Omental Islet Transplant
Condition: Type 1 Diabetes
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 of a deceased
      organ donor. After the cells are carefully prepared, the islets are transplanted into
      patient's body. These transplanted islets may produce insulin for the patient. Patient may be
      able to reduce or eliminate the need for insulin injections for an unknown period of time.
      Patients who receive an islet transplant may need to stay on powerful immunosuppressive drugs
      for as long as the islets remain alive and working. These drugs help to prevent the immune
      system from attacking the transplanted islets.

      Under current standard of care procedure, islets are transplanted into patient's liver. The
      investigators have learned that some of these cells do not survive the current procedure and
      are lost around the time of transplant. Therefore in this study, the investigators are
      studying a new transplant procedure that may help prevent this islet cell loss. The new
      procedure involves transplanting the islets into an omental pouch instead of into the liver.
      The omentum is a large apron-like fold of membrane inside the abdomen that drapes over the
      intestines. This study will test to see if omental islet transplantation is safe and
      effective. Standard immunosuppressive medicines (anti-thymocyte globulin, tacrolimus,
      mycophenolic acid, sirolimus, etanercept) will be used in this study to prevent rejection of
      the islets.

      This study is a collaborative research with the University of Miami, and the same study
      protocol has been in use over there. Recruitment in Edmonton will continue until all subjects
      [N=6] needed for the study are transplanted. All subjects in this study will receive islet
      transplants using the study procedure.
    

Detailed description: 
      BACKGROUND

      Current islet transplantation into the portal vein of the liver has shown the unique ability
      of islets to stabilize blood glucose levels and prevent severe hypoglycemia in a selected
      group of subjects with type 1 diabetes. The main limitations of islet transplantation are the
      need for systemic immunosuppression to maintain function and the loss of islet function over
      time. Additionally, many studies have demonstrated that the current site of transplantation
      in the liver is not an ideal site due to several factors. These factors include (1)
      significant liver inflammation following islet infusion; (2) potential for life-threatening
      procedure-related complications such as bleeding and thrombosis; (3) high levels of
      immunosuppressive drugs and GI toxins in the liver contributing to islet toxicity; (4) the
      inability to retrieve islets after infusion; and (5) development of graft dysfunction in a
      number of recipients of intrahepatic allogeneic and autologous islets.

      Based on these premises, development of a clinical protocol for the implantation of islets
      into the omentum is a desirable goal. As an attempt to maximize the engraftment of islet cell
      clusters onto the omentum, implantation site should promote islet adherence to the omental
      peritoneal layer and avoid cell pelleting. Dr. Alejandro's team at University of Miami has
      recently performed a series of experiments in animal models of diabetes to assess the
      feasibility of transplanting pancreatic islets in the omentum using a plasma-thrombin gel.
      With that approach, the islets are re-suspended in either donor or autologous plasma and
      distributed in the omental pouch (created by sutures) to avoid pelleting. Cell adherence is
      achieved by addition of clinical-grade recombinant human thrombin that reacts with plasma to
      create a biocompatible, degradable gel containing the islet graft.

      The investigators have outlined the initial patient trial as 6 subjects, based on clinical
      judgment and extensive experience in clinical islet transplantation trials. If initial safety
      and efficacy is satisfactory (no adverse events related to the transplantation and efficacy
      in 2 of the 3 first transplanted subjects), the investigators will transplant 3 additional
      subjects.

      OBJECTIVES

      Primary Objective

      Safety: To demonstrate the safety of islet transplantation into an omental pouch site for the
      treatment of subjects with type 1 diabetes (T1D).

      Secondary Objective

      Efficacy: To demonstrate the efficacy of islet transplantation into an omental pouch site for
      the treatment of T1D in subjects with hypoglycemia unawareness and a history of severe
      hypoglycemic episodes.

      Primary Endpoints

      The primary safety endpoint is to demonstrate patient safety throughout all stages of the
      trial.

      The primary efficacy endpoint is the proportion of subjects with HbA1c ≤6.5% at 1 year AND
      free of severe hypoglycemic events from Day 28 to Day 365, inclusive, after the islet
      transplant.

