Transplants and Implants
Conditions
Keywords
kidney transplantation, tacrolimus, Prograf, mycophenolate mofetil, CellCept, corticosteroid withdrawal, prednisone withdrawal, prednisone maintenance, rabbit antithymocyte globulin, Thymoglobulin
Brief summary
The purpose of the study was to determine if rapid discontinuation of corticosteroids (also known as prednisone withdrawal) and maintenance immunosuppression with Prograf (tacrolimus) and CellCept (mycophenolate mofetil) while using Thymoglobulin (Rabbit antithymocyte globulin) will give similar safety and efficacy results compared to continuation of corticosteroids (also known as prednisone maintenance) and standard maintenance immunosuppression with Prograf (tacrolimus), CellCept (mycophenolate mofetil) while using Thymoglobulin (Rabbit antithymocyte globulin).
Detailed description
Corticosteroids (one specific type is prednisone) have been used in clinical transplantation for more than 30 years. There are many side effects of corticosteroids including significant bone disease, diabetes (elevated blood sugar levels), fluid retention and hypertension (high blood pressure), psychosis, peptic ulcer disease, hyperlipidemia (elevated lipid levels such as cholesterol and triglycerides), obesity (overweight), acne, and susceptibility to infections. It is hoped that the new generation of potent immunosuppressive medications (such as Prograf and CellCept) will permit avoidance or withdrawal of corticosteroids for the majority of patients to avoid both short- and long-term complications of corticosteroid use in kidney transplant recipients.
Interventions
DRUGprednisone
In this group, participants had prednisone rapidly decreased until completely eliminated by day 6 after transplant. Participants began on 500mg of intravenous methylprednisolone on the day of transplant, followed by the following doses of oral prednisone: 160mg on day 1, 120mg on day 2, 80mg on day 3, 40mg on day 4, 20mg on day 5, none from day 6-on.
Participants in both groups received 3 to 5 doses of an intravenous medication to prevent rejection called Thymoglobulin (rabbit antithymocyte globulin) as per our standard of care. This drug was dosed at 1.5 milligrams/killograms per dose and dosing was then based on body weight. The dose was decreased in half or held if the participant had a low white blood cell count or if the participant a low platelet count. The first dose was given intravenously in the operating room and subsequent intravenous doses were administered either while participants were inpatients or outpatients for a total of 3 to 5 doses for a total of up to 6mg/kg. The number of doses was based on transplant kidney function and risk factors for rejection.
DRUGTacrolimus
Participants in both groups received tacrolimus per our standard of care. This medication helped to prevent rejection and was initially dosed at 0.1-0.2 milligrams/killograms/day in two divided doses, given orally, based on participant's body weight. We then looked at the trough levels of this medication(the lowest level before the next dose), and aimed to keep the trough level between 5-10 nanograms/milliliter throughout the study.
DRUGPrednisone
Participants in this group continued on prednisone indefinitely. Participants began with 500mg of intravenous methylprednisolone on the day of transplant, followed by the following doses of oral prednisone: 160mg on day 1, 120mg on day 2, 80mg on day 3, 40mg on day 4, 20 mg days 5-9, 15 mg day 10-19, 10 mg day 20-24, 7.5 mg day 25-29, and 5mg from day 30-on indefinitely.
DRUGMycophenolate mofetil
Participants in both groups received mycophenolate mofetil by mouth twice daily indefinitely. Dosing for patients in the Prednisone withdrawal group was 1000mg orally twice daily. The dose was decreased or held at the discretion of the physician, for side effects such as low white blood cell count, or low platelet count, or if the participant experienced stomach side effects such as heartburn, nausea, vomiting or diarrhea.
Sponsors
University of Pennsylvania
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* First time kidney transplant recipients who receives a kidney from a cadaveric, living related or living unrelated donor * Age greater than 18 years and less than 75 years * Caucasian recipients * Patients with current low panel reactive antibody (PRA) levels (\<10%) * Patients with signed and dated informed consent * Women of childbearing potential must have a negative pregnancy test at baseline and agree to use a medically acceptable method of contraception throughout the treatment period.
