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Islet Transplantation Using Abatacept

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ClinicalTrials.gov Identifier: NCT00276250
Recruitment Status : Completed
First Posted : January 13, 2006
Results First Posted : July 27, 2016
Last Update Posted : July 27, 2016
Sponsor:
Collaborator:
Juvenile Diabetes Research Foundation
Information provided by (Responsible Party):
Nicole Turgeon MD, Emory University

Tracking Information
First Submitted Date  ICMJE January 12, 2006
First Posted Date  ICMJE January 13, 2006
Results First Submitted Date  ICMJE April 25, 2016
Results First Posted Date  ICMJE July 27, 2016
Last Update Posted Date July 27, 2016
Study Start Date  ICMJE December 2005
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2016)
The Number of Insulin-independent Subjects at Day 75 (± 5 Days) Following the First Islet Cell Transplantation [ Time Frame: 75 days post-transplantation ]
Original Primary Outcome Measures  ICMJE
 (submitted: January 12, 2006)
The proportion of insulin-independent subjects at day 75 (± 5 days) following the first islet cell infusion.
Change History Complete list of historical versions of study NCT00276250 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 16, 2016)
  • Number of Insulin-independent Subjects Following Islet Transplantation [ Time Frame: 1, 3, 6, 9,12,18 and 24 months post-transplantation ]
    Participants who did not need to take insulin at 1, 3, 6, 9, 12, 18, and 24 months following islet transplantation
  • Number of Subjects With HbA1C Less Than 6.5% [ Time Frame: 6 months post-transplantation ]
    HbA1C was assessed in the subjects 6 months after transplantation and the number of subjects with values less than 6.5% was recorded which indicated better control of blood glucose levels.
  • Number of Subjects With HbA1C Levels < 6.5% [ Time Frame: 12 months post-transplantation ]
    HbA1C was assessed in the subjects 12 months after transplantation and the number of subjects with levels < 6.5% was recorded which indicated better control of blood glucose levels.
  • Number of Subjects With HbA1C < 6.5% [ Time Frame: 24 months post-transplant ]
    HbA1C was assessed in the subjects 24 months after transplantation and the number of subjects with levels < 6.5% was recorded which indicated better control of blood glucose levels.
  • Number of Subjects With HbA1C < 6.5% [ Time Frame: 36 months post-transplantation ]
    HbA1C was assessed in the subjects 36 months after transplantation and the number of subjects with values < 6.5% was recorded which indicated better control of blood glucose levels.
  • Number of Participants With Endogenous Insulin Production Post-transplant, Assessed by Fasting C-peptide Levels [ Time Frame: 1, 3, 6, 9,12,18 and 24 months post-transplantation ]
    The number of subjects exhibiting C-peptide levels ≥ 0.5 ng/mL was recorded.
  • The Number of Study Participants Exhibiting a Successful Response to a Standard Mixed Meal Test, Measured by Stimulated C-peptide Levels After Islet Transplant. [ Time Frame: 1, 3, 6, 9,12,18 and 24 months post-transplantation ]
    The number of study participants who have detectable C-peptide levels after stimulation from a Mixed Meal Test. An increase of C-peptide indicates that insulin is being released normally in response to food consumption.
  • Number of Subjects With Normal Renal Function, as Measured by Serum Creatinine Levels [ Time Frame: 24 months after transplant ]
    Renal function was assessed by measuring levels of serum creatinine. Normal values range from 0.7 to 1.3 mg/dL for men and 0.6 to 1.1 mg/dL for women.
Original Secondary Outcome Measures  ICMJE
 (submitted: January 12, 2006)
  • The proportion of patients achieving insulin independence and a normal HbA1C at one year after a single islet infusion
  • The proportion of patients attaining and maintaining insulin independence and a normal HbA1C at one year after their completion transplant.
  • The proportion of study participants exhibiting IV arginine-stimulated acute C-peptide response in blood of > 0.17 nmol/L (0.51 ng/mL) at 1, 3, and 6 Months and 1, 2 and 3 years after the completed islet transplant.
  • The proportion of study participants exhibiting IV glucose-stimulated acute C-peptide response in blood of > 0.30 nmol/L (0.90 ng/mL) at 1, 3, and 6 Months and 1, 2 and 3 years after the completed islet transplant.
  • The proportion of study participants exhibiting IV glucose-stimulated acute insulin response in blood of > 15.0 mU/L (104.2 pmol/L) at 1, 3, and 6 Months and 1, 2 and 3 years after the completed islet transplant.
  • The proportion of study participants exhibiting HbA1C values less than 6.5% at 3 and 6 months and at 1 and 2 years after the completed islet transplant.
  • The proportion of study participants exhibiting a successful response to a standard mixed meal test at 1, 3, 6, 9 and 12, 15, 18, 21, 27, 30 and 33 months after the completed islet transplant.
  • Safety, including incidence of post-transplant infections, malignancies, morbidity, and other adverse events (e.g., increased body weight and hypertension) associated with conventional immunosuppression.
  • Renal function as measured by serum creatinine, GFR by cold iothalamate clearance, and other relevant laboratory parameters
  • Lipid profiles (triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol) over time.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Islet Transplantation Using Abatacept
Official Title  ICMJE Development of Immunosuppression Regimens to Facilitate Single Donor Islet Transplantation Using Abatacept
Brief Summary Islet transplantation in type 1 diabetics with hypoglycemic unawareness using abatacept as a part of a novel calcineurin-inhibitor-sparing immunosuppressive regimen.
Detailed Description

More than 1 million North Americans have type 1 diabetes. Each year, approximately 30,000 new cases of type 1 diabetes are diagnosed in the United States. Type 1 diabetes destroys islets, a cluster of cells within the pancreas that produce insulin. Insulin is a hormone with many effects. However, the most important effect of insulin is to control the level of sugar in the blood. People with Type 1 diabetes no longer produce insulin and must take insulin injections to live. Despite steady improvements in the management of this disease, its victims remain at increased risk for stroke, heart attack, kidney failure, amputation, blindness, nerve damage and premature death. The life expectancy of a teenager is reduced by thirty years from the time of onset of the disease [1]. Unfortunately, many type 1 diabetics cannot control their blood sugars in spite of very careful monitoring and the frequent injection of insulin. This group of patients is considered to have labile or "brittle" diabetes. These "brittle" diabetics can often have wide swings in their blood sugar levels that can be life threatening. Hypoglycemia, or low blood sugars occur when too much insulin is in the bloodstream. When this occurs, it is vital that patients eat or drink something right away that will increase their blood sugars. Many diabetics lose the ability to recognize when their blood sugars are getting dangerously low. These episodes of hypoglycemia can lead to coma, and possibly death, if not recognized and treated right away. Patients can also experience extreme increases in blood sugars, or hyperglycemia, as a result of emotional or physical stress. Hyperglycemia can result in dehydration, confusion, and a condition called ketoacidosis, which can lead to death. When this happens, insulin must be given as soon as possible.

Islet transplantation can restore the body's ability to make insulin and, in turn, restore normal blood sugar levels.

Since the 1960's, doctors and scientists have attempted to replace this islet function by performing whole organ pancreas transplantation. While the results of pancreas transplantation have improved dramatically in recent years, this approach has largely been limited to patients with kidney disease who have also needed a kidney transplant. This is because of the risks associated with the surgical procedure and the immunosuppressive drugs required to prevent rejection or the destruction of the transplanted pancreas by the body's immune system [2]. Transplantation of a whole pancreas requires a major operation that is done through an incision in the abdomen. The patient must be under general anesthesia, or asleep, for the entire procedure. Recent clinical experience suggests that islet transplantation may be a useful approach to correct diabetes in humans [3].

Islet transplantation offers a direct approach to the treatment of type 1 diabetes. A large number of experimental studies carried out in many laboratories over the last decade have documented the beneficial effects of islet transplants in experimental animals. These experiments have confirmed both the efficiency and safety of islet transplantation [4,5].

The inability to isolate enough islets from a single pancreas has been one obstacle to successful islet transplantation. A certain number of islets must be isolated, or separated, from a single pancreas in order to use them for transplant. If this minimum number of islets is not obtained, then the islets do not effectively reverse diabetes. Progress in isolating the islets from a human pancreas has been dramatic in the last several years. Advances in equipment and technology have lead to increases in the number of islets that can be isolated from a single pancreas.

After successful isolation, the islets can be injected through a catheter into the patient's liver during a thirty-minute procedure. A group of doctors at the University of Alberta in Edmonton, Canada has had promising results in human islet transplantation. Normal sugar levels have been documented after human islet transplants. Also, recent improvements in immunosuppressive drug treatments have resulted in sustained insulin-independence in selected type 1 diabetic patients [6-9,10,11,12]. The traditional method of transplant immunosuppression includes using some form of a steroid drug. Steroids have been found to injure or kill the islets after transplant. The doctors in Edmonton, Canada established an immunosuppression formula that does not use steroids. The objective of the study here at Emory University is to reproduce the successful results of human islet transplantation that have been achieved by the doctors at the University of Alberta using steroid free immunosuppression.

The Emory Islet Transplant Program will enroll up to 20 participants, ages 18 to 65, in this study. Each of the twenty patients will receive up to 3 islet infusions from three different cadaver donors. Each patient will be placed on immunosuppressive drugs to prevent the body from rejecting or destroying the transplanted islets. In this study we are using a medication, abatacept, to help prevent organ rejection. This medication has been previously used in people to treat psoriasis. The participants will also receive basiliximab and sirolimus as immunosuppressant medications.

Each patient will have his/her blood sugar levels and insulin requirements monitored very closely after each transplant. The patients will also have various tests to determine if their diabetic complications improve, remain the same, or become worse. The patients will be asked to record any episodes of hypoglycemia or low blood sugars while participating in this study. Emory will examine whether or not there is a decrease in how often the episodes occur. Patients will also undergo regular eye exams to document retinal changes or improvements that may occur after transplant. At this time it is not known whether islet transplantation slows or stops the progression of common diabetic complications. More experience and research is needed before this can be determined. One focus of our research will be to study diabetic complications in patients who receive islet transplants.

