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Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial

Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial
Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial
Background
Data from in-vitro, animal, and human lung injury models suggest that keratinocyte growth factor (KGF) might be beneficial in acute respiratory distress syndrome (ARDS). The objective of this trial was to investigate the effect of KGF in patients with ARDS.

Methods
We did a double-blind, allocation concealed, randomised, placebo-controlled phase 2 trial in two intensive care units in the UK, involving patients fulfilling the American-European Consensus Conference Definition of ARDS. Patients were randomly assigned (1:1) by computer-generated randomisation schedule with variable block size stratified by site and presence of severe sepsis requiring vasopressors to receive either recombinant human KGF (palifermin 60 μg/kg) or placebo (0·9% sodium chloride solution) daily for a maximum of 6 days. Both patients and investigators were masked to treatment. The primary endpoint was oxygenation index (OI) at day 7. Analyses were by intention to treat. The trial is registered with International Standard Randomised Controlled Trial Registry, number ISRCTN95690673.

Findings
Between Feb 23, 2011, and Feb 26, 2014, 368 patients were assessed for eligibility for inclusion in the trial. Of the 60 patients recruited, 29 patients were randomly assigned to receive KGF and 31 to placebo; all were included in the analysis of the primary outcome. There was no significant difference between the two groups in OI at day 7 (mean 62·3 [SD 57·8] in the KGF group, 43·1 [33·5] in the placebo group; mean difference 19·2, 95% CI −5·6 to 44·0, p=0·13). Of interest, although not defined as outcome measures a priori, the KGF group, compared with placebo, had fewer median ventilator-free days (1 day [IQR 0 to 17] in the KGF group vs 20 days [13–22] in the placebo group; difference −8 days, 95% CI −17 to −2; p=0·0002), a longer median duration of ventilation in survivors to day 90 (16 days [IQR 13–30] in the KGF group vs 11 days [8–16] in the placebo group; difference 6 days, 95% CI 2 to 14; p=0·002), and a higher mortality at 28 days (nine [31%] vs three [10%] deaths; risk ratio 3·2, 95% CI 1·0 to 10·7, p=0·054). Adverse events were more frequent in the KGF group than the placebo group (14 vs 5 events; odds ratio 4·9, 95% CI 1·3 to 20·3, p=0·008). The two adverse events assessed as related to KGF were due to pyrexia.

Interpretation
KGF did not improve physiological or clinical outcomes in ARDS and might be harmful to patient health.

Funding
The Northern Ireland Public Health Agency Research and Development Division.
2213-2600
484-491
McAuley, Daniel F.
03fd8aff-b05b-4bd6-8f4c-952f598095c1
Cross, L. J. Mark
a73a7d27-e6f9-40bb-82f1-411b97aa5b11
Hamid, Umar
91ea996e-498a-40ff-be5b-2b71b6b50cda
Gardner, Evie
e1af8759-5269-4bf7-aaa3-847b4b57ea8a
Elborn, J. Stuart
f2603b1b-d09d-403f-a677-07662cc6226a
Cullen, Kathy M.
bdd3886e-3fa7-45da-82c6-f22b04864222
Dushianthan, Ahilanandan
f4d6308b-91ae-4073-a18d-288db1f70893
Grocott, Michael P. W.
1e87b741-513e-4a22-be13-0f7bb344e8c2
Matthay, Michael A.
d470db7c-31de-4374-bfa9-44e7cdf075e4
O'Kane, Cecilia M.
67033ab5-9527-4a98-bf08-3c5560e91098
McAuley, Daniel F.
03fd8aff-b05b-4bd6-8f4c-952f598095c1
Cross, L. J. Mark
a73a7d27-e6f9-40bb-82f1-411b97aa5b11
Hamid, Umar
91ea996e-498a-40ff-be5b-2b71b6b50cda
Gardner, Evie
e1af8759-5269-4bf7-aaa3-847b4b57ea8a
Elborn, J. Stuart
f2603b1b-d09d-403f-a677-07662cc6226a
Cullen, Kathy M.
bdd3886e-3fa7-45da-82c6-f22b04864222
Dushianthan, Ahilanandan
f4d6308b-91ae-4073-a18d-288db1f70893
Grocott, Michael P. W.
1e87b741-513e-4a22-be13-0f7bb344e8c2
Matthay, Michael A.
d470db7c-31de-4374-bfa9-44e7cdf075e4
O'Kane, Cecilia M.
67033ab5-9527-4a98-bf08-3c5560e91098

