Islet Cell Transplantation Clinical Trials

Study Purpose
The purpose of this study is to determine if early reduction of T-cells in the recipient will improve islet transplant results in patients with type 1 diabetes. T-cells are special white blood cells that recognize and destroy unwanted things like infections but can also attack transplanted cells and organs. Reducing the number of T-cells at the time of transplant is expected to protect islets and improve long-term transplant results. This study hopes to show the safety of islet transplantation using an immunosuppression regimen which reduces T-cells; determine if islets survive longer using this immunosuppression regimen; better understand the reasons for islet cell dysfunction and rejection; and, assess for changes in the quality of life after islet transplantation.

Who Can Participate?
Because islet transplantation remains an experimental procedure, criteria for study participation are very strict.

To qualify for the study, candidates must have type 1 diabetes, be between the ages of 18 and 68, and have the ability and willingness to comply with a post-transplant regimen that includes taking immunosuppression medications, attending frequent clinic visits and laboratory testing, using reliable contraception, maintaining detailed records of blood glucose levels, insulin doses, medications and completing detailed follow-up studies for up to five (5) years.
Candidates never receiving a previous pancreas or islet cell transplant will have hypoglycemic episodes more than once a week, have hypoglycemic unawareness or have experienced one or more severe hypoglycemic episodes in the last 12 months. A severe hypoglycemic event has one or more of the following symptoms: memory loss, confusion, uncontrollable or irrational behavior, unusual difficulty awakening, suspected or confirmed seizure, loss of consciousness or visual disturbances for which the patient was unable to treat her/himself and which was associated with a blood glucose level less than or equal to 54mg/dL, or prompt recovery after receiving oral carbohydrates, IV glucose or glucagon.

Candidates who have had a previous pancreas or islet cell transplant must also have had a failed pancreas transplant more than 6 months prior to screening for this study or have received two or fewer islet transplants greater than 1 months prior to screening, still need injectable insulin, and/or have a hemoglobin A1c level greater than 6.5%.

Candidates who have received a prior kidney transplant for diabetic kidney failure must also have a stable kidney transplant for at least 3 months prior to screening, and be on stable doses of anti-rejection medications. Permissible medications include tacrolimus alone or together with sirolimus, and mycophenolate (mofetil or sodium) or azathioprine; OR cyclosporine alone or together with sirolimus, and mycophenolate (mofetil or sodium) or azathioprine. Candidates must also be taking 10mg or less of steroids daily, have no history of kidney rejection in the past 12 months, be considered at low risk for rejection, and be under the care of a transplant doctor who will provide a letter of support for the candidate’s participation in this study.

Note: Interested study candidates on anti-rejection medications other than the combinations above SHOULD NOT make any changes to their anti-rejection medication regimen on their own. Changing anti-rejection medications or doses may increase the risk of rejecting the kidney transplant and should only be done under the supervision of the patient's transplant doctor.

Before being accepted onto the TCD study, patients must undergo a detailed physical exam, blood tests, and other tests to ensure that they (and their kidney transplant, if applicable) are healthy enough to undergo islet transplantation and meet the study eligibility criteria. Patients cannot participate in this research study if they have diseases of the heart, liver, gallbladder, and/or kidney, if they have cancers other than basal or squamous skin cancer, infections or other chronic illnesses.

Pre-transplant Evaluation
Qualified patients will be placed on the United Network of Organ Sharing (UNOS) waiting list for islet transplantation.

When islets from a potential donor are identified, the patient will be admitted to City of Hope for advanced testing to crossmatch the donor and patient and to confirm that the patient is healthy enough to receive the islets. If the match is acceptable and the patient is healthy, the transplant can proceed and induction immunosuppression using antithymoglobulin and other agents (etanercept, anakinra) can begin.

Islet transplantation is performed by an Interventional Radiologist under the direction of a Transplant Surgeon. The Radiologist inserts a small tube through the liver into the portal vein using ultrasound for guidance. Once the tube is in position, the islets are infused into the vein and lodge in the liver. The process usually takes about 30 minutes. Patients are sedated for comfort, but remain awake for the procedure. After all the islets are infused, the tube is removed and the site is sealed to prevent bleeding. The patient is then taken to the recovery room.

Because additional doses of antithymoglobulin are planned, patients may be kept in the hospital for observation and treatment for up to a week. When the antithymoglobulin course is completed and the patient is stable, s/he can be sent home with medications and a plan for follow-up visits.

Patients will need to continue taking immunosuppressive and other medications after islet transplantation to protect the islets and prevent infection. Patients who have had a previous kidney transplant will continue on the anti-rejection medications previously prescribed by the transplant doctor. Other patients will be started on a course of anti-rejection medications including tacrolimus and mycophenolate mofetil. At two months after the transplant, the tacrolimus will be replaced by sirolimus.

Additional medications to prevent infection (Vancomycin, Imipenem, Bactrim, clotrimazole, valganciclovir) will be given.

Other medications are given for a short period to prevent blood clots (enoxaparin) or stimulate the creation of white blood cells (filgrastim).

Supplements to promote the health of the islets and the patient (Vitamin E, Nicotinamide, Pravastatin, Iron) and medications believed to help the islets grow (Januvia, Nexium) are also prescribed.

After Islet Transplantation
Patients will need to continue testing their blood sugar (glucose) levels frequently (before and after meals and at bedtime) with frequent adjustments being made to insulin doses over the next several weeks as the islets settle into their new home.  Although a goal of the study is to provide and maintain enough islets to eliminate the need for injectable insulin and/or eliminate life-threatening hypoglycemic events with a single transplant, patients are eligible for up to three islet transplant procedures under this trial. As previously mentioned, patients will be asked to return for follow-up clinic visits for up to 5 years after islet transplant to monitor for patient safety, assess islet function, monitor the patient’s immune response to the transplanted islets and assess for changes in quality of life, as described below. The visit frequency will decrease over time from a few times per week immediately after transplant to once every 6 months after 2 years.

To find out how quality of life will be affected after islet transplant, patients will be asked to complete a set of questionnaires before islet transplantation and periodically after islet transplantation. The questions asked patients to rank their feelings about their overall health, diabetes, diabetes treatment, the impact diabetes has on work, relationships and life, and the frequency and severity of potential diabetes-related symptoms.

Possible Complications
Islet transplantation is an experimental procedure and may have side-effects related to the transplant itself and the anti-rejection medications.

Islet transplantation may cause bleeding at the site of islet infusion, infection, blood clot in the veins of the liver, and abdominal pain. Islet transplant may also cause the immune system to make antibodies to donor tissue. This could increase the risk of rejecting the previous kidney transplant (if applicable) and may make it difficult to find a matching donor should future organ transplantation become necessary.

Anti-rejection medications can have several side effects. Some of the most common include mouth ulcers, anemia (low red blood cells that cause symptoms of tiredness), leg swelling, nausea, vomiting, diarrhea, high cholesterol or fat levels in the blood, liver problems, high blood pressure, fatigue, kidney problems, abnormal menstrual periods in women, and an increased risk of infection. Anti-rejection medications may also increase the risk of developing cancer.
Interested in participating?
If you think you meet the criteria and are interested in the T-cell Depleting (TCD) study, you may visit to the Contact Information Page. You may also call our toll-free patient screening line 866-44-ISLET (47538) or e-mail us at [email protected].
Study Purpose
The purpose of this protocol is to collect medical information from islet transplant recipients after they have completed (or withdrawn) from participation in their original islet transplant protocol.  This allows continued assessment of the safety and effectiveness of the procedure and for continued reporting to the islet transplant registries.

Who Can Participate?
Adults (age 18 yrs old or greater) with type 1 diabetes previously treated with islet transplantation who are no longer participating in the original islet transplant treatment study can be considered for study participation.

What Will be Done?
Subjects will continue to be followed by their primary medical team with visits to COH every 6 months for follow-up assessment.  If subjects are unable or unwilling to attend in-person follow-up visits to COH, they may choose to participate in telephone interviews conducted by a COH study staff member. Six month visits/phone calls are scheduled based on the date of the subject’s last islet transplant.

Subjects who return to City of Hope for follow-up will be monitored for:
1) Diabetic Complications
Participants are evaluated for complications related to their diagnosis of diabetes. They are asked to provide their blood sugar/insulin records, complete a symptom checklist, undergo a physical exam, including testing of the feet for diabetic neuropathy and testing eyes for retinal function. A small amount of blood is also drawn for routine lab tests.  Collection of a 24-hour urine sample is performed annually to monitor kidney function.

2) Islet Transplant Function
Specialized blood tests are performed which measure how well the transplanted islets are working, including:
  • Hemoglobin A1c measures average blood sugar levels over the previous 2-3 months.
  • Continuous glucose monitoring involves wearing a small pager-like device connected to a tiny sensor inserted just under the skin. The sensor measures sugar levels continuously for 3 days and results are downloaded to a computer for analysis by the islet cell transplant team.
  • C-peptide to glucose, creatinine ratio testing requires fasting overnight.  Blood is drawn in the morning to measure the C-peptide, glucose, creatinine insulin and proinsulin levels, to determine how much insulin the transplanted islets are producing.
  • Glucagon stimulation also requires overnight fasting and involves taking a blood sample to measure glucose levels before and after a glucagon injection. Glucagon stimulates the liver to release stored sugars which should cause the transplanted islets to make insulin.
  • Intravenous (through the vein) glucose tolerance test (IVGTT) involves measuring how effective the transplanted islets are in reducing blood sugar levels in response to a sugar (glucose) injection. Multiple blood samples are taken before and for 30 minutes after the injection to measure blood sugar levels.

3) Immune System Monitoring
The immune system consists of organs, tissues, and cells that normally fight infections or respond to the presence of other foreign substances. After a transplant, this process may lead to rejection of the islets. Several biological markers are measured from blood samples to monitor for signs of rejection including islet autoantibodies and a panel of common tissue types to which antibodies may have formed (PRA). The presence or absences of these antibodies help doctors determine if the body’s immune system is reacting to the islet transplant.  If positive results are detected, additional blood samples may be requested for further testing.

4) Quality of Life
To find out how quality of life is affected after islet transplant, patients are asked to complete a set of questionnaires every 12 months. The questions ask subjects to rank their feelings about their overall health, being diagnosed with diabetes, their diabetes treatment, the impact diabetes has on their work, relationships and life, the frequency with which they experience diabetes-related symptoms and how bothersome they are.

Subjects who are NOT able to return to City of Hope:
Subjects who are not able to come to City of Hope for check-ups will be contacted by City of Hope a study staff member by telephone every six months to obtain information about their health.  Telephone interviews are expected to last 10-20 minutes.  Subjects are asked about their health and to list any illnesses, severe low blood sugar episodes, hospitalizations, surgery or other health problems that he/she might have experienced since last contact.  Subjects contacted by phone will also be asked to provide detailed blood sugar and insulin records as well as copies of recent laboratory tests drawn by their treating physician.

Possible Complications
Although uncommon, complications may occur with blood draws and specific metabolic studies:
  • Blood Draw: The risks of drawing blood include temporary discomfort, bleeding or bruising from the needle stick, anemia, dizziness, and very rarely, an infection where the needle was inserted.
  • Glucagon stimulation: The risks of glucagon stimulation testing include temporary nausea, vomiting, abdominal pain and rash.
  • IVGTT: Risks related to IVGTT are temporary pain and bruising at the IV site, pain from the injection of the sugar water solution, and potential temporary high blood sugar levels.

If you have questions about this Long-Term Follow-Up Study, contact the ICT Coordinator at (626) 256-HOPE (4673) ext. 60057.
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