Clinical Trial Results:
Allogenic stem cell transplantation in children and adolescents with acute lymphoblastic leukaemia
Summary
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EudraCT number |
2005-005106-23 |
Trial protocol |
AT IT |
Global end of trial date |
31 Dec 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
12 Apr 2024
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First version publication date |
12 Apr 2024
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ALLSCT06BFMi
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01423500 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
St. Anna Kinderkrebsforschung GmbH
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Sponsor organisation address |
Zimmermannplatz 10, Vienna , Austria, 1090
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Public contact |
Univ.Prof. Dr. Ruth Ladenstein, St. Anna Kinderkrebsforschung GmbH, +43 1 40470 4750, ruth.ladenstein@ccri.at
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Scientific contact |
Univ.Prof. Dr. Christina Peters,
St. Anna Kinderkrebsforschung GmbH, +43 1 40410 3100, christina.peters@stanna.at
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
21 Dec 2023
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Dec 2021
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
*To evaluate whether HSCT from matched family or unrelated donors
(MD) is equivalent to the HSCT from matched sibling donors (MSD)
*To evaluate the efficacy of HSCT from mismatched family or unrelated
donors (MMD) as compared to HSCT from MSD/MD.
*To determine whether therapy has been carried out according to the
main HSCT protocol recommendations. The standardisation of the
treatment options during HSCT from different donor types aims at the
achievement of an optimal comparison of survival after HSCT with survival after chemotherapy only.
*To prospectively evaluate and compare the incidence of acute and chronic GvHD after HSCT from MSD, from MD and from MMD.
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Protection of trial subjects |
Detailed supportive care measures have been specified in the trial protocol.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
21 Feb 2007
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Austria: 40
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Country: Number of subjects enrolled |
Italy: 23
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Country: Number of subjects enrolled |
Czechia: 34
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Country: Number of subjects enrolled |
Denmark: 19
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Country: Number of subjects enrolled |
France: 71
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Country: Number of subjects enrolled |
Israel: 14
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Country: Number of subjects enrolled |
Netherlands: 50
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Country: Number of subjects enrolled |
Poland: 131
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Country: Number of subjects enrolled |
Slovakia: 17
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Country: Number of subjects enrolled |
Sweden: 5
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Country: Number of subjects enrolled |
Turkey: 46
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Worldwide total number of subjects |
450
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EEA total number of subjects |
390
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
19
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Children (2-11 years) |
276
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Adolescents (12-17 years) |
146
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Adults (18-64 years) |
9
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment in the period from 21.02.2007 until 9 September 2011 in 12 countries. | ||||||||||||
Pre-assignment
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Screening details |
Principal inclusion criteria: - age at time of initial diagnosis or relapse ≤18 years (until 19th birthday) - indication for hematopoietic stem cell transplantation (HSCT) - complete remission - no pregnancy - no secondary malignancy - no previous HSCT - written consent | ||||||||||||
Period 1
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Period 1 title |
Overall study period (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Matched Sibling Donor (MSD) | ||||||||||||
Arm description |
HSCT with HLA-genotypically identical sibling donor or a 10 out of 10 (high resolution – 4 digits per allel) matched sibling donor if the parental haplotypes are unknown. Assigned Interventions: TBI/VP16 based conditioning regimen for patients older than 24 months - VP16 at a dose of 60mg/kg/d on day -3; Total body irradiation (TBI) at a dose of 2x2Gy/day for 3 days (total 12Gy in 6 fractions) on days -6, -5, -4. Patients younger than 24 months receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). Patients with ALL and translocation t(4;11) who receive stem cells from a MSD or MD and infants with indication for allogeneic HSCT (according to the INTERFANT-protocol) are prepared for HSCT with a specific triple-drug-conditioning: Bu (BW adjusted)/Cyclo (60 mg/kg)/MEL (140mg/m2). | ||||||||||||
Arm type |
Active comparator | ||||||||||||
Investigational medicinal product name |
Etoposid/VP16
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Investigational medicinal product code |
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Other name |
Etopophos
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Etoposide is administered as a single infusion over 4 hours. The dosage is 60mg/kg BW (maximum 1800mg/m2 BS, absolute dose 3,6 g max. ) or 40mg/kg BW (maximum 1200mg/m2 BS, absolute dose 2,4 g max.) respectively, depending on the conditioning regimen. The infusion is to be performed in accordance with the guidelines of the transplantation centre. VP16 is administered on day -3 in patients with TBI or on day -4 before allogeneic HSCT in those without TBI. If etoposide phosphate is used, the dosage is adapted to the aliquot etoposide according to the recommendations of the pharmaceutical drug description.
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Investigational medicinal product name |
Melphalan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Melphalan is given intravenous once at a dose of 140 mg/m2. Melphalan is chemically instable in solution and should be given as soon as possible (within 1 hour) after being dissolved. It can only be diluted with normal saline and may not come in contact with glucose. Parenteral nutrition containing amino acids has to be stopped 2 hours before administration of Melphalan to prevent competition with cellular uptake of the drug.
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Investigational medicinal product name |
Cyclophosphamid
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total dose for Cyclophosphamide is 120 mg/kg BW. It is administered in 2 single doses of 60mg/kg given over 1 hour i.v. on 2 consecutive days (-3 and -2). Between the last BUX application and the infusion of CYCLO an interval of 24 hours is mandatory.
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Investigational medicinal product name |
Busulfan
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Investigational medicinal product code |
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Other name |
Busilfex®
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
BUX is given at weight-adjusted doses. As i.v. Busulfan is registered as orphan drug and because of its more predictable pharmacology and decreased hepatic toxicity by lack of first-pass effect, only i.v. Busulfan is used in this study. BUX is administered in 16 single doses. The BUX infusions are given over 2 hours in six hours distance on 4 consecutive days. Seizure prophylaxis with Phenytoin is started before Busulfan i.v. application, continued for 2 days after the last dose, and then tapered.
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Arm title
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Matched Donor (MD) | ||||||||||||
Arm description |
HSCT with related or unrelated stem cell donors, 10 or 9 out of 10 HLA matches determined by high resolution typing (4 digits per allele) and MMD BM 8/10. Assigned Interventions: TBI/VP16 based conditioning regimen - VP16 (60mg/kg/d on day -3); Total body irradiation (TBI) (2x2Gy/day over 3 days on day -6, -5, -4); Patients younger than 24 months receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). ATG is given to both age groups at a dose of 20mg/kg/d on days -3, -2, -1. Patients with ALL and translocation t(4;11) who receive stem cells from a MSD or MD and infants with indication for allogeneic HSCT (according to the INTERFANT-protocol) are prepared for HSCT with a specific triple-drug-conditioning: Bu (BW adjusted)/Cyclo (60 mg/kg)/MEL (140mg/m2). | ||||||||||||
Arm type |
Active comparator | ||||||||||||
Investigational medicinal product name |
Etoposid/VP16
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Investigational medicinal product code |
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Other name |
Etopophos
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Etoposide is administered as a single infusion over 4 hours. The dosage is 60mg/kg BW (maximum 1800mg/m2 BS, absolute dose 3,6 g max. ) or 40mg/kg BW (maximum 1200mg/m2 BS, absolute dose 2,4 g max.) respectively, depending on the conditioning regimen. The infusion is to be performed in accordance with the guidelines of the transplantation centre. VP16 is administered on day -3 in patients with TBI or on day -4 before allogeneic HSCT in those without TBI. If etoposide phosphate is used, the dosage is adapted to the aliquot etoposide according to the recommendations of the pharmaceutical drug description.
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Investigational medicinal product name |
Melphalan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Melphalan is given intravenous once at a dose of 140 mg/m2. Melphalan is chemically instable in solution and should be given as soon as possible (within 1 hour) after being dissolved. It can only be diluted with normal saline and may not come in contact with glucose. Parenteral nutrition containing amino acids has to be stopped 2 hours before administration of Melphalan to prevent competition with cellular uptake of the drug.
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Investigational medicinal product name |
Cyclophosphamid
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total dose for Cyclophosphamide is 120 mg/kg BW. It is administered in 2 single doses of 60mg/kg given over 1 hour i.v. on 2 consecutive days (-3 and -2). Between the last BUX application and the infusion of CYCLO an interval of 24 hours is mandatory.
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Investigational medicinal product name |
Busulfan
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Investigational medicinal product code |
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Other name |
Busilfex®
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
BUX is given at weight-adjusted doses. As i.v. Busulfan is registered as orphan drug and because of its more predictable pharmacology and decreased hepatic toxicity by lack of first-pass effect, only i.v. Busulfan is used in this study. BUX is administered in 16 single doses. The BUX infusions are given over 2 hours in six hours distance on 4 consecutive days. Seizure prophylaxis with Phenytoin is started before Busulfan i.v. application, continued for 2 days after the last dose, and then tapered.
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Investigational medicinal product name |
ATG Fresenius
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
ATG-Fresenius S is an anti-human T-lymphocyte immunoserum which is obtained from rabbits immunised with human T-lymphoblasts of the Jurkat cell-line. ATG-Fresenius S is administered at a dose of 20 mg/kg BW on three consecutive days (day –3 until day –1). The infusion is hypotonic and may only be dissolved with normal saline. Furthermore, Heparin may not be administered as mixed infusion or via the same vascular access, as this can lead to a shift in the pH-value. The infusion may be given over 4 hours, and a premedication with steroids (max. 2mg/kg BW) is recommended. The respective emergency medicines need to be ready for immediate intervention, and frequent checks of the vital parameters are required.
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Arm title
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Mismatched Donor (MMD) | ||||||||||||
Arm description |
Patients with a MMD receive stem cells extracted from bone marrow, cord blood or peripheral blood from a haploidentical donor (parent) or from a non-related donor with a match less or equal to 8/10. Assigned Interventions for patients with a BM 8/10 donor and older than 24 months: TBI/VP16 based conditioning regimen - VP16 (60mg/kg/d on day -3); Total body irradiation (TBI) (2x2Gy/day over 3 days on day -6, -5, -4); Patients younger than 24 months with a BM 8/10 donor receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). They all receive ATG (20mg/kg/d on day -3,-2,-1). Assigned Interventions for patients with Haploidentical and cord blood HSCT: Fludarabine (30mg/m²/d on day -9 to -5), OKT3 (0,0125-0,1mg/kg on day -9 to 0), ATG fresenius (20mg/kg/d on day -3,-2,-1), Treosulfan (14g/m²/d on day -7 to -5) and Thiotepa (2x5mg/kg/d on day -4). | ||||||||||||
Arm type |
Active comparator | ||||||||||||
Investigational medicinal product name |
Etoposid/VP16
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Investigational medicinal product code |
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Other name |
Etopophos
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Etoposide is administered as a single infusion over 4 hours. The dosage is 60mg/kg BW (maximum 1800mg/m2 BS, absolute dose 3,6 g max. ) or 40mg/kg BW (maximum 1200mg/m2 BS, absolute dose 2,4 g max.) respectively, depending on the conditioning regimen. The infusion is to be performed in accordance with the guidelines of the transplantation centre. VP16 is administered on day -3 in patients with TBI or on day -4 before allogeneic HSCT in those without TBI. If etoposide phosphate is used, the dosage is adapted to the aliquot etoposide according to the recommendations of the pharmaceutical drug description.
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Investigational medicinal product name |
ATG Fresenius
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
ATG-Fresenius S is an anti-human T-lymphocyte immunoserum which is obtained from rabbits immunised with human T-lymphoblasts of the Jurkat cell-line. ATG-Fresenius S is administered at a dose of 20 mg/kg BW on three consecutive days (day –3 until day –1). The infusion is hypotonic and may only be dissolved with normal saline. Furthermore, Heparin may not be administered as mixed infusion or via the same vascular access, as this can lead to a shift in the pH-value. The infusion may be given over 4 hours, and a premedication with steroids (max. 2mg/kg BW) is recommended. The respective emergency medicines need to be ready for immediate intervention, and frequent checks of the vital parameters are required.
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Investigational medicinal product name |
Busulfan
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Investigational medicinal product code |
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Other name |
Busilfex®
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Pharmaceutical forms |
Concentrate for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
BUX is given at weight-adjusted doses. As i.v. Busulfan is registered as orphan drug and because of its more predictable pharmacology and decreased hepatic toxicity by lack of first-pass effect, only i.v. Busulfan is used in this study. BUX is administered in 16 single doses. The BUX infusions are given over 2 hours in six hours distance on 4 consecutive days. Seizure prophylaxis with Phenytoin is started before Busulfan i.v. application, continued for 2 days after the last dose, and then tapered.
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Investigational medicinal product name |
Fludarabine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Patients with Mismatched Family Donor (MMFD) HSCT receive Fludarabine i.v. as single dose of 40mg/m2 over 30 minutes at noon for 4 consecutive days. The total dose is 160 mg/m2.
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Investigational medicinal product name |
Treosulfan
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Treosulfan is an alkylating agents with a half-life of 88 minutes. It is administered at a dose of 14g/m²/d for 3 days (total dose 42g/m²) and for babies < 9kg BW 12g/m²/d for 3 days (total dose 36g/m²). The infusion is given over 1 hour. The solution remains stable at room temperature for 4 days.
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Investigational medicinal product name |
Orthoclone OKT3
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
OKT3 is a murine monoclonal antibody with specific affect against a glycoprotein of the CD-3 complex on human T-lymphocytes. T
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Investigational medicinal product name |
Thiotepa
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Concentrate and solvent for solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Thiopeta is an alkylating agents with cytolytic and radiomimetic effects. It is administered at a dose of 2x5mg/kg for 1 day (total dose 10mg/kg) and for babies < 9 kg BW 2x3,5mg/kg for 1 day (total dose 7mg/kg).
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Investigational medicinal product name |
Cyclophosphamid
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Powder for solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Total dose for Cyclophosphamide is 120 mg/kg BW. It is administered in 2 single doses of 60mg/kg given over 1 hour i.v. on 2 consecutive days (-3 and -2). Between the last BUX application and the infusion of CYCLO an interval of 24 hours is mandatory.
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Baseline characteristics reporting groups
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Reporting group title |
Overall study period
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
MSD
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients with MSD (matched sibling donor), having indication for HSCT from MD or MMD
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Subject analysis set title |
MD
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients with MD (matched donor), having indication for HSCT from MD or MMD
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Subject analysis set title |
MMD
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients with MMD (mismatched donor), having indication for HSCT from MMD
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Subject analysis set title |
MSD/MD
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Patients with MSD or MD (matched sibling donor or matched donor), having indication for HSCT from MMD
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End points reporting groups
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Reporting group title |
Matched Sibling Donor (MSD)
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Reporting group description |
HSCT with HLA-genotypically identical sibling donor or a 10 out of 10 (high resolution – 4 digits per allel) matched sibling donor if the parental haplotypes are unknown. Assigned Interventions: TBI/VP16 based conditioning regimen for patients older than 24 months - VP16 at a dose of 60mg/kg/d on day -3; Total body irradiation (TBI) at a dose of 2x2Gy/day for 3 days (total 12Gy in 6 fractions) on days -6, -5, -4. Patients younger than 24 months receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). Patients with ALL and translocation t(4;11) who receive stem cells from a MSD or MD and infants with indication for allogeneic HSCT (according to the INTERFANT-protocol) are prepared for HSCT with a specific triple-drug-conditioning: Bu (BW adjusted)/Cyclo (60 mg/kg)/MEL (140mg/m2). | ||
Reporting group title |
Matched Donor (MD)
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Reporting group description |
HSCT with related or unrelated stem cell donors, 10 or 9 out of 10 HLA matches determined by high resolution typing (4 digits per allele) and MMD BM 8/10. Assigned Interventions: TBI/VP16 based conditioning regimen - VP16 (60mg/kg/d on day -3); Total body irradiation (TBI) (2x2Gy/day over 3 days on day -6, -5, -4); Patients younger than 24 months receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). ATG is given to both age groups at a dose of 20mg/kg/d on days -3, -2, -1. Patients with ALL and translocation t(4;11) who receive stem cells from a MSD or MD and infants with indication for allogeneic HSCT (according to the INTERFANT-protocol) are prepared for HSCT with a specific triple-drug-conditioning: Bu (BW adjusted)/Cyclo (60 mg/kg)/MEL (140mg/m2). | ||
Reporting group title |
Mismatched Donor (MMD)
|
||
Reporting group description |
Patients with a MMD receive stem cells extracted from bone marrow, cord blood or peripheral blood from a haploidentical donor (parent) or from a non-related donor with a match less or equal to 8/10. Assigned Interventions for patients with a BM 8/10 donor and older than 24 months: TBI/VP16 based conditioning regimen - VP16 (60mg/kg/d on day -3); Total body irradiation (TBI) (2x2Gy/day over 3 days on day -6, -5, -4); Patients younger than 24 months with a BM 8/10 donor receive Bu (BW adjusted)/VP16 (40mg/kg)/Cyclo (60 mg/kg). They all receive ATG (20mg/kg/d on day -3,-2,-1). Assigned Interventions for patients with Haploidentical and cord blood HSCT: Fludarabine (30mg/m²/d on day -9 to -5), OKT3 (0,0125-0,1mg/kg on day -9 to 0), ATG fresenius (20mg/kg/d on day -3,-2,-1), Treosulfan (14g/m²/d on day -7 to -5) and Thiotepa (2x5mg/kg/d on day -4). | ||
Subject analysis set title |
MSD
|
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Patients with MSD (matched sibling donor), having indication for HSCT from MD or MMD
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Subject analysis set title |
MD
|
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Patients with MD (matched donor), having indication for HSCT from MD or MMD
|
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Subject analysis set title |
MMD
|
||
Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Patients with MMD (mismatched donor), having indication for HSCT from MMD
|
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Subject analysis set title |
MSD/MD
|
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
Patients with MSD or MD (matched sibling donor or matched donor), having indication for HSCT from MMD
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End point title |
EFS (Event free survival) | ||||||||||||||||||||
End point description |
Event are defined as: leukemic relapse at any site, secondary malignancy, death of any cause.
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End point type |
Primary
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End point timeframe |
Starting point of the analysis: date of HSCT. End point of the analysis is the date of event or the last available follow up date.
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Statistical analysis title |
EFS (study question 1) | ||||||||||||||||||||
Statistical analysis description |
The null hypothesis was that HSCT from MD was inferior to SCT from MSD.
The calculation is done by a one-sided confidence interval for the difference of the Kaplan-Meier estimates of 4-year Event-free Survival (EFS) between both subgroups.
Only patients with indication for MD or MMD were included into this analysis.
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Comparison groups |
MSD v MD
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Number of subjects included in analysis |
345
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
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Analysis type |
non-inferiority [1] | ||||||||||||||||||||
Method |
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Parameter type |
Difference of KM estimates of 4y-EFS | ||||||||||||||||||||
Point estimate |
0.04
|
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Confidence interval |
|||||||||||||||||||||
level |
95% | ||||||||||||||||||||
sides |
1-sided
|
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lower limit |
- | ||||||||||||||||||||
upper limit |
0.14 | ||||||||||||||||||||
Notes [1] - One sided confidence interval of the difference of the Kaplan-Meier (KM) estimates of the 4-years EFS of both subgroups (MSD and MD) is calculated. Hematopoietic stem cell transplantation from a matched donor (MD) is considered non-inferior to that from a matched sibling donor (MSD) if the pEFS of patients from MD does not fall below that of patients from MSD by more than 0.15. |
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Statistical analysis title |
EFS (study question 2) | ||||||||||||||||||||
Statistical analysis description |
Kaplan-Meier method was used to estimate EFS, and Log Rank test to compare both subgroups.
Null hypothesis: The EFS of patients with MMS does not differ from that of patients with MSD/MD.
Only patients with indication for MMD were included into this analysis.
|
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Comparison groups |
MMD v MSD/MD
|
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Number of subjects included in analysis |
223
|
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Analysis specification |
Pre-specified
|
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Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.08 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
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End point title |
Occurrence of acute Graft-versus-Host-Disease (GvHD) | ||||||||||||||||||||
End point description |
The incidence of acute GvHD equals the proportion of patients with at least one episode of acute GvHD > grade I up to Day+100 after HSCT.
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End point type |
Secondary
|
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End point timeframe |
The period up to day +100 after HSCT.
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Statistical analysis title |
Comparison of acute GVHD grade > 1 - MSD vs MD | ||||||||||||||||||||
Comparison groups |
MSD v MD
|
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Number of subjects included in analysis |
345
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.562 | ||||||||||||||||||||
Method |
Fisher exact | ||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
Statistical analysis title |
Comparison of acute GVHD grade > 1 - MSD/MD vs MMD | ||||||||||||||||||||
Comparison groups |
MMD v MSD/MD
|
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Number of subjects included in analysis |
223
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.349 | ||||||||||||||||||||
Method |
Fisher exact | ||||||||||||||||||||
Confidence interval |
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End point title |
Occurrence of chronic Graft-versus-Host-Disease (GvHD) | ||||||||||||||||||||
End point description |
The incidence of GvHD equals the proportion of patients with at least one episode of chronic GvHD (limited or extended) up to a period of five years after HSCT.
These endpoint was estimated using the approach of Prentice and Kalbfleisch, allowing for competing risks, which were death in remission and relapse.
|
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End point type |
Secondary
|
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End point timeframe |
Time period between the HSCT and end of 5-year Follow-up.
|
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Statistical analysis title |
Comparison of chronic GVHD - MSD vs MD | ||||||||||||||||||||
Comparison groups |
MSD v MD
|
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Number of subjects included in analysis |
345
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.003 | ||||||||||||||||||||
Method |
Gray | ||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
Statistical analysis title |
Comparison of chronic GVHD - MSD and MD vs MMD | ||||||||||||||||||||
Comparison groups |
MMD v MSD/MD
|
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Number of subjects included in analysis |
223
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.979 | ||||||||||||||||||||
Method |
Gray | ||||||||||||||||||||
Confidence interval |
|
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End point title |
OS (Overall survival) | ||||||||||||||||||||
End point description |
|||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
Starting point of the analysis: date of HSCT. End point is the date of death of any cause or the last available follow up date.
|
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Statistical analysis title |
(OS study question 1) | ||||||||||||||||||||
Statistical analysis description |
Kaplan-Meier method was used to estimate OS, and the Log Rank test to compare both subgroups.
Only patients with indication for MD and MMD were used for this analysis.
|
||||||||||||||||||||
Comparison groups |
MSD v MD
|
||||||||||||||||||||
Number of subjects included in analysis |
345
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.336 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
Statistical analysis title |
(OS study question 2) | ||||||||||||||||||||
Statistical analysis description |
Kaplan-Meier method was used to estimate OS, and the Log Rank test to compare both subgroups.
Only patients with indication for MD and MMD were used for this analysis.
|
||||||||||||||||||||
Comparison groups |
MMD v MSD/MD
|
||||||||||||||||||||
Number of subjects included in analysis |
223
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.02 | ||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||
Confidence interval |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Period from start of conditioning until end of 5-year follow-up
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Adverse event reporting additional description |
All adverse events that occur from start of conditioning are reported in the patient’s records and according to national standards on adverse event reporting. Those meeting the definition of a serious adverse event must be reported using the Serious Adverse Event (SAE) Report form.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
3
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Reporting groups
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Reporting group title |
MSD (matched sibling donors)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
MD (matched family or unrelated donors)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
MMD (mismatched donors)
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: Non-serious adverse events have not been reported explicitly, but rather the maximum grade of toxicity for each of the predefined toxicity categories and time intervals. |
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Frequency threshold for reporting non-serious adverse events: 0.5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
28 Aug 2009 |
Extension of recruitment for 2 further years;
Definition of HSCT options and stem cell source for patients with a MMD donor;
Complement and new conditioning schemes for MMD HSCT;
Exclusion of TBI based conditioning for MMD HSCT;
Definition of GvHD prophylaxis;
Correction of study period;
Additional consent for patients reaching 18 years of age during participation in a study, |
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Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
|||
http://www.ncbi.nlm.nih.gov/pubmed/31319153 |