A Study to Investigate Safety and Effectiveness of Porcine Pancreatic Cells (OPF-310) in Patients With Type 1 Diabetes Mellitus

Prior treatment

• Previous history of insulin resistance (defined as an average insulin dose requirement ≥ 0.8 unit/kg/day for 1 week prior to enrollment).
• Adrenal insufficiency being treated with corticosteroids
• Previous pan-peritonitis
• Previous cardiovascular or cerebrovascular disease. NOTE: For the purposes of this exclusion criterion, "previous cardiovascular disease" is defined as the presence of co-existing cardiac disease, characterized by any of the following conditions:
  • Recent myocardial infarction (within past one year), or
  • Angiographic evidence of non-correctable coronary artery disease, or
  • Evidence of ischemia on functional cardiac exam (with a stress echo test recommended for subjects with a history of ischemic disease), or
  • Heart failure \> NYHAII For subjects aged 65 to \<70 years who do not meet Exclusion Criterion 12 but have a history of cardiovascular or cerebrovascular disease related to the conditions above, a cardiology consultation (and consultation with other relevant specialists, as appropriate) will be required during the screening period to confirm suitability for general anesthesia and laparoscopic surgery.
• Patients who received a blood transfusion in the previous 90 days, are anticipated to undergo surgery during the 1-year study period that may require transfusion, or have donated blood within the previous 90 days.
• Previous receipt of an organ, skin allograft, or other tissue transplant from an allogeneic human or animal donor.
• Treatment with immunosuppressive medication.
• Previous abdominal surgery, excluding uncomplicated appendectomy, cholecystectomy, exploratory laparoscopy and hernia repair performed prior to 12 weeks prior to enrollment.
• Treatment with any hypoglycemic medication prescribed for glycemic control, other than insulin therapy.
• Treatment with acetaminophen or hydroxycarbamide.
• Use of any investigational products within 12 weeks of enrollment (before entering run-in) or 5 half-lives of the investigational product, whichever is greater.
• Previous history of insulin allergy (including porcine insulin), pork product allergy or alginate/seaweed allergy.
• Panel reactive antibodies (PRA) \> 80 %.
• Active drug, substance or alcohol addiction.

Other illness

• Subject has latent autoimmune diabetes in adults (LADA), ketosis-prone (Flatbush) diabetes, or maturity onset diabetes of the young (MODY).
• Clinically unstable thyroid disease (thyroid stimulating hormone (TSH)\< the lower limit of the normal range of TSH at the site.) Patients with subclinical hyperthyroidism can be rescreened once TSH levels normalize due to treatment or other factors.
• History of malignancies within the past 5 years, excluding basal and squamous cell carcinoma
• Positive serologies or nucleic acid testing for human immunodeficiency virus (HIV), hepatitis C, and hepatitis B.
• Patients with hematopoietic stem cell abnormalities (e.g., aplastic anemia, myelodysplastic syndrome)
• Subject has history of allergy to antibiotics (Amphotericin B, Cefazolin, Ciprofloxacin, Gentamicin), which are used during manufacture of OPF-310.
• Any other condition that, in the opinion of the Investigator, may interfere with adherence to the study protocol, including dementia, psychiatric disorder, medical condition, or a history of non-adherence to appointments or treatments

Lab values

• Serious comorbid conditions that are likely to affect participation in the study, including:
  • Within the last 12 months, peripheral vascular disease with previous amputation.
  • History of New York Heart Association (NYHA) class II, III or IV congestive heart failure (CHF) and/or chronic atrial fibrillation.
  • Chronic obstructive pulmonary disease (COPD) or asthma with previous hospitalization for decompensation; a requirement for mechanical ventilation at any stage; or long- term treatment with oral corticosteroids.
  • Macroalbuminuria (\> 300 mg albumin/gm creatinine).
  • Estimated glomerular filtration rate (eGFR) cut-off of \< 30 ml/min for all per Kidney Disease Improving Global Outcomes (KDOQI) and Kidney Disease Outcomes Quality Initiative (KDIGO) consensus.
• Use of warfarin or other anticoagulant therapy (except aspirin), or prothrombin time and international normalized ratio (PT-INR) \> 1.5

Other

• CRP ≥ 10 mg/L.
• Active or untreated proliferative diabetic retinopathy. Subjects may be rescreened once they are successfully treated.
• Body mass index (BMI) \>27 kg/m2.

• Subject must be aged 35 to 70 years of age inclusive, at the time of signing the informed consent.
• Subject has an established diagnosis of type 1 diabetes mellitus (T1DM) (in accordance with the American Diabetes Association's criteria), with a minimum duration since diagnosis of 5 years.
• If one of the following criteria (either a or b) applies:
  • Subject has unstable T1DM, not achieving adequate control after receiving CLS (CGM:Dexcom G6, insulin pump: Omnipod® 5 or t:slim X2) under care of a qualified diabetes team for at least 6 months prior to enrollment.
  • Subject has unstable T1DM, not achieving adequate control after receiving CLS (CGM:Dexcom G7, insulin pump: Omnipod® 5, t:slim X2, iLet Bionic Pancreas or The Tandem Mobi System) under care of a qualified diabetes team for at least 6 months prior to enrollment.
• If one of the following criteria (either a, b or c) applies:
  • Subject has had a Level 3 (severe) hypoglycemic episode (defined as having cognitive impairment requiring external assistance for recovery) at least three times within the 1 year prior to enrollment recorded in the medical record or patient log.
  • Subject has had a Level 3 (severe) hypoglycemic episode at least once within the 1 year prior to enrollment and demonstrates a Clarke Score ≥4, assessed by trained study personnel. The SHE(s) and Clarke Score must be recorded in the medical record or patient log.
  • Subject has had TBR \>1% at glucose levels below 70mg/dL and demonstrates a Clarke Score≥4, assessed by trained study personnel. TBR data used for screening and Clarke score must be recorded in the medical record or patient log.
• Subject has C-peptide \<0.3 ng/mL following a mixed meal tolerance test or undetectable fasting C-peptide.
• Hemoglobin A1C (HbA1c) ≤ 9.0
• Contraceptive use must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
• Subject who can agree to cooperate with lifetime follow-up after transplantation.
• Subject is capable of providing signed informed consent