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

End Stage Renal Disease Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT01154387
• Other study ID #: TTI-121
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• First received: June 26, 2010
• Last updated: June 10, 2013
• Start date: July 2010
• Est. completion date: June 2013

Study information

• Verified date: June 2013
• Source: Tolera Therapeutics, Inc
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 85
• Est. completion date: June 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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)

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• End Stage Renal Disease
• Kidney Failure, Chronic
• Renal Transplant

Intervention

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
• 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
• 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
• Steroids
IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months
• Tacrolimus
Oral administration started by 6 days post-transplantation and continued for 6 months
• Mycophenolate mofetil (MMF)
Oral administration started by Day 1 post-transplantation and continued for 6 months

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	University of Colorado Denver	Aurora	Colorado
United States	Montefiore Medical Center	Bronx	New York
United States	Buffalo General Hospital	Buffalo	New York
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia Health System	Charlottesville	Virginia
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	Baylor All Saints	Fort Worth	Texas
United States	University of Kentucky	Lexington	Kentucky
United States	St Barnabas Medical Center	Livingston	New Jersey
United States	University of Utah	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Tolera Therapeutics, Inc

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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	6 months	Yes
Secondary	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)	No
Secondary	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	No
Secondary	Biopsy-proven acute organ rejection		6 months	No
Secondary	Graft survival		6 months	No
Secondary	Patient survival		6 months	Yes
Secondary	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	No
Secondary	Delayed graft function		first 7 days post-transplant	No
Secondary	Immunogenicity of TOL101 by measurement of anti-TOL101 antibodies		at 14 and 28 days post-transplant	No
Secondary	The presence of Donor Specific Antibody at 3 months (Part B only) and 6 months post-transplant		6 months	No