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

Summary
EudraCT number	2011-005815-10
Trial protocol	GB
Global end of trial date	12 Feb 2015

Results information
Results version number	v1(current)
This version publication date	11 Aug 2016
First version publication date	11 Aug 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

AJSEB001

ISRCTN number

ISRCTN95325384

US NCT number

NCT01653665

WHO universal trial number (UTN)

Other trial identifiers

UKCRN ID: 12337, REC Ref: 12/YH/0083, IRAS ID: 91653

Sponsor organisation name

Newcastle Upon Tyne Hospitals NHS Foundation Trust

Sponsor organisation address

Freeman Hospital, Freeman Rd, Newcastle upon Tyne, United Kingdom, NE7 7DN

Public contact

Professor John Simpson,, Newcastle Upon Tyne Hospitals NHS Foundation Trust, 44 01912087770, j.simpson@ncl.ac.uk

Scientific contact

Professor John Simpson,, Newcastle Upon Tyne Hospitals NHS Foundation Trust, 44 01912087770, j.simpson@ncl.ac.uk

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

06 Oct 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Feb 2015

Global end of trial reached?

Yes

Global end of trial date

12 Feb 2015

Was the trial ended prematurely?

Main objective of the trial

Will GM-CSF (a drug used to stimulate white blood cells) be able to restore the ingestion of germs by neutrophils (the most important white blood cells in fighting bacterial and fungal infection) to fight off infection in critically ill patients on intensive care?

Protection of trial subjects

Participants were treated in routine critical care setting. All patients enrolled in the study received daily monitoring.

Background therapy

Patients received background care in keeping with their critical illness.

Evidence for comparator

In controlled trials, the incidences of renal and hepatic dysfunction were comparable between Leukine and placebo treated patients. Patients who took part in the RCT component of the received either, an injection of the drug (GM-CSF) or an injection of a solution, with no effect (placebo or dummy drug). We then compared whether those patients who received the GM-CSF injection had an improvement in the function of their neutrophils compared to those who did not.

Actual start date of recruitment

17 Sep 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 38

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The incapacitating nature of the condition precluded obtaining prospective informed consent from nearly all participants. Informed consent was sought from patients or a Personal or Professional Legal Representative. Due to the time dependent factors, a time limit of up to 24 hours to make a decision was given, but within 6 hrs if possible.

Screening details

Daily screening of patients was performed on ICU (within 72hrs of admission). After consent, a blood sample was taken for assessment of neutrophil phagocytosis. If a patient’s phagocytosis index was >50% the patient was not recruited, ie not all patients consented were included in the dose-finding study or RCT.

Number of subjects started

3634 ^[1]

Intermediate milestone: Number of subjects

screening completed: 3634

Intermediate milestone: Number of subjects

assessed for eligibility: 926

Intermediate milestone: Number of subjects

consented: 64

Intermediate milestone: Number of subjects

Eligibility confirmed by phagocytosis: 38

Number of subjects completed

Reason: Number of subjects

screen fail: 3596

Notes
[1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: The total number of patients screened in ICUs was 3634. Of these only 38 were randomised into the trial and therefore 3596 patients were ineligible at various points during the screening process. Consent was obtained for 64 patients, however 26 of these were were not eligible on the basis of phagocytosis screening following consent.

Period 1 title

RCT (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Single blind

Roles blinded

Subject

Blinding implementation details

Randomisation was a 1:1 ratio, with stratification by site, using a web-based randomisation service in NCTU. The randomised allocation schedule was generated by a statistician with no other involvement in the study to ensure independence and concealment of allocation. Permuted blocks of variable length were used to reduce the risk of breach of concealment of allocation. A treatment number was generated for each participant that links to the corresponding allocated study drug/placebo.

Are arms mutually exclusive

Yes

GMCSF

Arm description

Each participant was randomly allocated to receive either study drug or placebo. As a placebo controlled, single-blind trial, patients, clinicians and the PIs were blinded to each patient's allocation. All trial drugs, whether GM-CSF or placebo, were packaged identically at the point of administration and identified only by a unique trial identifier.

Arm type

Experimental

Investigational medicinal product name

Leukine

Investigational medicinal product code

LO3AA09

Other name

Sargramostim, Granulocyte-macrophage colony-stimulating factor, GM-CSF

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each patient randomised to the GMCSF arm received up to 4 days of treatment with GM-CSF (sargramostim, Leukine®) as a subcutaneous injection. GM-CSF (Sargramostim, Leukine®, 250 microgram/vial) dosed on actual body weight (3mcg/kg) up to a maximum dose of 450mcg/volume 1.8ml. The dose/volume administered was prescribed according to the weight ranges given to give the dose to the nearest 5kg.

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Each patient randomised to the placebo arm received up to 4 days of treatment with either 0.9% sodium chloride as a subcutaneous injection. 0.9% sodium chloride (placebo, 5ml /ampoule) dosed on actual body weight (3mcg/kg) up to a maximum dose of 450mcg/volume 1.8ml. The dose/volume administered was prescribed according to the weight ranges given to give the dose to the nearest 5kg.

Number of subjects in period 1	GMCSF	Placebo
Started	17	21
Eligibility confirmed by phagocytosis	17	21
Primary endpoint met	13 ^[2]	20 ^[3]
Day 9 data collected	11 ^[4]	17 ^[5]
Day 30 data collected	17	21
Completed	17	21

Notes
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: milestones relate to the number randomised, and those for whom primary endpoint data was collected at Day 2, and then further data collected at Day 9 and Day 30. Some data was not collected at Days 9, however data was collected at Day 30 for all participants. Primary endpoint data would be missing if, for example, a patient died before day 2.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: milestones relate to the number randomised, and those for whom primary endpoint data was collected at Day 2, and then further data collected at Day 9 and Day 30. Some data was not collected at Days 9, however data was collected at Day 30 for all participants. Primary endpoint data would be missing if, for example, a patient died before day 2.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: milestones relate to the number randomised, and those for whom primary endpoint data was collected at Day 2, and then further data collected at Day 9 and Day 30. Some data was not collected at Days 9, however data was collected at Day 30 for all participants. Primary endpoint data would be missing if, for example, a patient died before day 2.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: milestones relate to the number randomised, and those for whom primary endpoint data was collected at Day 2, and then further data collected at Day 9 and Day 30. Some data was not collected at Days 9, however data was collected at Day 30 for all participants. Primary endpoint data would be missing if, for example, a patient died before day 2.

Baseline characteristics

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Reporting group title

GMCSF

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group values	GMCSF	Placebo	Total
Number of subjects	17	21	38
Age categorical
Units: Subjects
In utero	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0
Newborns (0-27 days)	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0
Children (2-11 years)	0	0	0
Adolescents (12-17 years)	0	0	0
Adults (18-64 years)	7	8	15
From 65-84 years	8	13	21
85 years and over	2	0	2
Age continuous
Units: years
arithmetic mean (standard deviation)	65.2 ( 16.7 )	63.4 ( 15.7 )	-
Gender categorical
Units: Subjects
Female	7	6	13
Male	10	15	25
Case mix of patients in GRIP trial. Circumstances that led to them being recruited into the trial
Circumstances that led to patients being recruited into the trial.
Units: Subjects
Elective medical	0	0	0
Elective surgical	2	2	4
Emergency medical	14	15	29
Emergency surgical	1	4	5
Weight
Patients weight at baseline
Units: kg
arithmetic mean (standard deviation)	72.6 ( 15.6 )	83 ( 23.9 )	-
Length of stay in ICU
Time in days that the patients stayed in the intensive care unit
Units: days
arithmetic mean (standard deviation)	15.6 ( 10.4 )	14.9 ( 10.1 )	-
Number of days of mechanical ventilation
Number of days of mechanical ventilation
Units: days
arithmetic mean (standard deviation)	10.9 ( 10.7 )	10.3 ( 10.4 )	-
Baseline Neutrophil phagocytic capacity
baseline measure of Neutrophil phagocytic capacity
Units: percentage of neutrophils ingesting ≥ 2
arithmetic mean (standard deviation)	45.08 ( 4.59 )	40.14 ( 8.21 )	-
Baseline reactive oxygen species (ROS) generation –primed cells
Baseline measures of reactive oxygen species (ROS) generation –primed cells
Units: nmoles of superoxide
arithmetic mean (standard deviation)	1.49 ( 1.36 )	1.84 ( 1.65 )	-
Baseline reactive oxygen species (ROS) generation –second stimulus
Baseline meaures of reactive oxygen species (ROS) generation –second stimulus
Units: nmoles per superoxide
arithmetic mean (standard deviation)	1.98 ( 1.53 )	1.93 ( 1.77 )	-
baseline distance migrated on chemotaxis assay
baseline measures of distance migrated on chemotaxis assay
Units: micrometers
arithmetic mean (standard deviation)	418.3 ( 303.4 )	404.4 ( 399.9 )	-
Baseline Early apoptosis - Apoptotic rate
Baseline measures for Early apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)
Units: percentage of cells
arithmetic mean (standard deviation)	16.14 ( 13.26 )	16.85 ( 12.45 )	-
baseline late apoptosis - Apoptotic rate
late apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)
Units: percentage of cells
arithmetic mean (standard deviation)	11.98 ( 10.78 )	7.42 ( 5.39 )	-
Baseline Sequential monocyte HLA-DR expression (QTB results)
Baseline measures of Sequential monocyte HLA-DR expression (QTB results)
Units: antibodys per cell
arithmetic mean (standard deviation)	6178.7 ( 4145.8 )	6381.9 ( 5149.3 )	-
Baseline CD88 - (relative median fluorescence)
Baseline measure CD88 - (relative median fluorescence)
Units: ratio
arithmetic mean (standard deviation)	4.33 ( 3.93 )	4.13 ( 2.47 )	-
Baseline percentage of T cells (naïve/memory t reg cells) CD45RO+RA-
Baseline measure of percentage of T cells (naïve/memory t reg cells) CD45RO+RA-
Units: percentage
arithmetic mean (standard deviation)	48.15 ( 12.7 )	48.76 ( 15.35 )	-
Baseline Percentage of T cells (naïve/memory t reg cells) CD45RA+RO-
Baseline measure of Percentage of T cells (naïve/memory t reg cells) CD45RA+RO-
Units: percentage
arithmetic mean (standard deviation)	36.49 ( 12.84 )	35.26 ( 12.82 )	-
Baseline Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-6
Baseline measure of Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-6
Units: pg/ml
arithmetic mean (standard deviation)	256.5 ( 276.3 )	4017.6 ( 14641.3 )	-
baseline Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-8
Baseline measure of Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-8
Units: pg/ml
arithmetic mean (standard deviation)	147.78 ( 131.75 )	516.04 ( 1096.31 )	-
Baseline Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-1β
Baseline measure of Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-1β
Units: pg/ml
arithmetic mean (standard deviation)	11.86 ( 15.66 )	7.74 ( 12.02 )	-
Baseline Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-10
Baseline measure of Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-10
Units: pg/ml
arithmetic mean (standard deviation)	15.22 ( 13.59 )	128.75 ( 483.82 )	-
Baseline Cytokine data measure of pro/anti-inflammatory mediators in serum - TNF
Baseline measure of Cytokine data measure of pro/anti-inflammatory mediators in serum - TNF
Units: pg/ml
arithmetic mean (standard deviation)	6.74 ( 9.99 )	7.53 ( 13.71 )	-
Baseline Cytokine data measure of pro/anti-inflammatory mediators in serum -IL-12 p70
Baseline measures of Cytokine data measure of pro/anti-inflammatory mediators in serum -IL-12 p70
Units: pg/ml
arithmetic mean (standard deviation)	3.52 ( 6.39 )	4.81 ( 9.85 )	-
Apache II score at admission
Apache II score at admission
Units: score
median (inter-quartile range (Q1-Q3))	19.5 (16 to 27.5)	21 (18 to 23)	-
Baseline sequential organ failure assessment (SOFA)
Baseline sequential organ failure assessment (SOFA)
Units: count
median (inter-quartile range (Q1-Q3))	9 (4 to 10.5)	8 (6 to 10)	-
Baseline ratio of lowest PaO2 to FiO2
Baseline ratio of lowest PaO2 to FiO2
Units: ratio
arithmetic mean (standard deviation)	23 ( 11 )	27.4 ( 13.2 )	-
Baseline ratio of highest PaO2 to FiO2
Baseline ratio of highest PaO2 to FiO2
Units: ratio
arithmetic mean (standard deviation)	33.9 ( 14.9 )	38.3 ( 17.7 )	-

End points

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Reporting group title

GMCSF

Reporting group description

Reporting group title

Placebo

Reporting group description

Primary: Neutrophil phagocytic capacity 2 days after administration of GM-CSF/placebo

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End point title

Neutrophil phagocytic capacity 2 days after administration of GM-CSF/placebo

End point description

Biological measure. Neutrophil phagocytic capacity 2 days after administration of GM-CSF/placebo as measured by the percentage of neutrophils ingesting ≥ 2 zymosan particles ex vivo

End point type

Primary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	21
Units: percentage of neutrophils ingesting ≥ 2
arithmetic mean (standard deviation)	57.21 ( 13.17 )	49.77 ( 13.41 )

Unadjusted difference phagocytic capacity at 2days

Statistical analysis description

Primary outcome measure - Neutrophil phagocytic capacity 2 days after administration of GM-CSF/placebo. We used the 2 sample t test to assess difference between the neutrophil phagocytic capacity 2 days after administration of GM-CSF/placebo by arm

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1075 ^[1]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

7.44

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

16.58

Variability estimate

Standard error of the mean

Dispersion value

4.5

Notes
[1] - Accept the null hypothesis and conclude no differences in the mean neutrophil phagocytic capacity between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates

Adjusted difference phagocytic capacity after 2day

Statistical analysis description

Primary outcome measure - Neutrophil phagocytic capacity 2 days after administration of GM-CSF/placebo. Difference in mean neutrophil phagocytic capacity at day 2 adjusted for the effects of site and baseline neutrophil phagocytic capacity

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7295 ^[2]

Method

ANCOVA

Confidence interval

Notes
[2] - Adjusted for the effects of site and baseline neutrophil phagocytic capacity, there is no significance difference in mean neutrophil phagocytic capacity at day 2 between the 2 arms

Secondary: Neutrophil phagocytic capacity 4/5 days after administration of GM-CSF/placebo

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End point title

Neutrophil phagocytic capacity 4/5 days after administration of GM-CSF/placebo

End point description

Biological measure. Neutrophil phagocytic capacity 4/5 days after administration of GM-CSF/placebo (as measured by the percentage of neutrophils ingesting ≥ 2 zymosan particles ex vivo).

End point type

Secondary

End point timeframe

4/5 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	12	16
Units: percentage
arithmetic mean (standard deviation)	62.28 ( 15.69 )	50.34 ( 14.29 )

Unadjusted difference phagocyte cacapacity 4/5days

Statistical analysis description

Secondary outcome measure - Neutrophil phagocytic capacity 4/5 days after administration of GM-CSF/placebo. We used the 2 sample t test to assess difference between the neutrophil phagocytic capacity 4/5 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0456 ^[3]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

11.95

Confidence interval

level

95%

sides

2-sided

lower limit

0.25

upper limit

23.64

Variability estimate

Standard error of the mean

Dispersion value

5.69

Notes
[3] - Reject the null hypothesis and conclude that there are significant differences in the mean neutrophil phagocytic capacity between arms 4/5 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted difference phagocyte capacity 4/5days

Statistical analysis description

Secondary outcome measure - Neutrophil phagocytic capacity 4/5 days after administration of GM-CSF/placebo. Difference in mean neutrophil phagocytic capacity at day 4/5 adjusted for the effects of site and baseline neutrophil phagocytic capacity

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1512 ^[4]

Method

ANCOVA

Confidence interval

Notes
[4] - Adjusted for the effects of site and baseline neutrophil phagocytic capacity, there is no significance difference in mean neutrophil phagocytic capacity at day 4/5). No site effect (p=0.0956) or baseline dependence (p=0.0505)

Secondary: Neutrophil phagocytic capacity 6/7 days after administration of GM-CSF/placebo

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End point title

Neutrophil phagocytic capacity 6/7 days after administration of GM-CSF/placebo

End point description

Neutrophil phagocytic capacity 6/7 days after administration of GM-CSF/placebo (as measured by the percentage of neutrophils ingesting ≥ 2 zymosan particles ex vivo).

End point type

Secondary

End point timeframe

6/7 days after administration of GM-CSF/placebo

End point values	GMCSF	Placebo
Number of subjects analysed	10	16
Units: percentage of neutrophils ingesting ≥ 2
arithmetic mean (standard deviation)	64.03 ( 11.36 )	52.66 ( 15.01 )

Unadjusted difference phagocytic capacity 6/7days

Statistical analysis description

Secondary outcome measure - Neutrophil phagocytic capacity 6/7 days after administration of GM-CSF/placebo. We used the 2 sample t test to assess difference between the neutrophil phagocytic capacity 6/7 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0513 ^[5]

Method

t-test, 2-sided

Parameter type

Mean difference (net)

Point estimate

11.37

Confidence interval

level

95%

sides

2-sided

lower limit

-0.07

upper limit

22.82

Variability estimate

Standard error of the mean

Dispersion value

5.54

Notes
[5] - Accept the null hypothesis and conclude no differences in the mean neutrophil phagocytic capacity between arms 6/7 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted difference phagocytic capacity 6/7days

Statistical analysis description

Secondary outcome measure - Neutrophil phagocytic capacity 6/7 days after administration of GM-CSF/placebo Difference in mean neutrophil phagocytic capacity at day 6/7 adjusted for the effects of site and baseline neutrophil phagocytic capacity

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1575 ^[6]

Method

ANCOVA

Confidence interval

Notes
[6] - Adjusted for the effects of site and baseline neutrophil phagocytic capacity, there is no significance difference in mean neutrophil phagocytic capacity at day 6/7 (P=0.1575). No site effect (p=0.4833) or Baseline dependence (p=0.3120)

Secondary: Neutrophil phagocytic capacity 8/9 days after administration of GM-CSF/placebo

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End point title

Neutrophil phagocytic capacity 8/9 days after administration of GM-CSF/placebo

End point description

Biological measure. Neutrophil phagocytic capacity 8/9 days after administration of GM-CSF/placebo (as measured by the percentage of neutrophils ingesting≥ 2 zymosan particles ex vivo).

End point type

Secondary

End point timeframe

8/9 days after administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	9	11
Units: percentage of neutrophils ingesting ≥ 2
arithmetic mean (standard deviation)	68.33 ( 9.12 )	57.22 ( 16.64 )

Unadjusted difference phagocytic capacity 8/9days

Statistical analysis description

Secondary outcome measure - Neutrophil phagocytic capacity 8/9 days after administration of GM-CSF/placebo. We used the 2 sample t test to assess difference between the neutrophil phagocytic capacity 8/9 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.09 ^[7]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

11.12

Confidence interval

level

95%

sides

2-sided

lower limit

-1.93

upper limit

24.16

Variability estimate

Standard error of the mean

Dispersion value

6.21

Notes
[7] - Accept the null hypothesis and conclude no differences in the mean neutrophil phagocytic capacity between arms 8/9 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted difference phagocytic capacity 8/9days

Statistical analysis description

Secondary outcome measure - Neutrophil phagocytic capacity 8/9 days after administration of GM-CSF/placebo. Difference in mean neutrophil phagocytic capacity at day 8/9 adjusted for the effects of site and baseline neutrophil phagocytic capacity

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2452 ^[8]

Method

ANCOVA

Confidence interval

Notes
[8] - Adjusted for the effects of site and baseline neutrophil phagocytic capacity, there is no significance difference in mean neutrophil phagocytic capacity at day 8/9 (P=0.2452). No site effect (p=0.9648) or Baseline dependence (p=0.8611)

Secondary: Percentage of patients <50% Neutrophil phagocytic capacity at day 2

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End point title

Percentage of patients <50% Neutrophil phagocytic capacity at day 2

End point description

Number of patients with less than 50% Neutrophil phagocytic capacity at day 2

End point type

Secondary

End point timeframe

2 days after administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	21
Units: number with <50% Neutrophil capacity	3	12

Percentage of patients <50% and >=50% at day 2

Statistical analysis description

Secondary outcome measure - Neutrophil phagocytic capacity: Percentage of patients <50% and >=50% at day 2 Difference between GMCSF and placebo at day 2 for all patients (at 50% split)

Comparison groups

Placebo v GMCSF

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.041 ^[9]

Method

Fishers exact test

Parameter type

difference in proportions

Confidence interval

Notes
[9] - Reject the null hypothesis and conclude that there are differences in proportion of patients having neutrophil phagocytic capacity<50% in either arm at day2.

