INfluenza VaccInation To Mitigate typE 1 Diabetes (INVITED)

INfluenza VaccInation To Mitigate typE 1 Diabetes (INVITED Trial)

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.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 1
• Intervention / Treatment: Biological: Vaxigrip Tetra Sanofi Pasteur Europe

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.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Ole Frøbert, MD, PhD; Phone Number: 0046730895413; Email: olefro@clin.au.dk

Study Locations

• Denmark
  • Aarhus, Denmark
    • Recruiting
    • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Influenza vaccination; Influenza vaccine, 0.5 mL.	Biological: Vaxigrip 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.
Placebo Comparator: Placebo; Placebo, 0.5 mL saline.	Biological: Vaxigrip 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.

What is the study measuring?

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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with stimulated C-peptide >0.2 pmol/mL	Proportion of participants in each of the treatment groups with stimulated C-peptide >0.2 pmol/mL	12 months
HbA1c time in range	Defined as percentage time in range (48mmol/mol or below)	12 months.
Insulin Dose Adjusted A1c	Defined as: IDAA1c = HbA1c (%) +4*total daily insulin dose (IE/kg/24 h)	12 months
Variation of blood glucose.	Determined as percent coefficient of variation of blood glucose over 14 days.	6 months.
Change in GAD 65 antibodies.	Laboratory method to be determined	12 months.
Change in GAD 65 antibodies.	Laboratory method to be determined.	6 months.
Change in regulatory T cells.	Defined as percentage change.	12 months.
Change in insulin autoantibodies.	Laboratory method to be determined.	12 months.
Change in zinc transporter-8 autoantibodies	Laboratory method to be determined.	12 months.
Change in islet cell autoantibodies.	Laboratory method to be determined.	12 months.
Change in cytokine levels.	Markers to be determined: IL2, IL6, IL8, IL10, TNFα. Laboratory method to be determined.	12 months.
Change in cytokine levels.	Markers to be determined: IL2, IL6, IL8, IL10, TNFα. Laboratory method to be determined.	6 months.
Unplanned hospitalizations.	Number of unplanned hospitalizations with reasons for hospitalizations.	12 months.
Serum hemagglutinin inhibition antibody titers against the four viruses included in the vaccine	Antibody titers.	12 months.
Serum hemagglutinin inhibition antibody titers against the four viruses included in the vaccine	Antibody titers.	6 months.
Clnical endpoints.	Hospitalizations and unplanned hospital contacts.	Up to 5 years.
Treatment-emergent hypoglycemic events (safety outcome)	Hypoglycemic events reported according to the American Diabetes Association classification	Up to 12 months.
Treatment-emergent events of diabetic ketoacidosis (safety outcome)	Events of diabetic ketoacidosis.	Up to 12 months.

Collaborators and Investigators

• Sponsor: Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2022
• Primary Completion (Anticipated): April 1, 2025
• Study Completion (Anticipated): June 1, 2026

Study Registration Dates

• First Submitted: October 15, 2022
• First Submitted That Met QC Criteria: October 15, 2022
• First Posted (Actual): October 19, 2022

Study Record Updates

• Last Update Posted (Actual): April 5, 2023
• Last Update Submitted That Met QC Criteria: April 4, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: INVITED-2022

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No