Clinical Trial Results:
A Randomized, Multi-Center, Phase III Trial of Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus Host-Disease
Summary
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EudraCT number |
2015-000602-18 |
Trial protocol |
DE |
Global end of trial date |
05 Oct 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Aug 2023
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First version publication date |
03 Aug 2023
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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 |
BMT-CTN#1301
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02345850 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
National Heart, Lung, and Blood Institute (NHLBI)
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Sponsor organisation address |
401 N. Washington St., Suite 700, Rockville, United States,
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Public contact |
Clinical Trials Information, EMMES Corporation, 001 301-251-1161,
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Scientific contact |
Clinical Trials Information, EMMES Corporation, 001 301-251-1161,
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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 |
22 Oct 2020
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
05 Oct 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
05 Oct 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 |
The primary objective of the randomized trial is to compare chronic GVHD/relapse-free survival (CRFS) after HSCT across two CNI-free interventions and Tac/Mtx control.
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Protection of trial subjects |
The trial compared standard of care interventions using IMPs with marketing authorization/ authorities approval in EEA.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
09 Oct 2015
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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: 2
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Country: Number of subjects enrolled |
United States: 344
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Worldwide total number of subjects |
346
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EEA total number of subjects |
2
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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) |
2
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Adults (18-64 years) |
344
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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 |
- | ||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
NA | ||||||||||||||||||||||||||||
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 | ||||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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CD34 Selection Arm | ||||||||||||||||||||||||||||
Arm description |
Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Allogeneic stem cells from peripheral blood CD34 selected
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Mobilized CD34-selected Peripheral Blood Stem Cell graft: Mobilized CD34-selected PBSC grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.
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Arm title
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Post-Transplant Cyclophosphamide | ||||||||||||||||||||||||||||
Arm description |
Unmanipulated Bone Marrow Graft with Cyclophosphamide | ||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Human allogeneic hematopoietic stem cells from bone marrow
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Unmanipulated BM grafts will be administered on Day 0 to all patients according to individual institutional guidelines after appropriate processing and quantification has been performed by the local laboratory. Stem cells are administered through an indwelling central venous catheter. If infusion occurs over two days, Day 0 is the first day the infusion is initiated.
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Investigational medicinal product name |
Cyclophosphamide
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Mesna will be given in divided doses IV 30 min pre- and at 3, 6, and 8 hours post-cyclophosphamide or administered per institutional standards. Mesna dose will be based on the cyclophosphamide dose being given. The total daily dose of Mesna is equal to 80% of the total daily dose of cyclophosphamide. Cyclophosphamide 50 mg/kg will be given on Day 3 post-transplant (between 60 and 72 hours after marrow infusion) and on Day 4 post-transplant (approximately 24 hours after Day 3 cyclophosphamide). Cyclophosphamide will be given as an IV infusion over 1-2 hours (depending on volume).
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Arm title
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Tacrolimus(Cyclosporin)/Methotrexate Control Arm | ||||||||||||||||||||||||||||
Arm description |
Unmanipulated bone marrow graft with Tacrolimus(Cyclopsorin)/Methotrexate GVHD prophylaxis. Tacrolimus(Cyclosporin) will be maintained at therapeutic doses for a minimum of 90 days. Methotrexate will be dosed at 5-15mg/m^2 for a maximum of 4 doses post-transplant. Cyclosporine may be substituted for tacrolimus in germany or if the patient is intolerant of tacrolimus or per institutional practice. | ||||||||||||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||||||||||||
Investigational medicinal product name |
Cyclosporin
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion, Capsule, soft, Oral solution
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Routes of administration |
Intravenous use, Oral use
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Dosage and administration details |
Tacrolimus (Cyclosporin) will be given orally or intravenously per institutional standards starting Day -3. The dose of tacrolimus (Cyclosporin) may be rounded to the nearest 0.5 mg for oral formulations. Subsequent dosing will be based on blood levels, with a target of 5-15 ng/ml. If patients are on medications which alter the metabolism of tacrolimus (Cyclosporin) (e.g. azoles), the initial starting dose and subsequent doses should be altered as per institutional practices. Tacrolimus (Cyclosporin) taper can be initiated at a minimum of 90 days post HSCT if there is no evidence of active GVHD. The rate of tapering will be done according institutional practices but patients should be off tacrolimus (Cyclosporin) by Day 180 post HSCT if there is no evidence of active GVHD.
