Type 1 Diabetes
Conditions
Keywords
Rapamycin, Mycophenolate Mofetil (MMF), Kidney-Pancreas Transplant
Brief summary
This study was designed to determine which maintenance immunosuppressive agent, rapamycin or mycophenalate mofetil, resulted in better outcome in patients with type 1 diabetes and renal failure, who presented for a kidney-pancreas transplant.
Detailed description
This is a randomized, prospective single center study evaluating the two maintenance drugs above.
Interventions
DRUGRapamycin
Rapamycin was initiated on day 1 postoperatively, 4mg/day;levels were maintained 5-8ng/ml. Those patients randomized to receive mycophenolate mofetil were given 1gm twice/day starting on the first post-operative day.
DRUGMycophenolate Mofetil
MMF 1 gm BID beginning 1st day postoperative day
DRUGTacrolimus
Part of standard maintenance.
DRUGSteroids
Part of standard maintenance
Sponsors
Astellas Pharma Inc
University of Miami
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Patient with Type 1 diabetes and end stage renal disease. * Women of childbearing potential must have had a negative pregnancy test (serum or urine). * Patient agrees to participate in the study and sign an informed consent. * Patient has no known contraindication to the administration of rapamycin or mycophenolate mofetil. * Patient has no history of hypersensitivity to rapamycin or mycophenolate mofetil.
Exclusion criteria
* Patient has history of a malignancy within two years, with the exception of adequately treated localized squamous or basal cell carcinoma of the skin without evidence of recurrence. * Patient is currently abusing drugs or alcohol. * Patient is known or suspected to have an active infection or be seropositive for hepatitis B surface antigen (HBsAg), hepatitis C (HCV) or human immunodeficiency virus (HIV).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-Specific Survival Comparisons | over 1-10 years post-transplant | Freedom from biopsy-proven acute rejection of the kidney allograft; Freedom from biopsy-proven acute rejection of the pancreas allograft; Death-censored kidney graft survival; Death-censored pancreas graft survival; Death-uncensored graft (kidney and pancreas) survival; and Patient survival. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Kidney Transplant Function at 12, 36, and 60 Months Post-transplant. | at 1-5 years post-transplant | Comparisons of renal function (eGFR, measured in mL/min/1.73 m\^2) at 12, 36, and 60 months post-transplant. |
| Overall Pancreas Transplant Function at 12, 36, and 60 Months Post-transplant. | at 1-5 years post-transplant | Comparisons of pancreas function (C-peptide in ng/mL) at 12, 36, and 60 months post-transplant. |
Countries
United States
Participant flow
Recruitment details
From September 1, 2000 through December 15, 2009, 170 consecutive patients with type 1 diabetes and ESRD were randomized to receive either Rapamycin (N=84) or MMF (N=86) immediately prior to transplant. Post-transplant clinical follow-up of patients continued through January 15, 2011.
Pre-assignment details
A randomized block design was implemented for the randomization scheme using Proc Plan in SAS. Patients were randomly assigned (allocation ratio of 1:1) to the two treatment arms in blocks of 4 and 6 patients (block sizes were also chosen randomly), ensuring a balance of patients across treatment arms after each block of patients was randomized.
Participants by arm
| Arm | Count |
|---|---|
| Tacrolimus Plus MMF Plus Steroids This group of kidney-pancreas recipients was randomized to receive mycophenolate mofetil and tacrolimus after transplantation.
Tacrolimus and mycophenolate mofetil: MMF 1 gm BID beginning 1st day postoperative day | 86 |
| Tacrolimus Plus Rapamycin Plus Steroids Patients randomized to this arm received Sirolimus, after kidney-pancreas transplantation.
Rapamycin: Rapamycin was initiated on day 1 postoperatively, 4mg/day;levels were maintained 5-8ng/ml. Those patients randomized to receive mycophenolate mofetil were given 1gm twice/day starting on the first post-operative day.
Rapamune and Tacrolimus: Sirolimus 2 mg/day beginning 1st postoperative day (trough target levels:
10-15ng/ml)
Mycophenolate Mofetil: Patients randomized to receive mycophenolate mofetil were given 1gm twice/day starting on the first post-operative day. | 84 |
| Total | 170 |
Baseline characteristics
| Characteristic | Tacrolimus Plus MMF Plus Steroids | Tacrolimus Plus Rapamycin Plus Steroids | Total |
|---|---|---|---|
| Age, Continuous | 43.4 years STANDARD_DEVIATION 9.3 | 41.5 years STANDARD_DEVIATION 8.2 | 42.5 years STANDARD_DEVIATION 8.8 |
| Race/Ethnicity, Customized African-American | 11 Participants | 6 Participants | 17 Participants |
| Race/Ethnicity, Customized Caucasian | 55 Participants | 47 Participants | 102 Participants |
| Race/Ethnicity, Customized Hispanic | 19 Participants | 31 Participants | 50 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Female | 31 Participants | 34 Participants | 65 Participants |
| Sex: Female, Male Male | 55 Participants | 50 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 16 / 86 | 15 / 84 |
| other Total, other adverse events | 3 / 86 | 5 / 84 |
| serious Total, serious adverse events | 40 / 86 | 38 / 84 |
Outcome results
Primary
Event-Specific Survival Comparisons
Freedom from biopsy-proven acute rejection of the kidney allograft; Freedom from biopsy-proven acute rejection of the pancreas allograft; Death-censored kidney graft survival; Death-censored pancreas graft survival; Death-uncensored graft (kidney and pancreas) survival; and Patient survival.
Time frame: over 1-10 years post-transplant
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Tacrolimus Plus MMF Plus Steroids | Event-Specific Survival Comparisons | Biopsy-Proven Acute Rejection of the Kidney | 22 Participants |
| Tacrolimus Plus MMF Plus Steroids | Event-Specific Survival Comparisons | Biopsy-Proven Acute Rejection of the Pancreas | 9 Participants |
| Tacrolimus Plus MMF Plus Steroids | Event-Specific Survival Comparisons | Death-Censored Kidney Graft Failure | 18 Participants |
| Tacrolimus Plus MMF Plus Steroids | Event-Specific Survival Comparisons | Death-Censored Pancreas Graft Failure | 7 Participants |
| Tacrolimus Plus MMF Plus Steroids | Event-Specific Survival Comparisons | Death-Uncensored Graft (Kidney&Pancreas) Survival | 26 Participants |
| Tacrolimus Plus MMF Plus Steroids | Event-Specific Survival Comparisons | Patient Death | 16 Participants |
| Tacrolimus Plus Rapamycin Plus Steroids | Event-Specific Survival Comparisons | Death-Uncensored Graft (Kidney&Pancreas) Survival | 25 Participants |
| Tacrolimus Plus Rapamycin Plus Steroids | Event-Specific Survival Comparisons | Biopsy-Proven Acute Rejection of the Kidney | 8 Participants |
| Tacrolimus Plus Rapamycin Plus Steroids | Event-Specific Survival Comparisons | Death-Censored Pancreas Graft Failure | 2 Participants |
| Tacrolimus Plus Rapamycin Plus Steroids | Event-Specific Survival Comparisons | Biopsy-Proven Acute Rejection of the Pancreas | 1 Participants |
| Tacrolimus Plus Rapamycin Plus Steroids | Event-Specific Survival Comparisons | Patient Death | 15 Participants |
| Tacrolimus Plus Rapamycin Plus Steroids | Event-Specific Survival Comparisons | Death-Censored Kidney Graft Failure | 10 Participants |
Comparison: Biopsy-Proven Acute Rejection of the Kidney (logrank test).p-value: 0.01Log Rank
Comparison: Biopsy-Proven Acute Rejection of the Pancreas (logrank test).p-value: 0.01Log Rank
Comparison: Death-Censored Kidney Graft Failure (logrank test).p-value: 0.16Log Rank
Comparison: Death-Censored Pancreas Graft Failure (logrank test).p-value: 0.12Log Rank
Comparison: Death-Uncensored (Kidney \& Pancreas) Graft Survival (logrank test).p-value: 0.96Log Rank
p-value: >0.99Log Rank
Secondary
Overall Kidney Transplant Function at 12, 36, and 60 Months Post-transplant.
Comparisons of renal function (eGFR, measured in mL/min/1.73 m\^2) at 12, 36, and 60 months post-transplant.
Time frame: at 1-5 years post-transplant
Population: Number analyzed here includes all patients alive with a functioning graft that had an available measurement taken at that time
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus Plus MMF Plus Steroids | Overall Kidney Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean eGFR at 12 months | 71.2 mL/min/1.73m^2 | Standard Error 2.4 |
| Tacrolimus Plus MMF Plus Steroids | Overall Kidney Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean eGFR at 36 months | 63.0 mL/min/1.73m^2 | Standard Error 3.1 |
| Tacrolimus Plus MMF Plus Steroids | Overall Kidney Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean eGFR at 60 months | 56.5 mL/min/1.73m^2 | Standard Error 4.1 |
| Tacrolimus Plus Rapamycin Plus Steroids | Overall Kidney Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean eGFR at 12 months | 67.2 mL/min/1.73m^2 | Standard Error 2 |
| Tacrolimus Plus Rapamycin Plus Steroids | Overall Kidney Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean eGFR at 36 months | 61.5 mL/min/1.73m^2 | Standard Error 2.6 |
| Tacrolimus Plus Rapamycin Plus Steroids | Overall Kidney Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean eGFR at 60 months | 61.9 mL/min/1.73m^2 | Standard Error 3.8 |
Comparison: Comparison of Mean eGFR at 12 Months Post-Transplant (t-test).p-value: 0.21t-test, 2 sided
Comparison: Comparison of Mean eGFR at 36 Months Post-Transplant (t-test).p-value: 0.71t-test, 2 sided
Comparison: Comparison of Mean eGFR at 60 Months Post-Transplant (t-test).p-value: 0.33t-test, 2 sided
Secondary
Overall Pancreas Transplant Function at 12, 36, and 60 Months Post-transplant.
Comparisons of pancreas function (C-peptide in ng/mL) at 12, 36, and 60 months post-transplant.
Time frame: at 1-5 years post-transplant
Population: Number analyzed here includes all patients alive with a functioning graft that had an available measurement taken at that time
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Tacrolimus Plus MMF Plus Steroids | Overall Pancreas Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean Log {C-peptide at 12 months} | 1.15 ng/mL | Standard Error 0.08 |
| Tacrolimus Plus MMF Plus Steroids | Overall Pancreas Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean Log {C-peptide at 36 months} | 0.990 ng/mL | Standard Error 0.08 |
| Tacrolimus Plus MMF Plus Steroids | Overall Pancreas Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean Log {C-peptide at 60 months} | 1.17 ng/mL | Standard Error 0.1 |
| Tacrolimus Plus Rapamycin Plus Steroids | Overall Pancreas Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean Log {C-peptide at 12 months} | 1.08 ng/mL | Standard Error 0.07 |
| Tacrolimus Plus Rapamycin Plus Steroids | Overall Pancreas Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean Log {C-peptide at 36 months} | 0.986 ng/mL | Standard Error 0.08 |
| Tacrolimus Plus Rapamycin Plus Steroids | Overall Pancreas Transplant Function at 12, 36, and 60 Months Post-transplant. | Mean Log {C-peptide at 60 months} | 1.22 ng/mL | Standard Error 0.1 |
Comparison: Comparison of Mean Log {C-Peptide Level} at 12 Months Post-Transplant (t-test).p-value: 0.47t-test, 2 sided
Comparison: Comparison of Mean Log {C-Peptide Level} at 36 Months Post-Transplant (t-test).p-value: 0.97t-test, 2 sided
Comparison: Comparison of Mean Log {C-Peptide Level} at 60 Months Post-Transplant (t-test).p-value: 0.75t-test, 2 sided