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Rituximab in Renal Allograft Recipients Who Develop Early De Novo Anti-HLA Alloantibodies

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ClinicalTrials.gov Identifier: NCT00307125
Recruitment Status : Completed
First Posted : March 27, 2006
Results First Posted : March 23, 2015
Last Update Posted : March 23, 2015
Sponsor:
Collaborators:
Clinical Trials in Organ Transplantation
Cooperative Clinical Trials in Pediatric Transplantation (CCTPT)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Kidney Transplant
Kidney Transplant Recipient
Graft Function/Survival
de Novo HLA Antibodies Development
Interventions Drug: Rituximab plus immunosuppression
Drug: Placebo plus immunosuppression
Enrollment 757
Recruitment Details N=757 subjects were enrolled in the screening phase (Stage 1: Screening) of the study and followed for development of de novo anti-HLA antibodies for up to 60 months post-kidney (renal) transplant.N=22 subjects from the screening cohort were enrolled in the treatment phase. Refer to Detailed Description and Eligibility Sections for more details.
Pre-assignment Details From the screening cohort, N=22 subjects were enrolled in the treatment phase of the study (Stage 2: Pilot Study). Refer to Detailed Description and Eligibility Sections for more details.
Arm/Group Title Screening Phase Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Hide Arm/Group Description Kidney (renal) transplant recipients with no detectable anti-human leukocyte antigen (HLA) antibodies prior to transplant. Participants were screened for the development of anti-HLA antibodies once every 3 months up to 36 months post-transplantation and yearly thereafter until Month 60.

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Period Title: Screening Phase
Started 757 0 0
Completed 303 0 0
Not Completed 454 0 0
Reason Not Completed
Adverse Event             1             0             0
Protocol Violation             27             0             0
Lost to Follow-up             87             0             0
Death             10             0             0
Withdrawal by Subject             77             0             0
Physician Decision             26             0             0
Sponsor Decision             4             0             0
Study Terminated             17             0             0
Graft Loss             3             0             0
Graft Failure             8             0             0
Follow-up period ended on Dec 31, 2011             83             0             0
Scheduling issues/Non-compliance             55             0             0
Moved or transferred facilities             34             0             0
Received Pancreas Transplant             8             0             0
Ineligible for pilot             4             0             0
Try to get pregnant             1             0             0
Developed acute leukemia             1             0             0
Metastatic colon cancer             1             0             0
Malignancy             1             0             0
PAK             1             0             0
Ineligible             1             0             0
Screen Error             1             0             0
Sample of Anti-HLA Ab was not obtained             1             0             0
AMR and treated with rituximab             1             0             0
Coronary artery bypass             1             0             0
Period Title: Pilot Phase
Started 0 15 7
Completed 0 13 [1] 6 [2]
Not Completed 0 2 1
Reason Not Completed
Lost to Follow-up             0             1             0
Withdrawal by Subject             0             1             1
[1]
2 participants had reduced follow-up
[2]
1 participant had reduced follow-up
Arm/Group Title Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression Total
Hide Arm/Group Description