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Investigational medicinal product name |
Methotrexate
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Methotrexate will be administered at the doses of 15 mg/m^2 IV bolus on Day +1, and 10 mg/m^2 IV bolus on Days +3, +6 and +11 after hematopoietic stem cell infusion. The Day +1 dose of methotrexate should be given at least 24 hours after the hematopoietic stem cell infusion. Dose reduction of MTX due to worsening creatinine clearance after initiation of conditioning regimen, high serum levels or development of oral mucositis is allowed according to institutional practices. Leucovorin rescue is allowed according to institutional practices.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Trial
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
CD34 Selection Arm
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Reporting group description |
Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. | ||
Reporting group title |
Post-Transplant Cyclophosphamide
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Reporting group description |
Unmanipulated Bone Marrow Graft with Cyclophosphamide | ||
Reporting group title |
Tacrolimus(Cyclosporin)/Methotrexate Control Arm
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Reporting group description |
Unmanipulated bone marrow graft with Tacrolimus(Cyclopsorin)/Methotrexate GVHD prophylaxis. Tacrolimus(Cyclosporin) will be maintained at therapeutic doses for a minimum of 90 days. Methotrexate will be dosed at 5-15mg/m^2 for a maximum of 4 doses post-transplant. Cyclosporine may be substituted for tacrolimus in germany or if the patient is intolerant of tacrolimus or per institutional practice. |
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End point title |
Chronic GVHD-free, Relapse-free Survival (CRFS) Probability | ||||||||||||||||||||||||
End point description |
The primary endpoint of the trial is Chronic GVHD/Relapse-Free Survival (CRFS), treated as a time to event variable. An event for this time to event outcome is defined as moderate to severe chronic GVHD, disease relapse, or death by any cause. Participant will be censored if lost to follow up prior to 2 years. Time is from randomization to the event of moderate to severe chronic GVHD, disease relapse, death, last follow up, or 2 years, whichever comes first. The primary analysis is performed using the intent-to-treat principle (ITT) so that all randomized patients are included in the analysis.
All randomized patients are analyzed for this endpoint.
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End point type |
Primary
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End point timeframe |
2 years
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
The primary null hypothesis of the study is that there is no difference of the CRFS hazard ratio between CD34 select graft vs. Tac/MTX Control. The data in primary outcome table provides point estimates at specific time points (1 year and 2 years post randomization). The statistics in this session provides comparisons between different arms for the entire period of the study.
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Comparison groups |
Tacrolimus(Cyclosporin)/Methotrexate Control Arm v CD34 Selection Arm
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Number of subjects included in analysis |
232
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.2368 [1] | ||||||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||||||
Point estimate |
0.805
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.562 | ||||||||||||||||||||||||
upper limit |
1.154 | ||||||||||||||||||||||||
Notes [1] - The primary pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3. |
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Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
The primary null hypothesis of the study is that there is no difference of the CRFS hazard ratio between Post-Transplant Cyclophosphamide vs. Tac/MTX Control. The data in primary outcome table provides point estimates. The statistics in this session provides comparisons between different arms for the entire period of the study.
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Comparison groups |
Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
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Number of subjects included in analysis |
232
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.4134 [2] | ||||||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||||||
Point estimate |
0.864
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.609 | ||||||||||||||||||||||||
upper limit |
1.228 | ||||||||||||||||||||||||
Notes [2] - The primary pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3. |
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Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||||||||||
Statistical analysis description |
The primary null hypothesis of the study is that there is no difference of the CRFS hazard ratio between CD34 select graft vs. Post-Transplant Cyclophosphamide. The data in primary outcome table provides point estimates. The statistics in this session provides comparisons between different arms for the entire period of the study.
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Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide
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Number of subjects included in analysis |
228
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.7166 [3] | ||||||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||||||
Point estimate |
0.933
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Confidence interval |
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level |
95% | ||||||||||||||||||||||||
sides |
2-sided
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lower limit |
0.643 | ||||||||||||||||||||||||
upper limit |
1.355 | ||||||||||||||||||||||||
Notes [3] - The primary pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3. |
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Statistical analysis title |
Statistical Analysis 4 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the CRFS hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk. The data in primary outcome table provides point estimates. The statistics in this session provides comparisons between different arms for the entire period of the study.
