| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Alpha (a)-thalassemia |
| alfa (a)-talassemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| blood condition resulting in the impaired production of hemoglobin |
| condizione del sangue con conseguente ridotta produzione di emoglobina |
|
| 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 | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054659 |
| E.1.2 | Term | Thalassemia alpha |
| 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 | 10054659 |
| E.1.2 | Term | Thalassemia alpha |
| 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 compare the erythroid response of luspatercept plus BSC vs placebo plus BSC on anemia in participants with a-thalassemia HbH disease |
| Confrontare la risposta eritroide di luspatercept più BSC rispetto a placebo più BSC sull’anemia in partecipanti con a-talassemia HbH |
|
| E.2.2 | Secondary objectives of the trial |
| To compare the RBC transfusion burden effect of luspatercept plus BSC vs placebo plus BSC in participants with a-thalassemia HbH disease |
| Confrontare l’effetto del carico trasfusionale di RBC di luspatercept più BSC rispetto al placebo più BSC in partecipanti con a-talassemia HbH |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Participant has documented diagnosis of a-thalassemia HbH disease (electrophoresis- or high-performance liquid chromatography [HPLC] based methods for Hb variant analyses are accepted), with or without transfusion dependence; compounded combination with ß-thalassemia is allowed if at least 1 non-mutated ß-chain gene is present
-Transfusion dependence:
•TD participant >= 6 RBC units/24 weeks AND no transfusion-free period for > 56 days during the 24 weeks prior randomization
•NTD participant: < 6 RBC units during the 24 weeks prior to randomization, RBC transfusion-free during at least 8 weeks prior to randomization AND Mean baseline Hb = 10 g/dL
- Participant must be = 18 years of age at the time of signing the informed consent |
- Il partecipante ha una diagnosi documentata di a-talassemia HbH (sono accettati metodi basati su elettroforesi¿ o cromatografia liquida ad alta risoluzione [HPLC] per le analisi della variante dell’emoglobina [Hb]), con o senza dipendenza trasfusionale; è consentita la combinazione composta con ß-talassemia se è presente almeno 1 gene della catena ß non mutato
Dipendenza dalla trasfusione:
• Partecipante TD: >=6 unità di RBC/24 settimane E nessun periodo senza trasfusioni per >56 giorni durante le 24 settimane precedenti la randomizzazione
• Partecipante NTD: < 6 unità di globuli rossi durante le 24 settimane prima della randomizzazione, senza trasfusione di globuli rossi durante almeno 8 settimane prima della randomizzazione E Hb basale media = 10 g/dL
- I partecipanti devono avere un’età =18 anni al momento della firma del consenso informato |
|
| E.4 | Principal exclusion criteria |
- Diagnosis of a-thalassemia Trait, Hb Bart hydrops, ATRx a-thalassemia, hemoglobin S/ß-thalassemia, myelodysplasia subtype anemia, or with HbE homozygous beta gene mutation
- Anemia related to nutritional deficiency, anemia of chronic disease, autoimmune hemolytic anemia or any other hemolytic anemias (eg, severe G6PD deficiency, pyruvate kinase deficiency, etc)
- Bleeding disorders manifested by frequent bleeding episodes (eg, menorrhagia, epistaxis, clotting disorders)
- Undergone episodes of hemolysis not related to a-thalassemia, eg, after use of hemolysis predisposing drugs (eg, anti-malarial, nonsteroidal anti-inflammatory drug [NSAID]), within the 8 weeks prior to randomization
- Women who are pregnant, plan to get pregnant during the study, or who are breastfeeding
- Physical and Laboratory Test Findings
a) Platelet count > 1,000 × 109 /L b)
b) Thrombocytopenia with < 70 × 109 /L if not associated with hypersplenism
c) No concurrent or history of severe hepatic disease or histopathological evidence of liver cirrhosis/fibrosis on liver biopsy: i) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3× the upper limit of normal (ULN) ii) Albumin < 3 g/dL
d) Heart disease, heart failure as classified by the New York Heart Association (NYHA; see Appendix 6) classification 3 or higher, or significant arrhythmia requiring treatment, or recent myocardial infarction within 6 months of randomization
