS 2. Secondary MDS, ie MDS that is known to have arisen as the result of chemical injury or treatment with chemotherapy and/or radiation for other diseases 3. Hypoplastic MDS or other subtype with eligibility for treatment with immunotherapy 4. CMML, atypical chronic myeloid leukemia (CML) and unclassifiable myeloproliferative disease (MPD) 5. Prior treatment with any of the following: - Azacitidine (any formulation), decitabine or other hypomethylating agent - Lenalidomide 6. Prior allogeneic or autologous stem cell transplant 7. History of inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis), celiac disease (ie, sprue), prior gastrectomy or upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption, distribution, metabolism or excretion of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity 8. Thrombocytopenia secondary to other possible causes, including medication(s), congenital disorder(s), immune disorder(s) (eg, idiopathic thrombocytopenic purpura [ITP]), or microvascular disorder(s) (eg, disseminated intravascular coagulation, hemolytic uremic syndrome, thrombotic thrombocytopenic purpura) 9. Use of any of the following within 28 days prior to randomization: - cytotoxic, chemotherapeutic, targeted or investigational agents/therapies - thrombopoiesis-stimulating agents (TSAs; eg, Romiplostim, Eltrombopag, Interleukin-11) - ESAs and other RBC hematopoietic growth factors (eg, Interleukin-3) - hydroxyurea 10. Ongoing adverse events from previous treatment, regardless of the time period 11. Concurrent use of any of the following: - iron-chelating agents, except for subjects on a stable dose for at least 8 weeks (56 days) prior to randomization - corticosteroid, except for subjects on a stable or decreasing dose for ≥ 1 week prior to randomization for medical conditions other than MDS 12. Prior history of malignancies, other than MDS, unless the subject has been free of the disease for ≥ 3 years. However, subjects with the following history/concurrent conditions are allowed: - Basal or squamous cell carcinoma of the skin - Carcinoma in situ of the cervix - Carcinoma in situ of the breast - Incidental histologic finding of prostate cancer (T1a or T1b using the tumor, nodes, metastasis [TNM] clinical staging system) 13. Significant active cardiac disease within the previous 6 months, including: - New York Heart Association (NYHA) class IV congestive heart failure; - Unstable angina or angina requiring surgical or medical intervention; and/or - Myocardial infarction 14. Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment) 15. Known Human Immunodeficiency Virus (HIV) or Hepatitis C (HCV) infection, or evidence of active Hepatitis B Virus (HBV) infection 16. Abnormal coagulation parameters (PT > 15 seconds, PTT > 40 seconds, and/or INR > 1.5) 17. Any of the following laboratory abnormalities: - Serum AST/SGOT or ALT/SGPT > 2.5 x upper limit of normal (ULN) - Serum bilirubin > 1.5 x ULN. Higher levels are acceptable if these can be attributed to active red blood cell precursor destruction within the bone marrow (ie, ineffective erythropoiesis). Subjects are excluded if there is evidence of autoimmune hemolytic anemia manifested as a corrected reticulocyte count of > 2% with either a positive Coombs' test or over 50% of indirect bilirubin - Serum creatinine > 2.5 x ULN 18. Known clinically significant anemia due to iron, vitamin B12, or folate deficiencies, or autoimmune or hereditary hemolytic anemia, or gastrointestinal bleeding.......

La presenza di uno dei seguenti fattori potrà escludere un soggetto dall'arruolamento:
1. SMD a rischio (Appendice B) più elevato secondo l’IPSS (rischio INT-2 o elevato)
2. SMD secondaria, ad es. SMD causata da danno chimico o dal trattamento con chemioterapia e/o da radiazioni per altre malattie
3. SMD ipoplastica o altro sottotipo candidate al trattamento con immunoterapia
LMMC, Leucemia Mieloide Cronica Atipica (LMC) e malattia mieloproliferativa non classificabile (MMP)
5. Precedente trattamento con uno dei farmaci seguenti:
• Azacitidina (una qualsiasi formulazione), decitabina o altro agente ipometilante
• Lenalidomide
6. Precedente trapianto di cellule staminali autologo o allogenico
7. Storia di malattia infiammatoria dell'intestino (ad es. morbo di Crohn, colite ulcerosa), celiachia, precedente gastrectomia o asportazione del tratto intestinale superiore o qualsiasi patologia o difetto gastrointestinale di altro tipo in grado di interferire con l'assorbimento, la distribuzione, il metabolismo o l'eliminazione del farmaco sperimentale e/o predisporre il soggetto a un aumentato rischio di tossicità gastrointestinale
8. Trombocitopenia secondaria ad altre possibili cause, compresa l’assunzione di farmaco/i, patologia/e congenita/e, disturbo/i del sistema immunitario (ad es. porpora trombocitopenica idiopatica [PIT]) o disturbo/i microvascolare/i (ad es. coagulazione intravascolare disseminata, sindrome uremico emolitica, porpora trombocitopenica trombotica)
9. Uso di uno qualsiasi dei farmaci seguenti nei 28 giorni precedenti la randomizzazione:
• Agenti citotossici, agenti chemioterapici, agenti/terapie mirati/e o/sperimentali
• Agenti stimolanti la formazione di trombi (AST; ad es. Romiplostim, Eltrombopag, Interleukina-11)
• ESA e altri fattori di crescita ematopoietica (ad es. Interleukina-3)
• Idrossiurea
10. Eventi avversi da trattamento precedente ancora in corso, a prescindere dall'arco di tempo
11. Uso concomitante di uno dei farmaci seguenti:
• Agenti ferrochelanti, tranne per soggetti che ricevono un trattamento a dosaggio stabile da almeno 8 settimane (56 giorni) prima della randomizzazione
• Corticosteroidi, tranne per soggetti che, per condizioni mediche diverse dalla SMD, ricevono un trattamento a dosaggio stabile o in diminuzione da ≥ 1 settimana prima della randomizzazione
12. Storia precedente di tumori maligni diversi dalla SMD, a meno che il soggetto non presenti tracce di malattia da ≥ 3 anni. Sono ammessi i soggetti con storia/condizioni concomitanti seguenti:
• Carcinoma della pelle a cellule basali o cellule squamose
• Carcinoma in situ della cervice
• Carcinoma mammario in situ
• Riscontro istologico di cancro alla prostata (T1a o T1b secondo il sistema di classificazione clinica di tumore, nodi, metastasi [TNM])
13. Malattia cardiaca significativamente attiva nei 6 mesi precedenti, tra cui:
• Insufficienza cardiaca congestizia di classe IV secondo la New York Heart Association (NYHA)
• Angina instabile o angina che richiede intervento medico o chirurgico; e/o
• Infarto del miocardio
14. Infezione fungina, batterica, o virale sistemica non controllata (definita come presenza di segni/sintomi correlati all'infezione e senza miglioramento nonostante una terapia antibiotica o antivirale appropriata e/o altro trattamento)
15. Virus da immunodeficienza umana (HIV) o infezione da epatite C (HCV) note, o evidenza di infezione attiva da virus dell’epatite B (HBV)
16. Parametri di coagulazione del sangue anomali (PT > 15 secondi, PTT > 40 secondi e/o INR > 1.5)
17. Una delle seguenti anomalie nei valori di laboratorio:
• AST/SGOT o ALT/SGPT sieriche ≥ 2,5 volte il limite superiore della norma (ULN)
• Bilirubina sierica > 1,5 x ULN. Livelli più elevati sono accettabili se attribuibili a distruzione di precursori dei globuli rossi attiva all'interno del ......

