Aralast NP in Islet Transplant
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Islet transplantation is a relatively new procedure used in people with difficult to control
      Type 1 diabetes. Insulin producing cells (islets) are isolated from a pancreas donated by the
      next of kin of a person who is brain dead. After the cells are prepared, the islets are
      transplanted into the recipient's liver and produce insulin. Patients who receive an islet
      transplant take medication that suppresses their immune system and prevent rejection of the
      islet tissue.

      The investigators have also learned that there is general inflammation at the time of the
      transplant that is not fully controlled with our standard medications. The investigators
      believe this inflammation may cause some islet cell death around the time of transplant. Due
      to this islet death around the time of transplant, most recipients need 2 or 3 separate
      transplant procedures.

      The investigators are studying the use of Alpha-1 Antitrypsin (AAT) in islet transplant to
      decrease the amount of cell death caused by general inflammation. In this study, the
      investigators hope to decrease the need for more than one transplant procedure by controlling
      inflammation, before and after transplant, with Alpha-1 Antitrypsin (Aralast NP).

      Alpha-1 Antitrypsin is a protein made in healthy humans that helps to prevent tissue damage
      during times of inflammation. Alpha-1 Antitrypsin is obtained from healthy plasma donors.
      There have been studies in Islet Transplant in monkeys using this medication and it has shown
      to protect the islets from inflammation.

      This study involves using Alpha-1 Antitrypsin in addition to our current Standard of Care
      medications used in Islet Transplant.
    

Detailed description: 
      METHODS & PROCEDURES:

      This clinical trial will be a non-randomized, open-label, single arm, prospective trial to
      asses the efficacy of AAT in preventing non-immunologic loss of transplanted islet mass in a
      single-donor islet transplant. Enrolled patients (n=12) will participate in the study for 1
      year, with outcomes assessed during islet isolation, 90 days post-transplant and at 1 year
      post-transplant.

      The current Standard of Care treatment for Islet Transplant includes induction
      (Alemtuzumab/Basiliximab) and long-term immunosuppression (Prograf/Cellcept). The engraftment
      regimen includes anti-inflammatory medications (Etanercept/Anakinra) and intravenous insulin
      and heparin. We will utilize the current Islet Standard of Care Protocol. The only additional
      intervention used in this pilot trial is the addition of the investigational agent,
      alpha-1-antitrypsin to islet processing, culture, and patient treatment pre- and
      post-transplant.

      Islet Dosage and Culture

      Islets will be treated with AAT (to a final dilution of 0.5mg/mL) throughout the isolation
      and culture process. Islet treatment will include:

        -  Flushing through the superior mesenteric artery and splenic artery (final dilution
           0.5mg/mL)

        -  Culturing with AAT (final dilution 0.5mg/mL)

      Participant Dosing

      Subjects undergoing intraportal clinical islet transplantation will receive treatment (AAT at
      120mg/kg intravenously, based on Day -1 admission weight and rounded to the nearest 20mg) at
      the following time points:

        -  Day -1 prior to transplant

        -  Day 3 post-transplant

        -  Day 7 post-transplant

        -  Day 14 post-transplant Recipient management including the transplant procedure,
           postoperative care, immunosuppression and other medications, and post-transplant
           monitoring will follow standard of care protocols.

      SCOPE & DURATION:

      Recruitment will take place at the Clinical Islet Transplant Program at the University of
      Alberta Hospital, Edmonton, Alberta. Participants (N=12) will be adult patients, assessed and
      deemed appropriate to activate on the waiting list for islet transplantation. Anticipated
      duration of enrollment is 12 months, with follow-up at 90 days and 12 months.

      In this pilot study control data will be obtained from a Standard of Care control cohort as
      comparison.

      We will also obtain 2 year and 3 year long-term follow-up data from standard of care testing.
      This long-term follow up will review data collected within 3 years post-transplant and will
      include the following: patient and graft survival data, biochemical data from routine blood
      work, routine and for cause imaging, metabolic testing, initiation of interventions to treat
      complications, and reporting of any adverse or serious adverse events.

      STUDY FOLLOWUP:

      As follow-up, this study will use a number of blood tests and parameters used by the clinical
      program. We will obtain the following information regarding participant outcomes from routine
      blood testing, metabolic testing, and clinic visits:

        -  Complete blood count (CBC)-differential to monitor white and red blood cells

        -  Liver function tests

        -  Kidney function tests

        -  Blood sugar tests, including the Hemoglobin A1c (HbA1c) which estimates average blood
           sugars over 3 months.

        -  C-peptide testing, a chemical produced only be healthy, working islets.

      These clinics will occur weekly x 4weeks, then at 1 month, 3 months, 6, months and 12 months.
      Participants will then have annual clinic visits, all as standard of care. Clinic visits
      include vital signs, physician assessment, review of recorded blood glucose records, and
      determination of patient requiring insulin or becoming insulin independent by a set of
      criteria based on the above blood sugar testing and glucose records.
    

Intervention name(s): Alpha-1 Antitrypsin
Intervention type(s): Drug
Intervention description(s): Subjects will receive their islets treated with Aralast NP during islet isolation process.
Subjects will receive Aralast NP at a dose of 120 mg/kg (at an infusion rate of 0.2 mL/kg/min or less), dependent on patient tolerance, based on Day -1 admission weight and dose rounded to the nearest 20 mg) at the following time points:
Pre-transplant Day -1
Post-transplant Day 3
Post-transplant Day 7
Post-transplant Day 14
Intervention MeSH terms: Alpha 1-Antitrypsin; Protein C Inhibitor
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Islet Transplantation