Experimental Medicine Studies of the Brain in Patients With Rheumatoid Arthritis REALISE

NCT05090124 | Completed

• 1 other identifier: GN18MH540
• Study Type: interventional
• Target: 46
• Locations: 1 country
• Sites: 2

Brief Summary

The rationale for this study is to use immune molecule-specific drug treatment to leverage a mechanistic understanding of the brain changes that drive sickness behaviour. This will combine current therapy with innovative neuroimaging technologies to obtain data in humans that has hitherto only been available in animal studies. Data supporting the role of inflammatory molecules in sickness behaviours and other cognitive disorders are increasingly compelling. A putative mechanism linking inflammatory proteins to sickness behaviour is Tumour Necrosis Factor (TNF)-driven increases in extracellular glutamate leading to changes in neural function and brain network integrity and ultimately to sickness behaviour. Investigators hypothesise that TNF antagonism will effect changes in brain network connectivity and sickness behaviour score, that Rheumatoid Arthritis (RA) patients will show changes in brain network connectivity and glutamate quantification in the brain and that RA patients will show changes in monocyte infiltration into the brain that are correlated with changes in sickness behaviours. This is a randomised, placebo-controlled waiting list study. All patients will be eligible for anti-TNF treatment i.e. moderate to severe active disease as defined by Physician. Participants will be randomised to immediate (fast tracked) treatment or to treatment after 6-8 weeks (the routine waiting time). The latter group will receive placebo during the treatment phase.

Conditions

Rheumatoid Arthritis

Keywords

Sickness Behaviour; Tumour Necrosis Factor

Outcome Measures

Primary Outcomes (2)

• Change in sickness score as measured using the sickness questionnaire

  The sickness questionnaire is a 10-item instrument used to capture perceived sickness behaviour. It was developed to display sensitivity to an inflammatory challenge and have adequate psychometric properties.

  Visit 1 (Baseline, Day 0), Visit 2 (14 ± 2 days from Visit 1 or Visit 1A), Visit 3 (14 ± 2 days from Visit 2), and Visit 4 (14 ± 2 days from Visit 3).

• Change in brain connectivity as measured by 7T MRI

  Changes in dorsal attention network (DAN) - left inferior parietal lobule (LIPL) brain connectivity as measured by 7T MRI

  Visit 1 (Baseline, Day 0) and Visit 4 (14 ± 2 days from Visit 3).

Secondary Outcomes (21)

• Changes in fatigue from Baseline to Visit 4 via BRAF Severity

  Visit 1 (Baseline, Day 0), Visit 2 (14 ± 2 days from Visit 1 or Visit 1A), Visit 3 (14 ± 2 days from Visit 2), and Visit 4 (14 ± 2 days from Visit 3).

• Changes in fatigue from Baseline to Visit 4 via PROMIS Fatigue

  Visit 1 (Baseline, Day 0), Visit 2 (14 ± 2 days from Visit 1 or Visit 1A), Visit 3 (14 ± 2 days from Visit 2), and Visit 4 (14 ± 2 days from Visit 3).

• Changes in Hyperalgesia from Baseline to Visit 4 via ACR-FM Scale

  Visit 1 (Baseline, Day 0), Visit 2 (14 ± 2 days from Visit 1 or Visit 1A), Visit 3 (14 ± 2 days from Visit 2), and Visit 4 (14 ± 2 days from Visit 3).

• Changes in pain from Baseline to Visit 4 via McGill Pain Questionnaire

  Visit 1 (Baseline, Day 0), Visit 2 (14 ± 2 days from Visit 1 or Visit 1A), Visit 3 (14 ± 2 days from Visit 2), and Visit 4 (14 ± 2 days from Visit 3).

• Changes in pain from Baseline to Visit 4 via Michigan Body Map Regional Pain Intensity

  Visit 1 (Baseline, Day 0), Visit 2 (14 ± 2 days from Visit 1 or Visit 1A), Visit 3 (14 ± 2 days from Visit 2), and Visit 4 (14 ± 2 days from Visit 3).

Other Outcomes (1)

• Changes in monocyte infiltration into the brain measured using SPECT

  Visit 1A (1-7 days from Visit 1 Baseline, Day 0) and Visit 4A (1-7 days from Visit 4).

Study Arms (2)

anti-TNF treatment

EXPERIMENTAL

Adalimumab 40mg, will be administered as a subcutaneous injection once fortnightly on four occasions. No dose adjustments are permitted. The actual Adalimumab product selected at site will be dictated by what is used in standard care. The single-use, pre-filled syringe will be removed from storage at 2-8oC at least 30 minutes prior to administration to allow the contents to come to room temperature. The pre-filled syringe will be visually inspected for discolouration and particulates as per the product Summary of Product Characteristics.To facilitate maintenance of the blind, the pre-filled syringe (PFS) presentation will be used. The pen presentation will not be used.

Drug: Adalimumab

Placebo

PLACEBO COMPARATOR

Sodium chloride 0.9% for injection will be used as a placebo to adalimumab. An equal volume will be drawn up into a suitable sized syringe and labelled in accordance with standard practice at site. The dose will be administered as a subcutaneous injection once fortnightly on four occasions. No dose adjustments are permitted. Prior to administration, the prepared placebo syringe will be visually inspected for discolouration and particulate matter prior to administration.

Drug: Placebo

Interventions

Adalimumab DRUG

Adalimumab 40mg, will be administered as a subcutaneous injection once fortnightly on four occasions. The actual Adalimumab product selected at site will be dictated by what is used in standard care.

Also known as: Humira, Amgevita, Imraldi, Hyrimoz, Hulio

anti-TNF treatment

Placebo DRUG

Sodium chloride 0.9% for injection will be used as a placebo. An equal volume will be drawn up into a suitable sized syringe and labelled in accordance with standard practice at site. The dose will be administered as a subcutaneous injection once fortnightly on four occasions.

Also known as: Sodium chloride 0.9% for injection

Placebo

Eligibility Criteria

• Age: 18 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults ≥ 18 years \< 75 years.
• Physician diagnosed moderate to severe RA.
• No previous biologic disease modifying antirheumatic drug therapy
• Note: Participant consent to treatment with adalimumab will have been obtained by the usual care team as per standard practice at site and will be prior to any approach for this study.
• Participant agrees to either immediate or delayed commencement of adalimumab.
• Self-reported sickness behaviour (fatigue, depression, anxiety) with one component \> 4 on NRS
• Right-handed (to reduce neuroimaging heterogeneity).
• Women of Child-Bearing Potential (WoCBP) must be willing to use of effective contraception for study duration. Further information is provided in appendix 1
• Willing to participate and give informed consent for this research study.

You may not qualify if:

• Inability to provide written informed consent.
• Severe physical impairment (e.g. blindness, deafness, paraplegia).
• Pregnant, planning pregnancy or breast feeding.
• Serious infection including sepsis, tuberculosis and opportunistic infections such as invasive fungal infections.
• Severe liver or renal disease.
• Clinically diagnosed major confounding neurological disease including Multiple Sclerosis, Stroke, Traumatic Brain Injury, Parkinson's Disease, Alzheimer's Disease or similar neurodegenerative disease.
• Previous biologic disease modifying antirheumatic drug therapy with adalimumab, etanercept, qolimumab, infliximab, certolizumab, abatacept, tocilizumab, sarilumab, rituximab, tofacitinib or upadacitinib.
• Recent (within 4 weeks prior to Visit 1 baseline) use of intra-muscular or intra-articular steroid injections.
• Contraindications to MRI (e.g. metal implants, claustrophobia).
• Contraindications to Adalimumab.
• Concurrent or previous use of any other medicinal product (excluding vaccinations) that may, in the Principal Investigator's opinion, influence underlying disease activity through effects on immune and/or inflammatory responses.
• Haemoglobin less than 100g/L
• Contraindications to SPECT protocol (e.g. hypersensitivity to Technetium or Stannous Chloride, recent Nuclear Medicine Procedure)
• Unwilling not to donate body fluids such as blood, sperm etc. for at least 24 hours after SPECT imaging at visits 1A and 4A.
• Unwilling to avoid close contact with children or people who are pregnant for 24 hours following SPECT imaging

Sponsors & Collaborators

• NHS Greater Glasgow and Clyde: lead
• University of Glasgow: collaborator

Study Sites (2)

Addenbrooks Hopsital

Cambridge, United Kingdom

Location

Neil Basu

Glasgow, United Kingdom

Location

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Adalimumab; Sodium Chloride; Injections

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Jonathan Cavanagh, MD, PhD

  University of Glasgow

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: This is a single-blind study, participants will be blinded to their study arm throughout.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will be randomised 1:1 to receive adalimumab or placebo. Upon exiting the study, those in the treatment arm will continue to receive adalimumab without delay and those in the placebo arm will begin adalimumab therapy under NHS standard of care.

Study Record Dates

• First Submitted: July 20, 2021
• First Posted: October 22, 2021
• Study Start: November 4, 2022
• Primary Completion: November 29, 2024
• Study Completion: November 29, 2024
• Last Updated: January 14, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)