e) Lung disease, including pulmonary fibrosis or pulmonary hypertension, which are clinically significant (ie, >= Grade 3 per NCI-CTCAE version 5.0 [current active minor version])
f)Creatinine clearance < 60 mL/min (per Cockroft-Gault formula) or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 (per modification of diet in renal disease [MDRD] study)
g)Proteinuria >= Grade 3 according to NCI-CTCAE version 5.0 (current active minor version) or protein/creatinine ratio > 350 mg/mmol, or albumin/creatinine ratio > 220 mg/mmol
h)Active hepatitis C virus (HCV) infection, as demonstrated by a positive HCV-RNA test of sufficient sensitivity, or active infectious hepatitis B virus (HBV) as demonstrated by the presence of HBsAg and/or HBV DNA-positive, or known positive human immunodeficiency virus (HIV)
- Prior/Concomitant Therapy:
•Treatment with another investigational drug or device <= 30 days (or 5 half-lives, whichever is longer) prior to randomization
•Previous exposure to sotatercept (ACE-011) or luspatercept (BMS-986346/ACE-536)
•Use of an erythropoiesis-stimulating agent (ESA) <= 24 weeks prior to randomization
•Iron chelation therapy initiated <= 24 weeks prior to randomization
•Use of hydroxyurea treatment <= 24 weeks prior to randomization
•Prior exposure to gene therapy
•Undergone HSCT |
- Diagnosi di tratto a-talassemico, idrope da Hb di Bart, a-talassemia con ATRx, emoglobina S/ß-talassemia, anemia da sottotipo di mielodisplasia o con mutazione del gene beta omozigote di HbE
- Anemia correlata a deficit nutrizionale, anemia da malattia cronica, anemia emolitica autoimmune o qualsiasi altra anemia emolitica (ad es. grave deficit di G6PD, deficit di piruvato chinasi, ecc.)
- Disturbi emorragici manifestati da frequenti episodi emorragici (ad es. menorragia, epistassi, disturbi della coagulazione)
- Episodi di emolisi non correlati all’a-talassemia, per es. dopo l’uso di farmaci predisponenti all’emolisi (per es. antimalarici, farmaci antinfiammatori non steroidei [FANS]), nelle 8 settimane precedenti la randomizzazione
- Donne in gravidanza, che pianificano una gravidanza durante lo studio o che allattano al seno
- Precedente esposizione alla terapia genica per il trattamento dell’a-talassemia
- Trapianto di cellule staminali ematopoietiche (HSCT)
- Risultati degli esami fisici e di laboratorio
a) Conta piastrinica >1.000 × 109/l
b) Trombocitopenia con <70 x 109/l se non associata a ipersplenismo
c) Nessuna concomitante o anamnesi di malattia epatica grave o evidenza istopatologica di cirrosi/fibrosi epatica alla biopsia epatica: i) alanina aminotransferasi (ALT) o aspartato aminotransferasi (AST) >3 volte il limite superiore della norma (ULN) ii) albumina <3 g/dl
d) Cardiopatia, insufficienza cardiaca secondo la classificazione della New York Heart Association (NYHA; vedere Appendice 6) classificazione 3 o superiore, o aritmia significativa che richiede trattamento o recente infarto miocardico entro 6 mesi dalla randomizzazione
e) Malattia polmonare, inclusa fibrosi polmonare o ipertensione polmonare, clinicamente significativa (ovvero, >= grado 3 secondo i criteri NCI-CTCAE versione 5.0 [versione minore attiva corrente])
f) clearance della creatinina < 60 ml/min (secondo la formula di Cockroft-Gault) o velocità di filtrazione glomerulare stimata (eGFR) < 60 ml/min/1,73 m2 (per modifica della dieta nello studio sulla malattia renale [MDRD])
g) Proteinuria >= Grado 3 secondo i criteri NCI-CTCAE versione 5.0 (versione secondaria attiva corrente) o rapporto proteine/creatinina >350 mg/mmol o rapporto albumina/creatinina >220 mg/mmol
h)Infezione attiva da virus dell’epatite C (HCV), come dimostrato da un test HCV-RNA positivo di sensibilità sufficiente, o virus dell’epatite B (HBV) infettivo attivo come dimostrato dalla presenza di HBsAg e/o HBV DNA-positivo o virus dell’immunodeficienza umana (HIV) positivo noto
- Terapia precedente/concomitante:
•Trattamento con un altro farmaco o dispositivo sperimentale <= 30 giorni (o 5 emivite, a seconda di quale periodo sia più lungo) prima della randomizzazione
•Precedente esposizione a sotatercept (ACE-011) o luspatercept (BMS-986346/ACE-536)
•Uso di un agente stimolante l’eritropoiesi (ESA) <= 24 settimane prima della randomizzazione
•Terapia ferrochelante iniziata <= 24 settimane prima della randomizzazione
•Uso del trattamento con idrossiurea <= 24 settimane prima della randomizzazione
•Precedente esposizione alla terapia genica
•È stato sottoposto a HSCT |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Transfusion dependent
Achievement of >= 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 12 weeks during Weeks 13-48 compared to the 12-week interval immediately prior to the date of first dose
Non-Transfusion dependent
Achievement of an increase from baseline of >= 1.0 g/dL in mean hemoglobin values over the continuous 12-week interval from Week 13 to Week 24 in the absence of transfusion |
Dipendenza dalla trasfusione:
Raggiungimento di una riduzione =50% rispetto al basale del carico trasfusionale di RBCa con una riduzione di almeno 2 unità ogni 12 settimane consecutive durante le settimane 13-48 rispetto all’intervallo di 12 settimane immediatamente prima della data della prima dose
Non dipendenza dalla trasfusione:
Raggiungimento di un aumento rispetto alla baseline di >= 1.0 g/dL nei valori medi di emoglobina nell’intervallo continuo di 12 settimane dalla Settimana 13 alla Settimana 24 in assenza di trasfusione |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 13 to Week 24 |
| Dalla Settimana 13 alla Settimana 24 |
|
| E.5.2 | Secondary end point(s) |
Transfusion dependent
Achievement of = 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 24-week interval on treatment compared to the 24-week interval immediately prior to the date of first dose
The longest duration with = 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units
Number of RBC transfusion units from Week 1 to Week 48
Non-Transfusion dependent
Change from baseline to Week 24 in hemoglobin in the absence of transfusion
The longest duration of an increase from baseline of = 1.0 g/dL in mean hemoglobin values starting from Week 13 in the absence of transfusion
The cumulative time (in weeks) with an increase from baseline of = 1.0 g/dL in hemoglobin values in the absence of transfusion within 48 weeks
Achievement of = 3 FACT-An FS score increase from baseline to Week 13 to Week 24 |
Transfusion dependent
Achievement of = 33% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units during any continuous 24-week interval on treatment compared to the 24-week interval immediately prior to the date of first dose
The longest duration with = 50% reduction from baseline in RBC transfusion burden with a reduction of at least 2 units
Number of RBC transfusion units from Week 1 to Week 48
Non-Transfusion dependent
Change from baseline to Week 24 in hemoglobin in the absence of transfusion
The longest duration of an increase from baseline of = 1.0 g/dL in mean hemoglobin values starting from Week 13 in the absence of transfusion
The cumulative time (in weeks) with an increase from baseline of = 1.0 g/dL in hemoglobin values in the absence of transfusion within 48 weeks
Achievement of = 3 FACT-An FS score increase from baseline to Week 13 to Week 24 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Up to 6 years |
| Up to 6 years |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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 | No |
| 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 | 4 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| China |
| Taiwan |
| Thailand |
| Greece |
| Italy |
| Turkey |
|
| 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
|
| End of trial is defined as the date all participants complete the OLP, if eligible, or discontinue earlier, or the date of receipt of the last data point from the last participant that is required for primary, secondary, and/or exploratory analysis as prespecified in the protocol, whichever is the later date |
| End of trial is defined as the date all participants complete the OLP, if eligible, or discontinue earlier, or the date of receipt of the last data point from the last participant that is required for primary, secondary, and/or exploratory analysis as prespecified in the protocol, whichever is the later date |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| 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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