INfluenza VaccInation To Mitigate typE 1 Diabetes

Study Overview
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Brief Summary
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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
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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.

Official Title
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INfluenza VaccInation To Mitigate typE 1 Diabetes (INVITED Trial)

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Biological: Vaxigrip Tetra Sanofi Pasteur Europe


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In this double blind, placebo-controlled clinical trial participants are allocated to either influanza vaccination (active) or to placebo (control).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Influenza vaccination<br>Influenza vaccine, 0.5 mL. | Biological: Vaxigrip Tetra Sanofi Pasteur Europe<br>* 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.<br>|
| Placebo Comparator: Placebo<br>Placebo, 0.5 mL saline. | Biological: Vaxigrip Tetra Sanofi Pasteur Europe<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in fasting residual β cell (C-peptide) function. | 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) | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in fasting residual β cell (C-peptide) function. | 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) | 6 months. | 
| Change in HbA1c | Measured as standard laboratory test in mmol/mol | 12 months. | 
| Change in insulin requirements. | Measured as total insulin dose per kg body weight per day as a mean for the last 14 days. | 12 months. | 
| Time-In-Range of blood glucose. | Defined as percentage time in range (3.9-10.0 mmol/L) of continuous glucose monitoring over 14 days. | 12 months. | 
| Variation of blood glucose. | Determined as percent coefficient of variation of blood glucose over 14 days. | 12 months. |