Developmental Clinical Studies: Does GM-CSF restore effective neutrophil function in critically ill patients?

Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine

Abstract

Patients admitted to intensive care units (ICUs) are at very high risk of developing new infections in hospital. These hospital infections are commonly caused by bacteria that do not respond to antibiotics and are often termed ?superbugs?. Patients in ICU who develop new infections are more likely to die, or to have longer stays in ICU. Despite a variety of approaches aiming to prevent these hospital infections, they remain unacceptably common in the ICU.

We have recently shown that the key blood cells (called neutrophils) mainly responsible for fighting bacteria commonly fail to work efficiently in ICU patients. This seems to contribute to the increased risk of infection. Adding a drug (GM-CSF) to such non-functioning neutrophils in the laboratory invariably improves their function. This suggests that, if high-risk patients with poorly functioning neutrophils could be identified, GM-CSF may be able to prevent infections. However GM-CSF has never been specifically targeted to ICU patients with non-functioning neutrophils before. The next crucial step in establishing whether GM-CSF may prevent infections in ICU is therefore to test whether GM-CSF improves the function of neutrophils in high-risk patients.

Our aim is therefore to identify ICU patients who have poorly functioning neutrophils, using a simple laboratory test. The patients will be randomly assigned to receive either GM-CSF or a dummy drug (placebo). Neither the patient nor the doctors will be aware whether GM-CSF or placebo has been given until after the project is completed, when the research team will analyse the results. This type of study is called a randomised placebo controlled double blind trial and is widely accepted to be the best way to find out if a treatment really works or not. In this way we shall establish whether GM-CSF improves the function of neutrophils. If this ?proof of concept? study does demonstrate benefit for GM-CSF, it would rapidly pave the way for large studies establishing if GM-CSF can prevent development of infection in ICU when targeted specifically at patients whose neutrophils function poorly.

Technical Summary

Despite introduction of multiple preventive measures, nosocomial infection rates remain unacceptably high, particularly in the intensive care unit (ICU) where 20-40% of patients acquire new nosocomial infections. Novel strategies are therefore urgently required. The neutrophil is the key cellular effector for clearance of bacterial and fungal pathogens. We have demonstrated that: impaired neutrophil phagocytosis is common in ICU patients; patients with impaired neutrophil phagocytosis in ICU are at significantly increased risk of nosocomial infection; and granulocyte-macrophage colony-stimulating factor (GM-CSF) applied to patients? impaired neutrophils ex vivo restores effective phagocytosis. If subcutaneous (s/c) GM-CSF, targeted to high risk patients with proven neutrophil dysfunction, also restored effective phagocytosis, GM-CSF would be well positioned for comprehensive assessment/development as a novel measure to prevent nosocomial infection in ICU. GM-CSF has never been evaluated as a therapy specifically targeted to critically ill patients with neutrophil dysfunction in the ICU.
We therefore propose a) to determine the optimal dose/duration of GM-CSF in this specific setting in order b) to perform the first proof of concept, double-blind randomised controlled trial of s/c GM-CSF specifically targeting critically ill patients with proven neutrophil dysfunction, and therefore at high risk of nosocomial infection. The primary endpoint will be neutrophil phagocytic capacity. A proven beneficial effect for GM-CSF would rapidly pave the way for larger studies assessing its capacity to prevent nosocomial infections in the ICU.

Publications

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Title RCT database 
Description Database from our RCT - held by Newcastle CTU. 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact None known to date. 
 
Description GRiP 
Organisation City Hospitals Sunderland NHS Foundation Trust
Department Critical Care
Country United Kingdom 
Sector Hospitals 
PI Contribution We led the partnership
Collaborator Contribution We set it up. At the time of writing we are about to perform a multi centre RCT. update 8.11.14 - we have secured an extension for our RCT, with our final report due with MRC by May 2015. At the time of writing 30 of 38 patients have been recruited to the trial. Our recruitment averages around 3 per month, so we estimate that recruitment will end, on time, at around the end of January 2015. update 13.3.17 - the RCT is complete, a manuscript is prepared, and is about to be sent round the authors for final checks prior to submission to a good quality journal. Update 13.3.18 - the manuscript is under revision at Thorax, a leading respiratory and critical care journal.
Impact Outputs will come after publication of the manuscript from the trial.
Start Year 2011
 
Description GRiP 
Organisation Newcastle upon Tyne Hospitals NHS Foundation Trust
Department Critical Care Services
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution We led the partnership
Collaborator Contribution We set it up. At the time of writing we are about to perform a multi centre RCT. update 8.11.14 - we have secured an extension for our RCT, with our final report due with MRC by May 2015. At the time of writing 30 of 38 patients have been recruited to the trial. Our recruitment averages around 3 per month, so we estimate that recruitment will end, on time, at around the end of January 2015. update 13.3.17 - the RCT is complete, a manuscript is prepared, and is about to be sent round the authors for final checks prior to submission to a good quality journal. Update 13.3.18 - the manuscript is under revision at Thorax, a leading respiratory and critical care journal.
Impact Outputs will come after publication of the manuscript from the trial.
Start Year 2011
 
Description GRiP 
Organisation Queen Elizabeth Hospital, Gateshead
Country United Kingdom 
Sector Hospitals 
PI Contribution We led the partnership
Collaborator Contribution We set it up. At the time of writing we are about to perform a multi centre RCT. update 8.11.14 - we have secured an extension for our RCT, with our final report due with MRC by May 2015. At the time of writing 30 of 38 patients have been recruited to the trial. Our recruitment averages around 3 per month, so we estimate that recruitment will end, on time, at around the end of January 2015. update 13.3.17 - the RCT is complete, a manuscript is prepared, and is about to be sent round the authors for final checks prior to submission to a good quality journal. Update 13.3.18 - the manuscript is under revision at Thorax, a leading respiratory and critical care journal.
Impact Outputs will come after publication of the manuscript from the trial.
Start Year 2011
 
Title GM-CSF in impaired neutrophil phagocytosis 
Description I'm not sure the drop down menus allow an accurate reflection of where we are! We have completed a preliminary open label study of GM-CSF in critically ill patients and a proof of concept RCT is due to start on 18.11.13 Update 8.11.14 - I'm still not sure if i am answering this question properly, but we are nearing completion of our RCT - at the time of writing we have recruited 30 of a planned 38 patients, and we are on course to complete around the end of January 2015, with a final report due to MRC in May 2015. The medical product is GM-CSF, its "stage of development" is that this is the first evaluation in this specific setting (ie does GM-CSF restore abnormal neutrophil function in critically ill patients?). The "current principle source of funding for this development" is solely through the grant. Please note that the ISRCTN and EudraCT numbers entered above refer to the ongoing trial (ie not to a completed trial). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact The notable impact(s) cannot be judged until after the RCT (as above, this is due to end in January 2015, with statistical analysis thereafter).