Exclusion criteria
* Other than Caucasian ethnicity * Patients with HIV+ or * Patients with HbsAg+ or Hepatitis C positive * Patients with a history of malignancy in the past 5 years * Patients with active systemic or localized major infection * Patients with a history of chronic steroid use for other diseases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Participants With Acute Rejection Episodes | 6 and 12 months post-transplant | Acute rejection episodes would have been measured by the number of participants who underwent a kidney transplant biopsy, and had the results of the biopsy reported as acute rejection by the transplant pathologist. Biopsies were only performed if clinically indicated. The cumulative number of participants with recorded rejection episodes by 6 and 12 months post-transplant would have been reported. |
| The Number of Participants With Graft Survival | 6 and 12 months | The number of participants who did not experience graft failure (defined as return to dialysis) at 6 and 12 months would have been reported. |
| Participant Survival | 6 and 12 months | The number of participants alive at 6 and 12 months post-transplant would have been posted as a measure of patient survival. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Length of Stay Associated With Hospital Readmissions | 12 months | The time from admission to discharge for each readmission for patients readmitted in the first 12 months post-transplant. |
| Participant Renal Function as Measured by MDRD Formula | 3, 6 and 12 months | The above methods focus on estimating or determining actual glomerular filtration rate (GFR) (or renal function) of the kidney transplant. The MDRD (Modification of Diet in Renal Disease) calculation includes age, sex and serum creatinine would have provided an estimate of GFR. This was to be performed at 3,6 and 12 months post-transplant. |
| Participant Renal Function as Measured by 24 Hour Urine Collection | 3 and 12 months post-transplant | Results would have been reported from patients undergoing 24 hour urine collections at 3 and 12 months post-transplant. This is a way to measure glomerular function rate (GFR) or renal function. |
| The Number of Participants With the Need for Rabbit Antithymocyte Globulin to Treat Rejection Episodes. | 12 months | The incidence and severity of rejection episodes per participant would have been identified by kidney transplant biopsy results read by a transplant pathologist. Treatment of rejection episodes in each participant would have been determined by the treating transplant physician. |
| The Number of Participants With Leukopenia | 12 months | All participants would have been assessed for the presence at any time during the trial of: leukopenia (defined by lab results as a white count less than 3,000 cells/uL). |
| The Number of Participants With Infections | 12 months | Participants would have been monitored throughout the study for any infectious complications as confirmed by the principal investigator. Patients would have been monitored by urine cytology and blood polymerase chain reaction for BK virus at baseline, and months 3, 6 and 12 post-transplant. |
| The Number of Participants With Treatment Failures | 12 months | This measure was defined as the percentage of participants that did not remain on initial therapy (ie were withdrawn from each arm of the trial) |
| The Number of Participants With Hypertension | 12 months | The number of participants who developed hypertension defined as blood pressure greater than 140/90 throughout the first 12 months of the study. |
| The Number of Participants With Hyperlipidemia | 12 months | Fasting lipid profiles were to be performed at 3,6 and 12 months post-transplant. Definitions based on ATP III guidelines. |
| The Number of Participants With Bone Disease | baseline (within 1 month post-transplant), 3, 6, 12 and 24 months | Bone densitometry by Computed tomography of peripheral skeleton and DEXA scans were performed at baseline (within one month after transplant) Urine and blood samples to measure markers of bone turnover: Alkaline phosphatase, pyridinoline, serum 1-25 vit D 3 levels (calcitriol) and 25 hydroxy vit D (calcidiol) levels and serum osteocalcin levels were drawn at baseline, 3, 6, 12 and 24 months. |
| The Number of Participants With Post Transplant Diabetes Mellitus | pre-transplant in living donor recipients, baseline (within one month post-transplant) and at 3, 6 and 12 months | Glucose tolerance test performed in non-diabetic participants only at pre transplant in living donor recipients and at baseline (within 1 mo after transplant) and 6 mo and 12 months. Blood test for hemoglobin A1C in non diabetic participants only: at baseline, 3, 6, and 12 months. Insulin and C peptide levels at baseline, 3,6 and 12 months in all participants. |
| The Number of Participants With Weight Gain | 12 months | Height, weight will be used to calculate change in BMI for all participants. |
| The Number of Participants With Malignancy | 12 months | Participants would have been monitored throughout the study with any reports of malignancy being confirmed by principal investigator. |
| Length of Hospital Stay After Transplant | 12 months | The length of the hospital stay would have assessed the number of days a participant was in the hospital after the kidney transplant was performed. This is calculated from date of admission to date of discharge. |
| The Number of Participants With Hospital Readmissions | 12 months | The number of readmissions during the study period for each participant would have been assessed, as well as the reason for readmissions. |
Countries
United States
Participant flow
Recruitment details
Study was terminated early due to low enrollment.
Participants by arm
| Arm | Count |
|---|---|
| Prednisone Withdrawal Participants randomized to the prednisone withdrawal group , were started on 4 drugs; Thymoglobulin (Rabbit antithymocyte globulin) Prograf (tacrolimus), CellCept (mycophenolate mofetil) and corticosteroids initially given as Solu-medrol (methylprednisolone) through a vein in the arm, and then given orally daily as prednisone tablets. The dose of prednisone for participants in this group was rapidly decreased until it was completely eliminated by day 6 after transplant. | 9 |
| Prednisone Maintenance Participants randomized to the prednisone maintenance arm were started on 4 drugs; Thymoglobulin (Rabbit antithymocyte globulin) Prograf(tacrolimus), CellCept (mycophenolate mofetil) and corticosteroids, initially as Solu-medrol(methylprednisolone) given through the vein in the arm and then as daily oral prednisone tablets. Participants in this arm received all drugs according to their doctors' standard of care and the prednisone was not be eliminated. | 9 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | study halted due to low enrollment | 5 | 3 |
Baseline characteristics
| Characteristic | Prednisone Maintenance | Prednisone Withdrawal | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants | 9 Participants | 18 Participants |
| Age, Continuous | 50.6 years STANDARD_DEVIATION 13.2 | 47.5 years STANDARD_DEVIATION 12.3 | 49.2 years STANDARD_DEVIATION 12.5 |
| Region of Enrollment United States | 9 participants | 9 participants | 18 participants |
| Sex: Female, Male Female | 4 Participants | 0 Participants | 4 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 9 |
| other Total, other adverse events | 8 / 9 | 8 / 9 |
| serious Total, serious adverse events | 4 / 9 | 4 / 9 |
Outcome results
Primary
Participant Survival
The number of participants alive at 6 and 12 months post-transplant would have been posted as a measure of patient survival.
Time frame: 6 and 12 months
Population: data not interpretable due to low patient enrollment
Primary
The Number of Participants With Acute Rejection Episodes
Acute rejection episodes would have been measured by the number of participants who underwent a kidney transplant biopsy, and had the results of the biopsy reported as acute rejection by the transplant pathologist. Biopsies were only performed if clinically indicated. The cumulative number of participants with recorded rejection episodes by 6 and 12 months post-transplant would have been reported.
Time frame: 6 and 12 months post-transplant
Population: data not interpretable due to low patient enrollment
Primary
The Number of Participants With Graft Survival
The number of participants who did not experience graft failure (defined as return to dialysis) at 6 and 12 months would have been reported.
Time frame: 6 and 12 months
Population: data not interpretable due to low patient enrollment
Secondary
Length of Hospital Stay After Transplant
The length of the hospital stay would have assessed the number of days a participant was in the hospital after the kidney transplant was performed. This is calculated from date of admission to date of discharge.
Time frame: 12 months
Population: unable to interpret results due to low number of patients enrolled.
Secondary
Participant Renal Function as Measured by 24 Hour Urine Collection
Results would have been reported from patients undergoing 24 hour urine collections at 3 and 12 months post-transplant. This is a way to measure glomerular function rate (GFR) or renal function.
Time frame: 3 and 12 months post-transplant
Population: Unable to interpret data due to low number of patients enrolled.
Secondary
Participant Renal Function as Measured by MDRD Formula
The above methods focus on estimating or determining actual glomerular filtration rate (GFR) (or renal function) of the kidney transplant. The MDRD (Modification of Diet in Renal Disease) calculation includes age, sex and serum creatinine would have provided an estimate of GFR. This was to be performed at 3,6 and 12 months post-transplant.
