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Allogeneic Regulatory Dendritic Cell (DCreg) Renal Study

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ClinicalTrials.gov Identifier: NCT03726307
Recruitment Status : Recruiting
First Posted : October 31, 2018
Last Update Posted : April 25, 2019
Sponsor:
Collaborator:
University of Pittsburgh
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:

This study will evaluate the safety and feasibility of treatment involving a single infusion of donor-derived regulatory dendritic cells (DCreg) in first time, living donor renal transplant recipients.

DCreg will be prepared from monocytes obtained by leukapheresis from prospective (non-mobilized) living kidney donors and infused into the respective recipients 7 days before renal transplantation. This study will enroll 28 subjects (14 recipients, 14 donors). The duration of follow-up will be:

  • 1 week following the leukapheresis procedure for donors and
  • 2 years following their DCreg infusion for kidney recipients.

Condition or disease Intervention/treatment Phase
Kidney Transplant Renal Transplant Recipients Biological: DCreg: 0.5 million cells/kg+SOC Biological: DCreg: 1.2 million cells/kg+SOC Biological: DCreg:2.5 to 5.0 million cells/kg+SOC Phase 1

Detailed Description:

This clinical trial is a single-center, open-label, dose-escalation, phase 1 study, enrolling N=14 de novo kidney transplant recipients and their respective living donors. The study objective is to evaluate the safety and feasibility of a single infusion of donor-derived regulatory dendritic cell (DCreg) treatment.

Transplant recipients will receive combination immunosuppressive agents according to the site's Standard of Care (SOC) regimen, with two exceptions:

  • mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
  • the pre-transplant dose of MPA will be half the standard post-transplant dose, due to increased drug bioavailability in recipients with low kidney function defined by glomerular filtration rate (GFR).

Consequently, participants will be maintained on triple immunosuppressive therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.

Note: Participants will not be withdrawn from known effective therapy for the purpose of participating in this research.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 28 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Open-label, dose-escalation, phase 1 clinical trial.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Allogeneic Regulatory Dendritic Cell (DCreg) Therapy in Live-Donor Renal Transplant Recipients
Actual Study Start Date : April 10, 2019
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: DCreg: 0.5 million cells/kg+SOC

N=3 participants will receive 0.5 (± 0.1) million cells/kg body weight as a single infusion.

Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions:

  • mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
  • the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR).

Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.

Biological: DCreg: 0.5 million cells/kg+SOC

DCreg 0.5 (±0.1) million cells/kilogram body weight infused as a single dose.

Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions:

  • mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
  • the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR).

Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.

Other Name: Regulatory Donor-Derived Dendritic Cells (DCreg)

Experimental: DCreg: 1.2 million cells/kg+SOC

N=3 participants will receive 1.2 (± 0.2) million cells/kg body weight as a single infusion.

Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions:

  • mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
  • the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR).

Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.

Biological: DCreg: 1.2 million cells/kg+SOC

DCreg 1.2 (±02) million cells/kilogram body weight infused as a single dose.

Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions:

  • mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
  • the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR).

Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.

Other Name: Regulatory Donor-Derived Dendritic Cells (DCreg)

Experimental: DCreg:2.5 to 5.0 million cells/kg+SOC

N=8 participants will receive 25 to 5.0 million cells /kg body weight as a single infusion.

Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions:

  • mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
  • the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR).

Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.

Biological: DCreg:2.5 to 5.0 million cells/kg+SOC

DCreg 2.5 to 5.0 million cells/kilogram body weight infused as a single dose.

Standard of Care (SOC) immunosuppressive agents (ISA): Participants will receive combination ISA according to the site's SOC regimen, with two exceptions:

  • mycophenolic acid (MPA) will be initiated 7 days before transplant, at the time of donor DCreg infusion, instead of on the day of transplant; and
  • the pre-transplant dose of MPA will be half the standard post-transplant dose due to increased drug bioavailability in recipients with low glomerular filtration rate (GFR).

Participants will be maintained on triple IS therapy with MPA, tacrolimus, and prednisone after transplant, a combination regimen widely applied as SOC at many transplant centers in North America and worldwide.

Other Name: Regulatory Donor-Derived Dendritic Cells (DCreg)




Primary Outcome Measures :
  1. Composite Outcome: Proportion of Participants who Experience any of the Pre-Specified Safety Events [ Time Frame: Seven Days Prior to Transplant Surgery(e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant ]

    Safety will be assessed by summarizing the proportion of participants who experience any of the following events from the initiation of the regulatory dendritic cells (DCreg) infusion administered 7 days prior to kidney transplant to 1 year post-transplant:

    • Recipient death attributed to receipt of DCreg,
    • NCI-CTCAE Grade 4 or higher DCreg infusion reaction,
    • NCI-CTCAE Grade 4 or higher infection,
    • Malignancy other than non-melanoma skin cancer,
    • Pre-transplant allo-sensitization,
    • Post-transplant allo-sensitization,
    • Biopsy-proven acute rejection (BPAR) by BANFF 2013 criteria (grade ≥2A), or
    • Non-surgical graft loss.

      • Reference: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).


Secondary Outcome Measures :
  1. Incidence of Death Attributed to Participant Receipt of Regulatory Dendritic Cells (DCreg) [ Time Frame: Seven Days Prior to Transplant Surgery (e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant ]
    The occurrence of death among participants who receive DCreg treatment.

  2. Incidence of Adverse Event: CTCAE Grade 4 or Higher Infusion Reaction [ Time Frame: Seven Days Prior to Transplant Surgery (e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant ]
    The number of Grade 4 or higher infusion reaction(s) among participants who receive regulatory dendritic cells (DCreg) infusion, graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).

  3. Incidence of Adverse Event:CTCAE Grade 4 or Higher Infection [ Time Frame: Seven Days Prior to Transplant Surgery (e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant ]
    The number of Grade 4 or higher infection(s) among participants who receive regulatory dendritic cells (DCreg) infusion, graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, version 5.0).

  4. Incidence of Adverse Event: Malignancy [ Time Frame: Seven Days Prior to Transplant Surgery(e.g. Day of Regulatory Dendritic Cells (DCreg) Infusion) up to 1-Year Post-Transplant ]
    The number of malignancies among participants who receive regulatory dendritic cells (DCreg) infusion. Not included in this incidence outcome: non-melanoma skin cancer(s).

  5. Incidence of Pre-Transplant Allo-Sensitization [ Time Frame: Baseline (Seven Days Prior to Transplant Surgery, "Pre" -Regulatory Dendritic Cells (DCreg)) Infusion) up to within 48 Hours of Transplant ]
    The number of pre-transplant allo-sensitization(s) among participants occurring after DCreg infusion and before transplant.

  6. Incidence of Post-Transplant Allo-Sensitization [ Time Frame: Day 0 (Transplant Surgery) up to 1-Year Post-Transplant ]
    A de novo donor-specific allo-antibody (DSA) occurring within the first year post-transplant.

  7. Incidence of Biopsy-Proven Acute Rejection [ Time Frame: Day 0 (Transplant Surgery) up to 1-Year Post-Transplant ]
    Acute kidney allograft rejection is defined by a kidney (renal) allograft biopsy classification of grade 2A or higher. Classification method: Banff 2013. The Banff 2013 classification for antibody-mediated rejection is a recognized standard in renal allograft pathology.

  8. Incidence of Non-Surgical Graft Loss [ Time Frame: Day 0 (Transplant Surgery) up to 1-Year Post-Transplant ]
    Graft loss not associated with the transplant surgery.



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 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Donor Eligibility Criteria:

    1. Able to understand and provide informed consent;
    2. Fulfills all standard institutional criteria for kidney donation and compliant with FDA regulations;
    3. For females of childbearing potential, a negative urine or serum pregnancy test;
    4. Negative for Human Immunodeficiency Virus type 1 (HIV) -1 (antigen and Nucleic Acid Testing (NAT)), HIV-2, Human T-cell leukemia virus type 1 (HTLV-1), HTLV-2;
    5. Negative for hepatitis C (antibody and NAT), hepatitis B (surface antigen and core antibody), and Treponema pallidum infection.
    6. No live vaccines within 8 weeks prior to leukapheresis;
    7. No medical condition that the investigator deems incompatible with participation in the trial.
  • Recipient Inclusion Criteria:

    1. Must be able to understand and provide informed consent;
    2. Undergoing de novo (first) living donor renal transplant;
    3. Negative for tuberculosis by either negative :

      • Purified Protein Derivative (PPD) test or
      • Result using an approved interferon-gamma release assay (IGRA) blood test, such as QuantiFERON®-Gold TB or T-SPOT.TB assay.

