Cilostazol and Methotrexate in Rheumatoid Arthritis

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

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).

Study Overview

• Status: Recruiting
• Conditions: Rheumatoid Arthritis
• Intervention / Treatment: Drug: Placebo; Drug: Cilostazol; Drug: Methotrexate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 70
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Tarek Mohamed Mostafa, Professor; Phone Number: +201154594035; Email: tarek.mostafa@pharm.tanta.edu.eg
• Study Contact Backup: Name: Samar Mahmoud Eldadamouny, Pharmacist; Phone Number: +201008456735; Email: samer.abdelfattah99@gmail.com

Study Locations

• Egypt
  • Mansoura, Egypt
    • Recruiting
    • Faculty of medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cilostazol and Methotrexate; Participants in this arm will receive Cilostazol 50 mg twice daily with Methotrexate for rheumatoid arthritis for 12 weeks.	Drug: Cilostazol; Cilostazol 50 MG; Drug: Methotrexate; 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.
Placebo Comparator: Placebo and Methotrexate; Participants in this arm will receive Placebo with Methotrexate for rheumatoid arthritis for 12 weeks.	Drug: Placebo; Placebo; Drug: Methotrexate; 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.

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Numbers of participants with treatment-related adverse events	The adverse events in each group will be observed and documented during the whole procedure to show the safety of the treatment.	Baseline,12weeks

Collaborators and Investigators

• Sponsor: Tanta University

Publications and helpful links

General Publications

• Kim HY, Lee SW, Park SY, Baek SH, Lee CW, Hong KW, Kim CD. Efficacy of concurrent administration of cilostazol and methotrexate in rheumatoid arthritis: pharmacologic and clinical significance. Life Sci. 2012 Sep 17;91(7-8):250-7. doi: 10.1016/j.lfs.2012.07.003. Epub 2012 Jul 20.
• Park SY, Lee SW, Kim HY, Lee SY, Lee WS, Hong KW, Kim CD. Suppression of RANKL-induced osteoclast differentiation by cilostazol via SIRT1-induced RANK inhibition. Biochim Biophys Acta. 2015 Oct;1852(10 Pt A):2137-44. doi: 10.1016/j.bbadis.2015.07.007. Epub 2015 Jul 11.
• Kirino Y, Takeno M, Murakami S, Kobayashi M, Kobayashi H, Miura K, Ideguchi H, Ohno S, Ueda A, Ishigatsubo Y. Tumor necrosis factor alpha acceleration of inflammatory responses by down-regulating heme oxygenase 1 in human peripheral monocytes. Arthritis Rheum. 2007 Feb;56(2):464-75. doi: 10.1002/art.22370.
• Park SY, Lee SW, Shin HK, Chung WT, Lee WS, Rhim BY, Hong KW, Kim CD. Cilostazol enhances apoptosis of synovial cells from rheumatoid arthritis patients with inhibition of cytokine formation via Nrf2-linked heme oxygenase 1 induction. Arthritis Rheum. 2010 Mar;62(3):732-41. doi: 10.1002/art.27291.

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2022
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: October 18, 2022
• First Submitted That Met QC Criteria: October 25, 2022
• First Posted (Actual): October 26, 2022

Study Record Updates

• Last Update Posted (Actual): April 10, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Arthritis; Arthritis, Rheumatoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Neuroprotective Agents; Protective Agents; Dermatologic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Reproductive Control Agents; Phosphodiesterase Inhibitors; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Phosphodiesterase 3 Inhibitors; Methotrexate; Cilostazol
• Other Study ID Numbers: cilostazol in rheumatoid

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No