Developmental Clinical Studies - development of vitamin D therapy to prevent acute lung injury.

Lead Research Organisation: University of Birmingham
Department Name: Clinical and Experimental Medicine

Abstract

The aim of this research is to develop vitamin D as a therapy to prevent acute lung injury. Acute lung injury ALI is a major cause of lung failure in critically ill patients. Most patients affected are of working age and survivors experience a significant reduction in health-related quality of life, with 46% unable to return to work within 12 months. Currently, apart from invasive protective ventilation, no therapy has been conclusively proven to reduce mortality or improve functional outcome in survivors. This represents a major unmet health need.
By undertaking this research we will establish if simple and cheap replacement of vitamin D influences the development and severity of acute lung injury.

Technical Summary

ALI is a major cause of respiratory failure in critically ill patients. Most patients affected are of working age and survivors experience a significant reduction in health-related quality of life, with 46% unable to return to work within 12 months. Currently, apart from protective ventilation strategies, no therapy has been conclusively proven to reduce mortality or improve functional outcome in survivors. Clearly this represents a major unmet health need.

ALI is the final common pathway of response to a variety of direct pulmonary insults such as bacterial /viral pneumonia and gastric aspiration, or indirect insults such as abdominal sepsis or battlefield trauma. However, only a relatively small proportion of patients develop ALI, with research suggesting that genetic, demographic (age), social (smoking, alcohol abuse) and other factors play a role in determining who develops ALI.

Patients undergoing transthoracic oesophagectomy are at significant risk of developing post operative lung injury (~28%), with the development of lung injury associated with a doubling of in hospital stay and significant mortality.Hospital episode statistics show that ~1500 to 2000 oesophagectomies are performed in England annually. There are no current readily available tests that can clearly identify those who are at high risk of ALI following oesophagectomy, and no therapeutic interventions proven to prevent its occurrence.

Epidemiological studies have suggested a role for vitamin D deficiency in the risk of developing both viral and bacterial infection. Vitamin D has profound effects on human immunity acting as an immune system modulator, preventing excessive expression of inflammatory cytokines and increasing the ?oxidative burst? potential of macrophages, therefore enhancing bacterial killing. In preliminary studies we have found that vitamin D deficiency/ insufficiency is ubiquitous in both patients with ALI and oesophagectomy cases who are at risk of ALI. Severe deficiency is associated with elevated systemic inflammatory response and an increased risk of developing lung injury in the oesophagectomy group.

This proposal aims in a series of clinical studies to determine the proof of concept and optimal dosing strategy for administering cholecalciferol liquid preoperatively to prevent lung injury in oesophagectomy using established markers of bioactivity /efficacy in the setting of ALI.

The proposed treatment is simple and if effective could be easily incorporated into widespread clinical practice. The results from this trial will provide the basis for future clinical studies investigating this and other preventative strategies in broader subject groups known to be at risk of ARDS such as pneumonia and sepsis.

Publications

10 25 50

publication icon
Grudzinska FS (2017) Statin therapy in patients with community-acquired pneumonia. in Clinical medicine (London, England)

publication icon
Grudzinska FS (2017) Statin therapy in patients with community-acquired pneumonia. in Clinical medicine (London, England)

 
Description Birmingham Experimental Cancer Medicine Centre
Amount £10,000 (GBP)
Organisation University of Birmingham 
Sector Academic/University
Country United Kingdom
Start 07/2018 
End 07/2019
 
Description Chief Investigator Development Award
Amount £104,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Clinical Research Network West Midlands
Sector Academic/University
Country United Kingdom
Start 06/2017 
End 06/2019
 
Description Global Birth Health Research
Amount £75,000 (GBP)
Organisation University of Birmingham 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 03/2021
 
Description Intensive care society Young investigator Award
Amount £15,000 (GBP)
Organisation Intensive Care Society 
Sector Academic/University
Country United Kingdom
Start 07/2014 
End 06/2016
 
Description NIHR HTA
Amount £2,000,080 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 05/2018 
End 11/2022
 
Description Neurological prognosis after cardiac arrest in kids: derivation, validation and impact assessment of a clinical prediction model
Amount £984,000 (GBP)
Funding ID CS-2015-15-016 
Organisation National Institute for Health Research 
Department NIHR Fellowship Programme
Sector Public
Country United Kingdom
Start 01/2017 
End 12/2021
 
Description New Research on Use and Usefulness of Patients Expereicne and Reflective Learning (PEARL Project)
Amount £723,698 (GBP)
Funding ID 14/156/23 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 10/2016 
End 09/2019
 
Description Post-surgery delirium PhD Fellowship
Amount £75,000 (GBP)
Organisation Heart of England NHS Foundation Trust 
Sector Public
Country United Kingdom
Start 03/2018 
End 02/2021
 
Description Resilient Cities Theme
Amount £300,000 (GBP)
Organisation University of Birmingham 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 03/2021
 
Description The mechanism of microRNA-21 on lipoxin promoting alveolar fluid.
Amount £150,000 (GBP)
Organisation National Science Foundation China 
Sector Public
Country China
Start 09/2015 
End 08/2017
 
Description VITDALIZE UK - a randomised placebo controlled trial of vitamin D therapy in critically ill patients
Amount £950,000 (GBP)
Organisation NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC) 
Sector Public
Country United Kingdom
Start 06/2019 
End 05/2023
 
Description mrc entry training mr/j011266/1
Amount £200,000 (GBP)
Funding ID mr/j011266/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 06/2012 
End 06/2014
 
Description DUSP1_TTP 
Organisation University of Birmingham
Department Institute of Inflammation and Ageing
Country United Kingdom 
Sector Academic/University 
PI Contribution Intellectual, samples and analysis. Hypothesis generation. Murine studies.
Collaborator Contribution Intellectual
Impact Application to Wellcome and MRC fellowships; PhD studentship
Start Year 2016
 
Description IMPACT Study 
Organisation National Institute for Health Research
Department NIHR Clinical Research Network (CRN)
Country United Kingdom 
Sector Academic/University 
PI Contribution I had the original idea on evaluating IMPACT of UK critical care RCTs which was accepted by the Intensive Care Foundation and NIHR CRN for Critical Care specialty. Dr Jaimin Patel, Clinician Scientist, University of Birmingham (from my team) under my and Dr Paul Dark (Prof in University of Manchester) supervision leads this prospective national evaluation of impact of these RCTs (including Balti-2) on changes of clinical practice.
Collaborator Contribution Professor Paul Dark, Chair of the NIHR Critical Care CRN, supported the idea, contributed to the protocol and supported to obtain a CRN funding £5000 for the study,
Impact 1. to raise awareness in the UK critical care community on impact of clinical research; 2. to evaluate the outputs and outcomes of the UK Intensive Care Foundation funded clinical trials.
Start Year 2015
 
Description University of East Anglia 
Organisation University of East Anglia
Country United Kingdom 
Sector Academic/University 
PI Contribution This collaboration was set up to appropriately measure vitamin D levels in the clinical samples from the vindaloo trial
Collaborator Contribution provide expertise and high value equipment access to enable tandem mass spec and DEQAS controlled ELISA
Impact all in progress still
Start Year 2012
 
Description UoB 
Organisation University of Birmingham
Department Institute of Inflammation and Ageing
Country United Kingdom 
Sector Academic/University 
PI Contribution Expertise, Intellectual input, supporting recruitment of patients, laboratory work and analysis of data, training of staff and supervising medical/BMedSci students
Collaborator Contribution Expertise and intellectual input. Research training. Access to laboratory space and equipment ad facilities
Impact Publications Presentations Prizes Bmedsci Student Projects PhD Supervision
Start Year 2012
 
Description VITDALIZE Trial 
Organisation University of Graz
Country Austria 
Sector Academic/University 
PI Contribution Intellectual, trial development
Collaborator Contribution Trial co-ordination, intellectual
Impact N/A
Start Year 2017
 
Description Vitamin D Metabolome 
Organisation University of Birmingham
Department Institute of Metabolism and Systems Research (IMSR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Measurements of Vitamin D Metabolomics in patient samples. Collaboration together to hypothesis generation and application to Clinician Scientist Fellowship programmes
Collaborator Contribution Measurements of Vitamin D Metabolomics in patient samples. Collaboration together to hypothesis generation and application to Clinician Scientist Fellowship programmes
Impact N/A
Start Year 2015
 
Description collaborations with other universities, NHS organisations, NIHR CRN, Royal College of Anaesthetists, Royal College of Surgeons, Research Trainees network, UK Perioperative Medicine Clinical Trials Network, NIAA, ACTAC, NIAA HSRC PCPIE and PPIs 
Organisation NHS England
Country United Kingdom 
Sector Public 
PI Contribution Assisted co-applicants with expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Collaborator Contribution Co-applicants contributed expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Impact Further £2,000,000 funding received.
Start Year 2018
 
Description collaborations with other universities, NHS organisations, NIHR CRN, Royal College of Anaesthetists, Royal College of Surgeons, Research Trainees network, UK Perioperative Medicine Clinical Trials Network, NIAA, ACTAC, NIAA HSRC PCPIE and PPIs 
Organisation National Institute of Academic Anaesthesia
Country United Kingdom 
Sector Academic/University 
PI Contribution Assisted co-applicants with expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Collaborator Contribution Co-applicants contributed expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Impact Further £2,000,000 funding received.
Start Year 2018
 
Description collaborations with other universities, NHS organisations, NIHR CRN, Royal College of Anaesthetists, Royal College of Surgeons, Research Trainees network, UK Perioperative Medicine Clinical Trials Network, NIAA, ACTAC, NIAA HSRC PCPIE and PPIs 
Organisation Royal College of Surgeons of England
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Assisted co-applicants with expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Collaborator Contribution Co-applicants contributed expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Impact Further £2,000,000 funding received.
Start Year 2018
 
Description collaborations with other universities, NHS organisations, NIHR CRN, Royal College of Anaesthetists, Royal College of Surgeons, Research Trainees network, UK Perioperative Medicine Clinical Trials Network, NIAA, ACTAC, NIAA HSRC PCPIE and PPIs 
Organisation The Royal College of Anaesthetists
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Assisted co-applicants with expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Collaborator Contribution Co-applicants contributed expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Impact Further £2,000,000 funding received.
Start Year 2018
 
Description collaborations with other universities, NHS organisations, NIHR CRN, Royal College of Anaesthetists, Royal College of Surgeons, Research Trainees network, UK Perioperative Medicine Clinical Trials Network, NIAA, ACTAC, NIAA HSRC PCPIE and PPIs 
Organisation UK Perioperative Medicine Clinical Trials Network
Sector Academic/University 
PI Contribution Assisted co-applicants with expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Collaborator Contribution Co-applicants contributed expertise from different institutions, active contributions to economic growth and increase influence of PPIs and strengthen trainee research networks.
Impact Further £2,000,000 funding received.
Start Year 2018
 
Title vitamin d 
Description we are currently testing this in the clinical trials funded by the mrc 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact we have established the dose to use for patients undergoing oesophagectomy to replace vitamin d preoperatively 
URL http://www.controlled-trials.com/ISRCTN27673620