Wang et al. Trials (2017) 18:2 DOI 10.1186/s13063-016-1747-9 STUDY PROTOCOL Open Access Efficacy and safety of Lian-Ju-Gan-Mao capsules for treating the common cold with wind-heat syndrome: study protocol for a randomized controlled trial Shengjun Wang1, Hongli Jiang1*, Qin Yu2, Bin She1 and Bing Mao1* Abstract Background: The common cold is a common and frequent respiratory disease mainly caused by viral infection of the upper respiratory tract. Chinese herbal medicine has been increasingly prescribed to treat the common cold; however, there is a lack of evidence to support the wide utility of this regimen. This protocol describes an ongoing phase II randomized controlled clinical trial, based on the theory of traditional Chinese medicine (TCM), with the objective of evaluating the efficacy and safety of Lian-Ju-Gan-Mao capsules (LJGMC), a Chinese patent medicine, compared with placebo in patients suffering from the common cold with wind-heat syndrome (CCWHS). Methods/design: This is a multicenter, randomized, double-blind, placebo-controlled phase II clinical trial. A total of 240 patients will be recruited and randomly assigned to a high-dose group, medium-dose group, low-dose group, and placebo-matched group in a 1:1:1:1 ratio. The treatment course is 3 consecutive days, with a 5-day follow-up. The primary outcome is time to all symptoms’ clearance. Secondary outcomes include time to the disappearance of primary symptoms and each secondary symptom, time to fever relief, time to fever clearance, and change in TCM symptom and sign scores. Discussion: This trial is a well-designed study according to principles and regulations issued by the China Food and Drug Administration (CFDA). The results will provide high-quality evidence on the efficacy and safety of LJGMC in treating CCWHS and help to optimize the dose for the next phase III clinical trial. Moreover, the protocol presents a detailed and practical methodology for future clinical trials of drugs developed based on TCM. Trial registration: Chinese Clinical Trial Registry, ChiCTR-IPR-15006504. Registered on 4 June 2015. Keywords: Lian-Ju-Gan-Mao capsules, Common cold, Wind-heat syndrome, Randomized controlled trial, Chinese herbal medicine Background mild and self-limiting, with a mean duration of 7–10 days The common cold, a conventional term for a mild upper [3, 4], its economic burden on society is significant in respiratory tract infection (URTI), is a common and fre- terms of visits to health care providers, treatments, and quent respiratory disease mainly caused by a virus [1, 2]. absences from work and school [5, 6]. Besides, in some Adults may have about two to four episodes annually, cases, viral pathogens may spread to adjacent organs, whereas children may experience up to six to eight colds resulting in different clinical manifestations, and, occa- per year [2, 3]. Although the common cold is usually sionally, colds predispose to bacterial complications [7]. Symptoms of a cold often include fever, headache, fatigue, nasal stuffiness and discharge, sneezing, sore * Correspondence: [email protected]; [email protected] throat, and cough [4]. Although great progression has 1Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, been achieved in Western medicine, there are still no China clinically proven “gold standard” medications directly Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wang et al. Trials (2017) 18:2 Page 2 of 9 targeting the causative pathogen for treating a cold. Current This phase II clinical trial is well designed to evaluate treatments are limited to symptomatic supportive options that the efficacy and safety of LJGMC compared with placebo maximize the comfort of patients by reducing symptom severity in patients with CCWHS. Additionally, it is expected to and limiting the occurrence of complications; these treatments find a dose-efficacy relationship and to help determine include antihistamines, decongestants, expectorants, antitussives, the optimum dose for the next phase III clinical trial. antipyretics, and analgesics. However, a series of adverse reac- Moreover, the protocol presents a detailed and practical tions to these drugs, such as drowsiness, dizziness, dry mouth, methodology for future clinical trials of patent drugs de- digestive system dysfunction, and epistaxis, occasionally occur veloped based on TCM. [8–10]. Accordingly, Chinese herbal medicine as well as zinc and/or vitamin C, garlic, echinacea and vitamin D3,ascomple- Methods/design mentary and alternative therapies, have been developed and Study design used in patients with the common cold [11–15]. This study is a multicenter, parallel group, double-blind, Traditional Chinese medicine (TCM) is a unique, well- prospective, randomized, placebo-controlled