Research Study of ATG and Rituximab in Renal Transplantation

NCT01318915 | Terminated Early Phase 1 Results DMC FDA Drug

• 1 other identifier: DAIT ITN039ST
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 6

Brief Summary

The purpose of this study is see if a combination of two drugs, (ATG and rituximab), given at the time of the transplant surgery, will help reduce or eliminate the need for long term immunosuppressive medication.

Conditions

Renal Transplant Recipients

Keywords

Kidney transplantation; Living donor transplant; Graft rejection; Graft loss; Induction with rituximab and ATG; Immunosuppression (IS)

Outcome Measures

Primary Outcomes (1)

• Percent of Participants Successfully Withdrawn From Immunosuppression and Remained Off Immunosuppression for at Least 52 Weeks

  Participants are considered successfully withdrawn from immunosuppression if they remained off immunosuppression for at least 52 weeks without evidence of rejection, as determined by a biopsy performed 52 weeks after completion of immunosuppression withdrawal. All participants who failed to complete immunosuppression withdrawal, regardless of reason, or failed to have a biopsy 52 weeks after completion of immunosuppression withdrawal, were considered to have failed. The endpoint is summarized with a two-sided, 95% exact binomial confidence interval.

  Transplantation through 52 weeks after discontinuation of all immunosuppression

Secondary Outcomes (21)

• Percent of Transplanted Participants Who Remain Off Immunosuppression for at Least 52 Weeks Including Those in Whom the 52 Week Biopsy Was Not Performed

  Transplantation through 52 weeks after discontinuation of all immunosuppression

• Percent of Transplanted Participants Who Remain Off Immunosuppression for the Duration of the Study as Defined as Completion of All Schedules of Events/Followed Through August 25, 2017

  Transplantation through study completion (up to 4.4 years post-transplant)

• Percent of Transplanted Participants Who Achieve Sirolimus Monotherapy Within 52 Weeks Post-transplant

  Transplantation through 52 weeks post-transplantation

• Percent of Transplanted Participants Who Achieve MMF or Mycophenolic Acid Monotherapy Within 52 Weeks Post-transplant in Those Participants Intolerant of Sirolimus

  Transplantation through 52 weeks post-transplantation

• Percent of Transplanted Participants Who Achieve Either Sirolimus Monotherapy or Monotherapy on a Mycophenolic Compound Within 52 Weeks Post-transplant

  Transplantation through 52 weeks post-transplantation

Study Arms (1)

Induction (Rituximab and ATG)

EXPERIMENTAL

Study participants will undergo induction with rituximab and ATG and an initial maintenance therapy with tacrolimus, mycophenolate mofetil (MMF) and sirolimus. MMF will be discontinued on day 12. Participants will be evaluated for eligibility for tacrolimus withdrawal which must be initiated between weeks 26 and 38. Tacrolimus withdrawal must be completed in no fewer than 4 weeks and no more than 8 weeks. Then after at least 26 weeks on sirolimus monotherapy, participants will be evaluated for eligibility for sirolimus withdrawal which must be initiated between weeks 56 and 88. Sirolimus withdrawal must be completed in no fewer than 12 weeks and no more than 26 weeks.

Drug: ATG; Drug: Rituximab; Drug: Tacrolimus; Drug: Sirolimus; Drug: MMF

Interventions

ATG DRUG

1.5 mg/kg IV infusion on day of transplant, and 3 additional on days 2 through 7 after transplant.

Also known as: Thymoglobulin, Antithymocyte globulin

Induction (Rituximab and ATG)

Rituximab DRUG

375 mg/m\^2 IV infusion on day -6 before transplant and on day 1 after transplant.

Also known as: Rituxan

Induction (Rituximab and ATG)

Tacrolimus DRUG

Taken orally. Tacrolimus dose adjusted to maintain target blood levels of 6-10 ng/mL.

Also known as: Prograf, FK-506, Fujimycin

Induction (Rituximab and ATG)

Sirolimus DRUG

Taken orally. Initial dose, 2 mg daily on day 10 post-transplant, subsequently adjusted to achieve trough levels of 8-12 ng/mL through week 56. Sirolimus withdrawal will be initiated between week 56 and week 88 in eligible participants.

Also known as: Rapamune, Rapamycin

Induction (Rituximab and ATG)

MMF DRUG

1 g twice daily on days 0 through 12

Also known as: mycophenolate mofetil

Induction (Rituximab and ATG)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Recipient of a first renal allograft from a single haplotype matched or greater living related donor who is no older than 65, or a second degree relative with an Human Leukocyte Antigen(HLA) type that is consistent with a single haplotype match with the recipient.
• Demonstration of absence of anti-HLA antibodies using solid phase micro particle technology (by Luminex® phenotype panel or Luminex single antigen bead test) performed 7 days or less prior to the first dose of rituximab, as assessed by local laboratories.No evidence of anti-HLA antibodies in current or past sera.Negative T- and B-cell crossmatch as determined by flow cytometric assay measured 7 days or less prior to the first dose of rituximab.
• Single-organ recipients (kidney only).
• Serologic evidence of prior exposure to Epstein-Barr virus (EBV).
• For women of childbearing potential: a negative serum or urine pregnancy test with sensitivity less than 50 mIU/m within 72 hours before the start of study medication.
• Use of FDA-approved methods of contraception (those with less than a 5% failure rate) by all participants from the time that study treatment begins until 104 weeks (24 months) after renal transplantation.
• Ability to receive oral medication.
• Ability to understand and provide informed consent.

You may not qualify if:

• Recipient of a kidney from a donor who is older than 65 years.
• History of cancer within the last 5 years, except for nonmelanoma skin cell cancers cured by local resection and cervical carcinoma in situ.
• Women who are breastfeeding.
• Uncontrolled hyperlipidemia (total serum cholesterol more than 300 mg/dL and/or triglycerides more than 400 mg/dL).
• Platelet count less than 100,000/μL at study entry.
• Seropositivity for HIV-1, Hepatitis C virus (HCV) (confirmed by HCV PCR), hepatitis B surface antigen, or Hepatitis B virus (HBV) core antibody (confirmed by HBV PCR).
• Active tuberculosis (TB) within the previous 3 years regardless of treatment history for TB. Participants with a known positive purified protein derivative (PPD) or positive Quantiferon assay will not be eligible for the study unless they have completed treatment for latent TB and have a negative chest x-ray at the time of enrollment. PPD testing or Quantiferon testing done within 52 weeks before transplant is acceptable as long as there is documentation of the results. Prior recipients of a Bacille Calmette-Guérin vaccination (BCG) are not exempt.
• Underlying renal disease with a high risk of disease recurrence in the transplanted kidney, including focal segmental glomerulosclerosis, types I or II membranoproliferative glomerulonephritis, and hemolytic-uremic syndrome/thrombotic thrombocytopenic purpura.
• The presence of any medical condition that the investigator deems incompatible with participation in the trial.
• Known sensitivity to antithymocyte globulin, rituximab, tacrolimus, sirolimus, MMF, or corticosteroids.
• Current use of systemic corticosteroids or antibody-based therapies (e.g., infliximab, adalimumab, or etanercept).
• Use of any investigational drug within 30 days of transplantation.
• Receipt of a live vaccine within 3 months of enrollment.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator

Study Sites (6)

University of California San Francisco Medical Center

San Francisco, California, 94143, United States

Location

University of Maryland Medical Center

Baltimore, Maryland, 21201, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

Location

Rogosin Institute/New York Presbyterian-Cornell

New York, New York, 10021, United States

Location

Hospital at the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

University of Wisconsin

Madison, Wisconsin, 53792, United States

Location

Related Publications (1)

• Solez K, Colvin RB, Racusen LC, Haas M, Sis B, Mengel M, Halloran PF, Baldwin W, Banfi G, Collins AB, Cosio F, David DS, Drachenberg C, Einecke G, Fogo AB, Gibson IW, Glotz D, Iskandar SS, Kraus E, Lerut E, Mannon RB, Mihatsch M, Nankivell BJ, Nickeleit V, Papadimitriou JC, Randhawa P, Regele H, Renaudin K, Roberts I, Seron D, Smith RN, Valente M. Banff 07 classification of renal allograft pathology: updates and future directions. Am J Transplant. 2008 Apr;8(4):753-60. doi: 10.1111/j.1600-6143.2008.02159.x. Epub 2008 Feb 19.

  PMID: 18294345 BACKGROUND

Related Links

• National Institute of Allergy and Infectious Diseases (NIAID)
• Division of Allergy, Immunology, and Transplantation (DAIT)
• Immune Tolerance Network (ITN)

MeSH Terms

Interventions

thymoglobulin; Antilymphocyte Serum; Rituximab; Tacrolimus; Sirolimus; Mycophenolic Acid

Intervention Hierarchy (Ancestors)

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

Limitations and Caveats

The stopping rule for the incidence of rejection was met in December 2015, and enrollment was stopped in January 2016. After another rejection in May 2016, all participants were removed from protocol therapy and into reduced safety follow-up.

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• James Markmann, MD, PhD

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 15, 2011
• First Posted: March 21, 2011
• Study Start: July 25, 2011
• Primary Completion: June 17, 2016
• Study Completion: August 25, 2017
• Last Updated: November 29, 2018
• Results First Posted: October 4, 2017

Record last verified: 2018-11

Data Sharing

• IPD Sharing: Will share
• Time Frame: After completion of the study.
• Access Criteria: Will be available to the public.

Locations

US (6)