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| ID | Type | Description | Link |
|---|---|---|---|
| UM1AI109565 | U.S. NIH Grant/Contract | View source | |
| NIAID CRMS ID#: 38481 | Other Identifier | DAIT NIAID |
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The study was terminated by the Sponsor prior to any participants receiving the investigational product.
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| Name | Class |
|---|---|
| Immune Tolerance Network (ITN) | NETWORK |
| PPD Development, LP | INDUSTRY |
| Rho Federal Systems Division, Inc. | INDUSTRY |
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This is a single-center, prospective, open-label, non-randomized clinical trial exploring cellular therapy to facilitate immunosuppression withdrawal in liver transplant recipients.
The researchers in this study plan to enroll 9 participants. Eligible participants will receive a single dose of Treg product (arTreg). The target dose is at least 90 to 500 x 10^6 total cells.
Participants who successfully withdraw from all immunosuppression (IS) will undergo a research biopsy at 52 weeks following IS discontinuation to determine whether they meet the primary efficacy outcome of operational tolerance. Participants determined to be operationally tolerant will be followed until 104 weeks following IS discontinuation. Participants who fail drug withdrawal after 52 weeks but before 104 weeks will be followed until week 104 or 12 weeks after resuming immunosuppression, whichever is longer.
Participants who do not successfully withdraw from all IS will complete 104 weeks of High Intensity Safety Follow-up after failing immunosuppression withdrawal.
*** IMPORTANT NOTICE: *** The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network 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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| arTreg | Experimental | arTreg: alloantigen-reactive T regulatory cells The investigational product is donor alloantigen-reactive regulatory T cells (arTreg). Supportive regimen for receipt of arTregs includes everolimus, leukapheresis, cyclophosphamide, and mesna. Note: Participants who receive at least the minimum Treg product (arTreg) dose of 30 to <90 x10^6 total cells will be included in intent-to-treat analysis. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| arTreg | Biological | Eligible participants will receive a single dose of Treg product (arTreg). The target dose is at least 90 x 10^6 total cells. Method of receipt: peripheral intravenous (IV) infusion, administered over 20 to 30 minutes. |
| Measure | Description | Time Frame |
|---|---|---|
| Number and Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg |
| From arTreg infusion through completion of study participation |
| Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna |
| From ≤3 days prior to arTreg infusion through completion of study participation (Up to 3 months) |
| Number of Operationally Tolerant Participants | Operational tolerance is defined as:
| 52 (± 4 weeks) after the last dose of immunosuppression |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Participants Who Develop a Malignancy | The number of participants that are diagnosed with malignancy, any type. | Time of enrollment through completion of study participation (Up to 1.8 years) |
| Incidence of ≥Grade 3 Infections Following arTreg Infusion |
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Inclusion Criteria:
Eligibility:
Recipient:
Individuals must meet all of the following criteria to be eligible for this study:
Able to understand and provide informed consent
End-stage liver disease and listed for a living or deceased-donor primary solitary liver transplant
Agreement to use contraception
For candidates with a history of hepatitis C virus (HCV), completed treatment for HCV, maintaining a sustained viral response of ≥24 weeks duration by the day of transplant
Positive Epstein-Barr virus (EBV) antibody test, and
Immunizations are up-to-date based on the Advisory Committee on Immunization Practices (ACIP) recommendations for individuals with Liver Disease and Adult Vaccination, unless the investigator determines that administering a recommended immunization is not in the patient's best interest.
Living Donor:
Living donors must meet all of the following criteria to be eligible for this study:
Deceased Donor:
Deceased donors must meet the following criteria for their recipients to remain eligible:
Note:
Exclusion Criteria:
Recipient:
Individuals who meet any of the following criteria will not be eligible for this study:
History of previous organ, tissue or cell transplant
For cytomegalovirus (CMV) antibody negative recipients, a (CMV) antibody positive donor
Known contraindication to cyclophosphamide or mesna
Serologic evidence of human immunodeficiency virus (HIV)-1/2 infection
The need for chronic anti-coagulation or anti-platelet agents other than aspirin that cannot be safely discontinued for a minimum of 1 week to safely perform a liver biopsy
End stage liver disease secondary to autoimmune etiology (autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis) or other contraindications to drug withdrawal
Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule
Any condition that, in the opinion of the investigator, may interfere with study compliance
History of cardiac disease (ischemic heart disease requiring revascularization, history of or current treatment for dysrhythmia, or evidence of congestive heart failure), unless cleared by a cardiologist
Any past or current medical problems, treatments or findings that are not listed above, which, in the opinion of the investigator, may:
pose additional risks from participation in the study,
interfere with the candidate's ability to comply with study requirements, or
impact the quality or interpretation of the data obtained from the study.
History of malignancy or any concomitant malignancy, except:
Chronic use of systemic glucocorticoids or other immunosuppressives, or biologic immunomodulators.
