Tolerance to Islet Allotransplants in Diabetes

Evaluation of the Efficacy and Safety of ToleraCell (Apoptotic Donor Leukocytes) and Induction Immunosuppression With Anti-CD40 Monoclonal Antibody DFI105, Sirolimus, Etanercept, and Tocilizumab for Induction of Tolerance to Islet Allotransplants in Subjects With Predominantly β-Cell Failure-mediated Type 2 Diabetes

The goal of this phase 1, first-in-human, interventional study is to test if the therapy can allow for successful islet transplantation from an unrelated donor without the use of long-term immunosuppression (or induce tolerance to islets). The study will examine results of six islet transplants performed in patients with a specific form of insulin-dependent type 2 diabetes. The main questions it aims to answer are:

• Is the tolerance inducing therapy safe; and
• Can the tolerance inducing therapy allow for the transplanted islets to survive and produce insulin without the use of the long-term immunosuppression commonly used after islet transplant.

Participants will be asked to undergo islet transplant and repeat metabolic testing (requires hospitalization), track their blood glucose with a study provided continuous glucose monitor, and self-administer some of the therapy drugs. Over 75 days, treatments given in addition to standard of care for islet transplant (only if a suitable transplant donor is identified) are:

An experimental cell therapy made from the donor's spleen (ToleraCell) An experimental antibody (DFI-105) Three other drugs that have been previously used in islet transplantation (sirolimus, etanercept, tocilizumab) Researchers will track your blood glucose, metabolic status, and insulin use over one year post-transplant and follow your overall health status for 5 years.

Study Overview

• Status: Not yet recruiting
• Conditions: Diabetes Mellitus Type 2 - Insulin-Treated
• Intervention / Treatment: Biological: ToleraCell-001; Biological: ToleraCell-002; Drug: DFI-105; Drug: Etanercept; Drug: Tocilizumab; Drug: Sirolimus

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Clinical history compatible with predominantly β-cell failure-mediated type 2 diabetes (PBF-T2D), with onset of disease at 31 to 60 years of age, <5 years from diagnosis to insulin use, and with insulin dependence for ≥5 years at the time of enrollment
• Low islet β-cell mass, indicated by acute C-peptide response to IV arginine of <1.0 ng/mL
• Low islet β-cell function, defined by β-cell responsivity index ≤10 x10e-9 min-1, estimated from plasma glucose and C-peptide concentrations measured during a mixed meal tolerance test by using the oral C-peptide minimal model
• Partially preserved insulin sensitivity, defined as SI ≥10 x10e-5 dL/kg/min per pmol/L, from plasma glucose and insulin concentrations measured during the MMTT by using the oral minimal model.

• Absence of autoimmune etiology of diabetes (type 1 diabetes, late autoimmune diabetes in adults, or severe autoimmune diabetes), suggested by meeting the following three criteria:

  1. No first degree relative diagnosed with T1D
  2. No detectable islet cell antibodies (ICA) and no GADA, IA-2A, and ZnT8A islet autoantibodies (positive IAA alone are not indicative of autoimmune etiology of diabetes in insulin-treated individuals)
  3. Low type 1 diabetes genetic risk score 2 (GRS2) of <8
• Involvement in intensive diabetes management defined as self-monitoring of glucose values, including continuous glucose monitoring (CGM) with the CGM device being utilized at least 70% of the time for approximately 10 days per month, and by administration of 3 or more insulin injections each day or insulin pump therapy. Such management must be under the direction of an endocrinologist with at least 3 clinical evaluations during the 12 months prior to study enrollment.

• Not meeting glycemic goals (ADA 2023) despite intensive diabetes management, patient compliance, and considering patient and disease factors, indicated by meeting one of the following criteria:

  • Inability to achieve and maintain HbA1c levels <8.0%.
  • Inability to achieve and maintain HbA1c levels <7.0% in previous 12 months without spending >1.0% time in Level 2 hypoglycemia or experiencing severe hypoglycemic episodes.
  • At least one unexplained severe hypoglycemic event (defined as neuroglycopenia requiring active intervention for treatment from a third party) (Seaquist 2013) or a pattern of unexplained and recurrent Level 2 hypoglycemia (<54 mg/dL) in previous 12 months, or documentation of Level 1 hypoglycemia (<70 mg/dL) for >8.0% of time, or documentation of Level 2 hypoglycemia for >2.0% of time during the screening period.
  • Daytime (0600 am to 1159 pm) glucose time in range (70-180 mg/dL), ≤50%
  • Daytime (0600 am to 1159 pm) glucose time above range >250 mg/dL, ≥10%
  • Marked glycemic lability characterized by wide swings in blood glucose defined by a daytime (0600 am to 1159 pm) lability index score, mean amplitude of glycemic excursion (MAGE), or glucose coefficient of variation (CV) derived from CGM greater than or equal to the 75th percentile in a reference T2D cohort during the
• Fluent in English.
• Mentally stable and able to comply with the procedures of the study protocol.
• Consistent use of CGM for at least 4 weeks before screening for study eligibility.
• Willingness to use the study-provided professional CGM system for a minimum of 20 consecutive days during the pretransplant screening period and for a minimum of 14 consecutive days immediately posttransplant and every 3 months thereafter with more than 70% data obtainment throughout the posttransplant study follow-up and as instructed and willingness to comply with system requirements for the duration of the study.
• Willing and able to comply with daily entries on a study diary. The subject must demonstrate compliance with daily entries on the diary between Visits 2 and 3
• Willing and able to comply with all scheduled visits, treatment plans, laboratory tests, fingerstick blood glucose monitoring, and other study procedures.
• Ability to provide written informed consent, indicating the subject has been informed of all aspects of the trial.

Exclusion Criteria:

• Body weight more than 80 kg or body mass index (BMI) >30 kg/m2
• Insulin requirements >0.8 units/kg/day or <15 U/day.
• Screening urine C-peptide creatinine ratio 120 minutes post MMTT ≥0.6 nmol/mmol
• HbA1c >9.0%.
• Subjects with substantial glycemic dysregulation, manifested by at least one episode of diabetic ketoacidosis in the year prior to enrollment.
• Untreated or unstable proliferative diabetic retinopathy.
• Presence or history of foot ulcers or amputations.
• Presence or history of severe peripheral neuropathy.
• Presence or history of panel-reactive anti-HLA antibodies above background by flow cytometry, positive cross-match, or presence or history of antibodies with demonstrated donor specificity using Luminex Single Antigen Bead (SAB) assays with a MFI >500 HLA antibody screening will be repeated regularly while on waiting list.
• Presence or history of donor-specific antibodies detected by Luminex SAB assay or a flow cytometry or complement-dependent cytotoxicity (CDC) crossmatch.
• Pre-existing donor HLA-specific memory B cells detected by donor-specific HLA antibodies via Luminex SAB assay in culture supernatants of polyclonally stimulated recipient peripheral blood lymphocytes (PBLs).
• IFN-γ ELISpot indicative of pre-existing direct or indirect pathway T cell sensitization against a panel of donors (followed post first ADL infusion by assay against actual donor using patient's baseline PBLs).
• A previous islet cell, kidney, pancreas, and/or another cell or organ transplant.
• Presence or history of active infections, including hepatitis B, hepatitis C, human immunodeficiency virus (HIV), human T-cell lymphotrophic viruses (HTLV1 and HTLV2) or tuberculosis. Subjects with laboratory evidence of active infection are excluded even in the absence of clinical evidence of active infection. Subjects with mild skin and nail fungal infections are not excluded.
• Negative screen for Epstein-Barr virus (EBV) by immunoglobulin G (IgG) determination.
• Negative screen for cytomegalovirus (CMV) by IgG determination.
• Invasive aspergillus, histoplasmosis, or coccidiomycosis infection within one year prior to enrollment.
• Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
• Male subjects with elevation of prostate-specific antigen (PSA) >4 unless malignancy has been excluded.
• Blood pressure: SPP >160 mmHg or DPB >100 mmHg. Subjects with well controlled hypertension on ≤2 antihypertensive agents are not excluded.
• Estimated glomerular filtration rate (GFR, using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation <80 mL/min/1.73 m2. Strict vegetarians and vegans with a calculated GFR <70 mL/min/1.73 m2 are excluded. The absolute (raw) GFR value will be used for subjects with body surface areas >1.73m2.
• Baseline Hb below the lower limits of normal; lymphopenia (<1,000/μL), neutropenia (<1,500/μL), or thrombocytopenia (platelets <100,000/μL). Subjects with lymphopenia are allowed if the investigator determines there is no additional risk and obtains clearance from a hematologist.
• Subjects that have received a blood transfusion or erythropoietin in the previous 9 months, plan to receive a red blood cell transfusion or erythropoietin over the course of study participation or have conditions that alter red blood cell turnover (such as thalassemia or anemia).
• Evidence of Factor V mutation or other known hypercoagulable states
• Any coagulopathy or medical condition (eg, valvular or non-valvular atrial fibrillation) requiring long-term anticoagulant therapy (eg, warfarin or direct oral anticoagulants) after transplantation (low-dose aspirin treatment [325 mg PO] is allowed) or subjects with an 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.
• Hyperlipidemia despite medical therapy (fasting low-density lipoprotein [LDL] cholesterol >130 mg/dL, treated or untreated; and/or fasting triglycerides >200 mg/dL).

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

  • Recent myocardial infarction (within past 6 months).
  • Evidence of ischemia on a functional cardiac exam within the last year.
  • Left ventricular ejection fraction <50%.
  • Severe valvular disease requiring medical management, repair, or replacement with prosthetic valve.
• Persistent elevation of liver function tests at the time of study entry. Persistent AST, ALT, ALP, with values >1.5 times upper limits of normal or total bilirubin >1.2 mg/dL, will exclude a subject.
• Portal hypertension.
• Symptomatic cholecystolithiasis.
• Active or chronic pancreatitis.
• Symptomatic peptic ulcer disease.
• Severe unremitting diarrhea, vomiting or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications.
• Uncontrolled or untreated thyroid disease or adrenal insufficiency. Subjects with treated autoimmune hypothyroidism are allowed if on stable treatment for at least 6 months.
• Receiving treatment for a medical condition requiring chronic use of systemic steroids, except for use of ≤5 mg prednisone daily, or an equivalent dose of hydrocortisone, for physiological replacement only.
• Treatment with inhaled corticosteroids at a dose known to have systemic effects (eg, >0.4 mg/day fluticasone).
• Treatment with any immunosuppressive regimen at the time of enrollment.
• Inability to discontinue any anti-diabetic medication other than insulin at enrollment.
• Subjects who plan to use during the study hydroxyurea or other substances (eg, uric acid, xylose, acetaminophen, L-DOPA) known to affect CGM accuracy.
• Use of any investigational agents within 4 weeks of enrollment.
• Administration with live attenuated vaccine(s) within 2 months of enrollment.
• 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 month after discontinuation or unwillingness to use effective measures of contraception. 45) Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Islet Transplant with Tolerance Induction; ToleraCell (spleen-derived apoptotic donor leukocytes); Dose: 0.075x10e9 cells/kg; Mode of administration: IV infusion on Days -7 (ToleraCell-001) and +1 (ToleraCell-002) relative to islet transplant on Day 0 DFI105 (anti-CD40 mAb); Dose: 30 mg/kg; Mode of administration: IV infusion on Days -7, -6, -5, 0, 7, 14, 21, 42 and 75 relative to islet transplant on Day 0 Etanercept (Enbrel) 50 mg IV Day -7 and 25 mg SQ Days -4, 0, 3, 7,10, 14, 21 Tocilizumab (Actemra) 8 mg/kg IV Days -7 and 21 Sirolimus (Rapamune), oral daily administered through Day 75 Seven Day Cultured Purified Human Pancreatic Islets will be transplanted on Day 0 according to previously established mini-laparotomy surgical procedure to access a mesenteric vein for intraportal delivery of islets.

Biological: ToleraCell-001; allogeneic human deceased donor spleen-derived, freshly prepared, pre-apoptotic leukocyte product; Biological: ToleraCell-002; allogeneic human deceased donor spleen-derived, CD19 selected, ex vivo expanded, pre-apoptotic leukocyte product; Drug: DFI-105; antagonistic recombinant humanized anti-CD40 monoclonal antibody; Drug: Etanercept; TNF blocker fusion protein; Drug: Tocilizumab; recombinant humanized anti-interleukin-6 receptor (IL-6R) monoclonal antibody; Drug: Sirolimus; small molecule mTOR inhibitor immunosuppressant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Near-normoglycemia or improvement in glycemic control in the absence of maintenance immunosuppression	glycated hemoglobin (HbA1c) ≤7.0% or ≥1% reduction in HbA1c from baseline	365 days posttransplant (+/- 14 days)
Protection from Level 2 and Level 3 (severe) hypoglycemia in the absence of maintenance immunosuppression	time below range <54 mg/dL <0.5% of time per day and free of severe hypoglycemic events	Day 75 (+/- 5 days) to day 365 (+/- 14 days) inclusive following the islet transplant
Near-normal islet β-cell function in the absence of maintenance immunosuppression	beta cell responsivity index ≥25 x 10e-9 min-1 estimated from plasma glucose and C-peptide concentrations measured during a mixed meal tolerance test by using the oral C-peptide minimal model	365 days posttransplant (+/- 14 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absence of de novo donor-specific antibody positivity		Days 28, 75, 180, 365 posttransplant
Proportion of Patients with Optimal, Good and Marginal β-cell graft function	Igls Criteria	Days 28, 75, 180, 365 posttransplant
Metabolic Testing (arginine stimulation and MMTT) and associated Calculations		Days 28, 75, 180, 365 posttransplant
Tracking Full Range of CGM Metrics		Days 28, 75, 180, 365 posttransplant
Change in HbA1c values		Days 28, 75, 180, 365 posttransplant
Beta score and Beta2 scores		Days 28, 75, 180, 365 posttransplant
Percent change from baseline in daily insulin requirements		Days 28, 75, 180, 365 posttransplant
Clarke Score		Days 28, 75, 180, 365 posttransplant
The number of severe hypoglycemia episodes		Days 28, 75, 180, 365 posttransplant
Incidence of anti-DFI105 antibody development		Days 28, 75, 180, 365 posttransplant
Incidence of immune sensitization		Days 28, 75, 180, 365 posttransplant
Frequency of circulating T cell subsets		Days 28, 75, 180, 365 posttransplant

Collaborators and Investigators

• Sponsor: Diabetes Free, Inc.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: November 29, 2023
• First Submitted That Met QC Criteria: November 29, 2023
• First Posted (Actual): December 7, 2023

Study Record Updates

• Last Update Posted (Actual): December 7, 2023
• Last Update Submitted That Met QC Criteria: November 29, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Physiological Effects of Drugs; Anti-Infective Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gastrointestinal Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Etanercept; Sirolimus
• Other Study ID Numbers: 2023TXI01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No