Islet Allotransplantation in Type 1 Diabetes
| Status: | Enrolling by invitation |
|---|---|
| Conditions: | Diabetes |
| Therapuetic Areas: | Endocrinology |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 3/22/2019 |
| Start Date: | November 2006 |
| End Date: | October 2021 |
Islet transplantation can provide physiologic insulin replacement to patients with type 1
diabetes without the complications associated with whole pancreas transplantation. The
purpose of this study is to achieve insulin-independence in patients with type 1 diabetes,
thereby eliminating the need for exogenous insulin injections to maintain normal glucose
levels, ameliorating severe hypoglycemia and potentially decreasing the development of
diabetes-related complications. This study will investigate islet transplantation in subjects
who have preserved renal function and subjects who have undergone cadaveric renal
transplantation, since the latter subjects are already on immunosuppression.
This is a single center, prospective trial of islet transplantation in subjects receiving
islets alone or islets after kidney transplant. This is a phase I study investigating the use
of islet transplantation for the treatment of type 1 diabetes. Subjects will be eligible for
an islet transplant if they meet all of the inclusion criteria and none of the exclusion
criteria outlined in the protocol. In brief, the aims of this study are to establish an islet
transplant program at the Ohio State University, determine the safety of islet
transplantation in islet alone and kidney transplant recipients, determine whether islet
transplantation will reduce the frequency of severe hypoglycemic events, determine whether a
novel steroid-free immunosuppressive protocol will prevent rejection in islet transplants and
to achieve insulin independence at one year after the final islet transplant.
diabetes without the complications associated with whole pancreas transplantation. The
purpose of this study is to achieve insulin-independence in patients with type 1 diabetes,
thereby eliminating the need for exogenous insulin injections to maintain normal glucose
levels, ameliorating severe hypoglycemia and potentially decreasing the development of
diabetes-related complications. This study will investigate islet transplantation in subjects
who have preserved renal function and subjects who have undergone cadaveric renal
transplantation, since the latter subjects are already on immunosuppression.
This is a single center, prospective trial of islet transplantation in subjects receiving
islets alone or islets after kidney transplant. This is a phase I study investigating the use
of islet transplantation for the treatment of type 1 diabetes. Subjects will be eligible for
an islet transplant if they meet all of the inclusion criteria and none of the exclusion
criteria outlined in the protocol. In brief, the aims of this study are to establish an islet
transplant program at the Ohio State University, determine the safety of islet
transplantation in islet alone and kidney transplant recipients, determine whether islet
transplantation will reduce the frequency of severe hypoglycemic events, determine whether a
novel steroid-free immunosuppressive protocol will prevent rejection in islet transplants and
to achieve insulin independence at one year after the final islet transplant.
Hypothesis - Insulin independence (insulin injections no longer needed) will be achieved in
subjects with type 1 diabetes receiving islet transplantation using the immunosuppressive
regimen of cyclosporine and sirolimus. Amelioration of severe hypoglycemia will also be
achieved in these groups.
Primary Objective
To determine the safety of islet transplantation in islet alone and in kidney transplant
recipients. Safety analyses include:
- Incidence, timing and severity of adverse events and their relationship to the
transplant protocol, islet infusion and immunosuppressive medications
- Proportion without protocol-related serious adverse events (SAE) at 1 year
- Incidence, type and severity of infectious complications
- Incidence and severity of procedural-related events, such as bleeding and portal vein
thrombosis
- Incidence and severity of liver function test elevations
- Incidence and severity of hypoglycemia
- Incidence and severity of creatinine clearance and urine microalbumin changes
- Incidence and severity of lipid abnormalities
- Proportion of those who develop donor-specific alloantibody
Secondary Objective
To determine the efficacy of islet transplantation in islet alone and in kidney transplant
recipients. Efficacy analyses include:
- Time to insulin independence, defined as freedom from insulin use (insulin injections
not needed) for 14 or more consecutive days
- Proportion of those that achieve insulin independence at any time during the first year
- Proportion of those one year after final transplant who have:
- Positive C-peptide (≥0.3 ng/ml after stimulation)
- Full function of their graft
- Partial function of their graft
- Marginal function of their graft
- Mixed meal stimulated C-peptide >1.0 ng/ml at 6, and 12 months
- Proportion of those that have an acute insulin response to glucose (AIRg) >20uU/ml
during frequently sampled intravenous glucose tolerance test (FSIGT) at 6 and 12 months
- Proportion of those with blood glucose level <140 mg/dl two hours after oral glucose
tolerance test (OGTT) at 6 and 12 months
- Proportion of those that have improved QOL at 6 and 12 months compared with baseline
- Proportion of those that have improved hypoglycemia and glycemic lability scores at 6
and 12 months compared with baseline
Definition of full islet function:
- Insulin independence
- A1C ≤ 6.5%
- Absence of severe hypoglycemic episodes
- Fasting glucose ≥140 mg/dl less than 3 times a week
- Post-prandial glucose (2 hours) >180 mg/dl less than 4 times a week
Definition of partial islet function:
- Insulin requirement less than 50% of pre-transplant insulin requirement
- C-peptide positive (≥0.3 ng/ml after stimulation)
- A1C ≤ 6.5%
- No severe hypoglycemia
Definition of marginal islet function:
- C-peptide positive (≥0.3 ng/ml after stimulation)
- A1C ≤ 7.5%
- No severe hypoglycemia
This trial will have two study groups consisting of N=10 subjects with type 1 diabetes. One
group (IA) will include subjects with preserved kidney function. A second group (IAK) will
include subjects with renal failure secondary to diabetes who have received a prior kidney
transplant at least 6 months previously and have stable renal function on a steroid-free
immunosuppressive regimen.