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Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
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Number of subjects included in analysis |
346
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.386 [4] | ||||||||||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||||||||||
Confidence interval |
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Notes [4] - Statistical significance was determined using a pre-specified threshold of 0.05. |
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Statistical analysis title |
Statistical Analysis 5 | ||||||||||||||||||||||||
Statistical analysis description |
Subgroup analyses are conducted for CRFS according to disease, disease risk and age. Interaction tests between treatment group and subgroup are conducted within a Cox proportional hazards regression model with treatment, subgroup, and a treatment*subgroup interaction term. The null hypothesis is that there is no Interaction between treatment group and disease risk (Low/Intermediate vs. High) for CRFS.
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Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
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Number of subjects included in analysis |
346
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.461 [5] | ||||||||||||||||||||||||
Method |
Cox proportional hazards regression | ||||||||||||||||||||||||
Confidence interval |
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Notes [5] - A Bonferroni adjusted significance level of 0.05/3=0.0167 is used for each of three interaction tests to account for multiple testing. |
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Statistical analysis title |
Statistical Analysis 6 | ||||||||||||||||||||||||
Statistical analysis description |
Subgroup analyses are conducted for CRFS according to disease, disease risk and age. Interaction tests between treatment group and subgroup are conducted within a Cox proportional hazards regression model with treatment, subgroup, and a treatment*subgroup interaction term. The null hypothesis is that there is no Interaction between treatment group and Age (<=50 vs. >50) for CRFS.
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Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
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Number of subjects included in analysis |
346
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.115 [6] | ||||||||||||||||||||||||
Method |
Cox proportional hazards regression | ||||||||||||||||||||||||
Confidence interval |
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Notes [6] - Cox proportional hazards regression |
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Statistical analysis title |
Statistical Analysis 7 | ||||||||||||||||||||||||
Statistical analysis description |
Subgroup analyses are conducted for CRFS according to disease, disease risk and age. Interaction tests between treatment group and subgroup are conducted within a Cox proportional hazards regression model with treatment, subgroup, and a treatment*subgroup interaction term. The null hypothesis is that there is no Interaction between treatment group and Disease (AML vs. ALL vs. MDS) for CRFS.
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Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
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Number of subjects included in analysis |
346
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.227 [7] | ||||||||||||||||||||||||
Method |
Cox proportional hazards regression | ||||||||||||||||||||||||
Confidence interval |
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Notes [7] - A Bonferroni adjusted significance level of 0.05/3=0.0167 is used for each of three interaction tests to account for multiple testing. |
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End point title |
Percentage of Participants With Overall Survival (OS) | ||||||||||||||||||||||||||||||||
End point description |
OS is a key secondary endpoint, with explicit control of the type I error rate through a gatekeeper approach. Formal significance testing of OS between a CNI-free strategy and the control will be conducted if the corresponding CRFS comparison is significant. This OS comparison will be done using a Bonferroni adjusted significance level of 0.05/3 to account for three potential CNI-free comparisons to the control. Otherwise, survival analyses will be considered exploratory. Death from any cause is considered as event for this endpoint. Participant is censored if lost to follow up.
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End point type |
Secondary
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End point timeframe |
2 years
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Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the OS hazard ratio between CD34 select graft vs. Tac/MTX Control.
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Comparison groups |
CD34 Selection Arm v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
232
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
= 0.0197 [8] | ||||||||||||||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||||||||||||||
Point estimate |
1.744
|
||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||
lower limit |
1.086 | ||||||||||||||||||||||||||||||||
upper limit |
2.8 | ||||||||||||||||||||||||||||||||
Notes [8] - The OS pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3. |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the OS hazard ratio between Post-Transplant Cyclophosphamide vs. Tac/MTX Control.
|
||||||||||||||||||||||||||||||||
Comparison groups |
Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
232
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
= 0.9525 [9] | ||||||||||||||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||||||||||||||
Point estimate |
1.016
|
||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||
lower limit |
0.599 | ||||||||||||||||||||||||||||||||
upper limit |
1.724 | ||||||||||||||||||||||||||||||||
Notes [9] - The OS pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3. |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the OS hazard ratio between CD34 select graft vs. Post-Transplant Cyclophosphamide.
|
||||||||||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
228
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
= 0.0185 [10] | ||||||||||||||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||||||||||||||
Parameter type |
Hazard ratio (HR) | ||||||||||||||||||||||||||||||||
Point estimate |
1.774
|
||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
level |
95% | ||||||||||||||||||||||||||||||||
sides |
2-sided
|
||||||||||||||||||||||||||||||||
lower limit |
1.093 | ||||||||||||||||||||||||||||||||
upper limit |
2.877 | ||||||||||||||||||||||||||||||||
Notes [10] - The OS pairwise comparisons are tested at a Bonferroni adjusted significance level of 0.05/3. |
|||||||||||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 4 | ||||||||||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the OS hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
|
||||||||||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||||||||||
Number of subjects included in analysis |
346
|
||||||||||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||||||||||
P-value |
= 0.026 [11] | ||||||||||||||||||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||||||||||
Notes [11] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||||||||||||||
End point title |
Percentage of Participants With Relapse-free Survival | ||||||||||||||||||||||||
End point description |
The events for this endpoint RFS are death and relapse of the underlying malignancy. The analyses of this endpoint use the transplanted populations and time is from transplant to the event of disease relapse or death, or last follow up, whichever comes first.
The analyses of this endpoint will use the transplanted population.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
2 years
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of Relapse-Free Survival between the treatment groups.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.029 [12] | ||||||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [12] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the RFS hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.145 [13] | ||||||||||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [13] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||||||||||||||
End point title |
Percentage of Participants With Treatment-related Mortality | ||||||||||||||||||||||||
End point description |
The events for this endpoint TRM are deaths prior to relapse of the underlying malignancy. The analyses of this endpoint will use the transplanted populations, and time will be from transplant to the first of disease relapse, death, or last follow up. TRM are evaluated using the cumulative incidence function. Deaths without relapse are the events for this endpoint and relapse is a competing risk for this endpoint.
The analyses of this endpoint will use the transplanted populations.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
2 years
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of Transplant-Related Mortality between the treatment groups.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.02 [14] | ||||||||||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [14] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the TRM hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.04 [15] | ||||||||||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [15] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||
End point title |
Participants With Immunosuppression-free Survival | ||||||||||||
End point description |
Patients who are alive, relapse-free, and do not need ongoing immune suppression to control GVHD at one year post HSCT are considered successes for this endpoint. Immune suppression is defined as any systemic agents used to control or suppress GVHD.
The analyses of this endpoint will use the transplanted populations. Two participant of CD34 Selected Graft arm and one participants of Post-Transplant Cyclophosphamide arm were lost to follow-up while alive and not relapsed, and they are considered as not evaluable for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
1 year
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of immunosuppression-free survival at 1-year post-transplant between the treatment groups.
|
||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||
Number of subjects included in analysis |
324
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.2389 [16] | ||||||||||||
Method |
Chi-squared | ||||||||||||
Confidence interval |
|||||||||||||
Notes [16] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||
Statistical analysis description |
The null hypothesis is that there is no agreement between CRFS and immunosuppression-free survival at 1-year post-transplant.
|
||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||
Number of subjects included in analysis |
324
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
< 0.0001 | ||||||||||||
Method |
Cohen's Kappa | ||||||||||||
Confidence interval |
|
|||||||||||||||||||||||||
End point title |
Percentage of Participants With Disease Relapse | ||||||||||||||||||||||||
End point description |
Relapse is defined by either morphological evidence of acute leukemia or MDS consistent with pre-transplant features, or radiologic evidence of lymphoma, documented or not by biopsy. The event is defined as increase in size of prior sites of disease or evidence of new sites of disease, documented or not by biopsy. Relapse is adjudicated by ERC. Disease relapse is analyzed using cumulative incidence function with death as a competing risk. The analyses of this endpoint use the transplanted populations, and the time will be measured from transplant to the earliest of death, relapse/progression, or last follow up.
