| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with IPSS low and intermediate-risk myelodysplastic syndrome with isolated del5q |
| Pazienti adulti affetti da Mielodisplasia rischio basso intermedio-1 con del(5q) come unica alterazione cariotipica |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with myelodysplastic syndrome |
| Pazienti affetti da mielodisplasia |
|
| 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 | LLT |
| E.1.2 | Classification code | 10028532 |
| E.1.2 | Term | Myelodysplasia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 eltrombopag treatment relative to placebo on the incidence of the “composite endpoint” (PLT<25 Gi/L or bleeding event with WHO bleeding score >1 or study discontinuation), in the first 24 weeks, after experiencing PLT<100 Gi/L |
| Valutare l'effetto del trattamento con Eltrombopag rispetto al placebo sull'incidenza del "endpoint composito" (PLT <25 Gi / L o episodio di sanguinamento con WHO bleeding > 1 o interruzione studio), nelle prime 24 settimane, dopo aver sperimentato PLT <100 Gi / L |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of eltrombopag treatment relative to placebo on:
1. The composite endpoint during the entire study period
2. Safety and tolerability in terms of frequency of adverse events (AE)s and serious adverse events (SAE).
3. Cytogenetic responses, according to IWG 2006 criteria.
4. Duration of cytogenetic response.
5. Hb changes within the first 24 weeks.
6. Erythroid response, transfusion-independence (TI) and duration of TI.
7. Changes in QOL scores.
8. Progression Free Survival (PFS) and Overall Survival (OS).
9. Maintenance of a 10 mg lenalidomide dosing.
|
Tra i pazienti che ricevono eltrombopag rispetto a quelli che ricevono placebo valutare l'effetto del trattamento su:
1. L’endpoint composito durante l’intero periodo della sperimentazione.
2. Sicurezza e tollerabilità in termini di frequenza di eventi avversi (AE)s e di eventi avversi gravi (SAE).
3. Le risposte citogenetiche, secondo i criteri IWG2006.
4. Durata della risposta citogenetica.
5. I cambiamenti di Hb durante le prime 24 settimane.
6. Risposta eritroide, trasfusione indipendenza (TI) e durata della TI
7. Cambiamenti degli scores qualità di vita.
8. Progression Free Survival e Overall Survival
9. Mantenimento del dosaggio della Lenalidomide a 10 mg/die
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult subjects (18 years of age or older) with MDS and low or intermediate-1 IPSS risk and del5q as a single abnormality, at the time of their screening and enrollment into the study
2. Subjects must not have received any prior treatment course with any immunomodulating agent nor TPO-R agonists
3. Subjects must be dependent on regular packed RBC transfusions, as defined by international working group 2006 criteria, and must have a PLT count taken within the 4 weeks prior to screening that is >25 Gi/L.[12]
4. Absolute Neutrophil Counts (ANC) = 0.5 GiL
5. Resistant or refractory to erythropoetic stimulating agents (ESAs) and/or serum erythropoetin levels > 500 miU/L
6. Subjects must be ineligible or relapsed or refractory to receive treatment options of azacitidine and decitabine.
7. Subjects must have PLT count and RBC and PLT transfusion data available over a period of 8 weeks prior to screening.
8. During the 2 months prior to randomization, subjects must have a baseline BM examination including all of the following: cytomorphology, cytogenetics and histology
9. ECOG Performance Status must be 0-3.
10. The following clinical chemistries MUST NOT exceed the upper limit of normal (ULN) reference range: creatinine, ALT, AST, total bilirubin (except for Gilbert's Syndrome), gamma-gt and alkaline phosphatase. In addition, albumin must not be below the lower limit of normal (LLN) by more than 10%.
11. If subject meets the criteria for childbearing potential:
a. Negative pregnancy test in female subjects within the 3 days prior to Day 1 of 1st cycle and effective contraception for at least 4 weeks.
b. Subject is practicing an acceptable method of contraception (documented in chart). Female subjects (or female partners of male subjects) must either be of non-childbearing potential (hysterectomy, bilateral oophorectomy, bilateral tubal ligation or post-menopausal >1 year), or of childbearing potential and use of an highly effective method of contraception from 2 weeks prior to administration of study medication, throughout the study, and 28 days after completion or premature discontinuation from the study.
