Type 1 Diabetes Mellitus
Conditions
Keywords
Newly diagnosed type 1 diabetes, New Onset type 1 diabetes, Preservation of insulin secretion, Type 1 diabetes, Juvenile Onset Diabetes, Insulin Dependent Diabetes, T1D
Brief summary
Type 1 diabetes is an autoimmune disease in which the immune system mistakenly attacks the insulin-producing beta cells in the pancreas. Without these beta cells, the body cannot maintain proper blood glucose levels in response to daily activities such as eating or exercise. With fewer insulin producing cells blood glucose increases, causing hunger, thirst, and unexplained weight loss. By the time these symptoms develop, 80-90% of a person's beta cells have already been destroyed. However, this also means that between 10-20% of these cells remain that continue to produce insulin. Scientists have learned that two types of immune cells, B cells and T cells, are involved in causing type 1 diabetes. T cells are responsible for attacking and destroying the beta cells that make insulin. Although they don't attack insulin producing cells, B cells may be what trigger the T cells to attack. This study will investigate the use of rituximab to see if it can help lower the number of immune B cells thereby preventing the destruction of any remaining insulin producing beta cells that remain at diagnosis. Rituximab is approved by the Food and Drug Administration (FDA) for the treatment of a condition called B-lymphocyte lymphoma. Its effects on the immune system are well understood through its use in organ transplantation. Research has shown that rituximab might be helpful in treating other conditions caused by T cells and B cells, including type 1 diabetes. The goal of this study is to find out if rituximab can preserve residual insulin secretion and prevent further beta cell destruction in type 1 diabetes.
Detailed description
The study is a randomized, two-arm, trial in which 2/3 of participants will receive the study drug, while the remaining 1/3 will receive a placebo (a pretend medicine that does nothing). The group you are assigned to is decided by chance (as by the toss of a coin or drawing straws). Neither you nor your doctor will be able to choose which group you are in. Also, neither you nor the researchers will know which group you are in. Participants will take rituximab, or the placebo, once a week during the first 4 weeks in the study. It will be given as an intravenous infusion at a clinical center. Participants will need to return to the clinical center for a visit about every 3 months for two years; those participants that continue to secrete insulin will have further follow-up for an additional two years.
Interventions
DRUGPlacebo Comparator
Placebo intravenous infusion
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
American Diabetes Association
Juvenile Diabetes Research Foundation
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
8 Years to 45 Years
Healthy volunteers
No
Inclusion criteria
* Between the ages of 8 and 45 years * Within 3 months of diagnosis of type 1 diabetes * Have presence of at least one diabetes-related autoantibody * Must have stimulated C-peptide levels of at least 0.2 pmol/ml measured during a mixed meal tolerance test (MMTT) within one month of randomization * If female with reproductive potential, willing to avoid pregnancy and undergo pregnancy testing while participating in the study * Have not received an immunization for at least one month * Must be willing to comply with intensive diabetes management * Must weigh at least 25 kg at study entry
Exclusion criteria
* Are immunodeficient or have clinically significant chronic lymphopenia * Have an active infection or positive purified protein derivative (PPD) test result * Currently pregnant or lactating; or anticipate becoming pregnant. * Require chronic use of steroids * Have current or past HIV, hepatitis B, or hepatitis C infection * Have any complicating medical issues that interfere with study conduct or cause increased risk * Have a history of malignancies * Currently using non-insulin pharmaceuticals that effect glycemic control * Currently participating in another type 1 diabetes treatment study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4-hour Mixed Meal Tolerance Test (MMTT) Administered at 1 Year | When all participants complete the 1 year visit | The primary outcome is the area under the stimulated C-peptide curve (AUC) based on data collected at time 0 to 2 hours of a 4-hour mixed meal glucose tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30 60, 90, and 120 minutes. The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the AUC mean and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis. |
Countries
Australia, Canada, Italy, United States
Participant flow
Recruitment details
Participants with newly diagnosed type 1 diabetes recruited from 12 TrialNet Clinical Centers between
Pre-assignment details
126 patients were assessed; 39 were excluded; 87 underwent randomization (57 were assigned to receive rituximab and 30 were assigned to receive placebo)
Participants by arm
| Arm | Count |
|---|---|
| Rituximab Treatment Four intravenous infusions (375 mg per square meter of body-surface area) were given on days 1, 8, 15, and 22 of the study | 57 |
| Placebo Placebo infusions were given to participants in control group on days 1, 8, 15, and 22. | 30 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Dificulting establishing IV | 1 | 0 |
| Overall Study | FDA Safety Alert | 4 | 1 |
| Overall Study | Pregnancy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 0 |
Baseline characteristics
| Characteristic | Rituximab Treatment | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 19.0 years STANDARD_DEVIATION 8.6 | 17.4 years STANDARD_DEVIATION 8 | 18.5 years STANDARD_DEVIATION 8.3 |
| Sex: Female, Male Female | 21 Participants | 12 Participants | 33 Participants |
| Sex: Female, Male Male | 36 Participants | 18 Participants | 54 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 56 / 57 | 29 / 30 |
| serious Total, serious adverse events | 11 / 57 | 9 / 30 |
Outcome results
Primary
Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4-hour Mixed Meal Tolerance Test (MMTT) Administered at 1 Year
The primary outcome is the area under the stimulated C-peptide curve (AUC) based on data collected at time 0 to 2 hours of a 4-hour mixed meal glucose tolerance test (MMTT) conducted at the primary endpoint visit. The timed measurements are done at: 0, 15, 30 60, 90, and 120 minutes. The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the AUC mean and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis.
Time frame: When all participants complete the 1 year visit
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rituximab Treatment | Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4-hour Mixed Meal Tolerance Test (MMTT) Administered at 1 Year | 0.58 pmol per mL |
| Placebo | Area Under the Stimulated C-peptide Curve Over the First 2 Hours of a 4-hour Mixed Meal Tolerance Test (MMTT) Administered at 1 Year | 0.429 pmol per mL |
Comparison: The calculation for the concentration of c-peptide is a weighted average of the 6 timed measurements of c-peptide in nano-moles/Liter. We try to distinguish this calculation from the AUC by referring to it as the AUC mean and may be expressed algebraically as the AUC/(120 min.); thus, the units are the same as the y-axis.p-value: 0.0595% CI: [-0.0699, 0.348]ANCOVA