Macrophage Therapy for Acute Liver Injury (MAIL): a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK

Christopher Humphries; Melisande Addison; Guruprasad Aithal; Julia Boyd; Lesley Briody; John D M Campbell; Maria Elena Candela; Ellise Clarke; James Coulson; Nicholas Downing-James; Robert John Fontana; Ailsa Geddes; Julia Grahamslaw; Alison Grant; Anna Heye; James A Hutchinson; Ashley Jones; Fiona Mitchell; Joanna Moore; Alice Riddell; Aryelly Rodriguez; Angela Thomas; Garry Tucker; Kim Walker; Christopher J Weir; Rachel Woods; Sharon Zahra; Stuart J Forbes; James W Dear

doi:10.1136/bmjopen-2024-089417

Macrophage Therapy for Acute Liver Injury (MAIL): a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK

Christopher Humphries, Melisande Addison, Guruprasad Aithal, Julia Boyd, Lesley Briody, John D M Campbell, Maria Elena Candela, Ellise Clarke, James Coulson, Nicholas Downing-James, Robert John Fontana, Ailsa Geddes, Julia Grahamslaw, Alison Grant, Anna Heye, James A Hutchinson, Ashley Jones, Fiona Mitchell, Joanna Moore, Alice RiddellAryelly Rodriguez, Angela Thomas, Garry Tucker, Kim Walker, Christopher J Weir, Rachel Woods, Sharon Zahra, Stuart J Forbes, James W Dear^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

INTRODUCTION: Acute liver failure (ALF) has no effective treatment other than liver transplantation and is commonly caused by paracetamol overdose. New treatments are needed to treat and prevent ALF. Alternatively-activated macrophages (AAMs) can promote resolution of liver necrosis and stimulate hepatocyte proliferation. Using AAMs in unscheduled care requires the use of an allogeneic product. A clinical trial is needed to determine the safety and tolerability of allogeneic AAMs.

METHODS AND ANALYSIS: A single-centre, open-label, dose-escalation, phase 1 randomised trial to determine whether there is dose-limiting toxicity of AAMs in patients with paracetamol-induced acute liver injury. Randomisation will occur at higher doses. Between 17 and 30 patients will receive treatment, subject to dose-limiting toxicity and an adaptive trial design which aims to reduce the risk of allocation bias through blinding and randomisation.

ETHICS AND DISSEMINATION: The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by North East-York Research Ethics Committee (reference 23/NE/0019), National Health Service Lothian Research and Development department, and the UK Medicines and Healthcare products Regulatory Agency. When the trial concludes, results will be shared by presentation and publication.

TRIAL REGISTRATION NUMBER: ISRCTN12637839.

Original language	English
Article number	e089417
Journal	BMJ Open
Volume	14
Issue number	12
DOIs	https://doi.org/10.1136/bmjopen-2024-089417
Publication status	Published - 9 Dec 2024

Keywords / Materials (for Non-textual outputs)

Adult
Female
Humans
Male
Acetaminophen
Analgesics, Non-Narcotic
Chemical and Drug Induced Liver Injury/therapy
Clinical Trials, Phase I as Topic
Liver Failure, Acute/chemically induced
Macrophage Activation
Macrophages
Randomized Controlled Trials as Topic
United Kingdom

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Centre for Precision Medicine For The Liverapy
Forbes, S. (Principal Investigator), Dear, J. (Co-investigator), Dhaliwal, K. (Co-investigator), Fallowfield, J. (Co-investigator) & Forbes, S. (Co-investigator)
NHS Lothian
1/06/22 → 31/05/27
Project: Research
Macrophage Therapy for Acute Liver failure (DPFS)
Forbes, S. (Principal Investigator), Forbes, S. (Principal Investigator), Dear, J. (Co-investigator), Dear, J. (Co-investigator) & Weir, C. (Co-investigator)
Medical Research Council
1/12/20 → 30/11/26
Project: Research

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Humphries, C., Addison, M., Aithal, G., Boyd, J., Briody, L., Campbell, J. D. M., Candela, M. E., Clarke, E., Coulson, J., Downing-James, N., Fontana, R. J., Geddes, A., Grahamslaw, J., Grant, A., Heye, A., Hutchinson, J. A., Jones, A., Mitchell, F., Moore, J., ... Dear, J. W. (2024). Macrophage Therapy for Acute Liver Injury (MAIL): a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK. BMJ Open, 14(12), Article e089417. https://doi.org/10.1136/bmjopen-2024-089417

Humphries, Christopher ; Addison, Melisande ; Aithal, Guruprasad et al. / Macrophage Therapy for Acute Liver Injury (MAIL) : a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK. In: BMJ Open. 2024 ; Vol. 14, No. 12.

