Solitary Islet Transplantation for Type 1 Diabetes Mellitus Using Steroid Sparing Immunosuppression
Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Diabetes Mellitus Type 1
Intervention: Islets (Procedure)
Phase: Phase 2
Status: Active, not recruiting
Sponsored by: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Official(s) and/or principal investigator(s): Kristina I Rother, M.D., Principal Investigator, Affiliation: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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.
Clinical Details
Official title: Solitary Islet Transplantation for Type 1 Diabetes Mellitus Using Steroid Sparing Immunosuppression
Study design: Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: Insulin independence one year following the transplant.
Secondary outcome: To estimate the islet cell survival by evaluating: Arginine Stimulated C-Peptide response, Insulin dose, incidence of severe hypoglycemia, monthly monitoring of Hgb A1c.
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.
Eligibility
Minimum age: 18 Years.
Maximum age: 65 Years.
Gender(s): Both.
Criteria:
- INCLUSION CRITERIA:
Patients with T1DM for at least 5 years will be eligible for the study provided they
exhibit one of the following:
- Hypoglycemia unawareness, as defined by inability to sense hypoglycemia until the
blood glucose falls to less than 54 mg/dl or greater than one hypoglycemia reaction
in the preceding 20 months and that required outside help and was not explained by a
clear precipitant;
- Metabolic instability, as defined by: a) recurrent hypoglycemic or ketoacidotic
events requiring more than two hospitalization within the preceding 12 months, b)
disruption in quality of life or direct potential danger to the patient or others
around them, with more than two hospital admissions or more than four weeks off
school or work, or where the individual is no longer able to provide essential care
for others; or
- Evidence of early but progressive secondary diabetic complications but which have not
progressed to end-stage renal failure
- Failure of intensive insulin management, as judged by an endocrinologist independent
of study investigators
EXCLUSION CRITERIA:
- Significant cardiac disease as defined by: a) a history of a myocardial infarction
with the past 6 months or b) coronary angiographic evidence of non-correctable
arteriopathy, or c) evidence of ischemia on a functional cardiac examination
- Active alcoholism or other substance abuse (including cigarette smoking) within the
past 6 months
- Failure to clear a psychological or psychiatric screen (as assessed by psychological
or psychiatric consultation)
- A history of non-adherence. If adherence has been questionable, then an adherence
agreement must be entered and compliance demonstrated for at least 3 months
- Active infection including hepatitis B or C, HIV positivity, a positive Mantoux test
(unless previously immunized with BCG), or any X-ray evidence of pulmonary infection
- History of malignancy except squamous and basal cell skin cancer, unless disease free
for at least 5 years, and cleared by an independent oncological consultation
- Obesity (defined by a body mass index of greater than 28) or total body weight
greater than 75 kilograms
- C-peptide values greater than or equal to 0. 3 pm/ml following a 5. 0 gram intravenous
arginine infusion
- Inability to provide informed consent
- Age less than 18 or older than age 65
- Creatinine clearance of less than 60 ml/min/m2, or macroalbuminuria of greater than
300 mg/24h
- Baseline Hb of less than 12 g/dl in women, or less than 13 g/dl in men
- WBC count of less than 3,000/mm(3) or a platelet count of less than 100,000/mm(3)
- Baseline LFTs outside of normal range
- Presence of gallstones, liver hemangioma, or evidence of portal hypertension on
baseline U/S
- Untreated proliferative retinopathy
- Female patients must not have a positive pregnancy test and must not have the intent
for future pregnancy. Any female subject of reproductive age must be able and willing
to use an acceptable method of contraception (oral contraceptives, Norplant,
Depo-Provera, and barrier devices are acceptable; condoms used alone are not
acceptable)
- Female subjects must not be breastfeeding
- Previous transplant, or evidence of known previous or current anti-HLA antibody
- Insulin requirement of greater than 0. 7 iU/kg/day
- HbA1C of greater than 12%
- Inability to reach the hospital for transplantation within 6 hrs of notification.
(Ability to reach NIH within the allotted time frame will be determined by the PI for
out of town patients)
- Untreated hyperlipidemia
Locations and Contacts
National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States
Additional Information
NIH Clinical Center Detailed Web Page
Related publications: Kemp CB, Knight MJ, Scharp DW, Lacy PE, Ballinger WF. Transplantation of isolated pancreatic islets into the portal vein of diabetic rats. Nature. 1973 Aug 17;244(5416):447. Ballinger WF, Lacy PE. Transplantation of intact pancreatic islets in rats. Surgery. 1972 Aug;72(2):175-86. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86.
Starting date: November 2000
Last updated: July 25, 2015
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