INfluenza VaccInation To Mitigate typE 1 Diabetes (INVITED)

• ClinicalTrials.gov Identifier: NCT05585983
• Recruitment Status: Recruiting
• First Posted: October 19, 2022
• Last Update Posted: March 5, 2024
• Sponsor: Aarhus University Hospital
• Information provided by (Responsible Party): Ole Frøbert, MD, PhD, Aarhus University Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Diabetes Mellitus, Type 1	Biological: Vaxigrip Tetra Sanofi Pasteur Europe	Phase 4

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: In this double blind, placebo-controlled clinical trial participants are allocated to either influanza vaccination (active) or to placebo (control).
• Masking: Quadruple (Participant, Care Provider, 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.

• Primary Purpose: Treatment
• Official Title: INfluenza VaccInation To Mitigate typE 1 Diabetes (INVITED Trial)
• Actual Study Start Date: December 14, 2022
• Estimated Primary Completion Date: April 1, 2025
• Estimated Study Completion Date: June 1, 2026

Arms and Interventions

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.

Outcome Measures

Primary Outcome Measures :

1. Change in fasting residual β cell (C-peptide) function. [ Time Frame: 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 Outcome Measures :

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

Other Outcome Measures:

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Ole Frøbert, MD, PhD; 0046730895413; olefro@clin.au.dk

Contact: Mads F. Kjølby, MD, PhD; 004560866653; mads@dandrite.au.dk

Locations

Denmark

Aalborg University Hospital; Recruiting

Aalborg, Denmark

Contact: Mette Madsen, MD

Aarhus University Hospital; Recruiting

Aarhus, Denmark

Contact: Kurt Kristensen, MD, PhD kurtkris@rm.dk

Gødstrup Hospital; Recruiting

Herning, Denmark

Contact: Jesper S Hjelle, MD

Randers Regional Hospital; Recruiting

Randers, Denmark

Contact: Britta Kremke, MD

Viborg Regional Hospital; Recruiting

Viborg, Denmark

Contact: Ditte Adolfsen, MD, PhD

Sponsors and Collaborators

Aarhus University Hospital

More Information

• Responsible Party: Ole Frøbert, MD, PhD, Professor, Aarhus University Hospital
• ClinicalTrials.gov Identifier: NCT05585983
• Other Study ID Numbers: INVITED-2022
• First Posted: October 19, 2022
• Last Update Posted: March 5, 2024
• Last Verified: March 2024

• 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

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 1; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases