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Rasburicase in Preventing Graft-Versus-Host Disease in Patients With Hematologic Cancer or Other Disease Undergoing Donor Stem Cell Transplant

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ClinicalTrials.gov Identifier: NCT00513474
Recruitment Status : Completed
First Posted : August 8, 2007
Results First Posted : April 11, 2017
Last Update Posted : May 25, 2017
Sponsor:
Information provided by (Responsible Party):
Bimalangshu Dey, Massachusetts General Hospital

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Supportive Care
Conditions Chronic Myeloproliferative Disorders
Graft Versus Host Disease
Leukemia
Lymphoma
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Interventions Drug: busulfan
Drug: cyclophosphamide
Drug: cyclosporin-A
Drug: etoposide
Drug: methotrexate
Drug: rasburicase
Drug: sirolimus
Drug: tacrolimus
Procedure: allogeneic hematopoietic stem cell transplantation
Procedure: peripheral blood stem cell transplantation
Radiation: total-body irradiation
Drug: fludarabine
Drug: allopurinol
Enrollment 46
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Rasburicase Group Control Group
Hide Arm/Group Description Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator’s discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant’s uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total. Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines.
Period Title: Overall Study
Started 25 21
Received Rasburicase Per Protocol 24 0
Completed 18 12
Not Completed 7 9
Reason Not Completed
Death             6             9
Participant Withdrew Consent             1             0
Arm/Group Title Rasburicase Group Control Group Total
Hide Arm/Group Description Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator’s discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant’s uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total. Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines. Total of all reporting groups
Overall Number of Baseline Participants 21 21 42
Hide Baseline Analysis Population Description
Intent-to-treat participants included in the analyses.
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 21 participants 21 participants 42 participants
42.9
(20 to 59)
45
(21 to 55)
44
(20 to 59)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 21 participants 42 participants
Female
7
  33.3%
12
  57.1%
19
  45.2%
Male
14
  66.7%
9
  42.9%
23
  54.8%
Graft-Versus-Host Disease (GVHD) Prophylaxis Intervention   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 21 participants 42 participants
MRD: Cyclsporine + Methotrexate
14
  66.7%
11
  52.4%
25
  59.5%
MRD: Tacrolimus + Methotrexate
2
   9.5%
2
   9.5%
4
   9.5%
MUD: Tacrolimus + Methotrexate + ATG
4
  19.0%
8
  38.1%
12
  28.6%
MUD: Tacrolimus + Methotrexate
1
   4.8%
2
   9.5%
3
   7.1%
[1]
Measure Description: Participants received GVHD prophylaxis at the investigator's discretion. MRD=matched related donor. MUD=matched unrelated donor. ATG=antithymocyte globulin.
Conditioning Protocol Interventions  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 21 participants 21 participants 42 participants
Busulfan + Cyclophosphamide
12
  57.1%
16
  76.2%
28
  66.7%
Busulfan + Fludarabine
2
   9.5%
0
   0.0%
2
   4.8%
Total Body Irradiation + Cyclophosphamide
7
  33.3%
5
  23.8%
12
  28.6%
1.Primary Outcome
Title Percentage of Participants With Grades II to IV Acute Graft-Versus-Host Disease (aGVHD)
Hide Description

aGVHD severity was determined using International Bone Marrow Transplant Registry (IBMTR) scale stage and grade of the skin, liver and gut. Stage 1: Skin=maculopapular rash <25% of body surface; Liver=Bilirubin 2-3 mg/dL and Gut=500-999 mL diarrhea/day or peristent nausea with histologic evidence of GvHD. Stage 2: Skin=maculopapular rash 25-50% of body surface; Liver=Bilirubin 3.1-6 mg/dL and Gut=1000-1499 mL diarrhea/day. Stage 3: Skin=maculopapular rash >50% of body surface; Liver=Bilirubin 6.1-15 mg/dL and Gut=≥1500 mL diarrhea/day. Stage 4: Skin=generalized erythroderma with bulla formation; Liver=Bilirubin >15 mg/dL and Gut=severe abdominal pain.

Grade 1: Stage 1-2 rash; no liver or gut involvement. Grade II: Stage 3 rash, or stage 1 liver involvement, or stage 1 gut involvement. Grade III: None to stage 3 skin rash with stage 2-3 liver, or stage 2-4 gut involvement. Grade IV: Stage 4 skin rash, or stage 4 liver involvement.

Time Frame Up to 71 months
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat participants included in the analyses.
Arm/Group Title Rasburicase Group Control Group
Hide Arm/Group Description:
Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator’s discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant’s uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.
Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines.
Overall Number of Participants Analyzed 21 21
Measure Type: Number
Unit of Measure: percentage of participants
24 57
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Rasburicase Group, Control Group
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value .036
Comments [Not Specified]
Method Gray's test for competing risks
Comments [Not Specified]
2.Secondary Outcome
Title Uric Acid Levels
Hide Description Blood was collected and analyzed at a laboratory for serum uric acid levels reported in milligrams(mg)/deciliter(dL). Data is presented for those participants who experienced Grade II to IV aGVHD and those participants who did not experience Grade II to IV aGVHD at pre-transplant and post-transplant.
Time Frame Pre-transplant Day -7 to Day -1 and Post-transplant Day 0 to Day 6
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat population with data available for analyses.
Arm/Group Title Rasburicase Group Control Group
Hide Arm/Group Description:
Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator’s discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant’s uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.
Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines.
Overall Number of Participants Analyzed 21 21
Mean (Standard Deviation)
Unit of Measure: mg/dL
Day -7 0.1  (0.209) 4.157  (1.886)
Day -6 0.075  (0.199) 3.419  (1.752)
Day -5 0.086  (0.24) 2.967  (1.437)
Day -4 0.1  (0.324) 2.579  (1.249)
Day -3 0.067  (0.2) 2.358  (1.21)
Day -2 0.081  (0.15) 1.867  (1.097)
Day -1 0.438  (0.611) 1.71  (0.931)
Day 0 0.938  (0.887) 2.163  (1.012)
Day 1 1.624  (1.205) 2.671  (1.056)
Day 2 2.076  (1.37) 2.778  (0.985)
Day 3 2.271  (1.303) 2.805  (1.028)
Day 4 2.548  (1.454) 2.758  (1.161)
Day 5 2.595  (1.729) 2.579  (1.318)
Day 6 2.705  (1.665) 2.653  (1.33)
3.Secondary Outcome
Title Number of Participant With Adverse Events (AE)
Hide Description An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
Time Frame Up to 71 months
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population included all participants who received at least one dose of protocol specified treatment and were in remission at the time of transplant.
Arm/Group Title Rasburicase Group Control Group
Hide Arm/Group Description:
Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator’s discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant’s uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.
Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines.
Overall Number of Participants Analyzed 21 21
Measure Type: Count of Participants
Unit of Measure: Participants
21
 100.0%
21
 100.0%
4.Secondary Outcome
Title Graft-versus-host and Host-versus-graft Immune Responses
Hide Description Laboratory tests such as limited dilution assay (LDA) were to be performed to assess graft-versus-host and host-versus-graft immune responses.
Time Frame Days -2, 0, and Days 14, 21 and 35 days post-transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Due to laboratory and budgetary issues the planned laboratory testing and assays were not performed and no data were collected.
Arm/Group Title Rasburicase Group Control Group
Hide Arm/Group Description:
Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator’s discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant’s uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total.
Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
Time Frame Up to 71 months
Adverse Event Reporting Description Safety population included all participants who received at least one dose of protocol specified treatment and were in remission at the time of transplant.
 
Arm/Group Title Rasburicase Group Control Group
Hide Arm/Group Description Myeloablative (bone marrow depletion) conditioning protocol as per standard of care at the investigator's discretion followed by granulocyte colony-stimulating factor (GCSF)-mobilized human leukocyte antigen (HLA)-matched, related or unrelated donor allogeneic peripheral blood stem cells (unmanipulated), standard graft-versus-host disease (GVHD) prophylaxis as per standard of care at the investigator’s discretion and rasburicase 0.20 mg/kg/day administered by intravenous infusion for 5 consecutive days. If after 5 days of rasburicase the participant’s uric acid plasma level remains above 5 mg/dL, rasburicase may be continued for up to 7 days in total. Historical chart review of patients from the Blood and Marrow Transplant database who received myeloablative allogeneic stem cell/bone marrow transplantation followed by standard GVHD prophylaxis in the past 10 years. Participants received allopurinol per institutional guidelines.
All-Cause Mortality
Rasburicase Group Control Group
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Rasburicase Group Control Group
Affected / at Risk (%) Affected / at Risk (%)
Total   10/21 (47.62%)   9/21 (42.86%) 
Blood and lymphatic system disorders     
Relapsed disease  [1]  7/21 (33.33%)  7/21 (33.33%) 
Immune system disorders     
Engraftment syndrome   1/21 (4.76%)  0/21 (0.00%) 
Infections and infestations     
Infection from aGVHD flare  [1]  0/21 (0.00%)  1/21 (4.76%) 
Respiratory failure  [1]  0/21 (0.00%)  1/21 (4.76%) 
H1N1 influenza  [1]  1/21 (4.76%)  0/21 (0.00%) 
Metapneumovirus  [1]  1/21 (4.76%)  0/21 (0.00%) 
Nervous system disorders     
Seizure   1/21 (4.76%)  0/21 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Hypoxia   1/21 (4.76%)  0/21 (0.00%) 
Vascular disorders     
Venoocclusive disease   1/21 (4.76%)  0/21 (0.00%) 
Indicates events were collected by systematic assessment
[1]
Resulted in death
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 4%
Rasburicase Group Control Group
Affected / at Risk (%) Affected / at Risk (%)
Total   21/21 (100.00%)   21/21 (100.00%) 
Blood and lymphatic system disorders     
Thrombocytopenia   1/21 (4.76%)  0/21 (0.00%) 
Hemolytic anemia   1/21 (4.76%)  0/21 (0.00%) 
Gastrointestinal disorders     
Vomiting   13/21 (61.90%)  11/21 (52.38%) 
Nausea   19/21 (90.48%)  19/21 (90.48%) 
Diarrhea   15/21 (71.43%)  9/21 (42.86%) 
Tongue numbness   1/21 (4.76%)  0/21 (0.00%) 
General disorders     
Fever   5/21 (23.81%)  9/21 (42.86%) 
Mucositis   20/21 (95.24%)  17/21 (80.95%) 
Metabolism and nutrition disorders     
Edema   5/21 (23.81%)  2/21 (9.52%) 
Skin and subcutaneous tissue disorders     
Rash   1/21 (4.76%)  2/21 (9.52%) 
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Bimalangshu R. Dey, MD, PhD
Organization: Massachusetts General Hospital
EMail: bdey@mgh.harvard.edu
Layout table for additonal information
Responsible Party: Bimalangshu Dey, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00513474     History of Changes
Other Study ID Numbers: CDR0000558480
MGH-07-071
DFCI-07-071
First Submitted: August 6, 2007
First Posted: August 8, 2007
Results First Submitted: February 27, 2017
Results First Posted: April 11, 2017
Last Update Posted: May 25, 2017