<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01705899</url>
  </required_header>
  <id_info>
    <org_study_id>IRB 2006H0200</org_study_id>
    <nct_id>NCT01705899</nct_id>
  </id_info>
  <brief_title>Islet Allotransplantation in Type 1 Diabetes</brief_title>
  <official_title>Islet Allotransplantation in Type 1 Diabetes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ohio State University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Ohio State University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Islet transplantation can provide physiologic insulin replacement to patients with type 1&#xD;
      diabetes without the complications associated with whole pancreas transplantation. The&#xD;
      purpose of this study is to achieve insulin-independence in patients with type 1 diabetes,&#xD;
      thereby eliminating the need for exogenous insulin injections to maintain normal glucose&#xD;
      levels, ameliorating severe hypoglycemia and potentially decreasing the development of&#xD;
      diabetes-related complications. This study will investigate islet transplantation in subjects&#xD;
      who have preserved renal function and subjects who have undergone cadaveric renal&#xD;
      transplantation, since the latter subjects are already on immunosuppression.&#xD;
&#xD;
      This is a single center, prospective trial of islet transplantation in subjects receiving&#xD;
      islets alone or islets after kidney transplant. This is a phase I study investigating the use&#xD;
      of islet transplantation for the treatment of type 1 diabetes. Subjects will be eligible for&#xD;
      an islet transplant if they meet all of the inclusion criteria and none of the exclusion&#xD;
      criteria outlined in the protocol. In brief, the aims of this study are to establish an islet&#xD;
      transplant program at the Ohio State University, determine the safety of islet&#xD;
      transplantation in islet alone and kidney transplant recipients, determine whether islet&#xD;
      transplantation will reduce the frequency of severe hypoglycemic events, determine whether a&#xD;
      novel steroid-free immunosuppressive protocol will prevent rejection in islet transplants and&#xD;
      to achieve insulin independence at one year after the final islet transplant.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hypothesis - Insulin independence (insulin injections no longer needed) will be achieved in&#xD;
      subjects with type 1 diabetes receiving islet transplantation using the immunosuppressive&#xD;
      regimen of cyclosporine and sirolimus. Amelioration of severe hypoglycemia will also be&#xD;
      achieved in these groups.&#xD;
&#xD;
      Primary Objective&#xD;
&#xD;
      To determine the safety of islet transplantation in islet alone and in kidney transplant&#xD;
      recipients. Safety analyses include:&#xD;
&#xD;
        -  Incidence, timing and severity of adverse events and their relationship to the&#xD;
           transplant protocol, islet infusion and immunosuppressive medications&#xD;
&#xD;
        -  Proportion without protocol-related serious adverse events (SAE) at 1 year&#xD;
&#xD;
        -  Incidence, type and severity of infectious complications&#xD;
&#xD;
        -  Incidence and severity of procedural-related events, such as bleeding and portal vein&#xD;
           thrombosis&#xD;
&#xD;
        -  Incidence and severity of liver function test elevations&#xD;
&#xD;
        -  Incidence and severity of hypoglycemia&#xD;
&#xD;
        -  Incidence and severity of creatinine clearance and urine microalbumin changes&#xD;
&#xD;
        -  Incidence and severity of lipid abnormalities&#xD;
&#xD;
        -  Proportion of those who develop donor-specific alloantibody&#xD;
&#xD;
      Secondary Objective&#xD;
&#xD;
      To determine the efficacy of islet transplantation in islet alone and in kidney transplant&#xD;
      recipients. Efficacy analyses include:&#xD;
&#xD;
        -  Time to insulin independence, defined as freedom from insulin use (insulin injections&#xD;
           not needed) for 14 or more consecutive days&#xD;
&#xD;
        -  Proportion of those that achieve insulin independence at any time during the first year&#xD;
&#xD;
        -  Proportion of those one year after final transplant who have:&#xD;
&#xD;
             -  Positive C-peptide (≥0.3 ng/ml after stimulation)&#xD;
&#xD;
             -  Full function of their graft&#xD;
&#xD;
             -  Partial function of their graft&#xD;
&#xD;
             -  Marginal function of their graft&#xD;
&#xD;
             -  Mixed meal stimulated C-peptide &gt;1.0 ng/ml at 6, and 12 months&#xD;
&#xD;
        -  Proportion of those that have an acute insulin response to glucose (AIRg) &gt;20uU/ml&#xD;
           during frequently sampled intravenous glucose tolerance test (FSIGT) at 6 and 12 months&#xD;
&#xD;
        -  Proportion of those with blood glucose level &lt;140 mg/dl two hours after oral glucose&#xD;
           tolerance test (OGTT) at 6 and 12 months&#xD;
&#xD;
        -  Proportion of those that have improved QOL at 6 and 12 months compared with baseline&#xD;
&#xD;
        -  Proportion of those that have improved hypoglycemia and glycemic lability scores at 6&#xD;
           and 12 months compared with baseline&#xD;
&#xD;
      Definition of full islet function:&#xD;
&#xD;
        -  Insulin independence&#xD;
&#xD;
        -  A1C ≤ 6.5%&#xD;
&#xD;
        -  Absence of severe hypoglycemic episodes&#xD;
&#xD;
        -  Fasting glucose ≥140 mg/dl less than 3 times a week&#xD;
&#xD;
        -  Post-prandial glucose (2 hours) &gt;180 mg/dl less than 4 times a week&#xD;
&#xD;
      Definition of partial islet function:&#xD;
&#xD;
        -  Insulin requirement less than 50% of pre-transplant insulin requirement&#xD;
&#xD;
        -  C-peptide positive (≥0.3 ng/ml after stimulation)&#xD;
&#xD;
        -  A1C ≤ 6.5%&#xD;
&#xD;
        -  No severe hypoglycemia&#xD;
&#xD;
      Definition of marginal islet function:&#xD;
&#xD;
        -  C-peptide positive (≥0.3 ng/ml after stimulation)&#xD;
&#xD;
        -  A1C ≤ 7.5%&#xD;
&#xD;
        -  No severe hypoglycemia&#xD;
&#xD;
      This trial will have two study groups consisting of N=10 subjects with type 1 diabetes. One&#xD;
      group (IA) will include subjects with preserved kidney function. A second group (IAK) will&#xD;
      include subjects with renal failure secondary to diabetes who have received a prior kidney&#xD;
      transplant at least 6 months previously and have stable renal function on a steroid-free&#xD;
      immunosuppressive regimen.&#xD;
&#xD;
      Potential study participants will be recruited from the Endocrinology and Transplant clinics&#xD;
      at the Ohio State University, and community physician referrals. Those who are potentially&#xD;
      eligible will undergo a screening evaluation after review of the medical records. If the&#xD;
      subject remains eligible, he/she will be enrolled in the islet transplant study and will be&#xD;
      placed on a waiting list for an islet transplant. Once a transplant becomes available, the&#xD;
      subject will be admitted to the hospital to undergo the transplant procedure. Frequent&#xD;
      follow-up visits in the transplant clinic will occur throughout the following year after the&#xD;
      transplant. Subjects will be closely monitored for adverse events and insulin requirements.&#xD;
      If the subject does not achieve insulin independence, he/she may be eligible for a subsequent&#xD;
      transplant.&#xD;
&#xD;
      There will be a 10-year enrollment with 12-month follow-up after last transplant. Since&#xD;
      subjects may be eligible for a subsequent transplant within 18 months of the first&#xD;
      transplant, the total duration may be up to 30 months after the first transplant in some&#xD;
      subjects.&#xD;
&#xD;
      The study will be completed one year after the last islet transplant. Subjects who have&#xD;
      undergone the islet transplant procedure and have completed the post-transplant evaluations&#xD;
      one year after their last transplant will be considered to have completed the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Suspended</overall_status>
  <why_stopped>
    Pausing of allotransplant program due to logistic issues.&#xD;
  </why_stopped>
  <start_date>November 2006</start_date>
  <completion_date type="Anticipated">October 2033</completion_date>
  <primary_completion_date type="Anticipated">October 2033</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of adverse events</measure>
    <time_frame>Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of serious adverse events</measure>
    <time_frame>Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant</time_frame>
    <description>Serious adverse events will be defined (in accordance with FDA Title 21 CFR 312.32) as the following:&#xD;
Death&#xD;
Life-threatening and placing the subject at immediate risk of death&#xD;
Hospitalization&#xD;
Persistent or significant disability or incapacity&#xD;
Congenital abnormal/birth defects&#xD;
Requiring medical or surgical intervention to prevent permanent damage</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of infectious complications</measure>
    <time_frame>Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of procedural-related events</measure>
    <time_frame>Day 1 post-transplant</time_frame>
    <description>Ex. Bleeding or portal vein thrombosis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 1 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 1 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of procedural-related events</measure>
    <time_frame>Day 2 post-transplant</time_frame>
    <description>Ex. Bleeding or portal vein thrombosis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 2 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 2 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of procedural-related events</measure>
    <time_frame>Day 3 post-transplant</time_frame>
    <description>Ex. Bleeding or portal vein thrombosis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 3 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 3 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 5 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 5 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 7 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 7 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 10 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 10 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 14 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 14 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 21 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 21 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of abnormalities in lipids</measure>
