Clinical Trial Results:
Elimination of the preleukemic clone in children with Down syndrome and transient myeloproloferative disorder (TMD) to prevent AML - Model of leukemia prevention
Summary
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EudraCT number |
2006-002962-20 |
Trial protocol |
DE NL |
Global end of trial date |
08 Feb 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
19 Jan 2025
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First version publication date |
19 Jan 2025
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Other versions |
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Summary report(s) |
Summary |
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 |
TMD01/2007
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Hannover Medical School
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Sponsor organisation address |
Carl-Neuberg-Str. 1, Hannover, Germany, 30625
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Public contact |
Zentrum für Klinische Studien, MHH, Hannover Medical School, EudraCT@mh-hannover.de
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Scientific contact |
Zentrum für Klinische Studien, MHH, Hannover Medical School, EudraCT@mh-hannover.de
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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 |
03 Dec 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
08 Feb 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Feb 2015
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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 demonstrate that monitoring of the GATA1s positive preleukemic clone in TMD and elimination of the clone with cytarabine can reduce the risk of DS-AMKL
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Protection of trial subjects |
The clinical trial was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and with the standards of International Conference on Harmonisation (ICH) Good Clinical Practice (GCP). A continuous risk assessment was performed during the study.
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Background therapy |
Monitoring of GATA1s positive preleukemic clones and low-dose cytaribine treatment in children with persisiting GATA1s clone according to a defined treatment algorithm. 43 patients were treated with Cytarabine, 27 received one cozrse, 10 two courses and six three courses of chemotheapy. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Jun 2007
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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 |
Germany: 224
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Country: Number of subjects enrolled |
Netherlands: 26
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Worldwide total number of subjects |
250
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EEA total number of subjects |
250
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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) |
97
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Infants and toddlers (28 days-23 months) |
153
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
0
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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 |
Enrollment to the study based on the diagnosis of transient leukemia within the first 4 weeks after birth, in-time initiation of the study site and the informed consent of the parents/guardians. Potentially in all 69 children’s hospitals with a department of pediatric hematology/oncology participating in the AML-BMF Studies (GER/NL). | |||||||||||||||
Pre-assignment
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Screening details |
Eligibility will be determined based upon the inclusion and exclusion criteria | |||||||||||||||
Period 1
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Period 1 title |
overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Not applicable
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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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TMD study population | |||||||||||||||
Arm description |
All children with trisomy 21 in Germany and the Netherlands that showed > 5% myeloid blasts or with detection of a GATA1-mutation (exon 1, 2, or 3) in the peripheral blood and/or bone marrow within the first 3 months of life were eligible for inclusion in the study. | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
cytarabin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion, Injection
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Routes of administration |
Intravenous use, Subcutaneous use
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Dosage and administration details |
Cytarabin 1,5mg/kgKG i.v./s.c. on day 1,2,3,4,5,6,7 (=one course) maximum treatment of three courses with blood count controls on day 0 or 1, day 4 and day 10 (including blood count,GOT and GST, creatinine)
cytostatic therapy indicated in following patients:
a)clinical symptoms due to TMD or "hepatopathy)
b) MRD ≤10-3MRD after 8 weeks
c) MRD: IP≤10-2 or qPCR≤10-3 after treatment
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Arm title
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Control Group | |||||||||||||||
Arm description |
The historical control group is a previously reported cohort of patients that were reported to the Acute Myeloid Leukemia Berlin-Frankfurt-Münster (AML-BFM) study group between 01 January 1993 and 31 December 2006 using similar criteria for in- and exclusion. | |||||||||||||||
Arm type |
historical control | |||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
TMD study population
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Reporting group description |
All children with trisomy 21 in Germany and the Netherlands that showed > 5% myeloid blasts or with detection of a GATA1-mutation (exon 1, 2, or 3) in the peripheral blood and/or bone marrow within the first 3 months of life were eligible for inclusion in the study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control Group
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Reporting group description |
The historical control group is a previously reported cohort of patients that were reported to the Acute Myeloid Leukemia Berlin-Frankfurt-Münster (AML-BFM) study group between 01 January 1993 and 31 December 2006 using similar criteria for in- and exclusion. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
TMD study population
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Reporting group description |
All children with trisomy 21 in Germany and the Netherlands that showed > 5% myeloid blasts or with detection of a GATA1-mutation (exon 1, 2, or 3) in the peripheral blood and/or bone marrow within the first 3 months of life were eligible for inclusion in the study. | ||
Reporting group title |
Control Group
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Reporting group description |
The historical control group is a previously reported cohort of patients that were reported to the Acute Myeloid Leukemia Berlin-Frankfurt-Münster (AML-BFM) study group between 01 January 1993 and 31 December 2006 using similar criteria for in- and exclusion. |
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End point title |
Incidence of acute megakaryoblastic leukemia | ||||||||||||
End point description |
The primary end point of the study was the cumulative incidence (CI) of ML-DS (constructed by the method of Kalbfleisch and Prentice) 3 years after diagnosis of TMD (3y-CI ML-DS). The null hypothesis (no difference from the historical control or higher rate in the study cohort) was tested using the 1-sided 95% confidence interval of the difference. In
addition, Gray’s test was used for comparisons.16 The secondary end point of the study was the MRD level (independent of prior treatment) at week 12.
