Efficacy and Safety of SID142 in Patients With Peripheral Arterial Disease: A Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel-Group, Phase III Clinical Trial



      Renexin® is a combination pill of cilostazol and Ginkgo biloba leaf extract that is used for the improvement of ischemic symptoms associated with peripheral arterial disease (PAD). SID142 is a controlled-release tablet of cilostazol (200 mg) and G biloba leaf extract (160 mg) that was developed to address the limitation of BID administration with Renexin. This study aimed to verify that SID142 was not inferior to Renexin in the treatment of patients with PAD.


      This was a multicenter, randomized, double-blind, active-controlled, parallel-group, Phase III clinical trial. Study subjects were randomized to receive SID142 once daily or Renexin twice a day for 12 weeks. The primary end point was a change in the patient assessment of lower leg pain intensity with the use of a visual analog scale (VAS) after 12 weeks of treatment. If the lower limit of the two-sided 95% CI was greater than –10, the study drug was declared noninferior to the reference drug. Secondary efficacy end points included cold sensation, ankle-brachial index, ankle systolic pressure, maximum walking distance, pain-free walking distance, and investigator's global assessment. Study group results were compared 4, 8, and 12 weeks after treatment. Adverse events were assessed as a safety end point.


      In total, 344 subjects from 19 medical centers were screened, and a total of 170 subjects were randomly assigned to either the SID142 (n = 86) or the Renexin (n = 84) group. Analysis of the change in lower extremity pain at 12 weeks compared with baseline revealed that SID142 was not inferior to Renexin (21.44 [19.23] vs 22.30 [17.75]; 95% CI, –7.70 to 5.97; P = 0.5942). No significant differences were found between groups in any secondary efficacy end point. However, the incidence of adverse reactions was significantly lower in the SID142 group (22.35% vs 39.29%; P = 0.0171).


      SID142 once daily was not inferior to Renexin twice a day for efficacy in patients with PAD. SID142 had a favorable safety profile. identifier: NCT03318276.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Shammas NW.
        Epidemiology, classification, and modifiable risk factors of peripheral arterial disease.
        Vasc Health Risk Manag. 2007; 3: 229-234
        • Allison MA
        • Ho E
        • Denenberg JO
        • Langer RD
        • Newman AB
        • Fabsitz RR
        • et al.
        Ethnic-specific prevalence of peripheral arterial disease in the United States.
        Am J Prev Med. 2007; 32: 328-333
        • Aday AW
        • Matsushita K.
        Epidemiology of peripheral artery disease and polyvascular disease.
        Circ Res. 2021; 128: 1818-1832
        • Gerhard-Herman MD
        • Gornik HL
        • Barrett C
        • Barshes NR
        • Corriere MA
        • Drachman DE
        • et al.
        2016 AHA/ACC guideline on the management of patients with lower extremity peripheral artery disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        Circulation. 2017; 135: e686-e725
        • Igawa T
        • Tani T
        • Chijiwa T
        • Shiragiku T
        • Shimidzu S
        • Kawamura K
        • et al.
        Potentiation of anti-platelet aggregating activity of cilostazol with vascular endothelial cells.
        Thromb Res. 1990; 57: 617-623
      1. Manolis AA, Manolis TA, Melita H, Mikhailidis DP, Manolis AS. Update on cilostazol: a critical review of its antithrombotic and cardiovascular actions and its clinical applications [published online ahead of print October 20, 2021]. J Clin Pharmacol. 2022; 62: 320–358.

