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
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
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
Parallel
rituximab
Biological/VaccineRituximab 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
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
Change in Average Daily Insulin Dose
The average weight-ajusted daily insulin dose will be calculated based on data recorded by participants in their electronic diary (eDiary). Will be assessed in both arms
Change in Glycosylated Hemoglobin
Change in content of glycosylated hemoglobin HbA1c in blood, % and mmol/mol. Will be assessed in both arms
Time in Range for Glycemia Control
Time in range (%) for glycemia control will be assessed using participant's continuous glucose monitoring (CGM) or flash glucose monitoring (FGM) device. Time in range is defined as daily average percentage of time a participant's glucose is ≥ 3.9 mmol/L and \<10 mmol/L. Will be assessed in both arms
Frequency of Clinically Significant Hypoglycemia
Frequency here = (clinically significant hypoglycemic episode)/(participant-year). A clinically significant hypoglycemia is defined as a blood glucose level of \<3.0 mmol/L or a hypoglycemia episode with severe cognitive impairment requiring external assistance (seizure, syncope, severe confusion) with or without a confirmatory low blood glucose. Hypoglycemia frequency will be calculated for each participant as (number of episodes)/365 days. The number of hypoglycemic episodes will be extracted from participant's eDiary. Will be assessed in both arms
Number of Participants With Adverse Events
Will be assessed only in the Rituximab Plus Insulin Therapy Arm (intervention arm)
Anti-Rituximab Antibody (ARitA) Titers
ARitA in serum will be measured by ELISA in the Rituximab Plus Insulin Therapy Arm (intervention arm) only
Anti-Beta-Cell Antibody (ABCA) Titers
ABCA will include determinations of serum autoantibodies to glutamic acid decarboxylase (GAD65), thyrosine phosphatase/Islet Antigen 2 (IA-2), zinc transporter 8 (ZnT8) by ELISA and cytoplasmic islet cell antibodies (ICA) by indirect immunofluorescence. ABCA will be measured in both arms
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