Islet Transplantation in Type 1 Diabetes

Official Title:

Islet Transplantation in Type 1 Diabetes

Basic Trial Information

Phase Type Age Sponsor Protocol IDs Status
Phase 3 Interventional 18 - 65 Years National Institute of Allergy and Infectious Diseases (NIAID) DAIT CIT-07
NCT00434811
Ongoing but not enrolling patients

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Andrew M. Posselt, M.D., Ph.D., FACS

Associate Professor of Surgery
Division of Transplant Surgery
Co-Director, Pancreatic Islet Cell Transplant Program


Trial Summary

Type 1 diabetes is an autoimmune disease in which the insulin-producing pancreatic beta cells are destroyed, resulting in poor blood sugar control. The purpose of this study is to determine the safety and effectiveness of islet transplantation, combined with immunosuppressive medications, for treating type 1 diabetes in individuals experiencing hypoglycemia unawareness and severe hypoglycemic episodes.

Eligibility

Inclusion Criteria:
  • Mentally stable and able to comply with study procedures
  • Clinical history compatible with type 1 diabetes with onset of disease at less than
    40 years of age, insulin dependence for at least 5 years at study entry, and a sum of
    age and insulin dependent diabetes duration of at least 28
  • Absent stimulated C-peptide (less than 0.3 ng/ml) 60 and 90 minutes post-mixed-meal
    tolerance test
  • Involvement of intensive diabetes management, defined as:
           Self-monitoring of glucose values no less than a mean of three times each day
           averaged over each week
           Administration of three or more insulin injections each day or insulin pump
           therapy
           Under the direction of an endocrinologist, diabetologist, or diabetes specialist
           with at least three clinical evaluations during the past 12 months prior to
           study enrollment
  • At least one episode of severe hypoglycemia in the past 12 months, defined as an
    event with one of the following symptoms: memory loss; confusion; uncontrollable
    behavior; irrational behavior; unusual difficulty in awakening; suspected seizure;
    seizure; loss of consciousness; or visual symptoms, compatible with hypoglycemia in
    which the individual required assistance of another subject was unable to treat
    him/herself person and which was associated with either a blood glucose level less
    than 54 mg/dl or prompt recovery after oral carbohydrate, intravenous glucose, or
    glucagon administration in the 12 months prior to study enrollment
  • Reduced awareness of hypoglycemia. More information about this criterion, including
    specific definition of hypoglycemia unawareness, is in the protocol.
Exclusion Criteria:
  • Body mass index (BMI) greater than 30 kg/m2 or weight less than or equal to 50 kg
  • Insulin requirement of more than 1.0 IU/kg/day or less than 15 U/day
  • HbA1c greater than 10%
  • Untreated proliferative diabetic retinopathy
  • Systolic blood pressure higher than 160 mmHg or diastolic blood pressure higher than
    100 mmHg
  • Measured glomerular filtration rate using iohexol of less than 80 ml/min/1.73mm2.
    More information about this criterion is in the protocol.
  • Presence or history of macroalbuminuria (greater than 300 mg/g creatinine)
  • Presence or history of panel-reactive anti-HLA antibody levels greater than
    background by flow cytometry. More information about this criterion is in the
    protocol.
  • Pregnant, breastfeeding, or unwilling to use effective contraception throughout the
    study and 4 months after study completion
  • Presence or history of active infection, including hepatitis B, hepatitis C, HIV, or
    tuberculosis.
  • Negative for Epstein-Barr virus by IgG determination
  • Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection in the past
    year
  • History of malignancy except for completely resected squamous or basal cell carcinoma
    of the skin
  • Known active alcohol or substance abuse
  • Baseline Hgb below the lower limits of normal, lymphopenia, neutropenia, or
    thrombocytopenia
  • History of Factor V deficiency
  • Any coagulopathy or medical condition requiring long-term anticoagulant therapy after
    transplantation or individuals with an INR greater than 1.5
  • Severe coexisting cardiac disease, characterized by any one of the following
    conditions:
           Heart attack within the last 6 months
           Evidence of ischemia on functional heart exam within the year prior to study
           entry
           Left ventricular ejection fraction less than 30%
  • Persistent elevation of liver function tests at the time of study entry
  • Symptomatic cholecystolithiasis
  • Acute or chronic pancreatitis
  • Symptomatic peptic ulcer disease
  • Severe unremitting diarrhea, vomiting, or other gastrointestinal disorders that could
    interfere with the ability to absorb oral medications
  • Hyperlipidemia despite medical therapy, defined as fasting LDL cholesterol greater
    than 130 mg/dl (treated or untreated) and/or fasting triglycerides greater than 200
    mg/dl
  • Currently receiving treatment for a medical condition that requires chronic use of
    systemic steroids except for the use of 5 mg or less of prednisone daily, or an
    equivalent dose of hydrocortisone, for physiological replacement only
  • Treatment with any antidiabetic medication other than insulin within the past 4 weeks
  • Use of any study medications within the past 4 weeks
  • Received a live attenuated vaccine(s) within the past 2 months
  • Any medical condition that, in the opinion of the investigator, might interfere with
    safe participation in the trial
        - Treatment with any immunosuppressive regimen at the time of enrollment.
        - A previous islet transplant.
        - A previous pancreas transplant, unless the graft failed within the first week
           due to thrombosis, followed by pancreatectomy and the transplant occurred more
           than 6 months prior to enrollment.

Detailed Description

Type 1 diabetes is commonly treated with the administration of insulin, either by multiple
insulin injections or by a continuous supply of insulin through a wearable pump. Insulin
therapy allows long-term survival in individuals with type 1 diabetes; however, it does not
guarantee constant normal blood sugar control. Because of this, long-term type 1 diabetic
survivors often develop vascular complications, such as diabetic retinopathy, an eye disease
that can cause poor vision and blindness, and diabetic nephropathy, a kidney disease that
can lead to kidney failure. Some individuals with type 1 diabetes develop hypoglycemia
unawareness, a life-threatening condition that is not easily treatable with medication and
is characterized by reduced or absent warning signals for hypoglycemia. For such
individuals, transplantation of pancreatic islets is a possible treatment option.
Unfortunately, insulin independence among islet transplant recipients tends to decline over
time. New strategies aimed at promoting engraftment of transplanted islets are needed to
improve the clinical outcomes associated with this procedure. The purpose of this study is
determine the safety and efficacy of islet transplantation, when combined with an
immunosuppressive medication regimen, for treating type 1 diabetes in individuals
experiencing hypoglycemia unawareness and severe hypoglycemic episodes. This study will also
seek to improve the understanding of determinants of success and failure of islet
transplants for type 1 diabetes.
Eligible participants will be randomly assigned to this study or a site-specific Phase 2
islet transplantation study. Participants in this study will receive up to three separate
islet transplants and a regimen of immunosuppressive medications consisting of antithymocyte
globulin (ATG), sirolimus, and low-dose tacrolimus. They will begin receiving ATG and
sirolimus 2 days prior to the first islet transplant. ATG will continue to be given until
Day 2 post-transplant, and sirolimus will be given for the duration of the study. On Day 1
post-transplant, participants will receive tacrolimus, which will also be taken for the
duration of the study. Etanercept will be taken on the day of transplant and Days 3, 7, and
10 post-transplant.
Transplantations will involve an inpatient hospital stay and infusion of islets into a
branch of the portal vein. Participants who do not achieve or maintain insulin independence
by Day 75 post-transplant will be considered for a second islet transplant. Participants who
remain dependent on insulin for longer than 1 month after the second transplant and who show
partial graft function will be considered for a third islet transplant. Basiliximab will be
used in place of ATG for the second and third transplants, if they are necessary.
Participants who do not meet the criteria for a subsequent transplant and do not have a
functioning graft will enter a reduced follow-up period.
There will be up to 19 study visits following each transplant. A physical exam, review of
adverse events, and blood collection will occur at most visits. A chest x-ray, abdominal
ultrasound, electrocardiogram, quality of life questionnaires, urine collection, and
glomerular filtrating rate (GFR) testing will occur at some visits. Participants will also
test their own blood glucose levels at least five times per day throughout the study. A
24-month follow-up period will take place after the participant's last transplant.

Important

Final eligibility is determined by the health professionals conducting the trial and the protocol approved by the Committee on Human Resources (CHR) at the University of California, San Francisco (UCSF). The Patient Consent Form for this trial is available upon request. For more information about this trial, please see the full posting at ClinicalTrials.gov.

For More Information

For questions about this trial:

Debbie Ramos, RN
415-353-8893
islettransplant@ucsfmedctr.org  

Information about this trial was obtained from the NIH Clinical Trials website, http://clinicaltrials.gov on 5/27/2014. UCSF specific information including the PI (Principal Investigator), trial enrollment status, and UCSF Study ID, supplement the ClinicalTrials.gov study posting.
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