The analyses of this endpoint use the transplanted populations.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
2 years
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of Disease Relapse between the treatment groups.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.076 [17] | ||||||||||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [17] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the Disease Relapse hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.106 [18] | ||||||||||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [18] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||||||
End point title |
Percentage of Participants With Neutrophil Engraftment | ||||||||||||||||
End point description |
Neutrophil recovery is defined as achieving an absolute neutrophil count (ANC) ≥ 500/mm^3 for three consecutive measurements on three different days. The first of the three days will be designated the day of neutrophil recovery. The competing event is death without neutrophil recovery.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 28
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of Neutrophil Engraftment post-transplantation between the treatment groups.
|
||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0764 [19] | ||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [19] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||||||
End point title |
Percentage of Participants With Platelet Recovery | ||||||||||||||||
End point description |
Platelet recovery is defined as the first day of a sustained platelet count >20,000/mm^3 with no platelet transfusion in the preceding seven days. The first day of sustained platelet count above this threshold will be designated the day of platelet engraftment. The competing event is death without platelet recovery.
The analyses of the endpoint use the transplanted populations. Three transplanted participants (one from the CD34 arm and two from the PTCy arm) are missing platelet data and are not included in the analyses.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 60
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of Platelet recovery post-transplantation between the treatment groups.
|
||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||
Number of subjects included in analysis |
324
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.0001 [20] | ||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||
Confidence interval |
|||||||||||||||||
Notes [20] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||
End point title |
Participants With Primary Graft Failure | ||||||||||||
End point description |
Primary graft failure is defined as no neutrophil recovery to > 500 cells/µL by Day 28 post HSCT.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 28
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||
End point title |
Percentage of Participants With Secondary Graft Failure | ||||||||||||||||
End point description |
Secondary graft failure will be assessed according to neutrophil count after initial hematologic recovery. Secondary graft failure is defined as initial neutrophil engraftment followed by subsequent decline in absolute neutrophil counts < 500 cells/µL, unresponsive to growth factor therapy, but cannot be explained by disease relapse or medications. Secondary graft failure will be analyzed using cumulative incidence function with death as a competing risk.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
2 years
|
||||||||||||||||
|
|||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of Secondary graft failure post-transplantation between the treatment groups.
|
||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||
Analysis type |
superiority | ||||||||||||||||
P-value |
= 0.1478 | ||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||
Confidence interval |
|
|||||||||||||||||||||||||
End point title |
Percentage of Participants With Acute GVHD | ||||||||||||||||||||||||
End point description |
Cumulative incidences of grade II-IV and III-IV acute GVHD were determined. Death prior to acute GVHD is treated as the competing risk. Grading of acute GVHD was derived by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Staging for skin: Stage 1. <25% rash; 2. 25-50%; 3. >50%; 4. generalized erythroderma with bullae. Staging for GI: Stage 1. Diarrhea>500ml/d or persistent nausea; 2. >1000ml/d; 3. >1500ml/d; 4. Large volume diarrhea and severe abdominal pain +- ileus. Staging for Liver: Stage 1. bilirubin 2-3mg/dl; 2. bilirubin 3-6 mg/dl; 3. bilirubin 6-15 mg/dl; 4. bilirubin>15mg/dl. Grade 4 is the worst outcome.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
Day 100
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of grade II-IV acute GVHD post-transplantation between the treatment groups.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0026 [21] | ||||||||||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [21] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of grade III-IV acute GVHD post-transplantation between the treatment groups.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0369 [22] | ||||||||||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [22] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 3 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the grade II-IV acute GVHD hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.002 [23] | ||||||||||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [23] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 4 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the grade III-IV acute GVHD hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.046 [24] | ||||||||||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [24] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||||||||||||||||||||||
End point title |
Participants With Maximum Acute GVHD | ||||||||||||||||||||||||||||||||
End point description |
Grading of acute GVHD was derived by consensus grading (Przepiorka 1995) per BMTCTN manual of procedures (MOP). The acute GVHD algorithm calculates the grade based on the organ (skin, GI and liver) stage and etiology/biopsy reported on the weekly GVHD form. Grade I aGVHD is defined as Skin stage of 1-2 and stage 0 for both GI and liver organs. Grade II aGVHD is stage 3 of skin, or stage 1 of GI, or stage 1 of liver. Grade III is stage 2-4 for GI, or stage 2-3 of liver. Grade IV is stage 4 of skin, or stage 4 of liver. Max acute GVHD by Day 100 was computed.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||
End point timeframe |
Day 100
|
||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||
End point title |
Percentage of Participants With Chronic GVHD | ||||||||||||||||||||||||
End point description |
The cumulative incidence of chronic GVHD will be determined. Death prior to acute GVHD is treated as the competing risk. Data will be collected directly from providers and chart review according to the recommendations of the NIH Consensus Criteria. Eight organs will be scored on a 0-3 scale to reflect degree of chronic GVHD involvement. Liver and pulmonary function test results and use of systemic therapy for treatment of chronic GVHD will also be recorded. This secondary endpoint of chronic GVHD will include mild, moderate and severe chronic GVHD based on NIH Consensus Criteria.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
2 years
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of chronic GVHD post-transplantation between the treatment groups.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.0024 [25] | ||||||||||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [25] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of the chronic GVHD hazard ratio between treatment groups after adjustment for age, donor type, performance status, primary disease, and disease risk.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.005 [26] | ||||||||||||||||||||||||
Method |
Regression, Cox | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [26] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||||||||||||||
End point title |
Percentage of Participants With Chronic GVHD-free Survival | ||||||||||||||||||||||||
End point description |
The event for this endpoint includes moderate to severe chronic GVHD according to NIH consensus criteria global score, or death by any cause.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||
End point timeframe |
2 years
|
||||||||||||||||||||||||
|
|||||||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of Chronic GVHD-free Survival post-transplantation between the treatment groups.
|
||||||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||||||
P-value |
= 0.229 [27] | ||||||||||||||||||||||||
Method |
Logrank | ||||||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||||||
Notes [27] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Participants With Grade ≥ 3 Toxicity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
All grades ≥ 3 toxicities according to CTCAE, version 4 will be tabulated for each intervention arm. The number of unique patients is counted.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
2 years
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||
End point title |
Participants Infected Post Transplant | ||||||||||||||||||||
End point description |
All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation will be reported. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each intervention arm.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||
End point timeframe |
2 years
|
||||||||||||||||||||
|
|||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 1 | ||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of Grades II-III infection post-transplantation between the treatment groups.
|
||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.0006 [28] | ||||||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
Notes [28] - Superiority - Statistical significance was determined using a pre-specified threshold of 0.05. |
|||||||||||||||||||||
Statistical analysis title |
Statistical Analysis 2 | ||||||||||||||||||||
Statistical analysis description |
The null hypothesis is that there is no difference of Grades III infection post-transplantation between the treatment groups.
|
||||||||||||||||||||
Comparison groups |
CD34 Selection Arm v Post-Transplant Cyclophosphamide v Tacrolimus(Cyclosporin)/Methotrexate Control Arm
|
||||||||||||||||||||
Number of subjects included in analysis |
327
|
||||||||||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||||||||||
Analysis type |
superiority | ||||||||||||||||||||
P-value |
= 0.0145 [29] | ||||||||||||||||||||
Method |
Gray's test for cumulative Incidence | ||||||||||||||||||||
Confidence interval |
|||||||||||||||||||||
Notes [29] - Statistical significance was determined using a pre-specified threshold of 0.05. |
|
|||||||||||||
End point title |
Incidence of Infections | ||||||||||||
End point description |
All grade 2 and grade 3 infections, as defined by the BMT CTN Technical MOP, occurring post transplantation will be reported. The incidence of definite and probable viral, fungal and bacterial infections will be tabulated for each intervention arm.
