Solitary Islet Transplantation for Type 1 Diabetes Mellitus Using Steroid Sparing Immunosuppression
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Diabetes, Diabetes |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 4/5/2019 |
| Start Date: | November 16, 2000 |
| End Date: | June 1, 2020 |
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.
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.
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.
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.
- 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
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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