@article{a3df8ee235c945c5ab2c07d1a02b92e8,

title = "Macrophage Therapy for Acute Liver Injury (MAIL): a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK",

abstract = "INTRODUCTION: Acute liver failure (ALF) has no effective treatment other than liver transplantation and is commonly caused by paracetamol overdose. New treatments are needed to treat and prevent ALF. Alternatively-activated macrophages (AAMs) can promote resolution of liver necrosis and stimulate hepatocyte proliferation. Using AAMs in unscheduled care requires the use of an allogeneic product. A clinical trial is needed to determine the safety and tolerability of allogeneic AAMs.METHODS AND ANALYSIS: A single-centre, open-label, dose-escalation, phase 1 randomised trial to determine whether there is dose-limiting toxicity of AAMs in patients with paracetamol-induced acute liver injury. Randomisation will occur at higher doses. Between 17 and 30 patients will receive treatment, subject to dose-limiting toxicity and an adaptive trial design which aims to reduce the risk of allocation bias through blinding and randomisation.ETHICS AND DISSEMINATION: The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by North East-York Research Ethics Committee (reference 23/NE/0019), National Health Service Lothian Research and Development department, and the UK Medicines and Healthcare products Regulatory Agency. When the trial concludes, results will be shared by presentation and publication.TRIAL REGISTRATION NUMBER: ISRCTN12637839.",

keywords = "Adult, Female, Humans, Male, Acetaminophen, Analgesics, Non-Narcotic, Chemical and Drug Induced Liver Injury/therapy, Clinical Trials, Phase I as Topic, Liver Failure, Acute/chemically induced, Macrophage Activation, Macrophages, Randomized Controlled Trials as Topic, United Kingdom",

author = "Christopher Humphries and Melisande Addison and Guruprasad Aithal and Julia Boyd and Lesley Briody and Campbell, \{John D M\} and Candela, \{Maria Elena\} and Ellise Clarke and James Coulson and Nicholas Downing-James and Fontana, \{Robert John\} and Ailsa Geddes and Julia Grahamslaw and Alison Grant and Anna Heye and Hutchinson, \{James A\} and Ashley Jones and Fiona Mitchell and Joanna Moore and Alice Riddell and Aryelly Rodriguez and Angela Thomas and Garry Tucker and Kim Walker and Weir, \{Christopher J\} and Rachel Woods and Sharon Zahra and Forbes, \{Stuart J\} and Dear, \{James W\}",

note = "{\textcopyright} Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.",

year = "2024",

month = dec,

day = "9",

doi = "10.1136/bmjopen-2024-089417",

language = "English",

volume = "14",

journal = "BMJ Open",

issn = "2044-6055",

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Humphries, C, Addison, M, Aithal, G, Boyd, J, Briody, L, Campbell, JDM, Candela, ME, Clarke, E, Coulson, J, Downing-James, N, Fontana, RJ, Geddes, A, Grahamslaw, J, Grant, A, Heye, A, Hutchinson, JA, Jones, A, Mitchell, F, Moore, J, Riddell, A, Rodriguez, A, Thomas, A, Tucker, G, Walker, K, Weir, CJ, Woods, R, Zahra, S, Forbes, SJ & Dear, JW 2024, 'Macrophage Therapy for Acute Liver Injury (MAIL): a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK', BMJ Open, vol. 14, no. 12, e089417. https://doi.org/10.1136/bmjopen-2024-089417

Macrophage Therapy for Acute Liver Injury (MAIL): a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK. / Humphries, Christopher; Addison, Melisande; Aithal, Guruprasad et al.
In: BMJ Open, Vol. 14, No. 12, e089417, 09.12.2024.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Macrophage Therapy for Acute Liver Injury (MAIL)

