- Study protocol
- Open Access
- Open Peer Review
A placebo-controlled trial of Korean red ginseng extract for preventing Influenza-like illness in healthy adults
- Ki-Chan Ha†1, 2,
- Min-Gul Kim†1,
- Mi-Ra Oh1,
- Eun-Kyung Choi1,
- Hyang-Im Back1, 2,
- Sun-Young Kim1, 2,
- Eun-Ok Park1, 2,
- Dae-Young Kwon4,
- Hye-Jeong Yang4,
- Min-Jeong Kim4,
- Hee-Joo Kang4,
- Ju-Hyung Lee5,
- Kyung-Min Choi6,
- Soo-Wan Chae1, 2 and
- Chang-Seop Lee1, 3Email author
© Ha et al; licensee BioMed Central Ltd. 2012
- Received: 12 January 2012
- Accepted: 8 February 2012
- Published: 8 February 2012
Standardized Korean red ginseng extract has become the best-selling influenza-like illness (ILI) remedy in Korea, yet much controversy regarding the efficacy of the Korean red ginseng (KRG) in reducing ILI incidence remains. The aim of the study is to assess the efficacy of the KRG extract on the ILI incidence in healthy adults.
We will conduct a randomized, double-blind, placebo-controlled study at the onset of the influenza seasons. A total of 100 subjects 30-70 years of age will be recruited from the general populations. The subjects will be instructed to take 9 capsules per day of either the KRG extract or a placebo for a period of 3 months. The primary outcome measure is to assess the frequency of ILI onset in participated subjects. Secondary variable measures will be included severity and duration of ILI symptoms. The ILI symptoms will be scored by subjects using a 4-point scale.
This study is a randomized placebo controlled trial to evaluate the efficacy of the KRG extract compared to placebo and will be provided valuable new information about the clinical and physiological effects of the KRG extract on reduction of ILI incidence including flu and upper respiratory tract infections. The study has been pragmatically designed to ensure that the study findings can be implemented into clinical practice if KRG extract can be shown to be an effective reduction strategy in ILI incidence.
- Ginseng Root
- Ginseng Extract
- Ginseng Polysaccharide
- High Natural Killer Cell
Respiratory viruses are a major cause of influenza-like illness(ILI) symptoms in children and adults, leading to substantial morbidity and mortality each year [1–5]. The complications of ILI symptoms may occur in young children (< 1 year old) and elderly people (> 65 years old), even though ILI symptoms is most often self-limited and restrained to the upper respiratory tract [6–8]. The ILI symptoms is characterized by sudden onset of symptoms such as high fever (> 38°C) and cough in the absence of other diagnosis [9, 10]. Other symptoms including myalgia, headache, chills and fatigue can only be used as optional inclusion criteria. Although it is known that rhinovirus infections cause 10% to 40% of the upper respiratory tract infection , with coronavirus, parainfluenza virus, adenovirus, echovirus, and coxsackievirus accounting for the remainder of cases [12, 13], these viruses produce clinically indistinguishable disease, making specific viral diagnosis difficult [14, 15].
Many patients use complementary and alternative medicine (CAM) therapies to treat and prevent the acute respiratory illness in the worldwide. Moreover, few physicians are familiar with their efficacy or safety. Ginseng has been traditionally used in Asia for thousands of years to treat a variety of ailments. The putative active compounds derived from ginseng root processing are the ginsenosides (saponin glycosides), and the water-soluble poly and oligosaccharides . Various studies have shown that both families of compounds can modulate various parameters of the immune response in vitro and in vivo. In clinical trials, healthy subjects that consumed a standardized ginseng extract had a lower incidence of influenza and colds, higher antibody titers, and higher natural killer cell activity , as well as increased numbers of total lymphocytes and T helper cells . Ginseng polysaccharide preparations increased cytokine production and mRNA expression by murine macrophages and spleen cells in vitro [19–21].
Currently, the ginseng was well known effect for improving the quality-of-life and immunomodulating effects [21–24]. However, there has been no data on the Korean red ginseng (KRG) accumulated for its preventive activity against ILI onset, as it has shown in American ginseng. The purpose of this study is to evaluate the efficacy of the KRG extract in reducing the frequency, severity and duration of ILI symptoms in healthy adults.
The objectives of this RCT are to study whether the concentrated KRG extract can reduce the frequency, severity, and duration of ILI symptoms in healthy subjects.
To evaluate the efficacy of the KRG extract on the frequency of ILI onset in healthy subjects after 12 weeks of consumption.
severity of ILI symptoms
duration of ILI symptoms
The study protocol and the written informed consent were approved by the Functional Foods Institutional Review Board of Chonbuk National University Hospital (CUH IRB 2010-02-016). Each subject will be notified regarding the study protocol. Written informed consent will be obtained from each subject.
Inclusion criteria for participation in the trial
Healthy volunteers aged 30 to 70 years
Ability to give informed consent
Influenza vaccinated subjects
HIV infected and cancer patients
Cardiovascular disease, neurologic or psychiatric disease, renal, pulmonary and hepatic abnormalities
Upper respiratory infection within two weeks before study
History of disease that could interfere with the test products or impede their absorption, such as gastrointestinal disease (Crohn's Disease) or gastrointestinal surgery (a caesum or enterocele surgery are included)
Taking medications such as immunosuppressive drugs, corticosteroids, warfarin, phenalzine, pentobarbital, haloperidol, cyclosporine
Allergic or hypersensitive to ginseng
Laboratory test, medical or psychological conditions deemed by the investigators to interfere with successful participation in the study
History of drug or alcohol abuse in prior 2 months
100 subjects will be recruited through local advertising and doctor referrals from hospital outpatients and general practice clinics. Interested subjects can telephone or email the trial coordinators at the trial conducting sites for further information. Subject information and consent forms will be sent to interested individuals to read over prior to scheduling their first visit.
After enrollment, subjects will be randomly assigned to one of the two groups, either the KRG group or placebo group. The allocation ratio will be 1:1 in blocks of 2. Randomization will be performed at a site remote from trial location. Random numbers will be generated by a computerized random-number generator through the block-randomization method of a software program (Excel, Microsoft Office 2007) for sequence generation. At the time of randomization subjects will draw an envelope. Each envelope contains a number that is concealed to the treatment allocation. Randomization sequence and allocation will be concealed to all study subjects, research staff, investigators and pharmacists until completion of the study. The allocation list will be protected by password access files and held by a non-investigator independent. In the event of an emergency medical situation the individual's randomization code and group allocation can be identify.
Subjects will be asked open-ended questions about frequency, severity, and duration of ILI symptoms during telephone follow-ups on days 1, 28, 57, and 85 of treatment and days 35 post-treatment. Subjects will be also asked to report the study nurse immediately (within 24 hours), at the onset of ILI symptoms. Any unfavorable or unintended sign or symptom will be documented.
The primary outcome is the frequency of ILI symptom onset. Subjects will be asked open-ended questions about frequency of ILI onset during study period. The frequency of ILI onset will be checked weekly via telephone.
A brief study schedule at every visit.
Informed consent form
Demographic information taking 1
Medical history taking
Inclusion/exclusion criteria check
Physician examination 2
Vital sign measurement
Concomitant drugs check
Questionnaires for symptoms related to ILI 3
Laboratory test 4
Study product distribution
Adverse event monitoring
Questionnaire for Influenza-Like Illness
□ 0 □ 1 □ 2 □ 3
□ 0 □ 1 □ 2 □ 3
□ 0 □ 1 □ 2 □ 3
□ 0 □ 1 □ 2 □ 3
□ 0 □ 1 □ 2 □ 3
□ 0 □ 1 □ 2 □ 3
□ 0 □ 1 □ 2 □ 3
□ 0 □ 1 □ 2 □ 3
□ 0 □ 1 □ 2 □ 3
□ 0 □ 1 □ 2 □ 3
Baseline data and Outcomes data
The effects of KRG extract or placebo treatment on the frequency, severity, and duration of symptoms related to ILI prior to the onset of influenza season will be analyzed. The Pearson chi-square test or Fisher's exact test (if the minimum expected count will be less than 2 or the ratio of expected counts lower than 5 will be more than 20%) will be used to compare the proportions of subjects reporting symptoms related to ILI and adverse events. The data will be analyzed for all of the subjects who had been randomly assigned to a group, excluding those who provided only baseline information. An intention-to-treat and per-protocol analysis will be performed.
