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1 대한한방내과학회지제 37 권 1 호 (2016 년 3 월 ) J. Int. Korean Med. 2016:37(1) 감기임상시험가이드라인제정을위한최신임상시험연구분석 김관일 1,3, 이호정 2,3, 이범준 1, 정희재 1, 정승기 1, 이준희 2,3 1 경희대학교한의과대학폐계내과학교실, 2 경희대학교한의과대학대학원임상한의학과교실 3 경희대학교한방병원한의약임상시험센터 Analysis of Recent Clinical Studies to Establish Korean Herbal Medicine Clinical Trial Guidelines for the Common Cold Kwan-il Kim 1,3, Ho-jung Lee 2,3, Beom-joon Lee 1, Hee-jae Jung 1, Sung-ki Jung 1, Jun-hee Lee 2,3 1 Division of Allergy, Immune & Respiratory System, Department of Internal Medicine, College of Korean Medicine, Kyung-Hee University 2 Dept. of Clinical Korean Medicine, Graduate School, Kyung-Hee University 3 Korean Medicine Clinical Trial Center, Kyung-Hee University Korean Medicine Hospital ABSTRACT Objectives: The aim of this study was to help develop a guideline for the common cold. We searched recent clinical studies of the common cold in Western medicine and reviewed their objectives, inclusion and exclusion criteria, primary outcome, secondary outcome, and assessment tools to establish evidenced-based guideline. Methods: We searched electronic databases (Cochrane Library, MEDLINE, EMBASE) to identify eligible randomized controlled trials (RCTs) about the common cold for the last 10 years. We included 29 RCTs and showed their research summary via their objectives, participants, interventions, control, treatment duration, and results. We also analyzed the definition of the common cold presented in the article, inclusion and exclusion criteria, primary and secondary outcomes, and assessment tools. Results: We reported the aforementioned areas in detail. At first, the definition of the common cold was confused across the articles. Second, herbal medication clinical trials for the common cold have been extensively studied recently. Third, the eligibility criteria frequently included the Jackson Symptom score. Fourth, validated assessment tools (i.e., the Wisconsin Upper Respiratory Symptom Survey-21) have only been used in a few recent studies. Conclusions: Our research will be helpful to establish Korean herbal medicine clinical trial guidelines for the common cold. Key words: common cold, randomized controlled trial, review Ⅰ. 서론 감기는경증의바이러스에의한상기도감염증후군으로콧물, 코막힘, 재채기, 기침등의증상을 투고일 : , 심사일 : , 게재확정일 : 교신저자 : 이준희서울시동대문구경희대로 23 경희대학교한방병원한의약임상시험센터 TEL: FAX: ssljh@daum.net 동반하는증후군이다 1. 감기를일으키는바이러스는총 200여종에달하며이중 rhinovirus 30-50%, corona virus 10%, respiratory syncytial virus(rsv) 가 5% 의원인을차지하여 rhinovirus 와 corona virus가흔한원인바이러스로알려지고있다 1,2. 감기는경증의질환이고, 자체한정기간을지니지만일상적인삶이나사회적활동에지장을초래하며막대한사회적비용을야기하고있다 3. 감기의원 109

2 감기임상시험가이드라인제정을위한최신임상시험연구분석 인이매우다양하여특정바이러스에대한치료는효율성이없는것으로밝혀져있으며 2, 기존에사용되던항생제, 항히스타민제모두뚜렷한효과가없고 4 오히려부작용이보고되고있어 5, 증상을치료하는대증치료에관심이모아지고있다. 이에서양에서는양약관련임상시험보다단일본초나대체요법에대한임상시험연구를최근들어진행하여왔고그에대한체계적리뷰도연구되었으나아직까지명확한효과를보이는약물은없는실정이다 4,6. 이에여러나라에서한약에대한관심이증대되고있는추세이다 7,8. 한약제제와관련된임상시험은최대한표준화된방법으로정교하게이루어져야하며, 이와관련하여 Consolidated Standards of Reporting Trials (CONSORT) 는한약제제에대해서지침을따로개정하여발표하기도하였다 9. 국내에서도잘설계된임상시험의중요성을절감하여한약제제에대한가이드라인을일부구축하였으나감기와관련된한약제제임상시험가이드라인은아직제정되지않은상태이다. 감기치료에서의한방적접근이필요하고이를위한임상시험요구가증대되는상황으로, 한약제제의안정성과유효성을객관적으로체계적으로밝히기위해임상시험을준비하는연구자들에게도움이되도록감기치료및예방에대한한방제제임상시험가이드라인제정이필요한시점이라판단하였다. 이에경희대학교한방병원한의약임상시험센터에서는국내한방호흡기내과교수진을전문가자문위로구성하고한의약임상시험센터협의체와공동으로가이드라인을제정하고자계획하였다. 가이드라인제정을위한기초단계로여러선행논문과유수외국참고서적및가이드라인을검색한결과외국에서발간된신뢰성있는가이드라인은없는상황이며, 중국에서발간된변증관련가이드라인이나진료지침을참고로할수있었다 10. 그러나감기에대한한약제제임상시험에필요한필수정보를제공하는참고할만한기존자료는없다 고판단하여, 최신의임상시험연구논문을분석하여가이드라인에필요한여러사항에대해정리할필요성이대두되었다. 선행연구를보더라도감기는임상적증상으로이루어진증후군인관계로증상포함범위가다양하였고, 이에따라선정제외기준도불명확한상황이었다. 앞서감기에대한임상시험의중요성을파악하고 년까지임상연구를고찰한논문이있었으나 11, 시일이지나최신의연구경향을반영하지못한다는점에서가이드라인관련하여정보를얻기에한계가있었다. 이에최근 10년간감기에대한세계적인임상시험경향을살펴보고, 감기에대한정의및선정, 제외기준, 평가도구등을분석하여, 향후국내에서시행될감기치료및예방에대한임상시험의가이드라인제정에도움이되고자본연구를시행하였다. Ⅱ. 연구방법및절차 1. 검색방법및연구대상선정 PubMed, EMBASE, the Cochrane Central Register of Controlled Trials(CENTRAL) 검색을통해감기에대한임상시험논문을선정하였다. common cold, upper respiratory tract infection, rhinovirus, corona virus 를검색어로하여 title & abstract 범주에서기간은 10년이내, 대상은 Human, 언어는 English로제한하여검색을시행하였다. 검색결과총 676편의논문이검색되었고, 중복으로 208편의논문을제외한총 468편의논문중에서제목초록을검토하여실시한 1차스크리닝결과, 무작위대조군임상시험이아닌경우, 영어가아닌경우, 실험논문등의이유에해당되는 343편의논문이제외되었다. 2차스크리닝은 125편논문중에서 title에 common cold 가포함된논문으로이루어졌다. 감기는상기도감염에포함되는증후군이나기존에용어가혼재되는경향이있어서이로인해감기에대한정의및증상에대한범주가모호하였으므로, 이에감기를명확하게제목에포 110

3 김관일 이호정 이범준 정희재 정승기 이준희 함하여진행된임상시험을간추려 1차적으로감기에대한정의및선정, 제외기준, 평가도구등에대한분석을해보는것이중요할것으로판단되었기때문이다. 위의과정을거쳐총 37편의논문이간추려졌으며, 전문을검토하여전문이없는경우 (n=3), RCT가아닌경우 (n=5) 의이유로 8편이제외하여총 29편 을선정하였다. 2. 연구내용최근 10년동안감기환자를대상으로진행된무작위대조군임상시험을대상으로연구개요와관련하여연구목적, 연구대상자수, 중재군및대조군, 치료기간, 연구결과순으로살펴보았다. 논문에서제시한감기의정의를살펴보고, 각논문의선정기준, 제외기준, 논문에서사용한 1차평가변수, 2차평가변수및평가도구를분석하여고찰하였다. Ⅲ. 결과 1. 연구개요 2006년부터 2014년에걸쳐총 29개의논문이선정되었다. 2006년 4편, 2007년 5편, 2008년 1편, 2009 년 1편, 2010년 4편, 2011년 3편, 2012년 4편, 2013년 4편, 2014년 1편으로최근 10년간감기와관련된무작위대조군임상시험이꾸준히진행되어온것을확인하였다. 연구개요는연구목적을분류하여연도순으로나열하여제시하였다 (Table 1). 1) 연구목적중재의감기치료에대한효능을살펴본논문이 21편, 감기예방에대한효능을살펴본논문이 8편이었다. 2) 연구대상자수모집된연구대상자수는치료에대한효능을보는임상시험은최소 35명에서최대 719명까지였고, 예방에대한효능을보는임상시험에서는최소 80명에서최대 755명이였다. 3) 중재군및대조군치료에대한효능은총 21편중비강내스프레이제제 5편 (23%), 한약복합제제 4편 (19%), 아연 3편 (14%), 양약 3편 (14%), Echinacea 1편 (5%) Pelargonium Sidoides 1편 (5%) 그외, 폴리페놀음료, 고온다습한공기, autologous blood therapy, 의사-환자유대관계각 1편 (5%) 씩이루어졌다. 예방에대한효능은총 8편중프로바이오틱박테리아 2편 (25%), 아연 2편 (25%), Echinacea 1편 (12.5%), 비타민 C 1편 (12.5%), 과일야채혼합주스 1편 (12.5%), 초유단백질 1편 (12.5%) 이진행되었다. 4) 중재기간치료에대한효능연구의중재기간은 7일이내가 6편 (29%), 7일이상 10일이내가 7편 (33%), 10 일이상 14일이내가 4편 (19%), 14일이상 21일이내 4편 (19%) 이었다. 예방에대한연구 3개월이 3편 (37.5%), 4개월 1 편 (12.5%), 7개월 1편 (12.5%), 8개월 (run-in-period 2개월 ) 1편 (12.5%), 관찰기간 1년 ( 중재투여기간불명확 ) 1편 (12.5%), 5년 1편 (12.5%) 이었다. 5) 연구결과총 29편중효능이있다고보고한논문은 17편 (59%), 제한적으로효능이있었던논문이 3편 (10%), 효능이없었던논문이 9편 (31%) 이었다. 제한적으로효능이있다고판단한논문은일차평가변수에대한효능은없었으나, 관련된이차평가변수에대한효능이있는것으로서술된논문이다. 효과가없다고판단한 Okabayashi 논문은대조군으로양약을사용하고제목에서비우월성 (non-superiority) 이라는용어를사용하여중재군과대조군의약효가같거나열등하다는것을보이려한것으로보였으나실제논문서술을토대로샘플사이즈를구하는방식이나전반적인연구설계를살펴볼때비우월성과관련된디자인이나가설을명확히제시하지않은것으로보여효과가없음으로판단하였다 (Table 1). 111

4 감기임상시험가이드라인제정을위한최신임상시험연구분석 Table 1. Characteristics of the Studies Included in the Review Author (years) Eby GA (2006) Hull D Kurugol Z Latte J Lizogob VG Mizoguchi H Eccles R (2008) Prasad AS (2008) Hensler S (2009) Barrett B Eccles R Pach D Schütz K Byun JS (2011) Objective Participants enrolled Participants analyzed Intervention group Control group Treatment duration (study duration) Results Treatment zinc placebo 7 days ineffective Treatment low ph gel nasal spray (for non-spec ific virus-hostile environment) placebo Treatment zinc sulphate placebo Treatment oral pseudoephedrine Treatment * Pelargonium sidoides placebo Treatment Treatment syrup (paracetamol, dextromethorphan, hydro bromide, doxylamine succinate, ephedrine sulfate) xylometazoline (Otrivin) nasal decongestant maximum 7 days maximum 7 days effective ineffective placebo 3 days ineffective maximum 10 days effective placebo 21 days effective placebo 10 days effective Treatment zinc acetate lozenges placebo 5 days effective Treatment Treatment Treatment Treatment Treatment Treatment autologous blood therapy (gluteal intramuscular injection of venous blood) echinacea(blinded)/ echinacea(open) iota-carrageenan nasal spray inhaling hot dry air (in sauna) polyphenol-rich beverage so-cheong-ryong-tang yeon-gyo-pae-dok-san placebo 7 days ineffective no pill /placebo (blinded) 14 days ineffective placebo 4 days effective dry air at room temperature 3 days effective placebo 10 days ineffective placebo maximum 8 days limited effective 112

5 김관일 이호정 이범준 정희재 정승기 이준희 Rakel D (2011) Yakoot M (2011) Chang J (2012) Fazekas T (2012) Ludwig M (2013) Picon PD (2013) Okabayashi S (2014) de Vress M (2006) Kurugol Z (2006) Sasazuki S (2006) Roll S Jawad M (2012) Treatment Treatment Treatment Treatment Treatment Treatment Treatment Prevention standard interaction enhanced interaction natural multiherbal formula (Immumax) containing echinacea, garlic powder, nigella sativa oil, and panax ginseng +vitamin C, elemental zinc shi-cha capsule /shi-cha capsule+placebo iota-carrageenan nasal spray carrageenan nasal spray paracetamol, chlorphenamine and phenylephrine kakkonto (Japanese herbal medicine) vitamin+mineral +probiotic bacteria no patient -practitioner interaction placebo maximum 7 days maximum 14 days effective effective placebo 3 days effective placebo 7 days ineffective placebo maximum 21 days effective placebo 10 days effective western-style multiple cold medicine (PabronGold-A) vitamin +mineral 4 days ineffective unclear (01 Jan-May, 01 Dec-02 June, 12 months) limited effective Prevention zinc sulphate placebo 7 months effective Prevention mg of vitamin C Prevention juice powder (fruit+vegetables) 50mg of vitamin C placebo 5 years (4 years after protocol amendment) 8 months, (including a 2-month run-in period) ineffective effective Prevention echinacea purpurea placebo 4 months effective 113

6 감기임상시험가이드라인제정을위한최신임상시험연구분석 Rerksuppaphol S (2012) Rerksuppaphol S (2013) Vitetta L (2013) prevention 80 Prevention (dropout: 4) 100 (dropout: 5) Prevention probiotic (lactobacillus acidophilus and bifidobacterium bifidum placebo 3 months effective chelated zinc placebo 3 months lactoferrin/whey protein Ig-rich faction (Lf/IgF) limited effective placebo 3 months effective 2. 감기정의총 29편논문중에서감기에대한정의가제시되지않고유병률이나역학만을제시한논문은 16 편에해당하였다. 13편에서정의된감기는 바이러스에의한상기도감염이다 가거의대부분이었으며, 1편은 전통적으로급성상기도감염으로통칭되 던감기는유병률이매우높은질환으로바이러스에의해발병된다. 라고정의되었다. 가장최신논문인 2014년에발표된 Okabayashi 논문에서는 바이러스에의해발생되는경증의상기도질환 으로정의되었다 (Table 2). Table 2. Definition about Common Cold in the Included Studies Treatment No Author (year) Definition 1 Eby GA (2006) not presented 2 Hull D Upper Respiratory Tract Infections (URTIs) of viral aetiology, commonly described as Common Cold and Flu, remain the most common of human illnesses. 3 Kurugol Z not presented 4 Latte J not presented 5 Lizogob VG The common cold is a viral infection with symptoms such as sneezing, sore throat, and running nose. 6 Mizoguchi H The common cold is a symptom complex resulting from viral infection of the upper respiratory tract. 7 Eccles R (2008) not presented 8 Prasad AS (2008) not presented 9 Hensler S (2009) not presented 10 Barrett B Acute viral respiratory infection (common cold) is humanity s most frequent illness. Etiologic agents include rhinovirus, coronavirus, influenza, parainfluenza, respiratory syncytial virus, adenovirus, enterovirus, and metapneumovirus. While influenza caused illness is the most serious and is often categorized separately, symptoms are usually indistinguishable from those produced by other viruses. 114

7 김관일 이호정 이범준 정희재 정승기 이준희 11 Eccles R Common cold is the most prevalent contagious viral disease in humans. It is caused by a variety of viral pathogens with human rhinoviruses (HRV) being the most abundant ones. Affecting the upper respiratory system, symptoms like blocked nose, cough and sneezing are most common. 12 Pach D Common cold, mainly caused by rhinoviruses or coronaviruses, is a frequent problem all over the world. 13 Schütz K Acute upper respiratory tract viral infection, also referred to as the common cold, is the most frequent infectious disease in human beings. 14 Byun JS (2011) The common cold is caused by various types of viruses, especially rhinovirus which has more than 100 different serotypes. 15 Rakel D (2011) not presented 16 Yakoot M (2011) not presented 17 Chang J (2012) not presented 18 Fazekas T (2012) Acute viral infection of the upper respiratory tract, also referred to as common cold. 19 Ludwig M (2013) Common colds are caused by respiratory viruses such as rhinovirus, coronavirus, parainfluenza, influenza, respiratory syncytial virus, adenovirus, enterovirus, or metapneumovirus. 20 Picon PD (2013) Acute respiratory infections are highly prevalent in the population, with the common cold, flu-like syndromes, t racheobronchitis, sinusitis, laryngitis and pneumonias being particularly important. 21 Okabayashi S (2014) The term common cold refers to virus-induced, relatively mild upper respiratory tract illnesses. Prevention No Author (year) Definition 1 de Vress M (2006) not presented 2 Kurugol Z (2006) not presented 3 Sasazuki S (2006) not presented 4 Roll S The common cold is viral infectious disease of the upper respiratory tract, caused by a variety of viruses, with rhinoviruses and corona viruses as the most common. 5 Jawad M (2012) not presented 6 Rerksuppaphol S (2012) not presented 7 Rerksuppaphol S (2013) not presented 8 Vitetta L (2013) Acute respiratory tract illnesses and acute upper respiratory tract infections (URTIs), traditionally referred to as common colds, are the most prevalent diseases experienced by the community. 3. 선정, 제외기준 1) 감기치료감기에대한중재의치료효과를보는논문 21 편중 2편 14,29 이소아를대상으로진행되었다. 선정기준에연구에포함되는감기증상및정도 를제시하였고, 감기의지속기간을고려하여모집당시시점부터증상이지속된기간의제한을두었다. 24시간이내가 3편 17,19,23, 24-48시간 2편 14,16, 36시간이내 4편 18,21,26,27, 48시간이내 7편 15,22,25,28,29,30,32, 그외 72시간 1편 31, 7일이 1편 20 이었다. 115

8 감기임상시험가이드라인제정을위한최신임상시험연구분석 감기증상을정의하는데있어출처없이증상기준을제시한논문이 10편 12,13,15,17-19,24,25,27,28 에해당하였고, Jackson 증상지표를이용한논문이 9편 16,20-22,26,29,30-32 이였다. 1편 23 은 prasad 가진행한연구를근거로하였으며 1편 14 은아연을중재로하는선행연구 15편을근거로하여불분명한출처를제시하였다. 제외기준은대부분감기와혼동될수있는질환이배제되었는데, 알레르기성비염, 부비동염, 편도염, 인두염, 후두염, 유양돌기염, 중이염등과호흡기질환 ( 천식, 만성폐쇄성폐질환 ) 등이이에해당되었다. 이외에도연구결과에영향을줄수있다고판단되는기타전신질환등이연구자의판단에의해제외기준에포함되어있었다. 감기증상에영향을줄수있는약물복용력이있거나 ( 항히스타민제, 항생제, 기타대증요법등 ), 여타임상시험진행에서도제외기준에포함되는임신여부, 기타임상시험참여여부, 낮은인지능력등이제외기준에포함되었다 (Appendix). 2) 감기예방감기에대한중재의예방효과를보는논문 8편중 3편이소아 34,38,39 를대상으로진행되었다. 아토피성위염환자를대상으로진행한연구한편 35 을제외하고모두건강한소아또는성인을대상으로진행되었다. 알레르기성향이있거나기타연구에영향을줄수있는전신질환, 낮은인지능력등이제외기준에포함되었다 (Appendix). 4. 1차, 2차평가변수및평가도구 1) 1차평가변수감기치료에대한연구 21편중, 1차평가변수는감기증상지속기간이 7편, 감기증상총점수또는점수변화량이 7편, Wisconsin Upper Respiratory Symptom Survey(WURSS-21) 3편, 비기도저항 (nasal airway resistance, NAR) 이 2편, 증상이악화된연구시험대상자수 1편, 감기증상의중증도를합하여그린곡선하면적 (area under the curve, AUC) 1편이었다. WURSS-21은감기증상의중증 도및삶의질을함께측정가능하게만든평가도구로신뢰도와타당도가검증된평가도구이다. 이중 2편은동일한임상시험에서발표된논문으로, 1 차변수에서중복으로체크되었다. 감기예방에대한연구 8편의 1차평가변수는한편을제외하고는모두감기의발병횟수였다. 한편은이상반응이 1차평가변수, 감기발병횟수가 2차변수였다 (Table 3). 2) 2차평가변수 (1) 감기치료연구감기증상과관련된변수로, 증상의중증도점수변화, 전신증상과국소증상을나눠서부분의합또는부분의증상중증도변화등이 2차평가변수에포함되었다. 시각적상사척도 (visual analogue scale, VAS) 역시 2차평가변수에포함되었다. 1차평가변수에서증상점수의합또는증상점수변화를선정한연구는 2차평가변수에증상의지속기간을포함하였다. 실험실적분석을보면, 아연중재연구 1편에서는혈청에서 zinc, soluble interleukin-1 receptor antagonist(sil-1ra), soluble tumor necrosis factor receptor(stnf-r), the plasma adhesion molecules, soluble vascular endothelial cell adhesion molecule(svcam)-1, soluble ICAM(sICAM)-1을살펴보았다. Echinacea 연구에서는 nasal wash에서 interlukin-8(il-8), 중성구수 (neutrophil count) 를 2차평가변수로분석하였다. 콧물에서바이러스검출여부등도포함되었다. 이외에는이상반응이 2 차평가변수에포함되었고, 감기로인한삶의질측면에서는 EuroQol-5D(EQ-5D), SF-8, SF-36 평가도구가총 2편에서사용되었다. 이외치료에대한만족도, 전반적몸상태, ( 콧물을닦기위한 ) 휴지사용횟수, 수면장애정도, 병용약물을허용한연구중에는병용약물투약횟수등이 2차평가변수에포함되었다 (Table 3). (2) 감기예방연구감기증상지속지간및중증도, 삶의질 (SF-12) 을살펴본연구 1 편, international physical activity questionnaire(ipaq), perceived stress scale-10 항 116

