Islet Transplantation in Type 1 Diabetic Recipients of Kidney Transplants
Condition: Diabetes; Kidney Transplantation
Study type: Interventional

Summary: 
      Study hypothesis is that we can reproduce results of islet transplantation in type one
      diabetics in patients with a kidney transplant.
    

Detailed description: 
      This trial is designed to replicate the protocol currently being tested by the Immune
      Tolerance Network (ITN) in a population of patients that have been previously transplanted
      (recipients of functioning renal allografts) and are therefore immunosuppressed.

      The data will be generated using substantially identical techniques for islet preparation, re
      transplantation with additional islets to meet the minimum islet cell mass, and an identical
      steroid-free post-transplant regimen utilizing sirolimus, low dose tacrolimus, and
      daclizumab.

      3.1. Primary and secondary endpoints and additional measures

      Study efficacy endpoints and additional measures are described in the following subsections.
      Measures relating to the islet preparation quality (Section 3.1.3) and other variables
      relating to key cellular and genetic markers (Section 3.1.4) followed during the study are
      not considered clinical outcome variables. Details describing requirements for efficacy
      testing are found in Section 6.1. Safety measures are described in Section 7.

      3.1.1. Primary endpoint

      The primary endpoint for this study is independence from insulin injections with adequate
      control of blood glucose in subjects with Type 1 diabetes at one year post final transplant.
      Subjects will be considered as a success when at the one year assessment they are not using
      insulin, they have a HbA1c <6.5% and they achieve fasting glucose levels not exceeding 7.8
      mmol/L (140 mg/dL) more than three times in a week (using the morning fasting glucose level),
      and not exceeding two hour post-prandial (using any post meal glucose level) values of 10
      mmol/L (180 mg/dL) more than four times in a week. A subject will still be considered a
      success if an intercurrent illness or other event (e.g., high tacrolimus level) causes a
      participant to require insulin use for a period not exceeding a total of 14 days, and
      assessment after this event demonstrates insulin independence and adequate glucose control as
      defined above. This assessment must be completed no later than two weeks after the scheduled
      one year assessment.

      3.1.2. Secondary parameters

      Secondary parameters that support the primary goal of the investigation will be assessed at
      generally the same intervals as the primary endpoint, with some taken more or less frequently
      as indicated in detail in Sections 5.2 and 6.1. Additional clinical measurements are also
      taken during the study that are not considered endpoints for formal analyses, but are to be
      carefully followed as a part of the study. The schedule for these additional elements is
      listed in Sections 5.2, 6.2 and 7.2. The secondary variables include the following measures:

        1. Basal C-peptide levels

        2. HbA1C levels

        3. Glucose tolerance

        4. C-peptide response to arginine

        5. MAGE improvement

        6. Mixed Meal Test

        7. Durability of insulin independence and adequate blood glucose control

      3.1.3. Islet quality endpoints

      Islet cell preparations for each transplant will be assessed using the following elements:

        1. Islet yield per isolation used for clinical transplantation, expressed as i) total islet
           equivalents and ii) islet equivalents per kg recipient body weight.

        2. Islet viability, as assessed by a fluorescent dye inclusion/exclusion assay to assess
           metabolic activity and membrane integrity.

        3. In vitro islet responsiveness to glucose challenge, as measured by 2-hour static
           incubation following 12-24 hour culture at 37º C in CMRL 1066 (10% FCS, 25 mmol HEPES).
           A stimulation index, a ratio of insulin secretion during high glucose over insulin
           secretion during low basal secretion is calculated as an index of islet function.

        4. Islet cell immunohistochemical composition and purity assessment, (as determined by JDRF
           Center for Islet Transplantation at Harvard Medical School - Islet Morphology Core
           Laboratory)

        5. Evidence of no microbial contamination, as documented by a negative Gram stain of the
           islet preparation immediately pre-transplant, and by negative microbial cultures
           reported after at least 5 days incubation for aerobes, anaerobes, fungi.