The major goal of the Emory Islet Transplant Program is for patients participating in this study to be free of the need for insulin injections after 2 islet transplants. Because many advances have been made in islet transplantation, the transplant team at Emory would like to participate in this promising treatment of type 1 diabetes and, most importantly, help those who suffer from this disease become free from daily insulin injections and avoid the devastating complications that happen as a result of diabetes.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Type 1 Diabetes Mellitus
Intervention  ICMJE
  • Drug: Efalizumab
    Efalizumab was a medication approved for use in psoriasis which was being explored to determine efficacy with immunosuppression following organ transplantation. Efalizumab was administered subcutaneously on a weekly basis. Upon efalizumab being withdrawn from the US market, the protocol was amended to alter the immunosuppressive regimen to abatacept for the study participants.
    Other Name: Raptiva
  • Drug: Abatacept
    Abatacept is drug used to treat autoimmune diseases. Abatacept is administered intravenously, monthly, in weight-based doses and is given for as long as transplanted islets are functioning.
    Other Name: Orencia
  • Drug: Belatacept
    Belatacept is a medication to provide extended graft survival while limiting the toxicity generated by standard immune suppressing regimens. Belatacept is administered intravenously. The protocol for this study was amended to substitute belatacept for abatacept for all newly enrolling participants (current participants remained on abatacept).
    Other Name: Nulojix
Study Arms  ICMJE
  • Experimental: Efalizumab Followed by Abatacept Regimen
    Participants with Type 1 diabetes with onset of disease at < 40 years of age and insulin-dependence for > 5 years received efalizumab-based immunosuppression regimen after islet-cell transplantation. During the course of the study, efalizumab was withdrawn from the US market due to safety concerns. The protocol was subsequently amended to alter the immunosuppressive regimen to abatacept for these participants.
    Interventions:
    • Drug: Efalizumab
    • Drug: Abatacept
  • Experimental: Abatacept Regimen
    Participants with Type 1 diabetes with onset of disease at < 40 years of age and insulin-dependence for > 5 years received abatacept immunosuppresion regimen after islet-cell transplantation.
    Intervention: Drug: Abatacept
  • Experimental: Belatacept Regimen
    Participants with Type 1 diabetes with onset of disease at < 40 years of age and insulin-dependence for > 5 years received Belatacept immunosuppresion regimen after islet-cell transplantation.
    Intervention: Drug: Belatacept
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 Completed
Actual Enrollment  ICMJE
 (submitted: September 26, 2013)
5
Original Enrollment  ICMJE
 (submitted: January 12, 2006)
20
Actual Study Completion Date  ICMJE December 2014
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male and Female patients age 18 to 65 years of age
  • Clinical history compatible with type 1 diabetes with onset of disease at <40 years of age and insulin-dependence for >5 years at the time of enrollment.
  • Body mass index less than or equal to 26
  • 18 to 65 years of age
  • Absent stimulated C-peptide (<0.3ng/ml) in response to a mixed meal tolerance test (Boost® 6 mL/kg body weight to a maximum of 360 mL; another product with equivalent caloric and nutrient content may be substituted for Boost) measured at 90min after the end of consumption.
  • Compliance with an optimized diabetic management plan as assessed by an Emory University endocrinologist
  • Checking and recording blood sugars at least 3 times per day
  • Involvement in intensive diabetes management defined as self monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy. Such management must be under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the previous 12 months.
  • At least one episode of severe hypoglycemia in the past 3 years defined as an event with symptoms compatible with hypoglycemia in which the subject required the assistance of another person and which was associated with either a blood glucose level <50 mg/dL [2.8 mmol/L] or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration).
  • Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more and a HYPO score greater than or equal to the 90th percentile (1047) within the last 6 months prior to randomization; OR Marked glycemic lability characterized by wide swings in blood glucose despite optimal diabetes therapy and defined by a glycemic lability index (LI) score greater than or equal to the 90th percentile (433 mM2/h/wk) within the last 6 months prior to randomization; OR A composite of a Clarke score of 4 or more and a HYPO score greater than or equal to the 75th percentile (423) and a LI greater than of equal to the 75th percentile (329) within the last 6 months prior to randomization.

Exclusion Criteria:

  • Severe co-existing cardiac disease, characterized by any one of these conditions:
  • Recent myocardial infarction (within past six months)
  • Left Ventricular Ejection Fraction < 30%
  • Evidence of ischemia on a functional echocardiogram
  • Active infection including hepatitis B, hepatitis C, HIV, or TB as determined by a positive skin test or clinical presentation, or under treatment for suspected TB. Positive tests are acceptable only if associated with a history of previous vaccination in the absence of any sign of active infection. Positive tests are otherwise not acceptable, even in the absence of any active infection at the time of evaluation
  • Invasive aspergillus infection within one year prior to study entry.
  • Negative screen for Epstein-Barr Virus (EBV) by IgG determination.
  • Administration of live vaccine within the past two months
  • Measured glomerular filtration rate using iohexol <70 mL/min/1.73 m2 for females and <80 mL/min/1.73 m2 for males (or a 24 hr. creatinine clearance with participants allergic to iodine <85mL/min/1.73m2).
  • Macroalbuminuria (urinary protein excretion rate >300 mg/24h)
  • Baseline Hgb below the lower limits of normal at the local laboratory; lymphopenia (<1,000/L), neutropenia (<1,500/L), or thrombocytopenia (platelets <100,000/ L).
  • Hyperlipidemia (fasting LDL cholesterol >130 mg/dL, treated or untreated; and/or fasting triglycerides >300 mg/dL)
  • Negative antibody test for Varicella zoster virus (subjects may be reconsidered if they receive the vaccination and convert to a positive antibody)
  • History of malignancy (except squamous or basal cell skin carcinoma) within the previous 5 years
  • Previous/concurrent organ transplantation
  • Presence of HLA Panel Reactive Antibodies >20%
  • Active peptic ulcer disease
  • Evidence of gallbladder disease including cholecystitis and cholelithiasis
  • Evidence of liver disease including: hepatic neoplasm, portal hypertension, or persistently abnormal liver function tests
  • Current use of systemic steroid medications
  • Evidence of insulin resistance (insulin requirements >0.8 units/kg/day)
  • Inability to provide informed consent
  • Severe unremitting diarrhea, vomiting or other gastrointestinal disorders potentially interfering with the ability to absorb oral medications.
  • Hyperlipidemia despite medical therapy (fasting LDL cholesterol >130 mg/dL, treated or untreated; and/or fasting triglycerides >200 mg/dL).
  • Acute or chronic pancreatitis.
  • Symptomatic peptic ulcer disease.
  • Use of any other investigational agents within 4 weeks of participation.
  • Any condition or any circumstance that makes it unsafe to undergo an islet cell transplant
  • Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after transplantation (low-dose aspirin treatment is allowed) or patients with an INR >1.5.
  • Sickle Cell Anemia (Subjects with Sickle Cell Anemia, trait HbSS, are at high risk for complications after transplantation related to immunosuppressive therapy. These complications include stroke and sickle cell crisis. Therefore, we will exclude these subjects from our study to minimize risks to study subjects.)
  • For female participants: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 3 months after discontinuation. For male participants: intent to procreate during the duration of the study or within 3 months after discontinuation or unwillingness to use effective measures of contraception. Oral contraceptives, Norplant®, Depo-Provera®, and barrier devices with spermicide are acceptable contraceptive methods; condoms used alone are not acceptable.
  • Active alcohol or substance abuse. This includes cigarette smoking (must be abstinent for six months). Active alcohol abuse should be considered using the current NIAAA definitions, whereby alcohol abuse is defined by a pattern of drinking that is accompanied by one or more of the following situations within a 12-month period:
  • Failure to fulfill major work, school, or home responsibilities
  • Drinking in situations that are physically dangerous, such as while driving a car or operating machinery
  • Recurring alcohol-related legal problems, such as driving under the influence of alcohol or for causing physical harm to someone while intoxicated
  • Continued alcohol abuse despite having ongoing relationship problems that are caused or worsened by the effects of alcohol
  • Psychiatric disorder making the subject not a suitable candidate for transplantation, e.g., schizophrenia, bipolar disorder, or major depression that is unstable or uncontrolled on current medication. (A psychological or psychiatric consultation is required only if considered necessary by some current indication or history.)
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 NCT00276250
Other Study ID Numbers  ICMJE IRB00021852
1136-2005 ( Other Identifier: Emory University )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Nicole Turgeon MD, Emory University
Study Sponsor  ICMJE Emory University
Collaborators  ICMJE Juvenile Diabetes Research Foundation
Investigators  ICMJE
Principal Investigator: Christian P Larsen, MD, D.Phil Emory University
Principal Investigator: Thomas C Pearson, MD, D,Phil Emory University
Study Director: Sallie C Carpentier, RN, BSN Emory University
Principal Investigator: Nicole Turgeon, MD Emory University
PRS Account Emory University
Verification Date June 2016

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