9 김관일 이호정 이범준 정희재 정승기 이준희 목을함께살펴본연구 1편, 면역학적지표를살펴본연구 1편 (CD45+(lymphocytes), CD45+, CD19+ (B-lymphocytes), CD45+, CD3+(T lymphocytes), CD45+, CD3+, CD4+(TH cells), CD45+, CD3+, CD8+(TS plus TC cells), CD 45+, CD 56+(natural killer cells)) 등이있었다 (Table 3). 3) 평가도구감기증상과관련해서는신뢰도와타당도가검증된 WURSS-21 을이용한연구가총 3편 21,25,26 이였다. 그외는연구진들이제시하였던증상도구를대부분감기일지 (cold diary) 를이용하여측정하였다. Table 3. Primary and Secondary Outcomes Treatment No Author (year) Primary outcome Secondary outcome 1 Eby GA duration of cold the change of severity score (2006) Hull D Kurugol Z Latte J Lizogob VG Mizoguchi H time to resolution of symptom time to resolution of cold symptom time to alleviation of symptoms and no rhinorrhoea time to alleviation of symptoms time to response of number to bothersome cold question none tnvol and tcsa subjective symptom score (100- mm visual analogue scale, VAS) mean nasal airway resistance (NAR) symptoms of nasal congestion, nasal runniness, and sneezing between the two visits. change of cold intensity score ability to work, activity level, general well-being sum of symptom intensity EQ-5D differences of the cold intensity score treatment outcome according to an from day 1-5 integrative medicine outcomes scale, and satisfaction with treatment according to the integrative medicine patient satisfaction scale the symptom relief composite scores 3 hours post-dosing the overall relief assessment upon arising on day 2 the day-2 symptom relief composite scores day-2 sleep satisfaction hour-3 relief assessments for the individual symptoms day-2 relief assessments for the individual symptoms 117

10 감기임상시험가이드라인제정을위한최신임상시험연구분석 Eccles R (2008) Prasad AS (2008) Hensler S (2009) Barrett B Eccles R Pach D Schütz K Byun JS (2011) Rakel D (2011) Yakoot M (2011) nasal airway resistance (NAR) average duration of cold symptoms illness duration Wisconsin Upper Respiratory Symptom Survey (WURSS-21) mean total symptom score for study days 2-4 VAS total and individual common cold symptoms plasma levels of - zinc - soluble interleukin-1 receptor antagonist (sil-1ra), soluble tumor necrosis factor receptor (stnf-r) - the plasma adhesion molecules, soluble vascular endothelial cell adhesion molecule (svcam)-1, soluble ICAM (sicam)-1. none short form (SF-8) scale SF-36 Cohen s Perceived Stress Scale (PSS-4) Ryff Personal Relationships (PR-9) scale the Life Orientation Test (LOT-6) IL-8, Neutrophil count (in nasal wash) total symptom score on separate study days 1/2/3/4/5 the mean total systemic symptom score (headache, muscle ache, chilliness) for study days 2-4 total systemic symptom score on separate study days 1/2/3/4/5 local symptom score (sore throat, blocked nose, runny nose, cough, sneezing) mean of study days 2-4 symptom severity scores use of medication for the common cold the area under the curve (AUC) which on days 1-7 summarised symptom severity over time general ill feeling adverse events disturbance of daily activities sleep disorders total score of the cold symptoms additional concurrent medication the number of tissues used WURSS-21-K WURSS-21 total symptom severity scores the duration of illness evaluation of perceived stress (PSS-4) general quality of life (physical and mental subscales of the (SF-8)) the feeling thermometer and optimism (LOT) none 118

11 김관일 이호정 이범준 정희재 정승기 이준희 Chang J (2012) Fazekas T (2012) Ludwig M (2013) Picon PD (2013) Okabayashi S (2014) symptom duration mean of total symptom scores duration of disease the sum of the scores of 10 common cold symptoms the aggravation of cold, nasal, throat or bronchial symptoms main symptom duration minor symptom duration the changes in main symptom score, minor symptom score cumulative symptom score 4 days after the treatment adverse events total symptom score on different study days total systemic and total local symptom scores presence of cold viruses in nasal fluid samples severity of common cold symptoms on separate study days number of days without symptoms during the observation period use of co-medication additional to the study treatment between days 8-21, the number of cleared or newly acquired viral infections during the observation period overall symptom duration time to return to usual activities use of rescue medication aggravation of cold symptoms within seven days after study entry and the severity of the main cold symptoms during the first five and seven days Prevention No Author (year) Primary outcome Secondary outcome de Vress M (2006) Kurugol Z (2006) Sasazuki S (2006) incidence of cold, duration, severity of cold symptoms the number of colds incidence of common cold flow cytometry - CD45+ (lymphocytes), - CD45+,CD19+ (B-lymphocytes) - CD45+, CD3+ (T lymphocytes), - CD45+, CD3+, CD4+ (TH cells) - CD45+, CD3+, CD8+ (TS plus TC cells), - CD 45+, CD 56+ (natural killer cells) virus infection fecal lactobacilli, bifidobacteria the duration and the severity of cold symptoms none 119

12 감기임상시험가이드라인제정을위한최신임상시험연구분석 Roll S Jawad M (2012) Rerksuppaphol S (2012) Rerksuppaphol S (2013) Vitetta L (2013) days with any common cold symptoms common cold-related days unable to the number of days with at least work moderate (i.e. moderate or severe) days with common cold-related medication common cold symptoms use health related quality of life (SF-12) adverse events occurrence of any symptom of cold occurrence of any symptom of cold cold events the number of cold episodes occurrence of vomiting diarrhea use of antibiotics school absence due to any cause school absence due to cold duration of all symptoms occurrence of vomiting diarrhea use of antibiotics school absence due to any cause school absence due to cold duration of all symptoms International Physical Activity Questionnaire (IPAQ), 3 day dietary recall questionnaire Perceived Stress Scale-10 item Ⅳ. 고찰감기는여러바이러스에의한경증의상기도감염증후군으로정의되며독감, 편도염, 급성기관지염, 급성비부비동염, 후두염등과구별되는증상이다 41. 전통적으로급성상기도감염과동일하게정의되기도했으나최근에는상기도감염은감기, 후두염, 인두염 / 편도염, 급성비염, 급성부비동염, 급성중이염을포함하는개념으로정의되었고 42, 감기는상기도감염에포함되는경증의자체한정적기간을가지는증후군으로정의되는추세이다. 미국의경우, 아이들은일년에약 5-7번정도의감기에걸리며성인은 2-3 번의감기에걸리는것으로보고되고있다. 감기로인해매해 2500만명이의사를찾으며, 2000만번정도의직장결근과 2200만번정도의학교결석의원인이되고있다 2. 한국의 2014년건강보험심사지표에따르면감기관련상병은외래진료일수의 11.8%(101,546천일 ), 외래요양급여비용의 6.03%(1 조3840 억원 ) 를차지한다고보고되었다 42. 이처럼감기는경증의증후군이지만, 사회생활과일상생활에지장을초래하며경제적손실도큰증후군으로, 감기치료에대한관심이높아지고있는실정이다. 특히감기를일으키는바이러스가 200종이넘어원인을규명하여치료하는방법자체가실효성을거두지못하고항생제에대한리뷰논문을통해서도치료에대한근거가없어지면서 5, 감기관련한많은임상시험이증상을회복시키는대증치료에초점을맞추고있다. 이를기반으로감기에대한한약제제의치료또는예방에대한효능에대한연구의필요성이제기되고있으며, 이를객관적으로규명할수있는 120

