Anti-Inflammatory Challenge in Schizophrenia

NCT05823532 | Recruiting Phase 4 DMC FDA Drug

• 2 other identifiers: STUDY00004430R01MH131910-01
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 2

Brief Summary

This research project will explore negative symptoms of schizophrenia, such as motivational deficits, by examining the relationship between inflammation and reward-related brain regions. To accomplish this, we will administer a single infusion of either the anti-inflammatory medication infliximab or placebo (n=10 per group) to patients with high inflammation. This study is important because schizophrenia can be a chronic and debilitating neuropsychiatric disorder and negative symptoms are some of the most difficult aspects of schizophrenia associated with worst functional outcomes. These symptoms do not typically respond to antipsychotic therapies, and as such, there are no current medications to treat negative symptoms.

Conditions

Schizophrenia

Keywords

Inflammation; Reward-related Brain Regions

Outcome Measures

Primary Outcomes (4)

• Changes in Monetary Incentive Delay Task (MID)

  Change in Bold Oxygen Level Dependent (BOLD) Activation in the Ventral Striatum during "Win" Monetary Incentive Delay (MID) Task between Infliximab and Placebo (time frame: 1-3 days between first scan and intervention and then 2 weeks between intervention and repeat scan). Activation response in ventral striatum in response to reward anticipation: Infliximab (vs placebo)-treated patients will exhibit a) increased activation in ventral striatum in response to reward. Mixed-effects models for repeated measures (MMRM) will first be employed to examine effects of group (infliximab vs. placebo), time and their interaction on blood oxygenation level-dependent (BOLD) signals (an index of regional brain activation) using a Region-of-Interest (ROI) approach.

  Study visits: 1-3 days before intervention and 6 weeks post-intervention

• Changes in Effort Based Decision Making Task (EBDM)

  Changes in BOLD Activation response in anterior insula in response to increasing effort between Infliximab and Placebo (time frame: 1-3 days between first scan and intervention and then 2 weeks between intervention and repeat scan). Activation response in insula in response to increasing effort: Infliximab (vs placebo)-treated patients will exhibit a) decreased activation in anterior insula in response to effort. Mixed-effects models for repeated measures (MMRM) will first be employed to examine effects of group (infliximab vs. placebo), time and their interaction on BOLD signals (an index of regional brain activation) using a Region-of-Interest (ROI) approach.

  Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention

• Changes in C-Reactive Protein (CRP)

  30ml study bloods per visit will be collected by venipuncture into EDTA-containing vacutainer tubes using standard sterile technique. Plasma for the evaluation of plasma concentrations of CRP will be obtained by centrifugation of whole blood at 1000 x g for 10 minutes at 4 C. Plasma CRP will be assessed with a high sensitivity turbidimetric assay. Assay sensitivity is rated at 0.18 mg/L, range of measure is 0.2 to 80 mg/L and functional sensitivity (at 20% CV) is 0.2 mg/L.

  Study Visits :1-3 days before intervention, immediately after the intervention, 1 day post-intervention, 3 days, 1 week and 2 weeks post-intervention

• Changes in Brief Negative Symptom Scale (BNSS)

  Infliximab (vs placebo) -treated patients will record their performance on the BNSS Motivation and Pleasure domain score. The BNSS is a 13-item scale designed for research studies in response to the 2005 National Institute of Mental Health (NIMH) consensus development conference on negative symptoms of schizophrenia.The BNSS measures the five commonly accepted domains of negative symptoms: blunted affect, alogia, asociality, anhedonia, and avolition. Items are scored on a 0 to 6 scale, with 0 indicating the symptom is absent and 6 indicating the symptom is severe. Items are summed for a total score that ranges between 0 and 78.

  Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention

Secondary Outcomes (14)

• Changes in Performance on the Effort Expenditure for Reward Task

  Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention

• Changes in Positive and Negative Syndrome Scale (PANSS)

  Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention

• Changes in Motivation and Pleasure Scale (MAPS-SR)

  Study Visits :1-3 days before intervention,3 days post intervention, 1 week and 2 weeks post-intervention

• Changes in Calgary Depression Scale for Schizophrenia (CDSS)

  Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention

• Changes in Inflammatory markers changes: IL-1

  Study Visits :1-3 days before intervention, immediately after the intervention, 1-day post-intervention, 3 days, 1 week and 2 weeks post-intervention

Study Arms (2)

Infliximab

EXPERIMENTAL

Subjects will be stratified by sex and randomized prior to this visit in preparation for the infusion. Vitals and safety labs will be drawn at this visit as well as urine testing for drugs of abuse and pregnancy testing for all biological females. Patients will receive breakfast followed by a double-blinded infusion of infliximab (5mg/kg body weight) in the GCSTA Clinical Research Center at Emory University Hospital. The infusion will last 3 hours, and subjects will be monitored during the infusion and for one hour after completion for the possible development of anaphylaxis, which occurs in less than 1% of patients receiving an initial dose of infliximab

