Rituximab in New Onset Type 1 Diabetes

NCT ID: NCT00279305

Last Updated: 2020-05-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 87 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2005-08-31
• Study Completion Date: 2009-11-30

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.

Detailed Description

The study is a randomized, two-arm, trial in which 2/3 of participants will receive the study drug, while the remaining 1/3 will receive a placebo (a pretend medicine that does nothing). The group you are assigned to is decided by chance (as by the toss of a coin or drawing straws). Neither you nor your doctor will be able to choose which group you are in. Also, neither you nor the researchers will know which group you are in. Participants will take rituximab, or the placebo, once a week during the first 4 weeks in the study. It will be given as an intravenous infusion at a clinical center.

Participants will need to return to the clinical center for a visit about every 3 months for two years; those participants that continue to secrete insulin will have further follow-up for an additional two years.

Conditions

Type 1 Diabetes Mellitus

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Rituximab Intravenous Infusion

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

Group Type: EXPERIMENTAL

Anti-CD20 (rituximab)

Intervention Type: DRUG

Placebo Intravenous Infusion

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

Group Type: PLACEBO_COMPARATOR

Placebo Comparator

Intervention Type: DRUG

Placebo intravenous infusion

Interventions

Anti-CD20 (rituximab)

Intervention Type: DRUG

Placebo Comparator

Placebo intravenous infusion

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

• Minimum Eligible Age: 8 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

American Diabetes Association

OTHER

Sponsor Role: collaborator

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role: collaborator

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carla Greenbaum, MD

Role: STUDY_CHAIR

Type 1 Diabetes TrialNet

Locations

Childrens Hospital of Los Angeles

Los Angeles, California, United States

University of California-San Francisco

San Francisco, California, United States

Stanford University

Stanford, California, United States

Barbara Davis Center for Childhood Diabetes

Aurora, Colorado, United States

University of Florida

Gainesville, Florida, United States

University of Miami

Miami, Florida, United States

Indiana University-Riley Hospital for Children

Indianapolis, Indiana, United States

Joslin

Boston, Massachusetts, United States

University of Minnesota

Minneapolis, Minnesota, United States

Columbia University

New York, New York, United States

University of Pittsburgh

Pittsburgh, Pennsylvania, United States

University of Texas

Dallas, Texas, United States

Benaroya Research Institute

Seattle, Washington, United States

Walter and Eliza Hall Institute of Medical Research

Victoria, , Australia

The Hospital for Sick Children

Toronto, Ontario, Canada

San Raffaele Hospital

Milan, , Italy

Countries

United States; Australia; Canada; Italy

References

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.

Reference Type: BACKGROUND

PMID: 15009836 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 9166663 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12531800 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 14615729 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15564721 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15598985 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15636611 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15201414 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12408054 (View on PubMed)

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.

Reference Type: RESULT

PMID: 19940299 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24026563 (View on PubMed)

Related Links

http://www.diabetestrialnet.org

Type 1 Diabetes TrialNet

http://www.diabetes.org

American Diabetes Association

http://www.jdrf.org

Juvenile Diabetes Foundation International

Other Identifiers

U01DK061055

Identifier Type: NIH

Identifier Source: secondary_id

View Link

TN05 Ritux

Identifier Type: -

Identifier Source: org_study_id