xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT05973734</url>
    </required_header>
    <id_info>
      <org_study_id>58350</org_study_id>
      <nct_id>NCT05973734</nct_id>
    </id_info>
    <brief_title>Islet Transplantation With Recipient T-Reg Cells or Deceased Donor Vertebral Bone Marrow Therapy</brief_title>
    <official_title>Clinical Islet Transplantation With Apheresis, Isolation and Reintroduction of Recipient Regulatory T Cells or Administration of Deceased Donor Vertebral Bone Marrow in Type 1 Diabetes</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Stanford University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>University of California, San Francisco</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>Stanford University</source>
    <oversight_info>
      <has_dmc>Yes</has_dmc>
      <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
    </oversight_info>
    <brief_summary>
      <textblock>
        The goal of this clinical trial is to learn if patients who have brittle type 1 diabetes&#xD;
        receiving an islet transplantation will have better control of their sugars if they also&#xD;
        receive one of 2 types of immune cells along with the islet transplant. The participants will&#xD;
        receive either their own immune cells, called regulatory T cells, or immune cells from the&#xD;
        bone marrow of the islet donor.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Islet transplantation success remains limited by the immediate loss of islet after&#xD;
        transplantation, rejection, and side effect from immunosuppression. Preclinical animal models&#xD;
        provide evidence that donor bone marrow cells OR regulatory T cells infused at the time of&#xD;
        islet transplantation can improve the survival of islets after transplantation and reduce the&#xD;
        need for immunosuppression. The purpose of this study is to evaluate the feasibility and&#xD;
        safety of combining an islet transplant with the recipient's Tregs OR deceased donor bone&#xD;
        marrow cells in patients with brittle type 1 diabetes.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">May 2028</completion_date>
    <primary_completion_date type="Anticipated">May 2025</primary_completion_date>
    <phase>Phase 1</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Non-Randomized</allocation>
      <intervention_model>Parallel Assignment</intervention_model>
      <intervention_model_description>All patients are planned to receive an islet transplantation. The patients will also receive either Arm 1) recipient T regulatory cell infusion or arm 2) same donor vertebral body derived bone marrow cell infusion. Attribution to either arm will be based on the availability of either cell product in specific cases.</intervention_model_description>
      <primary_purpose>Treatment</primary_purpose>
      <masking>None (Open Label)</masking>
    </study_design_info>
    <primary_outcome>
      <measure>Occurrence of Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration</measure>
      <time_frame>within 3 months</time_frame>
      <description>Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Occurrence of grade 4 or greater adverse events of islet transplantation</measure>
      <time_frame>Within two years</time_frame>
      <description>Adverse event grade 4 or greater</description>
    </primary_outcome>
    <primary_outcome>
      <measure>Number of patients who receive Treg infusions (Arm1) or Donor Derived Vertebral Bone Marrow (Arm2) and islet transplantation (feasibility)</measure>
      <time_frame>Within two years</time_frame>
      <description>Number of patients who received planned Treg or Donor Bone Marrow</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>HbA1c ≤6.5%</measure>
      <time_frame>assessed at 6, 12 and 24 months post-islet transplantation</time_frame>
      <description>HbA1c ≤6.5%</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Absence of severe hypoglycemic events</measure>
      <time_frame>assessed at 6, 12 and 24 months post-islet transplantation</time_frame>
      <description>Absence of severe hypoglycemic event , requiring intervention by other person than the patient</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Decrease of insulin mean requirements (u/kg) from prior to transplantation by 50% of total daily dose</measure>
      <time_frame>assessed at 6, 12 and 24 months post-islet transplantation</time_frame>
      <description>Reduction of exogenous insulin requirement by 50% from baseline</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Clarke hypoglycemia severity (HYPO) score less than 2 (0 to &gt;4, &gt;4 indicate severe hypoglycemia unawareness)</measure>
      <time_frame>assessed at 6, 12 and 24 months post-islet transplantation</time_frame>
      <description>Improvement of Clarke score to less than 2</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Basal C-peptide at levels e &gt;0.5 ng/mL (&gt;0.17 nmol/L) fasting or stimulated.</measure>
      <time_frame>assessed at 6, 12 and 24 months post-islet transplantation</time_frame>
