Rituximab in New Onset Type 1 Diabetes

Tracking Information
First Submitted Date ICMJE	January 17, 2006
First Posted Date ICMJE	January 19, 2006
Results First Submitted Date	May 12, 2016
Results First Posted Date	August 18, 2016
Last Update Posted Date	November 2, 2016
Study Start Date ICMJE	August 2005
Actual Primary Completion Date	April 2009 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: September 27, 2016)	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 [ Time Frame: When all participants complete the 1 year visit ]; 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.
Original Primary Outcome Measures ICMJE; (submitted: January 17, 2006)	Area under the stimulated C-peptide curve over the first 2 hours of a 4-hour MMTT administered at 1 year
Change History	Complete list of historical versions of study NCT00279305 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE	Not Provided
Original Secondary Outcome Measures ICMJE; (submitted: January 17, 2006)	-Area under stimulated C-peptide curve over the first 2 hours of a 4-hour MMTT administered at 2 years; Insulin dose (units/kg) and number of injections; Glycosylated hemoglobin (HbA1c)
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Rituximab in New Onset Type 1 Diabetes
Official Title ICMJE	Effects of Rituximab on the Progression of Type 1 Diabetes in New Onset Subjects
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.
Study Type ICMJE	Interventional
Study Phase	Phase 2
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
Condition ICMJE	Type 1 Diabetes Mellitus
Intervention ICMJE	Drug: Anti-CD20 (rituximab); Drug: Placebo Comparator Placebo intravenous infusion
Study Arms	Experimental: 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 Intervention: Drug: Anti-CD20 (rituximab); Placebo Comparator: Placebo Intravenous Infusion Participants will receive placebo given as an intravenous infusion with 4 administrations at weeks 0, 1, 2, and 3. Intervention: Drug: Placebo Comparator
Publications *	Pescovitz MD. The use of rituximab, anti-CD20 monoclonal antibody, in pediatric transplantation. Pediatr Transplant. 2004 Feb;8(1):9-21. Review.; 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.; 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.; 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.; Edwards JC, Leandro MJ, Cambridge G. B lymphocyte depletion in rheumatoid arthritis: targeting of CD20. Curr Dir Autoimmun. 2005;8:175-92.; 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.; 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.; 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.; 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.; 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 β-cell function: two-year results. Diabetes Care. 2014 Feb;37(2):453-9. doi: 10.2337/dc13-0626. Epub 2013 Sep 11.; 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: January 5, 2009)	87
Original Enrollment ICMJE; (submitted: January 17, 2006)	66
Actual Study Completion Date	November 2009
Actual Primary Completion Date	April 2009 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	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
Sex/Gender	Sexes Eligible for Study: All
Ages	8 Years to 45 Years (Child, Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	Australia, Canada, Italy, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00279305
Other Study ID Numbers ICMJE	Ritux (IND) (completed)
Has Data Monitoring Committee	Yes
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Plan to Share IPD: Yes
Responsible Party	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study Sponsor ICMJE	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Collaborators ICMJE	National Institute of Allergy and Infectious Diseases (NIAID); Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); American Diabetes Association; Juvenile Diabetes Research Foundation
Investigators ICMJE	Study Chair: Carla Greenbaum, MD Type 1 Diabetes TrialNet
PRS Account	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Verification Date	September 2016
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP