Sirolimus and Thymoglobulin to Prevent Kidney Transplant Rejection
Study Details
Study Description
Brief Summary
This study will test the safety and effectiveness of two drugs, Sirolimus and Thymoglobulin, for preventing rejection of transplanted kidneys. Standard anti-rejection therapy uses a combination of drugs, such as cyclosporine, tacrolimus, azathioprine, steroids, and others, that are taken daily for life. However, even with this daily therapy, more than half of kidney recipients slowly reject their transplant within 10 years. Both Thymoglobulin, an antibody, and Sirolimus, an anti-rejection drug, prevent rejection by lowering the response of the immune system to the transplanted organ. Thymoglobulin is given in the pre- and postoperative period, and Sirolimus is taken long term.
Patients who receive a kidney transplant at the National Institutes of Health Clinical Center are eligible for this study. Candidates will be screened with a medical history, physical examination, and blood and urine tests.
Participants will undergo a kidney transplant. Before the surgery, a central line (intravenous catheter), through which blood and medicine can be given, is placed in the neck or chest. Patients may also undergo leukapheresis, a procedure for collecting white blood cells. The cells can be stored for transfusion later if white cell counts drop following Thymoglobulin treatment. For this procedure, blood is drawn from a needle placed in the arm and flows into a machine that separates the blood components by spinning. The white cells are collected in a bag and the red cells and plasma are returned through a second needle in the other arm.
Thymoglobulin will be given intravenously the day before the transplant and days 1 through 9 after the operation. Sirolimus will be taken by mouth, mixed with water or orange juice. Sirolimus therapy starts the day of the transplant and continues for life.
Follow-up study visits will be scheduled weekly for the first month after the transplant, then every 6 months for 1 year and then once a year for 4 years. Procedures during these visits may include blood and urine tests, physical examination, and check of vital signs (i.e., blood pressure, heart rate, breathing rate, temperature). Kidney biopsies (removal of a small piece of tissue for examination under the microscope) will be done at 2 weeks, 1 month and 6 months after surgery and then yearly for 4 years to check for any damage to the kidney. In addition, a local doctor will do routine laboratory tests 2 to 3 times a week for the first 2 to 3 months aft...
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
This protocol will test a novel dual agent combination therapy for its ability to prevent human renal allograft rejection. Thymoglobulin (Sangstat), a FDA-approved polyclonal rabbit-IgG antithymocyte preparation, will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst), an oral immunosuppressant agent recently approved by the FDA. Rapamycin allows for antigen specific T cell activation but prevents T cell clonal expansion by interrupting IL-2 receptor beta-chain signal transduction. The rationale for this combination is to eliminate existing alloreactive T cell clones that could initiate a rejection at the time of transplantation, and to promote graft specific activation induced cell death (AICD) in repopulating T cells such that an allospecific T cell deficit is induced. The desired effect of this therapy is to prevent allograft rejection without the chronic use of calcineurin inhibitors or glucocorticosteroids, and in doing so, develop a regimen for transplantation that avoids most of the chronic drug toxicities inherent in the use of these two classes of immunosuppressants.
Twenty people will be evaluated in this pilot protocol. Ten will receive living donor kidney allografts and ten will receive cadaveric kidney allografts. Patients will be treated with Thymoglobulin beginning prior to graft implantation and continuing for ten days. Glucocorticosteroids will be given during the Thymoglobulin treatment to limit monocyte activation and prevent the cytokine release syndrome associated with this antibody preparation. Patients will be given Sirolimus orally beginning the day after transplantation and continuously thereafter. Patients will then be monitored for evidence of allograft rejection using standard functional parameters and protocol allograft biopsies. In addition, patients will be followed for a specific desired effect, allospecific AICD, that should promote the development of allospecific graft tolerance. This will be accomplished by assaying peripheral blood and allograft biopsies for apoptosis and peripheral blood for evidence of alloreactive T cell clone depletion.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Sirolimus and Thymoglobulin Thymoglobulin (Sangstat), a FDA-approved polyclonal rabbit-IgG antithymocyte preparation, will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst), an oral immunosuppressant agent recently approved by the FDA. |
Drug: Sirolimus
Drug: Thymoglobulin
|
Outcome Measures
Primary Outcome Measures
- Serum Creatinine Concentration [6 months after intervention]
measures at 6 months after intervention
- Serum Creatinine Concentration [12 months after intervention]
measures at 12 months after intervention
Secondary Outcome Measures
- Glomerular Filtration Rate (Flow Rate of Filtered Fluid Through the Kidney) [6 month after intervention]
measure 6 months after intervention
- Glomerular Filtration Rate (Flow Rate of Filtered Fluid Through the Kidney) [12 months after intervention]
measure at 12 months after intervention
Eligibility Criteria
Criteria
- INCLUSION CRITERIA:
Candidates for a kidney transplant performed at the NIH Clinical Center.
Willingness and legal ability to give informed consent.
Availability of donor tissue for testing. This could include splenic or peripheral blood lymphocytes from a cadaveric donor or a willing living donor enrolled on the Clinical Center Living Donor Protocol who consents to periodic phlebotomy for peripheral blood lymphocyte isolation.
EXCLUSION CRITERIA:
Immunosuppressive drug therapy at the time of or 2 months prior to enrollment. Specifically, candidates may not be taking prednisone, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, anti-lymphocyte agents, cyclophosphamide, methotrexate, or other agents whose therapeutic effect is immunosuppressive.
Any active malignancy or any history of a hematogenous malignancy or lymphoma. Patients with primary, cutaneous basal cell or squamous cell cancers may be enrolled providing the lesions are appropriately treated prior to transplant.
Significant coagulopathy or requirement for anticoagulation therapy that would contraindicate protocol allograft biopsies.
Platelet count less than 100,000/mm(3).
Any known immunodeficiency syndrome.
Any history of cardiac insufficiency, major vascular disease, symptomatic coronary artery disease.
Systemic or pulmonary edema.
Inability to be effectively dialyzed.
Any condition that would likely increase the risk of protocol participation or confound the interpretation of the data.
Any history of sensitization to rabbits or extensive exposure to rabbits.
Inability or unwillingness to comply with protocol monitoring and therapy, including, among others, a history of noncompliance, circumstances where compliance with protocol requirements is not feasible due to living conditions, travel restrictions, access to urgent medical services, or access to anti-rejection drugs after the research protocol is completed.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institutes of Health Clinical Center, 9000 Rockville Pike | Bethesda | Maryland | United States | 20892 |
Sponsors and Collaborators
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Additional Information:
Publications
- Matas AJ, Gillingham KJ, Sutherland DE. Half-life and risk factors for kidney transplant outcome--importance of death with function. Transplantation. 1993 Apr;55(4):757-61.
- Morris PJ. Renal transplantation: a quarter century of achievement. Semin Nephrol. 1997 May;17(3):188-95.
- Swanson SJ, Hale DA, Mannon RB, Kleiner DE, Cendales LC, Chamberlain CE, Polly SM, Harlan DM, Kirk AD. Kidney transplantation with rabbit antithymocyte globulin induction and sirolimus monotherapy. Lancet. 2002 Nov 23;360(9346):1662-4.
