Evaluating Safety and Efficacy of TOL101 Induction Versus Anti-Thymocyte Globulin to Prevent Kidney Transplant Rejection

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Tolera Therapeutics, Inc
ClinicalTrials.gov Identifier:
NCT01154387
First received: June 26, 2010
Last updated: June 10, 2013
Last verified: June 2013
  Purpose

Induction therapy with antibodies is administered during transplant surgery and for a short period of time following transplant surgery in an effort to render the immune system less able to mount an initial rejection response. In general, induction therapy is associated with better outcomes compared to the absence of induction therapy. However, currently used induction agents, some of which are not labeled or indicated for induction therapy in transplantation, have drawbacks related to long-term immune system suppression increasing susceptibility to opportunistic infections or malignancies, and other immune-mediated side effects.

An unmet medical need exists for a more specific approach to prevent acute organ rejection, without unnecessarily exposing the patient to non-specific or open-ended immune suppression, which may exacerbate the risks of infections and malignancies. TOL101 is a novel antibody that targets a very specific immune cell type that is critical in the acute organ rejection response. In this two-part study, TOL101 will be evaluated for the prophylaxis of acute organ rejection when used as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus in first time kidney transplant recipients.

This study will test the hypothesis that a more specific approach (with TOL101) to prevention of acute organ rejection may provide similar or better efficacy than the currently used induction antibodies (such as Anti-Thymocyte Globulin or Thymoglobulin) while carrying fewer risks in terms of opportunistic infections, malignancies and adverse effects.


Condition Intervention Phase
End Stage Renal Disease
Renal Transplant
Drug: Anti-Thymocyte Globulin
Drug: TOL101
Drug: Steroids
Drug: Tacrolimus
Drug: Mycophenolate mofetil (MMF)
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Two Part, Phase 1/2, Safety, PK and PD Study of TOL101, an Anti-TCR Monoclonal Antibody for Prophylaxis of Acute Organ Rejection in Patients Receiving Renal Transplantation

Resource links provided by NLM:


Further study details as provided by Tolera Therapeutics, Inc:

Primary Outcome Measures:
  • To assess the safety and tolerability of ascending doses of TOL101 and the effectiveness of TOL101 to target and downregulate T cells in patients undergoing first renal transplantation [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    The following safety parameters will be monitored: Adverse events, standard laboratory safety evaluations (hematology and serum chemistries), symptom constellation indicating cytokine release syndrome, serum concentrations of cytokines and nitric oxide, malignancies, CMV viremia, BKV viremia, EBV viremia and other infections


Secondary Outcome Measures:
  • The effects of ascending doses of TOL101 on CD3+ T lymphocyte numbers and other immune cell subsets [ Time Frame: 14 days post-transplant (Part A); 6 months (Part B) ] [ Designated as safety issue: No ]
  • The pharmacokinetic (PK) profile of TOL101 in renal transplant recipients and the exposure-response (PK parameter to CD3+ T lymphocyte numbers) relationship over time [ Time Frame: 14 days post-transplant ] [ Designated as safety issue: No ]
  • Biopsy-proven acute organ rejection [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Graft survival [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Patient survival [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  • Renal function by measured GFR at 6 months post-transplant and urine protein to creatinine ratio at 3 and 6 months post-transplant [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Delayed graft function [ Time Frame: first 7 days post-transplant ] [ Designated as safety issue: No ]
  • Immunogenicity of TOL101 by measurement of anti-TOL101 antibodies [ Time Frame: at 14 and 28 days post-transplant ] [ Designated as safety issue: No ]
  • The presence of Donor Specific Antibody at 3 months (Part B only) and 6 months post-transplant [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Estimated Enrollment: 85
Study Start Date: July 2010
Estimated Study Completion Date: June 2013
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Anti-Thymocyte Globulin
Anti-Thymocyte Globulin induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
Drug: Anti-Thymocyte Globulin
1.5mg/kg IV on Day of Transplant and 1.0-1.5 mg/kg IV once daily for a minimum of 4.5mg/kg and a maximum of 7.5mg/kg total cumulative dose
Other Name: Thymoglobulin
Drug: Steroids
IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months
Drug: Tacrolimus
Oral administration started by 6 days post-transplantation and continued for 6 months
Drug: Mycophenolate mofetil (MMF)
Oral administration started by Day 1 post-transplantation and continued for 6 months
Experimental: TOL101 (Dose A)
TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
Drug: TOL101
Potential Therapeutic Dose (PTD)-A (0.28-56 mg to be determined in Phase 1/Part A ) IV once daily x 6-10 doses starting on Day of Transplant
Drug: Steroids
IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months
Drug: Tacrolimus
Oral administration started by 6 days post-transplantation and continued for 6 months
Drug: Mycophenolate mofetil (MMF)
Oral administration started by Day 1 post-transplantation and continued for 6 months
Experimental: TOL101 (Dose B)
TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
Drug: TOL101
Potential Therapeutic Dose (PTD)-B (0.28-56 mg to be determined in Phase 1/Part A ) IV once daily x 6-10 doses starting on Day of Transplant
Drug: Steroids
IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months
Drug: Tacrolimus
Oral administration started by 6 days post-transplantation and continued for 6 months
Drug: Mycophenolate mofetil (MMF)
Oral administration started by Day 1 post-transplantation and continued for 6 months

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Recipient of a primary renal transplant from a living or standard criteria cadaveric donor
  • Male or female 18-60 years of age
  • Recipient with a PRA < 20%

Exclusion Criteria:

  • Previous solid organ transplant
  • Recipient of HLA-identical kidney allograft transplant
  • Recipient of an ABO incompatible donor kidney
  • Known HIV infection or other major infection
  • History of malignancy within 3 years (excluding treated basal cell or squamous cell carcinoma of the skin) prior to enrollment
  • History of tuberculosis
  • Recipient with cardiovascular disease
  • Treatment with immunosuppressive medications within 1 month prior to enrollment
  • Known or suspected allergy to mice
  • Pregnant or lactating
  • Unable or unwilling to participate in all required study activities for the duration of the study (6 months)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01154387

Locations
United States, Colorado
University of Colorado Denver
Aurora, Colorado, United States, 80045
United States, Kentucky
University of Kentucky
Lexington, Kentucky, United States, 40536
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, New Jersey
St Barnabas Medical Center
Livingston, New Jersey, United States, 07039
United States, New York
Montefiore Medical Center
Bronx, New York, United States, 10467
Buffalo General Hospital
Buffalo, New York, United States, 14203
United States, Ohio
Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
Baylor University Medical Center
Dallas, Texas, United States, 75246
Baylor All Saints
Fort Worth, Texas, United States, 76104
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
United States, Virginia
University of Virginia Health System
Charlottesville, Virginia, United States, 22908
Sponsors and Collaborators
Tolera Therapeutics, Inc
Investigators
Principal Investigator: Stuart Flechner, MD The Cleveland Clinic
  More Information

No publications provided

Responsible Party: Tolera Therapeutics, Inc
ClinicalTrials.gov Identifier: NCT01154387     History of Changes
Other Study ID Numbers: TTI-121
Study First Received: June 26, 2010
Last Updated: June 10, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Tolera Therapeutics, Inc:
Kidney
Renal
Transplant
Kidney Transplant
Kidney Failure
Induction
Monoclonal
Antibody
T cell
Anti-rejection
Immunosuppression

Additional relevant MeSH terms:
Kidney Diseases
Kidney Failure, Chronic
Urologic Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Antilymphocyte Serum
Mycophenolate mofetil
Tacrolimus
Mycophenolic Acid
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Immunosuppressive Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 30, 2014