E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Leukemia and immunedeficiency syndromes |
Leukemie en immuundeficientie syndromen |
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E.1.1.1 | Medical condition in easily understood language |
Leukemia and immune disorders |
Leukemie en immuunstoornissen |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | SOC |
E.1.2 | Classification code | 10021428 |
E.1.2 | Term | Immune system disorders |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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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 | 10024329 |
E.1.2 | Term | Leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate whether an individualized dosing regimen for Thymoglobulin leads to a better immune reconstitution after HCT (definition as in primary endpoint), as compared to historically non-individualized treated patients receiving Thymoglobulin as a fixed dose per kilogram body weight. The individualized dosing regimen is based on a previously treated pediatric cohort on which a population PK-PD analysis was performed. The dosing regimen was compiled using this cohort, taking into account the influence of body weight and pre-Thymoglobulin lymphocyte count and the observed variability. |
Het doel van dit onderzoek is het onderzoeken van de effecten van een geïndividualiseerd doseerregime voor Thymoglobuline op immuunherstel na HCT. Hierbij worden de uitkomsten vergeleken met historische niet-geindividualiseerd behandelde patiënten die Thymoglobuline kregen in een vaste dosis uitgedrukt in mg/kg. |
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E.2.2 | Secondary objectives of the trial |
not applicable |
niet van toepassing |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All patients eligible for a non-haplo-identical non-T-cell depleted HCT with Thymoglobulin as part of the conditioning regimen treated in the pediatric ward of the UMCU Utrecht or the LUMC Leiden
• Any stem cell source
• First transplantation
• Age at time of transplantation < 18 years
• Signed written informed consent according to local law and regulations
• Lansky/Karnofsky ≥ 80% |
Patiënten geschikt voor een non-haplo-identical non-T-cell gedepleteerde HCT met Thymoglobulin als onderdeel van de standaardbehandeling behandeld op de kinderafdeling van het UMC Utrecht of het LUMC Leiden.
• Elke bron van stamcellen
• Eerste transplantatie
• Leeftijd op het moment van transplantatie < 18 years
• getekend informed consent volgens wettelijke voorschriften en regelingen
• Lansky/Karnofsky schaal ≥ 80% |
|
E.4 | Principal exclusion criteria |
• Ex-vivo T-cell depleted grafts
• Other serotherapy in conditioning (e.g. Campath, or Campath in the bag)
• Received serotherapy within 3 months before this transplantation
• Pregnancy or breast-feeding or unwilling to use adequate contraceptive methods
• Sensibility to rabbit proteins or previous treatment with Thymoglobulin or other rabbit ATG
• Acute or chronic infections, in which each form of immune suppression is contra-indicated
• Patients not planned to receive or having received at least 90% or more than 110% of the intentioned dose of Thymoglobulin
• Ejection fraction < 30% or shortening fraction < 15%
• No complete morphological remission (CR-status) in bone marrow in case of malignancy
• History of serious immune-mediated reactions or hypersensitivity to any biological product
• Participation in other trial in which the dose of Thymoglobulin is fixed to amounts other than the individualized dose.
|
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of CD4+ T-cell immune reconstitution, defined as a CD4+ T-cell count > 50 x 10e6/L in 2 consecutive measurements within 100 days. |
CD4+ T-cell immuunherstel, gedefinieerd als een CD4+ T-cell getal > 50 x 10^6/L in 2 opeenvolgende metingen binnen 100 dagen. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Survival (overall survival, event free survival, non-relapse mortality, relapse mortality)
• Relapse incidence
• Incidence of viral reactivations (CMV, Adenovirus, EBV, HHV6, BK-virus)
• Acute graft versus host disease (according to Glucksberg criteria)
• Chronic graft versus host disease (according to Shulman criteria)
• Engraftment defined as a neutrophil count > 0.5 x 109/L with use of granulocyte-colony stimulating factor (G-CSF) within 40 days
• Rejection defined as >95% recipient chimerism, or reinfusion of donor cells after successful engraftment
• Prospective validation of the pharmacokinetic model
• Lymphocyte subset reconstitution monitored throughout the treatment (including some rare populations) for future studies |
Survival (overall survival, event free survival, therapie-gerelateerde mortaliteit, recidief-gerelateerde mortaliteit)
• Incidentie recidieven van maligniteiten
• Incidentie van virale reactivaties (CMV, Adenovirus, EBV, HHV6, BK-virus)
• Acute graft versus host disease (volgens Glucksberg criteria)
• Chronische graft versus host disease (volgens Shulman criteria)
• Engraftment gedefinieerd als een neutrofielengetal van > 0.5 x 10^9/L onder granulocyte-colony stimulating factor (G-CSF) binnen 40 days
• Afstoting gedefinieerd als >95% patient chimerisme, of reinfusie van donorcellen na succesvolle engraftment
• Prospectieve validatie van het PK-model
• Reconstitutie van lymfocyten subsets gedurende de behandeling (inclusief zeldzame populaties) voor toekomstige studies |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Within 6 months after last visit of last patient |
Binnen 6 maanden na laatste bezoek van laatste patient |
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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) | 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 | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Historische controles |
Historic controls |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | No |
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 | No |
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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LVLS |
Laatste patient laatste visite |
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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 | 3 |
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 | 3 |