Living Donor:
There are no exclusion criteria for living donors.
Deceased Donor:
-There are no exclusion criteria for deceased donors.
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| Name | Affiliation | Role |
|---|---|---|
| Sandy Feng, MD, PhD | University of California, San Francisco | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California, San Francisco | San Francisco | California | 94143 | United States |
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| Label | URL |
|---|---|
| National Institute of Allergy and Infectious Diseases (NIAID) | View source |
| Division of Allergy, Immunology, and Transplantation (DAIT) | View source |
| Immune Tolerance Network web site | View source |
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The plan is to share data upon completion of the study in ImmPort, a long-term archive of clinical and mechanistic data from DAIT-funded grants and contracts.
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The aim is to share data available to the public within 24 months upon completion of the study.
ImmPort public data access.
Participants were enrolled prior to transplant & had to wait for an available liver which was received per the institution's standard of care. If recipient rec'd a liver from a living donor, the donor also enrolled into the study to collect biological samples to aid in the manufacturing of the investigation product, arTregs. Immunosuppression medication was required to be stabilized and converted from tacrolimus to everolimus prior to transplant recipient receiving the investigational product
30 prospective transplant recipients and 12 living donors were enrolled from a single study center in the US between April 2021 and February 2023. The study was terminated by the sponsor in February 2023 prior to any participant receiving the investigational product, arTregs.
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| ID | Title | Description |
|---|---|---|
| FG000 | Enrolled Transplant Recipient, Did Not Receive arTregs | These participants were prospective transplant recipients who were consented and enrolled into the study, but did not receive arTregs. |
| FG001 | Enrolled Living Donor | These participants were living donors of the prospective transplant recipient who consented and enrolled into the study. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Transplanted participants who enrolled but did not receive arTregs and living donors of the prospective transplant recipient who consented and enrolled into the study
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| ID | Title | Description |
|---|---|---|
| BG000 | Enrolled, Transplant Recipient Did Not Receive arTregs | These participants were consented and enrolled into the study but did not receive arTregs. |
| BG001 | Enrolled Living Donor |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Number and Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg |
| Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe. | Posted | From arTreg infusion through completion of study participation |
|
Up to 1.8 years
Prior to study stage 2, only confirmed cases of COVID-19 were collected. All AEs were collected from the time of informed consent obtain during study stage 2 until the participant completes study participation or until 30 days after he/she prematurely withdraws (without withdrawing consent) or is withdrawn from the study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Enrolled Transplant Recipient, Did Not Receive arTregs | These participants were consented and enrolled into the study, but did not receive arTregs. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Cholangitis | Hepatobiliary disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
The study was terminated by the sponsor in February 2023 prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Director, Clinical Research Operations Program | DAIT/NIAID | 301-594-7669 | DAITClinicalTrialsGov@niaid.nih.gov |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 18, 2022 | Jul 20, 2023 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D007937 | Leukapheresis |
| D001781 | Blood Component Removal |
| D003520 | Cyclophosphamide |
| D015080 | Mesna |
| D000068338 | Everolimus |
| ID | Term |
|---|---|
| D016238 | Cytapheresis |
| D001691 | Biological Therapy |
| D013812 | Therapeutics |
| D047589 | Leukocyte Reduction Procedures |
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|
| leukapheresis | Procedure | Leukapheresis will be the method employed to recover peripheral blood mononuclear cells (PBMCs) from the allograft recipient. The recipient will undergo the procedure prior to initiating the cyclophosphamide conditioning regimen. Procedure on Day -3 (-1 day) prior to Treg product (arTreg) IV infusion. |
|
|
| cyclophosphamide | Drug | 40 mg/kg administered intravenously (IV) following leukapheresis and between 1 to 3 days prior to Treg product (arTreg) infusion, per institutional standard of care. |
|
|
| mesna | Drug | Mesna is administered:
|
|
|
| everolimus | Drug | EVR is approved for prophylaxis of allograft rejection in adults receiving a liver transplant. Per protocol: Post transplantation, subject will initially receive standard IS with tacrolimus (TAC),plus a mycophenolate product and/or steroids.Subsequently, evaluation for eligibility to be converted to EVR-based IS regimen will occur and, when applicable, proceed. Once the optimal EVR trough level is achieved,TAC dose will be reduced. When target EVR and TAC levels are maintained over two consecutive measurements, ALT liver function test (LFT) is ≤50 U/L, GGT LFT is ≤ the upper limit of normal or ≤ 1.5 times the baseline GGT, subject will be considered successfully converted to EVR-based IS regimen. EVR doses will be administered/monitored/adjusted over time. |
|
|
Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual [NCI-CTCAE version 5.0, published November 27, 2017]. |
| From arTreg infusion through completion of study participation |
| Number of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion | Definitions:
| From arTreg infusion through completion of study participation |
| Severity of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion | Intensity of AR and/or clinical rejection events will be graded. Definitions:
| From arTreg infusion through completion of study participation |
| Number of Chronic Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion | Diagnosed in accordance with Banff global assessment criteria. | From arTreg infusion through completion of study participation |
| Proportion of Participants Who Successfully Discontinue Tacrolimus | Proportion of participants who, per protocol:
| Post-transplant through Completion of Study Participation |
| Duration of Operational Tolerance | Durability of operational tolerance defined as the time from achieving the primary endpoint to immunosuppression (IS) reinitiation or to the end of trial participation. | Post-transplant through Completion of Study Participation |
| Study terminated by sponsor |
|
| Failure to initiate study therapy |
|
| Transplanted at another center |
|
| Failure to meet eligibility criteria |
|
| No longer transplant candidate |
|
| Manufacturing unable to accept specimens |
|
| Recipient ineligible |
|
| Received deceased liver |
|
These participants were living donors of the prospective transplant recipient who consented and enrolled into the study.
