Combination Immunosuppressive Therapy to Prevent Kidney Transplant Rejection in Adults

The Use of Campath-1H, Tacrolimus, and Sirolimus Followed by Sirolimus Withdrawal in Renal Transplant Patients

Transplant rejection occurs when a patient's body does not recognize the new organ and attacks it. Patients who have kidney transplants must take drugs to prevent transplant rejection. Alemtuzumab is a man-made antibody used to treat certain blood disorders. The purpose of this study is to test the safety and effectiveness of using alemtuzumab in combination with two other drugs, sirolimus and tacrolimus, to prevent organ rejection after kidney transplantation. This study will also test whether this combination of medications will allow patients to eventually stop taking antirejection medications entirely.

Study hypothesis: A new strategy of immunosuppression using alemtuzumab, tacrolimus, and sirolimus for human renal transplantation will permit a step-wise withdrawal from immunosuppressive drugs.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation; Kidney Disease
• Intervention / Treatment: Drug: Alemtuzumab; Drug: Sirolimus; Drug: Tacrolimus; Procedure: Kidney transplant; Drug: Methylprednisolone (or equivalent); Drug: Acetaminophen; Drug: Diphenhydramine; Drug: Trimethoprim (TMP)/Sulfa (Bactrim, Septra); Drug: Valgancyclovir; Drug: Acyclovir; Drug: Pentamidine; Drug: Clotrimazole; Drug: Nystatin

Detailed Description

Drugs that suppress the immune system, such as sirolimus and tacrolimus, have contributed to increased success of transplantation. However, to prevent organ rejection, transplant recipients need to take immunosuppressive drugs for the rest of their lives, and these drugs make patients more susceptible to infection, endangering their health and survival. Regimens that are less toxic to or can eventually be withdrawn from transplant recipients are needed. Alemtuzumab is a monoclonal antibody that binds to and depletes excess T cells in the bone marrow of leukemia patients. This study will determine the effects of intravenous alemtuzumab and oral sirolimus and tacrolimus after kidney transplantation. The study will also evaluate this regimen's potential to allow eventual discontinuation of components of long-term immunosuppressive therapy.

This study will last up to 4 years. Participants will undergo kidney transplantation on Day 0 and will receive intravenous doses of alemtuzumab, acetaminophen, and diphenhydramine on Days 0, 1, and 2, as well as methylprednisolone on Day 0. After transplant, patients will receive up to 10 days of valganciclovir or acyclovir. Participants will take tacrolimus daily by mouth for at least 60 days after transplant and sirolimus daily by mouth for at least 12 months after transplant. As part of opportunistic infection (OI) prophylaxis, participants will also take sulfamethoxazole-trimethoprim by mouth 3 times a week, valganciclovir or acyclovir for up to 10 days post-transplant, and clotrimazole or nystatin by mouth for at least 3 months post-transplant.

There will be a minimum of 62 study visits spread out over 4 years after transplant. Vital signs measurement, adverse event and OI reporting, medication history, physical exam, and blood collection will occur at selected visits. Sirolimus withdrawal will begin when a participant meets certain study criteria. The withdrawal process will occur over a minimum of 3 months at an approximate rate of 33% of the pre-withdrawal dose per month. Participants eligible for sirolimus withdrawal will undergo several kidney biopsies, including one 2 weeks prior to the start of withdrawal, 6 and 12 months after completion of withdrawal, 1 year after study enrollment, and annually thereafter.

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Wisconsin
    • Madison, Wisconsin, United States, 53792-1735
      • University of Wisconsin - Department of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Kidney transplant with primary cadaveric or non-Human Leukocyte Antigen (HLA)-identical living donor kidney (0-3 HLA-antigen mismatch)
• Receiving only a kidney and no other organs
• Able to take medications by mouth
• Willing to use acceptable methods of contraception

Exclusion Criteria

• Received HLA-identical living-donor kidney transplant
• HLA-antigen mismatch greater than 3
• Panel reactive antibody (PRA) value greater than 10% at any time prior to enrollment
• Received a non-heart-beating donor allograft
• Received a kidney from a donor who is greater than 60 years of age
• End-stage Renal Disease (ESRD) due to Focal Segmental Glomulerosclerosis (FSGS)
• Previous kidney transplant
• Received multiorgan transplant
• Concomitant systemic corticosteroid therapy for other medical diseases
• Known hypersensitivity to alemtuzumab, tacrolimus, methylprednisolone, or sirolimus
• Human Immunodeficiency Virus (HIV) infected
• Hepatitis C virus infected
• Positive for hepatitis B surface antigen
• Received dual or en-bloc pediatric kidneys
• Anti-human Globulin (AHG) or T cell crossmatch positive
• Investigational drug within 6 weeks of study entry
• Known clinically significant cardiovascular or cerebrovascular disease
• Previous or current history of cancer or lymphoma. Patients with adequately treated basal or squamous cell skin carcinoma are not excluded.
• Clinically significant coagulopathy or a requirement for chronic anti-coagulation therapy precluding biopsy
• Cytomegalovirus (CMV)-negative recipient, if received kidney is from a CMV-positive donor
• History of a psychological illness or condition that, in the opinion of the investigator, may interfere with the study
• Graves disease. Patients who have been previously adequately treated with radioiodine ablative therapy are not excluded.
• Active systemic infections
• Platelets less than 100,000 cells/mm^3 at study entry
• Pregnant or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Alemtuzumab

Drug: Alemtuzumab; 30mg intravenous infusion on days 0 (transplant), 1, and 2; Drug: Sirolimus; 2mg/day orally within 24-48 hrs post-transplant, and adjusted to achieve blood levels of 8-12 ng/mL for 1 year; Drug: Tacrolimus; 2mg orally twice daily, on days 1-60; Procedure: Kidney transplant; Kidney transplant with primary cadaveric or non-HLA-identical living donor kidney (0-3 HLA-antigen mismatch); Drug: Methylprednisolone (or equivalent); 250 mg intravenous infusion 60 minutes prior to first dose of alemtuzumab; Drug: Acetaminophen; 650 mg may be given 30-60 minutes prior to start of each infusion of alemtuzumab to prevent infusion related side effects such as fever, skin rash and pruritis; Drug: Diphenhydramine; 25 mg may be given 30-60 minutes prior to start of each infusion of alemtuzumab to prevent infusion related side effects such as fever, skin rash and pruritis; Drug: Trimethoprim (TMP)/Sulfa (Bactrim, Septra); 1 double strength tablet 3 times a week from day 1 through 1 year post-transplant.; Drug: Valgancyclovir; Given orally beginning on day 1 for up to 10 days post-transplant (until participant discharged from hospital if prior to 10 days). Dose adjusted based on participants calculated creatinine clearance; Drug: Acyclovir; 400 mg orally twice daily or 800 mg orally four times daily (dose adjusted based on calculated creatinine clearance and cytomegalovirus antibody serologic status of donor and recipient) for a minimum of 3 months starting when valganciclovir discontinued.; Drug: Pentamidine; 300 mg/6 mL inhalation therapy once monthly for a total of 6 treatments. First treatment given within one week post-transplant for participants with a known allergy or intolerance to sulfa; Drug: Clotrimazole; 10 mg orally four times daily for a minimum of 3 months post-transplant (subjects take either clotrimazole or nystatin, not both); Drug: Nystatin; 500,000 units/5 mL orally four times daily for a minimum of 3 months post-transplant (subjects take either nystatin or clotrimazole, not both)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Acute Rejections in All Enrolled Participants	Number of acute rejections[1] in all enrolled subjects from the time of transplantation to the end of the trial (four years post-transplant); Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff[2] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine.; Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999	Four years post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Acute Rejections in All Enrolled Participants Following Sirolimus Withdrawal	Following sirolimus withdrawal, the number of acute rejections[1] in all enrolled participants 1] Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff[2] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. [2] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999	Transplantation to end of study (up to four years post-transplant)
Number of Acute Rejections Between Initiation of Sirolimus Withdrawal and End of Study	Acute rejections[1] between initiation of sirolimus withdrawal and end of study 1] Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff[2] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. [2] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999	Initiation of sirolimus to end of study (up to four years post-transplant)
Time From Transplantation to Acute Rejection in Participants for Whom Sirolimus Withdrawal Was Not Initiated	Time (days) to acute rejection[1] for participants where sirolimus was not initiated 1] Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff[2] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. [2] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999	Transplantation to acute rejection (up to four years post-transplantation)
Time From Transplantation to Acute Rejection in Participants for Whom Acute Rejection Occurred During the 1 Year Post-transplant Period	Time (days) to acute rejection[1] for participants occurring during the year following transplantation 1] Acute rejection is defined as a biopsy-proven rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff[2] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. [2] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999	Transplantation to acute rejection (up to one year post-transplant)
Number of Deaths Stratified by Sirolimus Withdrawal Status	Participants who died during the study, all cause(s)	Transplantation to Death (up to four years post-transplant)
Number of Participants Who Experienced Graft Loss Stratified by Sirolimus Withdrawal Status	Participants who experienced graft loss[1] during study [1]Graft loss is defined as the institution of chronic dialysis (at least 6 consecutive weeks, excluding participants with delayed graft function), transplant nephrectomy, or retransplantation	Transplantation to Graft Loss (up to four years post-transplantation)
Number of Severe Acute Rejections Stratified by Sirolimus Withdrawal Status	Participants who experienced severe acute rejections[1] during study; Severe acute rejection is defined as that which requires treatment with anti-lymphocyte antibody or is histologically evaluated as Type IIA or greater using the Banff 1997 criteria[2]; Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999	Transplantation to severe acute rejection (up to four years post-transplantation)
Number of Participants Requiring Anti-lymphocyte Therapy for an Acute Rejection, Stratified by Sirolimus Withdrawal Status	Participants who experienced acute rejection[1] during study which required anti-lymphocyte (OKT3, ATG) therapy 1] Acute rejection is defined as a biopsy-prove rejection: a renal biopsy demonstrates acute cellular or humoral rejection of Banff[2] Grade 1B or greater; or presumed rejection in the absence of biopsy-proven rejection, the participant is treated for an unexplained 20% increase in serum creatinine. [2] Reference: Racusen LC, Solez K, Colvin RB et al,The Banff 97 working classification of renal allograft pathology. Kidney Int,55: 713-723, 1999	Transplantation to acute rejection (up to four years post-transplantation)
Number of Alemtuzumab Associated Adverse Events, Stratified by Sirolimus Withdrawal Status		Transplantation to end of study (up to four years post-transplant)
Number of Tacrolimus Associated Adverse Events, Stratified by Sirolimus Withdrawal Status		Transplantation to end of study (up to four years post-transplant)
Number of Sirolimus Associated Adverse Events, Stratified by Sirolimus Withdrawal Status		Transplantation to end of study (up to four years post-transplant)
Number of Side Effects of Conventional Immunosuppression, Stratified by Withdrawal Status	Side effects of conventional immunosuppression include increased body weight and hypertension	Transplantation to end of study (up to four years post-transplant)
Change in Renal Function as Measured by Serum Creatinine, Stratified by Withdrawal Status	Mean change from transplantation to Month 48 in serum creatinine. Normal serum creatinine range is from 0.7 - 1.4 mg/dL. In a transplant population, starting serum creatinine is higher than normal range. A negative change indicates better renal function	Transplantation to end of study (up to four years post-transplant)

