Using Donor Stem Cells and Alemtuzumab to Prevent Organ Rejection in Kidney Transplant Patients

Pilot Study Using Donor Stem Cells and Campath-1H to Induce Renal Transplant Tolerance (ITN022ST)

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00183248

Enrollment

Registered

2005-09-16

Start date

2004-09-30

Completion date

2009-11-30

Last updated

2012-10-02

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Kidney Disease, Kidney Failure, Kidney Transplantation

Keywords

kidney, kidney transplant, kidney transplantation, transplant, transplantation, renal, renal transplant, renal transplantation, kidney disease, chronic, renal failure, kidney failure

Brief summary

Alemtuzumab is a man-made antibody used to treat certain blood disorders. This study will evaluate treatment of kidney transplant recipients with alemtuzumab and other immune system suppressing medications with or without infusions of bone marrow stem cells from the kidney donor. The purpose of this study is to find out which strategy is more effective in preventing organ rejection and maintaining patient health.

Detailed description

Organ transplantation is a common procedure in hospitals, but organ rejection and serious side effects are potential problems for the patient. Mycophenolate mofetil, sirolimus, and tacrolimus are drugs used to decrease immune system activity in people who have received organ transplants so that the new organ will not be rejected. Alemtuzumab is a monoclonal antibody that binds to and depletes excess T cells in the bone marrow of leukemia patients. In this study, alemtuzumab will be used to destroy the recipient's white blood cells (WBCs) at the time of transplantation. It is hoped that WBCs produced after alemtuzumab administration will recognize the transplanted liver as self and will not attack the new kidney. To further assist the immune system in accepting the donor kidney, some patients in this study will also receive two infusions of bone marrow stem cells from the kidney donor. Bone marrow stem cells are adult blood cells from which other specialized blood cells, such as T cells, develop. Treatment with these cells is believed to create a state of chimerism in the body, where the immune cells of both the donor and recipient can coexist and tolerate the presence of a donor organ. This study will evaluate the safety and effectiveness of an antirejection regimen including alemtuzumab and other immunosuppressive medications and donor bone marrow stem cell infusions in patients undergoing kidney transplantation. This study will last 3 years. Participants will be randomly assigned to receive either the full immunosuppressive therapy and donor bone marrow stem cell infusions (Group 1) or immunosuppressive therapy alone (Group 2). Patients will undergo kidney transplantation at the start of the study on Day 0. Patients will receive inpatient infusions of alemtuzumab on Days 0 and 4. Starting on Day 0, patients will begin taking mycophenolate mofetil; starting on Day 1, patients will also begin taking tacrolimus. On Day 5, patients in Group 1 will receive their first of 2 infusions of purified stem cells taken from the kidney donor's bone marrow; their second infusion of stem cells will occur sometime between Months 4 and 6 post-transplant. Beginning between Months 4 and 6 post-transplant, all participants will begin receiving low-dose maintenance immunosuppressive therapy with sirolimus, as is typical for post-transplant antirejection therapy. One year post-transplant, patients will be evaluated for the potential to withdraw some or all of this maintenance immunotherapy. Participants will be monitored for 3 years post-transplant. Urine collection will occur at Week 1 and Months 1, 3, 6, and 9. At Months 12, 24, and 30, participants will undergo kidney biopsies. Blood collection will occur at regular intervals for laboratory tests to evaluate the immune system's response to the transplanted kidney.

Interventions

DRUGAlemtuzumab

Immunosuppressant; 2 doses of drug by intravenous (IV) infusion on Days 0 and 4

DRUGMycophenolate mofetil

Immunosuppressant; oral daily dose starting Day 0 until withdrawal or end of the study

DRUGSirolimus

Immunosuppressant; oral daily dose starting between Months 4 and 6 post-transplant until withdrawal or end of the study

DRUGTacrolimus

Immunosuppressant; daily dose starting Day 1 until withdrawal or end of the study

PROCEDUREDonor bone marrow stem cell infusion

2 doses of kidney donor's bone marrow stem cells by IV infusion on Day 5 and sometime between Months 4 and 6

PROCEDUREKidney transplant

Occurs at study entry

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

SINGLE (Subject)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

* Weight greater than 40 kg (88.2 lbs) * Will be receiving a living-related (1-haplotype-matched donor/recipient) primary kidney allograft * Negative B-cell and T-cell cytotoxic and flow cytometry crossmatch (1-haplotype-matched donor/recipient pairs with a minimum of 1 HLA DR 1A and 1B locus in common and panel-reactive antibodies \[PRA\] of less than 10%) * Normal echocardiogram (ECG) with an ejection fraction of greater than 50% * Received full course of vaccination for hepatitis B virus (HBV), completed at least 6 weeks before transplantation, OR has naturally acquired immunity * Willing to comply with the study visits * Willing to use acceptable forms of contraception

Exclusion criteria

* Previously received or is receiving an organ transplant other than a kidney * Receiving an ABO (blood type) incompatible donor kidney * Human Immunodeficiency Virus (HIV) infected * Antibody positive for hepatitis C virus (HCV) * Surface antigen positive for hepatitis B virus (HBV) * Recipient or donor is positive for tuberculosis (TB), under treatment for suspected TB, or previously exposed to TB (positive Mantoux test) * Current cancer or a history of cancer within the 5 years prior to study entry. Patients who have had successfully treated nonmetastatic basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix are not excluded. * Significant liver disease, defined as having continuously elevated aspartate aminotransferase (AST SGOT) or alanine aminotransferase (ALT SGPT) levels greater than 3 times the upper value of the normal range within 28 days prior to study entry * Uncontrolled concomitant infections, severe diarrhea, vomiting, active upper gastrointestinal tract malabsorption, active peptic ulcer, or any other unstable medical condition that could interfere with this study * Currently receiving an investigational drug or received an investigational drug within 30 days prior to transplant * Currently receiving any immunosuppressive agent * Anticipated contraindication to taking medications orally or via nasogastric tube by the morning of Day 2 following completion of the transplant procedure * Require certain medications * Known hypersensitivity to any of the study medications, thymoglobulin daclizumab, or corticosteroids * Certain screening laboratory values. More information on this criterion can be found in the protocol. * Any form of substance abuse, psychiatric disorder, or other condition that, in opinion of the investigator, may interfere with the study * Anticipated contraindication to tacrolimus administration for longer than 5 days post-transplant * Currently undergoing peritoneal dialysis * PRA value less than 10% at any time prior to study entry * Graves disease. Patients with Graves disease adequately treated with radioiodine ablative therapy are not excluded. * Cytomegalovirus (CMV) or Epstein-Barr virus (EBV) negative kidney recipient receiving a kidney from a CMV or EBV positive donor * Pregnancy or breastfeeding

Design outcomes

Primary

Measure	Time frame	Description
Overall Participant Survival at One Year Post Kidney Transplant	One year post kidney transplant	—
Overall Kidney Graft Survival at One Year Post-Transplant	One year post kidney transplant	Number of participants that did not experience kidney graft failure\[1\] at one year post-transplant \[1\]Graft failure is defined as the institution of chronic dialysis (at least 6 consecutive weeks, excluding participants with delayed graft function), transplant nephrectomy, or retransplantation.

