Multicenter Trial of the Effect of AAT on Islet Transplant Engraftment and Durability After Renal Transplant

Inclusion Criteria:

- Male and female subjects age 18 to 70 years.

- Subjects who are able to provide written informed consent and to comply with the
procedures of the study protocol.

- Subjects must have one of the following payment mechanisms in place:

1. Medicare,

2. A third-party insurer who agrees, via pre-authorization, to pay for participation
in the study, or

3. Another mechanism of payment (self-pay, hospital, university, donations, etc.)
for participation in the study.

- Clinical history compatible with T1D with disease onset < 40 years of age and
insulin-dependence for ≥ 5 years at the time of enrollment.

- Absent stimulated c-peptide (< 0.3 ng/mL) in response to a MMTT [Boost® 6 mL/kg body
weight (BW) 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 start
of consumption.

- Subjects who are ≥ 3 months post-renal transplant who are taking appropriate
calcineurin inhibitor (CNI) based maintenance immunosuppression ([tacrolimus alone or
in conjunction with sirolimus, mycophenolate mofetil, myfortic, or azathioprine; or
cyclosporine in conjunction with sirolimus, mycophenolate mofetil, or myfortic] ±
Prednisone ≤ 10 mg/day).

- Stable renal function as defined by a creatinine of no more than one third greater
than the average creatinine determination performed in the 3 previous months prior to
islet transplantation, until rejection, obstruction or infection is ruled out.

- Subjects who meet one of the options in the following criterion are eligible for
transplantation:

- Reduced awareness of hypoglycemia manifested by a Clarke score of 4 or more
measured upon study enrollment and at least one episode of severe hypoglycemia in
the 12 months prior to study enrollment.

- A subject must have a reduced awareness of hypoglycemia manifested by a Clarke
score of 4 or more and at least 1 episode of severe hypoglycemia;

- Any subject not meeting the hypoglycemia option must have an HbA1c > 7.5%.

Exclusion Criteria:

- Weight more than 100 kg or body mass index (BMI) > 33 kg/m2.

- Insulin requirement of >1.0 U/kg/day or, > 60 U/day total, or <15 U/day.

- Other (non-kidney) organ transplants except prior failed pancreatic graft where graft
failure is attributed to thrombosis within the first 4 weeks or to other technical
reasons that require graft pancreatectomy; with the graft pancreatectomy occurring
more than 6 months ago.

- Untreated or unstable proliferative diabetic retinopathy.

- Blood Pressure: SBP > 160 mmHg or DBP >100 mmHg despite treatment with
antihypertensive agents.

- Calculated GFR of ≤ 40 mL/min/1.73 m2 using the subject's measured serum creatinine
and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation1. Strict
vegetarians (vegans) will be excluded only if their estimated GFR is ≤ 35 mL/min/1.73
m2.

7. Proteinuria (albumin/creatinine ratio or ACr > 300mg/g) of new onset since kidney
transplantation.

- Calculated panel-reactive anti-HLA antibodies > 50%. Subjects with calculated panel
reactive anti-HLA antibodies ≤ 50% will be excluded if any of the following are
detected:

- Positive cross-match,

- Islet donor-directed anti-HLA antibodies detected by Luminex Single
Antigen/specificity bead assay including weakly reactive antibodies that would
not be detected by a flow cross-match, or

- Antibodies to the renal donor (i.e. presumed de novo).

- For female subjects: 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. Oral contraceptives, Norplant®, Depo-Provera®,
and barrier devices with spermicide are acceptable contraceptive methods; condoms used
alone are not acceptable.

- 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.

- Negative screen for Epstein-Barr virus (EBV) by IgG determination at time of screening
or previous kidney transplant.

- Invasive aspergillus, histoplasmosis, and coccidoidomycosis infection within the last
year.

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

- Known active alcohol or substance abuse.

- Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g.
warfarin) after islet transplantation (low-dose aspirin treatment [325 mg PO] is
allowed) or subjects with international normalized ratio (INR) > 1.5. The use of
Plavix is allowed only in conjunction with mini- laparotomy procedure at the time of
islet transplant.

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

- Recent MI (within past 6 months);

- Evidence of ischemia on functional cardiac exam within the last year;

- Left ventricular ejection fraction < 30%; or

- Valvular disease requiring replacement with prosthetic valve.

- Persistent serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate
pyruvate transaminase (SGPT [ALT],) alkaline phosphatase or total bilirubin, with
values > 1.5 times normal upper limits will exclude a subject.

- Active infections (except mild skin and nail fungal infections).

- Acute or chronic pancreatitis.

- Active peptic ulcer disease, symptomatic gallstones, or portal hypertension.

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

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

- Any medical condition that, in the opinion of the investigator, will interfere with
the safe participation in the trial. (Cancer screenings should be performed per
current American Cancer Society guidelines).

- Positive screen for BK virus by polymerase chain reaction (PCR) performed at time of
screening.

- A kidney transplant patient with type 1 diabetes who has an HbA1c < 7.5 and no history
of severe hypoglycemia.

- Selective or severe IgA deficiency (levels < 5-7 mg/dL)

- AAT deficiency (defined as < 1.0ng/mg AAT)