Potential study participants will be recruited from the Endocrinology and Transplant clinics
at the Ohio State University, and community physician referrals. Those who are potentially
eligible will undergo a screening evaluation after review of the medical records. If the
subject remains eligible, he/she will be enrolled in the islet transplant study and will be
placed on a waiting list for an islet transplant. Once a transplant becomes available, the
subject will be admitted to the hospital to undergo the transplant procedure. Frequent
follow-up visits in the transplant clinic will occur throughout the following year after the
transplant. Subjects will be closely monitored for adverse events and insulin requirements.
If the subject does not achieve insulin independence, he/she may be eligible for a subsequent
transplant.
There will be a 10-year enrollment with 12-month follow-up after last transplant. Since
subjects may be eligible for a subsequent transplant within 18 months of the first
transplant, the total duration may be up to 30 months after the first transplant in some
subjects.
The study will be completed one year after the last islet transplant. Subjects who have
undergone the islet transplant procedure and have completed the post-transplant evaluations
one year after their last transplant will be considered to have completed the study.
subjects with type 1 diabetes receiving islet transplantation using the immunosuppressive
regimen of cyclosporine and sirolimus. Amelioration of severe hypoglycemia will also be
achieved in these groups.
Primary Objective
To determine the safety of islet transplantation in islet alone and in kidney transplant
recipients. Safety analyses include:
- Incidence, timing and severity of adverse events and their relationship to the
transplant protocol, islet infusion and immunosuppressive medications
- Proportion without protocol-related serious adverse events (SAE) at 1 year
- Incidence, type and severity of infectious complications
- Incidence and severity of procedural-related events, such as bleeding and portal vein
thrombosis
- Incidence and severity of liver function test elevations
- Incidence and severity of hypoglycemia
- Incidence and severity of creatinine clearance and urine microalbumin changes
- Incidence and severity of lipid abnormalities
- Proportion of those who develop donor-specific alloantibody
Secondary Objective
To determine the efficacy of islet transplantation in islet alone and in kidney transplant
recipients. Efficacy analyses include:
- Time to insulin independence, defined as freedom from insulin use (insulin injections
not needed) for 14 or more consecutive days
- Proportion of those that achieve insulin independence at any time during the first year
- Proportion of those one year after final transplant who have:
- Positive C-peptide (≥0.3 ng/ml after stimulation)
- Full function of their graft
- Partial function of their graft
- Marginal function of their graft
- Mixed meal stimulated C-peptide >1.0 ng/ml at 6, and 12 months
- Proportion of those that have an acute insulin response to glucose (AIRg) >20uU/ml
during frequently sampled intravenous glucose tolerance test (FSIGT) at 6 and 12 months
- Proportion of those with blood glucose level <140 mg/dl two hours after oral glucose
tolerance test (OGTT) at 6 and 12 months
- Proportion of those that have improved QOL at 6 and 12 months compared with baseline
- Proportion of those that have improved hypoglycemia and glycemic lability scores at 6
and 12 months compared with baseline
Definition of full islet function:
- Insulin independence
- A1C ≤ 6.5%
- Absence of severe hypoglycemic episodes
- Fasting glucose ≥140 mg/dl less than 3 times a week
- Post-prandial glucose (2 hours) >180 mg/dl less than 4 times a week
Definition of partial islet function:
- Insulin requirement less than 50% of pre-transplant insulin requirement
- C-peptide positive (≥0.3 ng/ml after stimulation)
- A1C ≤ 6.5%
- No severe hypoglycemia
Definition of marginal islet function:
- C-peptide positive (≥0.3 ng/ml after stimulation)
- A1C ≤ 7.5%
- No severe hypoglycemia
This trial will have two study groups consisting of N=10 subjects with type 1 diabetes. One
group (IA) will include subjects with preserved kidney function. A second group (IAK) will
include subjects with renal failure secondary to diabetes who have received a prior kidney
transplant at least 6 months previously and have stable renal function on a steroid-free
immunosuppressive regimen.
Potential study participants will be recruited from the Endocrinology and Transplant clinics
at the Ohio State University, and community physician referrals. Those who are potentially
eligible will undergo a screening evaluation after review of the medical records. If the
subject remains eligible, he/she will be enrolled in the islet transplant study and will be
placed on a waiting list for an islet transplant. Once a transplant becomes available, the
subject will be admitted to the hospital to undergo the transplant procedure. Frequent
follow-up visits in the transplant clinic will occur throughout the following year after the
transplant. Subjects will be closely monitored for adverse events and insulin requirements.
If the subject does not achieve insulin independence, he/she may be eligible for a subsequent
transplant.
There will be a 10-year enrollment with 12-month follow-up after last transplant. Since
subjects may be eligible for a subsequent transplant within 18 months of the first
transplant, the total duration may be up to 30 months after the first transplant in some
subjects.
The study will be completed one year after the last islet transplant. Subjects who have
undergone the islet transplant procedure and have completed the post-transplant evaluations
one year after their last transplant will be considered to have completed the study.
Inclusion Criteria:
1. Type 1 diabetes > 5 years
2. First islet transplant
3. Demonstrate intensive efforts to manage diabetes for last 6 months (≥4 SMBG/day, ≥3
injections of insulin/day or use of pump and ≥3 contacts with diabetes care team in
last 12 months)
4. Metabolic complications: at least one of the following:
•Reduced hypoglycemia awareness (inability to sense hypoglycemia until blood glucose
falls to < 54 mg/dl or > one hypoglycemic episode in last 12 months requiring outside
help and not explained by clear precipitant)
•≥2 severe hypoglycemic events or ≥2 hospitalizations for diabetic ketoacidosis (DKA)
in last year.
5. Ability to provide written informed consent
6. Age 18-65
7. Specific for group 2: All of above (1-6) with renal transplant at least 6 months
previous
Exclusion Criteria:
1. Age < 18 years or > 65 years
2. Inability to provide informed consent
3. Body Mass Index > 29 kg/m2
4. Insulin requirement of > 50 units/day
5. Stimulated C-peptide ≥ 0.2 ng/ml
6. Current panel reactive anti-HLA antibodies >20%
7. Cardiovascular instability
8. Previous islet transplant
9. History of malignancy except squamous and basal cell skin cancer unless disease-free
for > 2 years determined by independent oncologist
10. Active peptic ulcer disease
11. Condition that may interfere with absorption of medications
12. Hemoglobin A1C > 12%
13. Invasive aspergillus infection within one year
14. Varicella titer index <1.0
15. Rubella titer <10 IU/ml
16. Psychiatric disorder
17. Untreated hyperlipidemia: fasting total cholesterol >240 mg/dl, low density
lipoprotein>130 mg/dl, or triglycerides >200 mg/dl
18. Hemoglobin <10 g/dl for females, and <11 g/dl for males, white blood cell count <
3,000/µL, platelet count of <150,000/microliter, CD4+ count <500/microliter
19. Liver function test abnormalities (if any value > 1.5 times normal, candidate will be
excluded. If 1-1.5 times normal, test will be repeated. If re-test value remains above
normal, candidate will be excluded).
20. Prostate specific antigen >4.0 ng/ml
21. Presence of gallstones, liver hemangioma, cirrhosis or evidence of portal hypertension
22. Untreated proliferative diabetic retinopathy
23. Females: positive pregnancy test, intent for future pregnancy, or any subject of
reproductive age who is not surgically sterile and is unable or unwilling to use
acceptable method of contraception
24. Female subjects who are breast-feeding
25. Adrenal insufficiency: 8am cortisol >19 mcg/dl adequate. Values 19 mcg/dl will be
followed by Adreno-Corticotropic Hormone stimulation test
26. Any disease or condition that requires use of chronic steroids
27. Coagulopathy or use of chronic anticoagulation
28. Hyperthyroidism unless treated with radioactive iodine or surgery
29. Thyroid function tests outside normal range
30. Active alcoholism or other substance abuse within the past six months
31. History of non-adherence. Questionable adherence requires agreement entered and
compliance demonstrated for at least 3 months
32. Active infection including hepatitis B or C, human immunodeficiency virus positive,
positive Mantoux test [unless previously immunized with Bacillus Calmette-Guerin], or
X-ray evidence of pulmonary infection
33. Inability to reach hospital within 6 hours of notification
34. Failure to clear psychological or psychiatric screen
35. Medical condition or circumstance that investigator finds will interfere with safe
completion of the study
Exclusion criteria specific for group 1:
1. Receipt of previous transplant (excluding pancreas)
2. Creatinine clearance <50 ml/minute for females and <60 ml/minute for males or
macroalbuminuria (>500 mg/24h)
Exclusion criteria specific for group 2:
1. Creatinine clearance <40ml/minute
2. Renal transplant in last 6 months
3. Current use of corticosteroids
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