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Inflammatory Response In Schizophrenia (IRIS)

Primary Purpose

Schizophrenia

Status
Recruiting
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Natalizumab
Placebo: normal saline
Sponsored by
King's College London
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Schizophrenia

Eligibility Criteria

18 Years - 50 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion criteria:

  1. Aged 18-50 years
  2. Diagnosis of schizophrenia or other psychotic disorder (Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5);
  3. Symptomatic, defined as one or more positive symptom >3 AND one or more negative symptom >3 on the Positive and Negative Syndrome Scale (PANSS);
  4. No acute relapse and psychiatrically stable for >1 month before screening;

Exclusion criteria:

  1. History of significant co-morbid CNS disorder (including significant head trauma or significant loss of consciousness, Parkinson's Disease, Epilepsy, Alzheimer's Dementia, Huntington's Disease).
  2. Any absolute contraindications to natalizumab, as per natalizumab SPC
  3. Current or recent (last 3 months) infection, or history of significant infection, or an immunocompromised state
  4. Previous use of natalizumab or previous use of other monoclonal antibody.
  5. Ongoing long-standing use of oral steroids or non-steroidal anti-inflammatory drugs.
  6. Pregnancy and/or breast-feeding.
  7. Substance dependence/abuse other than to cigarettes.

Sites / Locations

  • Institute of Psychiatry, Psychology and Neuroscience, King's College LondonRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Patient Group: Natalizumab

Patient Group: Placebo

Arm Description

Natalizumab 300mg, intravenous, once monthly, total of 3 doses

Saline, intravenous, once monthly, total of 3 doses

Outcomes

Primary Outcome Measures

Change in Translocator Protein (TSPO) availability pre- and post-natalizumab or placebo administration
TSPO availability assessed using Positron Emission Tomography (PET)

Secondary Outcome Measures

Correlation of TSPO availability with brain functional measures at baseline.
Both TSPO availability (as measured using PET imaging) and brain functional measures (as measured using functional magnetic resonance imaging and magnetic resonance spectroscopy) will be measured simultaneously using a combined PET/MRI scanner.
Correlation of cerebrospinal fluid (CSF) inflammatory markers with brain functional measures at baseline.
Brain functional measures assessed using functional magnetic resonance imaging and magnetic resonance spectroscopy. CSF inflammatory markers: measurements of cytokine concentrations (e.g. C-reactive protein, Interleukin-6)
Correlation of blood inflammatory markers with brain functional measures at baseline.
Brain functional measures assessed using functional magnetic resonance imaging and magnetic resonance spectroscopy. Blood inflammatory markers: measurements of cytokine concentrations (e.g. C-reactive protein, Interleukin-6)
Longitudinal change in TSPO availability correlated with longitudinal change in brain functional measures.
Both TSPO availability (as measured using PET imaging) and brain functional measures (as measured using functional magnetic resonance imaging and magnetic resonance spectroscopy) will be measured simultaneously using a combined PET/MRI scanner. There will be two separate scans - before and after administration of natalizumab/placebo.

Full Information

First Posted
February 23, 2017
Last Updated
March 23, 2023
Sponsor
King's College London
Collaborators
South London and Maudsley NHS Foundation Trust
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1. Study Identification

Unique Protocol Identification Number
NCT03093064
Brief Title
Inflammatory Response In Schizophrenia
Acronym
IRIS
Official Title
The Role of Inflammation in Brain and Cognitive Function in Mental Disorders
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Recruiting
Study Start Date
April 1, 2017 (Actual)
Primary Completion Date
September 30, 2023 (Anticipated)
Study Completion Date
September 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
King's College London
Collaborators
South London and Maudsley NHS Foundation Trust

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Schizophrenia affects a significant proportion of the population and current levels of understanding of the illness is inadequate to treat it effectively. Converging lines of evidence suggest that neuroinflammation occurs in schizophrenia, and specifically over-activity of brain-resident immune cells called microglia. It is however unclear whether activated microglia play a primary role in schizophrenia, or whether this is a secondary phenomenon of no pathophysiological significance. The investigators therefore plan to test the effect of a monoclonal antibody (natalizumab) on psychotic symptoms in a cohort of first episode psychosis patients.
Detailed Description
One of the key aims of the study is to determine if there is a relationship between change in imaging inflammation markers from baseline to follow-up and changes in other markers of inflammation over the same period. In September 2021, an open label arm for natalizumab was added to the study. The relationship between changes in imaging inflammation markers and changes in other markers of inflammation will be analysed within subjects including all patients who received natalizumab.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Schizophrenia

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Model Description
This is an experimental medicine study, the purpose of which is provide a mechanistic understanding of neuroinflammation in schizophrenia by investigating response to natalizumab (phase 1b).
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Patient Group: Natalizumab
Arm Type
Experimental
Arm Description
Natalizumab 300mg, intravenous, once monthly, total of 3 doses
Arm Title
Patient Group: Placebo
Arm Type
Placebo Comparator
Arm Description
Saline, intravenous, once monthly, total of 3 doses
Intervention Type
Drug
Intervention Name(s)
Natalizumab
Other Intervention Name(s)
Tysabri
Intervention Description
Natalizumab is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin, currently licensed for the treatment of multiple sclerosis and Crohn's disease.
Intervention Type
Other
Intervention Name(s)
Placebo: normal saline
Intervention Description
Normal saline, intravenous infusion
Primary Outcome Measure Information:
Title
Change in Translocator Protein (TSPO) availability pre- and post-natalizumab or placebo administration
Description
TSPO availability assessed using Positron Emission Tomography (PET)
Time Frame
Baseline TSPO availability will be assessed at day -14 prior to first administration of natalizumab/placebo (day zero). TSPO availability will be re-assessed post administration of natalizumab/placebo at day +57(+14 days)
Secondary Outcome Measure Information:
Title
Correlation of TSPO availability with brain functional measures at baseline.
Description
Both TSPO availability (as measured using PET imaging) and brain functional measures (as measured using functional magnetic resonance imaging and magnetic resonance spectroscopy) will be measured simultaneously using a combined PET/MRI scanner.
Time Frame
Baseline combined PET/MRI scan will be performed at day -14 prior to administration of natalizumab/placebo (day zero)
Title
Correlation of cerebrospinal fluid (CSF) inflammatory markers with brain functional measures at baseline.
Description
Brain functional measures assessed using functional magnetic resonance imaging and magnetic resonance spectroscopy. CSF inflammatory markers: measurements of cytokine concentrations (e.g. C-reactive protein, Interleukin-6)
Time Frame
Baseline PET/MRI scan will be performed at day -14 prior to administration of natalizumab/placebo (day zero). CSF collection will be performed between the time points day -14 to day -1 prior to administration of natalizumab/placebo (day zero).
Title
Correlation of blood inflammatory markers with brain functional measures at baseline.
Description
Brain functional measures assessed using functional magnetic resonance imaging and magnetic resonance spectroscopy. Blood inflammatory markers: measurements of cytokine concentrations (e.g. C-reactive protein, Interleukin-6)
Time Frame
Baseline PET/MRI scan will be performed at day -14 prior to administration of natalizumab/placebo (day zero). Blood collection will be performed between the time points day -14 to day -1 prior to administration of natalizumab/placebo (day zero).
Title
Longitudinal change in TSPO availability correlated with longitudinal change in brain functional measures.
Description
Both TSPO availability (as measured using PET imaging) and brain functional measures (as measured using functional magnetic resonance imaging and magnetic resonance spectroscopy) will be measured simultaneously using a combined PET/MRI scanner. There will be two separate scans - before and after administration of natalizumab/placebo.
Time Frame
Baseline combined PET/MRI scan will be performed at day -14 prior to administration of natalizumab/placebo (day zero). Repeat combined PET/MRI scan will be performed at day +57(+14 days).

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion criteria: Aged 18-50 years Diagnosis of schizophrenia or other psychotic disorder (Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5); Symptomatic, defined as one or more positive symptom >3 AND one or more negative symptom >3 on the Positive and Negative Syndrome Scale (PANSS); No acute relapse and psychiatrically stable for >1 month before screening; Exclusion criteria: History of significant co-morbid CNS disorder (including significant head trauma or significant loss of consciousness, Parkinson's Disease, Epilepsy, Alzheimer's Dementia, Huntington's Disease). Any absolute contraindications to natalizumab, as per natalizumab SPC Current or recent (last 3 months) infection, or history of significant infection, or an immunocompromised state Previous use of natalizumab or previous use of other monoclonal antibody. Ongoing long-standing use of oral steroids or non-steroidal anti-inflammatory drugs. Pregnancy and/or breast-feeding. Substance dependence/abuse other than to cigarettes.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Tiago Marques, MD, PhD
Phone
+44 207 848 0728
Email
tiago.marques@kcl.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Yuya Mizuno, MD, PhD
Phone
+44 207 848 0434
Email
yuya.mizuno@kcl.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Oliver D Howes
Organizational Affiliation
King's College London
Official's Role
Principal Investigator
Facility Information:
Facility Name
Institute of Psychiatry, Psychology and Neuroscience, King's College London
City
London
ZIP/Postal Code
SE5 8AF
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Yuya Mizuno, MD, PhD
Phone
+44 207 848 0434
Email
yuya.mizuno@kcl.ac.uk

12. IPD Sharing Statement

Plan to Share IPD
No

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Inflammatory Response In Schizophrenia

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