The Effect of Cilostazol on Rheumatoid Arthritis Patients

Sponsor

Ain Shams University (Other)

Overall Status

Recruiting

CT.gov ID

NCT05671497

Collaborator

Misr International University (Other), Al-Azhar University (Other)

Enrollment

Location

Arms

Anticipated Duration (Months)

6.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The goal of this study is to evaluate the effect of cilostazol on Rheumatoid Arthritis patients. It aims to answer the questions of :

Will Cilostazol improve the disease severity and quality of life in Rheumatoid arthritis patients?
Will Cilostazol decrease the oxidative stress, inflammation and endothelial dysfunction in Rheumatoid arthritis patients?

Participants will be randomized into two arms either treatment or control the treatment group will be asked to take Cilostazol 100 mg twice daily in addition to the usual DMARD (Methotrexate , Sulfasalazine , Hydroxychloroquine or Leflunomide), while the control group will be taking the usual DMARDs only.

Patients in both arms will be followed-up every 2 weeks through out the 6-month duration of the study.

Condition or Disease	Intervention/Treatment	Phase
Rheumatoid Arthritis	Drug: Cilostazol 100 MG Drug: conventional synthetic antirheumatic drugs	Phase 2/Phase 3

Detailed Description

Rheumatoid Arthritis (RA) is an autoimmune disease affecting joints. It usually affects females more. The available treatment aims to slow down disease progression and control the disease symptoms. Treatment is classified into either the conventional DMARDs (Methotrexate , Sulfasalazine , Hydroxychloroquine or Leflunomide) or Biological DMARDs such as an Anti-TNF alpha ( Certolizumab, Infliximab , Etanercept or Golimumab) or non-TNF biologics (Rituximab, Abatacept or Tocilizumab). Both classes have their drawbacks. The conventional DMARDs is not effective for many patients and the biological DMARDs have a high cost making their use limited to patients with medical insurance or patients who can afford it, thus making it necessary to find new medications which can improve the outcomes in patients with RA.

Cilostazol is an antiplatelet agent used mainly for intermittent Claudication. Recently many preclinical trials have shown efficacy of cilostazol in RA via it's anti-inflammatory action. it also decreases the oxidative stress which is high in ٌRA patients.

Patients will be randomized into two arms , one which is treatment and the other is control the treatment group will be asked to take Cilostazol 100 mg twice daily in addition to the usual DMARD (Methotrexate , Sulfasalazine , Hydroxychloroquine or Leflunomide), while the control group will be taking the usual DMARDs only.

Patients in both arms will be followed-up every 2 weeks through out the 6-month duration of the study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

70 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Evaluation of the Effect of Cilostazol on the Clinical Outcomes of Rheumatoid Arthritis Patients

Actual Study Start Date :

Nov 1, 2022

Anticipated Primary Completion Date :

Oct 1, 2023

Anticipated Study Completion Date :

Oct 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cilostazol arm 35 patients receiving conventional synthetic disease modifying antirheumatic drugs in addition to Cilostazol 100 mg twice daily for 6 months.	Drug: Cilostazol 100 MG An antiplatelet agent used for intermittent claudication , it has an anti-inflammatory effect which will help control patients with Rheumatoid arthritis Drug: conventional synthetic antirheumatic drugs methotrexate 7.5-15 mg once weekly hydroxychloroquine 200 mg twice daily sulfasalazine 500 mg to 3 g once daily leflunomide 20 mg once daily
Active Comparator: Control 35 patients receiving conventional synthetic disease modifying antirheumatic drugs for 6 months.	Drug: conventional synthetic antirheumatic drugs methotrexate 7.5-15 mg once weekly hydroxychloroquine 200 mg twice daily sulfasalazine 500 mg to 3 g once daily leflunomide 20 mg once daily

Arm

Intervention/Treatment

Experimental: Cilostazol arm

35 patients receiving conventional synthetic disease modifying antirheumatic drugs in addition to Cilostazol 100 mg twice daily for 6 months.

Drug: Cilostazol 100 MG

An antiplatelet agent used for intermittent claudication , it has an anti-inflammatory effect which will help control patients with Rheumatoid arthritis

Drug: conventional synthetic antirheumatic drugs

methotrexate 7.5-15 mg once weekly hydroxychloroquine 200 mg twice daily sulfasalazine 500 mg to 3 g once daily leflunomide 20 mg once daily

Active Comparator: Control

35 patients receiving conventional synthetic disease modifying antirheumatic drugs for 6 months.

Drug: conventional synthetic antirheumatic drugs

methotrexate 7.5-15 mg once weekly hydroxychloroquine 200 mg twice daily sulfasalazine 500 mg to 3 g once daily leflunomide 20 mg once daily

Outcome Measures

Primary Outcome Measures

Change in the DAS-28 CRP score [Baseline, after 3 months , After 6 months]
DAS-28 score is used to asses disease severity in Rheumatoid Arthritis. It incorporates the swollen and tender joints present in 28 joints together with the c-reactive protein measurement into an equation to calculate the disease severity. 0.56* √(TJC28) + 0.28* √(SJC28) + 0.36*ln (CRP + 1) +0.014*(GH) + 0.96 where TJC:is tender joint count SJC is : swollen joint count GH:patient assessment of disease activity using a 100 mm visual analogue scale (VAS) with 0 = best, 100 = worst a number is given which is equal to a specific disease severity. website to calculate the DAS-28 score : https://www.4s-dawn.com/DAS28/

Secondary Outcome Measures

Health Assessment Questionnaire [Baseline, after 3 months , After 6 months]
Rheumatoid arthritis health assessment questionnaire is a self-administered questionnaire help assess patients' functional status. Health assessment questionnaire is validated and present in Arabic language to be administered to Egyptian patients. There are 8 categories in the HAQ assessing the daily activities. In each category the highest score is taken. There are 2 to 3 questions in each category with a scale from 0 to 3 where 0 means no functional limitation and 3 means unable to do this activity. If the patient is using an assistive device the minimum score for this category should be 2. At the end the patient category score is added and divided by 8. The final score is given from 0 to 3 where 3 indicates a poor quality of life.
Total antioxidant capacity (TAC) [Baseline and at 6 months]
Oxidative stress is linked to the pathogenesis of various diseases including RA, cilostazol was shown to decrease the oxidative stress in other disease. so measuring the total antioxidant capacity in order to show the oxidative stress levels.
Malondialdehyde (MDA) [Baseline and at 6 months]
Malondialdehyde is a reactive oxygen species molecule. the level of MDA reflect the oxidative stress present which is important for the pathogenesis of various diseases including Rheumatoid arthritis
TNF α [Baseline and at 6 months]
TNF-alpha is a pro-inflammatory marker used to detect degree of inflammation , and as Rheumatoid arthritis is an inflammatory disease , TNF-alpha measurement would give an insight to RA inflammatory state. TNF-alpha is
phosphorylated Adenosine monophosphate-activated protein kinase (p-AMPK) [Baseline and at 6 months]
p-AMPK is an important marker of inflammatory response as it inhibits inflammatory pathway, measuring p-AMPK would give an insight on the inflammatory response present in Rheumatoid arthritis
Vascular cell adhesion protein 1(VCAM-1) [baseline and at 6 months]
ilostazol was reported to improve the endothelial dysfunction associated with diabetes in diabetic rats through decreasing the adhesion molecules, such as VCAM-1 by an AMPK dependent action which could be beneficial in RA associated endothelial dysfunction
Cilostazol safety [From date of randomization then every two weeks up to 6 months]
Cilostazol safety will be monitored by asking patients through monthly visits and using phone calls every 2 weeks about occurrence of any side effects. The expected side effects of cilostazol are; headache, diarrhea and nausea and stomach pain. Some serious side effects can occur such as bruising , bleeding , palpations and swelling of the arms, hands, feet, ankles, or lower legs

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adult patients. (>18 years old).
Moderate to high disease activity (DAS28-CRP>3.2).
Patients receiving stable cDMARD regimen for at least 3 months before inclusion in the study.