Clinical trial NCT03936634: An Innovative Approach Towards Understanding and Arresting Type 1 Diabetes (INNODIA)
Official title: An Innovative Approach Towards Understanding and Arresting Type 1 Diabetes (INNODIA)
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Type 1 Diabetes Mellitus
Keywords: Observation study
First degree relatives
Beta cell
C-Peptide
Immune cells
Disease progression
Lead sponsor: University of Cambridge
Sponsor class: OTHER
Collaborators: name: Innovative Medicines Initiative
name: Juvenile Diabetes Research Foundation
name: The Leona M. and Harry B. Helmsley Charitable Trust
First posted: 2019-05-03
Enrollment: 6000
Sex: ALL
Minimum age (years): 1
Maximum age (years): 44
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Newly diagnosed patients with Type 1 diabetes.

Unaffected first degree family members of patients with type 1 diabetes.

Brief summary: INNODIA is a global consortium linking 26 academic institutions, 4 industrial partners, a small to medium enterprise (SME), and 2 patient organisations, bringing their knowledge and experience together with one common goal: "To fight type 1 diabetes". (www.innodia.eu).

The project, approved in November 2015 and launched in January 2016, runs under the framework of the Innovative Medicines Initiative - Joint Undertaking (https://www.imi.europa.eu/projects-results/project-factsheets/innodia) with a dedicated governance structure ensuring close interaction, communication and adherence to the objectives and deliverables of the consortium.

The overall aim of INNODIA is to advance in a decisive way how to predict, stage, evaluate and prevent the onset and progression of type 1 diabetes (T1D). For this, INNODIA has established a comprehensive and interdisciplinary network of clinical and basic scientists, who are leading experts in the field of T1D research in Europe, with complementary expertise from the areas of immunology, Beta-cell biology, biomarker research and T1D therapy, joining forces in a coordinated fashion with industry partners and two foundations, as well as with all major stakeholders in the process, including regulatory bodies and patients with T1D and their families.

One of the objectives of INNODIA is to develop a new European clinical research network with standardized protocol based on repeated measures of C-peptide (including home measurements) and comprehensive collection of appropriate biological samples for 'omics', immune, viral and microbiome studies in new onset T1D patients and high-risk auto-antibody positive subjects. A protocol for the harmonization of sample collections in newly diagnosed type 1 diabetic patients and first degree relatives of patients with type 1 diabetes was developed following extensive preliminary work involving partners from across all specialities. Core laboratories with experience in their respective field were set up for analysis of auto-antibodies, fresh immune cells, handling of frozen immune cells, C-peptide measures. A series of standard operating procedures for sample collections and analysis were agreed. Sample tracking between clinical centres and central laboratories was included into a purposely designed electronic case report form (eCRF) into which all clinical and laboratory data collected are captured.

Detailed description: This is a longitudinal observational study of the relationship between measures of β-cell function, genotype, immunological phenotype and potential environmental factors over time, in individuals with new onset T1D or first degree relatives at higher risk for T1D due to the presence of auto-antibodies.

It is a multicentre international study involving clinical centres across Europe which is unique in the following ways:

1. The first such collaboration in Europe
2. Novel evaluation of C-peptide/β-cell function using both home dried blood spots and regular hospital mixed meal tolerance tests or oral glucose tolerance tests
3. Identical study procedures across all clinical centres
4. Centralised analysis/storage of clinically relevant samples
5. The creation of a living 'Biobank' whereby participants can be recalled for study on the basis of specific genotype/phenotypes
6. Linkage to innovative study of novel biomarkers to inform future interventional strategies
7. A potential pipeline for future recruitment and consent to novel innovative interventional strategies

The study is divided into 2 arms:

In arm A, the investigators plan to recruit 1500 newly diagnosed T1D patients within 6 weeks from diagnosis. The last study visit will be planned 2 years from diagnosis or until the end of the study. Therefore, the duration of the study will be approximately 2 years consisting of 5 visits. At baseline, C-peptide and immunophenotyping are evaluated. Follow up consists of regular mixed meal tolerance test (MMTT) and providing blood, urine and stool samples for 'omics', immune, viral and microbiome studies. Home dried blood spots (DBS) pre and post a standardized meal will be collected monthly for the duration of the study.

These recruited participants will be included for further observational study, confirmation of potential biomarkers and will ultimately provide a pipeline for future recruitment to interventional studies.

In arm B, the investigators plan to screen approximately 4500 unaffected first degree family members across all centres during the first 3 years. The family members will be screened for 4 auto-antibodies (GAD65, IA-2A, IAA, ZnT8A).

Unaffected family members who are auto-antibody positive will be followed up for approximately 4 years consisting of visits every 6 months for the first 2 years and then every 12 months until the end of the study. Follow up will consist of regular oral glucose tolerance test (OGTT) and providing blood, urine and stool samples for 'omics', immune, viral and microbiome studies. Home dried blood spots (DBS) will be collected monthly for the duration of the study.

Unaffected participants who are auto-antibody negative will be sent annual questionnaires until the end of the study.

All study participants will be consented to a living 'Biobank' where we will be able to request participants to be recalled by genotype/phenotype for further studies involving blood, urine and stool samples.

Eligibility criteria: Newly diagnosed:

Inclusion Criteria:

* Have given written informed consent to participate.
* Be aged between 1 year and \<45 years.
* Less than 6 weeks from diagnosis of type 1 diabetes and requiring insulin treatment.

Exclusion Criteria:

* Non-type 1 diabetes (type 2, monogenic diabetes and secondary diabetes)
* Concurrent use of long term immunosuppressive agents including oral steroids or medication likely to confound the interpretation of study results.
* Expected non-compliance with the protocol.
* Any medical history or clinical relevant abnormality that is deemed by the principal investigator and/or co-investigator to make the patient ineligible for inclusion because problems in interpreting data or safety concern.
* Participating in interventional or other drug research studies which could affect the primary objectives of the study.

Unaffected Family Members:

Inclusion Criteria:

* Have given written informed consent to participate.
* Be aged between 1 year and \<45 years.
* Have a first degree relative with type 1 diabetes (parent, child, full or half siblings) diagnosed \<45 years of age

Exclusion Criteria:

* The affected first degree relative has type 2 diabetes, monogenic diabetes or diabetes secondary to another medical condition.
* Concurrent use of long term immunosuppressive agents including oral steroids or medication likely to confound the interpretation of study results.
* Expected non-compliance with the protocol.
* Any medical history or clinical relevant abnormality that is deemed by the principal investigator and/or co-investigator to make the patient ineligible for inclusion because problems in interpreting data or safety concern.
* Participating in interventional or other drug research studies which could affect the primary objectives of the study.

Primary outcomes:
measure: Arm A - Newly Diagnosed people with Type 1 diabetes
timeFrame: 24 months
measure: Arm B - Auto-antibody positive first degree family members
timeFrame: 48 months
Secondary outcomes:
measure: Arm A - Newly diagnosed patients with Type 1 diabetes
timeFrame: 24 months
measure: Arm A - Newly diagnosed patients with Type 1 diabetes - Systematic evaluation of biological samples
timeFrame: 24 months
measure: Arm A - Newly diagnosed patients with Type 1 diabetes - Framework
timeFrame: 24 months
measure: Arm B - Auto-antibody positive first degree family members - glucose tolerance
timeFrame: 48 months
measure: Arm B - Auto-antibody positive first degree family members - Systematic evaluation of biological samples
timeFrame: 48 months
measure: Arm B - Auto-antibody positive first degree family members - Framework
timeFrame: 48 months
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz
city: Brussels
country: Belgium
facility: Universitee Libre de Bruxelles
city: Leuven
country: Belgium
facility: Katholieke Universiteit Leuven
city: Copenhagen
country: Denmark
facility: University of Copenhagen
city: Helsinki
country: Finland
facility: University of Helsinki
city: Oulu
country: Finland
facility: University of Oulu
city: Turku
country: Finland
facility: Turku University Hospital
city: Paris
country: France
facility: Institut National de la Sante et de la Recherche Medicale (INSERM)
city: Hanover
country: Germany
facility: Children's Hospital Auf der Bult, Hannover Medical School
city: Ulm
country: Germany
facility: University of Ulm
city: Milan
country: Italy
facility: San Raffaele Hospital
city: Rome
country: Italy
facility: Ospedale Pediatrico Bambino Gesu
city: Siena
country: Italy
facility: University of Studi di Siena
city: Luxembourg
country: Luxembourg
facility: University of Luxembourg
city: Oslo
country: Norway
facility: Oslo Universitetssytehus HF
city: Katowice
country: Poland
facility: Medical University of Silesia Katowice
city: Ljubljana
country: Slovenia
facility: University of Ljubljana
city: Malmö
country: Sweden
facility: University of Lund
city: Cambridge
country: United Kingdom
facility: University of Cambridge
Study officials:
affiliation: University of Cambridge
name: David B Dunger
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Helsinki
name: Mikael Knip
role: PRINCIPAL_INVESTIGATOR
affiliation: Katholieke Universteit Leuven
name: Chantal Mathieu
role: STUDY_CHAIR
References:
citation: Wilhelm-Benartzi CS, Miller SE, Bruggraber S, Picton D, Wilson M, Gatley K, Chhabra A, Marcovecchio ML, Hendriks AEJ, Morobe H, Chmura PJ, Bond S, Aschemeier-Fuchs B, Knip M, Tree T, Overbergh L, Pall J, Arnaud O, Haller MJ, Nitsche A, Schulte AM, Mathieu C, Mander A, Dunger D. Study protocol: Minimum effective low dose: anti-human thymocyte globulin (MELD-ATG): phase II, dose ranging, efficacy study of antithymocyte globulin (ATG) within 6 weeks of diagnosis of type 1 diabetes. BMJ Open. 2021 Dec 7;11(12):e053669. doi: 10.1136/bmjopen-2021-053669.