Does GM-CSF Restore Neutrophil Phagocytosis in Critical Illness?

NCT01653665 | Completed Phase 1 DMC

• 4 other identifiers: AJSEB001G11002332011-005815-10ISRCTN95325384
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 4

Brief Summary

Despite the introduction of multiple preventative measures rates of hospital acquired infection in the intensive care unit remain high. New approaches to tackling this problem are required. The neutrophil (a type of white blood cell) is the key cell fighting bacterial and fungal infection in the body. This research group has already shown that the majority of patients on intensive care have neutrophils which don't ingest germs effectively and are therefore less able to fight infection. These patients, whose white blood cells don't work properly, are much more likely to develop a second infection whilst in hospital (hospital acquired infection). Previous work done by this group has shown that by adding a drug called granulocyte macrophagecolony stimulating factor (GM-CSF) to a sample of blood from these patients in the lab, it is possible to restore the ability of the white blood cells to ingest bacteria and fight infection. This study will test whether it is possible to restore the capacity of patients' white blood cells to eat germs by giving them GM-CSF as an injection while they are on intensive care. The study will involve identifying adult patients on intensive care whose white blood cells don't work properly in this way. Patients taking part in the study will receive an injection, under the skin, of either the drug, GM-CSF, or a solution which will have no effect (placebo). The investigators will compare whether those patients who have received the GM-CSF injection have an improvement in the function of the white blood cells compared to those who don't. As well as looking at the function of the white blood cells the investigators will also study whether there is a difference in the rates of infection picked up in hospital between the two groups. This study is funded by the Medical Research Council.

Conditions

Critical Illness; Sepsis; Immuno-suppression

Outcome Measures

Primary Outcomes (1)

• Neutrophil phagocytosis

  neutrophil phagocytic capacity will be measured as the percentage of neutrophils ingesting 2 or more zymosan particles ex vivo

  2 days after GMCSF/placebo administration

Secondary Outcomes (10)

• neutrophil phagocytic capacity on alternate study days

  0 - 9 days

• Other measures of neutrophil function

  0-9 days

• Monocyte HLA-DR expression

  0-9 days

• Serum measures of inflammatory response

  0-9 days

• Sequential organ failure assessment (SOFA)

  up to end of study participation, a maximum of 30 days for each participant

Study Arms (2)

Leukine (Sargramostim, GM-CSF)

ACTIVE COMPARATOR

Participants in dose finding study will receive either 3 or 6 micrograms per kilo per day as a daily subcutaneous injection for either 4 or 7 days. Within the Randomised controlled trial, participants will receive the dose as chosen following the dose finding study.

Drug: Leukine

Placebo (normal saline)

PLACEBO COMPARATOR

Participants in the randomised controlled trial may be randomised to receive a daily subcutaneous injection of normal saline (placebo) for 4 or 7 days as decided following the results of the dose finding study

Drug: Normal Saline

Interventions

Leukine DRUG

Daily subcutaneous injection of either 3 or 6 micrograms per kilo per day, for either 4 or 7 days.

Also known as: Sargramostim, GM-CSF

Leukine (Sargramostim, GM-CSF)

Normal Saline DRUG

Patients in the randomised controlled trial may receive this placebo as a single daily subcutaneous injection. The volume will match that of the active drug.

Also known as: placebo

Placebo (normal saline)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Fulfil criteria for systemic inflammatory response syndrome on admission to ICU (see appendix 1)
• Has required support of one or more organ systems (invasive ventilation, inotropes or haemofiltration) during current ICU stay
• Survival over next 48 hours deemed most likely outcome by responsible ICU clinician
• Admitted to ICU within last 72 hours
• Neutrophil phagocytic capacity \<50%

You may not qualify if:

• Absence/refusal of informed consent
• Current prescription of a colony stimulating factor
• Any history of allergy/adverse reaction to GM-CSF
• Total white cell count \>30x109/litre at time of screening
• Haemoglobin \< 7.5g/dl at the time of screening
• Age \< 18 years
• Pregnancy or lactation
• Known in-born errors of neutrophil metabolism
• Known haematological malignancy and/or known to have \>10% peripheral blood blast cells
• Known aplastic anaemia or pancytopaenia
• Platelet count \<50x109/litre
• Chemotherapy or radiotherapy within the last 24 hours
• Solid organ or bone marrow transplantation
• Use of maintenance immunosuppressive drugs other than maintenance corticosteroids (allowed up to 10mg prednisolone/day or equivalent)
• Known HIV infection

Sponsors & Collaborators

• Newcastle-upon-Tyne Hospitals NHS Trust: lead
• Medical Research Council: collaborator
• Newcastle University: collaborator

Study Sites (4)

Queen Elizabeth Hospital

Gateshead, Tyne and Wear, NE9 6SX, United Kingdom

Location

Royal Victoria Infirmary

Newcastle upon Tyne, Tyne and Wear, NE1 4LP, United Kingdom

Location

Freeman Hospital

Newcastle upon Tyne, Tyne and Wear, NE7 7DN, United Kingdom

Location

Sunderland Royal Hospital

Sunderland, United Kingdom

Location

MeSH Terms

Conditions

Critical Illness; Sepsis

Interventions

sargramostim; Granulocyte-Macrophage Colony-Stimulating Factor; Saline Solution

Condition Hierarchy (Ancestors)

Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Infections; Systemic Inflammatory Response Syndrome; Inflammation

Intervention Hierarchy (Ancestors)

Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• John Simpson

  Newcastle University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 16, 2012
• First Posted: July 31, 2012
• Study Start: August 1, 2012
• Primary Completion: January 1, 2015
• Study Completion: February 1, 2015
• Last Updated: February 13, 2018

Record last verified: 2018-02

Locations

GB (4)