Preventive Effects of Ginseng Against Atherosclerosis and Subsequent Ischemic Stroke: A Randomized Controlled Trial
Phase: NA
Conditions: Ischemic Stroke, Atherosclerosis
Sponsor: Dae Chul Suh

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CLINICAL STUDY PROTOCOL
Title: Preventive Effects of Ginseng against Atherosclerosis and SUbsequent ischemic Stroke: 
A randomized controlled trial 
(PEGASUS)
Study Type: Single-center, Randomized, Double-blind, Placebo-controlled trial; Investigator-
initiated trial
Protocol Number: KGC2026-26
NCT Number: NCT02796664
Version of the document: 6.3, Final version
Date of the document: March 02, 2018

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1. Ethical considerations
This trial will be conducted in compliance with Good Clinical Practice (GCP) and 
Declaration of Helsinki. This trial will start after the written approval of the institutional 
review board (IRB) of our institution is obtained. 
2. Introduction or background information
Atherosclerotic stenosis in a cerebral artery progressing more than 70% caused cerebral 
ischemia, leading to developing collateral circulation. Ischemic symptoms of a patient are 
varying by the development of collateral circulation, which is caused by not only anatomical 
differences but also angiogenesis factors. Recent study reported that Korean red ginseng 
(KRG) had a good effect on cardiovascular system by affecting nitric oxide (NO). 
Endothelial nitric oxide synthase (eNOS) was studied a lot because that NO produced by 
eNOS was associated with anti-inflammation and anti-atherosclerosis. Moreover, KRG was 
reported that it had a vasodilation effect, a blood pressure stabilizing effect and an anti-
platelet effect such as reducing platelet aggregation. Several effects mentioned above 
suggests that KRG had the preventive effect in cardiovascular system and ischemic cerebral 
stroke. 
Therefore, we hypothesize that ginseng has prevention effects against atherosclerosis and 
subsequent ischemic stroke. The preventive effects of ginseng on cerebral ischemic stroke 
will be evaluated in the group of the patients with advanced atherosclerosis such as severe 
stenosis or occlusion in the intracranial arteries. In addition, the changes of collateral 
perfusion state on an ischemic territory caused by atherosclerosis will be evaluated using 

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quantitative magnetic resonance angiography as a surrogate marker.
3. Literature review
A. Some reports showed that ginseng had a good effect on cardiovascular system 
through affecting NO.
B. It was reported that NO produced by endothelial nitric oxide synthase (eNOS) was 
related to anti-inflammation and anti-atherosclerosis. 
C. Ginseng had effects of reducing platelet aggregation, lowering mean systolic 
pressure, and vasodilatation.
4. Study objectives and purpose
The aim of this trial is to study prevention effects of ginseng against atherosclerosis and 
subsequent cerebral ischemic stroke in high-risk patients with severe steno-occlusive lesions 
in internal carotid artery, middle cerebral artery, and posterior circulation.
5. Expected study duration
From the date of institutional review board (IRB) approval to July 31, 2018.
6. Study subjects

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A. Selection criteria
1)
Inclusion criteria
i.
Aged between 20 and 80.
ii.
Severe stenosis or occlusion at an internal carotid artery, middle cerebral 
artery and vertebrobasilar system in cerebral angiography.
iii.
Any stroke risk factors such as hypertension, diabetes, hyperlipidemia, 
smoking and alcohol drinking.
iv.
No adverse effect history of ginseng administration.
2)
Exclusion criteria
i.
Genetic cerebrovascular diseases.
ii.
Adverse reaction to contrast medium.
iii.
Pregnant women.
iv.
History of previous intra-arterial thrombolysis, cerebral angioplasty and/or 
stenting, carotid endarterectomy, and bypass surgery.
v.
History of cardioembolic stroke or possibility of cardioembolic stroke.
vi.
Possibility of cancer stroke.
vii.
Renal failure (GFR< 30 ml/min) or liver disease.
B. Risk and benefit evaluation
1)
Potential risk of this study: Although additional risks are considered as minimal, 
potential risks participating in this trial are showed as follows: any adverse 
effects related to ginseng; pain, bruise or hematoma at puncture site, dizziness, 
syncope, or infection related to cerebral catheter angiography.
2)
Potential benefit of this study: Although there would be no potential benefit for 

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participants, their participations in this trial would help medical advancements.
3)
Conclusion of risk and benefit analysis: It is considered that a potential benefit 
would be bigger than a potential risk because of less adverse effect of ginseng on 
subjects, and an important suggestion to future treatment.
C. Eligible patients
Any inpatients or outpatients who are referred to the department of radiology for 
transfemoral cerebral angiography will become eligible patients. Among them 
fulfilled selection criteria, investigators will obtain written informed consent 
individually.
7. Study design
A. Type of a trial design
A single-center, double-blind, parallel-group, placebo-controlled randomized trial.
B.
Outcomes
1)
Primary outcome: 
i.
Presence of ischemic stroke or TIA (Transient Ischemic Attacks) assessed 
by symptom history during one-year follow-up and measured by number of 
patients in each group.
ii.
Presence of other cerebro-cardiovascular morbidity or mortality assessed 
by aggravation of patient status (mRS, modified Rankin Scale) at out-patient 
clinic during one-year follow-up and measured by the number of patients.
2)
Secondary outcome:
i.
Changes in volumetric blood flow (ml/Sec) in quantitative MRA measured 

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by percentage change from the baseline study.
ii.
Changes in velocity (cm/Sec) in quantitative MRA measured by 
percentage change from the baseline study.
iii.
New FLAIR MR lesions assessed on one-year follow-up MRI and 
measured by the number of patients.
C.
Sample size calculation
Assuming the proportion of 0.1 in the ginseng group and the proportion of 0.4 in 
placebo group in the analyses of primary and secondary outcomes, calculated sample 
size would be 29 patients each group for determining difference between two groups 
in the level of alpha of 0.05, power of 0.8 and 1:1 sampling ratio (equality test).
D. Randomization and follow-up of outcomes
There are two study groups as follows: a ginseng group as an intervention group, a 
promising placebo group as a control group. The participants will be randomly 
allocated to either the ginseng group or the placebo group by 1:1 ratio according to 
random permuted block with a block size of 20. Both groups will be followed up at 1,
3, 6 and 12 months after randomization. At each follow-up, history of the primary 
outcome, any adverse effects, any co-administration drugs, and study drug 
compliance will be evaluated. The secondary outcomes will be evaluated by 
comparison of the results of quantitative MR angiography studies performed at 
baseline and 12 months after randomization.
E.
Study drugs and administration
Two study drugs are identical in appearance. In the intervention group, 2-gram 
ginseng per day (0.5 grams/capsule, 2 capsules twice a day) will be administrated for 

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12 months. In the control group, 2-gram placebo per day (0.5 grams/capsule, 2 
capsules twice a day) will be administrated for 12 months.
F.
Safety evaluation and reporting
If any adverse effects are occurred, the participants will report the problem to an 
investigator. The investigator will appoint outpatient clinic. When the subject visits 
the outpatient clinic, the investigator will evaluate allergic symptoms such as redness,
swelling, respiratory difficulty and grade the symptom severity. The investigator will 
gather other subject symptoms as patient says.
G. Primary outcome evaluation
The presence of any cerebral ischemic symptoms is the primary outcome. The 
history of cerebral ischemic symptoms includes transient ischemic attack (TIA) and 
cerebral ischemic infarction. If the related history is reported, a diffusion-weight 
MRI will be performed. It will be evaluated whether new ischemic lesion is related to 
the steno-occlusive lesion confirmed by cerebral angiography at baseline. 
H. Secondary outcome evaluation
 A quantitative MR angiography (QMRA) with noninvasive optimal vessel analysis 
(NOVA) will be performed for evaluating secondary outcomes at baseline and 12 
months after randomization. QMRA with NOVA will measure blood flow at the 
predetermined sites. The results would become an indirect measurement of collateral 
flow state of a steno-occlusive vascular lesion.

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8. Data collection forms and items
Subject No.
Sex
Age
Results of cerebral catheter angiography
The presence of 
acute ischemic 
lesions
The presence of a steno-occlusive 
lesion at internal carotid artery, middle 
cerebral artery, and vertebrobasilar 
system
Stenosis severity
(Severe/moderate/mild)
Complete total 
occlusion
Medication Information
Duration (mo)
Dose
Date Start
Date End
Compliance
※ Compliance
Drug name
Expected administration 
days
Actual administration 
days
Compliance (%)
Ginseng
Placebo

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Non-invasive Optimal Vessel Analysis (NOVA) 
(at baseline)
Non-invasive Optimal Vessel Analysis (NOVA) 
(at 12 months after randomization)
Brain-MRI (New lesions on FLAIR) 
(at baseline)
Brain-MRI (New lesions on FLAIR) 
(at 12 months after randomization)
The presence of any ischemic stroke 
history at 3 months follow-up
The presence of any ischemic stroke 
history at 6 months follow-up
The presence of any ischemic stroke 
history at 9 months follow-up
The presence of any ischemic stroke 
history at 12 months follow-up
The follow-ups can be conducted in outpatient clinics or by telephone interview performed by experienced nurses since the presence of 
ischemic stroke or TIA history is asked, and mRS is evaluated in the interview. The investigators can do neurologic evaluations if needed.

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9. Blood laboratory test and imaging test
A. Blood laboratory test
none
B. Imaging test
1)
A quantitative MR angiography (QMRA) with noninvasive optimal vessel 
analysis (NOVA) for the changes of cerebral blood flow.
2)
A brain MRI including FLAIR for the presence of new cerebral ischemic lesions.
10. Subject discontinuation (Drop-out)
1)
Difficulty in administration of study drugs.
2)
Impossible to follow up.
11. Patient data safety
Any identifiable human material and data will be excluded in the research. And a subject will 
be given a subject number. Collected data will be managed with a password by only the 
principle investigator and investigators. The data will be discarded after 3-year mandatory 
storage period.
12. Audit
The principle investigator will carry out inspections at finishing data collection and at 

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finishing data analysis.
13. Statistical analysis
The results will be analyzed in intention-to-treat method. For analysis of primary outcome, 
Fisher’s exact test will be used for a dichotomized variable. 
14. Detailed study schedule
Visits
Screening
baseline
1st F/U
(Telephone/
OPD visit)
2nd F/U
(Telephone/
OPD visit)
3rd F/U
(Telephone/
OPD visit)
4th F/U
(Telephone/
OPD visit)
Date
0 day
1 month 
(±  2 
weeks)
3 months 
(±  2 
weeks)
6 months 
(±  2 
weeks)
12 months 
(±  2 
weeks)
Obtaining consent

MR


Drug compliance




15. References
1) Suh DC, Kim JK, Choi CG, Kim SJ, Pyun HW, Ahn C, et al. Prognostic factors for 
neurologic outcome after endovascular revascularization of acute symptomatic occlusion of 
the internal carotid artery. AJNR Am J Neuroradiol. 2007;28:1167-1171
2) Lau AJ, Toh DF, Chua TK, Pang YK, Woo SO, Koh HL. Antiplatelet and anticoagulant 
effects of panax notoginseng: Comparison of raw and steamed panax notoginseng with panax 
ginseng and panax quinquefolium. J Ethnopharmacol. 2009;125:380-386
3) Wee J.J., Kim Y.S., Kyung JS, Song YB, Do J, H., , Kim DC, et al. Identification of 
anticoagulant components in korean red ginseng. 2010; J Ginseng Res:355-362

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4) Lee CH, Kim J-H. A review on the medicinal potentials of ginseng and ginsenosides on 
cardiovascular diseases. J Ginseng Res. 2014;38:161-166