Cilostazol and Methotrexate in Rheumatoid Arthritis

Study Overview
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Brief Summary
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This study aims at evaluating the therapeutic effects of Cilostazol as adjuvant therapies to low dose of Methotrexate in patients with Rheumatoid Arthritis and to evaluate their impact on Cyclic adenosine monophosphate(CAMP), Heme Oxygenase-1(HO-1).

Detailed Description
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Rheumatoid arthritis (RA) is characterized by the presence of hyperplastic synovium in association with immune-mediated inflammatory synovitis associated with chronic production of proinflammatory cytokines, which lead to cartilage and bone degradation .This study is a randomized, controlled double blind placebo-controlled ,prospective study to evaluate the potential therapeutic effects of Cilostazol on synovial inflammation when administered as add-on treatments to the low dose of Methotrexate. A total of 70 RA patients with active disease will be recruited from Outpatient Clinic of Physical Medicine, Rheumatology and Rehabilitation at Mansoura University hospitals, Mansoura, Egypt will be included in the study. They will be diagnosed with RA according to the American College of Rheumatology/European League Against Rheumatism criteria 2010 (the ACR/EULAR 2010 criteria). RA Patients who will meet the inclusion criteria will be enrolled in the study. They will be classified into two groups: Group 1: 35 RA patients who will receive Methotrexate and placebo for 12 weeks and serve as the control group. Group 2: 35 RA patients who will receive Methotrexate and Cilostazol 50 mg twice daily for 12 weeks.

Official Title
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The Phosphodiesterase 3 Inhibitor Cilostazol as Adjunct to Methotrexate in Patients With Rheumatoid Arthritis

Conditions
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Rheumatoid Arthritis

Intervention / Treatment
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* Drug: Cilostazol
* Drug: Methotrexate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with active rheumatoid arthritis (not in remission) according to American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2010 criteria (13) i.e 28 joints disease activity score (DAS-28) >2.6. Age range between 18 and 60 years old. Patients receive methotrexate; approximately the same doses of non steroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, acetaminophen, and low dose of oral corticosteroids (Prednisolone < 15 mg) will be allowed to enroll the trial. Intravenous, intra-articular or intramuscular corticosteroids; intra articular hyaluronate sodium; biological DMARDs and other conventional DMARDs will not be permitted less than 4 weeks before the first dose of cilostazol. Exclusion Criteria: Patients with diabetes, congestive heart failure, other heart disease (arrhythmia, hypertension, ischemic heart diseases), severe anemia, bleeding problems, other inflammatory diseases, active infection, other illness except rheumatoid arthritis. Patients on low doses of aspirin Patients on anticoagulants. Patients with renal or hepatic diseases. Patients receiving oral prednisolone greater than 15 mg/day. Patients receiving biological DMARDs. Patients with hypersensitivity to study medications. Patients using antioxidants . Pregnant and lactating females.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cilostazol and Methotrexate<br>Participants in this arm will receive Cilostazol 50 mg twice daily with Methotrexate for rheumatoid arthritis for 12 weeks. | Drug: Cilostazol<br>* Cilostazol 50 MG<br>Drug: Methotrexate<br>* Methotrexate (MTX) is the first-line therapy for treatment of RA patients. MTX suppresses proliferation of synovial fibroblasts, modulates cytokine synthesis and superoxide anion production, and inhibits neutrophil chemotaxis.<br>|
| Placebo Comparator: Placebo and Methotrexate<br>Participants in this arm will receive Placebo with Methotrexate for rheumatoid arthritis for 12 weeks. | Drug: Methotrexate<br>* Methotrexate (MTX) is the first-line therapy for treatment of RA patients. MTX suppresses proliferation of synovial fibroblasts, modulates cytokine synthesis and superoxide anion production, and inhibits neutrophil chemotaxis.<br>Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in DAS-28 CRP score | Clinical assessment by calculating of 28-joint count Disease Activity score (DAS-28) using C-reactive protein according to calculating formula(DAS28 (CRP) = 0.56*√(Tender joint count28) +0.28*√(Sowallen joint count28)+0.36*ln (CRP+1)*1.10+1.15 will done where high disease activity ≥ 5.1, low disease activity ≤ 3.2, and remission < 2.6. | Baseline,12 weeks | 
| Change in Multi Dimensional Health Assessment score | Functional assessment will be assessed through Multi Dimensional Health Assessment score that include 14 items Health Assessment Questionaire .The score of the HAQ Questionnaire is calculated from the mean of the sum of the responses of the items where each item is scored from 0-3, where 0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do. in addition, MDHAQ includes the assessment of morning stiffness (MS) duration in minutes. | Baseline,12weeks | 
| Change in Visual analog scale for pain | Visual analog scales which ranges from 0 to 10,it is a psychometric scale that is generally used in hospitals and clinics by doctors to conduct pain scale surveys to understand varying degrees of pain or discomfort experienced by a patient. | Baseline,12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the serum level of the assessed biological marker C-reactive protein | C-reactive protein :CRP value (normal range <1.0 mg/dl). If the value is increased, the disease activity worsened. If the value is reduced the disease activity is improved. | Baseline,12weeks | 
| Change in the serum level of the assessed biological marker Nuclear factor kabba-B p65 | Transcriptional factor involved intracellular responses to stimuli and stress .So If the value is increased, the disease activity worsened. If the value is reduced the disease activity is improved. | Baseline,12weeks | 
| Change in the serum level of the assessed biological marker Hemeoxygenase-1 | Hemeoxygenase-1 . | Baseline,12weeks | 
| Change in the serum level of the assessed biological marker Cyclic adenosine monophosphate | Cyclic adenosine monophosphate level. | Baseline,12weeks |