Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis

PIMS Collaboration

doi:10.1136/bmjopen-2022-067944

Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis

PIMS Collaboration

Research output: Contribution to journal › Article (Academic Journal) › peer-review

7 Citations (Scopus)

Abstract

INTRODUCTION: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis.

METHODS AND ANALYSIS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis.

ETHICS AND DISSEMINATION: The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means.

TRIAL REGISTRATION NUMBER: ISRCTN23256704.

Original language	English
Article number	e067944
Number of pages	10
Journal	BMJ Open
Volume	13
Issue number	3
DOIs	https://doi.org/10.1136/bmjopen-2022-067944
Publication status	Published - 24 Mar 2023

Bibliographical note

Funding Information:
The PIMS trial is funded by a Medical Research Council (MRC) grant to RU and GMK; Grant Ref: MR/S037675/1. ÉMF is supported by an MRC Integrative Epidemiology Unit PhD Studentship (MC_UU_00011/1). AM is supported by funding from the MRC for doctoral training (MR/2434208). FC-Z receives a PhD Fellowship from the São Paulo Research Foundation (2019/13229-2 and 2021/07448-3). HH is supported by the PIMS Trial MRC grant (MR/S037675/1). DJ is supported by the Cambridge Arthritis Research Endeavour and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014). NMB acknowledges funding support from the MRC (MR/R006008/1 and MR/N019016/1), Ministry of Defence (702931454), Diabetes UK (20/0006296), NIHR (14/WM/0093) and Innovate UK (84361). RU has grants from MRC, NIHR: Health Technology Assessment, European Commission - Research: The Seventh Framework Programme and personal fees from Sunovion, outside the submitted work. RU is funded/supported by the NIHR Oxford Health Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GMK acknowledges funding support from the Wellcome Trust (grant number 201486/Z/16/Z), the MRC, UK (grant number MC_UU_00011/1; grant number MR/S037675/1; and grant number MR/W014416/1) and the NIHR Bristol Biomedical Research Centre, UK (grant number NIHR203315). The funders had no role in the design of this study.

Publisher Copyright:
© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.

Keywords

Humans
Double-Blind Method
Inflammation/drug therapy
Interleukin-6
Psychotic Disorders/psychology
Treatment Outcome
Proof of Concept Study

Access to Document

10.1136/bmjopen-2022-067944Licence: CC BY

Handle.net

Persistent link

Cite this

@article{262baad10d72477baa6540b1abcd6739,

title = "Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis",

abstract = "INTRODUCTION: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis.METHODS AND ANALYSIS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis.ETHICS AND DISSEMINATION: The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means.TRIAL REGISTRATION NUMBER: ISRCTN23256704.",

keywords = "Humans, Double-Blind Method, Inflammation/drug therapy, Interleukin-6, Psychotic Disorders/psychology, Treatment Outcome, Proof of Concept Study",

author = "{PIMS Collaboration} and Foley, {{\'E}imear M} and Griffiths, {Sian Lowri} and Alexander Murray and Jack Rogers and Fabiana Corsi-Zuelli and Hannah Hickinbotham and Ella Warwick and Martin Wilson and Muzaffer Kaser and Murray, {Graham K} and Bill Deakin and Deepak Jadon and John Suckling and Barnes, {Nicholas M} and Rachel Upthegrove and Khandaker, {Golam M}",

note = "Funding Information: The PIMS trial is funded by a Medical Research Council (MRC) grant to RU and GMK; Grant Ref: MR/S037675/1. {\'E}MF is supported by an MRC Integrative Epidemiology Unit PhD Studentship (MC_UU_00011/1). AM is supported by funding from the MRC for doctoral training (MR/2434208). FC-Z receives a PhD Fellowship from the S{\~a}o Paulo Research Foundation (2019/13229-2 and 2021/07448-3). HH is supported by the PIMS Trial MRC grant (MR/S037675/1). DJ is supported by the Cambridge Arthritis Research Endeavour and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014). NMB acknowledges funding support from the MRC (MR/R006008/1 and MR/N019016/1), Ministry of Defence (702931454), Diabetes UK (20/0006296), NIHR (14/WM/0093) and Innovate UK (84361). RU has grants from MRC, NIHR: Health Technology Assessment, European Commission - Research: The Seventh Framework Programme and personal fees from Sunovion, outside the submitted work. RU is funded/supported by the NIHR Oxford Health Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GMK acknowledges funding support from the Wellcome Trust (grant number 201486/Z/16/Z), the MRC, UK (grant number MC_UU_00011/1; grant number MR/S037675/1; and grant number MR/W014416/1) and the NIHR Bristol Biomedical Research Centre, UK (grant number NIHR203315). The funders had no role in the design of this study. Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.",

