Transplant; Failure, Kidney
Conditions
Keywords
adult, primary kidney transplant recipient
Brief summary
The purpose of the present study is to determine which antibody induction regimen will result in a safer and more effective method to use with steroid avoidance in renal transplant recipients. Patients receiving either first cadaveric or non-HLA identical living donor kidney transplants will be preoperatively randomized into 2 groups.
Detailed description
Antibody Induction: Group I: Our standard steroid avoidance protocol, i.e., 3 daily doses of 1 mg/kg of Thymoglobulin®, the first to be infused at surgery, accompanied by 2 doses of anti-CD25 humanized monoclonal antibody, the first also to be given at surgery, and the second 2 weeks later. (controls) Group II: A new steroid avoidance protocol in which 1 dose of 1 mg/kg of Thymoglobulin® is to be infused at surgery followed by 1 dose of alemtuzumab (Campath-1H) at 0.3 mg/kg within 24 hours. No further antibody therapy will be used. In both groups, Prograf® maintenance therapy will be rapidly initiated (vide-infra) with a targeting dosage to 12 hour trough levels of 4 to 8 ng/ml. In Group I, maintenance dosing Myfortic® will be targeted to 720 mg twice daily. In Group II, maintenance doses of Myfortic® will be targeted to 360 mg twice daily. Steroids are to be given equivalently in both groups only during the first week postoperatively. The regimen consists of 500 mg/day of Solumedrol intravenously for 3 postoperative days followed by daily oral methylprednisolone or IV Solumedrol at 1 mg/kg per day, decreasing to 0.5 mg/kg per day during the remainder of the week primarily to avoid hypersensitivity reactions to the induction antibodies. No further steroid use is planned.
Interventions
DRUGAlemtuzumab
Alemtuzumab used as part of combined Induction.
DRUGDaclizumab
Daclizumab used as part of combined induction.
DRUGThymoglobulin
Thymoglobulin used as part of combined induction.
Sponsors
University of Miami
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patient has been fully informed and has signed a dated IRB approval informed consent form and is willing to follow study procedures for the extent of the study (12 months). Parent or legal guardian must provide written consent for patients \<18 years of age. 2. Age 18-70 years 3. Weight \> 40 kg 4. Primary renal allograft: living or deceased donor 5. Negative standard crossmatch for T cells. All deceased donor-recipient pairs matched for a minimum of 1 HLA DR antigen. (Standard at our center.) 6. Women of childbearing potential will be required to have a negative qualitative serum pregnancy test and agree to use an adequate method of contraception for the study duration. 7. Males and females are to be studied equivalently as they become available for transplantation using these criteria. \-
Exclusion criteria
* 1\. Patient has previously received or is receiving an organ transplant other than a kidney. 2\. Patient is receiving an ABO incompatible donor kidney. 3. Recipient or donor is seropositive for human immunodeficiency (HIV), Hepatitis C viruses, or Hepatitis B virus antigenemia. 4\. Patient has a current malignancy or a history of malignancy (within the past 5 years), except non-metastatic basal or squamous cell carcinoma of the skin that has been treated successfully, or carcinoma in situ of the cervix that has been treated successfully. 5\. Patients with significant liver disease, defined as having during the past 28 days continuously elevated AST (SGOT) and/or ALT (SGPT) levels greater than 3 times the upper value of the normal range of this center. 6\. Patient has uncontrolled concomitant infections and/or severe diarrhea, vomiting, active upper gastro-intestinal tract malabsorption or an active peptic ulcer or any other unstable medical condition that could interfere with study objectives. 7\. Patient is currently participating in another clinical trial of an investigational drug in the 30 days prior to transplant. 8\. Patient will be receiving any immunosuppressive agent other than those prescribed in the study. 9\. Patient is unable to take medications orally or via nasogastric tube by the morning of the second day following completion of the transplant procedure (i.e., skin closure). 10\. Patient is receiving or may require warfarin, fluvastatin, or herbal supplements during the study. 11\. Concurrent use of astemizole, pimozide, cisapride, terfenadine, or ketoconazole. 