Common cold is one of the most frequently occurring illness present in primary healthcare services [
Recent evidence has demonstrated the clinical benefits and safety of complementary and alternative medicine (CAM) for common cold [
Treatment based on syndrome differentiation is the character and spirit of TCM. Along with wind-cold, wind-heat, and summer-heat dampness patterns, Qi-deficiency syndrome is one of the most frequent TCM pattern in common cold [
Shen Guo Lao Nian Granule (SGLNG) is based on an empirical formula of TCM for common cold of Qi-deficiency syndrome (CCQDS) and has been approved by the State Food and Drug Administration of China for a clinical trial (Certified Number: 2003L01916). It is composed of Platycarya strobilacea Sieb. et Zucc, Polygonum cuspidatum Sieb. et Zucc, Bidens pilosa L., Dendranthema indicum, E. sinica Stapf, Siraitia grosvenorii, Panax quinquefolius, Lentinus edodes, and Astragalus membranaceus Bunge (Table
Formulation and dose of SGLNG.
Chinese Pinyin name | English name | Latin name | Source | Weight (%) |
---|---|---|---|---|
Hua Xiang Shu Guo Xu | Infructescence of Platycarya strobilacea Sieb. | Platycarya strobilacea sieb.et Zucc | The dried infructescence of | 14.96 |
Hu Zhang | Polygonum cuspidatum | Polygonum cuspidatum Sieb.et Zucc | The dried rhizome and root of Polygonum cuspidatum | 11.97 |
Gui Zhen Cao | Bidens bipinnata | Bidens pilosa L. | The dried stems and leaves of | 14.96 |
Ye Ju Hua | Mother Chrysanthemum | Dendranthema indicum | The dried flowers of Mother Chrysanthemum | 11.97 |
Ma Huang | Ephedra | E. sinica Stapf | The dried herbaceous stem of Ephedra | 5.98 |
Luo Hang Guo | Siraitia | Siraitia grosvenorii | The dried fruit of | 14.96 |
Xi Yang Shen | American ginseng | Panax quinquefolius | The dried root of American ginseng | 2.99 |
Xiang Gu | Mushrooms | Lentinus edodes | The dried mushrooms without roots | 11.97 |
Huang Qi | Astragalus membranaceus | Astragalus membranaceus Bunge | The dried stems and leaves of Astragalus membranaceus | 9.97 |
Unpublished pharmacodynamic studies made a rat model of CCQDS by sulphur dioxide, smoke, and cold air stimulation [
A multicenter, randomized, active controlled clinical study was conducted from year 2005 to year 2007 to investigate the efficacy of SGLNG in treating common cold of Qi-deficiency syndrome (CCQDS) in patients aged between 45 and 75 years. Results showed that patients in the SGLNG group exhibited a greater reduction in symptom total score and relieving single symptoms like fatigue, muscle, and joint soreness, with no adverse event reported, compared to a classic TCM formula of Yin Qiao Jie Du Granule [
Therefore, we designed this randomized, double-blind, placebo-controlled, multicenter, phase II clinical trial to investigate the efficacy of SGLNG in treating CCQDS with the outcome measures focused on symptom reduction and to detect the optimal therapeutic dosage.
This is a multicenter, randomized, double-blind, placebo-controlled, phase II clinical study (Figure
Flowchart. 240 patients will be recruited in the study and randomly allocated to one of four groups (high-dose group = 60; middle-dose group = 60; low-dose group = 60; control group = 60). After 5 days of treatment, we analyze the data collected and make conclusion.
The main components of SGLNG are shown in Table
We advertise the study using advertisements and posters placed on billboards in the participating hospitals and communities. Potential participants are encouraged to visit the study offices immediately when they experience cold symptoms. Participants are recruited from the out-patient departments and emergency rooms of five participating centers: West China Hospital of Sichuan University, the Affiliated Hospital of Chengdu University of TCM, the Affiliated Hospital of Changchun University of TCM, the first Affiliated Hospital of Tianjin University of TCM, and the Second Affiliated Hospital of Tianjin University of TCM. West China Hospital is the leading unit of the five centers. These centers are defined primarily geographically. All patients are required to provide their written informed consent prior to study entry.
Enrolled participants are randomly allocated to one of four groups (high-dose group, middle-dose group, low-dose group, and control group) and undergo a 5-day treatment and a 5-day follow-up (Table
In each participating center, a chief investigator is appointed to be responsible for the whole clinical process (subject recruitment, intervention, follow-up, and data collection), adhering to the study protocol. All personnel involved in this trial are trained prior to trial initiation.
Ethical approval was obtained from the Ethics Committee of Clinical Trials and Biomedicine of West China Hospital of Sichuan University (number IRB-2014-12), and the other four centers received ethical approval from local ethics committees. The study is conducted in accordance with the Declaration of Helsinki and registered with the Chinese Clinical Trial Registry (registration number:
TCM symptoms of common cold and symptom score.
| None = 0 | Mild = 2 | Moderate = 4 | Severe = 6 | ||
---|---|---|---|---|---|---|
Main symptom | (1) | Aversion to cold | None | Slight aversion to cold, do not need to add cloth | Aversion to cold, need to add cloth | Aversion to cold, need to add thick cloth, or bedding |
Stuffy and running nose | None | Mild nasal congestion, runny nose occasionally, not affecting respiration | Nasal congestion, runny nose, affecting breathing | Obvious nasal congestion, running nose, mouth breathing | ||
(2) | Fatigue | None | Lack of energy, not resistant to labor, | Mental weariness, slightly affecting daily activities | Limb weakness, cannot support daily activities | |
Short of breath | None | Shortness of breath after labor | Shortness of breath after slight labor | Obvious shortness of breath when resting | ||
| ||||||
Symptom | None = 0 | Mild = 1 | Moderate = 2 | Severe = 3 | ||
| ||||||
Secondary symptom | Fever | None | 37.3–37.5°C | 37.6–37.9°C | ≧38.0°C | |
Sore throat | None | Dry throat with slight pain | Significant with obvious pain when swallowing | Sore and swollen throat with severe pain | ||
Headache | None | Slight and occasionally | Severe and lasting | Severe and affect working | ||
Cough | None | Occasionally in daytime, not affecting daily life | Occasionally day and night, slightly affecting sleep | Frequent cough day and night, affecting rest and sleep | ||
Expectoration | None | Stick sputum, not easy to cough out | Stick or yellow sputum | Stick or yellow sputum with large volume | ||
Spontaneous perspiration | None | Yes (severe than usual) | — | — | ||
Tongue and pulse | Tongue color | Pale □ Red □ | Others | |||
Tongue coat | Thin white □ Thin yellow □ | Others |
Study schedule for patients. On the 1st day, researchers collect the data of medical and treatment history, efficacy observation, safety assessment, and exclusive observation of patients, as well as randomization, allocation, and drug distribution. On the 4th day (fulfilled for 4 days to the first time of medicine consume), patients take the second visit for physical examination, and researchers record symptoms scores, combined medication, and adverse event (if any). The 6th ± 1 day (fulfilled for 6 days to the first time of medicine consume), patients take the third visit for physical examination and the second safety assessment, and researchers record symptoms scores, combined medication, adverse event (if any), and recycled medicines and pack box, and drug quantity statistics. On the 11th ± 2 day (fulfilled for 11 days to the first time of medicine consume), patients take the fourth visit for physical examination, and researchers record symptoms scores, combined medication, and adverse event (if any).
Stage | Visit period | |||
Treatment | Visit 1 | Visit 2 | Visit 3 | Visit 4 |
Day | 1 day | 4th day | 6th ± 1 day | 11th ± 2 days |
| ||||
| ||||
Informed consent signing | × | |||
General information recording | × | |||
Medical and treatment history recording | × | |||
Complication and symptoms recording | × | |||
Physical examining | × | × | × | × |
Combined medication recording | × | × | × | |
| ||||
Symptoms scores recording | × | × | × | × |
| ||||
Routine blood test | × | × | ||
Routine urine + urinary sediment microscopy | × | × | ||
Liver function test | × | × | ||
Renal function test | × | × | ||
Fasting blood glucose + 2 h postprandial blood glucose | × | × | ||
Electrocardiogram | × | × | ||
| ||||
Chest X-ray | × | |||
Urine pregnancy test (female) | × | |||
Fasting blood glucose + 2 h postprandial blood glucose | × | |||
| ||||
Adverse event recording | × | × | × | |
| ||||
Randomization and allocation | × | |||
Drug distribution | × | |||
Medicines and packing box recycling | × | |||
Drug quantity statistics | × |
Inclusion criteria are that participants are aged between 45 and 75 years; have symptoms of Qi-deficiency in normal times such as fatiguing easily, poor appetite, or suffering more frequent colds (≥6 times/year) when seasons and climates change; meet the diagnostic criteria of a common cold within 48 hours of onset; meet the diagnostic criteria of CCQDS; and possess an understanding of the trial procedure and a willingness to sign the consent form.
Although the name of the medication indicates that its possible target population might be the “elderly people,” based on the TCM pathology of common cold with Qi-deficiency, patients with younger age than the elderly patients may also present CCQDS. Therefore, in the RCT to assess the clinical efficacy of SGLNG, we extend the age of the study population from 45 to 75. This may provide broader target population for the medication and also provide evidence for phase III study in the future.
The participants are not eligible to participate in the trial if they meet any of the following criteria: (1) have acute viral pharyngitis and laryngitis, acute herpes angina, acute conjunctivitis pharynx, or acute tonsillitis, suspected influenza, and vaccination against influenza within 21 days before enrollment; (2) history of severe cardiovascular, pulmonary, renal or haematopoietic system disease, immunodeficiency disease (infection with human immunodeficiency virus, etc.), diabetes, and a previous abnormal glucose tolerance test or a significantly abnormal ECG test; (3) liver function test (alanine transferase (ALT), aspartate transferase (AST), total bilirubin (TBIL), albumin (ALB), alkaline phosphatase (ALP), and
To distinguish a cold event from an allergy, the participants who are allergic to or possess contraindications for the use of certain components of the study drugs will be excluded at enrollment. Additionally, all the clinical researchers involved in the study are educated on the difference between common cold and an allergic event and informed to distinguish between these events during enrollment, such that “cold symptoms occur one at a time, generally last for 5–7 days, with yellow/greenish nasal discharge, and may or may not be accompanied by a fever, with slight body aches and pains, but allergic symptoms occur rapidly and all at once and last as long as the allergy-causing agent is present, with clear and watery nasal discharge, not associated with a fever, and with no body aches or pains” [
The study participation will be terminated if the amount of study medication taken is poor (actual usage of trial drug <80% or =120%) or the participant is unable to cooperate with the trial investigators and/or unable to complete the follow-up. When an allergic reaction or a serious adverse event is revealed, a participant is unwilling to continue the trial, or symptoms do not improve or worsen after taking the study drugs for 72 hours, the patient will be withdrawn from the trial after a researcher’s assessment, and the data will be considered invalid but will be included in the full analysis set (FAS). If the participant drops out, he or she will be contacted via phone interviews, e-mail, or written letters. The reason for study discontinuation and the last time the medication was taken will be recorded. Participants who exit the trial due to allergies, poor curative effects, or other adverse events will receive appropriate treatment.
The sample size was determined using Encyclopaedia Medical Statistics 3.2 software (PEMS 3.2, Guangzhou Jing far Pharmaceutical Research Co., Ltd., Guangzhou, China) with 90% power and a significance level of 0.05 (two-sided). According to Lizogub et al. [
According to a stratified block randomization method, the PRCO PLAN function of the analysis system of SAS software (SAS Institute, Inc., Cary, NC, USA) was used to generate the random number grouping table according to the number of cases and the random proportion of the participating units. There are 5 centers and 4 groups (high-dose group, middle-dose group, low-dose group, and control group), and each group is divided into two layers in a 1 : 1 ratio, while one layer is aged between 45 and 60 years and the other layer is aged between 61 and 75 years. So each group in one single center will recruit 12 patients, with 6 patients between 45 and 60 years old and 6 patients between 61 and 75 years old. Eligible patients are randomly allocated to the high-dose group, middle-dose group, low-dose group, or control group in a 1 : 1 : 1 : 1 ratio. The randomization sequence was generated by the Health Statistics Department of the Fourth Military Medical University of China, which is independent of the trial. The details of randomization sequences are unknown to researchers and outcome assessors who participate in the study and kept in two copies in an opaque, sealed, and stapled envelope that will be kept concealed until the end of the outcome assessment.
The blinding codes are preserved and protected separately by West China Hospital and the other four participating centers. Emergency letters are prepared by a statistician in which the random code and group assignment are included. If the blind code is exposed, the corresponding patient will be excluded. Any of the following situations could call for a blind breaking and urgent measure: a serious adverse event, serious complication, or deteriorative condition.
Following the blinding principle, the five participating centers are isolated from the sponsor unit during the study and they will contact only the supervision agency (Beijing Chuangli Medical Technology Development Co., Ltd., China), which is responsible for contacting participating centers and monitoring the progress of research but is blind to group assignment.
Patients who meet the inclusion criteria and none of the exclusion criteria are randomized into one of four treatment groups: (1) high-dose group: 3 bags of SGLNG/time; (2) middle-dose group: 2 bags of SGLNG plus 1 bag of placebo granule/time; (3) low-dose group: 1 bag of SGLNG plus 2 bags of placebo granule/time; and (4) control group: 3 bags of placebo granule/time.
Each participant receives a large box and be instructed to dissolve one small box of the contents in approximately 200 mL of warm liquid and take orally after each meal, 3 times daily for 5 days. The participants are isolated from each other after enrollment and advised to take the drugs at home to avoid discussing the drugs. Participants, researchers, and outcome assessors will remain blinded to the treatment allocation throughout the study.
Throughout the study period, participants will not be permitted to use any other treatments for the common cold, including oral medications and TCM therapies such as cupping, massage, or acupuncture. Medications for concomitant diseases, such as hypertension, are allowed. The dosage, duration, and name of any concomitant medication or treatment will be recorded.
The follow-up visits will last for 5 days after the treatment. Details of the study procedures are shown in Table
The demographics, family history, past history, medical history, vital signs, and physical characteristics (body temperature, respiration rate, heart rate, blood pressure, and body weight) are obtained and recorded on the 1st day (day 1). Physical examination and a review of concomitant medications are conducted on the 4th, 6th, and 11th days of the intervention.
Safety assessments are taken on the 1st day (day 1) and the 6th day of the intervention including (1) vital signs and body weight; (2) full blood count, urine routine plus urinary sediment tests; (3) liver function tests (ALT, AST, TBIL, ALB, ALP, and
The chronic toxicity test in rats revealed that SGLNG may raise blood sugar during the dosing period (lasted for 3 weeks) in both 15 times and 50 times the clinical daily dose groups; it is possible that long-term high-dose of SGLNG taken may cause blood sugar disorders in diabetic patients. The fasting blood glucose and 2-hour postprandial blood glucose tests are used to observe the effect of SGLNG on blood glucose during the trial as a safety index. What is more, it can also exclude participants with unknown diabetes before enrollment. Although the earlier multicenter, randomized, active controlled clinical study did not report that SGLNG can cause abnormal blood glucose in patients [
Chest X-ray, urine pregnancy test (only for females), fasting blood glucose, and 2-hour postprandial blood glucose are assessed on the 1st day of the intervention.
The compliance of each participant is calculated from the total dose that was actually taken and the total dose required by the study protocol. The total actual dose is defined as the total number of bags that are actually used (by counting the number of consumed capsules), and the total required dose is defined as the number of bags that should be used during the 5-day treatment. Compliance is assessed on the 11th day after the intervention. The formula is as follows:
Because all the participants in the trial have Qi-deficiency syndrome and normally present certain Qi-deficiency symptoms (fatigue, shortness of breath, and spontaneous perspiration), we define the disappearance of Qi-deficiency symptoms (symptom score = 0) (Table
The symptom severity and score are assessed by researchers who are blind to the trial, and one participant is assessed by the same researcher consistently throughout trial. Participants will not be allowed to assess their overall illness or level of severity to avoid assessment bias.
Participants are required to truthfully report symptom changes. Any adverse events (such as worsening of symptoms, concomitant diseases, and abnormal laboratory results) during the test will be recorded and treated appropriately by the intervention administrators until the patient’s laboratory results return to normal and symptoms disappear. Follow-up will be performed via hospital visits and phone calls according to the severity of adverse event. In cases of severe adverse events, investigators are asked to record and report the events to the Drug Registration Department of the State Food and Drug Administration, the Safety Supervision Department, the Provincial Drug Supervision Bureau, the trial applicant, and the ethics committee within 24 hours.
The full analysis set (FAS) is the primary analysis set for efficacy with an intention-to-treat (ITT) principle. In the FAS, all patients will be treated with at least one dose of the study drug and at least one clinical observation will be recorded in the study. All subjects without any major protocol deviations will be involved in the per-protocol set (PPS). The safety analysis will be conducted for randomized subjects who have completed at least one study visit and have safety data. Descriptive statistics will be performed on continuous variables, frequencies, and categorical variables. All symptom durations, total score reductions on Jackson’s scale and TCM symptoms, the duration of each TCM symptom, the decreasing rate of TCM main symptoms, and the reduction score of TCM symptoms will be estimated with the Kaplan-Meier technique and compared using the stratified log-rank test. Comparisons among different dose groups and age layers will be conducted with an analysis of variance (ANOVA) and a least significant difference
There is an urgent necessity to develop an effective treatment for CCQDS due to its frequent occurrence and heavy burden. This study intend to examine the clinical efficacy and safety and find optimal dose of SGLNG for treating CCQDS, in a randomized, double-blind, and placebo-controlled trail.
We conduct this study not only to propose a new remedy for common cold, but also to practice the methodology of syndrome differentiation for clinical research in TCM. This is the first study that addresses the efficacy and safety of a TCM formula for this specific but frequently seen TCM syndrome, Qi-deficiency in common cold in a double-blind and placebo-controlled trail. We assume that this design, which is in line with TCM theory and also typical of individualized and phenotype-based medicine, will contribute to more convincing results and robust evidence for the efficacy of study medications and cause new insight into common cold treating. Apart from the syndrome differentiation-based selection of the study population, there is another strength in this study. We perform both Western and TCM scales to measure the effects of the study medication. They are overlapping in terms of certain symptoms, while TCM symptoms cover some other abnormal symptoms than Jackson’s scale, but the relationship between them has not been explored before. In this study, the scores of Jackson’s scale and TCM symptom scale are compared at each time point, so as to detect their merit and weak point, respectively, which may provide more powerful evidence for further measurements of common cold. To our knowledge, this is the first trial to evaluate the difference between Jackson’s scale and TCM symptom scale.
There are some limitations in this study. Due to limited budget, we do not perform culture assessing for inclusion of patients with common cold, which may cause mistakenly recruiting patients with potential influenza. To minimize this mistake, all the clinical researchers involved in the study are educated on the difference between common cold and influenza. Patients who experience severe symptoms will be excluded at enrollment, while those with symptoms which were slight at first but worsened rapidly during the study will be advised for culture assessing in clinical or even dropout from the trail. Apart from that, we employ Jackson’s scale for the outcome measurement, while other latest questionnaires such as the Wisconsin Upper Respiratory Symptom Survey [
In summary, by rigorous methodology for a clinical trial and syndrome differentiation-based approach, the results of this study will provide robust clinical evidence regarding the efficacy, safety, and optimal dose of SGLNG for treating CCQDS.
This trial asks if SGLNG reduces CCQDS symptoms and which is the optimal dose.
Albumin
Alkaline phosphatase
Alanine transferase
Analysis of variance
Aspartate transferase
Complementary and alternative medicine
Common cold with Qi-deficiency syndrome
Creatinine
Case report form
Electrocardiogram
Full analysis set
Good manufacturing practices
Intention-to-treat
Per-protocol set
Percentage of cumulative TCM symptom score reduction
State Food and Drug Administration
Shen Guo Lao Nian Granule
Total bilirubin
Traditional Chinese medicine
Upper respiratory tract infection
United States of America.
This trial is currently recruiting participants. The funding source had no role in the design of this study and does not have any responsibility for analyses, interpretation of the data, or the decision to submit results.
The research was funded by Hebei Baishan Pharmaceutical Co., Ltd., that manufacture Shen Guo Lao Nian Granule. Neither the funding agency nor any outside organization participated in the study design. Hebei Baishan Pharmaceutical Co., Ltd., had final approval of the manuscript.
Xuemei Liu and Juanjuan Fu are co-first authors; they contributed equally to this work and participated in the study design and development of the study protocol, ethics, trial registration, and the manuscript draft. Hongli Jiang, Bing She, Tao Fan, and Guanhong Li contributed to the development of the study protocol. Ying Lan and Wei Liu reviewed the manuscript. Riming Zhang, Hong Ding, Haimiao Yang, Siyuan Hu, and Yuhong Huang are identified as chief investigators and contributed to arrangement of clinical process at individual centers. Bing Mao is the general supervisor for this research and participated in the study design and protocol development. All authors critically reviewed the content and approved the final version.
The study is financially supported by Hebei Baishan Pharmaceutical Limited Company, Beijing, China.