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

NCT ID: NCT07041268

Last Updated: 2025-07-08

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 116 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-04-19
• Study Completion Date: 2028-03-31

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

Detailed Description

The study is a non-randomized, two-arm, open-label trial in which 1/2 of participants will receive repeated infusions of rituximab and their routine insulin therapy, while the remaining 1/2 will receive their routine insulin therapy only). The group the participant is assigned to is chosen by the participant himself/herself, participant's parent or another legally authorized representative, and by a doctor at the study Clinical Center. In the rituximab group, participants will receive fourteen intravenous infusions of rituximab over a period of 1 year at the study Clinical Center. Over this period, the participants will need to return to the Clinical Center for hospitalization 13 times. At each visit, detailed physical examination and laboratory evaluation will be performed. Participants of the insulin-only group will also need to visit the Clinical Center for physical examination and laboratory evaluation 5 times over a period of 1 year. In both groups, beta-cell survival and insulin-secreting capacity will be assessed by measuring blood C-peptide levels. C-peptide is a small protein secreted by beta-cells together with insulin in equal amounts, thus allowing to assess beta-cell secretory activity in individuals receiving insulin therapy. C-peptide will be measured in the fasting state and at 15, 30, 60, 90, and 120 minutes after oral liquid meal load. This test will be performed at the study start and in the 12th, 19th, 26th, and 52nd week after the start.

In both groups, those participants that continue to secrete insulin will have further follow-up for an additional one year

Conditions

Diabetes Mellitus, Type 1

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Intervention Arm: Rituximab Plus Insulin Therapy Arm

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

Group Type: EXPERIMENTAL

rituximab

Intervention Type: 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

Insulin Therapy Only Arm

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

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

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

Intervention Type: BIOLOGICAL

Eligibility Criteria

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

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Pirogov Russian National Research Medical University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Dmitry M Chudakov, Ph.D., D.Sc.

Role: STUDY_CHAIR

Institute of Translational medicine, Pirogov Russian National Research Medical University

Elena E Petryaykina, M.D.

Role: STUDY_DIRECTOR

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

Elena S Demina, M.D.

Role: PRINCIPAL_INVESTIGATOR

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

Locations

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

Moscow, , Russia

Site Status: RECRUITING

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

Moscow, , Russia

Site Status: RECRUITING

Countries

Russia

Central Contacts

Elena E Petryaykina, M.D.

Role: CONTACT

director@rdkb.ru

+79039756179

Alexei V Timofeev, Ph.D.

Role: CONTACT

alvaltim@gmail.com

+79161608994

Facility Contacts

Yulia V Tikhonovich, M.D.

Role: primary

tikhonovich_yu_v@staff.sechenov.ru

+79163266210

Tatiana E Ivannikova, M.D.

Role: backup

ivannikova_t_e@staff.sechenov.ru

+79166564245

Elena E Petryaykina, M.D.

Role: primary

director@rdkb.ru

+74959369251

Alexei V Timofeev, Ph.D.

Role: backup

alvaltim@gmail.com

+79161608994

References

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.

Reference Type: BACKGROUND

PMID: 24026563 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18628574 (View on PubMed)

Related Links

https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/062/176/original/2023-11-14.pdf?1686728191

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

Other Identifiers

2023-11-14

Identifier Type: -

Identifier Source: org_study_id