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

NCT00100178 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: TN02 MMF/DZBU01DK061055UC4DK097835
• Study Type: interventional
• Target: 126
• Locations: 2 countries
• Sites: 11

Brief Summary

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.

Conditions

Diabetes Mellitus, Type 1

Keywords

immunosuppressive therapy; Type 1 Diabetes TrialNet; TrialNet; POPPII; POPPII-1

Outcome Measures

Primary Outcomes (1)

• Mean Stimulated C-peptide Area Under the Curve

  The primary outcome is the area under the stimulated C-peptide curve (AUC) based on data collected at time 0 to 2 hours of a 4-hour mixed meal glucose tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30 60, 90, and 120 minutes.

  2 years

Study Arms (3)

MMF and DBZ

EXPERIMENTAL

DZB given by intravenous infusion (1 mg/kg)at baseline and 2 weeks later, and MMF given orally at dose of 600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years.

Drug: Mycophenolate mofeteil (MMF); Drug: Daclizumab (DZB)

MMF Alone

EXPERIMENTAL

MMF given orally at dose of 600 mg/m2 (2000 mg/day maximum) in 2-3 divided doses for 2 years and saline intravenous infusions given at baseline and two weeks later.

Drug: Mycophenolate mofeteil (MMF); Drug: Placebo control for Daclizumab (DZB)

Placebo

PLACEBO COMPARATOR

Placebo pills given daily for two years and saline intravenous infusions given at baseline and two weeks later.

Drug: Placebo control for Mycophenolate mofeteil (MMF); Drug: Placebo control for Daclizumab (DZB)

Interventions

Mycophenolate mofeteil (MMF) DRUG

MMF Alone; MMF and DBZ

Daclizumab (DZB) DRUG

MMF and DBZ

Placebo control for Mycophenolate mofeteil (MMF) DRUG

Placebo pills taken orally

Placebo

Placebo control for Daclizumab (DZB) DRUG

saline intravenous infusions

MMF Alone; Placebo

Eligibility Criteria

• Age: 8 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK): lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator
• Juvenile Diabetes Research Foundation: collaborator
• National Center for Research Resources (NCRR): collaborator

Study Sites (11)

Childrens Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

University of California-San Francisco

San Francisco, California, 94143, United States

Location

Stanford University

Stanford, California, 94305-5208, United States

Location

Barbara Davis Center for Childhood Diabetes, University of Colorado

Denver, Colorado, 80262, United States

Location

University of Florida

Gainesville, Florida, 32610, United States

Location

Indiana University

Indianapolis, Indiana, 46202, United States

Location

Joslin Diabetes Center

Boston, Massachusetts, 02215, United States

Location

University of Minnesota

Minneapolis, Minnesota, 55455, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Benaroya Research Institute

Seattle, Washington, 98101, United States

Location

Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

Related Publications (7)

• Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, Lachin JM, Polonsky KS, Pozzilli P, Skyler JS, Steffes MW. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes. 2004 Jan;53(1):250-64. doi: 10.2337/diabetes.53.1.250.

  PMID: 14693724 BACKGROUND

• Kaufman DB, Leventhal JR, Stuart J, Abecassis MM, Fryer JP, Stuart FP. Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases. Transplantation. 1999 Feb 27;67(4):586-93. doi: 10.1097/00007890-199902270-00017.

  PMID: 10071032 BACKGROUND

• Feutren G, Papoz L, Assan R, Vialettes B, Karsenty G, Vexiau P, Du Rostu H, Rodier M, Sirmai J, Lallemand A, et al. Cyclosporin increases the rate and length of remissions in insulin-dependent diabetes of recent onset. Results of a multicentre double-blind trial. Lancet. 1986 Jul 19;2(8499):119-24. doi: 10.1016/s0140-6736(86)91943-4.

  PMID: 2873396 BACKGROUND

• Placebo-controlled study of mycophenolate mofetil combined with cyclosporin and corticosteroids for prevention of acute rejection. European Mycophenolate Mofetil Cooperative Study Group. Lancet. 1995 May 27;345(8961):1321-5.

  PMID: 7752752 BACKGROUND

• Brazelton TR, Morris RE. Molecular mechanisms of action of new xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide. Curr Opin Immunol. 1996 Oct;8(5):710-20. doi: 10.1016/s0952-7915(96)80090-2.

  PMID: 8902398 BACKGROUND

• Gottlieb PA, Quinlan S, Krause-Steinrauf H, Greenbaum CJ, Wilson DM, Rodriguez H, Schatz DA, Moran AM, Lachin JM, Skyler JS; Type 1 Diabetes TrialNet MMF/DZB Study Group. Failure to preserve beta-cell function with mycophenolate mofetil and daclizumab combined therapy in patients with new- onset type 1 diabetes. Diabetes Care. 2010 Apr;33(4):826-32. doi: 10.2337/dc09-1349. Epub 2010 Jan 12.

  PMID: 20067954 RESULT

• Loechelt BJ, Boulware D, Green M, Baden LR, Gottlieb P, Krause-Steinrauf H, Weinberg A; Type 1 Diabetes TrialNet Daclizumab/Mycophenolic Acid Study Group. Epstein-Barr and other herpesvirus infections in patients with early onset type 1 diabetes treated with daclizumab and mycophenolate mofetil. Clin Infect Dis. 2013 Jan;56(2):248-54. doi: 10.1093/cid/cis848. Epub 2012 Oct 5.

  PMID: 23042974 DERIVED

Related Links

• TrialNet Study Group
• American Diabetes Association

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Daclizumab

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Peter Gottleib, MD
• Organization: Barbara Davis Center for Childhood Diabetes, Health Sciences Center, University of Colorado

Peter.Gottleib@uchsc.edu

303-724-6714

Study Officials

• Jay S Skyler, M.D.

  University of Miami

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 23, 2004
• First Posted: December 24, 2004
• Study Start: May 1, 2004
• Primary Completion: April 1, 2008
• Study Completion: April 1, 2008
• Last Updated: May 5, 2020
• Results First Posted: August 16, 2016

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will share

Locations

CA (1); US (10)