E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with acute myeloid leukaemia (AML)or myelodysplastic syndrome (MDS) considered ineligible to standard conditioning therapies prior to allogenic stem cell transplantation |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000881 |
E.1.2 | Term | Acute myeloid leukaemia (in remission) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028534 |
E.1.2 | Term | Myelodysplastic syndrome NOS |
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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 |
This randomised controlled clinical trial is designed to show at least non-inferiority of treosulfan based conditioning to reduced-intensity conditioning therapy based on i.v. busulfan and to compare the associated safety profiles. The aim of the study is to compare event-free survival within 1 year after the transplantation between treosulfan-based conditioning and busulfan-base conditioning. Events are defined as relapse of desease, graft failure or death (whatever occurs first). |
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E.2.2 | Secondary objectives of the trial |
1. Comparative evaluation of incidence of CTC grade III/IV mucositis/stomatitis between day - 6 and day + 28. 2. Comparative evaluation of overall survival (OS) and cumulative incidence of relapse (RI), non-relapse mortality (NRN) and transplantation-related mortality (TRM). 3. Comparative evaluation of day + 28 conditional comulative incidence of engraftment. 4. Comparative evaluation of day + 28 and day + 100 incidence of complete donor-type chimerism. 5. Comparative evaluation of cumulative incidence of acute and chronic GvHD. 6. Comparative evaluation of incidence of other CTC grade III/IV adverse events between day - 6 and day +28. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with acute myeloid leukemia acc. to WHO, 2001 (AML in complete remission at transplant, i.e. blast counts < 5 % in bone marrow) or myelodysplastic syndrome acc. to WHO, 2001 (MDS with blast counts < 20 % in bone marrow during disease history) indicated for allogeneic haematopoietic progenitor cell transplantation but considered to be at increased risk for standard conditioning therapies according to the following criteria: - patients aged &#8805; 50 years at transplant and / or - patients with a HCT-CI score> 2 [acc. to Sorror et al,, 2005]. 2. Availability of an HLA-identical sibling donor (MRD) or HLAidentical unrelated donor (MUD). Donor selection is based on molecular high-resolution typing (4 digits) of class Il alleles of the DRB1 and DQB1 gene loci and molecular (at least) low-resolution typing (2 digits) of class I alleles (i.e., antigens) of the HLA-A, B and C gene loci. In case, no class I and class II completely identical donor (10 out of 10 gene loci) can be identified, one antigen disparity (class I) and/or one allele disparity (class Il) between patient and donor are acceptable. Conversely, disparity of two antigens (irrespective of the involved gene loci) cannot be accepted. These definitions for the required degree of histocompatibility apply to the selection of related as well as unrelated donors. 3. Adult patients of both gender, age 18 - 70 years. 4. Karnofsky Index &#8805; 60%. 5. Written informed consent. 6. Men capable of reproduction and women of childbearing potential must be willing to consent using a highly effective metod of birth control such as condoms, implants, injectables, combined oral contraceptives, IUDs, sexual abstinence or vasectomised partner while on treatment and for at least 6 mounths thereafter. |
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E.4 | Principal exclusion criteria |
1. Patients with acute promyelocytic leukaemia with t(15;17)(q22;q12) in CR1. 2. Patients considered contra-indicated for allogeneic HSCT due to severe concomitant Illness (within three weeks prior to scheduled day -6): - patients with severe renal impairment like patients on dialysis or prior renal transplantation or S-creatinine> 3.0 x ULN or calculated creatinine-clearance < 60 ml/min; -patients with severe pulmonary impairment, DLCO/or FEV1 <50 % or severe dyspnoea at rest or requiring oxygen supply; - patients with severe cardiac impairment diagnosed by echocardiography and LVEF <40 % ; - patients with severe hepatic impairment indicated by hyperbilirubinaemia > 3 x ULN or ALT/AST> 5 x ULN . 3. Active malignant involvement of the CNS. 4. HIV-positivity, active non-controlled infectious disease under treatment (no decrease of CRP or PCT) including active viral liver infection. 5. Previous allogeneic HSCT. 6. Pleural effusion or ascites> 1.0 L. 7. Pregnancy or Lactation. 8 Known hypersensitivity to treosulfan, busulfan and/or related ingredients. 9. Participation in another experimental drug trial within 4 weeks prior to day - 6 of the protocol. 10. Non-cooperative behavior or non-compliance. 11. Psychiatric diseases or conditions that might compromise the ability to give informed consent. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Event-free survival (EFS) within 1 year after transplantation measured from time of start of HSCT (= day 0) to time of event. Events are defined as relapse of disease, graft failure or death (whatever occurs first). |
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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 | 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) | 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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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
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Come da protocollo (Capitolo 5.4) l`ultimo paziente verra` incluso nel secondo trimestre 2012. Poiche` il follow up dei pazienti dura 1 anno dopo il trapianto l`ultima visita dell`ultimo paziente e` prevista per il secondo trimestre del 2013. |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | |
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 | 6 |