Autoimmune Diseases, Diabetes Mellitus, Type 1, Glucose Metabolism Disorders (Including Diabetes Mellitus), Hypoglycemia, Hypoglycemic Episode, Immune System Diseases, Islet Cell Transplantation, Islet Transplantation in Diabetes Mellitus Type 1, Metabolic Disease, Severe Hypoglycemia, T1D, T1DM, T1DM - Type 1 Diabetes Mellitus, Type 1 Diabetes, Type 1 Diabetes Mellitus, Type 1 Diabetes (T1D), Xenotransplantation
Conditions
Keywords
Diabetes Mellitus, Diabetes Mellitus, Type1, T1DM, Hypoglycemia, islet cell transplantation, pig islet cell transplantation, Xenotransplantation, Porcine islet cell transplantation, Type 1 Diabetes Mellitus, Type 1 Diabetes
Brief summary
This study is First In Human study for Encapsulated Porcine Islet Cells for Xenotransplantation (OPF-310). The purpose of this study to assess the safety, tolerability, and efficacy of OPF-310 transplantation and to define the recommended Phase 2 dose (RP2D) in adult subjects with unstable Type 1 Diabetes Mellitus (T1DM) and a level 3 (severe) hypoglycemic episode at least three times within the 1 year prior to enrollment despite treatment with a closed loop system (CLS) for at least 6 months.
Interventions
COMBINATION_PRODUCTOPF-310
Dose(Part1): 6,000 islet equivalents (IEQ)/kg or 12,000 islet equivalents (IEQ)/kg Dose(Part2): Recommended Phase II Dose(RP2D), which will be determined based on the data of Part1 * In Part1, three subjects will be enrolled into the first dosing cohort (Cohort 1: 6,000 IEQ/kg) and they will undergo safety monitoring. Three subjects in Cohort 2 will be dosed with 12,000 IEQ/kg and will undergo safety monitoring. * In Part2, 7 subjects will be enrolled into the Part 2 dose-expansion part.
Sponsors
Otsuka Pharmaceutical Factory, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A Phase I/IIa, Single site, Open-Label, Ascending Dose Study
Eligibility
Sex/Gender
ALL
Age
35 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Subject must be aged 35 to 70 years of age inclusive, at the time of signing the informed consent. 2. 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. 3. If one of the following criteria (either a or b) applies: 1. 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. 2. 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. 4. If one of the following criteria (either a, b or c) applies: 1. 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. 2. 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. 3. 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. 5. Subject has C-peptide \<0.3 ng/mL following a mixed meal tolerance test or undetectable fasting C-peptide. 6. Hemoglobin A1C (HbA1c) ≤ 9.0 7. Contraceptive use must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies 8. Subject who can agree to cooperate with lifetime follow-up after transplantation. 9. Subject is capable of providing signed informed consent
Exclusion criteria
1. Previous history of insulin resistance (defined as an average insulin dose requirement ≥ 0.8 unit/kg/day for 1 week prior to enrollment). 2. Subject has latent autoimmune diabetes in adults (LADA), ketosis-prone (Flatbush) diabetes, or maturity onset diabetes of the young (MODY). 3. CRP ≥ 10 mg/L. 4. 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. 5. History of malignancies within the past 5 years, excluding basal and squamous cell carcinoma 6. Positive serologies or nucleic acid testing for human immunodeficiency virus (HIV), hepatitis C, and hepatitis B. 7. Active or untreated proliferative diabetic retinopathy. Subjects may be rescreened once they are successfully treated. 8. Serious comorbid conditions that are likely to affect participation in the study, including: 1. Within the last 12 months, peripheral vascular disease with previous amputation. 2. History of New York Heart Association (NYHA) class II, III or IV congestive heart failure (CHF) and/or chronic atrial fibrillation. 3. 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. 4. Macroalbuminuria (\> 300 mg albumin/gm creatinine). 5. 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. 9. Use of warfarin or other anticoagulant therapy (except aspirin), or prothrombin time and international normalized ratio (PT-INR) \> 1.5 10. Adrenal insufficiency being treated with corticosteroids 11. Previous pan-peritonitis 12. 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: 1. Recent myocardial infarction (within past one year), or 2. Angiographic evidence of non-correctable coronary artery disease, or 3. Evidence of ischemia on functional cardiac exam (with a stress echo test recommended for subjects with a history of ischemic disease), or 4. 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. 13. Patients with hematopoietic stem cell abnormalities (e.g., aplastic anemia, myelodysplastic syndrome) 14. 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. 15. Previous receipt of an organ, skin allograft, or other tissue transplant from an allogeneic human or animal donor. 16. Treatment with immunosuppressive medication. 17. Previous abdominal surgery, excluding uncomplicated appendectomy, cholecystectomy, exploratory laparoscopy and hernia repair performed prior to 12 weeks prior to enrollment. 18. Treatment with any hypoglycemic medication prescribed for glycemic control, other than insulin therapy. 19. Treatment with acetaminophen or hydroxycarbamide. 20. 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. 21. Subject has history of allergy to antibiotics (Amphotericin B, Cefazolin, Ciprofloxacin, Gentamicin), which are used during manufacture of OPF-310. 22. Previous history of insulin allergy (including porcine insulin), pork product allergy or alginate/seaweed allergy. 23. Panel reactive antibodies (PRA) \> 80 %. 24. Active drug, substance or alcohol addiction. 25. Body mass index (BMI) \>27 kg/m2. 26. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Reaching the Efficacy Goal | One year after transplant | A successful primary endpoint was defined as achieve both an HbA1c \< 7 % and a reduction of at least 0.5% from baseline, and absence of a Level 3 (severe) hypoglycemic episode from 12 weeks to 52 weeks post-transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Psychological impact as assessed by the Diabetes Distress Scale (DDS) and the Hypoglycemic Fear Survey (HFS) at each measuring point. | For one year after transplant | Patient Quality of Life Assessment with DDS and HFS |
| Percentage of subjects with improved awareness of hypoglycemia, as defined by a change in Clarke questionnaire score from ≥ 4 to < 4. | For one year after transplant | — |
| Percentage of subjects with an HbA1c ≤ 6.5 % assessed at 52 weeks post-transplant | One year after transplant | — |
| Percentage of subjects with positive porcine C-peptide qualitatively assessed by digital ELISA assay | One year after transplant | — |
| Percentage reduction in nocturnal hypoglycemic event rate | 12 week, 24 week 52 weeks after transplant | Change from baseline in nocturnal hypoglycemic event rate specified in the protocol |
| Percentage improvement in time below range (<70 mg/dl) by continuous glucose monitoring (CGM) | 12 week, 24 week 52 weeks after transplant | Change from baseline in the CGM data specified in the protocol |
| Percentage improvement in time in range (70-180 mg/dl) by CGM | 12 week, 24 week 52 weeks after transplant | Change from baseline in the CGM data specified in the protocol |
| Percentage improvement in time above range (>180 mg/dl) by CGM | 12 week, 24 week 52 weeks after transplant | Change from baseline in the CGM data specified in the protocol |
| Change in mean amplitude of glycemic excursion (MAGE) by CGM. | 12 week, 24 week 52 weeks after transplant | Change from baseline in MAGE based on the CGM data specified in the protocol |
| Percentage reduction in daily average of insulin use | 12 week, 24 week 52 weeks after transplant | Change from baseline in insulin use specified in the protocol |
| Values of porcine C-peptide, human c-peptide, and glucose during mixed meal tolerance test (MMTT) and Intravenous Glucose Tolerance Test (IVGTT) at each measuring point | For one year after transplant | Assesment of glucose metabolism function |
| Percentage of subjects with an HbA1c < 7.0 % assessed at 52 weeks post-transplant | One year after transplant | — |
Countries
United States
Contacts
CONTACTFor participant-focused inquiries, please contact:
CONTACTFor physician or professional inquiries, please contact:
Outcome results
None listed