      <description>C-petide production from islet transplant assessment</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Target of glucose variability and hypoglycemia duration derived from the CGMS &lt;Standard Deviation and Coefficient targets&gt;</measure>
      <time_frame>assessed at 6, 12 and 24 months post-islet transplantation</time_frame>
      <description>Monitoring of glucose control 24h sensor monitoring</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Measurement of donor Specific Antibody, cPRA</measure>
      <time_frame>assessed at 6, 12 and 24 months post-islet transplantation</time_frame>
      <description>Single bead luminex anti HLA class 1 and 2 assay</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Quality of life (QOL) assessment</measure>
      <time_frame>assessed at 6, 12 and 24 months post-islet transplantation</time_frame>
      <description>QOL questionnaire SF-12 (0-100, higher score is better outcome)</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">24</enrollment>
    <condition>Islet Transplantation</condition>
    <arm_group>
      <arm_group_label>Recipient T Regulatory Cell</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>T regulatory cells prior to islet transplantation, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Donor Derived Vertebral Bone Marrow</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Deceased donor vertebral bone marrow (VBM) cells, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).</description>
    </arm_group>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Infusion of recipient T regulatory cell</intervention_name>
      <description>Patients will undergo a single apheresis collection with a target total blood volume of 20-30 L and the collected cells used as the source of purified Tregs to be infused following the islet transplantation. In the event a patient is unable to meet the collection target, a second collection may be performed.</description>
      <arm_group_label>Recipient T Regulatory Cell</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Biological</intervention_type>
      <intervention_name>Infusion of concomitant Donor Derived Vertebral Bone Marrow</intervention_name>
      <description>The cells from the donor VB and spleen are processed under cGMP conditions and released for infusion after the respective recipient has undergone transplant and conditioning. Under this protocol, the donor's VB will be obtained at the same time as the pancreatic islets and will be the source of HSC for infusion with the intent to establish immune tolerance to the donor's pancreatic islet cells. Subjects will receive one infusion of allogeneic cadaveric islets. Subjects will receive induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF). After islet transplantation, the VBM cells will be infused in one time window: on day 0-1. Subjects will undergo closed-loop insulin pump glucose control peri-transplant.</description>
      <arm_group_label>Donor Derived Vertebral Bone Marrow</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Male and female patients age 18 to 70 years of age.&#xD;
  &#xD;
            -  Ability to provide written informed consent.&#xD;
  &#xD;
            -  Mentally stable and able to comply with the procedures of the study protocol.&#xD;
  &#xD;
            -  Clinical history compatible with T1D with onset of disease at &lt; 45 years of age,&#xD;
               insulin- dependence for ≥ 5 years at the time of enrollment, or a sum of patient age&#xD;
               and insulin dependent diabetes duration of ≥ 28.&#xD;
  &#xD;
            -  Absence of stimulated C peptide (&lt; 0.3 ng/mL) in response to a mixed meal tolerance&#xD;
               test measured at 60 and 90 minutes after the start of consumption&#xD;
  &#xD;
            -  Involvement in intensive diabetes management defined as self-monitoring of glucose&#xD;
               values no less than a mean of three times each day averaged over each week and by the&#xD;
               administration of three or more insulin injections each day or insulin pump therapy.&#xD;
               Such management must be under the direction of an endocrinologist, diabetologist, or&#xD;
               diabetes specialist with at least 3 clinical evaluations during the 12 months prior to&#xD;
               study enrollment.&#xD;
  &#xD;
            -  At least two episodes of severe hypoglycemia in the 12 months prior to study&#xD;
               enrollment.&#xD;
  &#xD;
            -  Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more OR a HYPO&#xD;
               score greater than or equal to the 90th percentile (1047) during the screening period&#xD;
               and within the last 6 months prior to randomization.&#xD;
  &#xD;
            -  Women of childbearing potential may be enrolled if a pregnancy test is negative, and&#xD;
               they agree to the use of 2 forms of contraception from Screening to the end of the&#xD;
               study. Males must agree to use 2 forms of contraception from Screening to the end of&#xD;
               the study if their partners are of childbearing potential.&#xD;
  &#xD;
            -  Acceptable methods of birth control which must be used together are:&#xD;
  &#xD;
                 -  Oral contraceptive and condom (combination oral contraceptives containing the&#xD;
