Diabetes Mellitus, Type 1
Conditions
Brief summary
In a multicenter, prospective, randomized, controlled clinical trial to compare influenza vaccination and placebo in sustaining β cell function in early type 1 diabetes mellitus.
Detailed description
Type 1 diabetes (T1D) is an autoimmune disease in which T cells attack and destroy the insulin-producing β cells in the pancreatic islets. In theory, immunotherapies aimed at re-programming the immune system to avoid β cell destruction is a promising strategy to prevent T1D or delay onset of overt disease. In this trial we test the hypothesis that influenza vaccination is superior to no influenza vaccination in sustaining β cell function in early T1D. Secondary outcome measures include change in autoantibodies directed against antigens present in the pancreatic islets, measures of severity of disease, change in inflammatory markers, and antibody titers against the four viruses included in the vaccine. Despite improvements in care, T1D is a leading cause of debilitating complications and early death globally. Children with residual β cell function are at lower risk for severe hypoglycemia, have better diabetes regulation, and have lower insulin requirements compared to children without residual β cell function. Thus, a simple, cheap treatment to mitigate T1D is highly warranted.
Interventions
BIOLOGICALVaxigrip Tetra Sanofi Pasteur Europe
We will use 0.5 mL standard dose quadrivalent influenza vaccine containing 15 μg of hemagglutinin per strain consistent with WHO recommendations according to season.
Sponsors
Aarhus University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The following are masked in the study: Participant, Care Provider, Investigator, Outcomes Assessor. The following are not masked: unblinded study nurses at participating sites randomizing participants in the eCRF system. The unblinded study nurses are not otherwise involved or participating in the study.
Intervention model description
In this double blind, placebo-controlled clinical trial participants are allocated to either influanza vaccination (active) or to placebo (control).
Eligibility
Sex/Gender
ALL
Age
7 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Patients hospitalized with newly diagnosed type 1 diabetes mellitus. * Written informed consent (parents, legal guardian).
Exclusion criteria
* Influenza vaccination during the current influenza season. * Strong indication for influenza vaccination for non-diabetic disease. * Severe allergy to eggs or previous allergic reaction to influenza vaccine. * Suspicion of febrile illness or acute, ongoing infection. * Hypersensitivity to the active substances or ingredients of Vaxigrip Tetra or against any residues, such as eggs (ovalbumin or chicken proteins), neomycin, formaldehyde and octoxinol. * Patients with endogenic or iatrogenic immunosuppression that may result in reduced immunization response. * Inability to provide informed consent from a parent or legal guardian. * Age \<7 or ≥18 years. * Previous randomization in the INVITED trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in fasting residual β cell (C-peptide) function. | 12 months | Measured as the area under the concentration-time curve (AUC) for mixed-meal tolerance test-stimulated C-peptide concentration over 4 hours relative to baseline (AUC 0-4 h, C-peptide, 12 months/ AUC 0-4 h, C-peptide, baseline) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in fasting residual β cell (C-peptide) function. | 6 months. | Measured as the area under the concentration-time curve (AUC) for mixed-meal tolerance test-stimulated C-peptide concentration over 4 hours relative to baseline (AUC 0-4 h, C-peptide, 6 months/ AUC 0-4 h, C-peptide, baseline) |
| Change in HbA1c | 12 months. | Measured as standard laboratory test in mmol/mol |
| Change in insulin requirements. | 12 months. | Measured as total insulin dose per kg body weight per day as a mean for the last 14 days. |
| Time-In-Range of blood glucose. | 12 months. | Defined as percentage time in range (3.9-10.0 mmol/L) of continuous glucose monitoring over 14 days. |
| Variation of blood glucose. | 12 months. | Determined as percent coefficient of variation of blood glucose over 14 days. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in insulin autoantibodies. | 12 months. | Laboratory method to be determined. |
| Change in zinc transporter-8 autoantibodies | 12 months. | Laboratory method to be determined. |
| Change in islet cell autoantibodies. | 12 months. | Laboratory method to be determined. |
| Change in cytokine levels. | 12 months. | Markers to be determined: IL2, IL6, IL8, IL10, TNFα. Laboratory method to be determined. |
| Proportion of participants with stimulated C-peptide >0.2 pmol/mL | 12 months | Proportion of participants in each of the treatment groups with stimulated C-peptide \>0.2 pmol/mL |
| Serum hemagglutinin inhibition antibody titers against the four viruses included in the vaccine | 12 months. | Antibody titers. |
| Clnical endpoints. | Up to 5 years. | Hospitalizations and unplanned hospital contacts. |
| Treatment-emergent hypoglycemic events (safety outcome) | Up to 12 months. | Hypoglycemic events reported according to the American Diabetes Association classification |
| Treatment-emergent events of diabetic ketoacidosis (safety outcome) | Up to 12 months. | Events of diabetic ketoacidosis. |
| Unplanned hospitalizations. | 12 months. | Number of unplanned hospitalizations with reasons for hospitalizations. |
| HbA1c time in range | 12 months. | Defined as percentage time in range (48mmol/mol or below) |
| Insulin Dose Adjusted A1c | 12 months | Defined as: IDAA1c = HbA1c (%) +4\*total daily insulin dose (IE/kg/24 h) |
| Variation of blood glucose. | 6 months. | Determined as percent coefficient of variation of blood glucose over 14 days. |
| Change in GAD 65 antibodies. | 12 months. | Laboratory method to be determined |
| Change in regulatory T cells. | 12 months. | Defined as percentage change. |
Countries
Denmark
Contacts
Primary ContactOle Frøbert, MD, PhD
Backup ContactMads F. Kjølby, MD, PhD
Outcome results
None listed