Omental Islet Transplant
Omental Islet Transplant
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.
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.
Inclusion Criteria:

 1. Male and female patients age 18 to 65 years of age.

 2. Ability to provide written informed consent.

 3. Mentally stable and able to comply with the procedures of the study protocol.

 4. Clinical history compatible with T1D with onset of disease at <40 years of age,
 insulin-dependence for > 5 years at the time of enrollment, and a sum of subject age
 and insulin-dependent diabetes duration of ≥28.

 5. Absent stimulated c-peptide (<0.3 ng/mL) in response to a MMTT (Boost® 6 mL/kg body
 weight to a maximum of 360 mL; another product with equivalent caloric and nutrient
 content may be substituted for Boost®) measured at 60 and 90 min after the start of
 consumption.

 6. Involvement in intensive diabetes management, defined as self-monitoring of glucose
 values no less than a mean of three times each day averaged over each week and by the
 administration of three or more insulin injections each day or insulin pump therapy.
 Such management must be under the direction of an endocrinologist, diabetologist, or
 diabetes specialist, with at least 3 clinical evaluations during the 12 months prior
 to study enrollment.

 7. At least one episode of severe hypoglycemia in the 12 months prior to study
 enrollment.

 8. Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more OR A HYPO
 score greater than or equal to the 90th percentile (1047) during the screening period;
 OR Marked glycemic lability characterized by wide swings in blood glucose (BG) despite
 optimal diabetes therapy and defined by an LI score greater than or equal to the 90th
 percentile (43 mmol/L2/h·wk-1) during the screening period; OR A composite of a Clarke
 score of 3 or less and a HYPO score greater than or equal to the 75th percentile (423)
 and a LI greater than or equal to the 75th percentile (329) during the screening
 period.

 Exclusion Criteria:

 1. Body Mass Index (BMI) >30 kg/m2 or patient weight ≤50 kg.

 2. Insulin requirement of >1.0 IU/kg/day or <15 U/day.

 3. HbA1c >10%.

 4. Untreated proliferative diabetic retinopathy.

 5. Blood Pressure: systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure
 (DBP) >100 mmHg.

 6. Measured glomerular filtration rate <80 mL/min/1.73 m2 calculated using the subject's
 measured serum creatinine and Chronic Kidney Disease Epidemiology Collaboration
 (CKD-EPI) equation1 or Modification of Diet in Renal Disease [MDRD] study estimation
 formula). Strict vegetarians (vegans) with a calculated GFR <70 mL/min/1.73m2 are
 excluded. The absolute (raw) GFR value will be used for subjects with body surface
 areas >1.73m2

 7. Presence or history of macroalbuminuria (>300mg/g creatinine).

 8. Presence or history of panel-reactive anti-HLA antibodies above background by flow
 cytometry.

 9. For female subjects: Serum or urine Positive pregnancy test, presently breast-feeding,
 or unwillingness to use effective contraceptive measures for the duration of the study
 and 4 months after discontinuation. For male subjects: intent to procreate during the
 duration of the study or within 4 months after discontinuation or unwillingness to use
 effective measures of contraception. If sexually active, subject must use at least two
 medically accepted methods of birth control from the following list: oral
 contraceptives, Norplant®, Depo-Provera®, intrauterine device (IUD), barrier devices
 with spermicide. Condoms used alone are not acceptable. Instead of the male condom, it
 is acceptable to use a female condom with one of the other methods for women listed
 above.

 10. Presence or history of active infection including hepatitis B, hepatitis C, HIV, or
 tuberculosis (TB) Subjects with laboratory evidence of active infection are excluded
 even in the absence of clinical evidence of active infection.

 11. Negative screen for Epstein-Barr Virus (EBV) by IgG determination.

 12. Invasive aspergillus, histoplasmosis, and coccidioidomycosis infection within one year
 prior to study enrollment.

 13. Any history of malignancy except for completely resected squamous or basal cell
 carcinoma of the skin.

 14. Known active alcohol or substance abuse.

 15. Baseline Hb below the lower limits of normal at the local laboratory; lymphopenia
 (<1,000/µL), neutropenia (<1,500/µL), or thrombocytopenia (platelets <100,000/µL).
 Participants with lymphopenia are allowed if the investigator determines there is no
 additional risk and obtain clearance from a hematologist.

 16. A history of Factor V deficiency.

 17. Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g.,
 warfarin) after transplantation (low-dose aspirin treatment is allowed) or patients
 with an international normalized ratio (INR) >1.5.

 18. Severe co-existing cardiac disease, characterized by any one of these conditions:

 1. recent myocardial infarction (within past 6 months).

 2. evidence of ischemia on functional cardiac exam within the last year.

 3. left ventricular ejection fraction <30%.

 19. Persistent elevation of liver function tests at the time of study entry. Persistent
 serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvate
 transaminase (SGPT [ALT]), Alk Phos or total bilirubin, with values >1.5 times normal
 upper limits will exclude a patient.

 20. Symptomatic cholecystolithiasis.

 21. Acute or chronic pancreatitis.

 22. Symptomatic peptic ulcer disease.

 23. Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders potentially
 interfering with the ability to absorb oral medications.

 24. Hyperlipidemia despite medical therapy (fasting low-density lipoprotein [LDL]
 cholesterol > 130 mg/dL (3.36 mmol/L), treated or untreated; and/or fasting
 triglycerides > 200 mg/dL (2.26 mmol/L)).

 25. Receiving treatment for a medical condition requiring chronic use of systemic
 steroids, except for the use of ≤5 mg prednisone daily, or an equivalent dose of
 hydrocortisone, for physiological replacement only.

 26. Treatment with any anti-diabetic medications other than insulin within 4 weeks of
 enrollment.

 27. Use of any investigational agents within 4 weeks of enrollment.

 28. Administration of live attenuated vaccine(s) within 2 months of enrollment.

 29. Any medical condition that, in the opinion of the investigator, will interfere with
 the safe participation in the trial.

 30. Treatment with any immunosuppressive regimen at the time of enrollment.

 31. A previous islet transplant.

 32. A previous pancreas transplant, unless the graft failed within the first week due to
 thrombosis, followed by pancreatectomy and the transplant occurred more than 6 months
 prior to enrollment.

 33. Inflammatory bowel disease.

 34. History of intestinal obstructions.

 35. Previous major abdominal surgery.

 36. History of peritonitis.