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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)

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.

Condition or disease Intervention/treatment Phase
Living-Donor Kidney Transplant Kidney Transplant Recipients Biological: lulizumab pegol Biological: antithymocyte globulin (rabbit) Drug: methylprednisolone Biological: tocilizumab Drug: Prednisone Drug: everolimus Biological: belatacept Drug: mycophenolate mofetil Drug: mycophenolic acid Phase 1 Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Regulatory T Cell Modulation in Kidney Transplantation With Biologic Blockade of Dual Effector Pathways, CD28 and IL-6 (CTOT-24)
Actual Study Start Date : December 11, 2019
Estimated Primary Completion Date : June 2022
Estimated Study Completion Date : December 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: lulizumab pegol + novel ISR
lulizumab pegol + novel ISR: lulizumab pegol plus immunosuppressive regimen (anti-thymocyte globulin (rabbit), steroids,) belatacept, tocilizumab, and everolimus)
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®




Primary Outcome Measures :
  1. 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.



Secondary Outcome Measures :
  1. 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.



Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.

  4. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04066114


Locations
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United States, Alabama
University of Alabama School of Medicine: Transplantation Not yet recruiting
Birmingham, Alabama, United States, 35233
Principal Investigator: Clifton E. Kew II, MD         
United States, California
University of California San Francisco School of Medicine: Transplantation Recruiting
San Francisco, California, United States, 94143
Contact: Crystal Hu    415-353-8380    Crystal.Hu@ucsf.edu   
Principal Investigator: Flavio Vincenti, MD         
United States, Colorado
University of Colorado (UC) Health Transplant Center - Anschutz Not yet recruiting
Aurora, Colorado, United States, 80045
Principal Investigator: Scott Davis, MD         
United States, Illinois
Northwestern Memorial Hospital: Transplantation Not yet recruiting
Chicago, Illinois, United States, 60611
Principal Investigator: John J. Friedewald, MD         
United States, Nebraska
University of Nebraska Medical Center: Transplantation Not yet recruiting
Omaha, Nebraska, United States, 68105
Principal Investigator: Roslyn B. Mannon, MD         
United States, North Carolina
Duke University Medical Center: Transplantation Not yet recruiting
Durham, North Carolina, United States, 27710
Principal Investigator: Allan D. Kirk, M.D., Ph.D.         
United States, Ohio
Cleveland Clinic Foundation: Transplantation Not yet recruiting
Cleveland, Ohio, United States, 44195
Principal Investigator: Emilio Poggio, MD         
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Bristol-Myers Squibb
Clinical Trials in Organ Transplantation
Investigators
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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
Additional Information:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT04066114    
Other Study ID Numbers: DAIT CTOT-24
NIAID CRMS ID#: 38581 ( Other Identifier: DAIT NIAID )
First Posted: August 26, 2019    Key Record Dates
Last Update Posted: July 16, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
adult living-donor kidney transplant recipients
novel immunosuppressive (IS) therapy regimen
lulizumab pegol (BMS-931699)
CD28 and IL-6 biologic blockade
CD28 and IL-6 receptor antagonists
T regulatory cells (Treg) modulation
Additional relevant MeSH terms:
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Mycophenolic Acid
Prednisone
Methylprednisolone
Methylprednisolone Hemisuccinate
Everolimus
Abatacept
Thymoglobulin
Antilymphocyte Serum
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Gastrointestinal Agents
Neuroprotective Agents
Protective Agents