Islet Transplantation Using PKX-001

Prior treatment

• Active alcohol or substance abuse, to include cigarette smoking (must be abstinent for 6 months prior to listing for transplant).
• Evidence of significant sensitization on panel reactive antibody (PRA) (at the discretion of the investigator).
• Patients with Graves disease will be excluded unless previously adequately treated with radioiodine ablative therapy.

Other illness

• History of enrollment in any other islet transplant trials (at the discretion of the investigator).
• Psychiatric disorder making the patient not a suitable candidate for transplantation (e.g., schizophrenia, bipolar disorder, or major depression that is unstable or uncontrolled on current medication).
• History of non-adherence to prescribed regimens.
• Active infection including Hepatitis C, Hepatitis B, HIV, or Tuberculosis (TB) (subjects with a positive purified protein derivative (PPD) performed within one year of enrollment, and no history of adequate chemoprophylaxis).
• Any history of, or current malignancies except squamous or basal skin cancer.
• Positive pregnancy test, intent for future pregnancy or male subjects' intent to procreate, failure to follow effective contraceptive measures, or presently breast-feeding.
• Under treatment for a medical condition requiring chronic use of steroids.
• Untreated Celiac disease.

Lab values

• Severe co-existing cardiac disease, characterized by any one of these conditions: (a) recent (within the past 6months) myocardial infarction; (b) left ventricular ejection fraction \<30%; or (c) evidence of ischemia on functional cardiac exam.
• Measured glomerular filtration rate (GFR) \<60 mL/min/1.73 m2.
• Presence or history of macroalbuminuria (\>300 mg/g creatinine).
• Clinical suspicion of nephritic (hematuria, active urinary sediment) or rapidly progressing renal impairment (e.g. Increase in serum creatinine of 25% within the last 3-6 months).
• Baseline Hb \< 105g/L (\<10.5 g/dL) in women, or \< 120 g/L (\<12 g/dL) in men.
• Baseline screening liver function tests outside of normal range, with the exception of uncomplicated Gilbert's Syndrome. An initial liver function test (LFT) panel with any values \>1.5 times the upper limit of normal (ULN) will exclude a patient without a re-test; a re-test for any values between ULN and 1.5 times ULN should be made, and if the values remain elevated above normal limits, the patient will be excluded.
• HbA1C \>12%.
• Uncontrolled hyperlipidemia \[fasting LDL cholesterol \> 3.4 mmol/L (133 mg/dL), treated or untreated; and/or fasting triglycerides \> 2.3 mmol/L (90 mg/dL)\].
• Use of coumadin or other anticoagulant therapy (except aspirin) or patient with prothrombin time (PT) / international normalized ratio (INR) \> 1.5.

Age

• Age less than 18 or greater than 68 years.

Other

• BMI \> 35 kg/m2 at screening visit.
• Untreated proliferative retinopathy.
• Insulin requirement \>1.0 U/kg/day

• To be eligible the participant must have had type 1 diabetes mellitus (T1DM) for more than 5 years, complicated by at least 1 of the following situations that persist despite intensive insulin management efforts:
  • Reduced awareness of hypoglycemia, as defined by the absence of adequate autonomic symptoms at plasma glucose levels \< 3.0 mmol/L, indicated by, 1 or more episodes of severe hypoglycemia requiring third party assistance within 12 months, a Clarke score ≥4, hypoglycemic (HYPO) score ≥1,000, lability index (LI) ≥400 or combined HYPO/LI \>400/\>300.
  • Metabolic instability, characterized by erratic blood glucose levels that interfere with daily activities and/or 1 or more hospital visits for diabetic ketoacidosis over the last 12 months.
  • Participants must be capable of understanding the purpose and risks of the study and must sign a statement of informed consent.
• Retrospective Control Inclusion Criteria:
  • All control participants will be included according to the immunosuppression / engraftment regimen used in this pilot, specifically the current standard of care islet transplant at the University of Alberta Hospital: Alemtuzumab/Basiliximab, Anakinra, Etanercept, Mycophenolate Mofetil and Tacrolimus.