12. Criteria for women of non-childbearing potential:
A female patient or a female partner of a male patient is considered to have childbearing potential unless she meets at least one of the following criteria:
a. Age = 50 years and naturally amenorrhoeic for = 1 year (amenorrhoea following cancer therapy or during lactation does not rule out childbearing potential).
b. Premature ovarian failure confirmed by a gynaecologist
c. Previous bilateral salpingo-oophorectomy, or hysterectomy
d. XY genotype, Turner syndrome, uterine agenesis.
13. Subject is able to understand and comply with protocol requirements and instructions.
14. Subject has signed and dated informed consent.
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1. Adulti (età =18 anni) con MDS stabile a rischio IPSS basso o intermedio-1 con del(5q) come ultima alterazione cariotipica
2. Soggetti trasfusioni dipendenti di RBC come definito dall’IWG2006 con conta piastrinica (PLT) > 25 Gi/L entro 4 settimane dallo screening.
3. Conta assoluta dei neutrofili (ANC) = 0.5 GiL
4. Resistente o refrattario agli agenti stimolanti dell’eritropoietina (ESAs) e/o livelli di eritropoietina > 500 miU/L
5. Ineleggibilità o recidiva o refrattarietà ad altre terapie come azacitidina o decitabina
6. Disponibilità di dati di conta PLT o di trasfusioni di PLT e RBC per il periodo di 8 settimane prima dello screening.
7. Entro 2 mesi dalla randomizzazione, i pazienti devono essere sottoposti ad un esame del midollo osseo che include la citomorfologia e la citogenetica. L'istopatologia dovrebbe essere eseguita.
8. ECOG Performance Status 0-3.
9. Bilirubina totale (eccezione fatta per la sindrome di Gilbert) = ULN
10. ALT e AST = ULN
11. Creatinina = ULN
12. Gamma-GT e fosfatasi alcalina = ULN
13. Albumina non deve essere inferiore al limite inferiore di normalità (LLN) di oltre il 10%.
14. Funzione d'organo basale adeguato
15. Se il soggetto è potenzialmente fertile deve soddisfare i seguenti criteri:
a. Test di gravidanza negativo in soggetti di sesso femminile entro 3 giorni prima del giorno 1 del 1 ° ciclo e una contraccezione efficace per almeno 4 settimane.
b. Praticare un metodo accettabile di contraccezione (documentato in cartella clinica). Soggetti di sesso femminile (o partner femminili di soggetti di sesso maschile) devono essere o potenzialmente non fertili (isterectomia, ovariectomia bilaterale, bilaterale legatura delle tube o post-menopausa >1 anno), o se potenzialmente fertili utilizzare un metodo altamente efficace di contraccezione da 2 settimane prima della somministrazione del farmaco in studio, durante lo studio, e per 28 giorni dopo il completamento o l'interruzione prematura dello studio.
16. Il soggetto non è potenzialmente fertile se rispetta almeno uno dei seguenti criteri:
a. Età = 50 anni e amenorrea naturale per = 1 anno (amenorrea dopo la terapia del cancro o durante l'allattamento non esclude la potenziale fertilità).
b. Insufficienza ovarica precoce confermata da un ginecologo
c. Precedente salpingo-ovariectomia bilaterale o isterectomia
d. Genotipo XY, sindrome di Turner, agenesia uterina.
17. Capace di intendere e di seguire le richieste e istruzioni del protocollo.
18. Consenso informato firmato e datato.
|
|
| E.4 | Principal exclusion criteria |
1. MDS with intermediate-2 or high IPSS risk
2. Additional cytogenetic abnormalities
3. Transfusion independence (TI) by IWG 2006 criteria [12]
4. ANC < 0.5 Gi/L and/or PLT counts < 25 Gi/L
5. History of treatment for cancer with systemic chemotherapy and/or radiotherapy within the last 2 years.
6. History of treatment with immunomodulatory drugs or other TPO-R agonists.
7. Thrombophilia, pre-existing history of thrombosis, cardiovascular disease (including congestive heart failure, New York Heart Association [NYHA] Grade III/IV), or arrhythmia known to increase the risk of thromboembolic events (e.g. atrial fibrillation), or subjects with a QTc >450 msec (QTc >480 msec for subjects with Bundle Branch Block)
8. BM fibrosis that leads to an inability to aspirate marrow for assessment.
9. Leukocytosis >=25,000/uL prior to Day 1 of study medication.
10. Monocytosis > 1000/ uL prior to Day 1 of study medication.
11. Female subjects who are nursing or pregnant (positive serum or urine Beta-human chorionic gonadotropin [B-hCG] pregnancy test).