Time frame: 3, 6 and 12 months
Population: Unable to interpret data due to low number of patients enrolled.
Secondary
The Length of Stay Associated With Hospital Readmissions
The time from admission to discharge for each readmission for patients readmitted in the first 12 months post-transplant.
Time frame: 12 months
Population: Unable to interpret data due to low number of patients enrolled.
Secondary
The Number of Participants With Bone Disease
Bone densitometry by Computed tomography of peripheral skeleton and DEXA scans were performed at baseline (within one month after transplant) Urine and blood samples to measure markers of bone turnover: Alkaline phosphatase, pyridinoline, serum 1-25 vit D 3 levels (calcitriol) and 25 hydroxy vit D (calcidiol) levels and serum osteocalcin levels were drawn at baseline, 3, 6, 12 and 24 months.
Time frame: baseline (within 1 month post-transplant), 3, 6, 12 and 24 months
Population: unable to interpret results due to low number of patients enrolled.
Secondary
The Number of Participants With Hospital Readmissions
The number of readmissions during the study period for each participant would have been assessed, as well as the reason for readmissions.
Time frame: 12 months
Population: Unable to interpret data due to low number of patients enrolled.
Secondary
The Number of Participants With Hyperlipidemia
Fasting lipid profiles were to be performed at 3,6 and 12 months post-transplant. Definitions based on ATP III guidelines.
Time frame: 12 months
Population: Unable to interpret data due to low number of patients enrolled.
Secondary
The Number of Participants With Hypertension
The number of participants who developed hypertension defined as blood pressure greater than 140/90 throughout the first 12 months of the study.
Time frame: 12 months
Population: unable to interpret results due to low number of patients enrolled.
Secondary
The Number of Participants With Infections
Participants would have been monitored throughout the study for any infectious complications as confirmed by the principal investigator. Patients would have been monitored by urine cytology and blood polymerase chain reaction for BK virus at baseline, and months 3, 6 and 12 post-transplant.
Time frame: 12 months
Population: Unable to interpret data due to low number of patients enrolled.
Secondary
The Number of Participants With Leukopenia
All participants would have been assessed for the presence at any time during the trial of: leukopenia (defined by lab results as a white count less than 3,000 cells/uL).
Time frame: 12 months
Population: unable to interpret results due to low number of patients enrolled.
Secondary
The Number of Participants With Malignancy
Participants would have been monitored throughout the study with any reports of malignancy being confirmed by principal investigator.
Time frame: 12 months
Population: Unable to interpret data due to low number of patients enrolled.
Secondary
The Number of Participants With Post Transplant Diabetes Mellitus
Glucose tolerance test performed in non-diabetic participants only at pre transplant in living donor recipients and at baseline (within 1 mo after transplant) and 6 mo and 12 months. Blood test for hemoglobin A1C in non diabetic participants only: at baseline, 3, 6, and 12 months. Insulin and C peptide levels at baseline, 3,6 and 12 months in all participants.
Time frame: pre-transplant in living donor recipients, baseline (within one month post-transplant) and at 3, 6 and 12 months
Population: unable to interpret results due to low number of patients enrolled.
Secondary
The Number of Participants With the Need for Rabbit Antithymocyte Globulin to Treat Rejection Episodes.
The incidence and severity of rejection episodes per participant would have been identified by kidney transplant biopsy results read by a transplant pathologist. Treatment of rejection episodes in each participant would have been determined by the treating transplant physician.
Time frame: 12 months
Population: unable to interpret results due to low number of patients enrolled.
Secondary
The Number of Participants With Treatment Failures
This measure was defined as the percentage of participants that did not remain on initial therapy (ie were withdrawn from each arm of the trial)
Time frame: 12 months
Population: Unable to interpret data due to low number of patients enrolled.
Secondary
The Number of Participants With Weight Gain
Height, weight will be used to calculate change in BMI for all participants.
Time frame: 12 months
Population: unable to interpret results due to low number of patients enrolled.