E.5 End points

E.5.1

Primary end point(s)

The proportion of subjects in the overall population achieving RBC transfusion independence with duration ≥ 84 days (12 weeks).

L'endpoint di efficacia primario è il numero di soggetti nella popolazione globale in studio che raggiungono un'indipendenza dalle trasfusioni di globuli rossi per un periodo ≥ a 84 giorni (12 settimane).

E.5.1.1

Timepoint(s) of evaluation of this end point

After all patients have either completed 12 months treatment or discontinued.

Dopo che tutti i pazienti hanno completato i 12 mesi di trattamento o hanno interrotto il trattamento.

E.5.2

Secondary end point(s)

OS; - HI-P (IWG 2006 criteria); - Duration of RBC transfusion independence; - Time to RBC transfusion independence; - Proportion of subjects progressing to AML and time to AML progression; - HI-E (IWG 2006 criteria); - Proportion of platelet transfusion-dependent subjects at baseline achieving platelet transfusion independence with duration ≥ 56 days (8 weeks); - Duration of platelet transfusion-independence; - Time to platelet transfusion independence; - Hematologic response (IWG 2006 criteria); - Proportion of subjects experiencing clinically significant bleeding events; - Safety (type, frequency, severity of AEs and relationship of AEs to oral azacitidine/placebo; monitoring for progression to AML and second primary malignancy); - HRQoL utilizing the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and EuroQoL Group EQ-5D-3L instruments; and - Measures of healthcare resource utilization.

Gli endpoint di efficacia secondari comprendono OS, HI-P (criteri IWG 2006), durata dell'indipendenza da trasfusioni di globuli rossi, tempo per raggiungere l'indipendenza da trasfusioni di globuli rossi, numero di soggetti che progrediscono a LAM, tempo all’insorgenza della progressione a LAM, HI-E (criteri IWG 2006), numero di soggetti dipendenti da trasfusioni di piastrine al basale che raggiungono l'indipendenza per un periodo ≥ a 56 giorni (8 settimane), durata dell'indipendenza da trasfusioni di piastrine, tempo trascorso prima del raggiungimento dell'indipendenza dalle trasfusioni di piastrine, risposta ematologica (criteri IWG 2006) e numero di soggetti che manifestano eventi di sanguinamento clinicamente significativi. Le valutazioni di sicurezza includono gli eventi avversi, il monitoraggio della progressione a LAM e dell’insorgenza del secondo tumore maligno primario. Valutazione della HRQoL utilizzando il FACT-An ed EQ-5D-3l. Misurazione della utilizzazione delle risorse sanitarie.

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy endpoints including interim OS with exception of AML progression: after all patients have either completed 12 months treatment or discontinued Mature OS: Approx 250 events in total.

Dopo che tutti i pazienti hanno completato i 12 mesi di trattamento o hanno interrotto il trattamento.
Sopravvivenza globale: a un totale di circa 250 eventi.

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

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

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

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

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

Canada

Israel

Mexico

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 study will conclude once the total number of events (n=250
deaths) have occurred.

Lo studio si concluderà una volta raggiunto il numero totale di eventi (250 decessi).

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

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)

Yes

F.1.3.1

Number of subjects for this age range:

300

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

213

F.4.2.2

In the whole clinical trial

386

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)

Standard of care

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

2013-02-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-11-26

P. End of Trial
P.	End of Trial Status	Completed

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Orphan Designation Number:
Results Status:
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