Solitary Islet Transplantation for Type 1 Diabetes Mellitus Using Steroid Sparing Immunosuppression
Condition: Diabetes Mellitus Type 1
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will test whether a new islet transplant procedure will enable patients with type
      1 diabetes mellitus to stop insulin therapy. Islets are cell clusters in the pancreas that
      contain insulin-producing cells. The new procedure features three important advances, first
      developed by a group in Edmonton, Canada, over the way islet transplants have traditionally
      been performed: 1) the islets are transplanted immediately after they are removed from the
      donor; 2) islets are transplanted from two different donors in order to obtain the number of
      islets in a normal pancreas; and 3) the anti-rejection drug regimen is designed to reduce the
      harmful side effects of "conditioning" chemotherapy. (In the standard transplant procedure,
      patients receive intensive chemotherapy following the transplant. This study will use no
      radiation and lower-dose chemotherapy.)

      Patients between the ages of 18 and 65 with the diagnosis of type 1 diabetes mellitus for at
      least 5 years may be eligible for this study. Candidates will be screened with a medical
      history and physical examination, blood tests, chest X-ray and tuberculin skin test,
      electrocardiogram and exercise test for heart function, abdominal ultrasound, psychological
      evaluation, and an arginine stimulated c-peptide test. The latter test determines if the
      patient is producing any insulin. Eligibility is restricted to patients who make no insulin
      at all.

      The study has an active phase lasting 15 months and follow-up that continues indefinitely.
      Patients will receive 10,000 "islet equivalents" per kilogram (2.2 pounds) of body weight.
      This will likely require two separate transplant procedures from two donors. Before the first
      surgery, patients will be given anti-rejection (immune suppressing) drugs, including FK506
      and rapamycin (orally) and daclizumab (intravenously). The islets will be infused through a
      tube placed in the portal vein (the large vein that feeds the liver). After surgery, patients
      will receive insulin intravenously for 24 hours. They will then have an abdominal ultrasound
      and blood tests to determine liver function. If fewer than 10,000 islets were transplanted,
      patients will continue insulin treatment, with the dosages adjusted to account for the
      transplanted islets. They will take Daclizumab every 2 weeks, and FK506 and rapamycin daily.
      Blood tests to follow how much of these drugs are in the blood stream will be performed daily
      at first and then weekly after blood levels of these drugs stabilize. They will be given
      antibiotics to prevent infections. The arginine test will be repeated 2 weeks after the
      transplant and periodically thereafter. Blood will be drawn weekly to check drug levels, and
      monthly for other tests. The investigators will track daily insulin requirements, and these
      will be recorded monthly.

      Patients who require a second transplant to achieve the required amount of islets will return
      for the procedure when a compatible organ is donated. The second procedure will be done as
      described above. As before, insulin will be infused for 24 hours following surgery. It will
      then be stopped, however, and will not be resumed unless blood glucose levels reach above 180
      milligrams/deciliter. Patients will continue taking FK506 and rapamycin indefinitely.
      Daclizumab will be given every 2 weeks for 4 doses following the second transplant, and then
      stopped. Patients will take an antiviral called ganciclovir for 14 weeks and another
      antibiotic for 1 year following surgery. For the first year after surgery, patients will have
      frequent blood tests to monitor drug levels and immune function. They will return to NIH for
      a complete history and physical examination 2 and 3 years after the final islet transplant
      and will be contacted yearly by phone to ascertain their general health status and whether
      they remain insulin independent.
    

Detailed description: 
      We will test whether pancreatic islets isolated from cadaveric human donor pancreata can be

      transplanted into the portal vein of patients with type 1 diabetes mellitus (T1DM) in such a
      way so as to achieve insulin independence for the recipient. The protocol will employ a
      defined islet isolation procedure, percutaneous islet infusion into the recipient s portal
      vein via an intra-portal catheter, tight glycemic control during the peri-transplant period,
      and a novel immunosuppressive protocol that avoids glucocorticoids. Up to 20 patients between
      the ages of 18 and 65 who have been diagnosed with T1DM for at least five years and who have
      no detectable endogenous insulin producing capacity will be enrolled. Since the study calls
      for at least 10,000 islet equivalents (IEQs) per kilogram recipient body weight to be
      transplanted, and since a typical human pancreas yields approximately 2.0 to 4.0 times 105
      IEQs, most protocol enrollees will require islets isolated from two different donors. Islets
      will be transplanted shortly after isolation, and since human donor pancreata are available
      at unpredictable times, the timing of the islet transplant procedure will also be
      unpredictable. The study s primary end-point will be insulin independence at one year
      following the transplantation of at least 10,000 IEQs per kilogram recipient body weight.
      Secondary endpoints will be evidence of partial islet function as reflected by stimulated
      c-peptide secretion, a Hgb A1c of 7.0% or less, and the absence of severe hypoglycemia.
      Additional secondary endpoints will be to determine: 1) if any immune parameters are
      predictive of islet loss, 2) if islet transplantation has any effect on renal function and 3)
      if the protocol influences fasting lipid profiles.
    

Intervention name(s): Islet Transplantation
Intervention type(s): Drug
Intervention description(s): Islet cell transplantation. This study will test whether a new islet transplant procedure will enable patients with type 1 diabetes mellitus to stop insulin therapy
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Islet Isolation; Diabetes