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End point type |
Primary
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End point timeframe |
Outcome was assessed at 10 different time points: week 0, 4 to 8, 8, and 12, as well as month 6, 9, 12, 18, 24 and 36 after diagnosis.
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Statistical analysis title |
Control versus TMD | ||||||||||||
Statistical analysis description |
Historical Control versus TMD, three-years cumulative incidence of AMKL
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Comparison groups |
TMD study population v Control Group
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Number of subjects included in analysis |
247
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.62 | ||||||||||||
Method |
t-test, 1-sided | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.2
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Confidence interval |
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level |
95% | ||||||||||||
sides |
1-sided
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lower limit |
-8.9 | ||||||||||||
upper limit |
- | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.04
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Notes [1] - Efficacy: Main target criterion is the proportion of patients who survive the TMD and develop AMKL within 3 years after diagnosis. The null hypothesis (no difference to the historical control group, AMKL-rate 22%) has been tested with a one-sided 95% confidence interval for the difference of the 3-years cumulative incidence of AMKL. |
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End point title |
MRD level at week 12 [2] | ||||||||||||
End point description |
The secondary end point of the study was the MRD level at week 12 irrespective of prior intervention. (GATA1s negativity (sensitivity 10-4) at week 12)
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End point type |
Secondary
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End point timeframe |
12 week
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Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: The endpoint MRD level at week 12 was evaluated exclusively in the TMD study population in the current trial. |
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No statistical analyses for this end point |
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End point title |
Overall survival | ||||||||||||
End point description |
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End point type |
Other pre-specified
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End point timeframe |
three years period
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Statistical analysis title |
Control versus TMD, overall survival | ||||||||||||
Comparison groups |
TMD study population v Control Group
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Number of subjects included in analysis |
250
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Analysis specification |
Pre-specified
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Analysis type |
superiority [3] | ||||||||||||
P-value |
= 0.16 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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Notes [3] - The Kaplan-Meier method was used to estimate survival rates.17 The 2-sided logrank test was used to compare differences between different groups. Standard errors were obtained using Greenwoods formula. |
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End point title |
Eventfree survival | ||||||||||||
End point description |
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End point type |
Other pre-specified
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End point timeframe |
three years
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Statistical analysis title |
Control versus TMD, eventfree survival | ||||||||||||
Statistical analysis description |
The Kaplan-Meier method was used to estimate survival rates. The 2-sided logrank test was used to compare differences between different groups.
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Comparison groups |
TMD study population v Control Group
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Number of subjects included in analysis |
250
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.17 | ||||||||||||
Method |
Logrank | ||||||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Throughout the entire study period
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
NCI CTC | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
2.0
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Reporting groups
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Reporting group title |
TMD study population
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Reporting group description |
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Frequency threshold for reporting non-serious adverse events: 1% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/29959152 http://www.ncbi.nlm.nih.gov/pubmed/18182574 |