RECRUITINGPhase 2INTERVENTIONAL

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

Evaluation of Effectiveness and Safety of the Rituximab Immunotherapy Plus Insulin Therapy Compared to Insulin Therapy Alone in Adolescents With Recent-Onset Type 1 Diabetes Mellitus

About This Trial

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

Who May Be Eligible (Plain English)

Who May Qualify: - 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 willing to sign a consent form Form - Citizenship of the Russian Federation Who Should NOT Join This Trial: - Has any autoimmune conditions (where your immune system attacks your own body) 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 weakened immune system virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) at screening - Has a history of primary weakened immune system - 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 willing to sign a consent form Form Always talk to your doctor about whether this trial is right for you.

Original Eligibility Criteria

View original clinical language

Inclusion Criteria: * 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 Exclusion Criteria: * 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

Treatments Being Tested

BIOLOGICAL

rituximab

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

Locations (2)

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

Moscow, Russia

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

Moscow, Russia