year = "2023",

month = mar,

day = "24",

doi = "10.1136/bmjopen-2022-067944",

language = "English",

volume = "13",

journal = "BMJ Open",

issn = "2044-6055",

publisher = "BMJ Publishing Group",

number = "3",

}

TY - JOUR

T1 - Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial

T2 - a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis

AU - PIMS Collaboration

AU - Foley, Éimear M

AU - Griffiths, Sian Lowri

AU - Murray, Alexander

AU - Rogers, Jack

AU - Corsi-Zuelli, Fabiana

AU - Hickinbotham, Hannah

AU - Warwick, Ella

AU - Wilson, Martin

AU - Kaser, Muzaffer

AU - Murray, Graham K

AU - Deakin, Bill

AU - Jadon, Deepak

AU - Suckling, John

AU - Barnes, Nicholas M

AU - Upthegrove, Rachel

AU - Khandaker, Golam M

N1 - Funding Information: The PIMS trial is funded by a Medical Research Council (MRC) grant to RU and GMK; Grant Ref: MR/S037675/1. ÉMF is supported by an MRC Integrative Epidemiology Unit PhD Studentship (MC_UU_00011/1). AM is supported by funding from the MRC for doctoral training (MR/2434208). FC-Z receives a PhD Fellowship from the São Paulo Research Foundation (2019/13229-2 and 2021/07448-3). HH is supported by the PIMS Trial MRC grant (MR/S037675/1). DJ is supported by the Cambridge Arthritis Research Endeavour and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014). NMB acknowledges funding support from the MRC (MR/R006008/1 and MR/N019016/1), Ministry of Defence (702931454), Diabetes UK (20/0006296), NIHR (14/WM/0093) and Innovate UK (84361). RU has grants from MRC, NIHR: Health Technology Assessment, European Commission - Research: The Seventh Framework Programme and personal fees from Sunovion, outside the submitted work. RU is funded/supported by the NIHR Oxford Health Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. GMK acknowledges funding support from the Wellcome Trust (grant number 201486/Z/16/Z), the MRC, UK (grant number MC_UU_00011/1; grant number MR/S037675/1; and grant number MR/W014416/1) and the NIHR Bristol Biomedical Research Centre, UK (grant number NIHR203315). The funders had no role in the design of this study. Publisher Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.

PY - 2023/3/24

Y1 - 2023/3/24

N2 - INTRODUCTION: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis.METHODS AND ANALYSIS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis.ETHICS AND DISSEMINATION: The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means.TRIAL REGISTRATION NUMBER: ISRCTN23256704.

AB - INTRODUCTION: Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis.METHODS AND ANALYSIS: A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6<0.7 pg/mL) and 30 matched healthy controls will be recruited to complete identical baseline assessments to allow for comparison of the characteristic features of inflammation-associated psychosis.ETHICS AND DISSEMINATION: The study is sponsored by the University of Bristol and has been approved by the Cambridge East Research Ethics Committee (reference: 22/EE/0010; IRAS project ID: 301682). Study findings will be published in peer-review journals. Findings will also be disseminated by scientific presentation and other means.TRIAL REGISTRATION NUMBER: ISRCTN23256704.

KW - Humans

KW - Double-Blind Method

KW - Inflammation/drug therapy

KW - Interleukin-6

KW - Psychotic Disorders/psychology

KW - Treatment Outcome

KW - Proof of Concept Study

U2 - 10.1136/bmjopen-2022-067944

DO - 10.1136/bmjopen-2022-067944

M3 - Article (Academic Journal)

C2 - 36963796

SN - 2044-6055

VL - 13

JO - BMJ Open

JF - BMJ Open

IS - 3

M1 - e067944

ER -

Protocol for the Psychosis Immune Mechanism Stratified Medicine (PIMS) trial: a randomised double-blind placebo-controlled trial of single-dose tocilizumab in patients with psychosis

Abstract

Bibliographical note

Keywords

Access to Document

Handle.net

Fingerprint

Cite this