                    second- generation progestin (levonorgestrel) and &lt;30 μg of estrogen should be&#xD;
                    utilized),&#xD;
  &#xD;
                 -  IUD and condom,&#xD;
  &#xD;
                 -  Diaphragm with spermicide and condom&#xD;
  &#xD;
            -  Subject must complete training on how to use the Tandem X2 pump with Control IQ&#xD;
               technology by a certified Diabetes Educator or physician. Patients must complete at&#xD;
               least 2 hour training to the satisfaction of the educator and show proficiency and&#xD;
               understanding in its use as judged by the educator.&#xD;
  &#xD;
            -  Patients with prior kidney transplantation on immunosuppressive medications are&#xD;
               eligible provided they meet all eligibility criteria above excluding the need for&#xD;
               hypoglycemia unawareness. Patients should not be candidates for solid organ pancreas&#xD;
               transplant or have declined the surgical option.&#xD;
  &#xD;
            -  Exclusion Criteria:&#xD;
  &#xD;
            -  Body mass index (BMI) &gt;30 kg/m2 or patient weight ≤50kg.&#xD;
  &#xD;
            -  Insulin requirement of &gt;1.0 IU/kg/day or &lt;15 U/day. 3. HbA1c &gt;10%.&#xD;
  &#xD;
            -  Treatment with any anti-diabetic medication other than insulin within 4 weeks of&#xD;
               Screening&#xD;
  &#xD;
            -  Untreated proliferative diabetic retinopathy.&#xD;
  &#xD;
            -  Blood Pressure: SBP &gt;180 mmHg or DBP &gt;100 mmHg on optimal treatment.&#xD;
  &#xD;
            -  Estimated glomerular filtration rate of &lt;50 mL/min/1.73m2.&#xD;
  &#xD;
            -  Presence or history of macroalbuminuria (&gt;500mg/g creatinine).&#xD;
  &#xD;
            -  Presence or history of panel-reactive anti-HLA antibodies &gt;50%. Negative cross- match&#xD;
               by flow cytometry and no DSA to organ donor by standard methods.&#xD;
  &#xD;
            -  For female subjects: Positive pregnancy test, presently breast-feeding, or&#xD;
               unwillingness to use effective contraceptive measures for the duration of the study&#xD;
               and 4 months after discontinuation. For male participants: intent to procreate during&#xD;
               the duration of the study or within 4 months after discontinuation or unwillingness to&#xD;
               use effective measures of contraception&#xD;
  &#xD;
            -  Presence of active infection including hepatitis B, hepatitis C, HIV, or tuberculosis&#xD;
               (TB). Subjects with laboratory evidence of active infection are excluded even in the&#xD;
               absence of clinical evidence of active infection.&#xD;
  &#xD;
            -  Negative screen for Epstein-Barr Virus (EBV) by IgG determination.&#xD;
  &#xD;
            -  Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year&#xD;
               prior to study enrollment.&#xD;
  &#xD;
            -  Any history of malignancy except for completely resected squamous or basal cell&#xD;
               carcinoma of the skin.&#xD;
  &#xD;
            -  Known active alcohol or substance abuse.&#xD;
  &#xD;
            -  Baseline Hb below the lower limits of normal; neutropenia (&lt;1,500/7L), or&#xD;
               thrombocytopenia (platelets &lt;100,000/7L).&#xD;
  &#xD;
            -  Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g.,&#xD;
               warfarin) after islet transplantation (low-dose aspirin treatment is allowed) or&#xD;
               patients with an international normalized ratio (INR) &gt;1.5.&#xD;
  &#xD;
            -  Severe co-existing cardiac disease, characterized by any one of these conditions:&#xD;
  &#xD;
                 -  recent myocardial infarction (within past 6 months).&#xD;
  &#xD;
                 -  evidence of uncorrectable ischemia on functional cardiac exam within the last&#xD;
                    year.&#xD;
  &#xD;
                 -  left ventricular ejection fraction &lt;30%.&#xD;
  &#xD;
            -  Persistent elevation of liver function tests at the time of study entry. Persistent&#xD;
               serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvate&#xD;
               transaminase (SGPT [ALT]), or total bilirubin, with values &gt; 1.5 times normal upper&#xD;
               limits will exclude a patient.&#xD;
  &#xD;
            -  Acute or chronic pancreatitis.&#xD;
  &#xD;
            -  Treatment with any anti-diabetic medication other than insulin within 4 weeks of&#xD;
               enrollment.&#xD;
  &#xD;
            -  Use of any investigational agents within 4 or more weeks of enrollment, depending upon&#xD;
               the pharmacokinetics of the investigational agent and durability of changes with&#xD;
               treatment in immune function or glycemic regulation.&#xD;
  &#xD;
            -  Administration of live attenuated vaccine(s) within 2 months of enrollment.&#xD;
  &#xD;
            -  Any medical condition that, in the opinion of the investigator, will interfere with&#xD;
               safe participation in the trial.&#xD;
  &#xD;
            -  A previous islet transplant.&#xD;
  &#xD;
            -  History of medical non-adherence or poor social support.&#xD;
  &#xD;
            -  Individuals with selective IgA deficiencies (IgA level less than 15 mg/dL) who have&#xD;
               known antibody against IgA.&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>18 Years</minimum_age>
      <maximum_age>70 Years</maximum_age>
      <healthy_volunteers>No</healthy_volunteers>
    </eligibility>
    <overall_official>
      <last_name>Stephan Busque, MD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Stanford University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Kevin Ly, BS</last_name>
      <phone>650-497-6057</phone>
      <email>kevinly@stanford.edu</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Stephan Busque, MD</last_name>
      <phone>650-498-6189</phone>
      <email>sbusque@stanford.edu</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>Stanford University</name>
        <address>
          <city>Palo Alto</city>
          <state>California</state>
          <zip>94305</zip>
          <country>United States</country>
        </address>
      </facility>
      <contact>
        <last_name>Kevin Ly, BS</last_name>
        <phone>650-497-6057</phone>
        <email>kevinly@stanford.edu</email>
      </contact>
      <contact_backup>
        <last_name>Stephan Busque, MD</last_name>
      </contact_backup>
      <investigator>
        <last_name>Stephan Busque, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Everett Meyer, MD</last_name>
        <role>Principal Investigator</role>
      </investigator>
      <investigator>
        <last_name>Marina Basina, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Avnesh S Thakor, MD, PhD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Thomas A Pham, MD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
      <investigator>
        <last_name>Kent P Jensen, PhD</last_name>
        <role>Sub-Investigator</role>
      </investigator>
    </location>
    <location_countries>
      <country>United States</country>
    </location_countries>
    <reference>
      <citation>Ryan EA, Shandro T, Green K, Paty BW, Senior PA, Bigam D, Shapiro AM, Vantyghem MC. Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes. 2004 Apr;53(4):955-62. doi: 10.2337/diabetes.53.4.955.</citation>
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    </reference>
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      <PMID>8171564</PMID>
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      <PMID>17488791</PMID>
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      <PMID>18365398</PMID>
    </reference>
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      <PMID>17391129</PMID>
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      <PMID>14961999</PMID>
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    <verification_date>August 2023</verification_date>
    <study_first_submitted>June 14, 2023</study_first_submitted>
    <study_first_submitted_qc>July 25, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 3, 2023</study_first_posted>
    <last_update_submitted>August 18, 2023</last_update_submitted>
    <last_update_submitted_qc>August 18, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 21, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Stanford University</investigator_affiliation>
      <investigator_full_name>Stephan Busque</investigator_full_name>
      <investigator_title>Protocol Director</investigator_title>
    </responsible_party>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Death</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT05973734
  org study id: 58350
  nct id: NCT05973734
  lead sponsor: 
  collaborator: 
  has dmc: Yes
  is fda regulated drug: Yes
  is fda regulated device: No
  The goal of this clinical trial is to learn if patients who have brittle type 1 diabetes
        receiving an islet transplantation will have better control of their sugars if they also
        receive one of 2 types of immune cells along with the islet transplant. The participants will
        receive either their own immune cells, called regulatory T cells, or immune cells from the
        bone marrow of the islet donor.
  Islet transplantation success remains limited by the immediate loss of islet after
        transplantation, rejection, and side effect from immunosuppression. Preclinical animal models
        provide evidence that donor bone marrow cells OR regulatory T cells infused at the time of
        islet transplantation can improve the survival of islets after transplantation and reduce the
        need for immunosuppression. The purpose of this study is to evaluate the feasibility and
        safety of combining an islet transplant with the recipient's Tregs OR deceased donor bone
        marrow cells in patients with brittle type 1 diabetes.
  allocation: Non-Randomized
  intervention model: Parallel Assignment
  intervention model description: All patients are planned to receive an islet transplantation. The patients will also receive either Arm 1) recipient T regulatory cell infusion or arm 2) same donor vertebral body derived bone marrow cell infusion. Attribution to either arm will be based on the availability of either cell product in specific cases.
