Rituximab in New Onset Type 1 Diabetes

Type 1 Diabetes Mellitus Clinical Trial

— TN05  

Official title:

Effects of Rituximab on the Progression of Type 1 Diabetes in New Onset Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00279305
• Other study ID #: TN05 Ritux
• Secondary ID: U01DK061055
• Status: Completed
• Phase: Phase 2
• Start date: August 2005
• Est. completion date: November 2009

Study information

• Verified date: April 2020
• Source: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 87
• Est. completion date: November 2009
• Est. primary completion date: April 2009
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 45 Years

Eligibility

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

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 1
• Type 1 Diabetes Mellitus

Intervention

Drug:
• Anti-CD20 (rituximab)

• Placebo Comparator
Placebo intravenous infusion

Locations

Country	Name	City	State
Australia	Walter and Eliza Hall Institute of Medical Research	Victoria
Canada	The Hospital for Sick Children	Toronto	Ontario
Italy	San Raffaele Hospital	Milan
United States	Barbara Davis Center for Childhood Diabetes	Aurora	Colorado
United States	Joslin	Boston	Massachusetts
United States	University of Texas	Dallas	Texas
United States	University of Florida	Gainesville	Florida
United States	Indiana University-Riley Hospital for Children	Indianapolis	Indiana
United States	Childrens Hospital of Los Angeles	Los Angeles	California
United States	University of Miami	Miami	Florida
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 California-San Francisco	San Francisco	California
United States	Benaroya Research Institute	Seattle	Washington
United States	Stanford University	Stanford	California

Sponsors (5)

Lead Sponsor	Collaborator
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)	American Diabetes Association, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Juvenile Diabetes Research Foundation, National Institute of Allergy and Infectious Diseases (NIAID)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Italy, 

References & Publications (10)

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. — View Citation

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. Erratum in: J Pediatr. 2004 Apr;144(4):558. — View Citation

Edwards JC, Leandro MJ, Cambridge G. B lymphocyte depletion in rheumatoid arthritis: targeting of CD20. Curr Dir Autoimmun. 2005;8:175-92. — View Citation

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. — View Citation

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. — View Citation

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. Rit — View Citation

Pescovitz MD. The use of rituximab, anti-CD20 monoclonal antibody, in pediatric transplantation. Pediatr Transplant. 2004 Feb;8(1):9-21. Review. — View Citation

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. Review. — View Citation

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. — View Citation

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. Epub 2003 Jan 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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

External Links

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