    <time_frame>Day 28 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 28 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of donor-specific antibody development</measure>
    <time_frame>Day 28 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 28 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 42 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 42 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 56 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 56 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 90 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 90 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of abnormalities in lipids</measure>
    <time_frame>Day 90 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of donor-specific antibody development</measure>
    <time_frame>Day 90 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 120 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 120 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 180 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 180 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of abnormalities in lipids</measure>
    <time_frame>Day 180 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of donor-specific antibody development</measure>
    <time_frame>Day 180 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 270 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 270 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of abnormalities in lipids</measure>
    <time_frame>Day 270 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of donor-specific antibody development</measure>
    <time_frame>Day 270 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of elevated liver function tests</measure>
    <time_frame>Day 365 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of abnormalities in lipids</measure>
    <time_frame>Day 365 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of hypoglycemia</measure>
    <time_frame>Day 365 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of donor-specific antibody development</measure>
    <time_frame>Day 365 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in microalbumin level</measure>
    <time_frame>Days 180 and 365 post-transplant</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in measured creatinine clearance</measure>
    <time_frame>Days 180 and 365 post-transplant</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Amount of daily insulin units required</measure>
    <time_frame>Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of C-peptide</measure>
    <time_frame>Days 1, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in c-peptide level from fasting following administration of mixed meal</measure>
    <time_frame>Days 180 and 365 post-transplant</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in acute insulin response to glucose</measure>
    <time_frame>Days 180 and 365 post-transplant</time_frame>
    <description>As determined by oral glucose tolerance test and/or intravenous glucose tolerance test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of blood glucose level &lt;140mg/dl two hours after oral glucose tolerance tests</measure>
    <time_frame>Days 180 and 365 post-transplant</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Quality of Life</measure>
    <time_frame>Days 180 and 365 post-transplant</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in hypoglycemia score</measure>
    <time_frame>Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in glycemic lability score</measure>
    <time_frame>Days 1, 2, 3, 5, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">20</enrollment>
  <condition>Type 1 Diabetes</condition>
  <arm_group>
    <arm_group_label>Subjects with preserved kidney function</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Subjects with prior kidney transplant</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Human Pancreatic Islets</intervention_name>
    <description>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.</description>
    <arm_group_label>Subjects with preserved kidney function</arm_group_label>
    <arm_group_label>Subjects with prior kidney transplant</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Type 1 diabetes &gt; 5 years&#xD;
&#xD;
          2. First islet transplant&#xD;
&#xD;
          3. Demonstrate intensive efforts to manage diabetes for last 6 months (≥4 SMBG/day, ≥3&#xD;
             injections of insulin/day or use of pump and ≥3 contacts with diabetes care team in&#xD;
             last 12 months)&#xD;
&#xD;
          4. Metabolic complications: at least one of the following:&#xD;
&#xD;
             •Reduced hypoglycemia awareness (inability to sense hypoglycemia until blood glucose&#xD;
             falls to &lt; 54 mg/dl or &gt; one hypoglycemic episode in last 12 months requiring outside&#xD;
             help and not explained by clear precipitant)&#xD;
&#xD;
             •≥2 severe hypoglycemic events or ≥2 hospitalizations for diabetic ketoacidosis (DKA)&#xD;
             in last year.&#xD;
&#xD;
          5. Ability to provide written informed consent&#xD;
&#xD;
          6. Age 18-65&#xD;
&#xD;
          7. Specific for group 2: All of above (1-6) with renal transplant at least 6 months&#xD;
             previous&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Age &lt; 18 years or &gt; 65 years&#xD;
&#xD;
          2. Inability to provide informed consent&#xD;
&#xD;
          3. Body Mass Index &gt; 29 kg/m2&#xD;
&#xD;
          4. Insulin requirement of &gt; 50 units/day&#xD;
&#xD;
          5. Stimulated C-peptide ≥ 0.2 ng/ml&#xD;
&#xD;
          6. Current panel reactive anti-HLA antibodies &gt;20%&#xD;
&#xD;
          7. Cardiovascular instability&#xD;
&#xD;
          8. Previous islet transplant&#xD;
&#xD;
          9. History of malignancy except squamous and basal cell skin cancer unless disease-free&#xD;
             for &gt; 2 years determined by independent oncologist&#xD;
&#xD;
         10. Active peptic ulcer disease&#xD;
&#xD;
         11. Condition that may interfere with absorption of medications&#xD;
&#xD;
         12. Hemoglobin A1C &gt; 12%&#xD;
&#xD;
         13. Invasive aspergillus infection within one year&#xD;
&#xD;
         14. Varicella titer index &lt;1.0&#xD;
&#xD;
         15. Rubella titer &lt;10 IU/ml&#xD;
&#xD;
         16. Psychiatric disorder&#xD;
&#xD;
         17. Untreated hyperlipidemia: fasting total cholesterol &gt;240 mg/dl, low density&#xD;
             lipoprotein&gt;130 mg/dl, or triglycerides &gt;200 mg/dl&#xD;
&#xD;
         18. Hemoglobin &lt;10 g/dl for females, and &lt;11 g/dl for males, white blood cell count &lt;&#xD;
             3,000/µL, platelet count of &lt;150,000/microliter, CD4+ count &lt;500/microliter&#xD;
&#xD;
         19. Liver function test abnormalities (if any value &gt; 1.5 times normal, candidate will be&#xD;
             excluded. If 1-1.5 times normal, test will be repeated. If re-test value remains above&#xD;
             normal, candidate will be excluded).&#xD;
&#xD;
         20. Prostate specific antigen &gt;4.0 ng/ml&#xD;
&#xD;
         21. Presence of gallstones, liver hemangioma, cirrhosis or evidence of portal hypertension&#xD;
&#xD;
         22. Untreated proliferative diabetic retinopathy&#xD;
&#xD;
         23. Females: positive pregnancy test, intent for future pregnancy, or any subject of&#xD;
             reproductive age who is not surgically sterile and is unable or unwilling to use&#xD;
             acceptable method of contraception&#xD;
&#xD;
         24. Female subjects who are breast-feeding&#xD;
&#xD;
         25. Adrenal insufficiency: 8am cortisol &gt;19 mcg/dl adequate. Values 19 mcg/dl will be&#xD;
             followed by Adreno-Corticotropic Hormone stimulation test&#xD;
&#xD;
         26. Any disease or condition that requires use of chronic steroids&#xD;
&#xD;
         27. Coagulopathy or use of chronic anticoagulation&#xD;
&#xD;
         28. Hyperthyroidism unless treated with radioactive iodine or surgery&#xD;
&#xD;
         29. Thyroid function tests outside normal range&#xD;
&#xD;
         30. Active alcoholism or other substance abuse within the past six months&#xD;
&#xD;
         31. History of non-adherence. Questionable adherence requires agreement entered and&#xD;
             compliance demonstrated for at least 3 months&#xD;
&#xD;
         32. Active infection including hepatitis B or C, human immunodeficiency virus positive,&#xD;
             positive Mantoux test [unless previously immunized with Bacillus Calmette-Guerin], or&#xD;
             X-ray evidence of pulmonary infection&#xD;
&#xD;
         33. Inability to reach hospital within 6 hours of notification&#xD;
&#xD;
         34. Failure to clear psychological or psychiatric screen&#xD;
&#xD;
         35. Medical condition or circumstance that investigator finds will interfere with safe&#xD;
             completion of the study&#xD;
&#xD;
        Exclusion criteria specific for group 1:&#xD;
&#xD;
          1. Receipt of previous transplant (excluding pancreas)&#xD;
&#xD;
          2. Creatinine clearance &lt;50 ml/minute for females and &lt;60 ml/minute for males or&#xD;
             macroalbuminuria (&gt;500 mg/24h)&#xD;
&#xD;
        Exclusion criteria specific for group 2:&#xD;
&#xD;
          1. Creatinine clearance &lt;40ml/minute&#xD;
&#xD;
          2. Renal transplant in last 6 months&#xD;
&#xD;
          3. Current use of corticosteroids&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Amer Rajab, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Ohio State University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The Ohio State University Medical Center</name>
      <address>
        <city>Columbus</city>
        <state>Ohio</state>
        <zip>43210</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>May 3, 2012</study_first_submitted>
  <study_first_submitted_qc>October 11, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 12, 2012</study_first_posted>
  <last_update_submitted>May 25, 2023</last_update_submitted>
  <last_update_submitted_qc>May 25, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 30, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Ohio State University</investigator_affiliation>
    <investigator_full_name>Amer Rajab</investigator_full_name>
    <investigator_title>Associate Professor of Surgery; Director of Pancreas and Islet Transplantation</investigator_title>
  </responsible_party>
  <keyword>Type 1 Diabetes</keyword>
  <keyword>Islet transplant</keyword>
  <keyword>Kidney transplant</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_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.</ipd_description>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01705899
org study id: IRB 2006H0200
nct id: NCT01705899
lead sponsor: 
has dmc: Yes
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.
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.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 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
measure: 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
description: 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
measure: 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
measure: Incidence of procedural-related events
time frame: Day 1 post-transplant
description: Ex. Bleeding or portal vein thrombosis
measure: Incidence of elevated liver function tests
time frame: Day 1 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 1 post-transplant
measure: Incidence of procedural-related events
time frame: Day 2 post-transplant
description: Ex. Bleeding or portal vein thrombosis
measure: Incidence of elevated liver function tests
time frame: Day 2 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 2 post-transplant
measure: Incidence of procedural-related events
time frame: Day 3 post-transplant
description: Ex. Bleeding or portal vein thrombosis
measure: Incidence of elevated liver function tests
time frame: Day 3 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 3 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 5 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 5 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 7 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 7 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 10 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 10 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 14 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 14 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 21 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 21 post-transplant
measure: Incidence of abnormalities in lipids
time frame: Day 28 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 28 post-transplant
measure: Incidence of donor-specific antibody development
time frame: Day 28 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 28 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 42 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 42 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 56 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 56 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 90 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 90 post-transplant
measure: Incidence of abnormalities in lipids
time frame: Day 90 post-transplant
measure: Incidence of donor-specific antibody development
time frame: Day 90 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 120 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 120 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 180 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 180 post-transplant
measure: Incidence of abnormalities in lipids
time frame: Day 180 post-transplant
measure: Incidence of donor-specific antibody development
time frame: Day 180 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 270 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 270 post-transplant
measure: Incidence of abnormalities in lipids
time frame: Day 270 post-transplant
measure: Incidence of donor-specific antibody development
time frame: Day 270 post-transplant
measure: Incidence of elevated liver function tests
time frame: Day 365 post-transplant
measure: Incidence of abnormalities in lipids
time frame: Day 365 post-transplant
measure: Incidence of hypoglycemia
time frame: Day 365 post-transplant
measure: Incidence of donor-specific antibody development
time frame: Day 365 post-transplant
measure: Change in microalbumin level
time frame: Days 180 and 365 post-transplant
measure: Change in measured creatinine clearance
time frame: Days 180 and 365 post-transplant
measure: 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
measure: Measurement of C-peptide
time frame: Days 1, 7, 10, 14, 21, 28, 42, 56, 90, 120, 180, 270 and 365 days post-transplant
measure: Change in c-peptide level from fasting following administration of mixed meal
time frame: Days 180 and 365 post-transplant
description: 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.
measure: Change in acute insulin response to glucose
time frame: Days 180 and 365 post-transplant
description: As determined by oral glucose tolerance test and/or intravenous glucose tolerance test
measure: Incidence of blood glucose level <140mg/dl two hours after oral glucose tolerance tests
time frame: Days 180 and 365 post-transplant
measure: Change in Quality of Life
time frame: Days 180 and 365 post-transplant
measure: 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
measure: 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
arm group label: Subjects with preserved kidney function
arm group type: Experimental
description: 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).
arm group label: Subjects with prior kidney transplant
arm group type: Experimental
description: 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 type: Drug
intervention name: Human Pancreatic Islets
description: 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.
arm group label: Subjects with preserved kidney function
arm group label: Subjects with prior kidney transplant
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Amer Rajab, MD, PhD
role: Principal Investigator
affiliation: Ohio State University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Ohio State University
investigator full name: Amer Rajab
investigator title: Associate Professor of Surgery; Director of Pancreas and Islet Transplantation
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
sharing ipd: No
ipd 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.