12. Women of childbearing potential unless all of the conditions of the Pregnancy Prevention Programme illustrated in sections 6.4 are met (see sections 6.4).
13. Known hypersensitivity to lenalidomide.
14. Current alcohol or drug abuse.
15. Treatment with an Investigational Product within 30 days or 5 half-lives (whichever is longer) preceding the first dose of study medication.
16. Active and uncontrolled infections.
17. Subjects infected with Hepatitis B, C or Human Immunodeficiency Virus (HIV).
|
1. MDS con rischio IPSS intermedio-2 o alto
2. Altra anomalia cariotipica oltre alla del(5q)
3. Trasfusione indipendenza (TI) secondo i criteri IWG 2006
4. ANC < 0,5 Gi/L e/o PLT < 25 Gi/L
5. Altra neoplasia maligna o MDS trattata con chemioterapia sistemica e/o radioterapia nei 2 anni precedenti lo studio.
6. Precedente trattamento con romiplostim o altri agonisti TPO-R.
7. Trombofilia, trombosi pre-esistente, malattia cardiovascolare pre-esistente o aritmia con rischio di evento tromboembolico associato o QTc >450 msec (QTc >480 in caso di blocco di branca).
8. Fibrosi midollare tale da impedire l'aspirazione del midollo osseo.
9. Monocitosi periferica > 1000/uL prima del giorno Day 1 dello studio
10. Leucocitosi = 25,000/uL prima del giorno Day 1 dello studio.
11. Soggetti di sesso femminile che allattano o in stato di gravidanza (siero positivo o urine gonadotropina corionica [B-hCG] test di gravidanza Beta-umana).
12. Le donne in età fertile a meno che seguano tutte le condizioni del Programma di Prevenzione della Gravidanza
13. Ipersensibilità alla Lenalidomide
14. Alcolismo o tossicodipendenza.
15. Trattamento con altro farmaco sperimentale entro 30 giorni dalla prima dose del farmaco sperimentale.
16. Infezione attiva ed incontrollata
17. Infezione da HBV, HCV o HIV
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects amongst those experiencing PLT < 100 Gi/L within the first 24 weeks experiencing the “composite endpoint” (PLT<25 Gi/L or bleeding event with WHO bleeding score >1 or study discontinuation), in the first 24 weeks after experiencing PLT<100 Gi/L |
| Proporzione dei pazienti, tra coloro che presenteranno PLT < 100 Gi/L entro le prime 24 settimane, che manifesteranno lo "endpoint composito" (PLT <25 Gi / L o episodio di sanguinamento con WHO bleeding > 1 o interruzione studio), nelle prime 24 settimane, dopo aver sperimentato PLT <100 Gi / L |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
| Overall proportion of subjects experiencing the composite endpoint during the entire study period; Safety and tolerability in terms of frequency of adverse events (AE)s and serious adverse events (SAE). ; Proportion of cytogenetic responses, according to IWG 2006 criteria; Duration of cytogenetic response; Hb changes within the first 24 weeks; Erythroid response, transfusion-independence (TI) and duration of TI; Changes in QOL scores; 3-year PFS and OS from baseline; Proportion of patients maintaining a 10 mg lenalidomide dosing during the first 24 weeks and in the follow-up period |
| Percentuale complessiva dei soggetti che ha manifestato l'endpoint composito durante l'intero periodo di studio; Sicurezza e tollerabilità in termini di frequenza di eventi avversi (AE)s e di eventi avversi gravi (SAE); Percentuale di risposte citogenetiche, secondo i criteri IWG 2006; Duration of cytogenetic response; Cambiamenti di Hb nelle prime 24 settimane; Risposta eritroide, Trasfusione indipendenza (TI) e durata della TI; Cambiamenti degli scores di qualita di vita; PFS e OS a 3 anni dal basale; Percentuale dei pazienti che mantengono il dosaggio della Lenalidomide a 10 mg/die durante le prime 24 settimane e nel periodo di follow-up. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| 36 months; 36 months; 36 months; 36 months; 24 weeks; 36 months; 36 months; 36 mesi; 36 months |
| 36 mesi; 36 mesi; 36 mesi; 36 mesi; 24 settimane; 36 mesi; 36 mesi; 36 mesi; 36 mesi |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| 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 | 30 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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