E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Graft versus host disease |
Malattia del trapianto verso l’ospite |
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E.1.1.1 | Medical condition in easily understood language |
Graft-versushost disease in patients receiving hematopoietic cell transplant |
Malattia del trapianto verso l’ospite in pazienti che hanno ricevuto un trapianto di cellule ematopoietiche |
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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 | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10018651 |
E.1.2 | Term | Graft versus host disease |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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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 evaluate the efficacy of AAT at the selected dose for the prevention of acute GVHD following HCT. |
L’obiettivo primario è valutare l'efficacia di AAT alla dose scelta per la prevenzione della GVHD acuta in seguito all’HCT. |
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E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of AAT, including the prevention of post-hematopoietic cell transplant complications.
2. To evaluate the safety of AAT, based on incidence of systemic infections and related adverse events.
3. To evaluate the pharmacokinetics of AAT in HCT recipients.
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1. Valutare ulteriormente l’efficacia di AAT, compresa la prevenzione di complicanze post-HCT. 2. Valutare la sicurezza di AAT in base all’incidenza di eventi avversi (AE) correlati al farmaco in studio. 3. Valutare la farmacocinetica (PK) di AAT allo stato stazionario nei riceventi di HCT. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female subjects, =12 years of age, undergoing HCT for hematological malignancies, including leukemia, lymphoma multiple myeloma, myelodysplastic syndrome, and myeloproliferative neoplasms. 2. Planned myeloablative conditioning regimen (see eligible regimens in Table 9). 3. Subjects must have an unrelated donor matched or mismatched (ie, 7/8 or 6/8) for HLA-A, -B, and -C at intermediate (or higher) resolution, or -DRB1 at high resolution using DNA-based typing. 4. Cardiac function: Ejection fraction at rest = 45.0% or shortening fraction of = 27.0% by echocardiogram or radionuclide scan (MUGA). 5. Estimated creatinine clearance greater than 50.0 mL/minute. 6. Pulmonary function: Diffusing capacity of the lung for carbon monoxide = 50% (adjusted for hemoglobin) of the predicted normal value, and forced expiratory volume in one second (FEV1) or forced vital capacity (FVC) = 50% of the predicted normal value. 7. Liver function: total bilirubin < 2x the upper limit of normal (unless elevated bilirubin is attributed to Gilbert's Syndrome) and alanine aminotransferase/ aspartate aminotransferase < 3.0x the upper limit of normal. 8. Signed written informed consent obtained before undergoing any study-specific procedures. |
1. Soggetti maschi o femmine, di età = 12 anni, sottoposti a HCT per neoplasie ematologiche, tra cui leucemia, linfoma, mieloma multiplo, sindrome mielodisplastica e neoplasie mieloproliferative. 2. Regime di condizionamento mieloablativo programmato (si vedano i regimi idonei nella Tabella 9). 3. I soggetti devono presentare una compatibilità o una non compatibilità (cioè, 7/8 o 6/8) con un donatore non parente per HLA-A, -B e -C a risoluzione media (o superiore), oppure -DRB1 a risoluzione alta mediante la tipizzazione basata sul DNA. 4. Funzionalità cardiaca: Frazione di eiezione a riposo = 45,0% oppure frazione di accorciamento = 27,0% mediante ecocardiogramma o scintigrafia (MUGA). 5. Clearance della creatinina stimata superiore a 50,0 mL/minuto. 6. Funzionalità polmonare: Capacità polmonare di diffusione del monossido di carbonio = 50% (aggiustata per l’emoglobina) del valore normale previsto, e volume respiratorio forzato in un secondo (Forced Expiratory Volume, FEV1) oppure capacità vitale forzata (Forced Vital Capacity, FVC) = 50% del valore normale previsto. 7. Funzionalità epatica: bilirubina totale < 2 volte il limite superiore di normalità (a meno che l’aumento della bilirubina non sia attribuito alla sindrome di Gilbert) e alanina aminotransferasi/aspartato aminotrasferasi < 3,0 volte il limite superiore di normalità. 8. Consenso informato scritto firmato ottenuto prima di sottoporre il soggetto a qualunque procedura specifica dello studio. |
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E.4 | Principal exclusion criteria |
1. Prior autologous or allogeneic HCT. 2. T-cell depleted transplant or planned use of anti-T cell antibody therapy either ex vivo or in vivo (ie, anti-thymocyte globulin [ATG], alemtuzumab) for GVHD prophylaxis. 3. Planned umbilical cord blood transplant. 4. Karnofsky Performance Score < 70%. 5. Active central nervous system involvement by malignant cells. 6. Uncontrolled bacterial, viral or fungal infections (currently taking medication and with progression or no clinical improvement) at time of enrollment. 7. Seropositive for human immunodeficiency virus (HIV)-1 or -2. 8. Seropositive for Human T-Lymphotrophic Virus-I or –II. 9. Active Hepatitis B or C viral replication by polymerase chain reaction. 10. Subjects who have received previous genetically engineered chimeric antigen receptor T-cell therapy (eg, CTL019, tisagenlecleucel, axicabtagene ciloleucel) as these patients are lifelong B-cell deficient and could have increased risk of infection. |
