Islet Transplant in Patients With Type I Diabetes

  • STATUS
    Recruiting
  • End date
    Dec 1, 2023
  • participants needed
    10
  • sponsor
    Kenneth Brayman, MD
Updated on 25 January 2021
diabetes
insulin
hypoglycemia
hypoglycemic episodes
insulin treatment
severe hypoglycaemia
hypoglycaemia unawareness
pancreatic islet transplantation
hypoglycemic drugs

Summary

The primary objective of this study is to demonstrate the safety of allogenic islet transplantation in type 1 diabetic patients performed at the University of Virginia.

The purpose is to demonstrate that islet transplantation can be performed safely and reliably achieves better glycemic control than state-of-the-art insulin treatment in management of type 1 diabetic patients with brittle control and a history of severe hypoglycemic episodes with hypoglycemia unawareness.

Description

Type 1 diabetes (T1D) is caused by islet autoimmunity followed by immune destruction of the -cells. In 2015 the International Diabetes Federation reported that 36 million people suffer from T1D globally, while it is estimated that 1.4 millions of Americans have T1D. Although life expectancy of patients with T1D has much improved since the introduction of insulin therapy, chronic complications, including blindness and renal failure, are hampering the quality of life and represent a multi-billion dollar annual burden on the health care system of industrialized countries. Keeping blood glucose levels under tight control represents the most effective way either to prevent the onset or to reduce the progression of the chronic complications of T1D. At present, such a goal may be accomplished by treating patients with intensified therapy regimens consisting of multiple insulin injections, which involve accurate blood glucose monitoring. However, administration of subcutaneous insulin can never approximate pulsatile insulin secretory patterns of the normal -cells, and rarely attains normal blood glucose levels without the risk of major hypoglycemic episodes. In addition, intensive insulin therapy is only suitable for selected patients.

Pancreas transplantation is an alternative therapeutic modality which can stop the progression of diabetic complications without increasing the incidence of hypoglycemic events. Unfortunately, this procedure, usually performed simultaneously with a kidney graft, has a high morbidity and a significant mortality rate. Pancreas transplantation, in spite of an important impact on the quality of life in successful cases, is often restricted to selected patients. In this context, islet transplantation offers and alternative treatment solution, normalizing glucose metabolism without the risk of hypoglycemia and avoiding the potentially life threatening complications of whole pancreas grafts.

Clinical islet transplantation has continuously advanced over the past two decades, with clear improvements in islet manufacturing and clinical outcomes, therefore restore insulin production and ameliorate glycemic instability in patients with T1D. Currently, the procedure is primarily indicated for patients with a history of life threatening severe hypoglycemia and hypoglycemia unawareness for which islet transplantation has been highly effective both in the short and long terms. According to the most recent public presentation from the collaborative islet transplant registry (CITR), 1055 allogeneic islet transplantations have been reported by 50 islet transplantation centers in North America, Europe, Australia, and South Korea. Of these cases, islet transplant alone was the most frequent procedure (n=858) followed by islet after kidney (IAK) and simultaneous islet and kidney transplantation (SIK) (n=197). CITR data has identified factors that predict the achievement and maintenance of insulin independence as recipient age over 35 years, more than half a million infused islet equivalent (IEQ), islet glucose stimulation index >1.5, induction therapy with Tcell depletion, and TNF- inhibitor and maintenance with calcineurin inhibitor and mTOR inhibition. The combination of these factors in 60 recipients resulted in stable insulin independence after 5 years in 60 % of the patients. Recipient age, IEQ, and calcineurin inhibitor (CNI) maintenance were also predictive of positive C-peptide levels (0.3 ng/ml; n=308) and HbA1c (<6.5 % or drop 2 %; n=530) and age and IEQ predicted absence of severe hypoglycemic events (SHE) (>90 % of patients at 5 years). As another indicator of improvements in the procedure, the number of adverse events has dropped significantly in the past 5 years, with 80 % free of any adverse events.

Details
Condition Insulin dependent diabetes mellitus, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 1, type 1 diabetes mellitus, type 1 diabetes, diabetes type 1, diabetes mellitus type 1, insulin-dependent diabetes, iddm, type i diabetes mellitus
Treatment Allogenic Islet Cell Transplantation
Clinical Study IdentifierNCT03698396
SponsorKenneth Brayman, MD
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

At least 1 episode of severe hypoglycemia in the past 3 years
Reduced awareness of hypoglycemia
Must be a qualified candidate for pancreas transplant

Exclusion Criteria

Diagnosis of co-existing cardiac diseased (ie, recent myocardial infarction within 6 months or angiographic evidence of non-correctable coronary artery disease or evidence of ischemia on functional cardiac exam
Active alcohol or substance abuse
Psychiatric disorder this is unstable or uncontrolled on current medication
History of non-compliance
Active infection including hepatitis C, hepatitis B, HIV
History of or active Tuberculosis
Any history of cancer, except skin cancer
History of stroke within past 6 months
BMI > 27 kg/m2
C-peptide fasting response to glucagon stimulation
Inability to provide informed consent
Creatinine Clearance < 60 ml/min
Macroalbuminuria
Baseline Hb <12 gm/dL
Baseline liver function test outside normal ranges
History of untreated proliferative retinopathy
Positive pregnancy test or male subjects intent to procreate while on study
Previous transplant (except islet transplant)
Insulin requirement of > 0.7 IU/kg/day
HbA1c . 12%
Hyperlipidemia
Under treatment for medical condition requiring chronic use of steroids
Use of coumadin or other antiplatelet therapy
History of Factor V deficiency
History of Addison's disease
Allergic to radiographic contrast material
Symptomatic cholecystolithiasis
Acute on chronic pancreatitis
Symptomatic peptic ulcer disease
Severe unremitting diarrhea, vomiting or other gastrointestinal disorders that could interfere with the ability to absorb oral medications
Treatment with antidiabetic medication other than insulin within 4 weeks of enrollment
Use of any investigational drug or device within 4 weeks of enrollment
Received a live attenuated vaccine within 2 months of listing
Active coagulopathy
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