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

Phase 1

• Conditions: Renal Transplant; End Stage Renal Disease
• Interventions: Drug: Anti-Thymocyte Globulin; Drug: TOL101; Drug: Steroids; Drug: Tacrolimus; Drug: Mycophenolate mofetil (MMF)

• Registration Number: NCT01154387
• Lead Sponsor: Tolera Therapeutics, Inc

Brief Summary

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.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study First Submitted: 2010-06-26
• Study First Submitted QC: 2010-06-28
• Study First Posted: 2010-06-30
• Study Start: 2010-07
• Status Verified: 2013-06
• Primary Completion: 2013-06
• Study Completion: 2013-06
• Last Update Submitted: 2013-06-10
• Last Update Posted: 2013-06-11

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 85

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%

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Anti-Thymocyte Globulin	Anti-Thymocyte Globulin	Anti-Thymocyte Globulin induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
Anti-Thymocyte Globulin	Steroids	Anti-Thymocyte Globulin induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
Anti-Thymocyte Globulin	Mycophenolate mofetil (MMF)	Anti-Thymocyte Globulin induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
TOL101 (Dose A)	Steroids	TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
TOL101 (Dose B)	Mycophenolate mofetil (MMF)	TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
TOL101 (Dose A)	Mycophenolate mofetil (MMF)	TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
TOL101 (Dose B)	Steroids	TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
Anti-Thymocyte Globulin	Tacrolimus	Anti-Thymocyte Globulin induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
TOL101 (Dose A)	TOL101	TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
TOL101 (Dose A)	Tacrolimus	TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
TOL101 (Dose B)	TOL101	TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.
TOL101 (Dose B)	Tacrolimus	TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.

Primary Outcome Measures

Name	Time	Method
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	6 months	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

Name	Time	Method
The effects of ascending doses of TOL101 on CD3+ T lymphocyte numbers and other immune cell subsets	14 days post-transplant (Part A); 6 months (Part B)
Biopsy-proven acute organ rejection	6 months
Patient survival	6 months
Graft survival	6 months
Renal function by measured GFR at 6 months post-transplant and urine protein to creatinine ratio at 3 and 6 months post-transplant	6 months
The presence of Donor Specific Antibody at 3 months (Part B only) and 6 months post-transplant	6 months
The pharmacokinetic (PK) profile of TOL101 in renal transplant recipients and the exposure-response (PK parameter to CD3+ T lymphocyte numbers) relationship over time	14 days post-transplant
Delayed graft function	first 7 days post-transplant
Immunogenicity of TOL101 by measurement of anti-TOL101 antibodies	at 14 and 28 days post-transplant

Trial Locations

Locations (12)

University of Colorado Denver; 🇺🇸 Aurora, Colorado, United States

University of Michigan; 🇺🇸 Ann Arbor, Michigan, United States

Buffalo General Hospital; 🇺🇸 Buffalo, New York, United States

Cleveland Clinic Foundation; 🇺🇸 Cleveland, Ohio, United States

Medical University of South Carolina; 🇺🇸 Charleston, South Carolina, United States

Baylor All Saints; 🇺🇸 Fort Worth, Texas, United States

University of Utah; 🇺🇸 Salt Lake City, Utah, United States

University of Virginia Health System; 🇺🇸 Charlottesville, Virginia, United States

St Barnabas Medical Center; 🇺🇸 Livingston, New Jersey, United States

University of Kentucky; 🇺🇸 Lexington, Kentucky, United States

Baylor University Medical Center; 🇺🇸 Dallas, Texas, United States

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States