Clinical Trials and Registration
• Islet Transplantation for People with Type 1 Diabetes
• How is an Islet Transplant Performed?
• What are the Risks Associated with an Islet Transplant?
• What are the Benefits Associated with an Islet Transplant?
• What is the Success Rate for Islet Transplants?
• How to Participate in our Clinical Trials
• Questions You May Wish to Consider Before Entering into a Clinical Trial
• Register to Participate in Our Clinical Trials
Islet Transplantation for People with Type 1 Diabetes
The purpose of an islet transplant is safe and effective treatment of Type 1 diabetes. Although islet transplants have been performed in clinical trials for years they are not yet considered standard medical care. What is exciting is that the outcomes of islet transplant clinical trials have significantly improved over the years. Continuing clinical trials are needed to further improve the success rate of islet transplantation.
Insulin therapy, whether by injection or insulin pump, is life-saving, however, insulin therapy is not perfect. Most people with type 1 diabetes still have blood glucose levels that are above normal, putting them at risk for long-term complications of diabetes. Patients able to keep their blood glucose levels near normal often have trouble with low blood glucose (hypoglycemia). After a number of years with type 1 diabetes some people lose the early symptoms such as sweating, dizziness, extreme hunger that warn them that their blood glucose level is at a low level. The inability to sense a low blood glucose is called hypoglycemia unawareness and raises the risk of severe hypoglycemia. Severe hypoglycemia is defined as needing help from someone else to raise the blood glucose such as giving juice, soda pop, or glucagon. The possible advantage of islet transplantation over giving insulin via injections or pump is that the transplanted islets would maintain normal blood sugar under all conditions, and would not produce excess insulin resulting in hypoglycemia.
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How is an Islet Transplant Performed?
Islets transplanted into people with diabetes come from the pancreas of a deceased organ donor. An overview of the process is shown below. The islets are isolated from a decreased donor’s pancreas and infused into the recipient’s liver via the portal vein. The transplanted islets then produce insulin in response to sugars found in the blood as it flows through the liver.
A number of critical steps must be taken in a timely fashion to complete an islet transplant.
1. The donor pancreas is obtained by a highly skilled group of physicians. The University of Minnesota has a dedicated team on call to obtain pancreases.
2. The pancreas is brought to a facility the University of Minnesota whose purpose is to make biological products such as human islets. At this facility, staff members isolate and purify the islets. This process takes more than six hours.
3. The pancreas is cut into small pieces and put in a special container with steel marbles. The container is shaken, and enzymes are added to break down the tissue so the islets are freed from the rest of the tissue.
4. The islet tissue cells are removed, washed, counted and checked to be sure they are not damaged. On average, approximately 500,000 of the 1 million islets in a pancreas can be retrieved. This number of islets can usually maintain normal blood sugar levels. If the number or quality of islets is not satisfactory, the transplant must be cancelled.
5. If the number or quality of islets is satisfactory, the islets are cultured for two days before transplant.
Islet transplantation is a usually done in the radiology (X-ray) department and it takes 30 minutes to 2 hours. The recipient receives some sedation but remains awake. Islets are put into the body through a catheter (tube) in a vein of the liver. This vein is called the portal vein. The catheter can be placed in two different ways. The study doctors will decide which way would be safest for you. The two possible ways are:
1. Placement of islets through a needle going through the skin into the liver. If you have this procedure it will be done in an x-ray room. You will receive medication to sedate you and medication to numb an area on your right side between two ribs. The doctor will insert a needle into your liver. A computed tomography (CT) scan or an ultrasound will be used to help the doctor get the needle into the portal vein. A kind of dye will be injected to make sure that the catheter is in this vein.
2. Placement of the islets through a small cut in the skin. If you have this small operation, you will receive a medication to sedate you and a local anesthetic (numbing medicine) will be injected into your upper abdomen. A cut (no longer than two inches) will be made and the catheter will be inserted into a branch of the portal vein. If you receive your islets in this way, after all the islets have been given, the catheter will be removed and the cut will be closed with stitches that will dissolve when the cut is healed.
Recipients recover quickly from the procedure and are typically discharged from the hospital 2-3 days after the infusion. To monitor the patient’s health status and to determine how the islets are functioning, the islet transplant recipient will have to visit the University of Minnesota numerous times in the first year post-transplant as an outpatient. A second or third islet transplant is considered if the first does not stop the need for insulin injections or if blood glucose control is not well managed.
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What are the Risks Associated with an Islet Transplant?
Although islet cell transplantation is being developed as a safe alternative to pancreas transplantation, people who participate in islet transplant trials may have more problems resulting from study participation than if they continued insulin treatment alone. Islet cell transplantation is an experimental treatment. As with any experimental treatment, there is a risk that rare or previously unknown complications can occur.
There are two main types of risks associated with islet cell transplantation:
First, the risks associated with the transplant procedure itself. These risks include slowed breathing from the anesthesia, severe bleeding, blood clots, abnormal liver function, accidental injury to organs, infection, decrease in blood pressure, pain, extra exposure to x-rays, allergic reaction to contrast dye, and very rarely, death.
Second, there are risks associated with the use of anti-rejection drugs, also known as immunosuppressive drugs or immunosuppressants. These drugs are needed for all transplants. Immunosuppressive drugs must be taken to prevent the body from rejecting a transplanted organ. Anti-rejection drugs may weaken the recipient’s immune system, which can lead to serious infections and even cancer.
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What are the Benefits Associated with an Islet Transplant?
If successful, the transplanted islets will produce enough insulin so that the transplant recipient will no longer need to take insulin shots or use an insulin pump. A successful transplant will also control blood sugar levels in a normal or close to normal range and therefore will prevent low blood sugars. If the transplant is partially successful, the recipient may benefit from more stable blood sugar control, needing less insulin, with fewer low blood sugars. Because improved control of blood sugar has been shown to slow the complications of diabetes, islet transplant recipients may benefit whether their transplant is fully successful or partially successful. Preliminary studies suggest that islet transplants also improve quality of life. At this time larger studies monitoring development and progression of diabetes complications and quality of life in more transplant recipients for longer durations are needed to assess the true benefits of islet transplantation.
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What is the Success Rate for Islet Transplants at our Program?
Since 2000, we have completed 4 islet transplant trials involving 32 patients with type 1 diabetes (Am J Transplantation 2004, 4:390-401; JAMA 2005, 293: 830-835; NEJM 2006, 355:1318-1330; Am J Transplant 2008 8:2463-70). All participating subjects had suffered from hypoglycemia unawareness that had persisted despite intensive efforts made by the patient in close coordination with their diabetes care team. None of our patients has experienced a serious, unexpected adverse event related to the islet transplant procedure or the immunosuppressive protocol.
Protection from hypoglycemia has been immediate post transplant in all cases. More than 80% of our recipients remain protected from severe hypoglycemia 5 years post transplant. About 90% of our recipients have become insulin-independent post transplant; more than 50% have maintained insulin independence at 5-year follow-up. These results are comparable to outcomes previously only attainable by whole organ pancreas transplantation.
Several of our past participants have agreed to share their stories with you. We are grateful to them for sharing their experiences. Read stories from...
David Larson
DeLynn Lalli
Donna Chandler
Joanie Videen
Lorna Zaworski
Lynn Hopperstad Mitchell
Tony Pecora
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How to Participate in our Clinical Trials
All clinical trials at the Schulze Diabetes Institute at the University of Minnesota have Inclusion and Exclusion criteria. These are the medical or social standards determining whether a person may or may not be allowed to enter a clinical trial. These criteria are based on such factors as age, gender, the type and stage of disease, previous treatment history, and other medical conditions. It is important to note that inclusion and exclusion criteria are not used to personally reject people but identify potential subjects and keep them safe.
Inclusion Criteria
In order to qualify for an islet transplant trial at the University of Minnesota, you must meet the following criteria:
• Have had Type 1 Diabetes for more than 5 years
• Be age 18 to 68
• Be checking blood sugar at least 3 times per day
• Be administering at least 3 insulin injections per day, or using an insulin pump
• Have a complication from diabetes, (such as not having warning symptoms when blood sugar is low)
• Have seen a diabetes care team at last 3 times in the last year
If your application demonstrates that you meet these criteria, you will be contacted and additional screening may be conducted to further determine your eligibility.
Exclusion Criteria
Any of the following situations will exclude you from being able to participate in an islet transplant trial at the University of Minnesota at this time:
• Females who are currently pregnant, intend to become pregnant, or are presently breast-feeding
• Males who intend to father children
• Have an active or past infection with hepatitis C, hepatitis B, HIV, or TB (or under treatment for suspected TB)
• Have any history of cancer except for adequately treated skin cancer
• Have had a heart attack within the past 6 months or extensive coronary artery disease
• Are under treatment for a medical condition requiring chronic use of steroids such as prednisone
Please do not be discouraged if you do not currently meet these criteria. We are working to expand the criteria so that in the future everyone with type 1 diabetes can benefit from an islet transplant, if they are eligible and wish to do so.
If you are not eligible to participate in an islet transplant clinical trial, you may want to consider getting a pancreas transplant.
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Questions You May Wish to Consider Before Entering into a Clinical Trial
Some factors that you should consider before you are contacted for possible enrollment in an islet transplant clinical trial include:
1. There are many follow-up appointments, usually involving 13-16 visits after the transplant. Ask yourself, am I willing to travel to the University of Minnesota for these visits? Can I afford this much travel?
2. If you choose to participate in an islet transplant clinical trial you will be asked to take immunosuppressive drugs. Ask yourself, am I willing to take immunosuppressive drugs on a continuous basis as long as the transplant is functioning either fully or partially?
3. Immunosuppressive drugs are paid for during clinical trial participation only. Coverage after the trial period may be available through your health insurance. If your transplant is successful at the end of the study and you have functioning islets, you will have to continue on immunosuppressive drugs indefinitely to keep the islets functioning. Ask yourself, how will the cost of immunosuppressive drugs be covered when the clinical trial ends?
4. Detailed record keeping is very important during study participation. Ask yourself, will I be able to check my blood glucose 5-7 times/day and maintain adequate records regarding insulin use and side affects of drugs?
5. The Islet Transplant Research team provides care for blood glucose management and immunosuppression dosing. All other medical care, including potential side effects of drugs, will be provided by your primary care physician, endocrinologist, and other specialists. Ask yourself, do I have a good relationship with my care providers?
6. Participating in research is voluntary. You have the right to decide whether you wish to become a research subject. Ask yourself, is being a research participant right for me? A participant can leave a clinical trial at any time. When withdrawing from the trial, the participant should let the research team know they wish to leave the study, and the reasons for leaving the study.
7. There is no guarantee that islet transplantation will be successful. It is possible that a transplant will not make you completely free from insulin use. If the transplant is partially successful, you may benefit from more stable blood sugar control, needing less insulin, with fewer insulin reactions. Because improved control of blood sugar can slow the complications of diabetes, islet transplant recipients may benefit whether their transplant is successful or partially successful. Preliminary studies suggest that islet transplants improve quality of life.
8. If you do become insulin independent, there is no guarantee that you will maintain this state for any specific length of time. It is unknown why this happens and it could occur at any time.
9. Should you consider a pancreas transplant? A pancreas transplant means the whole pancreas is transplanted, with islet cells intact. This procedure is considered part of standard medical care and has been done throughout the world for many years. The success rate for recipients being insulin-free one year after transplant is 80 to 85%; after three years it is 75 to 80%. A pancreas transplant is major surgery requiring general anesthesia and a longer recovery time. Complications from the surgery occur in about 10 to 15% of the recipients, requiring a longer hospital stay or readmission to the hospital.
In comparing an islet transplant and a pancreas transplant, keep in mind that an islet transplant means the islets are isolated from the pancreas and then are infused into a transplant recipient. This procedure has not yet received approval from the FDA as standard medical care; the safety and efficacy of the procedure are currently being evaluated through research studies called clinical trials. An islet transplant is a less invasive procedure, so patients experience shorter recovery times than those who have a pancreas transplant. People who have a functioning pancreas or islet transplant must be on immunosuppressive drugs to prevent their body from rejecting the foreign tissue.
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