T2 - a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK

AU - Humphries, Christopher

AU - Addison, Melisande

AU - Aithal, Guruprasad

AU - Boyd, Julia

AU - Briody, Lesley

AU - Campbell, John D M

AU - Candela, Maria Elena

AU - Clarke, Ellise

AU - Coulson, James

AU - Downing-James, Nicholas

AU - Fontana, Robert John

AU - Geddes, Ailsa

AU - Grahamslaw, Julia

AU - Grant, Alison

AU - Heye, Anna

AU - Hutchinson, James A

AU - Jones, Ashley

AU - Mitchell, Fiona

AU - Moore, Joanna

AU - Riddell, Alice

AU - Rodriguez, Aryelly

AU - Thomas, Angela

AU - Tucker, Garry

AU - Walker, Kim

AU - Weir, Christopher J

AU - Woods, Rachel

AU - Zahra, Sharon

AU - Forbes, Stuart J

AU - Dear, James W

PY - 2024/12/9

Y1 - 2024/12/9

N2 - INTRODUCTION: Acute liver failure (ALF) has no effective treatment other than liver transplantation and is commonly caused by paracetamol overdose. New treatments are needed to treat and prevent ALF. Alternatively-activated macrophages (AAMs) can promote resolution of liver necrosis and stimulate hepatocyte proliferation. Using AAMs in unscheduled care requires the use of an allogeneic product. A clinical trial is needed to determine the safety and tolerability of allogeneic AAMs.METHODS AND ANALYSIS: A single-centre, open-label, dose-escalation, phase 1 randomised trial to determine whether there is dose-limiting toxicity of AAMs in patients with paracetamol-induced acute liver injury. Randomisation will occur at higher doses. Between 17 and 30 patients will receive treatment, subject to dose-limiting toxicity and an adaptive trial design which aims to reduce the risk of allocation bias through blinding and randomisation.ETHICS AND DISSEMINATION: The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by North East-York Research Ethics Committee (reference 23/NE/0019), National Health Service Lothian Research and Development department, and the UK Medicines and Healthcare products Regulatory Agency. When the trial concludes, results will be shared by presentation and publication.TRIAL REGISTRATION NUMBER: ISRCTN12637839.

AB - INTRODUCTION: Acute liver failure (ALF) has no effective treatment other than liver transplantation and is commonly caused by paracetamol overdose. New treatments are needed to treat and prevent ALF. Alternatively-activated macrophages (AAMs) can promote resolution of liver necrosis and stimulate hepatocyte proliferation. Using AAMs in unscheduled care requires the use of an allogeneic product. A clinical trial is needed to determine the safety and tolerability of allogeneic AAMs.METHODS AND ANALYSIS: A single-centre, open-label, dose-escalation, phase 1 randomised trial to determine whether there is dose-limiting toxicity of AAMs in patients with paracetamol-induced acute liver injury. Randomisation will occur at higher doses. Between 17 and 30 patients will receive treatment, subject to dose-limiting toxicity and an adaptive trial design which aims to reduce the risk of allocation bias through blinding and randomisation.ETHICS AND DISSEMINATION: The trial will be conducted according to the ethical principles of the Declaration of Helsinki 2013 and has been approved by North East-York Research Ethics Committee (reference 23/NE/0019), National Health Service Lothian Research and Development department, and the UK Medicines and Healthcare products Regulatory Agency. When the trial concludes, results will be shared by presentation and publication.TRIAL REGISTRATION NUMBER: ISRCTN12637839.

KW - Adult

KW - Female

KW - Humans

KW - Male

KW - Acetaminophen

KW - Analgesics, Non-Narcotic

KW - Chemical and Drug Induced Liver Injury/therapy

KW - Clinical Trials, Phase I as Topic

KW - Liver Failure, Acute/chemically induced

KW - Macrophage Activation

KW - Macrophages

KW - Randomized Controlled Trials as Topic

KW - United Kingdom

U2 - 10.1136/bmjopen-2024-089417

DO - 10.1136/bmjopen-2024-089417

M3 - Article

C2 - 39653576

SN - 2044-6055

VL - 14

JO - BMJ Open

JF - BMJ Open

IS - 12

M1 - e089417

ER -

Humphries C, Addison M, Aithal G, Boyd J, Briody L, Campbell JDM et al. Macrophage Therapy for Acute Liver Injury (MAIL): a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK. BMJ Open. 2024 Dec 9;14(12):e089417. doi: 10.1136/bmjopen-2024-089417

Macrophage Therapy for Acute Liver Injury (MAIL): a study protocol for a phase 1 randomised, open-label, dose-escalation study to evaluate safety, tolerability and activity of allogeneic alternatively activated macrophages in patients with paracetamol-induced acute liver injury in the UK

Abstract

Keywords / Materials (for Non-textual outputs)

Access to Document

Fingerprint

Projects

Centre for Precision Medicine For The Liverapy

Macrophage Therapy for Acute Liver failure (DPFS)

Cite this