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Total of all reporting groups
Overall Number of Baseline Participants 15 7 22
Hide Baseline Analysis Population Description
Intent-to-treat
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants 7 participants 22 participants
<=18 years
3
  20.0%
1
  14.3%
4
  18.2%
Between 18 and 65 years
10
  66.7%
6
  85.7%
16
  72.7%
>=65 years
2
  13.3%
0
   0.0%
2
   9.1%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 15 participants 7 participants 22 participants
41.4  (19.5) 49.0  (15.0) 43.8  (18.2)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 15 participants 7 participants 22 participants
Female
3
  20.0%
2
  28.6%
5
  22.7%
Male
12
  80.0%
5
  71.4%
17
  77.3%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 15 participants 7 participants 22 participants
15 7 22
1.Primary Outcome
Title During Screening Phase: Incidence of Alloantibody Development
Hide Description Data were analyzed for 653 participants from the screening phase of the study. This outcome looked at the number of kidney transplant recipients that developed de novo HLA antibodies (anti-HLA Ab) post-transplant. Alloantibody is defined as an antibody produced following the introduction of an alloantigen into the system of an individual lacking that particular antigen. Alloantibodies are important mediators of acute and chronic rejection.
Time Frame During screening window of 3-60 months post kidney transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Screening sample
Arm/Group Title Screening Phase
Hide Arm/Group Description:
Participants who were analyzed during the screening phase/stage of the study
Overall Number of Participants Analyzed 653
Measure Type: Number
Unit of Measure: participants
79
2.Primary Outcome
Title During Screening Phase: Timing of Alloantibody Development
Hide Description Data were analyzed for 653 participants from the screening phase of the study. Of these, 79 (12%) developed de novo HLA-antibodies (anti-HLA Ab). This outcome looks at the average length of time (interval) from post kidney transplant until development of alloantibody. Alloantibody is defined as an antibody produced following the introduction of an alloantigen into the system of an individual lacking that particular antigen. Alloantibodies are important mediators of acute and chronic rejection
Time Frame During screening window of 3-60 months post kidney transplant
Hide Outcome Measure Data
Hide Analysis Population Description
Screening sample
Arm/Group Title Screening Phase
Hide Arm/Group Description:
Participants who were analyzed during the screening phase of the study
Overall Number of Participants Analyzed 653
Mean (Standard Deviation)
Unit of Measure: Months
16.2  (9.9)
3.Primary Outcome
Title Number of Participants With 50 Percent (%) Decrease in Circulating Anti-Human Leukocyte Antigen (HLA) Antibodies
Hide Description Number of participants with 50% decrease in circulating anti-HLA antibodies at any time within the first 12 months post kidney transplant by LuminexTM Beads Method. Luminex assays for quantitation and detection of cytokine and signal transduction proteins. Presence of circulating antibodies is indicative of the transplant recipient's immune system responding to the transplanted organ as a foreign object or infection.
Time Frame 1 year post treatment initiation
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Hide Arm/Group Description:

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Overall Number of Participants Analyzed 15 7
Measure Type: Number
Unit of Measure: participants
2 0
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pilot Phase-Rituximab Plus Immunosuppression, Pilot Phase-Placebo Plus Immunosuppression
Comments Analysis by Fisher's exact test counting participants with 50% decrease in anti-HLA antibodies at any time within 12 months post treatment initiation
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.999
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
4.Secondary Outcome
Title Number of Deaths 12 Months Post Treatment Initiation
Hide Description Number of participant deaths within 12 months post treatment initiation
Time Frame 12 months post treatment initiation
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Hide Arm/Group Description:

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Overall Number of Participants Analyzed 15 7
Measure Type: Number
Unit of Measure: participants
0 0
5.Secondary Outcome
Title Number of Participants Experiencing Graft Loss 12 Months Post Treatment Initiation
Hide Description Number of participants with graft loss, defined as the need for dialysis for greater than 30 days duration, allograft nephrectomy, or the decision to withdraw immunosuppression due to graft failure within 12 month post treatment initiation
Time Frame 1 year post treatment initiation
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Rituximab Plus Immunosuppression Placebo Plus Immunosuppression
Hide Arm/Group Description:

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects ≤18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject ≤18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression is site-specific.

Overall Number of Participants Analyzed 15 7
Measure Type: Number
Unit of Measure: participants
0 0
6.Secondary Outcome
Title Number of Participants Experiencing Biopsy-proven Post-Transplant Lymphoproliferative Disease (PTLD)
Hide Description Number of participants with PTLD within 12 month post treatment initiation. Diagnosis of PTLD was made by B cell proliferation after therapeutic immunosuppression.
Time Frame 1 year post treatment initiation
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Hide Arm/Group Description:

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Overall Number of Participants Analyzed 15 7
Measure Type: Number
Unit of Measure: participants
0 0
7.Secondary Outcome
Title Number of Participants Experiencing Loss of Peritubular Capillary (PTC) C4d Staining on Kidney Biopsy
Hide Description Number of participants with loss of PTC C4d staining on kidney (renal) biopsy within 12 months post treatment initiation. PTC C4d staining on biopsy indicates organ rejection.
Time Frame 1 year post treatment initiation
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Hide Arm/Group Description:

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Overall Number of Participants Analyzed 15 7
Measure Type: Number
Unit of Measure: participants
0 0
8.Secondary Outcome
Title Number of Participants With Viral Replication of Cytomegalovirus (CMV)
Hide Description Number of participants with viral replication of CMV within 12 month post treatment initiation. Measured by polymerase chain reaction (PCR) method. Evidence of viral replication is indicative of active CMV infection.
Time Frame 1 year post treatment initiation
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Hide Arm/Group Description:

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Overall Number of Participants Analyzed 15 7
Measure Type: Number
Unit of Measure: participants
Positive 3 2
Negative 12 5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pilot Phase-Rituximab Plus Immunosuppression, Pilot Phase-Placebo Plus Immunosuppression
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.999
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
9.Secondary Outcome
Title Number of Participants With Evidence of Viral Replication of Epstein-Barr Virus (EBV)
Hide Description Number of participants with positive viral replication of EBV within 12 month post treatment initiation. Measured by polymerase chain reaction (PCR) method. Evidence of EBV viral replication is indicative of active infection.
Time Frame 1 year post treatment initiation
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Hide Arm/Group Description:

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Overall Number of Participants Analyzed 15 7
Measure Type: Number
Unit of Measure: participants
Positive 7 3
Negative 8 4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Pilot Phase-Rituximab Plus Immunosuppression, Pilot Phase-Placebo Plus Immunosuppression
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.999
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
10.Secondary Outcome
Title Number of Participants With Viral Replication of Polyomavirus (BKV)
Hide Description Number of participants with viral replication of BKV within 12 month post treatment initiation. Measured by polymerase chain reaction (PCR) method. Evidence of viral replication is indicative of a BKV infection. Polyomavirus BK is a significant pathogen in transplant recipients.
Time Frame 1 year post treatment initiation
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat
Arm/Group Title Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Hide Arm/Group Description:

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Overall Number of Participants Analyzed 15 7
Measure Type: Number
Unit of Measure: participants
Positive 0 0
Negative 15 7
Time Frame From kidney (renal) transplant to the end of study
Adverse Event Reporting Description

Adverse events methods:

  • Observing the participant
  • Questioning the participant, which should be done in an objective manner.
  • Receiving an unsolicited complaint from the participant.
  • An abnormal value or result from a clinical or laboratory evaluation.
 
Arm/Group Title Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Hide Arm/Group Description

Adult Dosing (Subjects > 18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subjects <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

Adult Dosing (Subjects >18 years): 1000 mg on days 0 and 14; Pediatric Dosing (Subject <\=18 years): 375 mg/m^2/dose (maximum 500 mg/dose) in 4 doses, once per week (Days 0, 8, 15 and 22).

Standard immunosuppression was site-specific.

All-Cause Mortality
Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Hide Serious Adverse Events
Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   5/15 (33.33%)      1/7 (14.29%)    
Gastrointestinal disorders     
Duodenal fistula  1  0/15 (0.00%)  0 1/7 (14.29%)  1
General disorders     
Infusion related reaction  1  1/15 (6.67%)  1 0/7 (0.00%)  0
Immune system disorders     
Transplant rejection  1  1/15 (6.67%)  1 0/7 (0.00%)  0
Infections and infestations     
Chlamydial pelvic inflammatory disease  1  1/15 (6.67%)  1 0/7 (0.00%)  0
Pneumonia  1  1/15 (6.67%)  1 0/7 (0.00%)  0
Sepsis  1  0/15 (0.00%)  0 1/7 (14.29%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Prostate cancer  1  1/15 (6.67%)  1 0/7 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Pilot Phase-Rituximab Plus Immunosuppression Pilot Phase-Placebo Plus Immunosuppression
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/15 (20.00%)      2/7 (28.57%)    
Gastrointestinal disorders     
Diarrhoea  1  2/15 (13.33%)  4 1/7 (14.29%)  1
Respiratory, thoracic and mediastinal disorders     
Pharyngolaryngeal pain  1  1/15 (6.67%)  1 1/7 (14.29%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 11.1
Slow accrual. In order to ensure the study was completed within the time frame allotted, randomization to the control arm (Pilot Phase-Placebo plus immunosuppression) was suspended. Enrollment continued to lag. The study was stopped early.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Director, Clinical Research Operations Program (CROP)
Organization: DAIT/NIAID
Phone: 301-594-7669
EMail: DAITClinicalTrialsGov@niaid.nih.gov
Layout table for additonal information
Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00307125    
Other Study ID Numbers: DAIT CTOT-02
CCTPT-02 ( Other Identifier: NIAID )
First Submitted: March 23, 2006
First Posted: March 27, 2006
Results First Submitted: February 27, 2015
Results First Posted: March 23, 2015
Last Update Posted: March 23, 2015