A Trial of Two Steroid-Free Approaches Toward Mycophenolate Mofetil-Based Monotherapy Immunosuppression

Kidney Transplant Failure and Rejection Clinical Trial

— Cell220  

Official title:

A Phase IV, Single Center Pilot Study Using Alemtuzumab (Campath-1H) Induction Combined With Prednisone-Free, Calcineurin-Inhibitor-Free Immunosuppression in Kidney Transplantation

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00166712
• Other study ID #: STU8789 0811-007
• Secondary ID: CNV0042139
• Status: Terminated
• Phase: Phase 4
• First received: September 9, 2005
• Last updated: October 20, 2015
• Start date: April 2005
• Est. completion date: April 2010

Study information

• Verified date: October 2015
• Source: Northwestern University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

This is an open label, single-center, randomized phase IV pilot study of steroid and calcineurin inhibitor avoidance in renal transplant recipients. All patients will receive two doses of alemtuzumab to achieve peripheral T-cell depletion. Intravenous glucocorticoids will be administered prior to alemtuzumab administration to limit cytokine release syndrome in association with this monoclonal antibody, and continued for the first two days post-transplant. Thereafter, steroids will not be used for immunosuppression. All transplant recipients will be started on oral immunosuppressive therapy with mycophenolate mofetil (MMF) prior to transplant. Pretransplant, these patients will be randomized to receive, in addition, either tacrolimus (Tac) or sirolimus.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 40
• Est. completion date: April 2010
• Est. primary completion date: April 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

1. Patients who are male or female age 18-65 years

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:

1. Known sensitivity or contraindication to sirolimus, tacrolimus or MMF

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Kidney Transplant Failure and Rejection

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
United States	Northwestern University/Northwestern Memorial Hospital	Chicago	Illinois

Sponsors (2)

Lead Sponsor	Collaborator
Northwestern University	Roche Pharma AG

Country where clinical trial is conducted

United States, 

References & Publications (24)

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. — View Citation

Barry JM. Immunosuppressive drugs in renal transplantation. A review of the regimens. Drugs. 1992 Oct;44(4):554-66. Review. — View Citation

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. — View Citation

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. Review. — View Citation

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. Erratum in: Lancet 1998 Aug 1;352(9125):408. — View Citation

Calne RY. Initial Experience with Campath-1H in Renal Transplantation. Transplantation Reviews 2003, in press.

DeMario MD, Liebowitz DN. Lymphomas in the immunocompromised patient. Semin Oncol. 1998 Aug;25(4):492-502. Review. — View Citation

Eggers PW. Effect of transplantation on the Medicare end-stage renal disease program. N Engl J Med. 1988 Jan 28;318(4):223-9. — View Citation

Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998 Jun 11;338(24):1741-51. Review. — View Citation

Gaston RS. Maintenance immunosuppression in the renal transplant recipient: an overview. Am J Kidney Dis. 2001 Dec;38(6 Suppl 6):S25-35. Review. Erratum in: Am J Kidney Dis 2002 Apr;39(4):898. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

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. — View Citation

Reinsmoen NL. Cellular methods used to evaluate the immune response in transplantation. Tissue Antigens. 2002 Apr;59(4):241-50. Review. — View Citation

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. Review. — View Citation

Sia IG, Paya CV. Infectious complications following renal transplantation. Surg Clin North Am. 1998 Feb;78(1):95-112. Review. — View Citation

Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med. 1994 Aug 11;331(6):365-76. Review. — View Citation

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. — View Citation

* Note: There are 24 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Incidence of Biopsy-proven Acute Allograft Rejection During the First 12 Months of Transplant.	The incidence of rejection is determined by the proportion of patients experiencing biopsy proven acute allograft rejection during the first 12 months post-transplant.	Within 12 months post kidney transplant	Yes
Secondary	Severity of Acute Rejection During the First 6 and 12 Months Post-transplant	The diagnosis of rejection will be based on clinical symptoms and signs, laboratory tests, and confirmed by core renal allograft biopsy.	Months 6-12 post-transplant	No
Secondary	Renal Function at 12 Months Post-transplant	Laboratory tests for renal function include creatinine or iothalamate glomerular filtration rate (GFR).	At 12 months post-transplant	No
Secondary	Incidence of Donor Specific Hyporesponsiveness Allowing for the Conversion to Monotherapy	The proportion of subjects for both groups determine this measure: 1) Patients in tacrolimus arm who do not experience acute rejection and demonstrate evidence of donor specific hyporesonsiveness at 9 months post-transplant (those staying on TAC+MMF) or 3 months post-convertion (converted from TAC+MMF to Sirolimus+MMF) will be weaned to MMF monotherapy; 2) Those 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.	At 6 & 9 months post-transplant	Yes
Secondary	Patient and Graft Survival Rates at 6 and 12 Months Post-transplant		At 6 & 12 months post-transplant	Yes