BARIcitinib Cognitive Emotional and Neural signaTuRE

Rheumatoid Arthritis Clinical Trial

— BARICENTRE  

Official title:

BARIcitinib Cognitive Emotional and Neural signaTuRE (BARICENTRE)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT05238896
• Other study ID #: APHP190353
• Secondary ID: 2020-005773-27
• Status: Terminated
• Phase: Phase 4
• Start date: June 27, 2022
• Est. completion date: March 31, 2023

Study information

• Verified date: November 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Rheumatoid arthritis (RA) is a frequent and disabling disease, requiring early management to achieve clinical remission. Recently, baricitinib (jak1-jak2 inhibitor) has been shown to as an efficient treatment in placebo-controlled trials, and compared to the reference treatment with TNF inhibitor (adalimumab). Its efficacy has been reported on the inflammatory parameters, but more importantly on patient-reported outcomes. Baricitinib is thought to have anti-inflammatory effects, via its inhibition of the JAK pathway. Importantly, it has also been suggested to affect mood and pain.

Hypotheses: Inhibition of JAK Kinase pathway in patients with RA will improve emotional and cognitive processing involved in mood disorders and decrease pain sensitization.

The primary objective of this study is to evaluate early emotional impact of the JAK 1/2 inhibitor Baricitinib assessed by a facial emotion recognition task. This precocious effect on emotion processing is a surrogate marker of clinical imporvement in mood.

Phase 4 study, Double-blind randomized control study with patients receiving placebo or baricitinib for 7 days, then open label study until day 42 with all patients receiving baricitinib during 5 weeks.

Description:

Rheumatoid arthritis (RA) is a frequent and disabling disease, requiring early management to achieve clinical remission. Recently, baricitinib (jak1-jak2 inhibitor) has demonstrated its efficacy compared to placebo, and compared to the reference treatment with TNF inhibitor (adalimumab). Its efficacy has been reported on the inflammatory parameters but more importantly on patient reported outcomes. Inhibition of JAK pathway could have anti-inflammatory activity but also direct action on mood and pain.

Hypotheses: Inhibition of JAK Kinase pathway in patients with RA will improve emotional and cognitive processing involved in mood disorders and decrease pain sensitization.

The primary objective of this study is to evaluate early emotional impact of the JAK 1/2 inhibitor Baricitinib assessed by Harmer's cognitive and emotional battery, This emotional aspect is a surrogate marker of future mood impact.

The primary outcome is the number of accurate responses in facial emotion recognition task at day 1 using Harmer's cognitive battery (based on Harmer & Cowen evaluation protocol at day 1).

Phase 4 study,Double-blind randomized control study with patients receiving placebo or baricitinib for 7 days, then open label study until day 42 with all patients receiving baricitinib during 5 weeks. At baseline (day 0), RA activity, mood symptoms, the number of accurate responses in facial emotion recognition task (Harmer's cognitive battery), clinical pain sensitization, will be assessed.3 follow-up research visits will be conducted at day 1, 8 and 42 (final visit) at the Pitié Salpêtrière hospital.The first intake of the Investigational medicinal product (IMP) (baricitinib or placebo) is at day 1. At day 1, the number of accurate responses in facial emotion recognition task and RA activity will be evaluated (2 to 4 hours after intake of baricitinib). At day 8 and 42, RA activity and flares, mood symptoms, the number of accurate responses in facial emotion recognition task (Harmer's cognitive battery), clinical pain sensitization, will be assessed. In each group (placebo vs Baricitinib), 20 patients will underwent a non-contrast MRI at day 0 and 8 (with evaluation of mood modification using BOLD signal during the different experimental conditions of the Cyberball task with comparison to baseline condition, and pain evaluation using fMRI-based neurological pain signature provided by Wager et al.) During the follow-up until day 42, patients will conduct questionnaires (day 15 and 29) at home about RA activity, pain (Patient pain VAS, Patient global assessment of the disease, Flare RA questionnaire) and psychometric questionnaire (Hospital Anxiety and Depression Scale)

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 5
• Est. completion date: March 31, 2023
• Est. primary completion date: February 23, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Patients aged between 18 and 75 years

• Diagnosis of RA according to the ACR/EULAR 2010 classification criteria

• Active rheumatoid arthritis at inclusion (defined by a Disease Activity Score (DAS28) > 3.2)

• Patient eligible for baricitinib treatment in agreement with European label and French recommendations for RA treatment with dosage of 4mg (patients with 2mg dosage will not be included to ensure patient homogeneity)

• Informed and signed consent

• Affiliation to a french social security system (beneficiary or legal)

• For child-bearing aged women, efficient contraception

Exclusion Criteria:

• Patient under tutorship or guardianship, and incapable to give informed consent

• Diagnosis of a systemic autoimmune disease other than RA

• Treatment not allowed:

• DMARDS other than Methotrexate or Leflunomide or Hydroxychloroquine or Salazopyrine.

• Psychotropic treatments (antidepressive drugs, benzodiazepine, mood stabilizer) during the study or the month prior the study that could change the mood evaluation.

• Laboratory exclusions: o Total white blood cell count (WBC) less than 3 x 109 cells/L o Absolute lymphocyte count (ALC) less than 0.5 x 109 cells/L o Absolute neutrophil count (ANC) less than 1 x 109 cells/L o Hemoglobin less than 8.0 g/dl o eGFR < 60 mL/min/1.73 m² based on the most recent serum creatinine (Cockroft-Gault method) o ALT or AST > 5 times upper limit of normal o Any abnormality on screening laboratory tests that, in the opinion of the investigator, could represent a risk when participating in this protocol

• Any contraindications to baricitinib treatment or to Non-contrast MRI exam

• Hypersensitivity to the active substance or to any of the excipients

• History of active tuberculosis without treatment or chronic infectious diseasewith a need of regular use of antibiotic

• Active or prior bacterial or viral infection that required treatment with antibiotics within 30 days prior to screening

• History of lymphoma or leukemia or other malignancy besides non-melanoma skin cancer within 5 years

• Uncontrolled medical condition or planned major surgery during the study

• Pregnancy or breast-feeding

• Claustrophobia

• Patient unable to understand and follow recommendations or unable to perform self-evaluation

• Participation in another interventional study or being in the exclusion period at the end of a previous study.

• Patients with current suicidal intents or behaviors, Past or present depression or anxiety will be neither a criterion for inclusion nor a criterion for non-inclusion but will be collected in case report form.

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Rheumatoid
• Rheumatoid Arthritis

Intervention

Drug:
• Baricitinib Oral Tablet [Olumiant]
Baricitinib 4 mg/d oral route for 42 days
• Placebo
Placebo, 4 mg/d, oral route for 7 days, then Baricitinib 4 mg/d oral route for 5 weeks

Locations

Country	Name	City	State
France	CHU Pitié Salpêtrière	Paris

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of accurate responses in facial emotion recognition task	Percentage of accurate responses in facial emotion recognition task using Harmer's cognitive battery (based on Harmer & Cowen evaluation protocol)	Day 1
Secondary	DIfference in disease activity	DIfference in disease activity on DAS28 (disease activity score on 28 joints) - SDAI (Simplified Disease Activity Score)	Day 0, 8 and 42
Secondary	Difference in function improvement	Difference in function improvement on HAQ (health assessment questionnaire)	Day 0, 8 and 42
Secondary	Difference in pain	Difference in pain using Visual Analogic Scale (VAS) for pain	Day 0, 8 and 42
Secondary	Difference in patient global assessment of the disease	Difference in VAS for patient global assessment of the disease	Day 0, 8 and 42
Secondary	Number of accurate responses in facial emotion recognition task	The number of accurate responses in facial emotion recognition task using Harmer's cognitive battery (based on Harmer & Cowen evaluation protocol)	Day 8
Secondary	Difference in central and peripheral pain sensitization	Difference in central and peripheral pain sensitization using quantitative sensory testing	Day 0, 8 and 42
Secondary	Difference in the results of psychometric questionnaire	Difference in the results of psychometric questionnaire using Hospital Anxiety and Depression Scale	Day 0, 8 and 42
Secondary	Difference in blood-oxygen-level dependent (BOLD) signal activity in regions of interest (ROI) such as the subgenual anterior cingulate cortex (Sg-ACC) during a cyberball task	Main effect of group on social exclusion-related brain responses (e.g. actiavtion of the Sg_ACC ROI)	day 0 and day 8
Secondary	Difference in BOLD signal activity in pain-encoding brain regions	Main effect of group in pain-related brain responses	day 0 and day 8
Secondary	Differences in mood and pain assessments between patients with high or low expectations of the drug	Main effect of group on accurate responses during the facial emotion recognition task and pain assessment variables	Day 1,8 and 42
Secondary	Difference in BOLD signal activity in reward-learning related brain regions	Main effect of group reward-learning related brain responses (e.g. activation of the ventral striatum or vmPFC ROIs)	day 0 and day 8