For the subset of subjects who reported ILI-related symptoms, the total score of severity and the duration for which symptoms will be reported and the two groups will be compared using Mann Whitney U test between two groups. A value of p < 0.05 will be considered statistically significant.
Adverse events and monitoring safety
All unexpected adverse events related to KRG intake will be reported to the investigator by subjects and write on the individual case report form by the investigator. Safety will be assessed by the reporting of clinical laboratory tests, vital sign measurements, and adverse events. Clinical laboratory tests, including AST/ALT, BUN/creatinine, red blood cell (RBC) count, white blood cell (WBC) count, hemoglobin, hematocrit, number of platelets, and number of differentiated cells will be determined at weeks 0 (baseline) and 12 (end of the trial). Vital signs of each subject will be checked with monitoring of adverse events (nausea/vomiting, fatigue, allergic reaction, and any adverse events related to KRG extract intake) after each visit.
The KRG soft capsules remaining after each visit will be quantified in order to enhance medication compliance. Subjects whose compliance with the KRG extract capsules is ≤ 70% of the total dose will be considered to have dropped-out.
This pilot study is the first clinical trials using KRG extract for Korean population. So, there was limited information about the prevention of influenza incidence or symptom releases. Therefore, we had designed a preliminary test using total 100 participants (50:50).
In this study, we will examine whether the KRG extract administration can significantly reduce the frequency, severity, and duration of ILI symptoms. A 1000-mg dose of KRG will be taken 3 times daily by subjects for 12 weeks. Initial ILI symptoms will be confirmed by the collaborating physician at the screening visit of self-reported ILI symptoms, and relief of symptoms will be confirmed within 7 day of the subject's self-reported recovery. Subjects will be recorded daily symptom severity in a journal using a 4-point severity score.
The aim of this study is to evaluate the efficacy of the KRG extract on the frequency, severity, and duration of ILI symptoms. For this purpose, the ability of the KRG extract to reduce the ILI incidence will be assessed in 100 healthy volunteers.
In this study, we expect that the KRG extract can effectively reduce the ILI incidence. Some studies have assessed the relative potency of ginseng extracts by evaluating their ability to prevent the upper respiratory tract infections. The ginseng extracts has been studied in 3 recent RCTs to prevent the common cold, the flu, or upper respiratory infections. Two studies did not show differences between the ginseng extract and placebo in terms of decreasing duration, severity, or frequency of overall symptoms [25, 26]. One study demonstrated that the ginseng extracts decreased duration, severity, and frequency of symptoms .
To the best of our knowledge, there has been no report demonstrating the preventive efficacy of KRG extract on ILI incidence. Therefore, if this study will be successfully performed, the KRG extract may offer beneficial effects in reducing ILI incidence. And these results will be applied to children and elderly populations. To draw confirmative conclusion about the preventive efficacy and safety of the KRG extract on ILI incidence, a full-scale RCT is being conducted now. If there are any conclusions in the near future, we would like to publish them later.
This study was financially supported by a contract with Ministry for Food, Agriculture, Forestry and Fisheries (MIFAFF)/Korea Food Research Institute (KFRI)/Institute of Jinan Red Ginseng (IJRG) and is being conducted at the Clinical Trial Center for Functional Food of Chonbuk National University Hospital.
- Kaye M, Skidmore S, Osman H, Weinbren M, Warren R: Surveillance of respiratory virus infections in adult hospital admissions using rapid methods. Epidemiol Infect. 2006, 134 (4): 792-798. 10.1017/S0950268805005364.View ArticlePubMedPubMed CentralGoogle Scholar
- Jansen AG, Sanders EA, Hoes AW, van Loon AM, Hak E: Influenza- and respiratory syncytial virus-associated mortality and hospitalisations. Eur Respir J. 2007, 30 (6): 1158-1166. 10.1183/09031936.00034407.View ArticlePubMedGoogle Scholar
- Camps M, Ricart S, Dimova V, Rovira N, Munoz-Almagro C, Garcia JJ, Pons-Odena M, Marcos MA, Pumarola T: Prevalence of human metapneumovirus among hospitalized children younger than 1 year in Catalonia, Spain. J Med Virol. 2008, 80 (8): 1452-1460. 10.1002/jmv.21209.View ArticlePubMedGoogle Scholar
- Johnson BF, Wilson LE, Ellis J, Elliot AJ, Barclay WS, Pebody RG, McMenamin J, Fleming DM, Zambon MC: Fatal cases of influenza a in childhood. PLoS One. 2009, 4 (10): e7671-10.1371/journal.pone.0007671.View ArticlePubMedPubMed CentralGoogle Scholar
- Singleton RJ, Bulkow LR, Miernyk K, DeByle C, Pruitt L, Hummel KB, Bruden D, Englund JA, Anderson LJ, Lucher L: Viral respiratory infections in hospitalized and community control children in Alaska. J Med Virol. 2010, 82 (7): 1282-1290. 10.1002/jmv.21790.View ArticlePubMedGoogle Scholar
- Hall CB: Hospital-acquired pneumonia in children: the role of respiratory viruses. Semin Respir Infect. 1987, 2 (1): 48-56.PubMedGoogle Scholar
- Flamaing J, Engelmann I, Joosten E, Van Ranst M, Verhaegen J, Peetermans WE: Viral lower respiratory tract infection in the elderly: a prospective in-hospital study. Eur J Clin Microbiol Infect Dis. 2003, 22 (12): 720-725. 10.1007/s10096-003-1042-z.View ArticlePubMedGoogle Scholar
- Cilla G, Onate E, Perez-Yarza EG, Montes M, Vicente D, Perez-Trallero E: Viruses in community-acquired pneumonia in children aged less than 3 years old: High rate of viral coinfection. J Med Virol. 2008, 80 (10): 1843-1849. 10.1002/jmv.21271.View ArticlePubMedGoogle Scholar
- Aguilera JF, Paget WJ, Mosnier A, Heijnen ML, Uphoff H, van der Velden J, Vega T, Watson JM: Heterogeneous case definitions used for the surveillance of influenza in Europe. Eur J Epidemiol. 2003, 18 (8): 751-754.View ArticlePubMedGoogle Scholar
- Nichol KL: Heterogeneity of influenza case definitions and implications for interpreting and comparing study results. Vaccine. 2006, 24 (44-46): 6726-6728. 10.1016/j.vaccine.2006.05.064.View ArticlePubMedGoogle Scholar
- Kirkpatrick GL: The common cold. Prim Care. 1996, 23 (4): 657-675. 10.1016/S0095-4543(05)70355-9.View ArticlePubMedGoogle Scholar
- Engel JP: Viral upper respiratory infections. Semin Respir Infect. 1995, 10 (1): 3-13.PubMedGoogle Scholar
- Lowenstein SR, Parrino TA: Management of the common cold. Adv Intern Med. 1987, 32: 207-233.PubMedGoogle Scholar
- Tyrrell DA, Cohen S, Schlarb JE: Signs and symptoms in common colds. Epidemiol Infect. 1993, 111 (1): 143-156. 10.1017/S0950268800056764.View ArticlePubMedPubMed CentralGoogle Scholar
- Gwaltney JM: Rhinovirus infection of the normal human airway. Am J Respir Crit Care Med. 1995, 152 (4 Pt 2): S36-39.View ArticlePubMedGoogle Scholar
- Tan BK, Vanitha J: Immunomodulatory and antimicrobial effects of some traditional chinese medicinal herbs: a review. Curr Med Chem. 2004, 11 (11): 1423-1430.View ArticlePubMedGoogle Scholar
- Scaglione F, Cattaneo G, Alessandria M, Cogo R: Efficacy and safety of the standardised Ginseng extract G115 for potentiating vaccination against the influenza syndrome and protection against the common cold [corrected]. Drugs Exp Clin Res. 1996, 22 (2): 65-72.PubMedGoogle Scholar
- Scaglione F, Ferrara F, Dugnani S, Falchi M, Santoro G, Fraschini F: Immunomodulatory effects of two extracts of Panax ginseng C.A. Meyer. Drugs Exp Clin Res. 1990, 16 (10): 537-542.PubMedGoogle Scholar
- Lim DS, Bae KG, Jung IS, Kim CH, Yun YS, Song JY: Anti-septicaemic effect of polysaccharide from Panax ginseng by macrophage activation. J Infect. 2002, 45 (1): 32-38. 10.1053/jinf.2002.1007.View ArticlePubMedGoogle Scholar
- Song JY, Han SK, Son EH, Pyo SN, Yun YS, Yi SY: Induction of secretory and tumoricidal activities in peritoneal macrophages by ginsan. Int Immunopharmacol. 2002, 2 (7): 857-865. 10.1016/S1567-5769(01)00211-9.View ArticlePubMedGoogle Scholar
- Kim KH, Lee YS, Jung IS, Park SY, Chung HY, Lee IR, Yun YS: Acidic polysaccharide from Panax ginseng, ginsan, induces Th1 cell and macrophage cytokines and generates LAK cells in synergy with rIL-2. Planta Med. 1998, 64 (2): 110-115. 10.1055/s-2006-957385.View ArticlePubMedGoogle Scholar
- Wang M, Guilbert LJ, Ling L, Li J, Wu Y, Xu S, Pang P, Shan JJ: Immunomodulating activity of CVT-E002, a proprietary extract from North American ginseng (Panax quinquefolium). J Pharm Pharmacol. 2001, 53 (11): 1515-1523.View ArticlePubMedGoogle Scholar
- Tomoda M, Hirabayashi K, Shimizu N, Gonda R, Ohara N, Takada K: Characterization of two novel polysaccharides having immunological activities from the root of Panax ginseng. Biol Pharm Bull. 1993, 16 (11): 1087-1090. 10.1248/bpb.16.1087.View ArticlePubMedGoogle Scholar
- Shin KS, Kiyohara H, Matsumoto T, Yamada H: Rhamnogalacturonan II from the leaves of Panax ginseng C.A. Meyer as a macrophage Fc receptor expression-enhancing polysaccharide. Carbohydr Res. 1997, 300 (3): 239-249. 10.1016/S0008-6215(97)00055-4.View ArticlePubMedGoogle Scholar
- Vohra S, Johnston BC, Laycock KL, Midodzi WK, Dhunnoo I, Harris E, Baydala L: Safety and tolerability of North American ginseng extract in the treatment of pediatric upper respiratory tract infection: a phase II randomized, controlled trial of 2 dosing schedules. Pediatrics. 2008, 122 (2): e402-410. 10.1542/peds.2007-2186.View ArticlePubMedGoogle Scholar
- McElhaney JE, Goel V, Toane B, Hooten J, Shan JJ: Efficacy of COLD-fX in the prevention of respiratory symptoms in community-dwelling adults: a randomized, double-blinded, placebo controlled trial. J Altern Complement Med. 2006, 12 (2): 153-157. 10.1089/acm.2006.12.153.View ArticlePubMedGoogle Scholar
- Predy GN, Goel V, Lovlin R, Donner A, Stitt L, Basu TK: Efficacy of an extract of North American ginseng containing poly-furanosyl-pyranosyl-saccharides for preventing upper respiratory tract infections: a randomized controlled trial. CMAJ. 2005, 173 (9): 1043-1048. 10.1503/cmaj.1041470.View ArticlePubMedPubMed CentralGoogle Scholar
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1472-6882/12/10/prepub
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.