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
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 116
- 试验地点
- 2
- 主要终点
- Change in the Mean C-peptide Area Under Curve (AUC) Standardized by Duration of the Mixed Meal Tolerance Test
研究概览
简要总结
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
详细描述
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
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
No masking
入排标准
- 年龄范围
- 12 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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
干预措施: rituximab (Biological)
结局指标
主要结局
Change in the Mean C-peptide Area Under Curve (AUC) Standardized by Duration of the Mixed Meal Tolerance Test
时间窗: 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
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
次要结局
- 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)