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Delayed Infusion of DCreg in Living Donor Liver Transplantation

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04208919
Recruitment Status : Enrolling by invitation
First Posted : December 23, 2019
Last Update Posted : December 23, 2019
Sponsor:
Information provided by (Responsible Party):
Angus W. Thomson PhD DSc, University of Pittsburgh

Tracking Information
First Submitted Date  ICMJE December 19, 2019
First Posted Date  ICMJE December 23, 2019
Last Update Posted Date December 23, 2019
Actual Study Start Date  ICMJE December 18, 2019
Estimated Primary Completion Date November 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 19, 2019)
  • The proportion of recipients who experience CTCAE Grade 4 or higher infusion reaction [ Time Frame: 1 day ]
    Safety will be determined by assessing the proportion of subjects who experience CTCAE Grade 4 or higher infusion reaction
  • The proportion of recipients who experience CTCAE Grade 4 or higher infection [ Time Frame: 4 years ]
    Safety will be determined by assessing the proportion of subjects who experience CTCAE Grade 4 or higher infection
  • The proportion of recipients who experience experience malignancy other than non-melanoma skin cancer or HCC recurrence [ Time Frame: 4 years ]
    Safety will be determined by assessing the proportion of subjects who experience malignancy other than non-melanoma skin cancer or HCC recurrence
  • The proportion of recipients who experience rejection resulting in recipient death or retransplantation [ Time Frame: 4 years ]
    Safety will be determined by assessing the proportion of subjects who experience rejection resulting in recipient death or retransplantation
  • The proportion of recipients who experience biopsy-proven severe acute rejection [ Time Frame: 4 years ]
    Safety will be determined by assessing the proportion of subjects who experience biopsy-proven severe acute rejection
  • The proportion of recipients who experience any grade chronic rejection [ Time Frame: 4 years ]
    Safety will be determined by assessing the proportion of subjects who experience any grade chronic rejection
  • The proportion of recipients who experience non-surgical graft loss [ Time Frame: 4 years ]
    Safety will be determined by assessing the proportion of subjects who experience non-surgical graft loss
  • The proportion of recipients who die [ Time Frame: 4 years ]
    Safety will be determined by assessing the proportion of subjects who die
  • Preliminary Efficacy of using DCreg therapy to facilitate immunosuppression weaning [ Time Frame: 2 years ]
    Proportion of patients able to achieve immunosuppression withdrawal with operational tolerance 1 year after complete immunosuppression cessation based on specific liver biopsy criteria
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2019)
  • Donor Specific Antigen (DSA) levels [ Time Frame: 4 years ]
    DSA levels early (<4 wks) and late (>4 wks) after DCreg infusion
  • Change in renal function [ Time Frame: Change from baseline to 36 months post-weaning ]
    Change in renal function (defined as estimated GFR calculated by CKD-EPI: http://www.qxmd.com/calculate-online/nephrology/ckd-epiegfr) between time of enrollment and 1 year following immunosuppression weaning will be calculated.
  • Change in Quality of Life as measured by the Short Form 36 (SF-36) [ Time Frame: Change from baseline to 36 months post-weaning ]
    This 36-item questionnaire measures general health-related quality of life, with scores ranging from 0 to 100; a higher score indicates a better health state. Two component scores, Mental Component Score and Physical Component Score, are derived from 8 domain scores. The 8 domains [US Population Means] are: 1) Physical Functioning [84.2], 2) Role-physical [81.0], 3) Bodily Pain [75.2], 4) General Health [72.0], 5) Vitality [60.9], 6) Social Functioning [83.3], 7) Role-emotional [81.3], and 8) Mental Health [74.7]
  • Change in cardiovascular risk factors [ Time Frame: Change from baseline to 36 months post-weaning ]
    Cardiovascular factors assessed include incidence of hypertension necessitating medication, post-transplantation diabetes, hyperlipidemia, hypercholesterolemia as documented from medical record review at yearly post-transplant visits.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Delayed Infusion of DCreg in Living Donor Liver Transplantation
Official Title  ICMJE Safety and Preliminary Efficacy of Delayed Donor-derived Regulatory Dendritic Cell (DCreg) Infusion and Immunosuppression Withdrawal in Living Donor Liver Transplant (LDLT) Recipients
Brief Summary

Phase I/II, single center, prospective, open-label, non-controlled, non-randomized, interventional, cohort study in which low risk living donor liver transplant (LDLT) recipients who are between 1 and 3 years after transplantation and meet specific criteria (no DSA, no clinically treated rejection within 2 years preceding enrollment, permissive liver function tests (LFTs) within 30 days preceding enrollment, no prior liver biopsy showing significant fibrosis or ductopenia*) will be enrolled and will undergo a protocol liver biopsy unless they have had a permissive liver biopsy** within 90 days of anticipated immunosuppression weaning. Those patients with permissive liver biopsy** will then receive a single infusion of donor-derived DCreg and will remain on their current standard of care (SOC) immunosuppression. One week after DCreg infusion, immunosuppression weaning will be initiated. Recipients will be slowly weaned off immunosuppression. Successfully weaned participants who remain rejection-free will undergo 3 years of follow-up after the last dose of immunosuppression. They will undergo a liver biopsy at 1 yr and 3 yrs after immunosuppression withdrawal. Participants who are removed from the study protocol at any time will return to standard of care but will continue to be followed by the study team and will undergo a liver biopsy at the end of the study.

* Permissive LFTs are defined as ALT, AST and total bilirubin < 2.5 times the upper limit of normal.

**A permissive biopsy is based on 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology (the criteria detailed in Table 8, Demetris et al. 2016).

Detailed Description Not Provided
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: Other
Condition  ICMJE Living Donor Liver Transplantation
Intervention  ICMJE Biological: Donor-derived DCreg
Regulatory dendritic cells that were prepared from a donor leukapheresis will be infused into liver transplant recipients 7 days prior to the start of immunosuppression weaning.
Study Arms  ICMJE Experimental: DCreg Prior to Weaning
Regulatory dendritic cells that were derived from the recipient's liver donor will be infused into the recipient one week prior to the initiation of immunosuppression weaning.
Intervention: Biological: Donor-derived DCreg
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 Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: December 19, 2019)
24
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 2025
Estimated Primary Completion Date November 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Donor

  1. Able to understand and provide informed consent
  2. Male or female age 18 or older at the time of enrollment
  3. Have no contraindication to leukapheresis
  4. For females of childbearing potential, a negative urine or serum pregnancy test
  5. No live vaccines within 12 weeks prior to leukapheresis
  6. Negative health history for risk factors related to Zika Virus and Creutzfeldt-Jakob disease
  7. Negative for West Nile Virus(a)
  8. Negative for HIV (5th generation Test and NAT), HTLV-1, HTLV-2;(a)
  9. Negative for hepatitis C (antibody and NAT), hepatitis B (surface antigen and NAT)(a)

    1. does not preclude donors from undergoing leukapheresis but cells may not be infused into recipient.

Recipients

  1. Low risk LDLT recipients, irrespective of gender, race, or ethnic background. Low risk is defined by absence of exclusion criteria (below).
  2. Age 18 or older at the time of enrollment
  3. Underwent de novo (first) liver transplant 1 to 3 years prior to enrollment
  4. Female subjects of childbearing potential must have a negative pregnancy test upon study entry.
  5. Agreement to use contraception; according to the 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. Female participants of child-bearing potential must consult with their physician and determine the most suitable method(s) from this list to be used from the time that study treatment begins until 1 year after completion of immunosuppression withdrawal.

Exclusion Criteria:

Recipients

  1. History of positive DSA
  2. Clinically treated rejection episode within 2 years prior to enrollment
  3. Non-permissive LFTs within past 1 month
  4. Repeat liver transplant
  5. Prior other solid organ transplant
  6. Significant co-morbid conditions such as severe heart or lung disease
  7. Following etiology of liver disease: Primary Sclerosing Cholangitis (PSC), autoimmune, Primary Biliary Cirrhosis (PBC)
  8. If prior history of Hepatitis B or C (HBV or HCV) infection, Hepatitis B or C Virus (HBV or HCV) viral load positive at the time of enrollment (successfully treated HBV or HCV patients are not excluded)
  9. Positive antigen-antibody immunoassay for HIV-1/2
  10. Any prior biopsy showing significant fibrosis or ductopenia.
  11. Any medical condition that the investigator deems incompatible with participation in the trial.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04208919
Other Study ID Numbers  ICMJE PRO18090578
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
Plan to Share IPD: No
Responsible Party Angus W. Thomson PhD DSc, University of Pittsburgh
Study Sponsor  ICMJE Angus W. Thomson PhD DSc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Abhinav Humar University of Pittsburgh
PRS Account University of Pittsburgh
Verification Date December 2019

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