Work Packages

WP1 - Project Management and Dissemination

Lead: Eurice/NN

Work package 1 will provide a clear organizational framework and all necessary support mechanisms to enable a smooth project workflow in Hypo-RESOLVE and to ensure that all contractual commitments will be met on time. Our objectives:

• Provide optimal guidance and support to all partners through a quick set-up of effective management & communication structures.
• Transparency for consortium partners and the IMI through proper project documentation.
• Maximize effectiveness of project activities: ensure the timely and qualitative achievement of project results through scientific and administrative coordination.
• Ensure efficiency: use resources wisely, avoid duplication of efforts, reduce waste of time and energy to a minimum to prevent unnecessary spending of funds.
• Creating visibility, encouraging project outreach and disseminating results to the scientific community.

WP2 - Studies addressing the mechanisms and consequences of hypoglycaemia

Lead: UNIVDUN/NN

Work package 2 addresses the molecular/cellular and pathophysiological mechanisms as well as the consequences of hypoglycaemia through non-clinical and clinical studies.

• We will combine our expertise in the molecular biology and neural networks of hypoglycaemia-sensing and state-of-the-art transgenic approaches to define novel mechanisms that contribute to the development of impaired awareness of hypoglycaemia.
• Integrated neural circuits critical to generating counter-regulatory responses will be targeted and analysed as a means of enhancing protective counter-regulatory mechanisms.
• The molecular/cellular consequences of recurrent hypoglycaemia in rodents on organ function (cardiovascular and cognitive), tissue genetics and epigenetic profiles will be examined and aligned with WPs 3-5 where consequences of recurrent hypoglycaemia in clinical trials will be examined.
• We will characterise the inflammatory responses and markers of coagulation and vascular damage following hypoglycaemia and repeated exposure to hypoglycaemia. This work will be performed in complimentary rodent and human studies.
• Finally, we will investigate potential biomarkers that predict severe hypoglycaemia in people with type 1 diabetes using bio-samples from studies performed by the T1DExchange study group. In addition, we will develop a network of investigators tasked with developing bio-resources and shared approaches to the study of hypoglycaemia in humans.

WP3 - Establishment of pooled clinical database and analysis tools

Lead: SIB/SAN/Abbott

Work package 3 will harmonise, structure and integrate multiple clinical trial datasets and CGM data into pooled databases, develop the necessary computational tools to enable querying for statistical analysis of the data in WP4-7 and ensure the sustainability of the resulting platform by using current clinical and data sharing standards. Our objectives:

• Standardize and harmonise clinical trial and CGM data
• Create a secure project database containing the pooled data
• Develop and deploy query tools and API to enable statistical analysis
• Ensure sustainability of data and results

WP4 - Definition of hypoglycaemia and clinical analysis of hypoglycaemic events

Lead: USFD/NN

Work package 4 has the following objectives:

• Build on existing evidence to establish an extended classification of clinical categories of hypoglycaemia (including nocturnal episodes and biochemical hypoglycaemia identified by continuous glucose monitoring) as they apply to people with type 1 or 2 (insulin or sulphonylureas treated) diabetes.
• Determine the relative contribution of known predictors of hypoglycaemia with greater precision and identify new factors which can predict future episodes.
• Determine with greater precision the known consequences of hypoglycaemia and identify any new outcomes associated with hypoglycaemia.
• Establish a multi-stakeholder, expert group of clinical academics, patients and industry representatives whose objective will be to develop a recommended standardised approach for the collection of clinical and laboratory data to be used primarily in clinical trials but which could inform clinical practice.

WP5 - Evaluate glucose measurement techniques and define standard guidelines

Lead: KCL/Abbott/MDT

The overall aim of work package 5 is to understand the predictors for and impact of CGM-detected low values on biological, patient reported and health-economic outcomes in order to provide guidance to industry, academics and regulators for its successful use in clinical trials, particularly as an end point. WP5 will:

• evaluate the link between continuous glucose monitoring (CGM)-detected low values and documented severe and non-severe hypoglycaemia episodes in the clinical trial database and determine the minimum amount of CGM data that describes an individual’s hypoglycaemia risk;
• define gaps that have not been addressed in monitoring / detection of hypoglycaemia and map hypoglycaemia detection techniques;
• evaluate the use of and validation of in-silico modelling as a research tool to identify behavioural determinants for hypoglycaemia;
• conduct a clinical study to evaluate the relevance and the impact of asymptomatic CGM-detected low values on future hypoglycaemia risk as well as patient reported and health economic outcomes;
• collate information collected in WP4, 5, 6 and 7 to develop standard guidelines for the use and interpretation of CGM data in clinical trials.

WP6 - Psychological burden of hypoglycaemia: a 360 degree assessment

Lead: SDU/Lilly

The aim of work package 6 is to provide a comprehensive assessment of the impact of hypoglycaemia on the quality of life (QoL) of people with diabetes and their family members and to identify knowledge gaps by conducting: a) rapid and systematic reviews to summarise and critique the current evidence base, b) secondary analyses of pooled trial/CGM data, and c) innovative research that fills knowledge gaps.

WP6 will:

• Determine the impact of hypoglycaemia on (dimensions of) QoL in people with diabetes;
• Determine the impact of hypoglycaemia on (dimensions of) QoL in family members of people with diabetes;
• Determine the impact of hypoglycaemia on cognitive function and academic performance in people with diabetes;
• Summarise expressed care needs/wishes of people with diabetes and their family members regarding hypoglycaemia;
• Design/execute innovative research that fills identified knowledge gaps.

WP7 - Determine economic consequences of hypoglycaemia, the value of prevention and patient impact

Lead: USFD/SAN

Work package 7 will utilise our knowledge on valuing health related quality of life and economic evaluation to assess the quality of life impact of hypoglycaemia on day-to-day living for people with diabetes and the cost to health care systems of hypoglycaemia. To achieve this, we will undertake a set of tasks to assess and value the burden of hypoglycaemia in terms of patient reported outcomes and we will combine analyses of the pooled trial dataset and localised costs to estimate the costs of hypoglycaemia to the health care system in five European countries. WP7 will address the following objectives:

• Analyse current patient reported outcome instruments for assessing the burden of hypoglycaemia
• Reassess current patient questionnaires and correlation with CGM data
• Develop new or refine existing PRO instruments
• Provide a preference based valuation for the new / refined PRO to better understand the quality of life / economic impact of hypoglycaemia
• Assess the financial costs of hypoglycaemia to the health care system in five European countries.

WP8 - Engage with regulators and other stakeholders on outcomes to be used in clinical trials

Lead: MUG/NN/MDT

Work package 8 has the following objectives:

• Develop a comprehensive overview of existing guidelines on diabetes medicines and medical technologies from key regulatory agencies, HTA organizations, professional diabetes associations and patient organizations to assess their view on hypoglycaemia.
• Collate the outcomes of WP2 and WP4 – WP7 into a comprehensive summary for high-level communication.
• Identify and establish dialogue with a range of key regulatory agencies, HTA organisations, professional diabetes associations and patient organisations to create a consensus process.
• Develop and disseminate a consensus guideline with uniformly agreed definitions and data collection methods for the standardisation of clinical investigations with regard to hypoglycaemia.