        • Kimura Y
        • Tani T
        • Kanbe T
        • Watanabe K
        Effect of cilostazol on platelet aggregation and experimental thrombosis.
        Arzneimittelforschung. 1985; 35: 1144-1149
        • Jacobs BP
        • Browner WS.
        Ginkgo biloba: a living fossil.
        Am J Med. 2000; 108: 341-342
        • Kleijnen J
        • Knipschild P.
        Ginkgo biloba for cerebral insufficiency.
        Br J Clin Pharmacol. 1992; 34: 352-358
        • Diamond BJ
        • Shiflett SC
        • Feiwel N
        • Matheis RJ
        • Noskin O
        • Richards JA
        • et al.
        Ginkgo biloba extract: mechanisms and clinical indications.
        Arch Phys Med Rehabil. 2000; 81: 668-678
        • Shaito A
        • Thuan DTB
        • Phu HT
        • Nguyen THD
        • Hasan H
        • Halabi S
        • et al.
        Herbal medicine for cardiovascular diseases: efficacy, mechanisms, and safety.
        Front Pharmacol. 2020; 11: 422
        • Braquet P
        • Paubert-Braquet M
        • Koltai M
        • Bourgain R
        • Bussolino F
        • Hosford D.
        Is there a case for PAF antagonists in the treatment of ischemic states?.
        Trends Pharmacol Sci. 1989; 10: 23-30
        • Spinnewyn B
        • Blavet N
        • Clostre F
        • Bazan N
        • Braquet P.
        Involvement of platelet-activating factor (PAF) in cerebral post-ischemic phase in Mongolian gerbils.
        Prostaglandins. 1987; 34: 337-349
        • Kim HS
        • Kim GY
        • Yeo CW
        • Oh M
        • Ghim JL
        • Shon JH
        • et al.
        The effect of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of cilostazol and its active metabolites in healthy Korean subjects.
        Br J Clin Pharmacol. 2014; 77: 821-830
        • Ryu KH
        • Han HY
        • Lee SY
        • Jeon SD
        • Im GJ
        • Lee BY
        • et al.
        Ginkgo biloba extract enhances antiplatelet and antithrombotic effects of cilostazol without prolongation of bleeding time.
        Thromb Res. 2009; 124: 328-334
        • Dawson DL
        • Cutler BS
        • Meissner MH
        • Strandness Jr., DE
        Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial.
        Circulation. 1998; 98: 678-686
        • Lee HC
        • Lee SR
        • Han KR
        • Yu CW
        • Park CG
        • Ahn YK
        • et al.
        Efficacy and safety of DP-R202 in patients with chronic artery occlusive disease: multicenter randomized double-blind active-controlled parallel group phase III clinical study.
        Clin Ther. 2016; 38: 557-573
        • Hochberg MC
        • Fort JG
        • Svensson O
        • Hwang C
        • Sostek M.
        Fixed-dose combination of enteric-coated naproxen and immediate-release esomeprazole has comparable efficacy to celecoxib for knee osteoarthritis: two randomized trials.
        Curr Med Res Opin. 2011; 27: 1243-1253
        • Song YW
        • Lee EY
        • Koh EM
        • Cha HS
        • Yoo B
        • Lee CK
        • et al.
        Assessment of comparative pain relief and tolerability of SKI306X compared with celecoxib in patients with rheumatoid arthritis: a 6-week, multicenter, randomized, double-blind, double-dummy, phase III, noninferiority clinical trial.
        Clin Ther. 2007; 29: 862-873
        • Cardenas-Estrada E
        • Oliveira LG
        • Abad HL
        • Elayan F
        • Khalifa N
        El-Usseini T. Efficacy and safety of celecoxib in the treatment of acute pain due to ankle sprain in a Latin American and Middle Eastern population.
        J Int Med Res. 2009; 37: 1937-1951
        • Hofele CM
        • Gyenes V
        • Daems LN
        • Stypula-Ciuba B
        • Wagener H
        • Siegel J
        • et al.
        Efficacy and tolerability of diclofenac potassium sachets in acute postoperative dental pain: a placebo-controlled, randomised, comparative study vs diclofenac potassium tablets.
        Int J Clin Pract. 2006; 60: 300-307
        • Ministry of Food and Drug
        Safety of the Republic of Korea, and there is no reference data available.