phase II clin- established system of medicine with a history of several ical trial. A total of 240 patients will be recruited and ran- thousand years, which has been proven effective in the domly allocated into treatment groups or placebo group. treatment of many diseases, especially the common cold. All patients will receive the treatment for 3 consecutive As the most important component of TCM, Chinese days, with a 5-day follow-up. Efficacy and safety data will herbal medicine mainly derives from plants and usually be collected throughout the whole study. The flow chart is incorporates one or more herbs to treat diseases. The shown in Fig. 1. common cold can be divided into wind-cold, wind-heat, or summer-heat and dampness syndromes according to Ethics its TCM symptoms and signs, such as fever, aversion to This trial has been authorized by the China Food and Drug cold, tongue proper, tongue coating, and condition of Administration (CFDA) (Approval Number 2012 L01822) the pulse [16], which is called syndrome differentiation and registered in the Chinese Clinical Trial Registry (bian zheng lun zhi). Common cold with wind-heat syn- (ChiCTR-IPR-15006504). In addition, the study will be con- drome (CCWHS) is the most common type and is pri- ducted in compliance with the Declaration of Helsinki, marily characterized by fever, mild aversion to cold, sore Good Clinical Practice (GCP) guidelines, and the laws and throat, red tongue, thin yellow tongue coating, and a regulations of clinical trials issued by the CFDA. The proto- floating and fast pulse. col, informed consent form, and recruitment poster were Lian-Ju-Gan-Mao capsules (LJGMC) are a novel Chinese reviewed and approved by the West China Hospital of patent medicine, manufactured by Tasly Pharmaceutical Sichuan University Clinical Trials and Biomedical Ethics Co., Ltd. (Tianjin, China), composed of Yangerju (Inula Committee (number TCM-2015-03) and the ethics com- cappa), Chuanxinlian (herba andrographis),andShengshi- mittees of the other six hospitals. The investigators in all gao (Gypsum) (Table 1). The drug prescription has been seven trial centers are qualified and well trained. All eligible used as a decoction in clinical practice for years in South- participants will be fully informed about the protocol and west Guizhou Autonomous Prefecture Hospital of TCM, will sign an informed consent form prior to participation. and it has demonstrated notable efficacy in lowering body The privacy and data of all participants will be protected, temperature, improving patients’ symptoms, and shortening and their safety will be greatly guaranteed. the duration of the cold, with few side effects. Preclinical pharmacological and toxicological studies on animals Participants and recruitment showed that LJGMC was effective in clearing heat, relieving We will recruit eligible participants by advertising on pain, reducing inflammation, and alleviating cough, as well hospital notice boards, sending leaflets, or being recom- as producing antiallergic, antibacterial, and antiviral effects mended by doctors in outpatient clinics. A total of 240 with no evidence of toxic effects [17–20]. patients will be recruited at the following seven hospi- tals: (1) West China Hospital of Sichuan University, (2) Table 1 Pharmacological effects of each ingredient in a Lian-Ju- Shuguang Hospital Affiliated to Shanghai University of Gan-Mao capsule TCM, (3) First Affiliated Hospital of Guiyang College of Ingredient Latin name Pharmacological effects based on TCM TCM, 4) First Affiliated Hospital of Tianjin University of Yangerju Inula cappa Dispels wind heat, removes toxicity, and TCM, (5) Second Affiliated Hospital of Tianjin Univer- soothes throat sity of TCM, (6) Ruikang Hospital Affiliated to Guangxi Chuanxinlian Herba Clears heat and toxicity University of TCM, and (7) First Affiliated Hospital of andrographis Guangzhou University of TCM. Forty patients will be re- Shengshigao Gypsum Clears heat and purges lungs cruited at each of the first two centers and 32 at each of TCM Traditional Chinese medicine the latter ones. Wang et al. Trials (2017) 18:2 Page 3 of 9 Fig. 1 Study flow chart. AE adverse event, SAE serious adverse event Inclusion criteria 4. Patients who had used other drugs to treat common For inclusion, participants should fulfill all the following cold after the onset of the disease criteria: 5. Temperature ≥39.0 °C 6. Women who are pregnant or preparing to become 1. Diagnosis of common cold according to Western pregnant or breast feeding women medicine 7. Allergic condition or allergy to the drug 2. Diagnosis of common cold with wind-heat syndrome composition(s) according to TCM 8. Patients with mental or legal disabilities 3.