1. Precedente HCT autologo o allogenico. 2. Trapianto impoverito di cellule T oppure adozione programmata di una terapia di anticorpi anti-cellule T ex vivo oppure in vivo (ossia globulina antitimociti [Anti-Thymocyte Globulin, ATG], alemtuzumab) per la profilassi per GVHD. 3. Trapianto di sangue del cordone ombelicale programmato. 4. Punteggio scala di Karnofsky < 70%. 5. Coinvolgimento attivo del sistema nervoso centrale da parte delle cellule neoplastiche. 6. Infezioni batteriche, virali o fungine non controllate (in corso di assunzione di farmaci e con progressione o senza miglioramento clinico) al momento dell’arruolamento. 7. Sieropositività al virus dell’immunodeficienza umana (Human Immunodeficiency Virus, HIV) -1 o -2. 8. Sieropositività al virus umano T-linfotropico di tipo I o II. 9. Replicazione virale attiva di epatite B o C mediante reazione a catena della polimerasi. 10. Soggetti in precedenza sottoposti a terapia con cellule T modificate geneticamente con recettori chimerici per l’antigene (es. CTL019, tisagenlecleucel, axicabtagene ciloleucel), poiché trattasi di pazienti affetti da deficienza permanente di cellule B che potrebbero presentare un maggior rischio di infezione. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Grade II-IV acute graft versus host disease-free survival (aGFS)
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Sopravvivenza libera da GVHD acuta di grado II-IV (aGFS) nei 180 giorni post-HCT. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Through 180 days post-hematopoietic cell transplantation (HCT)
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Attraverso 180 giorni di trapianto di cellule post-ematopoietiche (HCT) |
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E.5.2 | Secondary end point(s) |
-Percent of subjects with Grade II-IV aGVHD or death (aGFS)
-Percent of subjects with Grade II-IV acute GVHD
-Percent of subjects with Grade III-IV acute GVHD
-Number of subjects with all-cause mortality
-Percent of subjects with Grade II aGVHD
-Percent of subjects with Grade III aGVHD
-Percent of subjects with Grade IV aGVHD
-Time to all-cause mortality
-Time to non-relapse mortality
-Percent of subjects with moderate-to-severe chronic GVHD
-Percent of subjects with discontinuation of immune suppression
-Time to neutrophil engraftmen
-Time to GVHD relapse-free survival
-Percent of subjects with relapse of primary malignancies
-Percent of subjects with systemic infections
-Percent of subjects with study drug related adverse events
-Maximum concentration (Cmax) of AAT
-Area under the concentration curve (AUC) for AAT
-Clearance (CL) of AAT
-Volume of distribution (V) for AAT |
- Incidenza di aGVHD di grado II-IV o mortalità nei 100 giorni e nei 180 giorni post-HCT - Incidenza di aGVHD di grado II-IV nei 100 giorni e 180 giorni post-HCT - Incidenza di aGVHD di Grado III-IV nei 100 giorni e 180 giorni post-HCT - Incidenza di aGVHD di Grado II, III o IV nei 100 giorni e 180 giorni post-HCT - Incidenza di mortalità per tutte le cause nei 180 giorni e 365 giorni post-HCT - Tempo intercorso fino alla mortalità per tutte le cause nei 365 giorni post-HCT - Tempo intercorso fino alla mortalità non per recidiva nei 365 giorni post-HCT - Incidenza di GVHD cronica medio-grave nei 180 giorni e 365 giorni post-HCT - Incidenza di interruzione della soppressione immunitaria nei 180 giorni e 365 giorni post-HCT - Tempo intercorso fino all’attecchimento dei neutrofili - Sopravvivenza libera da recidiva di GVHD nei 365 giorni post-HCT - Incidenza della recidiva di neoplasie primarie nei 180 e 365 giorni post-HCT - Incidenza di infezioni sistemiche ai Giorni 60 e 180 post-HCT - Incidenza di AE correlati al farmaco in studio |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Through 100 days and 180 days post-HCT
-Within 100 and 180 days post-HCT
-Within 100 and 180 days post-HCT
-Within 180 and 365 days post-HCT
-Within 100 and 180 days post-HCT
-Within 100 and 180 days post-HCT
-Within 100 and 180 days post-HCT
-Up to 365 days post-HCT
-Up to 365 days post-HCT
-Within 180 and 365 days post-HCT
-Within 180 and 365 days post-HCT
-Up to 365 days post-HCT
-Up to 365 days post-HCT
-Within 180 and 365 days post-HCT
-At Days 60 and 180 post-HCT
-Up to 365 days post-HCT
-Before and up to 72 after infusion of AAT
-Before and up to 72 after infusion of AAT
-Before and up to 72 after infusion of AAT
-Before and up to 72 after infusion of AAT |
-Tra 100 giorni e 180 giorni post-HCT -Entro 100 e 180 giorni post-HCT -Entro 100 e 180 giorni post-HCT -Con 180 e 365 giorni post-HCT -Entro 100 e 180 giorni post-HCT -Entro 100 e 180 giorni post-HCT -Entro 100 e 180 giorni post-HCT Fino a 365 giorni post-HCT Fino a 365 giorni post-HCT -Con 180 e 365 giorni post-HCT -Con 180 e 365 giorni post-HCT Fino a 365 giorni post-HCT Fino a 365 giorni post-HCT -Con 180 e 365 giorni post-HCT -A giorni 60 e 180 post-HCT Fino a 365 giorni post-HCT -Prima e fino a 72 dopo l'infusione di AAT -Prima e fino a 72 dopo l'infusione di AAT -Prima e fino a 72 dopo l'infusione di AAT -Prima e fino a 72 dopo l'infusione di AAT |
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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 | Yes |
E.6.3 | Therapy | No |
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 | Yes |
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) | 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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Sequenziale: i soggetti ricevono interventi dopo aver raggiunto gli obiettivi precedenti, ad es. Stu |
Sequential: Subjects receive interventions after reaching prior milestones, eg dose escalation study |
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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 | 5 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 |
United States |
Belgium |
France |
Germany |
Hungary |
Italy |
Poland |
Spain |
Sweden |
United Kingdom |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |
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 |