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Islet Allotransplantation in Type 1 Diabetes

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01705899
Recruitment Status : Enrolling by invitation
First Posted : October 12, 2012
Last Update Posted : March 20, 2019
Sponsor:
Information provided by (Responsible Party):
Amer Rajab, Ohio State University

Tracking Information
First Submitted Date  ICMJE May 3, 2012
First Posted Date  ICMJE October 12, 2012
Last Update Posted Date March 20, 2019
Study Start Date  ICMJE November 2006
Estimated Primary Completion Date October 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 11, 2017)
  • Incidence of adverse events [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Incidence of serious adverse events [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
    Serious adverse events will be defined (in accordance with FDA Title 21 CFR 312.32) as the following:
    • Death
    • Life-threatening and placing the subject at immediate risk of death
    • Hospitalization
    • Persistent or significant disability or incapacity
    • Congenital abnormal/birth defects
    • Requiring medical or surgical intervention to prevent permanent damage
  • Incidence of infectious complications [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Incidence of procedural-related events [ Time Frame: Day 1 post-transplant ]
    Ex. Bleeding or portal vein thrombosis
  • Incidence of elevated liver function tests [ Time Frame: Day 1 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 1 post-transplant ]
  • Incidence of procedural-related events [ Time Frame: Day 2 post-transplant ]
    Ex. Bleeding or portal vein thrombosis
  • Incidence of elevated liver function tests [ Time Frame: Day 2 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 2 post-transplant ]
  • Incidence of procedural-related events [ Time Frame: Day 3 post-transplant ]
    Ex. Bleeding or portal vein thrombosis
  • Incidence of elevated liver function tests [ Time Frame: Day 3 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 3 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 5 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 5 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 7 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 7 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 10 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 10 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 14 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 14 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 21 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 21 post-transplant ]
  • Incidence of abnormalities in lipids [ Time Frame: Day 28 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 28 post-transplant ]
  • Incidence of donor-specific antibody development [ Time Frame: Day 28 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 28 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 42 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 42 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 56 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 56 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 90 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 90 post-transplant ]
  • Incidence of abnormalities in lipids [ Time Frame: Day 90 post-transplant ]
  • Incidence of donor-specific antibody development [ Time Frame: Day 90 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 120 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 120 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 180 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 180 post-transplant ]
  • Incidence of abnormalities in lipids [ Time Frame: Day 180 post-transplant ]
  • Incidence of donor-specific antibody development [ Time Frame: Day 180 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 270 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 270 post-transplant ]
  • Incidence of abnormalities in lipids [ Time Frame: Day 270 post-transplant ]
  • Incidence of donor-specific antibody development [ Time Frame: Day 270 post-transplant ]
  • Incidence of elevated liver function tests [ Time Frame: Day 365 post-transplant ]
  • Incidence of abnormalities in lipids [ Time Frame: Day 365 post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Day 365 post-transplant ]
  • Incidence of donor-specific antibody development [ Time Frame: Day 365 post-transplant ]
  • Change in microalbumin level [ Time Frame: Days 180 and 365 post-transplant ]
  • Change in measured creatinine clearance [ Time Frame: Days 180 and 365 post-transplant ]
Original Primary Outcome Measures  ICMJE
 (submitted: October 11, 2012)
  • Incidence of adverse events [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Incidence of serious adverse events [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
    Serious adverse events will be defined (in accordance with FDA Title 21 CFR 312.32) as the following:
    • Death
    • Life-threatening and placing the subject at immediate risk of death
    • Hospitalization
    • Persistent or significant disability or incapacity
    • Congenital abnormal/birth defects
    • Requiring medical or surgical intervention to prevent permanent damage
  • Incidence of infectious complications [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Incidence of procedural-related events [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
    Ex. Bleeding or portal vein thrombosis
  • Incidence of elevated liver function tests [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Incidence of hypoglycemia [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Change in Measured Creatinine Clearance [ Time Frame: Days 180 and 365 post-transplant ]
  • Change in Microalbumin Level [ Time Frame: Days 180 and 365 post-transplant ]
  • Incidence of abnormalities in lipids [ Time Frame: Days 28, 90, 180, 270 and 365 days post-transplant ]
  • Incidence of donor-specific antibody development [ Time Frame: Days 28, 90, 180, 270 and 365 days post-transplant ]
Change History Complete list of historical versions of study NCT01705899 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 11, 2017)
  • Amount of daily insulin units required [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Measurement of C-peptide [ Time Frame: Days 1, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Change in c-peptide level from fasting following administration of mixed meal [ Time Frame: Days 180 and 365 post-transplant ]
    Patients fasting c-peptide will be measured, then patient will be given a mixed meal of Ensure. The c-peptide level will be checked again at 90 minutes after administration of mixed meal.
  • Change in acute insulin response to glucose [ Time Frame: Days 180 and 365 post-transplant ]
    As determined by oral glucose tolerance test and/or intravenous glucose tolerance test
  • Incidence of blood glucose level <140mg/dl two hours after oral glucose tolerance tests [ Time Frame: Days 180 and 365 post-transplant ]
  • Change in Quality of Life [ Time Frame: Days 180 and 365 post-transplant ]
  • Change in hypoglycemia score [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Change in glycemic lability score [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 11, 2012)
  • Achievement of Insulin Independence [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • C-peptide Positivity [ Time Frame: Days 1, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Determination of Graft Function [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Change in Measurement of Mixed Meal Stimulated C-peptide [ Time Frame: Days 180 and 365 post-transplant ]
  • Change in acute insulin response to glucose [ Time Frame: Days 180 and 365 post-transplant ]
    As determined by oral glucose tolerance test and/or intravenous glucose tolerance test
  • Incidence of blood glucose level <140mg/dl two hours after oral glucose tolerance tests [ Time Frame: Days 180 and 365 post-transplant ]
  • Change in Quality of Life [ Time Frame: Days 180 and 365 post-transplant ]
  • Change in Hypoglycemia Score [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
  • Change in glycemic lability score [ Time Frame: Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Islet Allotransplantation in Type 1 Diabetes
Official Title  ICMJE Islet Allotransplantation in Type 1 Diabetes
Brief Summary