- 000196
- 00-DK-0196
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | Sirolimus and Thymoglobulin |
|---|---|
| Arm/Group Description | Thymoglobulin (Sangstat) will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst) |
| Period Title: Overall Study | |
| STARTED | 12 |
| COMPLETED | 12 |
| NOT COMPLETED | 0 |
Baseline Characteristics
| Arm/Group Title | Sirolimus and Thymoglobulin |
|---|---|
| Arm/Group Description | Thymoglobulin (Sangstat) will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst) |
| Overall Participants | 12 |
| Age (Count of Participants) | |
| <=18 years |
0
0%
|
| Between 18 and 65 years |
12
100%
|
| >=65 years |
0
0%
|
| Age (years) [Mean (Standard Deviation) ] | |
| Mean (Standard Deviation) [years] |
45.0
(12.7)
|
| Sex: Female, Male (Count of Participants) | |
| Female |
4
33.3%
|
| Male |
8
66.7%
|
| Region of Enrollment (participants) [Number] | |
| United States |
12
100%
|
Outcome Measures
| Title | Glomerular Filtration Rate (Flow Rate of Filtered Fluid Through the Kidney) |
|---|---|
| Description | measure 6 months after intervention |
| Time Frame | 6 month after intervention |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Sirolimus and Thymoglobulin |
|---|---|
| Arm/Group Description | Thymoglobulin (Sangstat) will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst) |
| Measure Participants | 12 |
| Mean (Standard Deviation) [mL/min] |
69.1
(17.4)
|
| Title | Serum Creatinine Concentration |
|---|---|
| Description | measures at 6 months after intervention |
| Time Frame | 6 months after intervention |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis includes all participants in the study. Analysis was per protocol. |
| Arm/Group Title | Sirolimus and Thymoglobulin |
|---|---|
| Arm/Group Description | Thymoglobulin (Sangstat) will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst) |
| Measure Participants | 12 |
| Mean (Standard Deviation) [umol/L] |
112
(34)
|
| Title | Serum Creatinine Concentration |
|---|---|
| Description | measures at 12 months after intervention |
| Time Frame | 12 months after intervention |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Sirolimus and Thymoglobulin |
|---|---|
| Arm/Group Description | Thymoglobulin (Sangstat) will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst) |
| Measure Participants | 12 |
| Mean (Standard Deviation) [umol/L] |
107
(25)
|
| Title | Glomerular Filtration Rate (Flow Rate of Filtered Fluid Through the Kidney) |
|---|---|
| Description | measure at 12 months after intervention |
| Time Frame | 12 months after intervention |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Sirolimus and Thymoglobulin |
|---|---|
| Arm/Group Description | Thymoglobulin (Sangstat) will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst) |
| Measure Participants | 12 |
| Mean (Standard Deviation) [mL/min] |
74.2
(21.3)
|
Adverse Events
| Time Frame | ||
|---|---|---|
| Adverse Event Reporting Description | ||
| Arm/Group Title | Sirolimus and Thymoglobulin | |
| Arm/Group Description | Thymoglobulin (Sangstat) will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst) | |
All Cause Mortality |
||
| Sirolimus and Thymoglobulin | ||
| Affected / at Risk (%) | # Events | |
| Total | 0/12 (0%) | |
Serious Adverse Events |
||
| Sirolimus and Thymoglobulin | ||
| Affected / at Risk (%) | # Events | |
| Total | 3/12 (25%) | |
| Renal and urinary disorders | ||
| Acute cellular rejection | 3/12 (25%) | 3 |
Other (Not Including Serious) Adverse Events |
||
| Sirolimus and Thymoglobulin | ||
| Affected / at Risk (%) | # Events | |
| Total | 10/12 (83.3%) | |
| General disorders | ||
| varicella zoster reactivation | 1/12 (8.3%) | 1 |
| hernia | 2/12 (16.7%) | 2 |
| postpolio motor neuropathy | 1/12 (8.3%) | 1 |
| Sirolimus-side-effect (diarrhoea) | 3/12 (25%) | 3 |
| Sirolimus-side-effect (mouth ulcers) | 8/12 (66.7%) | 8 |
| Sirolimus-side-effect (arthralgias) | 2/12 (16.7%) | 2 |
| Sirolimus-side-effect (hyperlipidaemia) | 10/12 (83.3%) | 10 |
| Immune system disorders | ||
| lymphocoele | 1/12 (8.3%) | 1 |
| Metabolism and nutrition disorders | ||
| diabetic foot cellulitis | 1/12 (8.3%) | 1 |
| Renal and urinary disorders | ||
| bacterial urnary tract infection | 2/12 (16.7%) | 2 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE 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
| Name/Title | Dr. Allan D. Kirk |
|---|---|
| Organization | National Institutes of Health |
| Phone | |
| allank@intra.niddk.nih.gov |
- 000196
- 00-DK-0196