E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Graft Versus Host Disease |
Malattia acuta da trapianto contro l'ospite |
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E.1.1.1 | Medical condition in easily understood language |
Acute Graft Versus Host Disease (Complication of Bone Marrow Transplants) |
Malattia acuta da trapianto contro l'ospite (complicanza dei trapianti di midollo osseo) |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
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 | 10018799 |
E.1.2 | Term | GVHD |
E.1.2 | System Organ Class | 100000004870 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 22.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10059044 |
E.1.2 | Term | Allogeneic peripheral hematopoietic stem cell transplant |
E.1.2 | System Organ Class | 100000004865 |
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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 assess the efficacy of itolizumab versus placebo as initial therapy for aGVHD in combination with corticosteroids in achieving early disease response. |
Valutare l'efficacia di itolizumab rispetto al placebo come terapia iniziale per l'aGVHD in combinazione con corticosteroidi nel raggiungimento di una risposta precoce alla malattia. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the durability of response to itolizumab versus placebo as initial therapy for aGVHD in combination with corticosteroids. • To evaluate systemic corticosteroid use in subjects treated with itolizumab versus placebo. • To assess the impact of itolizumab versus placebo on other clinically relevant efficacy measures, including survival outcomes and cGVHD incidence. • To evaluate the safety and tolerability of itolizumab versus placebo as initial therapy for aGVHD in combination with corticosteroids |
• Valutare la durata della risposta a itolizumab rispetto al placebo come terapia iniziale per l'aGVHD in combinazione con corticosteroidi. • Valutare l'uso sistemico di corticosteroidi nei soggetti trattati con itolizumab rispetto al placebo. • Valutare l'impatto di itolizumab rispetto al placebo su altre misure di efficacia clinicamente rilevanti, inclusi i risultati di sopravvivenza e l'incidenza di cGVHD. • Valutare la sicurezza e la tollerabilità di itolizumab rispetto al placebo come terapia iniziale per l’aGVHD in combinazione con corticosteroidi. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age= 12 years and >40 kg at informed consent/assent. Subjects <18 years may only enroll after the initial DMC data review, if locally permitted. - Has had an initial allogeneic HSCT for any indication using any graft source, donor source, conditioning regimen intensity or prophylaxis. - Has evidence of myeloid engraftment, defined as an absolute neutrophil count =500/mm3 (or =0.5 × 10exp9/L) achieved and sustained for 3 laboratory values obtained on different days. Laboratory values prior to Screening may be used. - Has a clinical diagnosis of aGVHD Grades III-IV or Grade II with LGI involvement based on Mount Sinai Acute GVHD International Consortium (MAGIC) grading criteria. Biopsies to confirm aGVHD should be obtained but are not required and should not delay entry into the study. - Began systemic corticosteroid treatment for aGVHD =72 hours prior to the start of study drug dosing AND must receive 2 mg/kg/day methylprednisolone or equivalent on Day 1. |
- Età = 12 anni e >40 kg al consenso informato/assenso. I soggetti di età inferiore a 18 anni possono essere arruolati solo dopo la revisione iniziale dei dati DMC, se consentito a livello locale. - Ha avuto un HSCT allogenico iniziale per qualsiasi indicazione utilizzando qualsiasi fonte di innesto, fonte di donatore, intensità del regime di condizionamento o profilassi. - Presenta evidenza di attecchimento mieloide, definito come una conta assoluta dei neutrofili =500/mm3 (o =0,5 × 10exp9/L) raggiunta e mantenuta per 3 valori di laboratorio ottenuti in giorni diversi. Possono essere utilizzati valori di laboratorio prima dello screening. - Ha una diagnosi clinica di aGVHD di Grado III-IV o Grado II con coinvolgimento di LGI in base ai criteri di classificazione del Mount Sinai Acute GVHD International Consortium (MAGIC). Le biopsie per confermare l'aGVHD dovrebbero essere ottenute ma non sono richieste e non dovrebbero ritardare l'ingresso nello studio. - Ha iniziato il trattamento sistemico con corticosteroidi per aGVHD =72 ore prima dell'inizio della somministrazione del farmaco in studio E deve ricevere 2 mg/kg/die di metilprednisolone o equivalente il giorno 1. |
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E.4 | Principal exclusion criteria |
- Has evidence of morphological relapsed, progressive, persistent, or untreated malignancy, with the exception of nonmelanoma skin cancer and in situ ductal carcinoma of the breast. - Has an unplanned donor lymphocyte infusion for persistent or recurrent malignancy after HSCT. - Has evidence of persistent molecular disease requiring treatment (eg, standard chemotherapy or tyrosine kinase inhibitors) that was not specified prior to HSCT. -Has evidence of cGVHD or overlap syndrome, as defined by 2014 NIH Consensus Criteria. - Is using immunosuppressants other than corticosteroids for the treatment of aGVHD. Continued use of immunosuppressants as GVHD prophylaxis agents is permitted. - Has received any systemic corticosteroids of >0.5 mg/kg/day methylprednisolone or equivalent for any indication other than aGVHD within 7 days before the onset of aGVHD. Systemic corticosteroids administered as premedication before blood product transfusions or IV medications to prevent infusion-related reactions are allowed. - Has a clinically active, uncontrolled bacterial, viral, or fungal infection, despite adequate treatment. No signs of progression of the infection can be present at randomization. Asymptomatic cytomegalovirus (CMV), Epstein–Barr virus (EBV), or human Herpesvirus 6 (HHV-6) viremia based on viral load or a viral load that is declining with treatment does not constitute a clinically active infection.
Other protocol-defined exclusion criteria apply. |
- Presenta evidenza di neoplasia morfologica recidivante, progressiva, persistente o non trattata, ad eccezione del carcinoma cutaneo non melanoma e del carcinoma duttale in situ della mammella. - Ha un'infusione di linfociti del donatore non pianificata per tumore maligno persistente o ricorrente dopo HSCT. - Presenta evidenza di malattia molecolare persistente che richiede un trattamento (p. es., chemioterapia standard o inibitori della tirosin-chinasi) che non è stata specificata prima dell'HSCT. -Ha evidenza di cGVHD o sindrome da sovrapposizione, come definito dai 2014 NIH Consensus Criteria. - Utilizza immunosoppressori diversi dai corticosteroidi per il trattamento dell'aGVHD. È consentito l'uso continuato di immunosoppressori come agenti di profilassi della GVHD. - Ha ricevuto corticosteroidi sistemici >0,5 mg/kg/die di metilprednisolone o equivalente per qualsiasi indicazione diversa da aGVHD entro 7 giorni prima dell'insorgenza di aGVHD. Sono consentiti corticosteroidi sistemici somministrati come premedicazione prima di trasfusioni di emoderivati ¿¿o farmaci per via endovenosa per prevenire reazioni correlate all'infusione. - Presenta un'infezione batterica, virale o fungina clinicamente attiva, non controllata, nonostante un trattamento adeguato. Alla randomizzazione non possono essere presenti segni di progressione dell'infezione. La viremia asintomatica da citomegalovirus (CMV), virus di Epstein-Barr (EBV) o viremia umana da Herpesvirus 6 (HHV-6) basata sulla carica virale o una carica virale che diminuisce con il trattamento non costituisce un'infezione clinicamente attiva.
Si applicano altri criteri di esclusione definiti dal protocollo. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint Complete Response rate at Day 29. |
Endpoint primario Tasso di risposta completo al giorno 29. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Key secondary endpoints: 1) Overall response rate at day 29 2) Durable complete response rate from Day 29 through Day 99 |
Endpoint secondari chiave: 1) Tasso di risposta complessivo al giorno 29 2) Tasso di risposta completo e duraturo dal giorno 29 al giorno 99 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) Day 29 2) Day 29 through Day 99 |
1) Giorno 29 2) Dal giorno 29 al giorno 99 |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 57 |
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 |
Australia |
Canada |
India |
Israel |
Korea, Republic of |
United States |
Belgium |
France |
Germany |
Italy |
Portugal |
Spain |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |