Treg Modulation With CD28 and IL-6 Receptor Antagonists
NCT ID: NCT04066114
Last Updated: 2024-10-09
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1/PHASE2
24 participants
INTERVENTIONAL
2019-12-11
2023-09-14
Brief Summary
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Detailed Description
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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.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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lulizumab pegol + novel ISR
lulizumab pegol + novel ISR: lulizumab pegol plus immunosuppressive regimen (anti-thymocyte globulin (rabbit), steroids,) belatacept, tocilizumab, and everolimus)
lulizumab pegol
25 mg subcutaneously (SC) on Day 1 post transplantation then 12.5 mg SC weekly through day 77 (Week 11)
antithymocyte globulin (rabbit)
Study participants are administered four doses of rabbit anti-thymocyte globulin, total dose 6 mg/kg given in divided doses on the day of transplantation and days 1-3.
methylprednisolone
500 mg (IV) on Day 0 (day of transplantation), 250 mg (IV) on Day 1 and 125 mg (IV) on Day 2
tocilizumab
8 mg/kg (IV) on Day 2 post transplantation followed by 162 mg (SC) every 2 weeks through day 168 (Week 24)
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
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.
belatacept
5 mg/kg (IV) every 4 weeks starting on Day 84 (Week 12) and continuing through Day 364 (Week 52)
mycophenolate mofetil
mycophenolate mofetil is started no later than one day after transplant at 1000mg PO twice daily provided WBC count permits, staying on it until everoliumus level is within therapeutic range. Participants that do no tolerate everolimus can stay on or switch back to mycophenolate mofetil 1000 mg twice daily and remain in trial.
mycophenolic acid
mycophenolic acid is started no later than one day after transplant at 720mg PO twice daily provided WBC count permits, staying on it until everoliumus level is within therapeutic range. Participants that do not tolerate everolimus can stay on or switch back to 720 mg twice daily of mycophenolic acid and remain in trial.
Interventions
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lulizumab pegol
25 mg subcutaneously (SC) on Day 1 post transplantation then 12.5 mg SC weekly through day 77 (Week 11)
antithymocyte globulin (rabbit)
Study participants are administered four doses of rabbit anti-thymocyte globulin, total dose 6 mg/kg given in divided doses on the day of transplantation and days 1-3.
methylprednisolone
500 mg (IV) on Day 0 (day of transplantation), 250 mg (IV) on Day 1 and 125 mg (IV) on Day 2
tocilizumab
8 mg/kg (IV) on Day 2 post transplantation followed by 162 mg (SC) every 2 weeks through day 168 (Week 24)
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
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.
belatacept
5 mg/kg (IV) every 4 weeks starting on Day 84 (Week 12) and continuing through Day 364 (Week 52)
mycophenolate mofetil
mycophenolate mofetil is started no later than one day after transplant at 1000mg PO twice daily provided WBC count permits, staying on it until everoliumus level is within therapeutic range. Participants that do no tolerate everolimus can stay on or switch back to mycophenolate mofetil 1000 mg twice daily and remain in trial.
mycophenolic acid
mycophenolic acid is started no later than one day after transplant at 720mg PO twice daily provided WBC count permits, staying on it until everoliumus level is within therapeutic range. Participants that do not tolerate everolimus can stay on or switch back to 720 mg twice daily of mycophenolic acid and remain in trial.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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
18 Years
70 Years
ALL
No
Sponsors
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Bristol-Myers Squibb
INDUSTRY
Clinical Trials in Organ Transplantation
NETWORK
National Institute of Allergy and Infectious Diseases (NIAID)
NIH
Responsible Party
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Principal Investigators
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Flavio Vincenti, M.D.
Role: PRINCIPAL_INVESTIGATOR
University of California San Francisco School of Medicine: Transplantation
Sindhu Chandran, M.D.
Role: STUDY_CHAIR
University of California San Francisco School of Medicine: Transplantation
Locations
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University of Alabama School of Medicine: Transplantation
Birmingham, Alabama, United States
University of California San Francisco School of Medicine: Transplantation
San Francisco, California, United States
University of Colorado (UC) Health Transplant Center - Anschutz
Aurora, Colorado, United States
Northwestern Memorial Hospital: Transplantation
Chicago, Illinois, United States
University of Nebraska Medical Center: Transplantation
Omaha, Nebraska, United States
Duke University Medical Center: Transplantation
Durham, North Carolina, United States
Cleveland Clinic Foundation: Transplantation
Cleveland, Ohio, United States
Countries
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Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form: Donor ICF
Document Type: Informed Consent Form: Recipient ICF
Related Links
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National Institute of Allergy and Infectious Diseases
Division of Allergy, Immunology, and Transplantation
Clinical Trials in Organ Transplantation (CTOT)
Other Identifiers
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NIAID CRMS ID#: 38581
Identifier Type: OTHER
Identifier Source: secondary_id
DAIT CTOT-24
Identifier Type: -
Identifier Source: org_study_id
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