Secondary: Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 8/9

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End point title

Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 8/9

End point description

Area under curve is calculated by summing the areas between each time point. This procedure is known as the linear trapezoidal rule. In cases where there is missing data with no more data either before or after that point we do not calculate the area and treat that patient’s area under curve as missing. Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 8/9

End point type

Secondary

End point timeframe

From day o to day 9 after administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	9	11
Units: cells x 109/l x days
arithmetic mean (standard deviation)	553.9 ( 73.5 )	451.9 ( 85.2 )

Unadjusted difference phagocyte byArea under curve

Statistical analysis description

Secondary outcome measure - Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 8/9. We used the 2 sample t test to assess difference between ‘area under the curve’ (AUC) by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0112 ^[10]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

101.9

Confidence interval

level

95%

sides

2-sided

lower limit

26.14

upper limit

177.66

Variability estimate

Standard error of the mean

Dispersion value

36.06

Notes
[10] - Reject the null hypothesis and conclude there are significant differences in the ‘area under the curve’ between arms (GMSCF and Placebo) without adjustment for other covariates.

Adjusted difference phagocyte by Area under curve

Statistical analysis description

Secondary outcome measure - Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 8/9. Difference in the ‘area under the curve’ adjusted for the effects of site and baseline neutrophil phagocytic capacity

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.137 ^[11]

Method

ANCOVA

Confidence interval

Notes
[11] - Adjusted for effects of site and baseline neutrophil phagocytic capacity dependency, no significant difference in mean neutrophil phagocytic capacity as described by AUC. No site effect (p=0.4974) but evidence of baseline dependency (p=0.0323).

Secondary: Reactive oxygen species (ROS) generation –primed cells

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End point title

Reactive oxygen species (ROS) generation –primed cells

End point description

Biological measure. Other assessments of neutrophil function: Reactive oxygen species (ROS) generation (continuous measure)

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	17
Units: nmoles of superoxide
arithmetic mean (standard deviation)	1.66 ( 1 )	1.45 ( 1.01 )

Unadjusted difference in ROS primed cells

Statistical analysis description

Secondary outcome measure - Reactive oxygen species (ROS) generation –primed cellsWe used the 2 sample t test to assess difference between the reactive oxygen species (ROS) generation (primed cells) 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5606 ^[12]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

0.2091

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5165

upper limit

0.9347

Variability estimate

Standard error of the mean

Dispersion value

0.3553

Notes
[12] - Accept the null hypothesis and conclude there is no significant difference in the reactive oxygen species (ROS) generation (primed cells) between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted difference in ROS primed cells

Statistical analysis description

Secondary outcome measure - Reactive oxygen species (ROS) generation –primed cells Difference in mean neutrophil phagocytic capacity at day 2 adjusted for the effects of site and baseline reactive oxygen species (ROS) generation (primed cells)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.913 ^[13]

Method

ANCOVA

Confidence interval

Notes
[13] - Adjusted for the effects of site and baseline (ROS) generation (primed cells), no significant difference. No site effect (p=0.6529) or Baseline dependence (p=0.8255)

Secondary: Reactive oxygen species (ROS) generation – second stimulus

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End point title

Reactive oxygen species (ROS) generation – second stimulus

End point description

Biological measure. Other assessments of neutrophil function: Reactive oxygen species (ROS) generation (continuous measure)

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	17
Units: nmoles of superoxide
arithmetic mean (standard deviation)	2.49 ( 1.46 )	2.05 ( 1.42 )

Unadjusted difference ROS primed cell 2nd stimulus

Statistical analysis description

Secondary outcome measure - Reactive oxygen species (ROS) generation (second stimulus) 2 days after administration of GM-CSF/placebo. We used the 2 sample t test to assess difference between the reactive oxygen species (ROS) generation (second stimulus) 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.392 ^[14]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

0.4416

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5968

upper limit

1.48

Variability estimate

Standard error of the mean

Dispersion value

0.5085

Notes
[14] - Accept the null hypothesis and conclude there is no significant difference in the mean reactive oxygen species (ROS) generation (second stimulus) between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted difference ROS primed cells 2nd stimulus

Statistical analysis description

Secondary outcome measure - Reactive oxygen species (ROS) generation (second stimulus) 2 days after administration of GM-CSF/placebo. Difference in mean neutrophil phagocytic capacity at day 2 adjusted for the effects of site and baseline reactive oxygen species (ROS) generation (second stimulus)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.733 ^[15]

Method

ANCOVA

Confidence interval

Notes
[15] - Adjusted for the effects of site and baseline ROS generation (2nd stimulus), no significant difference in mean ROS generation (2nd stimulus) (P=0.7330). No site effect (p=0.6269) or Baseline dependency (p=0.3343)

Secondary: Distance migrated on chemotaxis assay

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End point title

Distance migrated on chemotaxis assay

End point description

Biological measure. Other assessments of neutrophil function: Distance migrated on chemotaxis assay

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	12	14
Units: micrometers
arithmetic mean (standard deviation)	415.15 ( 230.51 )	374.66 ( 268.81 )

Unadjusted Distance migrated on chemotaxis assay

Statistical analysis description

Secondary outcome measure - Distance migrated on chemotaxis assay We used the 2 sample Mann Whitney test to assess difference between chemotaxis assay 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5368 ^[16]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[16] - Accept the null hypothesis and conclude there is no significant difference in the mean distance migrated on chemotaxis assay between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted Distance migrated on chemotaxis assay

Statistical analysis description

Secondary outcome measure - Distance migrated on chemotaxis assay. Difference in mean distance migrated on chemotaxis assay at day 2 adjusted for the effects of site and baseline distance migrated on chemotaxis assay

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7945 ^[17]

Method

ANCOVA

Confidence interval

Notes
[17] - Adjusted for the effects of site and baseline distance migrated on chemotaxis assay, there is no significant difference in mean distance migrated on chemotaxis assay (P=0.7945). No site effect (p=0.5686) but apparent Baseline dependence (p=0.0379)

Secondary: Early apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

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End point title

Early apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

End point description

Biological measure. Other assessments of neutrophil function: Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	17
Units: percentage of cells
arithmetic mean (standard deviation)	15.14 ( 9.3 )	16.61 ( 8.23 )

Unadjusted Early apoptotic rate

Statistical analysis description

Secondary outcome measure – Early apoptosis, Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria). We used the 2 sample t test to assess difference between early apoptotic rate 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6395 ^[18]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-1.4659

Confidence interval

level

95%

sides

2-sided

lower limit

-7.7922

upper limit

4.8604

Variability estimate

Standard error of the mean

Dispersion value

3.0977

Notes
[18] - Accept the null hypothesis and conclude there is no significant difference in the early apoptotic rate between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted Early apoptotic rate

Statistical analysis description

Secondary outcome measure – Early apoptosis, Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria). Difference in mean apoptotic rate (late apotosis) at day 2 adjusted for the effects of site and baseline early apoptotic rate.

