A Trial of Two Steroid-Free Approaches Toward Mycophenolate Mofetil-Based Monotherapy Immunosuppression
NCT ID: NCT00166712
Last Updated: 2015-10-26
Study Results
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View full resultsBasic Information
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TERMINATED
PHASE4
40 participants
INTERVENTIONAL
2005-04-30
2010-04-30
Brief Summary
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After six months, patients in the tacrolimus arm who do not experience rejection will be randomized to continue on tacrolimus or to be converted to the combination of sirolimus and MMF. Individuals in this arm of the study who do not experience acute rejection, and demonstrate evidence of donor specific hyporesponsiveness at 9 months post-transplant (those staying on Tac + MMF) or 3 months post-conversion (those converted from Tac + MMF to sirolimus + MMF) will be weaned to MMF monotherapy.
Individuals in the sirolimus + MMF arm who do not experience acute rejection and demonstrate evidence of donor specific hyporesponsiveness at 6 months post-transplant will be weaned to MMF monotherapy.
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Detailed Description
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Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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Group 1: Alemtuzumab + TAC + MMF
Receive two doses of alemtuzumab (Campath-1H, 30mg) by intravenous (IV) infusion. One dose during kidney transplant surgery and the second dose on day 2 (post-surgery) to achieve peripheral T-cell depletion. IV glucocorticoids will be given prior to Campath administration to limit cytokine release syndrome in association with this monoclonal antibody. MMF on the day of surgery and continue taking it by mouth, twice daily. TAC started on the 1st day after surgery, and then taken by mouth twice daily.
Tacrolimus (TAC)
Tacrolimus (TAC) will be given standard of care by prescription twice a day (2.0 mg), orally. Doses will be adjusted by serum levels. The dose will be modified to achieve 12 hour trough concentrations of 5-8 ng/mL.
Alemtuzumab
Patients receiving alemtuzumab will be premedicated with 50mg of diphenhydramine hydrochloride, and 650mg of acetaminophen 30-60 minutes to the first Alemtuzumab infusion. The of 30mg will be diluted in 100cc sterile 0.9% normal saline and infused over 2 hours. The infusion line must contain an in-line 0.22-micron filter. Alemtuzumab will be administered on the day of transplant (intraoperatively), and on post-operative day 2. Both doses will be administered while the patient is in the hospital. Alemtuzumab is supplied in single-use clear glass ampoules containing 30mg of alemtuzumab in 3mL of solution.
Mycophenolate mofetil (MMF)
MMF will be given at 1.0-1.5gm, twice daily, orally. The first dose will be given pre-transplant, open label fashion.
Group 2: Alemtuzumab + Sirolimus + MMF
Sirolimus will be taken by mouth before transplant surgery and will continue taking once daily after surgery. Group 2 will also receive 2 doses of Alemtuzumab: one during surgery and the second will be given on the second day after surgery. Mycophenolate mofetil will be give on the day of surgery and twice daily, by mouth, as instructed by the doctor.
If subjects do not experience kidney rejection after 6 months after surgery, they will be weaned off of the sirolimus and continue taking the mycophenolate mofetil.
Sirolimus
Sirolimus will be given standard of care by prescription, dosed at 5mg daily. The dosage will be adjusted by serum level to achieve 24 hour trough concentrations of 8-12 ng/mL by HPLC assay.
Alemtuzumab
Patients receiving alemtuzumab will be premedicated with 50mg of diphenhydramine hydrochloride, and 650mg of acetaminophen 30-60 minutes to the first Alemtuzumab infusion. The of 30mg will be diluted in 100cc sterile 0.9% normal saline and infused over 2 hours. The infusion line must contain an in-line 0.22-micron filter. Alemtuzumab will be administered on the day of transplant (intraoperatively), and on post-operative day 2. Both doses will be administered while the patient is in the hospital. Alemtuzumab is supplied in single-use clear glass ampoules containing 30mg of alemtuzumab in 3mL of solution.
Mycophenolate mofetil (MMF)
MMF will be given at 1.0-1.5gm, twice daily, orally. The first dose will be given pre-transplant, open label fashion.
Interventions
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Tacrolimus (TAC)
Tacrolimus (TAC) will be given standard of care by prescription twice a day (2.0 mg), orally. Doses will be adjusted by serum levels. The dose will be modified to achieve 12 hour trough concentrations of 5-8 ng/mL.
Sirolimus
Sirolimus will be given standard of care by prescription, dosed at 5mg daily. The dosage will be adjusted by serum level to achieve 24 hour trough concentrations of 8-12 ng/mL by HPLC assay.
Alemtuzumab
Patients receiving alemtuzumab will be premedicated with 50mg of diphenhydramine hydrochloride, and 650mg of acetaminophen 30-60 minutes to the first Alemtuzumab infusion. The of 30mg will be diluted in 100cc sterile 0.9% normal saline and infused over 2 hours. The infusion line must contain an in-line 0.22-micron filter. Alemtuzumab will be administered on the day of transplant (intraoperatively), and on post-operative day 2. Both doses will be administered while the patient is in the hospital. Alemtuzumab is supplied in single-use clear glass ampoules containing 30mg of alemtuzumab in 3mL of solution.
Mycophenolate mofetil (MMF)
MMF will be given at 1.0-1.5gm, twice daily, orally. The first dose will be given pre-transplant, open label fashion.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
2. Donor age 18-65 years
3. Patients who are single-organ recipients (kidney only)
4. Women who are of childbearing potential must have a negative serum pregnancy test before transplantation and agree to use a medically acceptable method of contraception throughout the treatment period.
5. Subject (recipient) is able to understand the consent form and give written informed consent
Exclusion Criteria
2. Patient with significant or active infection
3. Patients with a positive lymphocytotoxic crossmatch using donor lymphocytes and recipient serum
4. Patients with PRA \> 20%
5. Patients who are pregnant or nursing mothers
6. Patients whose life expectancy is severely limited by diseases other than renal disease
7. Ongoing active substance abuse, drug or alcohol
8. Major ongoing psychiatric illness or recent history of noncompliance
9. Significant cardiovascular disease (e.g.):
* Significant non-correctable coronary artery disease
* Ejection fraction below 30%
* History of recent myocardial infarction
10. Malignancy within 3 years, excluding non-melanoma skin cancers
11. Serologic evidence of infection with HIV or HBVsAg positive
12. Patients with a screening/baseline total white blood cell count \< 4,000/mm3; platelet count \< 100,000/mm3; triglycerides \> 400 mg/dl; total cholesterol \> 300 mg/dl
13. Investigational drug within 30 days prior to transplant surgery
14. Anti-T cell therapy within 30 days prior to transplant surgery
15. Patients using Prednisone
16. Patients who are ABO incompatible
18 Years
65 Years
ALL
No
Sponsors
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Roche Pharma AG
INDUSTRY
Northwestern University
OTHER
Responsible Party
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Joseph Leventhal
Associate Professor
Principal Investigators
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Joseph R Leventhal, MD, PhD
Role: PRINCIPAL_INVESTIGATOR
Northwestern University
Locations
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Northwestern University/Northwestern Memorial Hospital
Chicago, Illinois, United States
Countries
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References
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Eggers PW. Effect of transplantation on the Medicare end-stage renal disease program. N Engl J Med. 1988 Jan 28;318(4):223-9. doi: 10.1056/NEJM198801283180406.
Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000 Mar 2;342(9):605-12. doi: 10.1056/NEJM200003023420901.
Barry JM. Immunosuppressive drugs in renal transplantation. A review of the regimens. Drugs. 1992 Oct;44(4):554-66. doi: 10.2165/00003495-199244040-00003.
Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med. 1994 Aug 11;331(6):365-76. doi: 10.1056/NEJM199408113310606. No abstract available.
Helderman JH, Van Buren DH, Amend WJ Jr, Pirsch JD. Chronic immunosuppression of the renal transplant patient. J Am Soc Nephrol. 1994 Feb;4(8 Suppl):S2-9. doi: 10.1681/ASN.V48s2.
Gaston RS. Maintenance immunosuppression in the renal transplant recipient: an overview. Am J Kidney Dis. 2001 Dec;38(6 Suppl 6):S25-35. doi: 10.1053/ajkd.2001.28923.
Pirsch JD, D'Alessandro AM, Sollinger HW, Knechtle SJ, Reed A, Kalayoglu M, Belzer FO. Hyperlipidemia and transplantation: etiologic factors and therapy. J Am Soc Nephrol. 1992 Jun;2(12 Suppl):S238-42. doi: 10.1681/ASN.V212s238.
Shaw LM, Kaplan B, Kaufman D. Toxic effects of immunosuppressive drugs: mechanisms and strategies for controlling them. Clin Chem. 1996 Aug;42(8 Pt 2):1316-21.
Boubenider S, Hiesse C, Goupy C, Kriaa F, Marchand S, Charpentier B. Incidence and consequences of post-transplantation lymphoproliferative disorders. J Nephrol. 1997 May-Jun;10(3):136-45.
Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998 Jun 11;338(24):1741-51. doi: 10.1056/NEJM199806113382407. No abstract available.
DeMario MD, Liebowitz DN. Lymphomas in the immunocompromised patient. Semin Oncol. 1998 Aug;25(4):492-502.
Sia IG, Paya CV. Infectious complications following renal transplantation. Surg Clin North Am. 1998 Feb;78(1):95-112. doi: 10.1016/s0039-6109(05)70637-x.
Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation. 1997 Apr 15;63(7):977-83. doi: 10.1097/00007890-199704150-00013.
Ahsan N, Hricik D, Matas A, Rose S, Tomlanovich S, Wilkinson A, Ewell M, McIntosh M, Stablein D, Hodge E. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil--a prospective randomized study. Steroid Withdrawal Study Group. Transplantation. 1999 Dec 27;68(12):1865-74. doi: 10.1097/00007890-199912270-00009.
Vincenti F, Ramos E, Brattstrom C, Cho S, Ekberg H, Grinyo J, Johnson R, Kuypers D, Stuart F, Khanna A, Navarro M, Nashan B. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation. 2001 May 15;71(9):1282-7. doi: 10.1097/00007890-200105150-00017.
Randhawa PS, Shapiro R, Jordan ML, Starzl TE, Demetris AJ. The histopathological changes associated with allograft rejection and drug toxicity in renal transplant recipients maintained on FK506. Clinical significance and comparison with cyclosporine. Am J Surg Pathol. 1993 Jan;17(1):60-8. doi: 10.1097/00000478-199301000-00007.
Birkeland SA. Steroid-free immunosuppression after kidney transplantation with antithymocyte globulin induction and cyclosporine and mycophenolate mofetil maintenance therapy. Transplantation. 1998 Nov 15;66(9):1207-10. doi: 10.1097/00007890-199811150-00016.
Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J, Bradley J, Smith K, Waldmann H. Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet. 1998 Jun 6;351(9117):1701-2. doi: 10.1016/S0140-6736(05)77739-4. No abstract available.
Calne RY. Initial Experience with Campath-1H in Renal Transplantation. Transplantation Reviews 2003, in press.
Knechtle SJ, Pirsch JD, H Fechner J Jr, Becker BN, Friedl A, Colvin RB, Lebeck LK, Chin LT, Becker YT, Odorico JS, D'Alessandro AM, Kalayoglu M, Hamawy MM, Hu H, Bloom DD, Sollinger HW. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant. 2003 Jun;3(6):722-30. doi: 10.1034/j.1600-6143.2003.00120.x.
Kirk AD, Hale DA, Mannon RB, Kleiner DE, Hoffmann SC, Kampen RL, Cendales LK, Tadaki DK, Harlan DM, Swanson SJ. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). Transplantation. 2003 Jul 15;76(1):120-9. doi: 10.1097/01.TP.0000071362.99021.D9.
Hricik DE, Rodriguez V, Riley J, Bryan K, Tary-Lehmann M, Greenspan N, Dejelo C, Schulak JA, Heeger PS. Enzyme linked immunosorbent spot (ELISPOT) assay for interferon-gamma independently predicts renal function in kidney transplant recipients. Am J Transplant. 2003 Jul;3(7):878-84. doi: 10.1034/j.1600-6143.2003.00132.x.
Gebauer BS, Hricik DE, Atallah A, Bryan K, Riley J, Tary-Lehmann M, Greenspan NS, Dejelo C, Boehm BO, Hering BJ, Heeger PS. Evolution of the enzyme-linked immunosorbent spot assay for post-transplant alloreactivity as a potentially useful immune monitoring tool. Am J Transplant. 2002 Oct;2(9):857-66. doi: 10.1034/j.1600-6143.2002.20908.x.
Reinsmoen NL. Cellular methods used to evaluate the immune response in transplantation. Tissue Antigens. 2002 Apr;59(4):241-50. doi: 10.1034/j.1399-0039.2002.590401.x.
Other Identifiers
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CNV0042139
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
STU8789 0811-007
Identifier Type: -
Identifier Source: org_study_id
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