Islet Transplantation Using Abatacept
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 1
Intervention: Efalizumab; Abatacept; Belatacept
Intervention description: 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 Upon efalizumab being withdrawn from the US market, the protocol was amended to alter the immunosuppressive regimen to abatacept for the study participants.; Abatacept is drug used to treat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.; 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).
Intervention MeSH terms: Abatacept
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 5.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      Islet transplantation in type 1 diabetics with hypoglycemic unawareness using abatacept as a
      part of a novel calcineurin-inhibitor-sparing immunosuppressive regimen.
    

Eligibility criteria:

        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.)