Collaborators and Investigators

• Sponsor: University of Wisconsin, Madison
• Collaborators: Immune Tolerance Network (ITN)
• Investigators: Principal Investigator: A. D'jamali, MD, MS, Immune Tolerance Network (ITN)

Publications and helpful links

General Publications

• First MR. Tacrolimus based immunosuppression. J Nephrol. 2004 Nov-Dec;17 Suppl 8:S25-31.
• Gourishankar S, Turner P, Halloran P. New developments in immunosuppressive therapy in renal transplantation. Expert Opin Biol Ther. 2002 Jun;2(5):483-501. doi: 10.1517/14712598.2.5.483.
• Watson CJ, Bradley JA, Friend PJ, Firth J, Taylor CJ, Bradley JR, Smith KG, Thiru S, Jamieson NV, Hale G, Waldmann H, Calne R. Alemtuzumab (CAMPATH 1H) induction therapy in cadaveric kidney transplantation--efficacy and safety at five years. Am J Transplant. 2005 Jun;5(6):1347-53. doi: 10.1111/j.1600-6143.2005.00822.x.

Helpful Links

• Click here for the Immune Tolerance Network Web site
• Related Info

Study record dates

Study Major Dates

• Study Start: November 1, 2003
• Primary Completion (Actual): February 1, 2010
• Study Completion (Actual): February 1, 2010

Study Registration Dates

• First Submitted: March 1, 2004
• First Submitted That Met QC Criteria: March 1, 2004
• First Posted (Estimate): March 2, 2004

Study Record Updates

• Last Update Posted (Actual): June 29, 2018
• Last Update Submitted That Met QC Criteria: May 29, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Keywords: Immunosuppression; Renal Failure
• Additional Relevant MeSH Terms: Urologic Diseases; Kidney Diseases; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents, Local; Anti-Infective Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anesthetics; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antipyretics; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Immunological; Dermatologic Agents; Anti-Bacterial Agents; Membrane Transport Modulators; Hypnotics and Sedatives; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Anesthetics, Local; Antibiotics, Antineoplastic; Hormone Antagonists; Antifungal Agents; Steroid Synthesis Inhibitors; Antiprotozoal Agents; Antiparasitic Agents; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Antimalarials; Folic Acid Antagonists; 14-alpha Demethylase Inhibitors; Trypanocidal Agents; Cytochrome P-450 CYP2C9 Inhibitors; Calcineurin Inhibitors; Anti-Dyskinesia Agents; Anti-Infective Agents, Urinary; Renal Agents; Cytochrome P-450 CYP2C8 Inhibitors; Ionophores; Methylprednisolone; Acetaminophen; Diphenhydramine; Promethazine; Clotrimazole; Miconazole; Tacrolimus; Valganciclovir; Sirolimus; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Alemtuzumab; Nystatin; Acyclovir; Pentamidine
• Other Study ID Numbers: DAIT ITN013ST; H-2003-0435 (Other Identifier: HS IRB)