McAuley, Daniel F., Cross, L. J. Mark, Hamid, Umar, Gardner, Evie, Elborn, J. Stuart, Cullen, Kathy M., Dushianthan, Ahilanandan, Grocott, Michael P. W., Matthay, Michael A. and O'Kane, Cecilia M. (2017) Keratinocyte growth factor for the treatment of the acute respiratory distress syndrome (KARE): a randomised, double-blind, placebo-controlled phase 2 trial. The Lancet Respiratory Medicine, 5 (6), 484-491. ().

Record type: Article

Abstract

Background
Data from in-vitro, animal, and human lung injury models suggest that keratinocyte growth factor (KGF) might be beneficial in acute respiratory distress syndrome (ARDS). The objective of this trial was to investigate the effect of KGF in patients with ARDS.

Methods
We did a double-blind, allocation concealed, randomised, placebo-controlled phase 2 trial in two intensive care units in the UK, involving patients fulfilling the American-European Consensus Conference Definition of ARDS. Patients were randomly assigned (1:1) by computer-generated randomisation schedule with variable block size stratified by site and presence of severe sepsis requiring vasopressors to receive either recombinant human KGF (palifermin 60 μg/kg) or placebo (0·9% sodium chloride solution) daily for a maximum of 6 days. Both patients and investigators were masked to treatment. The primary endpoint was oxygenation index (OI) at day 7. Analyses were by intention to treat. The trial is registered with International Standard Randomised Controlled Trial Registry, number ISRCTN95690673.

Findings
Between Feb 23, 2011, and Feb 26, 2014, 368 patients were assessed for eligibility for inclusion in the trial. Of the 60 patients recruited, 29 patients were randomly assigned to receive KGF and 31 to placebo; all were included in the analysis of the primary outcome. There was no significant difference between the two groups in OI at day 7 (mean 62·3 [SD 57·8] in the KGF group, 43·1 [33·5] in the placebo group; mean difference 19·2, 95% CI −5·6 to 44·0, p=0·13). Of interest, although not defined as outcome measures a priori, the KGF group, compared with placebo, had fewer median ventilator-free days (1 day [IQR 0 to 17] in the KGF group vs 20 days [13–22] in the placebo group; difference −8 days, 95% CI −17 to −2; p=0·0002), a longer median duration of ventilation in survivors to day 90 (16 days [IQR 13–30] in the KGF group vs 11 days [8–16] in the placebo group; difference 6 days, 95% CI 2 to 14; p=0·002), and a higher mortality at 28 days (nine [31%] vs three [10%] deaths; risk ratio 3·2, 95% CI 1·0 to 10·7, p=0·054). Adverse events were more frequent in the KGF group than the placebo group (14 vs 5 events; odds ratio 4·9, 95% CI 1·3 to 20·3, p=0·008). The two adverse events assessed as related to KGF were due to pyrexia.

Interpretation
KGF did not improve physiological or clinical outcomes in ARDS and might be harmful to patient health.

Funding
The Northern Ireland Public Health Agency Research and Development Division.

Full text not available from this repository.

More information

Accepted/In Press date: 1 April 2017
e-pub ahead of print date: 16 May 2017
Published date: 1 June 2017
Related URLs:

Identifiers

Local EPrints ID: 445066
URI: http://eprints.soton.ac.uk/id/eprint/445066
DOI:
ISSN: 2213-2600
PURE UUID: 7f4aab3c-b93c-483f-8c5f-4a4f6c52f178
ORCID for Michael P. W. Grocott:

Catalogue record

Date deposited: 18 Nov 2020 17:35
Last modified: 18 Nov 2020 17:35

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Contributors

Author: Daniel F. McAuley
Author: L. J. Mark Cross
Author: Umar Hamid
Author: Evie Gardner
Author: J. Stuart Elborn
Author: Kathy M. Cullen
Author: Ahilanandan Dushianthan
Author:
Author: Michael A. Matthay
Author: Cecilia M. O'Kane

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