New Onset of Type 1 Diabetes Mycophenolate Mofetil-Daclizumab Clinical Trial

New Onset of Type 1 Diabetes Mycophenolate Mofetil-Daclizumab Clinical Trial (Preservation of Pancreatic Production of Insulin Through Immunosuppression-POPPII #1)

The objective of this study is to identify immune intervention strategies that will preserve residual beta cell function at the onset of type 1 diabetes. Scientific evidence developed over the last 10 - 20 years suggests that type 1 diabetes is a chronic, slowly progressive autoimmune disease and that clinical symptoms do not develop until at least 80% - 90% of beta cell mass has been destroyed as a result of the autoimmune process. It is now recognized that preservation of remaining beta cells is clinically important as the ability to secrete, even small amounts of insulin, can make the disease easier to control and help minimize complications associated with having years of inadequate glycemic control.

This clinical trial is the first in a series of studies to be launched by the TrialNet Study Group to test various interventions for preserving residual beta cell function in new onset type 1 diabetes. Specifically, this study is designed to determine the ability of Mycophenolate Mofetil (MMF/CellCept) used alone, or in combination with Daclizumab (DZB/Zenapax) to see if it is possible to stop the immune system from destroying beta cells in new onset type 1 diabetes patients (within 3 months of diagnosis.)

Researchers have made great strides in understanding how the immune system works and in changing the activity of immune cells with medicines called immunotherapies. Some immunotherapies work by making the immune system less active. Scientists have discovered that key immune cells, called T cells, help to cause type 1 diabetes. These T cells are largely responsible for attacking the beta cells that produce insulin. Doctors have found medicines that slow or suppress the activity of T cells. It is hoped that these immunosuppressive medicines can help treat type 1 diabetes by stopping T cells before they destroy all of the beta cells.

Medicines that make the immune system less active have been developed and studied for other diseases. Mycophenolate mofetil (MMF) and Daclizumab (DZB) are two of these medicines. Their effects on the immune system are well understood. Researchers believe these medicines may lessen the immune system's destruction of beta cells that leads to type 1 diabetes. In addition, researchers hope the effect of these medicines will last longer than other therapies.

The goal of this study is to find out if two medicines are able to stop the ongoing destruction of beta cells which are still functioning at the time type 1 diabetes is diagnosed. The two immunosuppressive medications being tested are Mycophenolate mofetil (MMF/CellCept®) and Daclizumab (DZB/Zenapax®). They work by making the immune system less active. TrialNet researchers hope that these medications will help maintain insulin secretion from remaining beta cells and thus help to maintain better glycemic control. Even if the medications work, study participants will still need to take insulin injections but it may make it easier to control normal blood sugar levels which can help reduce long-term complications of diabetes such as blindness, kidney failure, nerve damage, heart attack and stroke.

The aim is to arrest beta cell destruction in newly diabetic subjects because immune modulation may not work well alone once the autoimmune process has progressed to complete or near complete destruction of beta cells. The study's rationale is to demonstrate a meaningful preservation of islet function with minimal immune system side effects over the 4-year course of this study.

The data from this clinical trial could serve as the basis for a larger trial if the results are sufficiently positive, or they could suggest other combined intervention trials that might achieve either better efficacy or potentially preserve C-peptide without the need for continued immunosuppression.

Design of Study:

The study is a multi-center, three-arm, randomized, double-masked, placebo-controlled clinical trial. Comparisons will be made among the three groups, which are:

• Mycophenolate mofetil active drug with Daclizumab (DZB) placebo IV
• Mycophenolate mofetil active drug with active Daclizumab IV
• Mycophenolate mofetil placebo with Daclizumab placebo IV

Participants that agree to enroll in the study will be asked to take study medications for two years. MMF is given by mouth twice a day. DZB is given by an intravenous infusion twice, once at the time of enrollment and again two weeks later. Both these medications are approved by the U.S. Food and Drug Administration and are used by people who have received an organ transplant. This study is testing a new use of these medications to preserve insulin secretion by delaying or stopping further destruction of insulin-secreting cells in people with newly diagnosed type 1 diabetes. Both MMF and DZB make the immune system less active. Participants will be monitored closely for any possible side effects that can occur from taking either DZB and/or MMF due to decreased activity of the immune system.

