Clinical trial NCT01154387: Evaluating Safety and Efficacy of TOL101 Induction Versus Anti-Thymocyte Globulin to Prevent Kidney Transplant Rejection
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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: End Stage Renal Disease
Renal Transplant
Keywords: Kidney
Renal
Transplant
Kidney Transplant
Kidney Failure
Induction
Monoclonal
Antibody
T cell
Anti-rejection
Immunosuppression
Lead sponsor: Tolera Therapeutics, Inc
Sponsor class: INDUSTRY
First posted: 2010-06-30
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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)

Primary outcomes:
measure: 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
timeFrame: 6 months
Secondary outcomes:
measure: The effects of ascending doses of TOL101 on CD3+ T lymphocyte numbers and other immune cell subsets
timeFrame: 14 days post-transplant (Part A); 6 months (Part B)
measure: The pharmacokinetic (PK) profile of TOL101 in renal transplant recipients and the exposure-response (PK parameter to CD3+ T lymphocyte numbers) relationship over time
timeFrame: 14 days post-transplant
measure: Biopsy-proven acute organ rejection
timeFrame: 6 months
measure: Graft survival
timeFrame: 6 months
measure: Patient survival
timeFrame: 6 months
measure: Renal function by measured GFR at 6 months post-transplant and urine protein to creatinine ratio at 3 and 6 months post-transplant
timeFrame: 6 months
measure: Delayed graft function
timeFrame: first 7 days post-transplant
measure: Immunogenicity of TOL101 by measurement of anti-TOL101 antibodies
timeFrame: at 14 and 28 days post-transplant
measure: The presence of Donor Specific Antibody at 3 months (Part B only) and 6 months post-transplant
timeFrame: 6 months
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado Denver
state: Colorado
city: Lexington
country: United States
facility: University of Kentucky
state: Kentucky
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Livingston
country: United States
facility: St Barnabas Medical Center
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Buffalo
country: United States
facility: Buffalo General Hospital
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Baylor All Saints
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia Health System
state: Virginia
Study officials:
affiliation: The Cleveland Clinic
name: Stuart Flechner, MD
role: PRINCIPAL_INVESTIGATOR
References: