PEGASUS: Preventive Effects of Ginseng Against Atherosclerosis

• Sponsor: Dae Chul Suh (Other)
• Overall Status: Completed
• CT.gov ID: NCT02796664
• Collaborator: Korea Ginseng Corporation (Industry)
• Enrollment: 58
• Location: 1
• Arms: 2
• Actual Duration (Months): 24.3
• Patients Per Site Per Month: 2.4

Study Details

Study Description

Brief Summary

This study is a 12-month, double-blind, randomized, placebo-controlled trial. The purpose of this study is to determine whether ginseng is effective in the prevention of atherosclerosis and subsequent ischemic stroke. High-risk patients with severe atherosclerosis in the major intracranial arteries and extracranial carotid artery were enrolled.

Condition or Disease	Intervention/Treatment	Phase
Ischemic Stroke; Atherosclerosis	Dietary Supplement: Ginseng; Dietary Supplement: Placebo	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Preventive Effects of Ginseng Against Atherosclerosis and Subsequent Ischemic Stroke: A Randomized Controlled Trial
• Actual Study Start Date: Jun 23, 2016
• Actual Primary Completion Date: Jul 4, 2018
• Actual Study Completion Date: Jul 4, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ginseng	Dietary Supplement: Ginseng; Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.
Placebo Comparator: Placebo	Dietary Supplement: Placebo; Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.

Outcome Measures

Primary Outcome Measures

1. The Composite of Cerebral Ischemic Stroke and Transient Ischemic Attack [Twelve months after randomization.]

   The 1-year composite of cerebral ischemic stroke and transient ischemic attack downstream to an atherosclerotic lesion

2. Modified Rankin Scale [Twelve months after randomization.]

   Presence of other cerebro-cardiovascular morbidity or mortality assessed by aggravation of patient status (modified Rankin Scale). The modified Rankin Scale is ranging from 0 to 5. The higher scale indicates the worse outcome.

Secondary Outcome Measures

1. The Changes in Volumetric Blood Flow (ml/Sec) in Intracranial Vessels. [At randomization and twelve months after randomization.]

   The changes in volumetric blood flow (ml/sec) in intracranial vessels assessed by quantitative magnetic resonance angiography with noninvasive optimal vessel analysis.

2. The Changes of White Matter Hyperintensities. [At randomization and twelve months after randomization.]

   The changes of white matter hyperintensities, assessed by the Fazekas scale using brain magnetic resonance imaging. The Fazekas scale is a 4 point white matter disease severity scale with values ranging from 0 to 3. It quantifies the amount of white matter T2 hyperintense lesions each in periventricular white matter and deep white matter. Higher scales mean a worse white matter status. In the region of the periventricular white matter, 0 means absence of the lesion; 1, caps or pencil-thin lining lesion; 2, smooth halo lesion; 3, irregular high intense signal extending into the deep shite matter. In the region of the deep white matter, 0 means absence of the lesion; 1, punctate foci lesions; 2, beginning confluence; 3, large confluent hyperintense areas.

3. Number of Participants With Changes of Parenchymal Ischemic Lesions [At randomization and twelve months after randomization.]

   The changes of ischemic parenchymal lesions, assessed by brain magnetic resonance images acquired at randomization and twelve months after randomization. We counted the number of participants who had new ischemic parenchymal lesions at twelve months after randomization.

Other Outcome Measures

1. Drug Compliance [At twelve months after randomization.]

   We calculated average drug compliance based on the number of remained drugs at each follow-up.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

"Inclusion Criteria"

Patients were included if they

1. were aged 20 to 80 years;

2. had occlusion or severe stenosis (≥ 70%) of extracranial carotid artery and major intracranial arteries (intracranial carotid artery, middle cerebral artery, anterior cerebral artery, intracranial vertebral, basilar, or posterior cerebral artery) as documented by cerebral catheter angiography;

3. had any risk factor for stroke, such as hypertension, diabetes mellitus, hypercholesterolemia, smoking, alcohol drinking, or previous stroke history;

4. had no adverse reactions to administration of ginseng; and

5. agreed to participate in the trial.

"Exclusion Criteria"

Patients were excluded if they

1. did not agree to participate in the trial;

2. had any genetic cerebrovascular diseases;

3. had adverse reactions to contrast medium;

4. were pregnant or planning to be pregnant;

5. had a history of cardioembolic stroke;

6. had an emboligenic cardiac disease such as atrial fibrillation, valve disease, congestive heart failure, or recent myocardial infarction;

7. had a risk of stroke of other determined etiology according to the TOAST classification;

8. had undergone any neurointervention procedure or surgery, such as intra-arterial thrombolysis, angioplasty procedures, carotid endarterectomy, or bypass surgery;

9. had chronic kidney disease (GFR < 30 ml/min); or

10. had severe hepatic dysfunction.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Asan Medical Center	Seoul		Korea, Republic of	05505

Sponsors and Collaborators

• Dae Chul Suh
• Korea Ginseng Corporation

Investigators

• Principal Investigator: Dae Chul Suh, Asan Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 2, 2018

More Information

Publications

• Aleshin S, Strokin M, Sergeeva M, Reiser G. Peroxisome proliferator-activated receptor (PPAR)β/δ, a possible nexus of PPARα- and PPARγ-dependent molecular pathways in neurodegenerative diseases: Review and novel hypotheses. Neurochem Int. 2013 Oct;63(4):322-30. doi: 10.1016/j.neuint.2013.06.012. Epub 2013 Jun 25. Review.
• Bao C, Wang Y, Min H, Zhang M, Du X, Han R, Liu X. Combination of ginsenoside Rg1 and bone marrow mesenchymal stem cell transplantation in the treatment of cerebral ischemia reperfusion injury in rats. Cell Physiol Biochem. 2015;37(3):901-10. doi: 10.1159/000430217. Epub 2015 Sep 18.
• Chen LM, Zhou XM, Cao YL, Hu WX. Neuroprotection of ginsenoside Re in cerebral ischemia-reperfusion injury in rats. J Asian Nat Prod Res. 2008 May-Jun;10(5-6):439-45. doi: 10.1080/10286020801892292.
• He B, Chen P, Yang J, Yun Y, Zhang X, Yang R, Shen Z. Neuroprotective effect of 20(R)-ginsenoside Rg(3) against transient focal cerebral ischemia in rats. Neurosci Lett. 2012 Sep 27;526(2):106-11. doi: 10.1016/j.neulet.2012.08.022. Epub 2012 Aug 19.
• Hong KS. Blood Pressure Management for Stroke Prevention and in Acute Stroke. J Stroke. 2017 May;19(2):152-165. doi: 10.5853/jos.2017.00164. Epub 2017 May 31. Review.
• Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP Jr, Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O'Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR; IRIS Trial Investigators. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016 Apr 7;374(14):1321-31. doi: 10.1056/NEJMoa1506930. Epub 2016 Feb 17.
• Liu XY, Zhou XY, Hou JC, Zhu H, Wang Z, Liu JX, Zheng YQ. Ginsenoside Rd promotes neurogenesis in rat brain after transient focal cerebral ischemia via activation of PI3K/Akt pathway. Acta Pharmacol Sin. 2015 Apr;36(4):421-8. doi: 10.1038/aps.2014.156. Epub 2015 Mar 16.
• Yang Y, Li X, Zhang L, Liu L, Jing G, Cai H. Ginsenoside Rg1 suppressed inflammation and neuron apoptosis by activating PPARγ/HO-1 in hippocampus in rat model of cerebral ischemia-reperfusion injury. Int J Clin Exp Pathol. 2015 Mar 1;8(3):2484-94. eCollection 2015.
• Zheng M, Xin Y, Li Y, Xu F, Xi X, Guo H, Cui X, Cao H, Zhang X, Han C. Ginsenosides: A Potential Neuroprotective Agent. Biomed Res Int. 2018 May 8;2018:8174345. doi: 10.1155/2018/8174345. eCollection 2018. Review.
• Zhou Y, Li HQ, Lu L, Fu DL, Liu AJ, Li JH, Zheng GQ. Ginsenoside Rg1 provides neuroprotection against blood brain barrier disruption and neurological injury in a rat model of cerebral ischemia/reperfusion through downregulation of aquaporin 4 expression. Phytomedicine. 2014 Jun 15;21(7):998-1003. doi: 10.1016/j.phymed.2013.12.005. Epub 2014 Jan 22.

• Responsible Party: Dae Chul Suh, Professor, Asan Medical Center
• ClinicalTrials.gov Identifier: NCT02796664
• Other Study ID Numbers: KGC2016-26
• First Posted: Jun 13, 2016
• Last Update Posted: Aug 24, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Dae Chul Suh, Professor, Asan Medical Center: Ginseng; Stroke; Quantitative magnetic resonance flow analysis
• Additional relevant MeSH terms: Stroke; Ischemic Stroke; Atherosclerosis

Study Results

Participant Flow

Recruitment Details	Patients in a single center, from June 2016 to June 2017.

Arm/Group Title	Ginseng	Placebo
Arm/Group Description	Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.	Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.
Period Title: Overall Study
STARTED	29	29
COMPLETED	28	24
NOT COMPLETED	1	5

Baseline Characteristics

Arm/Group Title	Ginseng	Placebo	Total
Arm/Group Description	Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.	Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.	Total of all reporting groups
Overall Participants	28	24	52
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.4 (12.5)	58.8 (13.6)	60.3 (13.0)
Sex: Female, Male (Count of Participants)
Female	13 46.4%	8 33.3%	21 40.4%
Male	15 53.6%	16 66.7%	31 59.6%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (Count of Participants)
South Korea	28 100%	24 100%	52 100%
Hypertension (Count of Participants)
Count of Participants [Participants]	20 71.4%	14 58.3%	34 65.4%
Diabetes mellitus (Count of Participants)
Count of Participants [Participants]	10 35.7%	4 16.7%	14 26.9%
Hyperlipidemia (Count of Participants)
Count of Participants [Participants]	23 82.1%	15 62.5%	38 73.1%
Previous stroke history (Count of Participants)
Count of Participants [Participants]	13 46.4%	9 37.5%	22 42.3%
Atrial fibrillation (Count of Participants)
Count of Participants [Participants]	0 0%	0 0%	0 0%
Myocardial infarction (Count of Participants)
Count of Participants [Participants]	0 0%	0 0%	0 0%
Angina pectoris (Count of Participants)
Count of Participants [Participants]	5 17.9%	2 8.3%	7 13.5%
Alcohol drinking (Count of Participants)
Count of Participants [Participants]	6 21.4%	9 37.5%	15 28.8%
Smoking (Count of Participants)
Count of Participants [Participants]	5 17.9%	13 54.2%	18 34.6%
Antiplatelet medication (Count of Participants)
Mono antiplatelet	8 28.6%	9 37.5%	17 32.7%
Dual antiplatelet	17 60.7%	14 58.3%	31 59.6%
Other antiplatelet	2 7.1%	1 4.2%	3 5.8%
None	1 3.6%	0 0%	1 1.9%
Antihypertensive medication (Count of Participants)
Count of Participants [Participants]	21 75%	13 54.2%	34 65.4%
Antidiabetic medication (Count of Participants)
Count of Participants [Participants]	9 32.1%	3 12.5%	12 23.1%
Antihyperlipidemic medication (Count of Participants)
Count of Participants [Participants]	25 89.3%	21 87.5%	46 88.5%
Baseline modified Rankin Scale (mRS) (Count of Participants)
mRS 0	21 75%	22 91.7%	43 82.7%
mRS 1	5 17.9%	1 4.2%	6 11.5%
mRS 2	0 0%	0 0%	0 0%
mRS 3	2 7.1%	1 4.2%	3 5.8%
mRS 4	0 0%	0 0%	0 0%
mRS 5	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	The Composite of Cerebral Ischemic Stroke and Transient Ischemic Attack
Description	The 1-year composite of cerebral ischemic stroke and transient ischemic attack downstream to an atherosclerotic lesion
Time Frame	Twelve months after randomization.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Ginseng	Placebo
Arm/Group Description	Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.	Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.
Measure Participants	28	24
Ischemic stroke	0 0%	0 0%
Transient ischemic attack	0 0%	1 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ginseng, Placebo
	Comments	The null hypothesis is that there is no relationship between ginseng administration and cerebral ischemic events including ischemic stroke and transient ischemic attack. The number of participants who suffered ischemic stroke and the number of paticipants who suffered transient ischemic attack were analyzed together to test the null hypothesis in two by two table.
	Type of Statistical Test	Other
	Comments	Equality test
Statistical Test of Hypothesis	p-Value	0.462
	Comments
	Method	Fisher Exact
	Comments

2. Primary Outcome

Title	Modified Rankin Scale
Description	Presence of other cerebro-cardiovascular morbidity or mortality assessed by aggravation of patient status (modified Rankin Scale). The modified Rankin Scale is ranging from 0 to 5. The higher scale indicates the worse outcome.
Time Frame	Twelve months after randomization.

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Ginseng	Placebo
Arm/Group Description	Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.	Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.
Measure Participants	28	24
mRS 0	21 75%	22 91.7%
mRS 1	5 17.9%	1 4.2%
mRS 2	0 0%	0 0%
mRS 3	2 7.1%	1 4.2%
mRS 4	0 0%	0 0%
mRS 5	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ginseng, Placebo
	Comments	The null hypothesis is that there is no relationship between ginseng administration and modified Rankin Scale at follow-up.
	Type of Statistical Test	Other
	Comments	Equality test
Statistical Test of Hypothesis	p-Value	0.34
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	The Changes in Volumetric Blood Flow (ml/Sec) in Intracranial Vessels.
Description	The changes in volumetric blood flow (ml/sec) in intracranial vessels assessed by quantitative magnetic resonance angiography with noninvasive optimal vessel analysis.
Time Frame	At randomization and twelve months after randomization.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ginseng	Placebo
Arm/Group Description	Ginseng: Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.	Placebo: Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.
Measure Participants	28	24
Improved	4 14.3%	5 20.8%
No change	17 60.7%	18 75%
Aggravated	7 25%	1 4.2%
Improved	7 25%	7 29.2%
No change	17 60.7%	9 37.5%
Aggravated	4 14.3%	8 33.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ginseng, Placebo
	Comments	The null hypothesis is that there is no relationship between ginseng administration and flow change in steno-occlusive lesion.
	Type of Statistical Test	Other
	Comments	Equality test
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ginseng, Placebo
	Comments	The null hypothesis is that there is no relationship between ginseng administration and flow change in collateral vessel.
	Type of Statistical Test	Other
	Comments	Equality test
Statistical Test of Hypothesis	p-Value	0.17
	Comments
	Method	Chi-squared
	Comments

