A Safety, Tolerability and Efficacy Study of Sernova's Cell Pouch™ for Clinical Islet Transplantation

The Sernova Cell Pouch is implanted against the abdominal musculature. A minimum of three weeks after Cell Pouch implantation, immunosuppression is initiated and optimized for another 3 weeks. This allows for vascularization of the Cell Pouch chambers and for the patient to be stabilized on immunosuppression prior to islet transplantation. A mass of highly purified islets will be transplanted in the Cell Pouch. The Cell Pouch will be assessed for safety and tolerability for up to five years (recently increased from 3 years) following the last transplant to Cell Pouch. Data for the primary and secondary endpoints will be summarized using descriptive statistics (such as counts and percentages).

Inclusion criteria

• Male and female patients 18 to 65 years of age.
• Ability to provide written informed consent.
• Mentally stable and able to comply with the procedures of the study protocol.
• Clinical history compatible with Type 1 Diabetes Mellitus (T1DM) with onset of disease at <40 years of age, insulin-dependence for ≥5 years at the time of consent, and a sum of patient age and insulin dependent diabetes duration of ≥28.
• Absent stimulated c-peptide (<0.3 ng/mL) in response to a mixed meal tolerance test (MMTT; measured during the 4 hour test).
• 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 consent.
• At least one episode of severe hypoglycemia in the 12 months prior to study consent.
• Reduced awareness of hypoglycemia. More information about this criterion, including specific definitions of hypoglycemia unawareness, is in the protocol.

Exclusion criteria

• Body mass index (BMI) >30 kg/m2
• Insulin requirement >1.0 IU/kg/day
• Glycated Haemoglobin (HbAlc) >13%.
• Untreated proliferative diabetic retinopathy.
• Blood Pressure: Systolic blood pressure (SBP) >160 mmHg or Diastolic Blood Pressure (DBP) >100 mmHg.
• Measured glomerular filtration rate <70 mL/min/1.73m2 (More information about this criterion is in the protocol
• Presence or history of macroalbuminuria (>300 mg/g creatinine).
• Presence or history of panel-reactive anti-HLA antibodies >30%
• For female subjects of child bearing potential: 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. More information about this criterion is in the protocol.
• 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.
• Patients with negative screen for Epstein Barr Virus by Immunoglobulin G (IgG) determination. More information about this criterion is in the protocol,
• Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year prior to study consent.
• Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
• Active smoking, vaping or marijuana use or known active alcohol or substance abuse.
• Baseline Hb below the lower limits of normal at the local laboratory for patients initially being enrolled into study.
• Severe co-existing cardiac disease, characterized by any one of these conditions:

• Recent myocardial infarction (within past 6 months).
• Left ventricular ejection fraction <30%.
• Uncontrolled coronary artery disease.
• Known hypercoagulative state or
• International Normalized Ratio > 1.8
• Uncontrolled hyperlipidemia (fasting LDL cholesterol >130mg/dL and/or fasting triglycerides >200mg/dL).
• Persistent elevation of liver function tests. More information on this criterion is in the protocol
• Severe unremitting diarrhea, vomiting or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications (for example untreated celiac disease).
• Untreated Graves' disease
• Portal hypertension
• 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.
• Treatment with any anti-diabetic medication other than insulin within 4 weeks of transplant, More information on this criterion is in the protocol
• Use of any investigational agents within 4 weeks of consent
• Administration of live attenuated vaccine(s) within 2 months of consent.
• Any medical condition that, in the opinion of the study investigator, will interfere with safe participation in the trial.
• Treatment with any immunosuppressive regimen at the time of consent.
• A previous islet transplant.
• A previous pancreas transplant. More information on this criterion is in the protocol
• Known allergy or hypersensitivity to polymers More information on this criterion is in the protocol
• Islets from non-heart beating donors will be excluded as well as from CDC high-risk donors.
• Presence of colostomy/ileostomy, incisional hernia or other deformity of the abdominal wall precluding implantation of the Cell Pouch.
• History of malignant hypertension or other conditions precluding general anesthesia.
• Use of coumadin or other anticoagulant therapy (except aspirin) or subject with prothrombin time (PT-INR) > 1.5.