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Understanding hypoglycaemia: the underlying mechanisms and addressing clinical determinants as well as consequences for people with diabetes by combining databases from clinical trials - IMI2-2016-10-01
Deadline: 14 Sep 2017   CALL EXPIRED

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Specific Challenge:

Diabetes represents an increasing global healthcare challenge. Controlling blood glucose is a cornerstone in diabetes management aiming to reduce the increased morbidity and mortality associated with this disease. However, only around 50% of patients achieve accepted international glycaemic targets.

Hypoglycaemia is common, and the importance of hypoglycaemia as a major concern for both healthcare professionals and patients is reflected by its impact on intrusions into daily living as well as serious consequences including hospitalisation and mortality. Hypoglycaemia and the fear of hypoglycaemia represent a recognised and measurable contributor to the burden of disease for people afflicted by diabetes, as well as their families, friends, and other parties – also known as ‘The Greater Patient’.

Thus, hypoglycaemia is an important clinical issue for many people with diabetes, and it constitutes a major concern for patients on glucose lowering treatment regimens, who face the daily challenge of achieving accepted glucose targets safely, without increasing the risk of hypoglycaemia.

In recent years we have seen an increasing number of phase III clinical trials in type 1 and type 2 diabetes, but despite the improved accuracy of glucose measuring devices and increased patient access to continuous glucose monitoring (CGM) technology, detecting and reliably registering hypoglycaemic events in clinical trials remain a challenge. No approved guidelines or methods for how hypoglycaemia should be measured exist. Regarding hypoglycaemia, detailed monitoring of blood glucose and the recording of daily events, including physical activity and diet, are rarely carried out. Although data on severe and in most cases, symptomatic hypoglycaemia are collected during the trial period, information on other types of hypoglycaemia, particularly asymptomatic as well as episodes wherein patient outcomes are not immediately noticeable is limited. Moreover, people with a past history of severe hypoglycaemia are often excluded from clinical trials and little if any information is routinely collected on other types of pre-trial hypoglycaemia; as a consequence, this type of information is rarely included in post-trial analyses.

The current gaps and challenges in our understanding of hypoglycaemia consequently limit the management of hypoglycaemia. Furthermore, a consensus between healthcare professionals and other professional bodies including the regulatory authorities on the definitions of the clinical categories of hypoglycaemia is lacking which makes analyses of hypoglycaemic episodes difficult. Thus the overarching objective of this call topic is to reduce the risk and burden of hypoglycaemia and, as a consequence, ultimately improve glycaemic control in people with diabetes. To achieve this we will focus on a number of related specific challenges including:

  1. The need for a better understanding of the clinical determinants and consequences of hypoglycaemia and hypoglycaemia unawareness;
  2. The need to adopt scientifically sound, consistent, and clinically meaningful definitions of hypoglycaemia that will be accepted by practicing clinicians, regulators, industry and academia in order to probe clinical data;
  3. The need for creating standard guidelines that will be accepted by regulators globally for how to measure hypoglycaemic events to test glucose lowering drugs with respect to occurrence rates or severity of hypoglycaemic episodes;
  4. The need for standardized collection of clinical and laboratory data within clinical trials to increase our understanding of hypoglycaemia;
  5. The need for including hypoglycaemia in the current approach to determine the ‘value for patients’ in the context of clinical development;

The need for better insights into the underlying pathophysiology and defects in the counter-regulatory mechanisms associated with hypoglycaemia ,recurrent hypoglycaemic episodes and hypoglycaemia unawareness.

Scope:

To achieve our objective of reducing the risk and burden of hypoglycaemia and ultimately improving glycaemic control in people with diabetes, we aim to gain a better understanding of hypoglycaemia through a series of integrated activities that are expected to include:

  • Non-clinical and clinical research into the mechanisms of counter-regulation and hypoglycaemia unawareness to identify targets for intervention;
  • Establishment of a large, consolidated database of hypoglycaemia captured in clinical trials across glucose lowering drug development programs from partner companies and a pooled CGM database collected using various glucose monitoring devices;
  • Probing the databases to characterize clinically relevant hypoglycaemia and to determine the causes and consequences of such events;
  • Evaluating glucose measuring techniques to define standard detection guidelines for measuring hypoglycaemia events and the accuracy of the detection;
  • Developing best practice for the collection of clinical and laboratory data in clinical trials in order to assess hypoglycaemic events;
  • Shaping health economic outcomes research (HEOR) to determine the value of reducing hypoglycaemia risk;
  • Identifying existing patient-driven qualitative and quantitative research (self-reporting studies, surveys, etc.) and conducting a related meta-analysis of the obtained data;

Opening a dialogue with regulatory agencies to define clinically meaningful endpoints/methods to document rates of hypoglycaemia and the potential to reduce these with pharmacological intervention.

Expected Impact:

The proposed programme will lead to:

  • The establishment of a unique clinical trial database developed specifically for this programme that will contain anonymized, standardized and harmonized data from patients with T1DM and/or T2DM on glucose lowering treatment regimens which will subsequently become available for other interested researchers to access;
  • Agreement amongst all stakeholders on the applicability of the definitions of clinically meaningful hypoglycaemia through examination of the combined clinical trial data set, clinical data and CGM;
  • Enhanced understanding and agreement of standard approaches for how best to design trials to assess hypoglycaemia and how to analyse the data;
  • Generation of information relating to existing and novel aspects of hypoglycaemia and hypoglycaemia risk leading to a better understanding of hypoglycaemia mechanisms, and novel targets for prevention and/or intervention;
  • Exploration of the relationship between clinical trial database findings and real-time glucose measurement datasets from continuous glucose monitoring;
  • Stronger evidence on the utility of non-laboratory glucose measurement and data analysis technologies
  • A 360° assessment of the burden of hypoglycaemia for patients and society that will enrich our understanding of hypoglycaemia, complement our understanding derived from clinical studies and add perspective to related clinical recommendations;

Generation of evidence-based data to support discussions with regulatory authorities on acceptable definitions of hypoglycaemia.



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