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7582 ^[19]

Method

ANCOVA

Confidence interval

Notes
[19] - Adjusted for the effects of site and baseline early apoptotic rate there is no significant difference in mean early apoptotic rate (P=0.7582). No site effect (p=0.6786) or Baseline dependence (p=0.2308)

Secondary: Late apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

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End point title

Late apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

End point description

Biological measure. Other assessments of neutrophil function: Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	17
Units: percentage of cells
arithmetic mean (standard deviation)	7.92 ( 7.99 )	10.12 ( 7.32 )

Unadjusted late apoptotic rate

Statistical analysis description

Secondary outcome measure – Late apoptosis, Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria) We used the 2 sample Mann Whitney test to assess difference between the late apoptotic rate 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo).

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2493 ^[20]

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard error of the mean

Notes
[20] - Accept the null hypothesis and conclude there is no significant difference in the early apoptotic rate between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates

Adjusted late apoptotic rate

Statistical analysis description

Secondary outcome measure – Late apoptosis, Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria) Difference in mean apoptotic rate (late apotosis) at day 2 adjusted for the effects of site and baseline late apoptotic rate

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4053 ^[21]

Method

ANCOVA

Confidence interval

Notes
[21] - Adjusted for the effects of site and baseline late apoptotic rate, there is no significant difference in mean late apoptotic rate (P=0.4053). No site effect (p=0.3252) or Baseline dependence (p=0.5647)

Secondary: Sequential monocyte HLA-DR expression (QTB results)

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End point title

Sequential monocyte HLA-DR expression (QTB results)

End point description

Biological measure. Other assessments of neutrophil function: Sequential monocyte HLA-DR expression (QTB results)

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	13	18
Units: Antibody per cell
arithmetic mean (standard deviation)	54998.86 ( 31239.32 )	6096.51 ( 4500.89 )

Unadjusted - Sequential monocyte HLA-DR

Statistical analysis description

Secondary outcome measure - Sequential monocyte HLA-DR expression (QTB results) We used the 2 sample Mann Whitney test to assess difference between the APC (antibody bound per cell) 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo).

Comparison groups

Placebo v GMCSF

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0012 ^[22]

Method

Wilcoxon (Mann-Whitney)

Parameter type

Mean difference (final values)

Confidence interval

sides

2-sided

lower limit

upper limit

Notes
[22] - Reject the null hypothesis and conclude there are significant difference in the mean APC between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted - Sequential monocyte HLA-DR

Statistical analysis description

Secondary outcome measure - Sequential monocyte HLA-DR expression (QTB results) Difference in mean between the APC (antibody bound per cell) 2 days after administration of GM-CSF/placebo by arm at day 2 adjusted for the effects of site and baseline APC.

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0 ^[23]

Method

ANCOVA

Confidence interval

Notes
[23] - Adjusted for the effects of site and baseline antibody bound per cell (APC), there are significant differences in mean APC (P=0.0000). No site effect (p=0.4692) but evidence of baseline dependence (p=0.0100).

Secondary: CD88 - (relative median fluorescence)

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End point title

CD88 - (relative median fluorescence)

End point description

Biological measure. Other assessments of neutrophil function: relative median fluorescence (CD88 results)

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	12	18
Units: ratio
arithmetic mean (standard deviation)	4.24 ( 1.45 )	4.8 ( 2.56 )

Uadjusted relative median fluorescence 2 days

Statistical analysis description

Secondary outcome measure - CD88 (relative median fluorescence) 2 days after administration of GM-CSF/placebo. We used the 2 sample t test to assess difference between the CD88 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4997 ^[24]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

-0.5581

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2299

upper limit

1.1137

Variability estimate

Standard error of the mean

Dispersion value

0.8162

Notes
[24] - Accept the null hypothesis and conclude there is no significant difference in the mean CD88 between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

adjusted relative median fluorescence

Statistical analysis description

Secondary outcome measure - CD88 (relative median fluorescence) 2 days after administration of GM-CSF/placebo. Difference in mean CD88 at day 2 adjusted for the effects of site and baseline CD88 measures

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3924 ^[25]

Method

ANCOVA

Confidence interval

Notes
[25] - Adjusted for the effects of site and baseline CD88 expression, there is no significant difference in mean CD88 (P=0.3924). No site effect (p=0.8062) or Baseline dependence (p=0.0595)

Secondary: Percentage of T cells (naïve/memory t reg cells) CD45RA+RO-

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End point title

Percentage of T cells (naïve/memory t reg cells) CD45RA+RO-

End point description

Biological measure. Other assessments of neutrophil function: Percentage of T cells (naïve/memory t reg cells) CD45RA+RO-

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	12	15
Units: percentage
arithmetic mean (standard deviation)	35.63 ( 12.24 )	34.66 ( 14.48 )

Unadjusted CD45RA+RO-

Statistical analysis description

Secondary outcome measure - Percentage of T cells (naïve/memory t reg cells) CD45RA+RO- We used the 2 sample t test to assess difference between the CD45RA+RO- 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8555 ^[26]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

0.965

Confidence interval

level

95%

sides

2-sided

lower limit

-9.835

upper limit

11.765

Variability estimate

Standard error of the mean

Dispersion value

5.244

Notes
[26] - Accept the null hypothesis and conclude there is no significant difference in the mean CD45RA+RO- between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted CD45RA+RO-

Statistical analysis description

Secondary outcome measure - Percentage of T cells (naïve/memory t reg cells) CD45RA+RO-. Difference in mean CD45RA+RO-.at day 2 adjusted for the effects of site and baseline CD45RA+RO-.

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.763 ^[27]

Method

ANCOVA

Confidence interval

Notes
[27] - Adjusted for the effects of site and baseline CD45RA+RO-, there is no significant difference in mean CD45RA+RO- (P=0.7630). No site effect (p=0.1729) but evidence of baseline dependence (p=0.0000).

Secondary: Percentage of T cells (naïve/memory t reg cells) CD45RO+RA-

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End point title

Percentage of T cells (naïve/memory t reg cells) CD45RO+RA-

End point description

Biological measure. Other assessments of neutrophil function: Percentage of T cells (naïve/memory t reg cells) CD45RO+RA-

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	12	15
Units: percent
arithmetic mean (standard deviation)	49.57 ( 13.89 )	48.25 ( 17.53 )

Unadjusted CD45RO+RA-

Statistical analysis description

Secondary outcome measure - Percentage of T cells (naïve/memory t reg cells) CD45RO+RA- We used the 2 sample t test to assess difference between the CD45RO+RA- 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8334 ^[28]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

1.32

Confidence interval

level

95%

sides

2-sided

lower limit

-11.467

upper limit

14.107

Variability estimate

Standard error of the mean

Dispersion value

6.209

Notes
[28] - Accept the null hypothesis and conclude there is no significant difference in the mean CD45RO+RA- between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted CD45RO+RA-

Statistical analysis description

Secondary outcome measure - Percentage of T cells (naïve/memory t reg cells) CD45RO+RA- Difference in mean CD45RO+RA- at day 2 adjusted for the effects of site and baseline CD45RO+RA-

Comparison groups

Placebo v GMCSF

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5344 ^[29]

Method

ANCOVA

Confidence interval

Notes
[29] - Adjusted for the effects of site and baseline CD45RO+RA-, there is no significant difference in mean CD45RO+RA- (P=0.5344). No site effect (p=0.1966) but evidence of baseline dependence (p=0.0001).

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-6

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End point title

Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-6

End point description

Biological measure. Other assessments of neutrophil function: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-6

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	19
Units: pg/ml
arithmetic mean (standard deviation)	94.16 ( 115.85 )	504.57 ( 1400.2 )

Unadjusted IL-6

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-6 We used the 2 sample Mann Whitney test to assess difference between IL-6 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo).

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8842 ^[30]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[30] - Accept the null hypothesis and conclude there is no significant difference in the mean IL-6 between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted IL-6

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-6 Difference in mean IL-6 at day 2 adjusted for the effects of site and baseline IL-6

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4031 ^[31]

Method

ANCOVA

Confidence interval

Notes
[31] - Adjusted for the effects of site and baseline IL-6, there is no significant difference in mean IL-6 (P=0.4031). No site effect (p=0.5312) but evidence of baseline dependence (p=0.0000).

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-8

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End point title

Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-8

End point description

Biological measure. Other assessments of neutrophil function: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-8

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	19
Units: pg/ml
arithmetic mean (standard deviation)	131.73 ( 155.18 )	314.66 ( 546.91 )

Ajusted IL-8

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-8 Difference in mean IL-8 at day 2 adjusted for the effects of site and baseline IL-8

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6575 ^[32]

Method

ANCOVA

Confidence interval

Notes
[32] - Adjusted for the effects of site and baseline IL-8, there is no significant difference in mean IL-8 (P=0.6575). No site effect (p=0.2552) but evidence of baseline dependence (p=0.0000).

Unadjused IL-8

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-8. We used the 2 sample Mann Whitney test to assess difference between IL-8 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo).

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1897 ^[33]

Method

Wilcoxon (Mann-Whitney)

Parameter type

Median difference (final values)

Confidence interval

Notes
[33] - Accept the null hypothesis and conclude there is no significant difference in the mean IL-8 between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-1β

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End point title

Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-1β

End point description

Biological measure. Other assessments of neutrophil function: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-1β

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	19
Units: pg/ml
arithmetic mean (standard deviation)	8.38 ( 14.71 )	10.31 ( 15.73 )

Unadjusted IL-1β

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-1β. We used the 2 sample Mann Whitney test to assess difference between IL-1β 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo).

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0654 ^[34]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[34] - Accept the null hypothesis and conclude there is no significant difference in the mean IL-1β between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted IL-1β

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-1β. Difference in mean IL-1β at day 2 adjusted for the effects of site and baseline IL-1β

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3268 ^[35]

Method

ANCOVA

Confidence interval

Notes
[35] - Adjusted for the effects of site and baseline IL-1β there is no significant difference in mean IL-1β (P=0.3268). No site effect (p=0.8772) or evidence of baseline dependence (p=0.1327).

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-10

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End point title

Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-10

End point description

Biological measure. Other assessments of neutrophil function: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-10

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	19
Units: pg/ml
arithmetic mean (standard deviation)	14.95 ( 21.1 )	9.64 ( 13.79 )

Unadjusted IL-10

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-10. We used the 2 sample Mann Whitney test to assess difference between IL-10 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo).

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2002 ^[36]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[36] - Accept the null hypothesis and conclude there is no significant difference in the mean IL-10 between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted IL-10

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-10. Difference in mean IL-10 at day 2 adjusted for the effects of site and baseline IL-10

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2583 ^[37]

Method

ANCOVA

Confidence interval

Notes
[37] - Adjusted for the effects of site and baseline IL-10 there is no significant difference in mean IL-10 (P=0.2583). No site effect (p=0.4597) but evidence of baseline dependence (p=0.0000).

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - TNF

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End point title

Cytokine data measure of pro/anti-inflammatory mediators in serum - TNF

End point description

Biological measure. Other assessments of neutrophil function: Cytokine data measure of pro/anti-inflammatory mediators in serum - TNF

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	19
Units: pg/ml
arithmetic mean (standard deviation)	9.06 ( 13.28 )	4.3 ( 9.52 )

Unadjusted TNF

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - TNF. We used the 2 sample Mann Whitney test to assess difference between TNF 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo).

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1687 ^[38]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[38] - Accept the null hypothesis and conclude there is no significant difference in the mean TNF between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted TNF

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - TNF Difference in mean TNF at day 2 adjusted for the effects of site and baseline TNF

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2241 ^[39]

Method

ANCOVA

Confidence interval

Notes
[39] - Adjusted for the effects of site and baseline TNF there is no significant difference in mean TNF (P=0.2241). No site effect (p=0.4524) but evidence of baseline dependence (p=0.0023).

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum -IL-12 p70

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End point title

Cytokine data measure of pro/anti-inflammatory mediators in serum -IL-12 p70

End point description

Biological measure. Other assessments of neutrophil function: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-12 p70

End point type

Secondary

End point timeframe

2 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	19
Units: pg/ml
arithmetic mean (standard deviation)	1.92 ( 4.04 )	1.27 ( 2.9 )

Unadjusted IL-12 p70

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-12 p70. We used the 2 sample Mann Whitney test to assess difference between IL-12 p70 2 days after administration of GM-CSF/placebo by arm (GMCSF v Placebo).

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4662 ^[40]

Method

Wilcoxon (Mann-Whitney)

Confidence interval

Notes
[40] - Accept the null hypothesis and conclude there is no significant difference in the mean IL-12 p70 between arms 2 days after administration of GM-CSF/placebo without adjustment for other covariates.

Adjusted IL-12 p70

Statistical analysis description

Secondary outcome measure - Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-12 p70. Difference in mean IL-12 p70 at day 2 adjusted for the effects of site and baseline IL-12 p70

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6186 ^[41]

Method

ANCOVA

Confidence interval

Notes
[41] - Adjusted for the effects of site and baseline IL-12 p70there is no significant difference in mean IL-12 p70 (P=0.6186). No site effect (p=0.9487) but evidence of baseline dependence (p=0.0000).

Secondary: sequential organ failure assessment (SOFA) at day 2

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End point title

sequential organ failure assessment (SOFA) at day 2

End point description

sequential organ failure assessment (SOFA) at day 2

End point type

Secondary

End point timeframe

2 days after treatment

End point values	GMCSF	Placebo
Number of subjects analysed	15	21
Units: integer
median (inter-quartile range (Q1-Q3))	7 (2 to 11)	7 (5 to 9)

No statistical analyses for this end point

Secondary: incidence of ICU aquired infections

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End point title

incidence of ICU aquired infections

End point description

Hospitals in Europe link for infection control through surveillance. incidence of ICU aquired infection (ICUIAs)i

End point type

Secondary

End point timeframe

2 days after administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	17	21
Units: count
number (not applicable)	0	0

No statistical analyses for this end point

Secondary: All cause mortality 30 days post randomisation

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End point title

All cause mortality 30 days post randomisation

End point description

All cause mortality 30 days post randomisation

End point type

Secondary

End point timeframe

30 days after randomization to the trial

End point values	GMCSF	Placebo
Number of subjects analysed	17	21
Units: number	4	6

No statistical analyses for this end point

Post-hoc: Neutrophil capacity measured as ‘area under curve’ (AUC) up to day4/5

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End point title

Neutrophil capacity measured as ‘area under curve’ (AUC) up to day4/5

End point description

Area under curve is calculated by summing the areas between each time point. This procedure is known as the linear trapezoidal rule. In cases where there is missing data with no more data either before or after that point we do not calculate the area and treat that patient’s area under curve as missing. The area under the curve up to day 4/5 is calculated for each patient. The summary statistics split by arm are then calculated.

End point type

Post-hoc

End point timeframe

up to day4/5 after administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	12	16
Units: cells x 109/l x days
arithmetic mean (standard deviation)	280.3 ( 56.1 )	234.9 ( 43.2 )

Unadjusted diff phagocyte Area under curve 4/5day

Statistical analysis description

Ad hoc outcome measure - Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 4/5. Secondary outcome measure - Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 4/5.

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0227 ^[42]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

45.4

Confidence interval

level

95%

sides

2-sided

lower limit

6.86

upper limit

83.94

Variability estimate

Standard error of the mean

Dispersion value

18.75

Notes
[42] - Reject the null hypothesis and conclude there are significant differences in the ‘area under the curve’ up to day 4/5 between arms (GMSCF and Placebo) without adjustment for other covariates.

Adjusted diffs phagocyte Area under curve 4/5days

Statistical analysis description

Ad hoc outcome measure - Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 4/5. Difference in the ‘area under the curve’ adjusted for the effects of site and baseline neutrophil phagocytic capacity

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.2813 ^[43]

Method

ANCOVA

Confidence interval

Notes
[43] - Adjusted for effects of site and baseline neutrophil phagocytic capacity, no significant difference in mean neutrophil phagocytic capacity as described by AUC up to day 4/5. There is site effect (p=0.0216) and evidence baseline dependency (p=0.0001)

Post-hoc: Area under curve for Leukocytes (WCC) up to day 8/9

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End point title

Area under curve for Leukocytes (WCC) up to day 8/9

End point description

Area under curve is calculated by summing the areas between each time point. This procedure is known as the linear trapezoidal rule. In cases where there is missing data with no more data either before or after that point we do not calculate the area and treat that patient’s area under curve as missing. The area under the curve up to day 8/9 is calculated for each patient. The summary statistics split by arm are then calculated

End point type

Post-hoc

End point timeframe

8/9 days after baseline measure and administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	10	15
Units: cells x 109/l x days
arithmetic mean (standard deviation)	160.2 ( 35.3 )	111.9 ( 34.5 )

Unadjusted diff Leukocytes Area under curve 8/9day

Statistical analysis description

Secondary outcome measure - Area under curve for Leukocytes (WCC) up to day 8/9. We used the 2 sample t test to assess difference between the ‘area under the curve’ for Leukocytes (LAUC) for day 0 to day 9 for all patients by arm (GMCSF v Placebo)

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Post-hoc

Analysis type

superiority

P-value

= 0.0025 ^[44]

Method

t-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

48.25

Confidence interval

level

95%

sides

2-sided

lower limit

18.87

upper limit

77.63

Variability estimate

Standard error of the mean

Dispersion value

14.2

Notes
[44] - Reject the null hypothesis and conclude there are significant differences in the ‘area under the curve’ for leukocytes between arms (GMSCF and Placebo) without adjustment for other covariates.

Adjusted diffs Leukocytes Area under curve 8/9day

Statistical analysis description

Ad hoc outcome measure - Area under curve for Leukocytes (WCC) up to day 8/9 Difference in the ‘area under the curve’adjusted for the effects of site and baseline leukocyte dependency

Comparison groups

GMCSF v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0039 ^[45]

Method

ANCOVA

Confidence interval

Notes
[45] - Adjusted for the effects of site and baseline leukocytes, significant differences in mean leukocytes as described by area under curve day0 to 9 (P=0.0039). No site effect (p=0.0722) but there is evidence of baseline leukocyte dependency (p=0.0427)

Post-hoc: ratio of lowest PaO2 to FiO2 at day 2

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End point title

ratio of lowest PaO2 to FiO2 at day 2

End point description

ratio of lowest PaO2 to FiO2 at day 2

End point type

Post-hoc

End point timeframe

2 days after administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	14	20
Units: ratio
arithmetic mean (standard deviation)	27.6 ( 9.7 )	27.3 ( 12.7 )

No statistical analyses for this end point

Post-hoc: ratio of highest PaO2 to FiO2 at day 2

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End point title

ratio of highest PaO2 to FiO2 at day 2

End point description

ratio of highest PaO2 to FiO2 at day 2

End point type

Post-hoc

End point timeframe

2 days after administration of treatment

End point values	GMCSF	Placebo
Number of subjects analysed	14	20
Units: ratio
arithmetic mean (standard deviation)	37 ( 15.3 )	38.8 ( 15.6 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from first visit until final visit

Adverse event reporting additional description

Researchers reviewed and recorded any adverse events on a daily basis from Day 0 to Day 9.

Assessment type

Systematic

Dictionary name

as reported verbatim

Dictionary version

Reporting group title

Leukine

Reporting group description

Participants randomised to GMCSF arm study will receive 4 days of treatment with 250 microgram/vial) Leukine as a subcutaneous injection. Dosed on actual body weight up to a maximum dose of 450microgram.

Reporting group title

Placebo

Reporting group description

Participants randomised to placebo arm study will receive 4 days of treatment with 0.9% sodium chloride (placebo, 5ml /ampoule) as a subcutaneous injection. Dosed on actual body weight up to a maximum dose of volume 1.8ml.

Serious adverse events	Leukine	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 17 (5.88%)	2 / 21 (9.52%)
number of deaths (all causes)	4	6
number of deaths resulting from adverse events	0	0
Surgical and medical procedures
desaturation
Additional description: sudden desaturation while ventilated. Required 100% o2 and endotracheal tube change
subjects affected / exposed	0 / 17 (0.00%)	1 / 21 (4.76%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Death
Additional description: admitted with bowel obstruction. Initially managed conservatively. underwent hemicolectomy. continued deterioration and Rx withdrawn
subjects affected / exposed	1 / 17 (5.88%)	0 / 21 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
Additional description: worsening acute hypoxic / hypercapnic respiratory failure
subjects affected / exposed	0 / 17 (0.00%)	1 / 21 (4.76%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 0%

Non-serious adverse events	Leukine	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	11 / 17 (64.71%)	4 / 21 (19.05%)
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 17 (5.88%)	0 / 21 (0.00%)
occurrences all number	1	0
Transaminases abnormal
Additional description: increase in hepatic transaminases ALT and AST
subjects affected / exposed	3 / 17 (17.65%)	0 / 21 (0.00%)
occurrences all number	3	0
Pyrexia
Additional description: Pyrexia up 39.1 day 2, 39.5 day 3 and 39.8 day 3, same patient
subjects affected / exposed	1 / 17 (5.88%)	0 / 21 (0.00%)
occurrences all number	3	0
Blood and lymphatic system disorders
Thrombocytopenia
subjects affected / exposed	2 / 17 (11.76%)	1 / 21 (4.76%)
occurrences all number	2	1
General disorders and administration site conditions
internal jugular vein thrombus
subjects affected / exposed	1 / 17 (5.88%)	1 / 21 (4.76%)
occurrences all number	1	1
fever
Additional description: Fever up to 38 degrees. Resolved with paracetamol
subjects affected / exposed	1 / 17 (5.88%)	0 / 21 (0.00%)
occurrences all number	1	0
transient hypoglycaemia
subjects affected / exposed	0 / 17 (0.00%)	1 / 21 (4.76%)
occurrences all number	0	1
increased oxygen
Additional description: Increased oxygen requirements on background of presumed necrotizing pneumonia with in situ thrombus.
subjects affected / exposed	0 / 17 (0.00%)	1 / 21 (4.76%)
occurrences all number	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

18 Oct 2013

conditions in place to allow IMP to be made up on site and delivered to blinded study team members

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

-number of patients screened relative to the number recruited -assay used labour-intensive and operator-dependent

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Clinical trials

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Neutrophil phagocytic capacity 2 days after administration of GM-CSF/placebo

Primary: Neutrophil phagocytic capacity 2 days after administration of GM-CSF/placebo

Secondary: Neutrophil phagocytic capacity 4/5 days after administration of GM-CSF/placebo

Secondary: Neutrophil phagocytic capacity 4/5 days after administration of GM-CSF/placebo

Secondary: Neutrophil phagocytic capacity 6/7 days after administration of GM-CSF/placebo

Secondary: Neutrophil phagocytic capacity 6/7 days after administration of GM-CSF/placebo

Secondary: Neutrophil phagocytic capacity 8/9 days after administration of GM-CSF/placebo

Secondary: Neutrophil phagocytic capacity 8/9 days after administration of GM-CSF/placebo

Secondary: Percentage of patients <50% Neutrophil phagocytic capacity at day 2

Secondary: Percentage of patients <50% Neutrophil phagocytic capacity at day 2

Secondary: Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 8/9

Secondary: Neutrophil capacity measured as ‘area under curve’ (AUC) up to day 8/9

Secondary: Reactive oxygen species (ROS) generation –primed cells

Secondary: Reactive oxygen species (ROS) generation –primed cells

Secondary: Reactive oxygen species (ROS) generation – second stimulus

Secondary: Reactive oxygen species (ROS) generation – second stimulus

Secondary: Distance migrated on chemotaxis assay

Secondary: Distance migrated on chemotaxis assay

Secondary: Early apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

Secondary: Early apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

Secondary: Late apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

Secondary: Late apoptosis - Apoptotic rate (proportion of cells identified as apoptotic by flow cytometric criteria, and/or by morphological criteria)

Secondary: Sequential monocyte HLA-DR expression (QTB results)

Secondary: Sequential monocyte HLA-DR expression (QTB results)

Secondary: CD88 - (relative median fluorescence)

Secondary: CD88 - (relative median fluorescence)

Secondary: Percentage of T cells (naïve/memory t reg cells) CD45RA+RO-

Secondary: Percentage of T cells (naïve/memory t reg cells) CD45RA+RO-

Secondary: Percentage of T cells (naïve/memory t reg cells) CD45RO+RA-

Secondary: Percentage of T cells (naïve/memory t reg cells) CD45RO+RA-

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-6

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-6

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-8

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-8

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-1β

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-1β

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-10

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - IL-10

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - TNF

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum - TNF

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum -IL-12 p70

Secondary: Cytokine data measure of pro/anti-inflammatory mediators in serum -IL-12 p70

Secondary: sequential organ failure assessment (SOFA) at day 2

Secondary: sequential organ failure assessment (SOFA) at day 2

Secondary: incidence of ICU aquired infections

Secondary: incidence of ICU aquired infections

Secondary: All cause mortality 30 days post randomisation

Secondary: All cause mortality 30 days post randomisation

Post-hoc: Neutrophil capacity measured as ‘area under curve’ (AUC) up to day4/5

Post-hoc: Neutrophil capacity measured as ‘area under curve’ (AUC) up to day4/5

Post-hoc: Area under curve for Leukocytes (WCC) up to day 8/9

Post-hoc: Area under curve for Leukocytes (WCC) up to day 8/9

Post-hoc: ratio of lowest PaO2 to FiO2 at day 2

Post-hoc: ratio of lowest PaO2 to FiO2 at day 2

Post-hoc: ratio of highest PaO2 to FiO2 at day 2

Post-hoc: ratio of highest PaO2 to FiO2 at day 2

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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