Drug: Infliximab

Placebo

PLACEBO COMPARATOR

Subjects will be stratified by sex and randomized prior to this visit in preparation for the infusion. Vitals and safety labs will be drawn at this visit as well as urine testing for drugs of abuse and pregnancy testing for all biological females. Patients will receive breakfast followed by a double-blinded infusion of saline in the GCSTA Clinical Research Center at Emory University Hospital. The infusion will last 3 hours, and subjects will be monitored during the infusion and for one hour after completion for the possible development of anaphylaxis, which occurs in less than 1% of patients receiving an initial dose of infliximab

Drug: Placebo

Interventions

Infliximab DRUG

Infliximab has FDA approval for the treatment of rheumatoid arthritis and inflammatory bowel syndrome. The current proposal represents the use of infliximab as an experimental tool to dissect the role of inflammatory processes leading to changes in brain reward circuitry and changes in specific symptom domains. Double-blinded infusions of infliximab will be administered in the GCTSA Clinical Research Center, located at Emory University Hospital. Independent pharmacists will dispense either infliximab or placebo in a 250ml saline bag according to a computer-generated randomization list provided by the study pharmacist.

Infliximab

Placebo DRUG

Double-blinded infusions of saline will be administered in the GCTSA Clinical Research Center, located at Emory University Hospital. Independent pharmacists will dispense either infliximab or placebo in a 250ml saline bag according to a computer-generated randomization list provided by the study pharmacist.

Placebo

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Men or women, 18-45 years of age with a primary diagnosis of Diagnostic and Statistical Manual of Mental Disorders (DSM-V) schizophrenia or schizoaffective disorder;
• Willing and able to give written informed consent;
• Plasma CRP 3mg/L;
• Significant motivational deficit as reflected by a score \>17 on the Motivation and Pleasure Domain of the Brief Negative Symptom Scale. Of note, for patients who exhibit CRP\>10mg/L, additional CRP testing will be conducted at 2-week intervals as per American Heart Association/ Center for Disease and Control Prevention guidelines to establish stability and rule out acute inflammation/infection (along with physical exam and laboratory testing).
• Patients must also have a negative urine drug screen at all study visits.

You may not qualify if:

• Any autoimmune disorder (as confirmed by laboratory testing);
• History of tuberculosis infection as determined by QuantiFERON Gold or high risk of tuberculosis exposure;
• Active hepatitis B or C infection or human immunodeficiency virus infection (as established by laboratory testing);
• History of any type of cancer;
• History of fungal infection;
• History of recurrent viral or bacterial infections;
• Unstable cardiovascular (including evidence of congestive heart failure as determined by physical examination and laboratory testing), endocrinologic, hematologic, hepatic, renal, and neurological disease (as determined by physical examination and laboratory testing);
• Demyelinating brain disease and/or a concerning structural abnormality seen on MRI;
• Substance abuse/dependence within 6 months of study entry (as determined by MINI and urine drug screen);
• Primary diagnosis of mood or anxiety disorder (i.e., major depressive disorder, bipolar disorder, post-traumatic stress disorder) as determined by the International Neuropsychiatric Interview for Schizophrenia and Psychotic Disorders (MINI).
• Active suicidal ideation or plan;
• An active eating disorder;
• A history of cognitive disorder or Mini-Mental State Exam (MMSE) \< 24 (indicating cognitive impairment);
• Pregnancy or lactation;
• Treatment with clozapine (given increased risk of neutropenia/agranulocytosis);

Sponsors & Collaborators

• Emory University: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (2)

Grady Memorial Hospital

Atlanta, Georgia, 30303, United States

NOT YET RECRUITING

Emory University Hospital

Atlanta, Georgia, 30322, United States

RECRUITING

MeSH Terms

Conditions

Schizophrenia; Inflammation

Interventions

Infliximab

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• David R Goldsmith, MD

  Assistant Professor

  PRINCIPAL INVESTIGATOR

Central Study Contacts

David R Goldsmith, MD

CONTACT

404-727-3735; drgolds@emory.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: February 8, 2023
• First Posted: April 21, 2023
• Study Start: April 18, 2024
• Primary Completion (Estimated): March 1, 2028
• Study Completion (Estimated): March 1, 2028
• Last Updated: April 30, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Two years after publication of the primary study results with no specified end date
• Access Criteria: Access criteria decisions will be made by the PI, via communication with him.

Locations

US (2)