Islet Transplantation Using Abatacept
Condition: Type 1 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 1
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Efalizumab; Abatacept; Belatacept
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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).
Other intervention name(s): Raptiva; Orencia; Nulojix
Intervention MeSH terms: Abatacept
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment