Inflammatory Response In Schizophrenia (IRIS)

• ClinicalTrials.gov Identifier: NCT03093064
• Recruitment Status: Completed
• First Posted: March 28, 2017
• Last Update Posted: March 8, 2024
• Sponsor: King's College London
• Collaborator: South London and Maudsley NHS Foundation Trust
• Information provided by (Responsible Party): King's College London

Tracking Information

• First Submitted Date: February 23, 2017
• First Posted Date: March 28, 2017
• Last Update Posted Date: March 8, 2024
• Actual Study Start Date: April 1, 2017
• Actual Primary Completion Date: June 15, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 22, 2017)

Change in Translocator Protein (TSPO) availability pre- and post-natalizumab or placebo administration [ 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) ]

TSPO availability assessed using Positron Emission Tomography (PET)

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 22, 2017)

• Correlation of TSPO availability with brain functional measures at baseline. [ Time Frame: Baseline combined PET/MRI scan will be performed at day -14 prior to administration of natalizumab/placebo (day zero) ]
  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. [ 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). ]
  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. [ 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). ]
  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. [ 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). ]
  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.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Inflammatory Response In Schizophrenia
• Official Title: The Role of Inflammation in Brain and Cognitive Function in Mental Disorders
• 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.
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science

• Condition: Schizophrenia

Intervention

• Drug: Natalizumab
  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.
  Other Name: Tysabri
• Other: Placebo: normal saline
  Normal saline, intravenous infusion

Study Arms

• Experimental: Patient Group: Natalizumab
  Natalizumab 300mg, intravenous, once monthly, total of 3 doses
  Intervention: Drug: Natalizumab
• Placebo Comparator: Patient Group: Placebo
  Saline, intravenous, once monthly, total of 3 doses
  Intervention: Other: Placebo: normal saline

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 7, 2024): 66
• Original Estimated Enrollment (submitted: March 22, 2017): 60
• Actual Study Completion Date: August 7, 2023
• Actual Primary Completion Date: June 15, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 50 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United Kingdom

Administrative Information

• NCT Number: NCT03093064
• Other Study ID Numbers: 208083
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: King's College London
• Original Responsible Party: Same as current
• Current Study Sponsor: King's College London
• Original Study Sponsor: Same as current
• Collaborators: South London and Maudsley NHS Foundation Trust

Investigators

• Principal Investigator: Oliver D Howes; King's College London

• PRS Account: King's College London
• Verification Date: March 2024