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Occurrence of Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration
  time frame: within 3 months
  description: Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration
  measure: Occurrence of grade 4 or greater adverse events of islet transplantation
  time frame: Within two years
  description: Adverse event grade 4 or greater
  measure: Number of patients who receive Treg infusions (Arm1) or Donor Derived Vertebral Bone Marrow (Arm2) and islet transplantation (feasibility)
  time frame: Within two years
  description: Number of patients who received planned Treg or Donor Bone Marrow
  measure: HbA1c ≤6.5%
  time frame: assessed at 6, 12 and 24 months post-islet transplantation
  description: HbA1c ≤6.5%
  measure: Absence of severe hypoglycemic events
  time frame: assessed at 6, 12 and 24 months post-islet transplantation
  description: Absence of severe hypoglycemic event , requiring intervention by other person than the patient
  measure: Decrease of insulin mean requirements (u/kg) from prior to transplantation by 50% of total daily dose
  time frame: assessed at 6, 12 and 24 months post-islet transplantation
  description: Reduction of exogenous insulin requirement by 50% from baseline
  measure: Clarke hypoglycemia severity (HYPO) score less than 2 (0 to >4, >4 indicate severe hypoglycemia unawareness)
  time frame: assessed at 6, 12 and 24 months post-islet transplantation
  description: Improvement of Clarke score to less than 2
  measure: Basal C-peptide at levels e >0.5 ng/mL (>0.17 nmol/L) fasting or stimulated.
  time frame: assessed at 6, 12 and 24 months post-islet transplantation
  description: C-petide production from islet transplant assessment
  measure: Target of glucose variability and hypoglycemia duration derived from the CGMS <Standard Deviation and Coefficient targets>
  time frame: assessed at 6, 12 and 24 months post-islet transplantation
  description: Monitoring of glucose control 24h sensor monitoring
  measure: Measurement of donor Specific Antibody, cPRA
  time frame: assessed at 6, 12 and 24 months post-islet transplantation
  description: Single bead luminex anti HLA class 1 and 2 assay
  measure: Quality of life (QOL) assessment
  time frame: assessed at 6, 12 and 24 months post-islet transplantation
  description: QOL questionnaire SF-12 (0-100, higher score is better outcome)
  arm group label: Recipient T Regulatory Cell
  arm group type: Experimental
  description: T regulatory cells prior to islet transplantation, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).
  arm group label: Donor Derived Vertebral Bone Marrow
  arm group type: Experimental
  description: Deceased donor vertebral bone marrow (VBM) cells, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).
  intervention type: Biological
  intervention name: Infusion of recipient T regulatory cell
  description: Patients will undergo a single apheresis collection with a target total blood volume of 20-30 L and the collected cells used as the source of purified Tregs to be infused following the islet transplantation. In the event a patient is unable to meet the collection target, a second collection may be performed.
  arm group label: Recipient T Regulatory Cell
  intervention type: Biological
  intervention name: Infusion of concomitant Donor Derived Vertebral Bone Marrow
  description: The cells from the donor VB and spleen are processed under cGMP conditions and released for infusion after the respective recipient has undergone transplant and conditioning. Under this protocol, the donor's VB will be obtained at the same time as the pancreatic islets and will be the source of HSC for infusion with the intent to establish immune tolerance to the donor's pancreatic islet cells. Subjects will receive one infusion of allogeneic cadaveric islets. Subjects will receive induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF). After islet transplantation, the VBM cells will be infused in one time window: on day 0-1. Subjects will undergo closed-loop insulin pump glucose control peri-transplant.
  arm group label: Donor Derived Vertebral Bone Marrow
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: 70 Years
  healthy volunteers: No
  last name: Stephan Busque, MD
  role: Principal Investigator
  affiliation: Stanford University
  last name: Kevin Ly, BS
  phone: 650-497-6057
  email: kevinly@stanford.edu
  last name: Stephan Busque, MD
  phone: 650-498-6189
  email: sbusque@stanford.edu
  facility: 
  contact: 
  contact backup: 
  investigator: 
  investigator: 
  investigator: 
  investigator: 
  investigator: 
  investigator: 
  country: United States
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  PMID: 15047610
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  PMID: 12453970
  citation: Streja D. Can continuous glucose monitoring provide objective documentation of hypoglycemia unawareness? Endocr Pract. 2005 Mar-Apr;11(2):83-90. doi: 10.4158/EP.11.2.83.
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  citation: Huber BC, Ransohoff JD, Ransohoff KJ, Riegler J, Ebert A, Kodo K, Gong Y, Sanchez-Freire V, Dey D, Kooreman NG, Diecke S, Zhang WY, Odegaard J, Hu S, Gold JD, Robbins RC, Wu JC. Costimulation-adhesion blockade is superior to cyclosporine A and prednisone immunosuppressive therapy for preventing rejection of differentiated human embryonic stem cells following transplantation. Stem Cells. 2013 Nov;31(11):2354-63. doi: 10.1002/stem.1501.