The analyses of the endpoint use the transplanted populations.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
2 years
|
||||||||||||
|
|||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Health-Related Quality of Life (HQL) - Medical Outcomes Study Short Form 36 (SF36) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
HQL will be measured post-transplant using patient-reported survey SF36. The SF36 is a 36 item general assessment of health quality of life with eight components: Physical Functioning, Role Physical, Pain Index, General Health Perceptions, Vitality, Social Functioning, Role Emotional, Mental Health Index. Each domain is positively scored, indicating that higher scores are associated with positive outcome. The total score ranges from 0 to 100. This scale is being used in this protocol as a generic measure of quality of life. To facilitate comparison of results with published norms, the Physical Component Summary and Mental Component Summary are used as the outcome measures in summarizing the SF36 data. These summary scores are derived by multiplying the z-score for each scale by its respective physical or mental factor score coefficient and summing the products. Resulting scores are then transformed into Tscores (mean=50; standard deviation=10). The SF36 takes 6 minutes to complete.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 100, Day 180, 1 year, 2 years
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Health-Related Quality of Life (HQL) - Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
The FACT-BMT is a 37 item scale comprised of a general core questionnaire, the FACT-G with a possible range of 0-108 points, that evaluates the health-related quality of life (HQL) of patients receiving treatment for cancer, and a specific module, BMT Concerns, that addresses disease and treatment-related questions specific to bone marrow transplant. The FACT-G consists of four subscales developed and normed in cancer patients: Physical Well-being, Social/Family Well-being, Emotional Wellbeing, and Functional Well-being. Each subscale is positively scored, with higher scores indicating better functioning. The FACT-BMT Trial Outcome Index, comprised of the physical well-being scale, the functional well-being scale and the BMT specific items, will be used as the outcome measure in summarizing the FACT-BMT data. The FACT-BMT takes 6 minutes to complete. The final score for FACT-BMT ranges from 0 to 196. Higher scores for the scales and subscales indicate better quality of life.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 100, Day 180, 1 year, 2 years
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point title |
Health-Related Quality of Life (HQL) - MDASI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
HQL will be measured post-transplant using patient-reported survey MD Anderson Symptom Inventory (MDASI). The MDASI is a 19 item instrument that captures 13 symptoms (0="not present" to 10="as bad as you can imagine") and 6 items measuring interference with life from 0 ("did not interfere") to 10 ("interfered completely"). MDASI Tool questions are negatively scored - higher levels indicate more severe symptoms and levels of interference. Codelist for each question is from 0 to 10. Scoring is taking the mean of items, so the range is 0-10. Lower scores for the scales indicate better quality of life. It provides two summary scales: symptoms and interference. The MDASI takes less than 5 minutes to complete.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe |
Baseline, Day 100, Day 180, 1 year, 2 years
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||
End point title |
Health-Related Quality of Life (HQL) - PedsQL [30] | ||||||||||||||||||
End point description |
HQL will be measured post-transplant using patient-reported survey PedsQL. The PedsQL™ Stem Cell Transplant Module is a 46-item instrument that measures health-related quality of life in children and adolescents undergoing hematopoietic stem cell transplant and is developmentally appropriate for self-report in ages 8 through 18 years. The score ranges from 0 to 100 with higher scores associated with positive outcome.
|
||||||||||||||||||
End point type |
Secondary
|
||||||||||||||||||
End point timeframe |
Baseline, Day 100, Day 180, 1 year, 2 years
|
||||||||||||||||||
Notes [30] - 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: Only 2 trial subjects were pediatrics, both randomized to Tacrolimus/Methotrexate Control arm. |
|||||||||||||||||||
|
|||||||||||||||||||
No statistical analyses for this end point |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Adverse event reporting and monitoring were conducted throughout the study, up to 2 years.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Adverse event (AE) reporting was conducted according to the BMT CTN's manual of operating procedures (MOP). Unexpected, grade 3-5 AE were reported through an expedited AE reporting system. Expected AEs were reported using National Cancer Institute (NCI)'s Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 at regular intervals and re
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
|
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Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
CD34 Selection Arm
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Mobilized CD34-selected Peripheral Blood Stem Cell graft Following screening and enrollment, the donor of patients randomized to the CD34-selection arm will receive mobilization therapy with once daily Granulocyte Colony Stimulating Factor (G-CSF). Mobilization will begin on Day -5 prior to the patient's transplant date. Leukapheresis will be performed on a continuous flow cell separator according to institutional standards and will commence on the morning of the fifth day of G-CSF treatment. The anti-coagulant used for the procedure will be acid citrate dextrose (ACD). Decisions concerning the need for further product collection will be based on the known or projected enriched CD34+ cell content of the previously collected products. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Post-Transplant Cyclophosphamide
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Unmanipulated Bone Marrow Graft with Cyclophosphamide | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tacrolimus(Cyclosporin)/Methotrexate Control Arm
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Reporting group description |
Unmanipulated bone marrow graft with Tacrolimus(Cyclopsorin)/Methotrexate GVHD prophylaxis. Tacrolimus(Cyclosporin) will be maintained at therapeutic doses for a minimum of 90 days. Methotrexate will be dosed at 5-15mg/m^2 for a maximum of 4 doses post-transplant. Cyclosporine may be substituted for tacrolimus in germany or if the patient is intolerant of tacrolimus or per institutional practice. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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29 May 2015 |
The major changes to the protocol include the addition of a requirement for informed consent from donors of patients randomized to the CD34 selection arm (the protocol document only includes the
informed consent for related donors, while the NMDP will have purview over consenting the unrelated donors); a modification to the way that chemotherapy doses are calculated; exclusion of
modifications to the conditioning regimens in Arms A and B and of modifications to MTX regimens; addition of information regarding data submission and adverse event reporting; addition of information about ethics and regulatory requirements and procedures; addition of risks for rATG and risk language for lymphoproliferative syndrome as well as Mesna. |
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21 Jul 2016 |
Major changes to the Protocol include:
1. Inclusion criteria for patients with CMML were added as follows: “Patients with CMML must have a WBC count ≤ 10,000 cells/μL and < 5% blasts in the marrow.” 2. FLT3 and other tyrosine kinase inhibitors for post-transplant maintenance and for prevention of disease relapse are now allowed. 3. The fourth dose of Mesna may now be infused 8-9 hours after the completion of cyclophosphamide.
4. Toxoplasmosis NAAT for patients on the CD34+ arm considered at risk for infection/reactivation has been replaced with placing such patients on prophylactic agents. 5. The window from randomization to initiation of conditioning has been removed. 6. After randomization of MDS patients, the bone marrow assessment must be repeated if it did not occur within 6 weeks prior to the initiation of the transplant conditioning regimen.
Patient Informed Consent: 1. Weekly monitoring of toxoplasmosis until Day 100 then at each clinical assessment until Day 180 was removed from §Health Evaluations After the Transplant, as for NAAT for toxoplasmosis were removed from the protocol. 2. The volume of optional blood samples to be collected after transplant was corrected from 80mL to 86mL as required by Table 1 of Appendix C, Laboratory Procedures.
Donor Informed Consent: 1. Language was updated to limit confusion with regards to charges for the cell manipulation procedure. The selection procedure will be paid for, for this study. 2. Clarification was provided to explain that the investigational device that is part of the cell selection system that will be used to remove T cells from your stem cell donation, called stem cell manipulation, prior to transplantation. 3. The costs section was updated to reflect that the patient will need to pay for the cell selection procedure and that the donor will not be charged for the selection procedure. |
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22 Aug 2017 |
Major changes to the Protocol include: Clarification of the definition of “leukemia in complete morphologic CR with or without hematologic recovery”. Added Inclusion Criteria statement: “Patients with > 5% blasts due to a regenerating marrow must contact the protocol chairs for review.”. Clarification for sites to declare planned post-transplant maintenance therapy prior to randomization. Addition of new Exclusion Criterion: “If it is known prior to enrollment that the hematopoietic stem cell product will need to be cryopreserved, the patient should not be enrolled.”. Addition of extra day of rest in the conditioning regimens of any treatment arm when delivery of the patient’s graft is delayed. Addition of cryopreservation language. Addition of new secondary endpoint “graft failure.” Primary graft failure defined as “no neutrophil recovery to > 500 cells/μL by Day 28 post HSCT.” Secondary graft failure defined as “initial neutrophil engraftment followed by subsequent decline in absolute neutrophil counts < 500 cells/μL for > 3 days, unresponsive to growth factor therapy, but cannot be explained by disease relapse or medications.” Clarification of systemic steroid usage to “if clinically indicated”. Loosened the requirement of the pre-transplant bone marrow aspirate for MDS patients prior to randomization. The protocol still requires that it must be repeated if not within 6 weeks prior to the initiation of the transplant conditioning regimen. Addition of Adverse Device Effect Reporting requirement.
Patient Informed Consent: A new “Risks and Toxicities Related to GVHD Prophylaxis” from Investigator’s Brochure v8.0 was added to the patient informed consent. A new complication from the Investigator’s Brochure v8.0 “PTLD can be fatal” was added to the “Lymphoproliferative Syndrome-other Complication section.
Donor Informed Consent: New information from the Investigator’s Brochure v8.0 was added to the protocol and donor informed consent on effectiveness of the device. |
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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. | |||
SPONSOR=NHLBI; COLLABORATORS=BMT-CTN, NCI;INVESTIGATORS=Study Director:Mary Horowitz, MD, CIBMTR | |||
Online references |
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http://www.ncbi.nlm.nih.gov/pubmed/34855460 http://www.ncbi.nlm.nih.gov/pubmed/33811823 |