| BG002 | Total | Total of all reporting groups |
| years |
|
| Age, Customized | Count of Participants | Participants |
|
| Sex/Gender, Customized | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|---|
| Participants |
|
| Primary | Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna |
| These participants were consented and enrolled into the study and received at least part of the supportive regimen of leukapheresis, cyclophosphamide, or mesna. | Posted | Count of Participants | Participants | From ≤3 days prior to arTreg infusion through completion of study participation (Up to 3 months) |
|
|
|
| Primary | Number of Operationally Tolerant Participants | Operational tolerance is defined as:
| Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe | Posted | 52 (± 4 weeks) after the last dose of immunosuppression |
|
|
| Secondary | Number of Participants Who Develop a Malignancy | The number of participants that are diagnosed with malignancy, any type. | Participants who enrolled, but did not receive arTregs | Posted | Number | participants | Time of enrollment through completion of study participation (Up to 1.8 years) |
|
|
|
| Secondary | Incidence of ≥Grade 3 Infections Following arTreg Infusion | Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual [NCI-CTCAE version 5.0, published November 27, 2017]. | Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe. | Posted | From arTreg infusion through completion of study participation |
|
|
| Secondary | Number of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion | Definitions:
| Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe. | Posted | From arTreg infusion through completion of study participation |
|
|
| Secondary | Severity of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion | Intensity of AR and/or clinical rejection events will be graded. Definitions:
| Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe. | Posted | From arTreg infusion through completion of study participation |
|
|
| Secondary | Number of Chronic Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion | Diagnosed in accordance with Banff global assessment criteria. | Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe. | Posted | From arTreg infusion through completion of study participation |
|
|
| Secondary | Proportion of Participants Who Successfully Discontinue Tacrolimus | Proportion of participants who, per protocol:
| Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe. | Posted | Post-transplant through Completion of Study Participation |
|
|
| Secondary | Duration of Operational Tolerance | Durability of operational tolerance defined as the time from achieving the primary endpoint to immunosuppression (IS) reinitiation or to the end of trial participation. | Data were not collected. The study was terminated prior to any participant receiving the investigational product, arTregs. The study's low enrollment would not allow for study completion within the necessary timeframe. | Posted | Post-transplant through Completion of Study Participation |
|
|
| 1 |
| 30 |
| 3 |
| 30 |
| 3 |
| 30 |
| EG001 | Enrolled Living Donor | These participants were living donors of the prospective transplant recipient who consented and enrolled into the study. | 0 | 12 | 0 | 12 | 0 | 12 |
| COVID-19 | Infections and infestations | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | Systematic Assessment |
|
| Bile duct stenosis | Hepatobiliary disorders | Systematic Assessment |
|
| Malignant melanoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | Systematic Assessment |
|
| Oedema peripheral | General disorders | Systematic Assessment |
|
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| D002469 |
| Cell Separation |
| D003584 | Cytological Techniques |
| D019411 | Clinical Laboratory Techniques |
| D008919 | Investigative Techniques |
| D010752 | Phosphoramide Mustards |
| D009588 | Nitrogen Mustard Compounds |
| D009150 | Mustard Compounds |
| D006846 | Hydrocarbons, Halogenated |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D063088 | Phosphoramides |
| D009943 | Organophosphorus Compounds |
| D000476 | Alkanesulfonates |
| D017738 | Alkanesulfonic Acids |
| D000473 | Alkanes |
| D006839 | Hydrocarbons, Acyclic |
| D013438 | Sulfhydryl Compounds |
| D013457 | Sulfur Compounds |
| D013451 | Sulfonic Acids |
| D013456 | Sulfur Acids |
| D020123 | Sirolimus |
| D018942 | Macrolides |
| D007783 | Lactones |