12\. Patient has a known hypersensitivity to tacrolimus, Thymoglobulin®, IL-2 receptor inhibitor monoclonal antibodies, alemtuzumab, sirolimus, MMF, Myfortic®, or corticosteroids. 13\. Patient is pregnant or lactating. 14. Patients with a screening/baseline (or within 96 hours of transplant) total white blood cell count \<4000/mm3; platelet count \<100,000/mm3; fasting triglycerides \>400 mg/dl (\>4.6 mmol/L); fasting total cholesterol \>300 mg/dl (\>7.8 mmol/L); fasting HDL-cholesterol \<30 mg/dl; fasting LDL-cholesterol \>200 mg/dl. 15\. Patient is unlikely to comply with the visits scheduled in the protocol. 16. Patient has any form of substance abuse, psychiatric disorder or a condition that, in the opinion of the investigator, may invalidate communication with the investigator. 17\. If tacrolimus cannot be instituted for longer than 5 days postoperatively.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Incidence of Acute Rejection at One Year Post-transplant | at one year post-transplant |
Secondary
| Measure | Time frame |
|---|---|
| Graft Survival | at 1 year post-transplant |
| Patient Survival | at 1 year post-transplant |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Thymoglobulin and Daclizumab Group I: Our standard steroid avoidance protocol, i.e., 3 daily doses of 1 mg/kg of Thymoglobulin®, the first to be infused at surgery, accompanied by 2 doses of anti-CD25 humanized monoclonal antibody, the first also to be given at surgery, and the second 2 weeks later. (controls)
Daclizumab: used in combination with Thymoglobulin as combined induction | 100 |
| Thymoglobulin and Alemtuzumab Group II: A new steroid avoidance protocol in which 1 dose of 1 mg/kg of Thymoglobulin® is to be infused at surgery followed by 1 dose of alemtuzumab (Campath-1H) at 0.3 mg/kg within 24 hours. No further antibody therapy will be used.
Alemtuzumab: used in conjunction with Thymoglobulin as combined Induction. | 100 |
| Total | 200 |
Baseline characteristics
| Characteristic | Thymoglobulin and Daclizumab | Total | Thymoglobulin and Alemtuzumab |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 9 Participants | 22 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 91 Participants | 178 Participants | 87 Participants |
| Age, Continuous | 49.9 participants STANDARD_DEVIATION 12 | 49.65 participants STANDARD_DEVIATION 12.5 | 49.4 participants STANDARD_DEVIATION 13 |
| Region of Enrollment United States | 100 participants | 200 participants | 100 participants |
| Sex: Female, Male Female | 28 Participants | 52 Participants | 24 Participants |
| Sex: Female, Male Male | 72 Participants | 148 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 75 | 8 / 70 |
| serious Total, serious adverse events | 29 / 100 | 25 / 100 |
Outcome results
Primary
Incidence of Acute Rejection at One Year Post-transplant
Time frame: at one year post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Thymoglobulin and Daclizumab | Incidence of Acute Rejection at One Year Post-transplant | 14 percentage of patients having BPAR |
| Thymoglobulin and Alemtuzumab | Incidence of Acute Rejection at One Year Post-transplant | 13 percentage of patients having BPAR |
Secondary
Graft Survival
Time frame: at 1 year post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Thymoglobulin and Daclizumab | Graft Survival | 92.9 actuarial percentage of participants |
| Thymoglobulin and Alemtuzumab | Graft Survival | 92.0 actuarial percentage of participants |
p-value: 0.78Log Rank
Secondary
Graft Survival
Time frame: at 3 years post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Thymoglobulin and Daclizumab | Graft Survival | 90.9 actuarial percentage of participants |
| Thymoglobulin and Alemtuzumab | Graft Survival | 86.9 actuarial percentage of participants |
p-value: 0.37Log Rank
Secondary
Patient Survival
Time frame: at 1 year post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Thymoglobulin and Daclizumab | Patient Survival | 96.9 actuarial percentage of participants |
| Thymoglobulin and Alemtuzumab | Patient Survival | 97 actuarial percentage of participants |
p-value: 0.99Log Rank
Secondary
Patient Survival
Time frame: at 3 years post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Thymoglobulin and Daclizumab | Patient Survival | 95.9 actuarial percentage of participants |
| Thymoglobulin and Alemtuzumab | Patient Survival | 91.8 actuarial percentage of participants |
p-value: 0.25Log Rank