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

NCT01154387 | Unknown Phase 1 DMC

• 1 other identifier: TTI-121
• Study Type: interventional
• Target: 85
• Locations: 1 country
• Sites: 12

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.

Conditions

End Stage Renal Disease; Renal Transplant

Keywords

Kidney; Renal; Transplant; Kidney Transplant; Kidney Failure; Induction; Monoclonal; Antibody; T cell; Anti-rejection; Immunosuppression

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (9)

• 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)

• 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

• Biopsy-proven acute organ rejection

  6 months

• Graft survival

  6 months

• Patient survival

  6 months

Study Arms (3)

Anti-Thymocyte Globulin

ACTIVE COMPARATOR

Anti-Thymocyte Globulin induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.

Drug: Anti-Thymocyte Globulin; Drug: Steroids; Drug: Tacrolimus; Drug: Mycophenolate mofetil (MMF)

TOL101 (Dose A)

EXPERIMENTAL

TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.

Drug: TOL101; Drug: Steroids; Drug: Tacrolimus; Drug: Mycophenolate mofetil (MMF)

TOL101 (Dose B)

EXPERIMENTAL

TOL101 induction as part of an immunosuppressive regimen that includes steroids, MMF, and tacrolimus.

Drug: TOL101; Drug: Steroids; Drug: Tacrolimus; Drug: Mycophenolate mofetil (MMF)

Interventions

Anti-Thymocyte Globulin DRUG

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

Also known as: Thymoglobulin

Anti-Thymocyte Globulin

TOL101 DRUG

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 (Dose A)

Steroids DRUG

IV methylprednisolone prior to first 3 doses of study drug; oral prednisone tapered to 5-10 mg over 6 months

Anti-Thymocyte Globulin; TOL101 (Dose A); TOL101 (Dose B)

Tacrolimus DRUG

Oral administration started by 6 days post-transplantation and continued for 6 months

Anti-Thymocyte Globulin; TOL101 (Dose A); TOL101 (Dose B)

Mycophenolate mofetil (MMF) DRUG

Oral administration started by Day 1 post-transplantation and continued for 6 months

Anti-Thymocyte Globulin; TOL101 (Dose A); TOL101 (Dose B)

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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%

You may not qualify if:

• 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)

Sponsors & Collaborators

• Tolera Therapeutics, Inc: lead

Study Sites (12)

University of Colorado Denver

Aurora, Colorado, 80045, United States

Location

University of Kentucky

Lexington, Kentucky, 40536, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

St Barnabas Medical Center

Livingston, New Jersey, 07039, United States

Location

Buffalo General Hospital

Buffalo, New York, 14203, United States

Location

Montefiore Medical Center

The Bronx, New York, 10467, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Baylor University Medical Center

Dallas, Texas, 75246, United States

Location

Baylor All Saints

Fort Worth, Texas, 76104, United States

Location

University of Utah

Salt Lake City, Utah, 84132, United States

Location

University of Virginia Health System

Charlottesville, Virginia, 22908, United States

Location

MeSH Terms

Conditions

Kidney Failure, Chronic; Renal Insufficiency

Interventions

Antilymphocyte Serum; thymoglobulin; TOL-101; Steroids; Tacrolimus; Mycophenolic Acid

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Immune Sera; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biological Products; Complex Mixtures; Fused-Ring Compounds; Polycyclic Compounds; Macrolides; Lactones; Organic Chemicals; Caproates; Acids, Acyclic; Carboxylic Acids; Fatty Acids; Lipids

Study Officials

• Stuart Flechner, MD

  The Cleveland Clinic

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 26, 2010
• First Posted: June 30, 2010
• Study Start: July 1, 2010
• Primary Completion: June 1, 2013
• Study Completion: June 1, 2013
• Last Updated: June 11, 2013

Record last verified: 2013-06

Locations

US (12)