Participants will need to go to the Clinical Center for visits and tests. For the first month participants will come in every week; then participants will come in at month 2 and month 3. After the month 3 visit, visits will occur about every three months. At most visits, blood will be drawn and participants will meet with a study physician to review their overall diabetes management, and be monitored for any possible side-effects from the study medication.

Participants will be asked to do a longer test called a Mixed Meal Tolerance Test (MMTT) at the initial visit and at five additional visits while taking the assigned study medication. The MMTT involves drinking a special drink which has a controlled amount of carbohydrates, protein, and fat to measure residual insulin secretion. The test requires having an IV inserted into the arm and having blood samples taken from the IV over a period of 2 to 4 hours. After completing the two year period of taking the study medication, participants will be asked to return every 3-6 months for an additional 1-2 years to evaluate their ability to secrete insulin after discontinuing the study medication.

Inclusion Criteria:

Potential participants must meet the following inclusion criteria:

• Be within 3-months of diagnosis of type 1 diabetes based on American Diabetes Association (ADA) criteria
• Be between the ages of 8 and 45 years old
• Must have stimulated C-peptide levels > 0.2 pmol/ml (measured during an MMTT administered no more than one month prior to the date of randomization)
• Must have either detectable anti-GAD, anti-ICA512/IA-2, insulin autoantibodies (unless received insulin therapy for 7 days or more), or islet cell autoantibodies.

[The reason for inclusion of these enrollment criteria is to avoid inclusion of patients with "Type 1B diabetes mellitus", which may not involve the immunologic criteria measured by the assays that will be utilized.]

• If participant has reproductive potential, he or she must be agreeable to an effective form of birth control (unless abstinence is the chosen method).
• If participant is female with reproductive potential, she must be willing to undergo pregnancy testing and to report possible or confirmed pregnancies promptly during the course of the MMF/DZB study.
• Must be willing to comply with intensive diabetes management. The goal of management will be an HbA1c of 7.0% for all participants, regardless of age. Participants will be expected to take a sufficient number of daily insulin shots to meet this goal. Alternatively, participants can use insulin pump therapy. Participants will also be expected to test their blood sugar at least 3-4 times per day. There will be a Certified Diabetes Educator working with study participants to achieve these goals.

Exclusion Criteria:

Potential participants must not meet any of the following exclusion criteria:

• Have any complicating medical issues that would interfere with blood drawing or monitoring.
• Have a Body Mass Index (BMI) that is greater than the 95th percentile for age and gender.
• Have serologic evidence of HIV infection.
• Have serologic evidence of Hepatitis B infection.
• Have serologic evidence of Hepatitis C infection.
• Have abnormal liver function tests.
• Have a history of leukopenia and/or neutropenia.
• Have a history of chronic peptic ulcer disease, erosive esophagitis, chronic inflammatory bowel disease and/or chronic colonic disease.
• Have a positive PPD test result.
• Have had any live vaccinations in the preceding 6 weeks (e.g. MMR-second dose, live flu vaccine, varicella vaccine, live polio vaccine, yellow fever vaccine).
• Resides outside reasonable geographical proximity to the clinic (i.e., residence outside the state in which the Investigator and study reside, residence outside an immediately neighboring state, or residence outside an area that the Investigator considers reasonable). It is left to the Investigator's discretion to decide if a patient's geographical residence is prohibitive to complete study participation.
• Require chronic use of steroids or other immunosuppressive agents for other conditions.
• Be currently pregnant or 3 months postpartum.
• Be currently nursing or within 6 weeks of having completed nursing.
• Anticipate getting pregnant, or fathering a child, during the study.