13 김관일 이호정 이범준 정희재 정승기 이준희 임상시험가이드라인이시급한실정이다. 감기에대한한약제제가이드라인을만들기위한기초자료조사로서우선최근 10년간시행된감기관련임상시험을분석하여, 감기의범위및선정제외기준, 1차 2차평가변수, 평가도구등에대한고찰을시행하였다. 우선, 감기에대한정의를살펴보니 바이러스에의한상기도감염 으로정의한논문이일반적이었다. 경증 이나 자체한정기간을가지는 등의용어는 1편외에는정의에포함되어있지않았으며감기의범위를다른편도염이나부비동염과한정짓는문구도거의사용되지않았다. 다만선정제외기준에서보면제외기준에감기와유사한질환을구분하고자한연구가 2-3편있어감기관련최신의정의를반영한논문도다소있었다. 향후진행되는임상시험에서는최신의정의를따라 경증의, 자체한정기간을가지는바이러스에의한상기도감염증후군 으로정의하는것이타당할것으로판단되며, 기타세균성으로일어나는편도염, 부비동염, 중이염, 후두염, 인두염등과구별짓는것이필요할것으로보인다. 연구개요를보면우선감기치료에대한효과를밝히고자한논문이 21편, 예방에대한논문이 8편으로이루어졌다 년임상연구를분석한논문과비교한결과 11, 기존에는 echinacea 에관한임상연구만있었던반면, 최근에는한약복합제제 ( 소청룡탕및연교패독산, Shi-cha 캡슐, Immuonomax (echinacea+ 마늘 + 인삼 +sativa oil+ 비타민 + 아연 ), Kakkonto( 갈근탕 )) 에대한연구가 2011 년부터 2014 년사이에발표되어감기치료에대한한약복합제제에대한연구가활발해지는것을확인할수있었다. 치료에대한효능연구에서중재군의투여기간은 7일이내혹은 7일에서 10일이내가 62% 에해당되어, 감기이환기간을고려하여일주일내외의투여기간을이용하는것을확인하였다. 연구결과는유의한효과가있었던논문이 59% 였으며, 한약제제에대한논문 4편에서보면 2편에서는유의한효 과를보고하였고, 1편은제한적효과를 1편은대조군과유의한차이를발견하지못하였다. 선정기준에서감기에대한중증도기준은 Jackson 이임상연구를위해발표한증상범주를가장빈용하고있었다 43,44. 많은연구들이이증상범주를기준으로그대로차용하거나한두문항을수정하여연구를진행하여왔다 년의임상연구를고찰한논문과비교할때 Jackson 증상범주를기존보다많이차용하고있음을알수있었는데, 이는객관적이고신뢰성있는기준을세우고자하는연구자들의고민이반영된것으로판단된다. Jackson 의증상도구는비록타당도연구가진행되지는않았으나, 많은연구자들이사용하고있는도구로증상은 4가지증상 ( 콧물, 코막힘, 재채기, 인후통 ) 또는 8가지증상 ( 콧물, 코막힘, 재채기, 기침, 인후통, 두통, 근육통, 오한 ) 으로구성된것을가장많이사용하였다. 최신임상연구를분석해볼때, 선정기준에서 Jackson 의증상도구로중증도를판단하거나일정점수이상을선정기준으로취하는것은적절하다고판단된다. 감기와관련된평가도구중신뢰도와타당도가입증된도구는 WURSS 였다. WURSS-21은감기증상을측정하는문항에삶의질을측정하는문항을추가한평가도구로, 이미한국어로번안하여신뢰도와타당도연구가진행되었으므로 46, 감기임상시험에서평가도구로 WURSS-21 를사용하는것을일차적으로권고할수있을것으로판단된다. 최근에는문항을간소화한 WURSS-11 도개발되어발표되었으므로 47, 이를번안하여국내에서적용해보는것도고려해야한다. WURSS-21에는 Jackson 의증상도구중 4가지증상은모두포함되며, 8가지증상도구중에서는두통, 오한, 근육통이제외되어있다. 보다간소화된 WURSS-11 평가도구에도 Jackson 증상도구 4가지증상은포함되며, 8가지증상도구중에서는동일하게두통, 오한, 근육통이제외되었다. 평가도구에서 WURSS-21을사용하는것은가능하지만, 한의학적변증형을포함한 121

14 감기임상시험가이드라인제정을위한최신임상시험연구분석 임상시험을진행할경우에, 변증진단에중요하게사용되는증후에대한포함여부에대해서는고민이필요할것으로판단된다. Ⅴ. 결론최근 10년간 PubMed, EMBASE, CENTRAL에발표된감기치료및예방에대한효능에대한임상시험논문을분석하여다음의결론을얻었다. 향후한국및중국을포함하여감기와관련된한약제제에대한임상시험을분석및고찰하여최근진행되고있는한약제제에대한임상시험을구체적으로살펴보고기존에발표된한의학적변증가이드라인을포함하여한의학적변증에대한분석도필요할것으로판단되며, 이는가이드라인제정을함에있어추후보고하고자한다. 감사의글 1. 감기에대한정의는최신지견이반영되지않고기존에사용되던정의가혼재되어있었다. 2. 감기에대한치료효과연구에서최근 3-4년간한약제제를중재로사용된연구가새로시행되었다. 기타단미한약재 2편및대체요법과관련한임상시험이주를이루었으며, 양약관련된임상시험의수는감소하는추세를보였다. 3. 선정기준에 Jackson 의증상도구가감기증상을채택하고중증도를결정하는도구로다수사용되었다. 4. 신뢰도와타당도를획득한 WURSS-21 평가도구가최근에개발되어연구에사용되었으나, 활용빈도수는높지않았다. 감기와관련된임상시험에서신뢰도와타당도가확보된평가도구는 WURSS-21 이였으며, 한국에서도번안되어신뢰도와타당도가입증되었으므로, 감기에대한한약제제임상시험을진행할때일차적으로고려할수있는평가도구로판단되었다. 감기라는임상증후군은실험실적지표등을평가변수로두기어려운관계로환자가기입하는주관적증상에의존해야하므로, 신뢰도와타당도가검증된평가도구의사용이더욱중요할것이다. 그외에본연구의자료를바탕으로감기의명확한정의, 그에따른선정제외기준, 중재기간, 연구설계등의국내감기임상시험가이드라인제정에기본이되는정보를제공할수있을것으로판단된다. 본연구는보건복지부한의약선도기술개발사업의지원에의하여이루어진것임 ( 과제고유번호 : HI13C0700). This study was supported by a grant of the Traditional Korean Medicine R&D Project, Ministry of Health & Welfare, Republic of Korea ( 과제고유번호 HI13C0700). 참고문헌 1. Heikkinen T, Järvinen A. The common cold. Lancet 2003;361(9351): Turner RB. Epidemiology, pathogenesis, and treatment of the common cold. Ann Allergy Asthma Immunol 1997;78(6): Benson V, Marrano MA. Current estimates from the National Health Interview Survey, Vital Health Stat ;199: Fashner J, Ericson K, Werner S. Treatment of the common cold in children and adults. Am Fam Physician 2012 Jul 15;86(2): Fahey T, Stocks N, Thomas T. Quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults. BMJ 1998;316: Pratter MR. Cough and the common cold: 122

15 김관일 이호정 이범준 정희재 정승기 이준희 ACCP evidence-based clinical practice guidelines. Chest 2006 Jan;129(1 Suppl):72S-4S. 7. Eisenberg DM, Davis RB, Ettner SL, Appel S, Wilkey S, Van Rompay M, et al. Trends in alternative medicine use in the United States, : results of a follow-up national survey. JAMA 1998;280(18): Roxas M, Jurenka J. Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations. Altern Med Rev 2007;12: Gagnier JJ, Boon H, Rochon P, Moher D, Barnes J, Bombardier C; CONSORT Group. Recommendations for reporting randomized controlled trials of herbal interventions: Explanation and elaboration. J Clin Epidemiol 2006;59(11): Jiao Y, Liu J, Jiang L, Liu Q, Li X, Zhang S, et al. Guidelines on common cold for traditional Chinese medicine based on pattern differentiation. J Tradit Chin Med 2013;33(4): 양수영, 변준섭, 황지호, 안정조, 홍권의, 강위창, 등. 감기임상연구의최신동향및평가도구에관한연구. 대한한의학회지 2008;29(2): Eby GA, Halcomb WW. Ineffectiveness of zinc gluconate nasal spray and zinc orotate lozenges in common-cold treatment: a double-blind, placebo-controlled clinical trial. Altern Ther Health Med 2006;12(1): Hull D, Rennie P, Noronha A, Poore C, Harrington N, Fearnley V, et al. Effects of creating a non-specific, virus-hostile environment in the nasopharynx on symptoms and duration of common cold. Acta Otorhinolaryngol Ital 2007; 27(2): Kurugöl Z, Bayram N, Atik T. Effect of zinc sulfate on common cold in children: randomized, double blind study. Pediatr Int 2007;49(6) : Latte J, Taverner D. Clinical trial of 3 days of treatment with oral pseudoephedrine for the common cold in the southern hemisphere. Am J Rhinol 2007;21(4): Lizogub VG, Riley DS, Heger M. Efficacy of a pelargonium sidoides preparation in patients with the common cold: a randomized, double blind, placebo-controlled clinical trial. Explore (NY) 2007;3(6): Mizoguchi H, Wilson A, Jerdack GR, Hull JD, Goodale M, Grender JM, et al. Efficacy of a single evening dose of syrup containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate and ephedrine sulfate in subjects with multiple common cold symptoms. Int J Clin Pharmacol Ther 2007;45(4): Eccles R, Eriksson M, Garreffa S, Chen SC. The nasal decongestant effect of xylometazoline in the common cold. Am J Rhinol 2008;22(5): Prasad AS, Beck FW, Bao B, Snell D, Fitzgerald JT. Duration and severity of symptoms and levels of plasma interleukin-1 receptor antagonist, soluble tumor necrosis factor receptor, and adhesion molecules in patients with common cold treated with zinc acetate. J Infect Dis 2008;197(6): Hensler S, Guendling PW, Schmidt M, Jork K. Autologous blood therapy for common cold--a randomized, double-blind, placebo-controlled trial. Complement Ther Med 2009;17(5-6): Barrett B, Brown R, Rakel D, Mundt M, Bone K, Barlow S, et al. Echinacea for treating the common cold: a randomized trial. Ann Intern Med 2010 ;153(12): Eccles R, Meier C, Jawad M, Weinmüllner R, 123

16 감기임상시험가이드라인제정을위한최신임상시험연구분석 Grassauer A, Prieschl-Grassauer E. Efficacy and safety of an antiviral Iota-Carrageenan nasal spray: a randomized, double-blind, placebocontrolled exploratory study in volunteers with early symptoms of the common cold. Respir Res 2010;11: Pach D, Knöchel B, Lüdtke R, Wruck K, Willich SN, Witt CM. Visiting a sauna: does inhaling hot dry air reduce common cold symptoms? A randomised controlled trial. Med J Aust 2010;193(11-12): Schütz K, Sass M, de With A, Graubaum HJ, Grünwald J. Immune-modulating efficacy of a polyphenol-rich beverage on symptoms associated with the common cold: a double-blind, randomised, placebo-controlled, multi-centric clinical study. Br J Nutr 2010;104(8): Byun JS, Yang SY, Jeong IC, Hong KE, Kang W, Yeo Y, et al. Effects of So-cheong-ryong-tang and Yeon-gyo-pae-dok-san on the common cold: randomized, double blind, placebo controlled trial. J Ethnopharmacol 2011;133(2): Rakel D, Barrett B, Zhang Z, Hoeft T, Chewning B, Marchand L, et al. Perception of empathy in the therapeutic encounter: effects on the common cold. Patient Educ Couns 2011;85(3) : Yakoot M, Salem A. Efficacy and safety of a multiherbal formula with vitamin C and zinc (Immumax) in the management of the common cold. Int J Gen Med 2011;4: Treatment of common cold patients with the shi-cha capsule: a multicenter, double-blind, randomized, placebocontrolled, dose-escalation trial. 28. Chang J, Dong SJ, She B, Zhang RM, Meng MB, Xu YL, et al. Treatment of common cold patients with the shi-cha capsule: a multicenter, double-blind, randomized, placebo-controlled, dose-escalation trial. Evid Based Complement Alternat Med 2012;2012: Fazekas T, Eickhoff P, Pruckner N, Vollnhofer G, Fischmeister G, Diakos C, et al. Lessons learned from a double-blind randomised placebo-controlled study with a iota-carrageenan nasal spray as medical device in children with acute symptoms of common cold. BMC Complement Altern Med 2012;12: Ludwig M, Enzenhofer E, Schneider S, Rauch M, Bodenteich A, Neumann K, P et al. Efficacy of a carrageenan nasal spray in patients with common cold: a randomized controlled trial. Respir Res 2013;14: Picon PD, Costa MB, da Veiga Picon R, Fendt LC, Suksteris ML, Saccilotto IC, et al. Symptomatic treatment of the common cold with a fixed-dose combination of paracetamol, chlorphenamine and phenylephrine: a randomized, placebo-controlled trial. BMC Infect Dis 2013; 13: Okabayashi S, Goto M, Kawamura T, Watanabe H, Kimura A, Uruma R, et al. Non-superiority of Kakkonto, a Japanese herbal medicine, to a representative multiple cold medicine with respect to anti-aggravation effects on the common cold: a randomized controlled trial. Intern Med 2014; 53(9): de Vrese M, Winkler P, Rautenberg P, Harder T, Noah C, Laue C, et al. Probiotic bacteria reduced duration and severity but not the incidence of common cold episodes in a double blind, randomized, controlled trial. Vaccine 2006; 24(44-46): Kurugöl Z, Akilli M, Bayram N, Koturoglu G. The prophylactic and therapeutic effectiveness 124

17 김관일 이호정 이범준 정희재 정승기 이준희 of zinc sulphate on common cold in children. Acta Paediatr 2006;95(10): Sasazuki S, Sasaki S, Tsubono Y, Okubo S, Hayashi M, Tsugane S. Effect of vitamin C on common cold: randomized controlled trial. Eur J Clin Nutr 2006;60(1): Roll S, Nocon M, Willich SN. Attenuation of common cold symptoms by encapsulated juice powder concentrate. Eur J Integr Med 2010; 2(4): Jawad M, Schoop R, Suter A, Klein P, Eccles R. Safety and Efficacy Profile of Echinacea purpurea to Prevent Common Cold Episodes: A Randomized, Double-Blind, Placebo-Controlled Trial. Evid Based Complement Alternat Med 2012;2012: Rerksuppaphol S, Rerksuppaphol L. Randomized controlled trial of probiotics to reduce common cold in schoolchildren. Pediatr Int 2012 Oct; 54(5): Rerksuppaphol S, Rerksuppaphol L. A randomized controlled trial of chelated zinc for prevention of the common cold in Thai school children. Paediatr Int Child Health 2013 Aug;33(3) : Vitetta L, Coulson S, Beck SL, Gramotnev H, Du S, Lewis S. The clinical efficacy of a bovine lactoferrin/whey protein Ig-rich fraction (Lf/IgF) for the common cold: a double blind randomized study. Complement Ther Med 2013 Jun;21(3) : National Institute for Health and Clinical Excellence (NICE 69). Prescribing of antibiotics for selflimiting respiratory tract infections in adults and children in primary care (Clinical guideline 69) 42. 건강보험심사평가원, 2014년건강보험통계지표. 43. Jackson GG, Dowling HF, Spiesman I, Boand AV. Transmission of the common cold to volunteers under controlled conditions. I. The common cold as a clinical entity. AMA Arch Intern Med 1958 Feb;101(2): Jackson GG, Dowling HF, Muldoon RL. Acute respiratory diseases of viral etiology. VII. Present concepts of the common cold. Am J Public Health Nations Health 1962;52: Barrett B, Brown RL, Mundt MP, Thomas GR, Barlow SK, Highstrom AD, et al. Validation of a short form Wisconsin Upper Respiratory Symptom Survey (WURSS-21). Health Qual Life Outcomes 2009;7: Yang SY, Kang W, Yeo Y, Park YC. Reliability and validity of Wisconsin Upper Respiratory Symptom Survey, Korean version. J Epidemiol 2011;21(5): Obasi CN, Brown RL, Barrett BP. Item reduction of the Wisconsin Upper Respiratory Symptom Survey (WURSS-21) leads to the WURSS-11. Qual Life Res 2014;23(4):

