CNI Side Effects
Conditions
Brief summary
Reducing drug side effects is a key issue in transplantation. One class of drugs commonly used, calcineurin inhibitors (CNIs), is associated with negative side effects, namely, toxicity to the transplanted kidney. In some patients, this toxicity is thought to be associated with loss of transplant function in those who have had their transplants for many years. The introduction of new immunosuppression medications however, has provided the opportunity to minimize or avoid CNIs, which may reduce the occurrence of toxicity to the kidney.
Detailed description
It is clear that minimizing the use of CNIs may be beneficial to some or all kidney transplant recipients. The purpose of this study is to determine whether minimization of these CNI drugs will improve patient survival rates and long-term kidney function. If the subject agrees to participate in this research project, they will be randomly assigned to one of two different immunosuppression drug combinations. All of the drugs used in this study are standard FDA Approved immunosuppressive drugs currently in use by transplant patients. It is unclear however, which combination provides a better long-term outcome. If after six months of being on the study the subject has not experienced a rejection episode that excludes them from participating in the second phase of this study, they will asked whether or not they would like to continue the study. If they decide to participate in Phase II, there will be another randomization to one of two different immunosuppression drug combinations. This will involve either being assigned to a group that will have their CNI dose lowered or a group that will have their CNI drug stopped and replaced with a non-CNI drug called Sirolimus. Phase II begins at 6 months post-transplant and a second consent will be obtained for those who participate in Phase II.
Interventions
DRUGCyclosporine & Cellcept
Dose and frequency determined as usual by transplant physicians. The drugs are not experimental drugs. The study is looking at reducing negative side effects of some of the drugs.
DRUGPrograf & Cellcept
Dose and frequency determined as usual by transplant physicians. The drugs are not experimental drugs. The study is looking at reducing negative side effects of some of the drugs.
DRUGLow Dose CNI (Cyclosporine or FK) and Cellcept
Dose and frequency determined as usual by transplant physicians. The drugs are not experimental drugs. The study is looking at reducing negative side effects of some of the drugs.
DRUGRapamune and Cellcept
Dose and frequency determined as usual by transplant physicians. The drugs are not experimental drugs. The study is looking at reducing negative side effects of some of the drugs.
Sponsors
Roche Pharma AG
Wyeth is now a wholly owned subsidiary of Pfizer
Genzyme, a Sanofi Company
University of Minnesota
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Kidney Transplant Recipients \> 18 years old * First or Second Kidney Transplant only
Exclusion criteria
* Kidney Transplant Recipients \< 18 years old * Kidney Transplant Recipients who have a history of \> 2 kidney transplants * Kidney Transplant Recipients with an already functioning non-renal transplant * Kidney Transplant Recipients who receive another organ simultaneously at the same time of their kidney transplant (example: Kidney/pancreas, kidney/liver) * Non-skin malignancy with 2 years previous to enrollment * Donor Specific Antibodies to kidney donor
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: The Minimization of Negative Side Effects - Patient Survival | 6 months | The percentage of patients alive at 6 month post transplant. |
| Phase II: The Minimization of Negative Side Effects - Patient Survival | up to 7 years | The percentage of patients alive at 7 years post transplant or at the end of study activities. Not all participants completed 7-year follow-up. |
| Phase I: The Minimization of Negative Side Effects - Graft Survival | 6 months | Percent of participants at 6 months with a functioning graft (without graft failure). |
| Phase II: The Minimization of Negative Side Effects - Graft Survival | up to 7 years | The percentage of patients with a functioning graft (without graft failure) at 7 years post transplant or at the end of study activities. Not all participants completed 7-year follow-up. |
| Phase I: Acute Rejection-Free Survival | 6 months | Percent of participants at 6 months without acute rejection. |
| Phase II: Acute Rejection-Free Survival | up to 7 years | The percentage of patients without acute rejection at 7 years post transplant or at the end of study activities. Not all participants completed 7-year follow-up. |
Countries
United States
Participant flow
Pre-assignment details
All patients consented at time of transplant for phase 1. At 6 months post-transplant, patients were re-consented for phase 2. All patients represented for phase 2 were included for phase 1. Patients who were not re-consented for phase 2, were followed for 7 years under phase 1 protocol.
Participants by arm
| Arm | Count |
|---|---|
| Arm1 (Phase 1 & 2) Participants from Phase 1, Arm 1 (CSA and MMF) and participants from Phase 2, Arm 1 (Low CNI and MMF) | 266 |
| Arm 2 (Phase 1 & 2) Participants from Phase 1, Arm 2 (FK and MMF) and participants from Phase 2, Arm 2 (Rapa and MMF) | 261 |
| Total | 527 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Phase 1 | Death | 10 | 17 | 0 | 0 |
| Phase 1 | Graft Failure | 12 | 8 | 0 | 0 |
| Phase 1 | Withdrawal by Subject | 1 | 1 | 0 | 0 |
| Phase 2 | Death | 0 | 0 | 8 | 3 |
| Phase 2 | Graft failure | 0 | 0 | 7 | 4 |
| Phase 2 | Physician Decision | 0 | 0 | 0 | 17 |
| Phase 2 | Protocol Violation | 0 | 0 | 0 | 3 |
| Phase 2 | Withdrawal by Subject | 0 | 0 | 0 | 7 |
Baseline characteristics
| Characteristic | Arm1 (Phase 1 & 2) | Arm 2 (Phase 1 & 2) | Total |
|---|---|---|---|
| Age, Categorical Phase 1 <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Phase 1 >=65 years | 52 Participants | 45 Participants | 97 Participants |
| Age, Categorical Phase 1 Between 18 and 65 years | 214 Participants | 215 Participants | 429 Participants |
| Age, Categorical Phase 2 <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Phase 2 >=65 years | 19 Participants | 13 Participants | 32 Participants |
| Age, Categorical Phase 2 Between 18 and 65 years | 67 Participants | 74 Participants | 141 Participants |
| Race (NIH/OMB) Phase 1 American Indian or Alaska Native | 6 Participants | 9 Participants | 15 Participants |
| Race (NIH/OMB) Phase 1 Asian | 18 Participants | 13 Participants | 31 Participants |
| Race (NIH/OMB) Phase 1 Black or African American | 19 Participants | 12 Participants | 31 Participants |
| Race (NIH/OMB) Phase 1 More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 1 Native Hawaiian or Other Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Phase 1 Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 1 White | 221 Participants | 227 Participants | 448 Participants |
| Race (NIH/OMB) Phase 2 American Indian or Alaska Native | 1 Participants | 4 Participants | 5 Participants |
| Race (NIH/OMB) Phase 2 Asian | 2 Participants | 7 Participants | 9 Participants |
| Race (NIH/OMB) Phase 2 Black or African American | 6 Participants | 6 Participants | 12 Participants |
| Race (NIH/OMB) Phase 2 More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2 Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2 Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Phase 2 White | 77 Participants | 70 Participants | 147 Participants |
| Region of Enrollment United States | 266 participants | 261 participants | 527 participants |
| Sex: Female, Male Phase 1 Female | 89 Participants | 94 Participants | 183 Participants |
| Sex: Female, Male Phase 1 Male | 177 Participants | 167 Participants | 344 Participants |
| Sex: Female, Male Phase 2 Female | 23 Participants | 31 Participants | 54 Participants |
| Sex: Female, Male Phase 2 Male | 63 Participants | 56 Participants | 119 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 10 / 266 | 17 / 261 | 8 / 86 | 3 / 87 |
| other Total, other adverse events | 0 / 0 | 0 / 0 | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 266 | 0 / 261 | 0 / 86 | 0 / 87 |
Outcome results
Primary
Phase I: Acute Rejection-Free Survival
Percent of participants at 6 months without acute rejection.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Arm 1 | Phase I: Acute Rejection-Free Survival | 80 percentage of participants |
| Phase I Arm 2 | Phase I: Acute Rejection-Free Survival | 85 percentage of participants |
Primary
Phase II: Acute Rejection-Free Survival
The percentage of patients without acute rejection at 7 years post transplant or at the end of study activities. Not all participants completed 7-year follow-up.
Time frame: up to 7 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Arm 1 | Phase II: Acute Rejection-Free Survival | 76 percentage of participants |
| Phase I Arm 2 | Phase II: Acute Rejection-Free Survival | 81 percentage of participants |
Primary
Phase II: The Minimization of Negative Side Effects - Graft Survival
The percentage of patients with a functioning graft (without graft failure) at 7 years post transplant or at the end of study activities. Not all participants completed 7-year follow-up.
Time frame: up to 7 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Arm 1 | Phase II: The Minimization of Negative Side Effects - Graft Survival | 80 percentage of participants |
| Phase I Arm 2 | Phase II: The Minimization of Negative Side Effects - Graft Survival | 78 percentage of participants |
Primary
Phase II: The Minimization of Negative Side Effects - Patient Survival
The percentage of patients alive at 7 years post transplant or at the end of study activities. Not all participants completed 7-year follow-up.
Time frame: up to 7 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Arm 1 | Phase II: The Minimization of Negative Side Effects - Patient Survival | 89 percentage of participants |
| Phase I Arm 2 | Phase II: The Minimization of Negative Side Effects - Patient Survival | 85 percentage of participants |
Primary
Phase I: The Minimization of Negative Side Effects - Graft Survival
Percent of participants at 6 months with a functioning graft (without graft failure).
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Arm 1 | Phase I: The Minimization of Negative Side Effects - Graft Survival | 99 percentage of participants |
| Phase I Arm 2 | Phase I: The Minimization of Negative Side Effects - Graft Survival | 99 percentage of participants |
Primary
Phase I: The Minimization of Negative Side Effects - Patient Survival
The percentage of patients alive at 6 month post transplant.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I Arm 1 | Phase I: The Minimization of Negative Side Effects - Patient Survival | 99 percentage of participants |
| Phase I Arm 2 | Phase I: The Minimization of Negative Side Effects - Patient Survival | 98 percentage of participants |