        6. Evidence of a low endotoxin content of the final islet preparation.

      3.1.4. Cellular and genetic markers

      Samples will be collected before and after transplant for immunologic studies to be processed
      in the laboratories of Dr. Terry Strom at the Beth Israel Deaconess Medical Center and Dr.
      Mohamed Sayegh at the Brigham and Women's Hospital.

      These include:

        1. Alteration in autoimmune markers for GAD65, ICA512, and mIAA, comparing blood samples
           drawn pre-transplant and 3, 6, 9, 12, 24 and 36 months after final transplant.

        2. Changes in autoantibody and other immune markers comparing blood samples drawn
           pre-transplant and 3, 6, 12, 24, and 36 months after final transplant

        3. Samples will also be taken for future laboratory and genetic studies comparing blood
           samples drawn pre-transplant and usually 3, 6, and 12 months after final transplant.

      3.2. Description of trial design and schematic diagram of procedures and stages

      Because this is an open-label, single-arm study, a schematic diagram of the design is omitted
      for simplicity. For a general description of the trial design, please refer to Section 2. A
      tabular listing of visit schedules and tests is found in Appendix 1.

      3.3. Measures to minimize bias

      This study is an open-label feasibility study with definitive clinical endpoints of insulin
      independence, blood glucose and C peptide production as measures of procedural success. As
      donor islets become available the appropriate ABO compatible blood types will be matched to
      eligible participants. Clinical investigators are not masked to treatment assignment or
      follow up assessment information for this pilot study.

      3.4. Description of trial treatments and dosage regimen & labeling

      Each islet cell transplantation procedure under this protocol is derived from an individual
      donor pancreas, processed for immediate transplantation. All containers and components are
      appropriately labeled during preparation. Each final islet preparation released for use is
      labeled to indicate its identity and date of preparation. Records regarding donor identity
      will be kept in a coded manner for quality control purposes and will be kept absolutely
      confidential in accordance with standard procedures.

      3.4.1. Islet Infusion(s)

      A target total of > 10,000 IE/kg recipient body weight will be infused via a percutaneous
      transhepatic catheter inserted into the portal vein (see Section 1.4.2). This will in all
      likelihood require more than one islet infusion to achieve this goal. The first infusion must
      contain at least 5,000 IE/kg recipient body weight. In the event that a subject does not
      achieve insulin-independence with normoglycemia after two fresh islet infusions, a third
      transplant may be considered as described in Section 5.1.

      3.4.2. Immunosuppressive Therapy

      Beginning with the initial transplant, a immunosuppressive regimen will be administered to
      all subjects. Subjects will receive initial doses of daclizumab, sirolimus, and low dose
      tacrolimus according to the following schedule.

      3.4.2.1. Daclizumab regimen

      Daclizumab will be administered at a dose of 1 mg/kg peripheral IV given immediately
      pre-transplant, and at 2, 4, 6, and 8 weeks after transplant, for a total of 5 doses (over 8
      weeks). If a subsequent islet infusion is required beyond this induction period, then a
      further 5 dose course of daclizumab will be given according to the same schedule. If the
      second (or third) transplant occurs and no daclizumab was given in the preceding 7 days, then
      the dosing regimen will begin at the time of transplant. If daclizumab has been administered
      within the past 7 days, then the dose at transplant is omitted, and the first dose given 2
      weeks post transplant.

      3.4.2.2. Sirolimus regimen

      All patients enrolled in this trial will already be on Sirolimus therapy. If needed, the dose
      will be increased to 0.1 mg/kg/day PO and adjusted to the target range of 12-15 ng/ml for the
      3 months following the most recent islet infusion. After three months following last
      transplant, the target whole blood level will be lowered to 7-10ng/mL.

      3.4.2.3. Tacrolimus regimen

      All patients enrolled in this trial will already be on Tacrolimus therapy. As soon as trough
      levels are available, the dose will be adjusted to the target range of 3-6 ng/ml throughout
      the study.
    

Intervention name(s): Islet Infusion
Intervention type(s): Procedure
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Diabetes; Islet Transplantation