Clinical Trial Results:
Comparison between 5 – azacytidine treatment and 5 – azacytidine followed by allogeneic stem cell transplantation in elderly patients with advanced MDS according to donor availability
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Summary
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EudraCT number |
2010-018467-42 |
Trial protocol |
DE |
Global end of trial date |
31 Jan 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
29 Sep 2021
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First version publication date |
29 Sep 2021
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Other versions |
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Summary report(s) |
Clinical study report Synopsis |
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 |
VidazaAlloStudy
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Additional study identifiers
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ISRCTN number |
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US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Universitätsklinikum Hamburg Eppendorf
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Sponsor organisation address |
Martinistrasse 52, Hamburg, Germany, 20246
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Public contact |
Principal Investigator, University Medical Center Hamburg Eppendorf, +49 40741055864, n.kroeger@uke.uni-hamburg.de
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Scientific contact |
Principal Investigator, University Medical Center Hamburg Eppendorf, +49 40741055864, n.kroeger@uke.uni-hamburg.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 |
13 Aug 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Jan 2019
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Jan 2019
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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 compare the overall survival at three years of patients who receive after 4 cycles of 5-azacytidine (Vidaza®) either allogeneic stem cell transplantation or continuous 5-azacytidine (Vidaza®) if no compatible donor is available.
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines, the general principles indicated in the Declaration of Helsinki, and all applicable regulatory requirements. Prior to study initiation the study protocol was reviewed and approved by an Independent Ethics Committee (IEC). The study, all study procedures and the risks and benefits were explained to the subjects by responsible investigators and written informed consent were collected prior to any study related examinations.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
04 Jul 2011
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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 |
Germany: 108
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Worldwide total number of subjects |
108
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EEA total number of subjects |
108
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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) |
0
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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) |
65
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From 65 to 84 years |
43
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85 years and over |
0
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Recruitment
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Recruitment details |
This study was conducted in Germany. 15 active study centers were involved. | |||||||||
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Pre-assignment
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Screening details |
- Screening periode: up to 28 days before first day of 5-Azacytidine administration - Pre-assignement period: start with 4 cycles of 5-azacytidine | |||||||||
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Pre-assignment period milestones
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Number of subjects started |
162 [1] | |||||||||
Number of subjects completed |
108 | |||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Adverse event, serious fatal: 12 | |||||||||
Reason: Number of subjects |
patient progressed: 26 | |||||||||
Reason: Number of subjects |
Adverse event, non-fatal: 7 | |||||||||
Reason: Number of subjects |
Consent withdrawn by subject: 2 | |||||||||
Reason: Number of subjects |
others: 7 | |||||||||
| Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: There were 190 patients assessed for eligibility. 20 patients were screening failures + 8 patients were discontinued from study for other reasons. 162 patients started the pre-assignement period (Start with 4 cycles of 5-azacytidine). |
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Period 1
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Period 1 title |
Treatment 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 | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Arm A: continued 5-Azacitidine | |||||||||
Arm description |
After 4 cycles of 5-aza all patients with response or stable disease were assigned to arm A (continued 5-azacyidine) until disease progression or unacceptable toxicity if no HLA compatible (10/10 alleles) donor had been found. | |||||||||
Arm type |
Active comparator | |||||||||
Investigational medicinal product name |
5-Azacyidine
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Investigational medicinal product code |
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Other name |
Vidaza
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Pharmaceutical forms |
Powder for solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
5-azacytidine 75 mg/m² day 1-7 (qd 28)
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Arm title
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Arm B: Allogeneic stem cell transplantation | |||||||||
Arm description |
After 4 cycles of 5-aza all patients with response or stable disease were assigned to arm B if an HLA-compatible donor had been identified (10/10 alleles). Patients assigned to allogeneic stem cell transplantation could receive up to 6 cycles of 5-aza if transplantation could not be performed immediately. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Allogeneic hematopoietic stem cells (allo-HSC)
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Investigational medicinal product code |
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Other name |
CD34+/ CD45+-cells
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
4-8 × 106 CD34+/ CD45+-cells per kg of body weight (allogen)
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Baseline characteristics reporting groups
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Reporting group title |
Arm A: continued 5-Azacitidine
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Reporting group description |
After 4 cycles of 5-aza all patients with response or stable disease were assigned to arm A (continued 5-azacyidine) until disease progression or unacceptable toxicity if no HLA compatible (10/10 alleles) donor had been found. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Arm B: Allogeneic stem cell transplantation
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Reporting group description |
After 4 cycles of 5-aza all patients with response or stable disease were assigned to arm B if an HLA-compatible donor had been identified (10/10 alleles). Patients assigned to allogeneic stem cell transplantation could receive up to 6 cycles of 5-aza if transplantation could not be performed immediately. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Arm A: continued 5-Azacitidine
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Reporting group description |
After 4 cycles of 5-aza all patients with response or stable disease were assigned to arm A (continued 5-azacyidine) until disease progression or unacceptable toxicity if no HLA compatible (10/10 alleles) donor had been found. | ||
Reporting group title |
Arm B: Allogeneic stem cell transplantation
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Reporting group description |
After 4 cycles of 5-aza all patients with response or stable disease were assigned to arm B if an HLA-compatible donor had been identified (10/10 alleles). Patients assigned to allogeneic stem cell transplantation could receive up to 6 cycles of 5-aza if transplantation could not be performed immediately. | ||
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End point title |
Overall survival at three years between both treatment arms | |||||||||
End point description |
To compare the overall survival at three years of patients who receive after 4 cycles of 5-azacytidine (Vidaza®) (and achieve at least stable disease) either allogeneic stem cell transplantation or continuous 5-azacytidine (Vidaza®) if no compatible donor is available.
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End point type |
Primary
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End point timeframe |
three years after start in both arms
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Statistical analysis title |
Primary statistical analysis | |||||||||
Statistical analysis description |
The primary endpoint overall survival at three years between both treatment arms was analysed with a two-sided z-test based on the Kaplan-Meier rates by using Greenwood’s formula. All two-sided alphas were 5%. One hundred and twelve days were added to all rates to represent the initial 5-aza therapy.
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Comparison groups |
Arm A: continued 5-Azacitidine v Arm B: Allogeneic stem cell transplantation
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Number of subjects included in analysis |
108
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Analysis specification |
Post-hoc
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Analysis type |
other | |||||||||
P-value |
= 0.5 | |||||||||
Method |
t-test, 2-sided | |||||||||
Confidence interval |
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End point title |
Comparison of event free survival in both treatment arms | |||||||||
End point description |
events being disease progression, relapse after complete remission or partial remission, death from any cause
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End point type |
Secondary
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End point timeframe |
at three years
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| No statistical analyses for this end point | ||||||||||
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End point title |
Comparison of treatment-related mortality in both treatment arms | |||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
at 1 year
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| No statistical analyses for this end point | ||||||||||
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End point title |
Comparison of response rate in both treatment arms | |||||||||
End point description |
The response rates were reported for each treatment arm with two-sided Pearson-Clopper confidence intervals and were tested for difference using the chi-squared test.
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End point type |
Secondary
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End point timeframe |
over the time period of 3 years
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All AEs were collected from the time point of signed inform consent, regardless of the relationship to the treatment. All AEs were collected and documented by investigators in the eCRF. SAEs were reported within 24 hours by Investigators to Sponsor.
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Adverse event reporting additional description |
Sponsor sent annual report of Serious Suspected Adverse Reaction (SSAR) to PEI + EC + Celgene GmbH (or on demand). SUSARs were sent within 15 days to PE +EC+Investigators by Sponsor (within 7 days if event is fatal or life-threatening).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.1
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Reporting groups
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Reporting group title |
Arm A : continous 5-Aza
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Reporting group description |
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Reporting group title |
Arm B: allogeneic stem cell transplantation
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Reporting group description |
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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26 Apr 2017 |
Changes of statistican; changes in secondary study endpoints; accrual of patients changed to 5.5 years; End of study changed to January 2019; Changes for statistical analysis: sample size estimation changed into 3 years + 112 days after study inclusion; number of patients reduced to 110 patients; Interim Analysis: efficacy interim analysis at 30-NOV-2017; changes in SAE classification (administration change only); additions on criteria to define event-free survival; Patient Information/Written Consent updated and changed to Version 04, 01.08.2013. |
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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. | |||
| SAE Listing represents an extract of the main SAEs occurred in this study. | |||
