Effectiveness of the Investigational Drug Campath-1H in Preventing Rejection of Transplanted Kidneys

NCT00001984 | Completed Phase 2 Results DMC

• 2 other identifiers: 00001300-DK-0013
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

This protocol will test a humanized monoclonal antibody known as Campath-1H for its ability to induce a state of permanent allograft acceptance, or tolerance, when administered in combination with a brief course of the immunosuppressive drug deoxyspergualin (DSG) at the time of human renal allotransplantation. Campath-1H is specific for the common lymphocyte and monocyte antigen CD52. Its administration temporarily depletes mature lymphocytes and some monocytes without altering neutrophils or hematopoietic stem cells. Deoxyspergualin inhibits the NFkB pathway thus preventing monocyte and macrophage activation. Recipients of living or cadaveric donor kidneys will be treated with one dose of Campath-1H prior to transplantation to insure that peripheral depletion is achieved at the time of graft reperfusion. Three subsequent doses of Campath-1H will be administered on the first, third and fifth days after the transplant to deplete passenger donor leukocytes and residual recipient cells that mobilize in response to the allograft. In addition, patients will be treated with DSG for 14 days beginning on the day prior to surgery. This trial expands on pilot studies at the NIH of 15 patients in which Campath was given alone at the time of transplantation. In those studies, excellent peripheral depletion occurred after just one dose of Campath though central depletion required additional dosing. This allowed for greatly reduced immunosuppression to be used to prevent rejection, but to date, all patients have required some immunosuppressive medication. It is hoped that the addition of DSG will eliminate the need for long-term immunosuppression. Patients will be followed closely in the post transplant period. If patients experience rejection, they will be treated with methylprednisolone and have immunosuppression added using sirolimus as the predominant immunosuppressive agent. In the previous phase of this study without DSG, this maneuver has in all cases been successful in returning the allograft to normal function. In addition to evaluating graft function following transplantation, this protocol will also characterize and evaluate the function of the immune system and the composition of the T cell repertoire following the administration of Campath-1H and DSG, and during immune system recovery after transplantation.

Conditions

Graft Rejection; Kidney Disease

Keywords

Immunosuppression; Tolerance; DSG; Alemtuzumab

Outcome Measures

Primary Outcomes (3)

• Number of Patients With Renal Allograft Rejection

  The renal allograft tolerance was evaluated clinically, by flow cytometry, and by protocol biopsies analyzed immunohistochemically and with real-time polymerase chain reaction.

  from day 1 to 24 months post operation

• Rejection Day of Onset

  The day on which the rejection onsets.

  From day 1 to 2 years post operation

• Rise in Serum Creatineine Above Posttransplant Nadir

  24-32 days post operation

Secondary Outcomes (4)

• Creatinine Level at 6 Month Post Operation

  6 month post operation

• Creatinine Level at Year 1 Post Operation

  1 year post operation

• Creatinine at 2 Years

  2 years post operation

• Monocyte Count

  4 day post operation

Study Arms (1)

Alemtuzumab and DSG

EXPERIMENTAL

The recipients of live donor kidneys were treated perioperatively with alemtuzumab and DSG and followed postoperatively without maintenance immunosuppression.

Drug: Alemtuzumab and DSG

Interventions

Alemtuzumab and DSG DRUG

Alemtuzumab was administered intravenously at 0.3 mg/kg/dose over 3 hr. Patients received one dose on each of days -1,+1,+3 and +5 relative to transplantation (total dose 1.2 mg/kg). Methylprednisolone was given prior to each dose to limit the cytokine release: 500 mg prior to dose 1, 125 mg prior to dose 2, and 60 mg prior to doses 3 and 4. Deoxyspergualin was dosed as follows. The first two patients received 4 mg/kg as a loading dose on the day of transplant and 2.5 mg/kg daily for 13 additional days (14 days of treatment; 36.5 mg/kg total dose). The next three patients received the same dosing regimen but it was initiated on postoperative day 12 to coincide with the resurgence of monocytes on days 12- 25.

Alemtuzumab and DSG

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Candidates for a kidney transplant performed at the Warren G. Magnuson Clinical Center.
• Willingness and legal ability to give informed consent, or permission from a legal guardian.
• Willingness to travel to the Clinical Center for protocol specific samples to be taken, or in some cases, the ability to send samples via overnight mail.
• 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 Clinic Center Living Donor Protocol who consents to periodic phlebotomy for peripheral blood lymphocyte isolation.

You may not qualify if:

• Immunosuppressive drug therapy at the time of or 2 months prior to enrollment. Specifically, candidates must not be taking prednisone, cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, antilymphocyte agents, cyclophosphamide, methotrexate, or other agents whose therapeutic effect is immunosuppressive.
• Any condition that precludes serial follow-up.
• 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).
• Hemoglobin less than 9.0 mg/dl. Patients may be on erythropoietin therapy, but will not be placed on therapy solely to facilitate research sample acquisition.
• Any known immunodeficiency syndrome.
• HLA identical status with a living donor.
• Any history of uncompensated cardiac insufficiency, major vascular disease, or symptomatic coronary artery disease.
• Systemic or pulmonary edema.
• Inability to be effectively dialyzed.
• Chronic hypotension (SBP less than 100 mmHg).
• Any condition that would likely increase the risk of protocol participation or confound the interpretation of the data.
• CMV negative status receiving an organ from a known CMV positive donor.
• EBV negative status receiving an organ from a known EBV positive donor.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (1)

• Santiago-Delpin EA. Trends in kidney transplantation in the United States. Transplant Proc. 1998 Sep;30(6):2867-8. doi: 10.1016/s0041-1345(98)00846-x. No abstract available.

  PMID: 9745602 BACKGROUND

MeSH Terms

Conditions

Kidney Diseases

Interventions

Alemtuzumab

Condition Hierarchy (Ancestors)

Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Dr. Alan Kirk
• Organization: NIDDK, NIH

allank@intra.niddk.nih.gov

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 26, 2000
• First Posted: January 27, 2000
• Study Start: November 1, 1999
• Primary Completion: June 1, 2008
• Study Completion: June 1, 2008
• Last Updated: October 27, 2016
• Results First Posted: October 5, 2010

Record last verified: 2016-09

Locations

US (1)