      Secondary Endpoints

      Secondary efficacy endpoints: At 75±7, 365 ± 14 ,and 730 ± 14 days following the islet
      transplant(s): the percent reduction in insulin requirements; HbA1c; Mean Amplitude of
      Glycemic Excursions (MAGE); Lability Index (LI); Ryan hypoglycemia severity (HYPO) score;
      Clarke score; number of severe hypoglycemic episodes; basal (fasting) and 90-min glucose and
      c-peptide derived from the mixed-meal tolerance test (MMTT); beta-score; C-peptide creatinine
      ratio; acute insulin response to glucose (AIRglu), insulin sensitivity, and disposition index
      derived from the insulin-modified frequently-sampled intravenous glucose tolerance (FSIGT)
      test; glucose variability and hypoglycemia duration derived from the continuous glucose
      monitoring system® (CGMS); and Quality of life (QOL) measures: EuroQol five dimensions
      questionnaire (EQ-5D), Hypoglycemia Fear Survey (HFS), SF-36v2, Diabetes Distress scale).

      Secondary safety endpoints: Safety, including incidence of post-transplant infections,
      malignancies, morbidity, and other adverse events (AEs) (e.g., increased body weight and
      hypertension) associated with conventional immunosuppression. Renal function as measured by
      serum creatinine, glomerular filtration rate (GFR) and other relevant laboratory parameters.
      Lipid profiles (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol) over
      time.

      At 75 ± 7 and 365 ± 14 days following the islet transplant, and at two years following the
      final islet transplant: the incidence and severity of AEs related to the islet transplant
      procedure including: bleeding (>2 g/dL decrease in hemoglobin concentration); wound
      complication (infection or subsequent hernia); torsion of omentum; gastrointestinal
      obstruction; abscess; cysts; need for surgical intervention. The incidence and severity of
      AEs related to the immunosuppression including: allergy; reduction in GFR; addition or
      intensification of antihyperlipidemic therapy; gastrointestinal toxicity; neutropenia,
      anemia, or thrombocytopenia; viral, bacterial, or fungal infections; and benign or malignant
      neoplasms. The incidence of immune sensitization defined by presence of anti-HLA antibodies
      absent prior to transplantation. The incidence of discontinuation of immunosuppression.

      PROCEDURES

      Prior to transplantation, the patient is screened, qualified, listed for transplant, and
      signs the informed consent form.

      At the time a suitable islet preparation becomes available, the patient will receive
      allogeneic islet cells placed in an omental pouch. The details of this surgical procedure
      will be addressed in Question 5.0.

      Islet transplant will be performed under Anti-Thymocyte Globulin (ATG, Thymoglobulin®)
      induction immunosuppression (5 doses, day -2 prior to transplant to day 2 post-transplant).
      Maintenance mycophenolate mofetil (MMF) therapy (1-2 g/day as BID dosing) will be started on
      Day -1 pre-transplant. Tacrolimus will be administered orally twice daily on Day 1
      post-transplant to maintain a trough level of 10-12 ng/mL for 3 months, then 6-10 ng/mL
      thereafter. Etanercept will be given IV before the islet transplant (50 mg), and then at 25
      mg (subcutaneously) on post-operative day (POD) +3, +7 and +10.

      FOLLOW UP

      Subject will undergo a 24-month follow-up period following their islet transplant. 19 study
      visits during the first year after the transplant, and 4 more study visits during the 2nd
      year after the transplant.
    

Intervention name(s): Omental Islet transplant; Anti-Thymocyte Globulin; Mycophenolate mofetil; Tacrolimus; Etanercept; Sirolimus
Intervention type(s): Procedure; Drug; Drug; Drug; Drug; Drug
Intervention description(s): The intervention is transplanting the islets into an omental pouch instead of into the liver. The omentum is a large apron-like fold of membrane inside the abdomen that drapes over the intestines. This study will test to see if omental islet transplantation is safe and effective. Standard immunosuppressive medicines (anti-thymocyte globulin, tacrolimus, mycophenolic acid, sirolimus, etanercept) will be used in this study to prevent rejection of the islets.; Sirolimus will be used in case of tacrolimus or/and mycophenolate mofetil intolerance.
Other intervention name(s): Thymoglobulin®
Intervention MeSH terms: Mycophenolic Acid; Sirolimus; Etanercept; Tacrolimus; Thymoglobulin; Antilymphocyte Serum
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment