Immunotherapy of the Recent-onset Type 1 Diabetes in Adolescents With Repeated Courses of Rituximab

NCT07041268 | Recruiting Phase 2

• 1 other identifier: 2023-11-14
• Study Type: interventional
• Target: 116
• Locations: 1 country
• Sites: 2

Brief Summary

Type 1 diabetes (T1D) is caused by destruction of pancreatic islet beta-cells that produce insulin - the hormone required for glucose uptake by body tissues and organs. Since loss of beta-cells leads to insulin deficiency, blood glucose increases and the symptoms of T1D (thirst, hunger, excessive urination) appear. Inability of patient's tissues and organs to utilize glucose results in rapid weight loss and life-threatening acute T1D complications - ketosis and coma. To ensure glucose consumption by tissues and organs and to prevent acute complications, all patients with T1D need lifelong therapy with insulin. Insulin therapy is also necessary to prevent long-term T1D complications (eye, renal, nerve, and heart problems). By the time T1D is diagnosed, 80-90% of beta-cells have already been destroyed. However, 10-20% viable insulin-producing beta-cells remain in the pancreas over several months and even years after T1D diagnosis. The higher the percentage of the remaining beta-cells, the smaller the risk of long-term complications. Destruction of beta-cells in T1D has an autoimmune origin. It means that the patient's immune system, which is normally targeted at microbes, viruses, and other non-self substances, mistakenly destroys the beta-cells. The key role in this autoimmune reaction is played by specific cells of the immune system: T- and B-lymphocytes. T-lymphocytes directly damage the beta-cells, while B-lymphocytes support T-lymphocytes activity via antigen presentation mechanisms. Rituximab is a drug that specifically eliminates B-lymphocytes from the blood based on the CD20 surface molecule expressed on their surface, as a target. Notably, a subset of currently active T cells, including those potentially associated with pathogenesis of multiple sclerosis, also express CD20 marker on their surface. This makes them a potentially another critically important target of rituximab. In 2009 - 2014, a multicenter study in the U. S. and Canada showed that a single three-week course of rituximab infusions slightly but significantly had improved survival of residual beta-cells and their insulin-producing capacity in patients with recent-onset T1D. However, this beneficial action of rituximab lasted for only one year. We hypothesized that the repeated courses of rituximab performed over a period of 5 months could produce more profound and durable elimination of pathogenic B- and T- cells, and as a consequence prolonged survival of residual beta-cells and insulin secretion without serious adverse events. Testing this hypothesis is the goal of our study

Conditions

Diabetes Mellitus, Type 1

Outcome Measures

Primary Outcomes (1)

• Change in the Mean C-peptide Area Under Curve (AUC) Standardized by Duration of the Mixed Meal Tolerance Test

  Calculation of the AUC is based on serum C-peptide measurements performed at 0, 15, 30, 60, 90, and 120 minutes of the MMTT. The AUC is computed using the trapezoidal rule and standardized by the duration of the MMTT, i.e., the mean AUC is expressed algebraically as the AUC/120 min (picomoles/liter/120 min). Commercial nutritional drink is used as a load for MMTT. The drink volume and carbohydrate content are adjusted to participant's weight

  In the Rituximab Plus Insulin Therapy Arm, MMTT will be conducted on study days -1 (the day before the first rituximab infusion), 84, 133, 181, and 365. In the Insulin Therapy Only Arm, MMTT will be conducted on study days 1, 84, 133, 181, and 365

Secondary Outcomes (4)

• Change in Average Daily Insulin Dose

  Baseline to Day 365

• Change in Glycosylated Hemoglobin

  Baseline to Day 365

• Time in Range for Glycemia Control

  Baseline to Day 365

• Frequency of Clinically Significant Hypoglycemia

  Baseline to Day 365

Other Outcomes (3)

• Number of Participants With Adverse Events

  During the entire study (from the first rituximab infusion to the last contact with the participant up to 365 days

• Anti-Rituximab Antibody (ARitA) Titers

  Days 63, 70, 77, 85, 119, 126, 134, 140, 181, and 365

• Anti-Beta-Cell Antibody (ABCA) Titers

  Days 0, 70, 85, 134, 140, 181, and 365

Study Arms (2)

Intervention Arm: Rituximab Plus Insulin Therapy Arm

EXPERIMENTAL

In the Rituximab Plus Insulin Therapy Arm, patients will receive repeated courses of rituximab along with their routine insulin therapy

Biological: rituximab

Insulin Therapy Only Arm

NO INTERVENTION

In the Insulin Therapy Only Arm, patients will receive their routine insulin therapy

Interventions

rituximab BIOLOGICAL

Rituximab will be administered intravenously in three courses. The 1st course (loading dose) will include six rituximab infusions on days 1, 3, 5, 8, 14, and 21 of the study. On days 1, 3, and 5 rituximab will be infused at doses of 50, 125, and 200 mg per m2 of the participant's body surface area, respectively. On days 8, 14, and 21 rituximab will be infused at doses of 375 mg/m2, but not more than 500 mg total dose. The 2nd course (maintenance therapy) will include four rituximab infusions on days 63, 70, 77, and 85 at doses of 375 mg/m2, but not more than 500 mg total dose. The 3rd course (maintenance therapy) will include four rituximab infusions on days 119, 126, 134, and 140 at doses of 375 mg/m2, but not more than 500 mg total dose

Intervention Arm: Rituximab Plus Insulin Therapy Arm

Eligibility Criteria

• Age: 12 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Is 12 years to 17 years 5 months of age, inclusive, at the time of randomization/initiation of rituximab administration
• Body weight 34-80 kg for males, and 37-80 for females
• Has received a diagnosis of type 1 diabetes mellitus (T1D), ICD-10 codes E10.1 or E10.9, according to the criteria from the Russian Association of Endocrinologists
• The duration of T1D (time from diagnosis to screening) is \< 4 months
• Is able to be randomized and initiate rituximab infusions within 4 months (122 days) of the formal T1D diagnosis
• Has a peak stimulated C-peptide of ≥ 200 pmol/L from a MMTT at screening
• Is positive for at least one of T1D-related autoantibodies (ICA, GADA, IA-2A, ZnT8A) at screening
• Participant AND his/her legally authorized representative have signed the Informed Consent Form
• Citizenship of the Russian Federation

You may not qualify if:

• Has any autoimmune disease other than T1D with the exception of stable thyroid or celiac disease
• Has an active infection and/or fever
• Has a history of or serologic evidence of current or past infection with Mycobacterium tuberculosis, human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) at screening
• Has a history of primary immunodeficiency
• Has a medical, psychological or social condition that, in the opinion of the Principal Investigator, would interfere with safe and proper completion of the trial
• Participant AND his/her legally authorized representative have not signed the Informed Consent Form

Sponsors & Collaborators

• Pirogov Russian National Research Medical University: lead

Study Sites (2)

I.M. Sechenov First Moscow State Medical University (Sechenov University)

Moscow, Russia

RECRUITING

Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University

Moscow, Russia

RECRUITING

Related Publications (2)

• 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 BACKGROUND

• Greenbaum CJ, Mandrup-Poulsen T, McGee PF, Battelino T, Haastert B, Ludvigsson J, Pozzilli P, Lachin JM, Kolb H; Type 1 Diabetes Trial Net Research Group; European C-Peptide Trial Study Group. Mixed-meal tolerance test versus glucagon stimulation test for the assessment of beta-cell function in therapeutic trials in type 1 diabetes. Diabetes Care. 2008 Oct;31(10):1966-71. doi: 10.2337/dc07-2451. Epub 2008 Jul 15.

  PMID: 18628574 BACKGROUND

Related Links

• Contains the complete version of the Study Protocol (in Russian)

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

Study Officials

• Dmitry M Chudakov, Ph.D., D.Sc.

  Institute of Translational medicine, Pirogov Russian National Research Medical University

  STUDY CHAIR

• Elena E Petryaykina, M.D.

  Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University

  STUDY DIRECTOR

• Elena S Demina, M.D.

  Russian Children's Clinical Hospital, Pirogov Russian National Research Medical University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Elena E Petryaykina, M.D.

CONTACT

+79039756179; director@rdkb.ru

Alexei V Timofeev, Ph.D.

CONTACT

+79161608994; alvaltim@gmail.com

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: No masking
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 19, 2025
• First Posted: June 27, 2025
• Study Start: April 19, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): March 31, 2028
• Last Updated: July 8, 2025

Record last verified: 2025-06

Data Sharing

• IPD Sharing: Will not share

Locations

RU (2)