  PMID: 24038578
  citation: Bellacen K, Kalay N, Ozeri E, Shahaf G, Lewis EC. Revascularization of pancreatic islet allografts is enhanced by alpha-1-antitrypsin under anti-inflammatory conditions. Cell Transplant. 2013;22(11):2119-33. doi: 10.3727/096368912X657701. Epub 2012 Oct 8.
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  citation: Baranovski BM, Ozeri E, Shahaf G, Ochayon DE, Schuster R, Bahar N, Kalay N, Cal P, Mizrahi MI, Nisim O, Strauss P, Schenker E, Lewis EC. Exploration of alpha1-antitrypsin treatment protocol for islet transplantation: dosing plan and route of administration. J Pharmacol Exp Ther. 2016 Dec;359(3):482-490. doi: 10.1124/jpet.116.236067. Epub 2016 Nov 7.
  PMID: 27821710
  citation: Weir GC, Ehlers MR, Harris KM, Kanaparthi S, Long A, Phippard D, Weiner LJ, Jepson B, McNamara JG, Koulmanda M, Strom TB; ITN RETAIN Study Team. Alpha-1 antitrypsin treatment of new-onset type 1 diabetes: An open-label, phase I clinical trial (RETAIN) to assess safety and pharmacokinetics. Pediatr Diabetes. 2018 Aug;19(5):945-954. doi: 10.1111/pedi.12660. Epub 2018 May 7.
  PMID: 29473705
  citation: Koulmanda M, Bhasin M, Fan Z, Hanidziar D, Goel N, Putheti P, Movahedi B, Libermann TA, Strom TB. Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival. Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15443-8. doi: 10.1073/pnas.1018366109. Epub 2012 Sep 4.
  PMID: 22949661
  citation: Wang J, Sun Z, Gou W, Adams DB, Cui W, Morgan KA, Strange C, Wang H. alpha-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction. Diabetes. 2017 Apr;66(4):970-980. doi: 10.2337/db16-1036. Epub 2017 Jan 9.
  PMID: 28069642
  citation: Berger M, Liu M, Uknis ME, Koulmanda M. Alpha-1-antitrypsin in cell and organ transplantation. Am J Transplant. 2018 Jul;18(7):1589-1595. doi: 10.1111/ajt.14756. Epub 2018 Apr 24.
  PMID: 29607607
  citation: Taylor GD, Kirkland T, Lakey J, Rajotte R, Warnock GL. Bacteremia due to transplantation of contaminated cryopreserved pancreatic islets. Cell Transplant. 1994 Jan-Feb;3(1):103-6. doi: 10.1177/096368979400300114.
  PMID: 8162286
  citation: Lloveras J, Farney AC, Sutherland DE, Wahoff D, Field J, Gores PF. Significance of contaminated islet preparations in clinical islet transplantation. Transplant Proc. 1994 Apr;26(2):579-80. No abstract available.
  PMID: 8171564
  citation: Rickels MR, Kamoun M, Kearns J, Markmann JF, Naji A. Evidence for allograft rejection in an islet transplant recipient and effect on beta-cell secretory capacity. J Clin Endocrinol Metab. 2007 Jul;92(7):2410-4. doi: 10.1210/jc.2007-0172. Epub 2007 May 8.
  PMID: 17488791
  citation: Rickels MR, Kearns J, Markmann E, Palanjian M, Markmann JF, Naji A, Kamoun M. HLA sensitization in islet transplantation. Clin Transpl. 2006:413-20.
  PMID: 18365398
  citation: Olack BJ, Swanson CJ, Flavin KS, Phelan D, Brennan DC, White NH, Lacy PE, Scharp DW, Poindexter N, Mohanakumar T. Sensitization to HLA antigens in islet recipients with failing transplants. Transplant Proc. 1997 Jun;29(4):2268-9. doi: 10.1016/s0041-1345(97)00327-8. No abstract available.
  PMID: 9193621
  citation: Mao Q, Terasaki PI, Cai J, Briley K, Catrou P, Haisch C, Rebellato L. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant. 2007 Apr;7(4):864-71. doi: 10.1111/j.1600-6143.2006.01711.x.
  PMID: 17391129
  citation: Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant. 2004 Mar;4(3):438-43. doi: 10.1111/j.1600-6143.2004.00360.x.
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  responsible party type: Principal Investigator
  investigator affiliation: Stanford University
  investigator full name: Stephan Busque
  investigator title: Protocol Director
  mesh term: Death
  sharing ipd: No