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.

Detailed Description

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Type 1 Diabetes
Intervention  ICMJE Drug: Human Pancreatic Islets
Pancreatic islet tissue suspended in 150 - 300 ml of phenol red-free CMRL-1066 Transplant Media supplemented with 4% (w/v) HSA and 16mM HEPES in a 600ml transfer pack. Heparin will be administered at 70 IU/kg recipient body weight. Administered by intra-portal vein infusion. To be administered once, however, if full graft function is not achieved, a second or third dose of Pancreatic Islets may be given within 18 months of the first transplant.
Study Arms  ICMJE
  • Experimental: Subjects with preserved kidney function
    Subjects with preserved renal function that have not previously received a kidney transplant will be treated with Human Pancreatic Islets (in the form of islets alone - IA).
    Intervention: Drug: Human Pancreatic Islets
  • Experimental: Subjects with prior kidney transplant
    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 will receive Human Pancreatic Islets (in the form of islets after kidney - IAK).
    Intervention: Drug: Human Pancreatic Islets
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Enrolling by invitation
Estimated Enrollment  ICMJE
 (submitted: October 11, 2012)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 2021
Estimated Primary Completion Date October 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01705899
Other Study ID Numbers  ICMJE IRB 2006H0200
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Individual participant data for patients who agree is entered into a multi-center islet transplant data registry (no personally identifiable information will be shared). Upon completion of the study, results may also be published in a peer-reviewed journal.
Responsible Party Amer Rajab, Ohio State University
Study Sponsor  ICMJE Ohio State University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Amer Rajab, MD, PhD Ohio State University
PRS Account Ohio State University
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP