| Eligibility |
Inclusion Criteria:
- Clinical history compatible with predominantly ß-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 ß-cell mass, indicated by acute C-peptide response to IV arginine of <1.0
ng/mL
- Low islet ß-cell function, defined by ß-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-? 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.
|