Secondary

Measure	Time frame	Description
Number of Kidney Biopsy-proven Acute Rejection	Three years post kidney transplant	Biopsy-proven acute renal (kidney) rejection\[1,2\]. 1. Diagnosis of acute rejection was made by renal biopsy using the Banff 97 criteria. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification. Acute rejection is defined by a renal biopsy demonstrating a Banff 97 classification of Grade IA or greater, with higher scores indicating more severe rejection\[2\] 2. Ref: Racusen LC et al. The Banff 97 working classification of renal allograft pathology. Kidney Int, 55: 713-723, 1999
Graft Survival at Three Years Post-Transplant	Three years post kidney transplant	Number of participants that did not experience kidney graft failure\[1\] at three years post-transplant \[1\]Graft failure is defined as the institution of chronic dialysis (at least 6 consecutive weeks, excluding participants with delayed graft function), transplant nephrectomy, or retransplantation.
Number of Graft-versus-host Disease (GVHD) Events	Three years post kidney transplant	A disease caused when cells from a donated stem cell graft attack the normal tissue of the transplant patient. Symptoms include jaundice, skin rash or blisters, a dry mouth, or dry eyes. Also called graft-versus-host disease.
Number of Chronic Allograft Nephropathies	Three years post kidney transplant	Number of chronic allograft nephropathies\[1,2,3\] at 3 years post kidney transplant. 1. Chronic allograft nephropathy is defined as renal biopsies with Banff 97 Grade I or greater\[2\] with higher numeric scores indicating more severe nephropathy 2. The Banff 97 diagnostic category for renal allograft biopsies is an international standardized histopathological classification\[3\] 3. Reference: Racusen LC, Solez K, Colvin RB et al. The Banff 97 working classification of renal allograft pathology. Kidney Int, 55: 713-723, 1999
Participant Survival at Three Years Post Kidney Transplant	Three years post kidney transplant	—

Countries

United States

Participant flow

Recruitment details

One center in the United States enrolled nine subjects who were recipients of living-related (1-haplotype-matched) donor kidney transplants between September 2004 and November 2006.

Pre-assignment details

Participants underwent procedures at screening to establish inclusion/exclusion criteria.

Participants by arm

Arm	Count
DBMCs Recipients of 1-haplotype human leukocyte antigen (HLA) matched living-donor related kidney transplantation were randomized to receive (CD34+ stem cell purified) Donor-specific Bone Marrow Cells (DBMCs). Induction therapy included alemtuzumab and steroid-free dose maintenance immunosuppression consisting of mycophenolate mofetil, tacrolimus and sirolimus. Refer to section titled 'Detailed Description' for additional treatment information.	4
Control Group Recipients of 1-haplotype human leukocyte antigen (HLA) matched living-donor related kidney transplantation were randomized to receive induction therapy with alemtuzumab and steroid-free dose maintenance immunosuppression consisting of mycophenolate mofetil, tacrolimus and sirolimus. Refer to section titled 'Detailed Description' for additional treatment information.	5
Total	9

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Focal glomerulosclerosis proteinuria	1	0
Overall Study	Lost to Follow-up	0	1

Baseline characteristics

Characteristic	Control Group	DBMCs	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	5 Participants	4 Participants	9 Participants
Age Continuous	41.8 years STANDARD_DEVIATION 7.9	41.0 years STANDARD_DEVIATION 12	41.4 years STANDARD_DEVIATION 9.7
Region of Enrollment United States	5 participants	4 participants	9 participants
Sex: Female, Male Female	0 Participants	2 Participants	2 Participants
Sex: Female, Male Male	5 Participants	2 Participants	7 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	4 / 4	5 / 5
serious Total, serious adverse events	4 / 4	3 / 5

Outcome results

Primary

Overall Kidney Graft Survival at One Year Post-Transplant

Number of participants that did not experience kidney graft failure\[1\] at one year post-transplant \[1\]Graft failure is defined as the institution of chronic dialysis (at least 6 consecutive weeks, excluding participants with delayed graft function), transplant nephrectomy, or retransplantation.

Time frame: One year post kidney transplant

Population: Intent-to-treat

Arm	Measure	Value (NUMBER)
DBMCs	Overall Kidney Graft Survival at One Year Post-Transplant	4 participants
Control Group	Overall Kidney Graft Survival at One Year Post-Transplant	5 participants

Primary

Overall Participant Survival at One Year Post Kidney Transplant

Time frame: One year post kidney transplant

Population: Intent-to-Treat

Arm	Measure	Value (NUMBER)
DBMCs	Overall Participant Survival at One Year Post Kidney Transplant	4 participants
Control Group	Overall Participant Survival at One Year Post Kidney Transplant	5 participants

Secondary

Graft Survival at Three Years Post-Transplant

Number of participants that did not experience kidney graft failure\[1\] at three years post-transplant \[1\]Graft failure is defined as the institution of chronic dialysis (at least 6 consecutive weeks, excluding participants with delayed graft function), transplant nephrectomy, or retransplantation.