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
Wang et al. Trials
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 Wang 0
Hongli Jiang 0
Qin Yu 1
Bin She 0
Bing Mao 0
0 Department of Integrated Traditional Chinese and Western Medicine, West China Hospital of Sichuan University , Chengdu 610041, Sichuan Province , China
1 National Clinical Trials Agency/GCP Center, West China Hospital of Sichuan University , Chengdu 610041, Sichuan Province , China
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.
Lian-Ju-Gan-Mao capsules; Common cold; Wind-heat syndrome; Randomized controlled trial; Chinese herbal medicine
The common cold, a conventional term for a mild upper
respiratory tract infection (URTI), is a common and
frequent respiratory disease mainly caused by a virus [1, 2].
Adults may have about two to four episodes annually,
whereas children may experience up to six to eight colds
per year [2, 3]. Although the common cold is usually
mild and self-limiting, with a mean duration of 7–10 days
[3, 4], its economic burden on society is significant in
terms of visits to health care providers, treatments, and
absences from work and school [5, 6]. Besides, in some
cases, viral pathogens may spread to adjacent organs,
resulting in different clinical manifestations, and,
occasionally, colds predispose to bacterial complications .
Symptoms of a cold often include fever, headache,
fatigue, nasal stuffiness and discharge, sneezing, sore
throat, and cough . Although great progression has
been achieved in Western medicine, there are still no
clinically proven “gold standard” medications directly
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targeting the causative pathogen for treating a cold. Current
treatments are limited to symptomatic supportive options that
maximize the comfort of patients by reducing symptom severity
and limiting the occurrence of complications; these treatments
include antihistamines, decongestants, expectorants, antitussives,
antipyretics, and analgesics. However, a series of adverse
reactions to these drugs, such as drowsiness, dizziness, dry mouth,
digestive system dysfunction, and epistaxis, occasionally occur
[8–10]. Accordingly, Chinese herbal medicine as well as zinc
and/or vitamin C, garlic, echinacea and vitamin D3, as
complementary and alternative therapies, have been developed and
used in patients with the common cold [11–15].
Traditional Chinese medicine (TCM) is a unique,
wellestablished system of medicine with a history of several
thousand years, which has been proven effective in the
treatment of many diseases, especially the common cold.
As the most important component of TCM, Chinese
herbal medicine mainly derives from plants and usually
incorporates one or more herbs to treat diseases. The
common cold can be divided into wind-cold, wind-heat,
or summer-heat and dampness syndromes according to
its TCM symptoms and signs, such as fever, aversion to
cold, tongue proper, tongue coating, and condition of
the pulse , which is called syndrome differentiation
(bian zheng lun zhi). Common cold with wind-heat
syndrome (CCWHS) is the most common type and is
primarily characterized by fever, mild aversion to cold, sore
throat, red tongue, thin yellow tongue coating, and a
floating and fast pulse.
Lian-Ju-Gan-Mao capsules (LJGMC) are a novel Chinese
patent medicine, manufactured by Tasly Pharmaceutical
Co., Ltd. (Tianjin, China), composed of Yangerju (Inula
cappa), Chuanxinlian (herba andrographis), and
Shengshigao (Gypsum) (Table 1). The drug prescription has been
used as a decoction in clinical practice for years in
Southwest Guizhou Autonomous Prefecture Hospital of TCM,
and it has demonstrated notable efficacy in lowering body
temperature, improving patients’ symptoms, and shortening
the duration of the cold, with few side effects. Preclinical
pharmacological and toxicological studies on animals
showed that LJGMC was effective in clearing heat, relieving
pain, reducing inflammation, and alleviating cough, as well
as producing antiallergic, antibacterial, and antiviral effects
with no evidence of toxic effects [17–20].
Pharmacological effects based on TCM
Clears heat and toxicity
Clears heat and purges lungs
This phase II clinical trial is well designed to evaluate
the efficacy and safety of LJGMC compared with placebo
in patients with CCWHS. Additionally, it is expected to
find a dose-efficacy relationship and to help determine
the optimum dose for the next phase III clinical trial.
Moreover, the protocol presents a detailed and practical
methodology for future clinical trials of patent drugs
developed based on TCM.
This study is a multicenter, parallel group, double-blind,
prospective, randomized, placebo-controlled phase II
clinical trial. A total of 240 patients will be recruited and
randomly allocated into treatment groups or placebo group.
All patients will receive the treatment for 3 consecutive
days, with a 5-day follow-up. Efficacy and safety data will
be collected throughout the whole study. The flow chart is
shown in Fig. 1.
This trial has been authorized by the China Food and Drug
Administration (CFDA) (Approval Number 2012 L01822)
and registered in the Chinese Clinical Trial Registry
(ChiCTR-IPR-15006504). In addition, the study will be
conducted in compliance with the Declaration of Helsinki,
Good Clinical Practice (GCP) guidelines, and the laws and
regulations of clinical trials issued by the CFDA. The
protocol, informed consent form, and recruitment poster were
reviewed and approved by the West China Hospital of
Sichuan University Clinical Trials and Biomedical Ethics
Committee (number TCM-2015-03) and the ethics
committees of the other six hospitals. The investigators in all
seven trial centers are qualified and well trained. All eligible
participants will be fully informed about the protocol and
will sign an informed consent form prior to participation.
The privacy and data of all participants will be protected,
and their safety will be greatly guaranteed.
Participants and recruitment
We will recruit eligible participants by advertising on
hospital notice boards, sending leaflets, or being
recommended by doctors in outpatient clinics. A total of 240
patients will be recruited at the following seven
hospitals: (1) West China Hospital of Sichuan University, (2)
Shuguang Hospital Affiliated to Shanghai University of
TCM, (3) First Affiliated Hospital of Guiyang College of
TCM, 4) First Affiliated Hospital of Tianjin University of
TCM, (5) Second Affiliated Hospital of Tianjin
University of TCM, (6) Ruikang Hospital Affiliated to Guangxi
University of TCM, and (7) First Affiliated Hospital of
Guangzhou University of TCM. Forty patients will be
recruited at each of the first two centers and 32 at each of
the latter ones.
Fig. 1 Study flow chart. AE adverse event, SAE serious adverse event
1. Diagnosis of common cold according to Western medicine
2. Diagnosis of common cold with wind-heat syndrome according to TCM
3. Aged between 18 and 65
4. Presenting within 36 hours after symptoms onset
5. Willingness to participate and to sign the informed consent form.
1. Patients with acute herpetic pharyngitis, acute viral pharyngitis, acute herpetic laryngitis, acute viral laryngitis, acute conjunctivitis or acute tonsillitis, pneumonia, and other diseases
2. Patients with severe primary diseases of cardiovascular, lung, kidney, or hematopoietic system or abnormal electrocardiogram with clinical significance
3. Patients with liver function (such as alanine
aminotransferase [ALT] and aspartate
aminotransferase [AST]) 1.5 times higher than the
normal upper limit, abnormal serum creatinine,
positive urine protein qualitative test, white blood
cell count <3.0 × 109/L or >10.0 × 109/L, and/or
neutrophil percentage >80%
4. Patients who had used other drugs to treat common cold after the onset of the disease
5. Temperature ≥39.0 °C
6. Women who are pregnant or preparing to become pregnant or breast feeding women
7. Allergic condition or allergy to the drug composition(s)
8. Patients with mental or legal disabilities
9. Patients who participated in clinical trials of other drugs within the past 3 months 10.Patients who are not suitable for the trial as decided by the researchers.
The withdrawal criteria include the following:
1. Worsening conditions during the trial, including no body temperature decline, a rising body temperature higher than 39.0 °C, or worsening symptoms in 48 hours
2. Experiencing anaphylaxis or serious adverse events during the trial
3. The study drug is not taken as required, or is taken
at doses <80% or >120% of the requirement
4. Quitting the clinical trial voluntarily.
Early suspension or termination of the entire study
The trial will be suspended early or terminated for the
1. A serious adverse event (SAE) which is probably or definitely related to the test drug occurs or more
than half of the population in any of the groups
experience adverse drug reactions.
2. The efficacy of the test drug is found to be poor or even ineffective.
3. The protocol is flawed, or there is significant deviation from the protocol.
4. The pharmaceutical supervisory and administrative department decides to terminate the study reasonably.
5. The sponsor decides to terminate the trial due to management or financial problems.
A diagnosis of the common cold in Western medicine is
established according to Practice of Internal Medicine
(2013, 14th edition) . A TCM diagnosis of CCWHS is
based on the chapter common cold (wind-heat syndrome)
of Internal Medicine of TCM  and TCM syndrome
and sign diagnostic criteria for common cold . The
TCM diagnostic criteria for CCWHS are listed in Table 2.
To be diagnosed with CCWHS, patients should have all
the primary symptoms and at least three of the secondary
symptoms, as well as TCM signs for the tongue and pulse.
Randomization and blinding
A total of 240 eligible participants will be randomly
allocated to the high-dose group, medium-dose group,
low-dose group, or placebo group in a 1:1:1:1 ratio.
Randomized sequences of each center and every packed
drug were generated by an independent professor at the
Drug Clinical Research Center of Shanghai University
of TCM, using a stratified block randomization method
with 30 blocks of block size 8 based on the PROC
PLAN function of the SAS 9.2 software analysis system
(SAS Institute, Cary, NC, USA).
Randomization sequences will be concealed in lightproof,
sealed envelopes kept by a specified project manager and
the sponsor, who are not involved in the recruitment,
intervention, assessment, or statistical analysis. The treatment
allocation will be blinded to the participants and
investigators throughout the study, and the outcome assessors and
statisticians will not be involved in the participants’
screening and allocation. Each patient will receive a unique
randomized number corresponding to the drug according to
Table 2 Diagnostic criteria of common cold based on TCM
Signs for the tongue
Signs for the pulse
Red tongue with thin yellow coating
Floating and rapid pulse
the group allocation. Furthermore, the intervention group
type will be replaced by the letter A, B, C, or D as blind
codes of allocation. The blind codes will not be disclosed
until the statistical analysis is completed. An emergency
envelope has been prepared for each randomized number
in each center and is to be opened for treatment only in
case of medical emergency which is most probably caused
by the study drug.
LJGMC and the placebo are provided and manufactured by
Tasly Pharmaceutical Co., Ltd. (Tianjin, China). Each
LJGMC or placebo weighs 0.28 g. The production batch
number is 20150101. All the drugs are packaged uniformly
with the same labels. Each package, which contains 3 plus
1 days’ dosage, must be sealed and kept in a cool, dry place.
The placebo, which contains no effective ingredients to
treat the common cold, is almost identical to the study drug
in appearance, smell, and taste. A clearly visible label on
each package states “FOR TRIAL USE ONLY” and other
information: name, dose, dosing schedule, indication of
storage condition, expiration date, and the manufacturer’s
name. An independent drug manager in each center is in
charge of receiving, handling, storing, and dispensing the
Patients in the high-dose group, medium-dose group,
low-dose group, or placebo-matched group will receive,
respectively, 1.12 g LJGMC, 0.56 g LJGMC plus 0.56 g
placebo, 0.28 g LJGMC plus 0.84 g placebo, or 1.12 g
placebo each time, three times per day. All medications
will be taken orally with 200 ml warm water. The
treatment duration is 3 consecutive days, with a 5-day
follow-up. During the study, patients will be visited four
times by the investigators. Details of the study
procedures are given in Table 3.
Concomitant treatments and forbidden drugs
Patients will be allowed to continue using medications for
underlying conditions, such as hypertension or diabetes.
The name, dosage, and duration of any concomitant
medication must be recorded carefully in the case report
form (CRF). If the body temperature of a participant rises
to higher than 39.0 °C for longer than 2 hours or becomes
≥39.5 °C, physical cooling and/or paracetamol can be used
to kill the fever. During the study period, any other
Western or Chinese therapy or medication that may affect the
study results is prohibited. Once forbidden drugs are used,
the patient will be withdrawn from the study.
Adverse events (AEs) concerning clinical symptoms and
signs as well as laboratory tests will be documented. Every
AE will be recorded in detail, and prompt, proper
Table 3 Study schedule for patients
ICF informed consent form
treatment will be given by researchers and therapists at
each center. If a serious adverse event (SAE) presents, a
decision on whether the participant needs to be
withdrawn from the study will be made by the principal
investigator and ethics committee. The causality and
relationship between AEs/SAEs and the study drug will
also be analyzed and evaluated on the basis of standard
operation procedures (SOPs) of the CFDA, which
define causality and relationship as clearly related,
probable, possible, doubtful, and clearly not. If an SAE
occurs, the investigator must record it in detail on the
SAE form, and it should be reported to the principal
investigator, the CFDA, ethics committee, and the
sponsor within 24 hours. A statistician will analyze the
frequency and proportion of AEs/SAEs. Continuous
care will be available until subjects who suffer harm
from the participation recover, and proper
compensation will also be given.
Primary vital signs, physical examinations, and some
laboratory tests will be performed both before and after
treatment for safety assessment. Primary vital signs
include body temperature, blood pressure, heart rate, and
respiration rate. Laboratory tests include routine blood,
urine, and stool analysis, liver function test (ALT, AST,
alkaline phosphatase (ALP), serum total bilirubin (STB),
and gamma-glutamyl transpeptidase (γ-GT)), renal
function test (serum creatinine, microalbuminuria, and serum
cystatin C), and electrocardiogram. Also, before treatment,
subjects who are suspected to have a lower respiratory
tract infection need have a chest X-ray, and female
patients with the potential to become pregnant must take a
urine pregnancy test.
The primary outcome is the time to all symptoms’
clearance, which is defined as the length from study enrollment
to the time when the symptoms completely disappear. Each
participant will be instructed to record any change in
symptoms in their patient diary.
Secondary outcomes include time to primary symptoms
and each secondary symptom disappearance, time to
fever relief, time to fever clearance, and change in TCM
symptom and sign scores.
Time to fever relief is defined as the time from the
first dosing to time when the body temperature drops by
at least 0.5 °C. Time to fever clearance is defined as the
time from the first dose administration to the time when
the body temperature drops below 37.3 °C and lasts for
In this study, all patients will be required to record
their body temperature in the patient diary every 2 hours
within the first 12 hours and every 4 hours during the
following 12 hours. After that, if the temperature is
≥37.3 °C, it should be recorded four times at a fixed time
every day, and if the temperature is lower than 37.3 °C,
then there is no need to record it.
Change in TCM symptom and sign scores
The TCM symptom scoring system used in the study
follows the Guidelines for Clinical Research of New
Chinese Medicine , in which all symptoms are graded
(Table 4). The change in cumulative TCM symptom and
sign scores is assessed by the percentage of symptom
and sign scores reduction (PSSSR), which is calculated
according to the following formula: PSSSR = (scores
before treatment – scores after treatment)/scores before
treatment*100%. A value greater than 50% is defined as
The sample size calculation is based on a comparison
between the intervention group and the placebo-controlled
group. The mean duration of all symptoms for the
common cold was estimated to be 7 ± 3 days [7, 25], and
reduction in the duration of all symptoms by 2 days is
assumed to be clinically significant. Using Power Analysis
and Sample Size (PASS) 11.0 with 90% power (1–β) and α
= 0.05 (two-sided), the sample size needs to be 48 cases
for each group. Considering a drop-out of 20%, we
decided to recruit 60 subjects in each group. According to
the latest edition of Provisions for Drug Registration
issued by the CFDA on phase II clinical trials, the total
sample size was set to be 240 patients.
Data management and statistical analysis
The Drug Clinical Research Center of Shanghai University
of TCM is in charge of data statistical analysis. The data
entry will be performed by two independent data
administrators using the software EpiData 3.1 based on the CRFs,
which should have been checked and reviewed for
accuracy and consistency by the clinical research
associate (CRA) and investigators. Finally, the database will
be locked and analyzed under the agreement and
confirmed review of the sponsor, principal investigator, and
The full analysis set (FAS), in which patients should be
dosed with LJGMG or placebo at least once with clinical
observation record in the study, is the primary analysis set
according to the intention-to-treat (ITT) principle using
the last observation carried forward (LOCF) approach
for missing values. All subjects without any major
protocol deviations will be included in the per-protocol
set (PPS). An efficacy assessment will be carried out
using the FAS and PPS. A safety evaluation will be
conducted for subjects who have experienced at least one
Table 4 Symptom and sign scoring system
<37.3 °C 37.3–37.9 °C
None (0) Mild (1)
No need for water
All symptom scores + sign score
Sometimes need water
≥38.5 °C, <39.0 °C
Need water frequently
Heavy, can’t insist on work
Terrible, can’t stretch freely
Cumulative symptom score
Primary symptom scores + secondary symptom scores
None (0) Mild (1)
Pharyngeal hyperemia/swelling –
Pharyngeal mucosa hyperemia Pharyngeal mucosa, pharynx palatine Pharyngeal swelling and heavy
arches and uvula hyperemia secretion
study visit and have safety data, which is defined as the
safety set (SS).
All continuous and normally distributed data are
presented as mean ± standard deviation, and median with
range for non-normal data. Categorical data are
summarized by frequency counts and percentages. Baseline
balance among groups will be conducted by performing
a chi-squared test or an analysis of variance (ANOVA).
Time to all symptoms’ clearance, time to primary
symptoms and each secondary symptom disappearance, time to
fever relief, and time to fever clearance will be estimated
and compared by the log-rank test. A Kaplan-Meier
survival curve will be constructed, and the median time will
be provided separately for each group with a two-sided
95% confidence interval. Comparisons among groups of
TCM symptom and sign scores will be conducted using
ANOVA and the Bonferroni method. All data will be
processed by a professional statistician using SAS 9.2
software (SAS Institute, Cary, NC, USA); a two-sided P value
of <0.05 is considered to be statistically significant.
Quality control and monitoring
Each trial center has a project manager who is
responsible for the quality of research. All investigators are
qualified and well trained. The principal investigator in
each center will be responsible for the trial conductance
based on the SOP. During the whole course,
independent trial inspectors will pay regular visits to each center,
check source documents and CRFs, and supervise the
research to make sure it complies with the protocol. Any
shortcomings or problems found by the inspectors
should be improved.
To ensure maximum compliance with drug taking and
diary recording, a series of measures will be taken which
include reminding subjects of their appointments,
conducting attentive follow-up by phone or email, and making
follow-up appointments at each participant’s convenience.
To date, no proven effective drugs or methods in clinical
practice can cure the common cold. Chinese herbal
medicine has been widely used to treat colds in China
for a long time and has gradually been accepted and
applied in many other countries. However, evidence-based
efficacy and safety data on Chinese herbs are limited,
because the studies have used small sample sizes or are of
poor quality .
It is widely recognized that a randomized
placebocontrolled trial is the gold standard to evaluate the safety
and efficacy of a drug or treatment method. LJGMC,
prescribed as a decoction, has been proven efficient and
safe in clinical practice for years in Southwest Guizhou
Autonomous Prefecture Hospital of TCM. To support its
wide use, we have designed this multicenter, double-blind,
placebo-controlled, randomized clinical trial in accordance
with the Consolidated Standards of Reporting Trials
(CONSORT) and Standard Protocol Items:
Recommendations for Interventional Trials (SPIRIT) guidelines [27, 28]
and the “One study, one primary outcome” methodology
for clinical trials published by the CFDA. The SPIRIT
checklist is given in Additional file 1. The study is expected
to provide high-quality evidence in evaluating the efficacy
and safety of LJGMC in treating CCWHS, and it may help
to optimize the dose for the next phase III clinical trial
based on the four parallel set groups. If proven beneficial,
it provides further proof for people to use this inexpensive,
easily accessible alternative choice to treat the common
cold. Moreover, the protocol presents a detailed and
practical methodology for future clinical trials of drugs
developed based on TCM.
Additional file 1: SPIRIT 2013 checklist: recommended items to address
in a clinical trial protocol and related documents. (DOCX 56 kb)
AE: Adverse event; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase;
ANOVA: Analysis of variance; AST: Aspartate aminotransferase; CCWHS: Common
cold with wind-heat syndrome; CFDA: China Food and Drug Administration;
CONSORT: Consolidated Standards of Reporting Trials; CRA: Clinical research
associate; CRF: Case report form; FAS: Full analysis set; GCP: Good Clinical Practice;
ITT: Intention-to-treat; LJGMC: Lian-Ju-Gan-Mao capsules; LOCF: Last observation
carried forward; PASS: Power Analysis and Sample Size; PPS: Per-protocol set;
PSSSR: Percentage of symptom and sign score reduction; SAE: Serious adverse
event; SOP: Standard operation procedure; SPIRIT: Standard Protocol Items
Recommendations for Interventional Trials; SS: Safety set; STB: Serum total
bilirubin; TCM: Traditional Chinese medicine; URTI: Upper respiratory tract infection;
γ-GT: Gamma-glutamyl transpeptidase
All the costs concerning the study are financially supported by Tasly
Pharmaceutical Co., Ltd., Tianjin, China (the sponsor), who has had and will
have no role in the study design, data collection and management, analysis,
or interpretation of data. We greatly appreciate those principal investigators
who contributed to the final study protocol from the other six centers: Wei
Zhang, Shuguang Hospital Affiliated to Shanghai University of TCM; Liangli
Liu, First Affiliated Hospital of Guiyang College of TCM; Guiwei Li, First
Affiliated Hospital of Tianjin University of TCM; Baolin Wei, Second Affiliated
Hospital of Tianjin University of TCM; Yuping Tan, Ruikang Hospital Affiliated
to Guangxi University of TCM; and Wei Zhang, First Affiliated Hospital of
Guangzhou University of TCM. We also express special thanks to the
Contract Research Organization (CRO) and all other participants in this study.
Availability of data and materials
All data will be made available.
SW, HJ, and BM contributed to the design and development of the trial. BM is
the principal investigator of this study. SW drafted the initial manuscript, and HJ
revised it carefully. QY and BS participated in the design and coordination of
the trial as well as in recruiting patients. All authors reviewed the content and
approved the final version.
Ethics approval and consent to participate
The protocol, informed consent form, and recruitment poster were reviewed
and approved by the West China Hospital of Sichuan University Clinical Trials
and Biomedical Ethics Committee (number TCM-2015-03), the Institutional
Review Board of Shuguang Hospital Affiliated to Shanghai University of TCM,
the Ethics Committee of the First Affiliated Hospital of Guiyang College of
TCM, the Institutional Ethics Committee of First Affiliated Hospital of Tianjin
University of TCM, the Ethics Committee of the Second Affiliated Hospital of
Tianjin University of TCM, the Ethics Committee of Ruikang Hospital of
Guangxi University of TCM, and the Institutional Review Board of the First
Affiliated Hospital of Guangzhou University of TCM. Written informed
consent will be obtained from each participant prior to enrollment.
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