Aralast NP in Islet Transplant

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.

Inclusion criteria

• 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, 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.

Exclusion criteria

• Hypersensitivity to Aralast NP, history of immunoglobulin A (IgA) deficiency, or assessed low IgA (< 0.70 g/L).
• 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.
• Active alcohol or substance abuse, to include cigarette smoking (must be abstinent for 6 months prior to listing for transplant).
• Psychiatric disorder making the subject 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.
• BMI > 35 kg/m2 at screening visit.
• Age less than 18 or greater than 68 years.
• Measured glomerular filtration rate <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 < 105 g/L in women, or < 120 g/L in men.
• Baseline screening liver function tests (LFT) outside of normal range, with the exception of uncomplicated Gilbert's Syndrome. An initial 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.
• Untreated proliferative retinopathy.
• Positive pregnancy test, intent for future pregnancy or male subjects' intent to procreate, failure to follow effective contraceptive measures, or presently breast-feeding.
• Previous transplant or evidence of significant sensitization on panel reactive antibody (PRA) (at the discretion of the investigator).
• Insulin requirement >1.0 U/kg/day
• Hemoglobin A1c (HbA1c) >12%.
• Uncontrolled hyperlipidemia [fasting LDL cholesterol > 3.4 mmol/L, treated or untreated; and/or fasting triglycerides > 2.3 mmol/L)].
• Under treatment for a medical condition requiring chronic use of steroids.
• Use of coumadin or other anticoagulant therapy (except aspirin) or subject with prothrombin time / international normalized ratio (PT/INR) > 1.5.
• Untreated Celiac disease.
• Patients with Graves disease will be excluded unless previously adequately treated with radioiodine ablative therapy.