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Treatment of Adrenal Insufficiency in neonates- Development of a Hydrocortisone Preparation for the treatment of Adrenal Insufficiency in neonatesand infants

Final Report Summary - TAIN (Treatment of Adrenal Insufficiency in neonates- Development of a Hydrocortisone Preparation for the treatment of Adrenal Insufficiency in neonatesand infants.)

Executive Summary:
TAIN stands for the Treatment of Adrenal Insufficiency in Neonates and Infants and is a collaborative project supported by the European Commission through its 7th Framework Programme (Project No: 281654). Adrenal insufficiency is a rare (or orphan) disorder with a prevalence of approximately 1 in 15,000 in Europe that prevents the body from producing sufficient amounts of the essential hormone cortisol. Cortisol is a stress hormone that is critical in the physiological response to challenges such as infection, injury or surgery. If a patient suffers from adrenal insufficiency then stress factors, such as an infection, will precipitate an adrenal crisis that includes hypotension, circulatory collapse and rapid death unless treated. In neonates and infants the commonest type of adrenal insufficiency is due to congenital adrenal hyperplasia caused by mutations in the cortisol synthesis pathway that prevent the child from producing cortisol. The off-patent drug hydrocortisone is a glucocorticoid hormone that has been used as a replacement therapy for the treatment of adrenal insufficiency across Europe for many years. However, effective hydrocortisone replacement is particularly acute among young patients (neonates and infants) for whom no licensed therapy exists. Current therapy requires adaption of adult formulations through crushing tablets. This is problematic and gives variable and inaccurate dosing as crushed tablets are relatively insoluble, provide an unpredictable pharmacokinetic profile, have no established stability, and are inconvenient for clinicians and parents. Current hydrocortisone preparations put the neonate at risk of over and under treatment with potential long term health consequences including obesity, ill health and sudden death. The aim of TAIN is to develop a new formulation of hydrocortisone – termed Infacort® by the project - that can be used from birth and specifically in the age range 0 – 2 years (neonates & infants). The Infacort® product will be manufactured using commercially proven technology in four doses – 0.5mg 1mg, 2mg and 5mg – to give maximum flexibility to clinicians to tailor the treatment to the child. Taste masking excipients that are acceptable for paediatric use will eliminate the bitter taste of hydrocortisone increasing compliance. Formal stability studies will ensure that the Infacort® product will have a long and practical shelf life for patients and clinicians. TAIN involves European leaders in drug development, neonatology and paediatric pharmacology. A Paediatric Investigation Plan (PIP) has been approved by the European Medicines Agency (EMEA-001283-PIP01-12) that will enable clinical trials to be carried out to provide sufficient evidence of safety and efficacy for Infacort® to allow submission of a Paediatric Use Medicines Authorisation (PUMA). The PUMA was successfully submitted to the European Medicines Agency in Nov-16. The project also aims to raise awareness of adrenal insufficiency to maximise its positive impact for patients, parents and clinicians.

Project Context and Objectives:
The TAIN project was completed on the 30th November 2016. The final results of the TAIN project comprise completion of the both scientific aspects and their potential impacts and wider societal and socio-economic implications. Scientifically, a series of clinical trials (Infacort 001, 002 and 003) have been completed demonstrating the short-term safety and efficacy of Infacort® and which are required to submit the market authorisation submission for the product. A further clinical study (Infacort 004) will be completed post study end to provide evidence of the long-term safety and efficacy of Infacort®. Infacort 001 and Infacort 002 have already been successfully completed in human adult volunteers and Infacort 003 and 004 will be in paediatric patients in accordance with the approved Paediatric Investigation Plan (EMEA-001283-PIP01-12). The required regulatory and local ethical approvals have already been received for all the above studies. Positive analysis and results from the Infacort 003 study allowed submission of a Paediatric Use Medicines Authorisation (PUMA) on the 25th November 2016. The impact of PUMA approval will be that the European Medicines Agency has confirmed that a new, safe and efficacious formulation of hydrocortisone has been developed. This will enable Infacort® to be available and to be marketed across Europe. Infacort® will be available for clinicians to prescribe to patients and therefore the key health impact will be in improved quality of life for patients, parents and caregivers.

Project Results:
The TAIN project also aims to raise awareness of the unmet needs in paediatric adrenal insufficiency patients and therefore to maximise its positive impact for patients, parents and clinicians across Europe. A number of socio-economic activities will supplement the scientific aspects of the projects. These are being led by Genetic Alliance UK – a patient charity. These currently include generation of new intellectual property and therefore increasing improved economic competitiveness in the EU. The development of a new pharmaceutical product that will have worldwide application outside of Europe will provide economic opportunities for the innovators within the EU who have come together in a collaborative effort to undertake such developments. Dissemination activities will include publication and communication of the TAIN results to academia, industry, patients and the public. Identification of target audiences and dissemination plans to ensure visibility and awareness of the achievements of TAIN project and effective knowledge transfer are in progress. Dissemination will be at European, national and regional level in partnership with patient organisations with interests in adrenal insufficiency and orphan diseases. Educational and information packs will be created and distributed to the widest possible audience. A proactive approach is being taken to secure the outputs of the TAIN through the development of a patient registry (I-CAH to capture knowledge about the rare disease adrenal insufficiency enabling data generated by TAIN to be persevered and indexed so that it can be accessed once the project has been completed.

Potential Impact:

Contact: Prof Martin Whitaker; The University of Sheffield;

List of Websites:
The full final report is provided in a PDF document listed as 'Other'