18 감기임상시험가이드라인제정을위한최신임상시험연구분석 Appendix Eby GA (2006) Hull D Kurugol Z Treatment Inclusion Exclusion patients with 2 or more signs and symptoms of common colds (with at least 1 nasal not presented symptom) healthy males and females between the ages of 18 and 65 years Children who developed symptoms of common cold within the first 24-48h Had two or more of the following 10 symptoms. 10 symptoms: cough, nasal drainage, nasal congestion, headache, hoarseness, muscle ache, scratchy throat, sneezing, sore throat, and fever (axillary temperature >37 ) were experiencing any of the symptoms of a Common Cold at the time of recruitment females who were pregnant, trying to become pregnant, or nursing history of hypersensitivity to zinc or any component of the nasal test formulations currently suffering from a chronic medical condition requiring medication taking any medication, with the exception of birth control pills and hormone replacement products, on a regular basis (3 or more times per week) frequent infections in the nose, lung or ear, problems related to upper or lower respiratory tract (e.g. nose bleeds, breathing difficulties or throat sensitivity) history of frequent headaches /migrain having been exposed to any investigational drug within 1 month prior to the start of the study, or if the subject planed to participate in any other investigational drug study while in this trial was currently suffering, or was prone to experiencing, the symptoms of respiratory allergy (rhinitis) was currently using decongestants, oral antihistamines or oral zinc products, or had experienced problems using nasal sprays patients with common cold symptoms for >48h immunodeficiency disorder, chronic disease, recent acute respiratory disease (diagnosed by a physician in the previous 2 weeks), zinc allergy, allergic disease or non-allergic rhinitis patients with a positive culture for group A Streptococcus and a positive cell culture for influenza A or B viruses children who received antibiotics, antihistamines, decongestants, steroids or other zinc preparations during the course of the study 126

19 김관일 이호정 이범준 정희재 정승기 이준희 4 5 Latte J Lizogob VG male and female subjects aged women were pregnant or lactating or not years old in good general health using an appropriate form of contraception currently suffering an episode of the history of perennial allergic rhinitis or common cold of no more than 48 hours any unstable medical condition duration before visit 1 presence of any other acute ear, nose, and throat and respiratory tract disease than the common cold (eg, tonsillitis, sinusitis, allergic rhinitis, otitis, bronchitis) positive rapid test for group A betahemolytic streptococcus recurrent tonsillitis, sinusitis or otitis of greater than or equal to three episodes or recurrent bronchitis of greater than or equal to six episodes during the 12 months prior to enrollment in the trial any chronic ear, nose, and throat and respiratory tract disease (eg, allergic rhinitis, bronchitis, bronchial asthma, obstructive male and female patients aged 18 to 55 pulmonary disease, cystic fibrosis years treatment with antibiotics, glucocorticostroids provision of written informed consent or antihistamines during the four weeks presence of either two major cold symptoms prior to enrollment in the trial, (nasal discharge, sore throat) and at least treatment with cold medications that might one minor cold symptom (nasal congestion, impair the trial results (eg, decongestants, sneezing, scratchy throat, hoarseness, cough, local anesthetics), cough or pain relief headache, muscle aches, and fever), or medications and/or any other treatment presence of one major and at least three for the common cold during the seven minor cold symptoms days prior to enrollment in the trial duration of cold symptoms for 24 to 48 Known or suspected hypersensitivity to hours the investigational product previous or existing severe cardiovascular disease or unstable diabetes mellitus, severe renal or hepatic dysfunction (serum creatinine, serum AST, ALT, or alkaline phosphatase more than three times the upper limit of normal) at any time during the 12 months prior to enrollment in the trial evidence of any malignant disease during the five years prior to enrollment in the trial pregnancy or breast-feeding participation in another clinical trial in the same time period or within three months prior to inclusion in the trial 127

20 감기임상시험가이드라인제정을위한최신임상시험연구분석 Mizoguchi H Eccles R (2008) Prasad AS (2008) allergic to any of the study medications were experiencing acute symptoms of respiratory allergies history of chronic aches/pains, chronic fatigue or mood disorders, or chronic common cold symptoms for at least 1 respiratory illness, or had a significant day and not longer than 5 days prior coexisting illness or medical condition symptoms within the last 24 hours of that would compromise their ability to enrollment must have included moderate swallow, absorb, metabolize or excrete the or severe nasal congestion, moderate or study medication severe runny nose, at least mild cough, at any medications/supplements within the least mild pain from one or more of the previous 24 hours that were indicated for following pain sore throat, sore chest, cold symptoms, pain relief or that could headache or body aches/pains and sleep produce drowsiness or promote alertness disturbance Taken any antihistamines within the previous 72 hours taken any sedatives within the previous weeks taken any antidepressants within the previous 3 weeks inability to abstain from smoking for 1 hour before and for the duration of each 18 years of age, with recent onset of visit nasal congestion associated with common NAR of 0.2 Pa/cm3 per second at cold screening visit 1 minimum nasal congestion score of 2 history of perennial allergic rhinitis, unless (moderate) according to a 4-point scale recruited out of season (0 not present; 1 mild; 2 moderate; and clinically significant abnormalities (e.g., 3 severe polyps and deviated septum) had cold symptoms of 36 hours duration history of transsphenoidal hypophysectomy before study entry or rhinitis medicamentosa presented with a minimum of two common bacterial sinusitis infection during the past cold symptoms (runny nose, blocked nose, 2 weeks before study entry; use of drugs sore throat, and/or cough) on entry to (antibiotics, adrenergics, glucocorticosteroids, the study antidepressants, or monoamine oxidase were male patients or a nonpregnant, inhibitors); use of any medication that may nonlactating female patient affect sleep as judged by the investigator were willing and able to undergo measurement known hypersensitivity to xylometazoline of total nasal airway or any of the excipients of Otrivin nasal resistance (NAR) using active posterior spray rhinomanometry and score symptoms alcohol intake uncontrolled arterial hypertension cold symptoms for 24 h or less pregnant >18 years of age had any known immune deficiency disorder at least two out of 10 common cold or chronic illness symptoms (cough, headache, hoarseness, symptoms of the common cold for >24h muscle ache, nasal drainage, nasal congestion, had previously used zinc lozenges to treat scratchy throat, sore throat, sneezing, and the common cold fever) 128

21 김관일 이호정 이범준 정희재 정승기 이준희 Hensler S (2009) Barrett B Eccles R illness duration before treatment longer than 7 days severe forms of respiratory infections (exacerbation of chronic obstructive patients (18-75 years of age) pulmonary disease by infection, exacerbation symptoms of common cold (cough, rhinitis, of asthma by infection, streptococcal tonsillitis, sore throat, fever etc.) which lasted not peritonsillar infection, pneumonia, mastoiditis, longer than 7 days and resulted in at etc.) least four points on a modified Jackson- other diseases with similar symptoms Score (e.g. allergic rhinitis) immunosuppressing diseases (e.g. AIDS) or medication (e.g. Cyclosporin), dementia or coagulopathy use of antibiotics, antivirals, nasal steroids, Yes" to either. Do you think that you decongestants, antihistamines, combination have a cold? or Do you think you are cold formulas, echinacea, zinc or vitamin coming down with a cold? C using Jackson s criteria, participants had to avoid confounding from allergy or to report at least one of four cold asthma symptoms, we excluded anyone symptoms: A) nasal discharge; B) nasal with a history of allergic rhinitis who obstruction; C) sneezing; and/or D) sore reported sneezing or itching of the nose throat. or eyes and anyone with a history of symptoms had to start within 36 hours asthma who reported current cough, before enrollment wheezing or shortness of breath participants needed a Jackson score of 2 people with autoimmune and immune or higher, summing symptom scores, with deficiency disease were excluded by 0=absent, 1=mild, 2=moderate, 3=severe self-report, as were pregnant women unwilling to sign the consent form known hypersensitivity or allergy to any component of the study medication clinically significant cardiovascular, endocrine, neurological, respiratory, or gastrointestinal disease history any other current disease that was considered by Jackson score, subjects had symptom by the investigator as an exclusion criteria, scores of 1 or greater for sore throat, e.g. current allergic rhinitis, chronic obstructive runny or blocked nose and a total pulmonary disease (COPD) symptom score of 9 or less for the sum history of alcohol/substance abuse Prescription of severity scores comprising headache, medication/concomitant therapy other than muscle ache, chilliness, sore throat, runny for contraception, e.g. systemic steroids, nose, blocked nose, cough, and sneezing intranasal medicines, antibiotics incidence of common cold or flu like symptoms for more than 48h current smoking relationship to any study personnel, administration of any investigational drug, participation in any other clinical trial within 4 weeks of entry into our study 129

22 감기임상시험가이드라인제정을위한최신임상시험연구분석 Pach D Schütz K Byun JS (2011) Rakel D (2011) between 18 and 60 years of age had any of these cold symptoms for more at least two out of 10 common cold than 24 hours symptoms cough, headache, hoarseness, circulatory problems muscle ache, nasal drainage (nasal drip), severe chronic illness nasal congestion, scratchy throat, sore systolic blood pressure below 100 mmhg throat, sneezing and fever (>38.5 ) for or above 160 mmhg 24 hours or less pregnancy active allergic rhinitis or asthma fever (body temperature 39.8 ) clinically relevant laboratory value deviations indicating severe organ or system disease bacterial tonsillitis pyorrhoea on the back of the throat cancer or AIDS (HIV positive) pregnancy or nursing aged between 20 and 65 years scoring in alcohol total at least 5 points on the severity of medication or drug dependence, participation five cold symptoms (maximum 15 points) in a clinical study within the previous 30 having present at least one cold-related days local finding intake of immune suppressants, immune stimulants, analgesics/anti-rheumatics, anti-inflammatories, antitussives, expectorants influenza remedies, mouth and throat therapeutics inability to comply due to language difficulties diagnosed with the common cold by research physicians. age under 18 years or over 60 years due to the onset of cold symptoms in pregnant or lactating less than 48 h, such as (i) runny nose, with allergic rhinitis, asthma, COPD, sore throat, and one of the 8 symptoms sinusitis (recurrent over 2 times per year) (plugged nose, sneezing, scratchy throat, anatomical nasal obstruction or deformity cough, hoarseness, headache, body aches, otitis, exudative pharyngitis, other chronic and fever) or (ii) either runny nose or illness sore throat and at least three of the 8 symptoms yes to one of two questions pregnancy Do you think you have a cold? or Do use of antibiotics, decongestants, antihistamines, you think you are coming down with a echinacea, zinc, vitamin C or a combination cold? The person then had to answer cold formula yes to at least one of the following four history of allergies or asthma with current symptoms (nasal discharge, nasal obstruction, symptoms of allergic rhinitis, cough, sneezing sore throat) shortness of breath, sneezing, nose or eye symptoms no more than 36 hours prior itching to enrollment 130

23 김관일 이호정 이범준 정희재 정승기 이준희 Yakoot M (2011) Chang J (2012) Fazecas T (2012) Ludwig M (2013) cold symptoms for 36 hours or less pregnancy two of the following 10 symptoms: cough, immune deficiency, cancer, severe liver headache, hoarseness, muscle aches, nasal /renal dysfunction, or critical illness discharge, nasal congestion, scratchy throat, symptoms of the common cold for more sore throat, sneezing, or an oral temperature than 36 hours 37.7 patient has suffered from acute viral pharyngitis or laryngitis, acute herpetic pharyngitis or laryngitis, acute conjunctivitis, as well as acute tonsillitis patient has taken any medication for 18 to 65 years of age relief of symptoms prior to study initiation diagnosis of common cold by a respiratory patient who has fever (>38.5 ) expert according to relevant criteria and patient who is on analgesic or antithe syndrome criteria of wind-cold type inflammatory regimen requiring treatment with in TCM analgesics, nonsteroidal anti-inflammatory patient within 48 hours of onset of drugs, or steroids common cold-like illness patient is pregnant, nursing, or a woman patient must be able to understand and of childbearing potential not practicing give written informed consent and report adequate contraception. Women, who are adverse events and concomitant medication uncertain if they are pregnant, may participate for the duration of the study in the study, if they undergo a pregnancy test, which shows a negative result patient has comorbid condition, uncontrolled metabolic condition or psychiatric condition that might make tolerance or evaluation of the symptoms difficult previously healthy, immunocompetent children and adolescents between 1 and 18 years of age with symptoms of acute rhinitis prevailing for less than 48 hours, and a total symptom score (TSS) 9 suspected bacterial infections, recent use of antimicrobial drugs, and intranasal treatment at first presentation hypersensitivity or allergy to any component adults (18 years and older) of the test product early symptoms of the common cold (onset concomitant disease or infection that could less than 48 hours before inclusion) interfere with participation in the study mild to moderate intensity (Total Symptoms other reasons for nasal obstruction and other Score [TSS], of 2 to 9) past or present conditions and treatments that could influence symptom scores 131

24 감기임상시험가이드라인제정을위한최신임상시험연구분석 20 Picon PD (2013) 21 Okabayashi S (2014) 1 2 de Vress M (2006) Kurugol Z (2006) pregnancy or breast feeding known hypersensitivity to any component of the study formulation use of alcohol or illicit drugs use of monoamine oxidase (MAO) inhibitors or barbiturates perennial or seasonal allergic rhinitis aged 18 to 60 years confirmed at screening duration of symptoms no longer than 72 any current acute disease or uncontrolled hours exacerbation of chronic disease the common cold was defined by the clinical evidence of immunosuppression presence of at least two of the following vaccination against influenza up to 1 10 symptoms: sneezing, rhinorrhoea, nasal week before inclusion congestion, headache, myalgia, throat need for antiviral therapy to treat influenza discomfort, sore throat, dysphonia, cough A or B infection and fever. need for antibacterial therapy to treat acute respiratory infection use of medication to treat conditions acquired before inclusion for a time shorter than two time intervals of administration of these drugs participation in another clinical trial less than 1 year before 18 to 65 years of age with throat discomfort and some feeling of chills without sweating history of colds during the preceding three years who visited a participating facility within 48 hours after the beginning of cold symptoms patients who were moderately or severely afflicted had a fever of 37.5 or more had already taken medicine for the cold had a serious underlying disease Prevention Inclusion Exclusion not vaccinated against influenza within the last 12 month healthy adults without known congenital or acquired immune defects or allergies history of sensitivity to or an idiosyncratic children were required to be in overall experience with zinc good health and to be 2 to 10 years of age parents were unwilling or unable to comply with clinical study procedures 132