Rituximab in New Onset Type 1 Diabetes

NCT00279305 | Completed Phase 2 Results DMC

• 2 other identifiers: TN05 RituxU01DK061055
• Study Type: interventional
• Target: 87
• Locations: 4 countries
• Sites: 16

Brief Summary

Type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks the insulin-producing beta cells in the pancreas. Without these beta cells, the body cannot maintain proper blood glucose levels in response to daily activities such as eating or exercise. With fewer insulin producing cells blood glucose increases, causing hunger, thirst, and unexplained weight loss. By the time these symptoms develop, 80-90% of a person's beta cells have already been destroyed. However, this also means that between 10-20% of these cells remain that continue to produce insulin. Scientists have learned that two types of immune cells, B cells and T cells, are involved in causing type 1 diabetes. T cells are responsible for attacking and destroying the beta cells that make insulin. Although they don't attack insulin producing cells, B cells may be what trigger the T cells to attack. This study will investigate the use of rituximab to see if it can help lower the number of immune B cells thereby preventing the destruction of any remaining insulin producing beta cells that remain at diagnosis. Rituximab is approved by the Food and Drug Administration (FDA) for the treatment of a condition called B-lymphocyte lymphoma. Its effects on the immune system are well understood through its use in organ transplantation. Research has shown that rituximab might be helpful in treating other conditions caused by T cells and B cells, including type 1 diabetes. The goal of this study is to find out if rituximab can preserve residual insulin secretion and prevent further beta cell destruction in type 1 diabetes.

Conditions

Type 1 Diabetes Mellitus

Keywords

Newly diagnosed type 1 diabetes; New Onset type 1 diabetes; Preservation of insulin secretion; Type 1 diabetes; Juvenile Onset Diabetes; Insulin Dependent Diabetes; T1D

Outcome Measures

Primary Outcomes (1)

• Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4-hour Mixed Meal Tolerance Test (MMTT) Administered at 1 Year

  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. The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the "AUC mean" and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis.

  When all participants complete the 1 year visit

Study Arms (2)

Rituximab Intravenous Infusion

EXPERIMENTAL

Participants will receive active rituximab (anti-CD20 monoclonal antibody) as an intravenous infusion, with 4 administrations at weeks 0, 1, 2, and 3 at a dose of 375mg/m2

Drug: Anti-CD20 (rituximab)

Placebo Intravenous Infusion

PLACEBO COMPARATOR

Participants will receive placebo given as an intravenous infusion with 4 administrations at weeks 0, 1, 2, and 3.

Drug: Placebo Comparator

Interventions

Anti-CD20 (rituximab) DRUG

Rituximab Intravenous Infusion

Placebo Comparator DRUG

Placebo intravenous infusion

Placebo Intravenous Infusion

Eligibility Criteria

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

You may qualify if:

• Between the ages of 8 and 45 years
• Within 3 months of diagnosis of type 1 diabetes
• Have presence of at least one diabetes-related autoantibody
• Must have stimulated C-peptide levels of at least 0.2 pmol/ml measured during a mixed meal tolerance test (MMTT) within one month of randomization
• If female with reproductive potential, willing to avoid pregnancy and undergo pregnancy testing while participating in the study
• Have not received an immunization for at least one month
• Must be willing to comply with intensive diabetes management
• Must weigh at least 25 kg at study entry

You may not qualify if:

• Are immunodeficient or have clinically significant chronic lymphopenia
• Have an active infection or positive purified protein derivative (PPD) test result
• Currently pregnant or lactating; or anticipate becoming pregnant.
• Require chronic use of steroids
• Have current or past HIV, hepatitis B, or hepatitis C infection
• Have any complicating medical issues that interfere with study conduct or cause increased risk
• Have a history of malignancies
• Currently using non-insulin pharmaceuticals that effect glycemic control
• Currently participating in another type 1 diabetes treatment 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
• American Diabetes Association: collaborator
• Juvenile Diabetes Research Foundation: collaborator

Study Sites (16)

Childrens Hospital of 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, United States

Location

Barbara Davis Center for Childhood Diabetes

Aurora, Colorado, 80010, United States

Location

University of Florida

Gainesville, Florida, 32610-0296, United States

Location

University of Miami

Miami, Florida, 33136, United States

Location

Indiana University-Riley Hospital for Children

Indianapolis, Indiana, 46202, United States

Location

Joslin

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

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

University of Texas

Dallas, Texas, 75235-8858, United States

Location

Benaroya Research Institute

Seattle, Washington, 98101, United States

Location

Walter and Eliza Hall Institute of Medical Research

Victoria, Australia

Location

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

Location

San Raffaele Hospital

Milan, Italy

Location

Related Publications (11)

• Pescovitz MD. The use of rituximab, anti-CD20 monoclonal antibody, in pediatric transplantation. Pediatr Transplant. 2004 Feb;8(1):9-21. doi: 10.1046/j.1397-3142.2003.00135.x.

  PMID: 15009836 BACKGROUND

• Noorchashm H, Noorchashm N, Kern J, Rostami SY, Barker CF, Naji A. B-cells are required for the initiation of insulitis and sialitis in nonobese diabetic mice. Diabetes. 1997 Jun;46(6):941-6. doi: 10.2337/diab.46.6.941.

  PMID: 9166663 BACKGROUND

• Zecca M, Nobili B, Ramenghi U, Perrotta S, Amendola G, Rosito P, Jankovic M, Pierani P, De Stefano P, Bonora MR, Locatelli F. Rituximab for the treatment of refractory autoimmune hemolytic anemia in children. Blood. 2003 May 15;101(10):3857-61. doi: 10.1182/blood-2002-11-3547. Epub 2003 Jan 16.

  PMID: 12531800 BACKGROUND

• Binstadt BA, Caldas AM, Turvey SE, Stone KD, Weinstein HJ, Jackson J, Fuhlbrigge RC, Sundel RP. Rituximab therapy for multisystem autoimmune diseases in pediatric patients. J Pediatr. 2003 Nov;143(5):598-604. doi: 10.1067/s0022-3476(03)00382-2.

  PMID: 14615729 BACKGROUND

• Edwards JC, Leandro MJ, Cambridge G. B lymphocyte depletion in rheumatoid arthritis: targeting of CD20. Curr Dir Autoimmun. 2005;8:175-92. doi: 10.1159/000082103.

  PMID: 15564721 BACKGROUND

• Sidner RA, Book BK, Agarwal A, Bearden CM, Vieira CA, Pescovitz MD. In vivo human B-cell subset recovery after in vivo depletion with rituximab, anti-human CD20 monoclonal antibody. Hum Antibodies. 2004;13(3):55-62.

  PMID: 15598985 BACKGROUND

• Bearden CM, Agarwal A, Book BK, Vieira CA, Sidner RA, Ochs HD, Young M, Pescovitz MD. Rituximab inhibits the in vivo primary and secondary antibody response to a neoantigen, bacteriophage phiX174. Am J Transplant. 2005 Jan;5(1):50-7. doi: 10.1111/j.1600-6143.2003.00646.x.

  PMID: 15636611 BACKGROUND

• Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004 Jun 17;350(25):2572-81. doi: 10.1056/NEJMoa032534.

  PMID: 15201414 BACKGROUND

• Serreze DV, Silveira PA. The role of B lymphocytes as key antigen-presenting cells in the development of T cell-mediated autoimmune type 1 diabetes. Curr Dir Autoimmun. 2003;6:212-27. doi: 10.1159/000066863. No abstract available.

  PMID: 12408054 BACKGROUND

• Pescovitz MD, Greenbaum CJ, Krause-Steinrauf H, Becker DJ, Gitelman SE, Goland R, Gottlieb PA, Marks JB, McGee PF, Moran AM, Raskin P, Rodriguez H, Schatz DA, Wherrett D, Wilson DM, Lachin JM, Skyler JS; Type 1 Diabetes TrialNet Anti-CD20 Study Group. Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N Engl J Med. 2009 Nov 26;361(22):2143-52. doi: 10.1056/NEJMoa0904452.

  PMID: 19940299 RESULT

• Pescovitz MD, Greenbaum CJ, Bundy B, Becker DJ, Gitelman SE, Goland R, Gottlieb PA, Marks JB, Moran A, Raskin P, Rodriguez H, Schatz DA, Wherrett DK, Wilson DM, Krischer JP, Skyler JS; Type 1 Diabetes TrialNet Anti-CD20 Study Group. B-lymphocyte depletion with rituximab and beta-cell function: two-year results. Diabetes Care. 2014 Feb;37(2):453-9. doi: 10.2337/dc13-0626. Epub 2013 Sep 11.

  PMID: 24026563 DERIVED

Related Links

• Type 1 Diabetes TrialNet
• American Diabetes Association
• Juvenile Diabetes Foundation International

MeSH Terms

Conditions

Diabetes Mellitus, Type 1

Interventions

Rituximab

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, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Carla Greenbaum, MD
• Organization: Type 1 Diabetes TrialNet

cjgreen@benaroyaresearch.org

Study Officials

• Carla Greenbaum, MD

  Type 1 Diabetes TrialNet

  STUDY CHAIR

Publication Agreements

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

Study Design

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

Study Record Dates

• First Submitted: January 17, 2006
• First Posted: January 19, 2006
• Study Start: August 1, 2005
• Primary Completion: April 1, 2009
• Study Completion: November 1, 2009
• Last Updated: May 6, 2020
• Results First Posted: August 18, 2016

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will share

Locations

IT (1); US (13); AU (1); CA (1)