        • Exception: If the participant has completed treatment for latent tuberculosis, and has a negative chest x-ray.

      Note:

      1. PPD or IGRA testing documented to have been performed within 52 weeks before transplant is acceptable.
      2. Prior recipients of a Bacille Calmette-Guérin (BCG) vaccination must follow the same requirements as referenced above.
    4. Female subjects of childbearing potential must have a negative pregnancy test upon study entry;
    5. Agreement to use contraception;

      --According to the Food and Drug Administration (FDA) Office of Women's Health (http://www.fda.gov/birthcontrol), there are a number of birth control methods that are more than 80% effective.

      Note: Female participants of child-bearing potential must consult with their physician and determine the most suitable method(s) from the FDA referenced list to be used from the time that study treatment begins until after study completion.

  • Recipient Exclusion Criteria:

    1. Panel Reactive Antibody (PRA >20%);
    2. Positive T or B Cell Flow Crossmatch prior to transplant;
    3. Any prior renal or extra-renal transplant;
    4. Cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) Immunoglobulin G (IgG) seronegative status;
    5. Seropositivity for HIV-1, hepatitis B core antigen, or hepatitis C virus (HCV) antibody (if hepatitis C antibody positive, confirm negative infection by HCV RNA), or positivity for hepatitis B surface antigen;
    6. History of malignancy other than non-melanomatous skin cancer;
    7. High risk for recurrence of renal disease:

      • Hemolytic Uremic Syndrome (HUS),
      • Thrombotic Thrombocytopenic Purpura (TTP),
      • Focal Segmental Glomerular Sclerosis (FSGS), or
      • aggressive native kidney disease;
    8. Significant coronary artery disease, Ejection Fraction <30% or prior acute myocardial infarction;
    9. Compensated and decompensated cirrhosis of liver and/or portal hypertension;
    10. Chronic Obstructive Pulmonary Disease requiring nasal oxygen, and/or pulmonary hypertension (mean pulmonary pressure >45mm/hg);
    11. Any history of stroke with neurological deficit;
    12. Any condition that, in the opinion of the investigator, confers excessive risk for participation in this phase 1 study;
    13. Presence of a condition that requires treatment with an immunosuppressive agent, other than a physiologic dose of corticosteroid;
    14. No live vaccines within 8 weeks prior to transplant;
    15. Use of investigational drugs within 12 weeks of participation;
    16. Women receiving a kidney from a man who has fathered her child(ren), whether or not carried to term; or
    17. Women receiving a kidney from her biological child.

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): NCT03726307


Locations
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United States, Pennsylvania
University of Pittsburgh, Starzl Transplantation Institute Recruiting
Pittsburgh, Pennsylvania, United States, 15213
Contact: Rita Johnson, RN    412-383-8616    Johnsonr1@upmc.edu   
Contact: Beth Elinoff, RN    412-624-6611    elinbd@upmc.edu   
Principal Investigator: Angus W. Thomson, PhD, DSC         
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
University of Pittsburgh
Investigators
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Study Chair: Sundaram Hariharan, MD University of Pittsburgh: Starzl Transplantation Institute

Additional Information:
Publications:
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03726307     History of Changes
Other Study ID Numbers: DAIT RTB-006
RTB-006 ( Other Identifier: Sponsor )
First Posted: October 31, 2018    Key Record Dates
Last Update Posted: April 25, 2019
Last Verified: April 2019

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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):
allogeneic regulatory dendritic cell therapy (DCreg)
DCreg therapy
de novo live-donor renal transplant recipients
Additional relevant MeSH terms:
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Mycophenolic Acid
Prednisone
Tacrolimus
Immunosuppressive Agents
Anti-Inflammatory Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Immunologic Factors
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents