Clinical Trial Results:
Prophylactic infusion of CD4 positive donor lymphocytes early after T-cell depleted stem cell transplantation
Summary
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EudraCT number |
2008-001447-19 |
Trial protocol |
NL |
Global end of trial date |
01 May 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
30 Nov 2021
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First version publication date |
30 Nov 2021
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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 |
LUMCCD4PROTOCOL
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Additional study identifiers
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ISRCTN number |
ISRCTN51398568 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Leids Universitair Medisch Centrum, department of hematology
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Sponsor organisation address |
Albinusdreef 2, Leiden, Netherlands, 2333ZA
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Public contact |
Dr. P van Balen, LUMC, department of hematology, 0031 715262267, P.van_Balen@lumc.nl
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Scientific contact |
Dr. P van Balen, LUMC, department of hematology, 0031 715262267, P.van_Balen@lumc.nl
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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 |
10 Nov 2021
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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 |
01 May 2020
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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 CD4+ lymphocytes infusion given three months after T-cell depleted allogeneic SCT improves immunological recovery (number of circulating CD4+ lymphocytes) with an incidence of GvHD requiring systemic treatment not exceeding 30% of the patients.
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Protection of trial subjects |
Patients are closely monitored in our outpatient clinic on a regular basis. A structured anamnesis was performed, as well as physical anamnesis and laboratory results. Furthermore bone marrow examination was performed (morphology, flow cytometry, bone marrow chimerism) at regular intervals ( after transplantation: 3 months, 4.5 months, 6 months, 9 months, 12 months).
(local lab, physical exam and structured anamnesis).
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Background therapy |
All patients after alloSCT are monitored and treated according to local guidelines with regards to immunosuppressive treatment, antibiotic treatment. | ||
Evidence for comparator |
At the time of initiation of this study all patients were eligible for prophylactic DLI 6 months after alloSCT. To assess whether prophylactic CD4 DLI 3 months after alloSCT would be benificial in addition to unmodified DLI at 6 months, we compared patients in the control group (treated according to standard protocol and eligible for prophylactic unmodified DLI 6 months after alloSCT) to the experimental arm with prophylactic CD4 DLI at 3 months (the expirimental arm was also eligible to receive unmodified prophylactic DLI at 6 months. | ||
Actual start date of recruitment |
04 Jan 2008
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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 |
Netherlands: 66
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Worldwide total number of subjects |
66
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EEA total number of subjects |
66
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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) |
56
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From 65 to 84 years |
10
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85 years and over |
0
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Recruitment
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Recruitment details |
All adult patients treated with 10/10 HLA matched alemtuzumab based T-cell depleted stem cell transplantation from a related donor in the Leiden University medical center are eligible for inclusion. Patients were recruited between and 4 January 2008 and 1 May 2020 in the departement of hematology. | |||||||||||||||
Pre-assignment
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Screening details |
Inclusion criteria: concomitant disease, WHO performance status of 0-2, Life expectancy longer than 3 months and providing informed consent. Exclusion criteria: progressive disease, severe GVHD, systemic immunosuppressive treatment, pregnancy, positive HIV test | |||||||||||||||
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 |
Randomised - controlled
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Blinding used |
Not blinded | |||||||||||||||
Blinding implementation details |
Patients were randomized to receive either CD4 DLI or no treatment at 3 months after alloSCT. All patients were eligible to receive unmodified DLI at 6 months.
Both patient and doctor were aware of randomization arm.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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CD4+ donor lymfocyten infusion | |||||||||||||||
Arm description |
Infusion of 1 x 10^6 CD4+ T-cells/kg 3 months after alloSCT | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
CD4 positive lymphocytes
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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 |
Infusion
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Dosage and administration details |
1x 10^6 CD4+ T cells/kg infused once at 3 months after alloSCT
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Arm title
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Control | |||||||||||||||
Arm description |
No intervention 3 months. Patients are eligible to receive unmodified DLI 6 months after alloSCT according to standard LUMc protocol | |||||||||||||||
Arm type |
No intervention | |||||||||||||||
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 |
CD4+ donor lymfocyten infusion
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Reporting group description |
Infusion of 1 x 10^6 CD4+ T-cells/kg 3 months after alloSCT | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Control
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Reporting group description |
No intervention 3 months. Patients are eligible to receive unmodified DLI 6 months after alloSCT according to standard LUMc protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
CD4+ donor lymfocyten infusion
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Reporting group description |
Infusion of 1 x 10^6 CD4+ T-cells/kg 3 months after alloSCT | ||
Reporting group title |
Control
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Reporting group description |
No intervention 3 months. Patients are eligible to receive unmodified DLI 6 months after alloSCT according to standard LUMc protocol |
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End point title |
CD4+ T-cell counts 6 months after alloSCT | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
The primary endpoint (CD4+ T-cell counts) is measured 3 months after randomization (6 months after alloSCT).
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Notes [1] - 4 patients did not survive until 3 months after alloSCT |
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Statistical analysis title |
CD4+ T-cell counts at 3 months | ||||||||||||
Statistical analysis description |
Mann Whitney U test between CD4+ T-cell counts the two treatment arms at 3 months after inclusion
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Comparison groups |
Control v CD4+ donor lymfocyten infusion
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Number of subjects included in analysis |
61
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.2917 | ||||||||||||
Method |
Wilcoxon (Mann-Whitney) | ||||||||||||
Confidence interval |
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End point title |
severe GvHD | |||||||||
End point description |
Cumulative incidence of GvHD requiring immunosuppressive treatment. We used a competing risk analysis with relapse, unmodified DLI and death as competing events.
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End point type |
Primary
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End point timeframe |
3 months after randomization
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Attachments |
Untitled (Filename: competing events at 3 months.png) Untitled (Filename: GvHD.png) |
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Statistical analysis title |
Cumulative incidence | |||||||||
Statistical analysis description |
Comparing cumulative incidence of developing GvHD requiring immunosuppressive treatment with log-rank test.
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Comparison groups |
CD4+ donor lymfocyten infusion v Control
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||
P-value |
= 0.8 | |||||||||
Method |
Logrank | |||||||||
Confidence interval |
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End point title |
Overall survival | |||||||||
End point description |
Probability of overall survival after randomization in intention to treat analysis
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End point type |
Secondary
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End point timeframe |
up to 5 years after randomization
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Attachments |
Untitled (Filename: Overall survival.png) |
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Statistical analysis title |
Overall Survival | |||||||||
Statistical analysis description |
Overall survival between two treatment arms
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Comparison groups |
CD4+ donor lymfocyten infusion v Control
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||
P-value |
= 0.5 | |||||||||
Method |
Logrank | |||||||||
Confidence interval |
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End point title |
Relapse | |||||||||
End point description |
Relapse requiring systemic treatment during follow-up. Competing risk analysis with death as a competing event
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End point type |
Secondary
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End point timeframe |
up to 5 years after randomization
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Attachments |
Untitled (Filename: relapse.png) |
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Statistical analysis title |
Relapse | |||||||||
Statistical analysis description |
Comparing relapse between two treatment arms
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Comparison groups |
CD4+ donor lymfocyten infusion v Control
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||
P-value |
= 0.5 | |||||||||
Method |
Logrank | |||||||||
Confidence interval |
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End point title |
Any sign of GvHD | |||||||||
End point description |
Cumulative incidence of any signs of GvHD. Patients did not need to receive immunosuppressive. We used a competing risk analysis with relapse, unmodified DLI and death as competing events.
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End point type |
Secondary
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End point timeframe |
3 months after randomization
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Attachments |
Untitled (Filename: anyGvHD.png) |
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Statistical analysis title |
Cumulative incidence | |||||||||
Comparison groups |
CD4+ donor lymfocyten infusion v Control
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Number of subjects included in analysis |
66
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | |||||||||
P-value |
= 0.6 | |||||||||
Method |
Logrank | |||||||||
Confidence interval |
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Adverse events information
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Timeframe for reporting adverse events |
Between randomization and 6 months after alloSCT
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
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Reporting groups
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Reporting group title |
CD4+ donor lymfocyten infusion
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Reporting group description |
All adverse events from randomization until 6 months after alloSCT Serious adverse events: severe GvHD, relapse, death, infections requiring hospitalization | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Controle
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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? 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. | |||
Since all patients were eligible to receive unmodified DLI at 6 months, the reported outcomes and all AE/SAE are reported until 6 months; afterwards the adverse events are probably related to the unmodified DLI. These results are not reported here. |