The GRK2 Inhibitor Paroxetine as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients

Study Overview
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Brief Summary
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Among three MAPK families, paroxetine was found to be able to decrease the phosphorylation of ERK. It was reported that paroxetine attenuates the symptoms of collage induced arthritis rats due to its inhibitory effect on T cell activation and infiltration to synovial tissue via suppression of ERK pathway. This study aimed to evaluate the therapeutic efficacy of paroxetine in rheumatoid arthritis. Paroxetine prevents the joint inflammation which is at the very early stage. paroxetine could inhibit GRK2 with selectivity over other GRKs. Medications developed for maintaining the immunologic equilibrium. such as GRK2 inhibitors, will be the novel trends in RA treatment that could avoid the adverse side effects that are common with current treatment options.

Official Title
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The GRK2 Inhibitor Paroxetine as a Novel Adjunct to Conventional Therapy in Rheumatoid Arthritis Patients. A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial.

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Paroxetine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: • Patients with active rheumatoid arthritis based on DAS28 score. Patients received the standard therapy (i.e. one or more conventional DMARDs) for at least three months. Exclusion Criteria: Known hypersensitivity to metformin. Patients who have a prior diagnosis with diabetes mellitus. Patients receive metformin for any other indications. Patients with congestive heart failure. Patients with a history of myocardial infarction. Patients with severe anemia. Patients with active infections or other inflammatory diseases. Patients receiving biological therapy. Pregnancy or lactation. Patients with impaired liver functions. Patients with impaired kidney functions (serum creatinine concentrations ≥1.5 and ≥1.4 mg/dL in males and females respectively). Patients with malignancies.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Paroxetine<br>Paroxetine 20 mg daily plus standard therapy | Drug: Paroxetine<br>* Paroxetine 20 mg tablet plus standard therapy<br>|
| Placebo Comparator: Placebo<br>Placebo tablet daily plus standard therapy | Drug: Placebo<br>* Placebo tablet plus standard therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ACR 20% improvement criteria (ACR20) response rate | based on tender and swollen joint counts, patient's assessment of pain, patient and physician global assessment of arthritis, Health Assessment Questionnaire Disability Index (HAQ DI), and CRP level | week 12 | 
| ACR50 & ACR70 response rate | based on tender and swollen joint counts, patient's assessment of pain, patient and physician global assessment of arthritis, Health Assessment Questionnaire Disability Index (HAQ DI), and CRP level | week 12 | 
| Disease activity scale in 28 joints (DAS-28) | Scale assessing severity of rheumatoid arthritis based on number of tender, swollen joints, erythrocyte sedimentation rate (ESR) levels, and patient self-assessment of his condition (global health assessment). Whereas 28 describes the number of different joints including in the measurement: proximal interphalangeal joints (10 joints), metacarpophalangeal joints (10), wrists (2), elbows (2), shoulders (2), knees (2). | week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| GRK2 expression | GRK2 expression in serum | week 12 | 
| TNF-α | Serum level Tumor necrosis factor- alpha (TNF-α) | week 12 | 
| Inteleukins | Serum levels of Interleukins (IL) IL-17, IL-1β , IL-6 & IL-10 | 12 weeks | 
| CRP | Serum level of C-reactive protein (CRP) | 12 weeks | 
| Drug Adverse effects | Adverse effect incidence: adverse effect will be reported by patients or their caregivers and recorded by investigator. | 12 weeks |