Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

Treg Modulation With CD28 and IL-6 Receptor Antagonists

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04066114
Recruitment Status : Recruiting
First Posted : August 26, 2019
Last Update Posted : July 16, 2020
Sponsor:
Collaborators:
Bristol-Myers Squibb
Clinical Trials in Organ Transplantation
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE August 21, 2019
First Posted Date  ICMJE August 26, 2019
Last Update Posted Date July 16, 2020
Actual Study Start Date  ICMJE December 11, 2019
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 21, 2019)
Proportion of participants who remain free of biopsy-proven acute T-cell mediated or antibody-mediated rejection as defined by Banff criteria [ Time Frame: 6 months post transplantation ]
Definitions:
  • Acute T cell Mediated Rejection: Biopsy proven rejection defined by histologic evidence of a Banff grade of ≥1A and clinical treatment for acute rejection.
  • Acute Antibody Mediated Rejection: Diffusely positive immunostaining staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury.
Reference: Banff 2007 Classification Renal Allograft Pathology definition of terms.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 21, 2019)
Proportion of participants who remain free of biopsy-proven acute T-cell mediated or antibody-mediated rejection as defined by Banff criteria [ Time Frame: 12 months post transplantation ]
Definitions:
  • Acute T cell Mediated Rejection: Biopsy proven rejection defined by histologic evidence of a Banff grade of ≥1A and clinical treatment for acute rejection.
  • Acute Antibody Mediated Rejection: Diffusely positive immunostaining staining for C4d, presence of circulating anti-donor antibodies, and morphologic evidence of acute tissue injury.
Reference: Banff 2007 Classification Renal Allograft Pathology definition of terms.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: August 21, 2019)
  • EXPLORATORY: Frequency of circulating T Regulatory Cells (Tregs) [ Time Frame: Day 0 (Pre-transplant) and -3, -6 and -12 months post transplantation ]
    Mechanistic assay. Evaluation of the frequency of circulating Tregs over time.Exploratory goal: To advance understanding in mechanisms of tolerance.
  • EXPLORATORY:T Regulatory Cells (Treg) suppressive activity [ Time Frame: Day 0 (Pre-transplant) and -3, -6 and -12 months post transplantation ]
    Mechanistic assay.Donor-specific suppression activity of recipient Tregs will be measured over time by using irradiated donor peripheral blood mononuclear cells (PBMCs) as stimulators. Exploratory goal: To advance understanding in mechanisms of tolerance.
  • EXPLORATORY:Alloreactive T cell frequency [ Time Frame: Day 0 (Pre-transplant) and -3, -6 and -12 months post transplantation ]
    Mechanistic assay that measures the frequency of circulating donor-reactive CD4 conventional T cells, CD8 T cells and Tregs analyzed over time. Exploratory goal: To advance understanding in mechanisms of tolerance.
  • EXPLORATORY:Expression of T cell checkpoint inhibition related genes [ Time Frame: Day 0 (Pre-transplant) and -3, -6 and -12 months post transplantation ]
    Methodology: Analysis of gene expression in peripheral blood mononuclear cells (PBMCs) stimulated with donor antigen presenting cells to explore genes implicated in T cell checkpoint inhibition (CTLA-4, SFASL, NFATC1, NFATC2, LAG3 and HAVCR2, as examples). Exploratory goal: To advance understanding in mechanisms of tolerance.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Treg Modulation With CD28 and IL-6 Receptor Antagonists
Official Title  ICMJE Regulatory T Cell Modulation in Kidney Transplantation With Biologic Blockade of Dual Effector Pathways, CD28 and IL-6 (CTOT-24)
Brief Summary The purpose of this study is to evaluate the safety of using lulizumab pegol with tocilizumab, belatacept, and everolimus in kidney transplant recipients.
Detailed Description

This research study is for adults who are planning to have a kidney transplant from a living donor.

In Brief:

Those who have a transplant take immunosuppressive therapy to prevent the body from rejecting the transplanted organ. Rejection occurs when the body's defense system (immune cells) recognizes the transplant as a foreign object. These immune cells and the substances they produce can damage the transplanted kidney. It is important to prevent rejection episodes, so the kidney transplant lasts as long as possible.

Most transplant doctors in the United States give a combination of two or three drugs to prevent rejection. People with a transplant must take these drugs every day. Although kidney transplant recipients usually do well in the first five years after transplant, researchers want to find new ways to prevent rejection and avoid the side effects that the current drugs can cause.

This study will test a new combination of four drugs to evaluate whether this combination is safe for kidney transplant recipients:

  • lulizumab pegol (BMS-931699)
  • tocilizumab
  • belatacept and
  • everolimus.

Belatacept and everolimus are already approved for use as anti-rejection drugs in kidney transplant recipients. Lulizumab pegol and tocilizumab act on specific molecules (specifically CD28 and interleukin 6, respectively) on immune cells: these actions are different from how the older rejection drugs work.

Summary: This is a prospective multicenter open-label clinical trial of 10 living donor kidney transplant recipients. Safety of lulizumab pegol (BMS-931699) in the context of a novel immunosuppressive regimen (anti-thymocyte globulin (rabbit) (ATG), steroids,) Nulojix® (belatacept), Actemra® (tocilizumab), and Zortress®(everolimus)) will be assessed. Study participation involves a minimum of one year of follow-up post-transplant.

*** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the Clinical Trials in Organ Transplantation (CTOT) do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Living-Donor Kidney Transplant
  • Kidney Transplant Recipients
Intervention  ICMJE
  • Biological: lulizumab pegol
    25 mg subcutaneously (SC) on Day 1 post transplantation then 12.5 mg SC weekly through day 77 (Week 11)
    Other Name: BMS-931699
  • Biological: antithymocyte globulin (rabbit)
    1.5 mg/kg intravenously (IV) on Day 0 (day of transplantation) and the day following (Day 1)
    Other Names:
    • ATG (rabbit)
    • Thymoglobulin®
  • Drug: methylprednisolone
    500 mg (IV) on Day 0 (day of transplantation), 250 mg (IV) on Day 1 and 125 mg (IV) on Day 2
    Other Name: Solu-Medrol ®
  • Biological: tocilizumab
    8 mg/kg (IV) on Day 2 post transplantation followed by 162 mg (SC) every 2 weeks through day 168 (Week 24)
    Other Name: Actemra®
  • Drug: Prednisone

    Beginning on Day 3 post transplantation, taken orally: 60 mg daily

    • Days 4 through 10: 30 mg daily
    • Days 11 through 17: 20 mg daily
    • Days 18 through 24: 10 mg daily
    • After Day 24: continued taper of dose to final maintenance dose of 5 mg, per protocol
    Other Names:
    • prednisone tablets
    • Rayos®
  • Drug: everolimus
    Initial dose of 0.75 mg taken orally twice daily on Day 14 days after transplantation. Dose will be titrated to target trough levels 3-8 ng/mL.
    Other Name: Zortress®
  • Biological: belatacept
    5 mg/kg (IV) every 4 weeks starting on Day 84 (Week 12) and continuing through Day 364 (Week 52)
    Other Name: Nulojix®
  • Drug: mycophenolate mofetil

    An option for participants who do not tolerate everolimus: to be switched to either

    • mycophenolate mofetil 1000 mg administered orally twice daily or
    • mycophenolic acid
    Other Names:
    • MMF
    • CellCept®
  • Drug: mycophenolic acid

    An option for participants who do not tolerate everolimus: to be switched to either

    • mycophenolic acid 720 mg taken orally twice daily or
    • mycophenolate mofetil
    Other Name: Myfortic®
Study Arms  ICMJE Experimental: lulizumab pegol + novel ISR
lulizumab pegol + novel ISR: lulizumab pegol plus immunosuppressive regimen (anti-thymocyte globulin (rabbit), steroids,) belatacept, tocilizumab, and everolimus)
Interventions:
  • Biological: lulizumab pegol
  • Biological: antithymocyte globulin (rabbit)
  • Drug: methylprednisolone
  • Biological: tocilizumab
  • Drug: Prednisone
  • Drug: everolimus
  • Biological: belatacept
  • Drug: mycophenolate mofetil
  • Drug: mycophenolic acid
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 21, 2019)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2022
Estimated Primary Completion Date June 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Individuals who meet all the following criteria are eligible for enrollment as study participants:

  1. Able to understand and provide informed consent
  2. Agreement to use highly effective (<1% failure rate) methods of contraception: Women of Childbearing Potential (WOCBP)-

    • Progestogen only hormonal contraception associated with inhibition of ovulation,
    • Hormonal methods of contraception including oral contraceptive pills containing a combination of estrogen + progesterone, vagina ring, injectables, implants and intrauterine devices (IUDs),
    • Non-hormonal IUDs,
    • Bilateral tubal occlusion,
    • Vasectomized partner,
    • Intrauterine hormone-releasing system (IUS), or
    • Complete abstinence.

    Note: Female participants of childbearing potential must consult with their physician and determine the most suitable method(s) from this list to be used for 12 months while on study drug regimen.

    Male Participants-

    --Must use a latex or other synthetic condom during any sexual activity with WOCBP until one month after the last dose of lulizumab (e.g., up to 3.5 months in duration).

  3. Recipient of primary, nonhuman leukocyte antigen identical living donor kidney transplant
  4. No donor specific antibodies prior to transplant that are considered to be of clinical significance by the site investigator
  5. Epstein-Barr virus (EBV) positive serology
  6. Cytomegalovirus (CMV) positive serology, unless donor-recipient pair are both CMV negative
  7. Negative testing for latent Tuberculosis (TB) infection within 3 months prior to transplant

    • Testing should be conducted using either a purified protein derivative (PPD) or an interferon-gamma release assay blood test for TB (i.e. QuantiFERON®-TB Gold in-Tube test or T-SPOT® TB test)
    • Subjects with a positive test for latent TB infection must complete appropriate therapy for Latent tuberculosis infection (LTBI). ---A subject is considered eligible only if they have a negative test for LTBI within 3 months prior to transplant or, they have appropriately completed LTBI therapy prior to transplant.

    Note: Latent TB infection treatment regimens should be among those endorsed by the CDC (Division of TB Elimination, 2016).

  8. In the absence of contraindication, vaccinations must be up to date for hepatitis B, influenza, pneumococcal, varicella and herpes zoster, and measles, mumps, and rubella (MMR)
  9. Hepatitis C Virus (HCV) antibody positive subjects with negative HCV by PCR testing are eligible if they:

    • have spontaneously cleared infection, or
    • are in sustained virologic remission for at least 12 weeks after treatment for HCV.
  10. Negative SARS-CoV-2 PCR test result performed within 2 weeks of transplant (SARS-CoV-2 is the virus that causes COVID-19)

Exclusion Criteria:

Individuals who meet any of these criteria are not eligible for enrollment as study participants-

  1. Prisoners or subjects who are compulsorily detained
  2. Inability or unwillingness of a participant to give written informed consent or comply with study protocol
  3. Candidate for a multiple solid organ or tissue transplants
  4. Prior history of organ or cellular transplantation
  5. Known to have idiopathic focal segmental glomerulosclerosis (FSGS) as the underlying cause of kidney failure (ESRD)
  6. Requirement for uninterrupted anticoagulation therapy, including Plavix.
  7. Known hypersensitivity to mechanistic target of rapamycin (mTOR) inhibitors or contraindication to everolimus (including history of wound healing complications)
  8. History of severe allergic and/or anaphylactic reactions to humanized or murine monoclonal antibodies
  9. Hypersensitivity to rabbit proteins or rabbit anti-thymocyte Globulin (ATG)
  10. Known hypersensitivity to ACTEMRA® (tocilizumab) or lulizumab pegol (BMS-931699)
  11. The human immunodeficiency virus (HIV) infected subjects, including those who are well controlled on antiretrovirals
  12. Positive hepatitis B surface antigen (HBSAg), or hepatitis B core antibody (HBcAB) serology
  13. Hepatitis C virus antibody positive (HCV Ab+) subjects who have failed to demonstrate sustained viral remission for more than 12 weeks after anti-viral treatment
  14. Subjects with a previous history of active Tuberculosis (TB)
  15. Known active current viral, fungal, mycobacterial or other infections (including, but not limited to tuberculosis and atypical mycobacterial disease, Hepatitis B and C, and herpes zoster)
  16. Donor or recipient residing in areas where the annual incidence ≥ 21 cases per 100,000) for coccidioidomycosis according to current CDC map: (https://www.cdc.gov/fungal/diseases/coccidioidomycosis/causes.html)

    • Donors or recipients residing in low risk zones (annual <21 cases per 100,000) will not require additional screening
  17. History of malignancy except treated basal cell cancer of the skin
  18. History of hemolytic-uremic syndrome/ thrombotic thrombocytopenia purpura
  19. History of demyelinating disorders (e.g., multiple sclerosis, chronic inflammation demyelinating polyneuropathy)
  20. History of gastrointestinal perforations, active inflammatory bowel disease or diverticulitis
  21. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation
  22. Receipt of a live vaccine within 30 days prior to transplantation.
  23. Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may:

    • pose additional risks from participation in the study,
    • may interfere with the participant's ability to comply with study requirements, or
    • that may impact the quality or interpretation of the data obtained from the study
  24. Severe hyperlipidemia (defined by total cholesterol >350 mg/dL, LDL >190 mg/dL, or triglycerides >500 mg/dL)
  25. Transaminase levels elevated more than 1.5 times the upper limit of normal (ULN) within 7 days prior to enrollment
  26. The absolute neutrophil count (ANC) < 2,000 per mm^3 within 7 days prior to enrollment
  27. Platelet count less than 100,000 per mm^3 within 7 days prior to enrollment
  28. More than 50% CD8+/ CD28- T-cells in peripheral blood
  29. A calculated panel reactive antibody (cPRA) ≥20%, as determined by each participating site's laboratory
  30. Positive pregnancy test in women of child bearing potential, currently breastfeeding, or planning to become pregnant during the timeframe of the study or follow-up period
  31. Participation in any other studies with investigational drugs or regimens in the preceding year
  32. A history of a positive SARS-CoV-2 PCR test result (SARS-CoV-2 is the virus that causes COVID-19)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04066114
Other Study ID Numbers  ICMJE DAIT CTOT-24
NIAID CRMS ID#: 38581 ( Other Identifier: DAIT NIAID )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE
  • Bristol-Myers Squibb
  • Clinical Trials in Organ Transplantation
Investigators  ICMJE
Principal Investigator: Flavio Vincenti, M.D. University of California San Francisco School of Medicine: Transplantation
Study Chair: Sindhu Chandran, M.D. University of California San Francisco School of Medicine: Transplantation
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP