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

The Cell Pouch™ is a novel implantable device, that is transplanted with therapeutic cells such as insulin producing islets. This combination product is designed for the treatment of Type 1 Diabetes Mellitus (T1D) with hypoglycemia unawareness and a history of severe hypoglycemic episodes. Upon implantation, the Cell Pouch is designed to form a natural environment, rich in tissue and microvessels for the transplant and function of therapeutic cells. The Cell Pouch is designed as a scaffold made of non-degradable polymers, formed into small cylindrical chambers which, when implanted against the abdominal muscle, becomes incorporated with vascularized tissue to the circumference of removable plugs within as early as two weeks as demonstrated in preclinical studies. After the tissue incorporation, the plugs are removed, leaving fully formed tissue chambers with central void spaces for the transplantation of therapeutic cells including Islets of Langerhans (islets). Tissue integration within and around the Cell Pouch forms a natural environment, rich in microvessels that allows the transplanted islets to engraft, resulting in a functional biohybrid organ. It is believed this engraftment will enable long-term survival and function of transplanted islets. This study aims to demonstrate the safety and tolerability of islet transplantation into the Cell Pouch for the treatment of T1D in subjects with hypoglycemia unawareness and a history of severe hypoglycemic episodes. The study also aims to establish islet release criteria that accurately characterize the islet product and are predictive of clinical transplant outcomes into the Cell Pouch, which will be demonstrated through defined efficacy measures.

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).

Eligibility Criteria:
Inclusion Criteria:

1. Male and female patients 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 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.
5. Absent stimulated c-peptide (\<0.3 ng/mL) in response to a mixed meal tolerance test (MMTT; measured during the 4 hour test).
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 consent.
7. At least one episode of severe hypoglycemia in the 12 months prior to study consent.
8. Reduced awareness of hypoglycemia. More information about this criterion, including specific definitions of hypoglycemia unawareness, is in the protocol.

Exclusion Criteria:

1. Body mass index (BMI) \>30 kg/m2
2. Insulin requirement \>1.0 IU/kg/day
3. Glycated Haemoglobin (HbAlc) \>13%.
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 \<70 mL/min/1.73m2 (More information about this criterion is in the protocol
7. Presence or history of macroalbuminuria (\>300 mg/g creatinine).
8. Presence or history of panel-reactive anti-HLA antibodies \>30%
9. 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.
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. Patients with negative screen for Epstein Barr Virus by Immunoglobulin G (IgG) determination. More information about this criterion is in the protocol,
12. Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year prior to study consent.
13. Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
14. Active smoking, vaping or marijuana use or known active alcohol or substance abuse.
15. Baseline Hb below the lower limits of normal at the local laboratory for patients initially being enrolled into study.
16. 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
17. Uncontrolled hyperlipidemia (fasting LDL cholesterol \>130mg/dL and/or fasting triglycerides \>200mg/dL).
18. Persistent elevation of liver function tests. More information on this criterion is in the protocol
19. Severe unremitting diarrhea, vomiting or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications (for example untreated celiac disease).
20. Untreated Graves' disease
21. Portal hypertension
22. 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.
23. Treatment with any anti-diabetic medication other than insulin within 4 weeks of transplant, More information on this criterion is in the protocol
24. Use of any investigational agents within 4 weeks of consent
25. Administration of live attenuated vaccine(s) within 2 months of consent.
26. Any medical condition that, in the opinion of the study investigator, will interfere with safe participation in the trial.
27. Treatment with any immunosuppressive regimen at the time of consent.
28. A previous islet transplant.
29. A previous pancreas transplant. More information on this criterion is in the protocol
30. Known allergy or hypersensitivity to polymers More information on this criterion is in the protocol
31. Islets from non-heart beating donors will be excluded as well as from CDC high-risk donors.
32. Presence of colostomy/ileostomy, incisional hernia or other deformity of the abdominal wall precluding implantation of the Cell Pouch.
33. History of malignant hypertension or other conditions precluding general anesthesia.
34. Use of coumadin or other anticoagulant therapy (except aspirin) or subject with prothrombin time (PT-INR) \> 1.5.