4. Secondary Outcome

Title	The Changes of White Matter Hyperintensities.
Description	The changes of white matter hyperintensities, assessed by the Fazekas scale using brain magnetic resonance imaging. The Fazekas scale is a 4 point white matter disease severity scale with values ranging from 0 to 3. It quantifies the amount of white matter T2 hyperintense lesions each in periventricular white matter and deep white matter. Higher scales mean a worse white matter status. In the region of the periventricular white matter, 0 means absence of the lesion; 1, caps or pencil-thin lining lesion; 2, smooth halo lesion; 3, irregular high intense signal extending into the deep shite matter. In the region of the deep white matter, 0 means absence of the lesion; 1, punctate foci lesions; 2, beginning confluence; 3, large confluent hyperintense areas.
Time Frame	At randomization and twelve months after randomization.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ginseng	Placebo
Arm/Group Description	Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.	Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.
Measure Participants	28	24
Fazekas scale 0	2 7.1%	1 4.2%
Fazekas scale 1	9 32.1%	11 45.8%
Fazekas scale 2	15 53.6%	10 41.7%
Fazekas scale 3	2 7.1%	2 8.3%
Fazekas scale 0	9 32.1%	6 25%
Fazekas scale 1	15 53.6%	15 62.5%
Fazekas scale 2	3 10.7%	2 8.3%
Fazekas scale 3	1 3.6%	1 4.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ginseng, Placebo
	Comments	The null hypothesis is that there is no relationship between ginseng administration and periventricular white matter lesions at follow-up.
	Type of Statistical Test	Other
	Comments	Equality test
Statistical Test of Hypothesis	p-Value	0.74
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ginseng, Placebo
	Comments	The null hypothesis is that there is no relationship between ginseng administration and deep white matter lesions at follow-up.
	Type of Statistical Test	Other
	Comments	Equality test
Statistical Test of Hypothesis	p-Value	0.95
	Comments
	Method	Fisher Exact
	Comments

5. Secondary Outcome

Title	Number of Participants With Changes of Parenchymal Ischemic Lesions
Description	The changes of ischemic parenchymal lesions, assessed by brain magnetic resonance images acquired at randomization and twelve months after randomization. We counted the number of participants who had new ischemic parenchymal lesions at twelve months after randomization.
Time Frame	At randomization and twelve months after randomization.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ginseng	Placebo
Arm/Group Description	Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.	Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.
Measure Participants	28	24
Ischemic lesion (+)	22 78.6%	15 62.5%
Ischemic lesion (-)	6 21.4%	9 37.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ginseng, Placebo
	Comments	The null hypothesis is that there is no relationship between ginseng administration and parenchymal ischemic lesions at follow-up.
	Type of Statistical Test	Other
	Comments	Equality test
Statistical Test of Hypothesis	p-Value	0.23
	Comments
	Method	Chi-squared
	Comments

6. Other Pre-specified Outcome

Title	Drug Compliance
Description	We calculated average drug compliance based on the number of remained drugs at each follow-up.
Time Frame	At twelve months after randomization.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ginseng	Placebo
Arm/Group Description	Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.	Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.
Measure Participants	28	24
Mean (Standard Deviation) [percentage of drug compliance]	97.4 (4.7)	97.8 (4.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ginseng, Placebo
	Comments	The null hypothesis is that there is no relationship between ginseng administration and drug compliance at follow-up.
	Type of Statistical Test	Other
	Comments	Equality test
Statistical Test of Hypothesis	p-Value	0.79
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	1, 3, 6 and 12 months after randomization.
Arm/Group Title	Ginseng		Placebo
Arm/Group Description	Korean Red Ginseng extract tablet (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.		Placebo (0.5 grams/tablet, 2 tablets twice a day) daily for 12 months.
All Cause Mortality
	Ginseng		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		1/29 (3.4%)
Serious Adverse Events
	Ginseng		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/29 (0%)		1/29 (3.4%)
General disorders
Death	0/29 (0%)	0	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	Ginseng		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/29 (3.4%)		2/29 (6.9%)
Gastrointestinal disorders
Constipation	0/29 (0%)	0	1/29 (3.4%)	1
Skin and subcutaneous tissue disorders
Bruise	0/29 (0%)	0	1/29 (3.4%)	1
Subjective hair loss	1/29 (3.4%)	1	0/29 (0%)	0

Limitations/Caveats

The difficulty in determining the size of the study population due to the lack of previous studies. The relatively short follow-up period considering chronic atherosclerotic disease. The absence of surrogate biochemical markers to confirm ginsenosides' effects.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.