Based on theprocess management of traditional Chinese medicine comprehensive intervention method on outcomes inpatients with mild/moderate chronic obstructivepulmonary disease:studyprotocol for apractical randomized controlled trial

Ming Ren,Li-Ping Guo,Xiao Sun,Yang Qiao,Lei Chen,Lei Zhang,Yan Shao,Xiang-Li Han,Huai-Ying Ding,Jian-Mei Zhao

1Baokang Hospital of Tianjin University of TCM,Tianjin,China.2Tianjin University of TCM,88 Yuquan Street,Nankai District,Tianjin,China. 3Fourth Teaching Hospital of Tianjin University of TCM,90 Hangzhou Street,Binhai District,Tianjin,China.

Introduction

Chronic obstructive pulmonary disease(COPD),as a kind of limited airflow chronic respiratory disease,seriously affects the health quality of people.COPD has become a major public health problem worldwild.A recent report estimates that COPD has already been the fourth cause of death in the world,only after tumor, cardiovascular disease and cerebrovascular disease.As well as the study of global burden disease speculate that COPD will be the third cause of death by the year of 2020[1].Therefore the researchers should focus on intervention methods to delay the occurrence and development of COPD.

Epidemiological characteristics of COPD

The occurrence of COPD has strong correlation with season.COPD easily happens in the period when autumn changes into winter,accounting for 68.28%.Then the following is in the spring and autumn,accounting for 14.13% and 11.96% [2]. The recurrence of COPD is similar to occurrence of it.Therefore considering the seasonal factors in the prevention and management of COPD is necessary,reflecting the theory of traditional Chinese medicine.The lung function in patients with COPD is progressively damaging along with the development of disease,mainly showing that FEV1 declines year by year.At the same time,the recurrence of COPD will speed up the lung function declining and seriously affect the life expectancy and quality of patients with COPD[3].So it is important to develop a reliable intervention strategy for the prevention and management of COPD to reduce the occurrence of COPD.

Prevention and treatment on COPD

The research of TORCH and UPLIFT had proved that the bromide inhalation therapy of Salmeterol/fluticasone 50/500ug,thiamethoxam can alleviate the breathing difficulties,improve the quality of life and reduce the occurrence of acute exacerbation of COPD[4-5].However the treatment have several disadvantages, such as increased incidence of pneumonia, increased application quantity of antibiotics, cardiovascular side effects. In comparison, the TCM treatment can reduce the occurrence of acute exacerbation,improve immune function and less adverse reaction.A systematic evaluation of COPD intervention, including 40 randomized controlled trials, showed that TCM treatment can improve the lung function,the quality of survival,the clinical curative effect and reduce the occurrence of acute exacerbation of COPD [6].Meanwhile Gao Feng considered that TCM treatment could relieving symptoms and improve the quality of life for patients with COPD[7].

We report in this article on a practical,randomized,double-blinded, placebo-controlled trial of TCM treatment with syndrome differentiation,based on the real-world study,to test the problem that patients will benefit from the therapy with TCM.

Methods

Research type

Practical randomized controlled trialEthical approval was given by the Tianjin University of traditional Chinese medicine Ethics Committee of Registering Clinical Trial (TJUTCM-EC) with following reference number TJUTCM-EC20170002.The trial was registered at the Chinese Clinical Trial Registry(Registration ID:ChiCTR-INR-17010972).

Screening of participants

Participants with mild/moderate COPD will be divided into the treatment group and the control group,who should be enrolled according to diagnosis criteria and inclusion criteria.

Diagnostic criteria for western medicine

Referring to global initiative on chronic obstructive pulmonary disease in 2010 and revision of the guidelines for diagnosis and treatment of chronic obstructive pulmonary disease issued by the chronic obstructive pulmonary disease group of the Chinese medical association in 2013.

Diagnostic criteria for traditional Chinese medicine

Referring to“asthma”and“pulmonary distention”issued in the lessthan syndrome of diagnosis and treatment of common diseases in traditional Chinese Medicine and the syndrome criteria of chronic obstructive pulmonary disease issued in the clinical guideline for the diagnosis and treatment of common disease in Traditional Chinese Medicine.

Lifestyle intervention

Researchers will develop an individual health guidance and be established health record, by educating and managing participants in order to improve their personal understanding of COPD,their own ability to deal with diseases,better cooperating with treatment and strengthen the preventive measures. Besides, the researchers will collective patients to do a breathing exercise.

Drug intervention

The period of drug intervention is 9 months.All participants have to visit researchers each month.The interventions are as follows: Chinese traditional medicine granules for treatment group and the placebo of Chinese traditional medicine granules for the control group.When the illness become serious,the patients of 2 groups can take western medicine.The treatment group take TCM intervention by phases,namely 14 days every month,according to the actual needs of patients .If the condition of patients changes,they can return to visit researchers in advance because of syndrome differentiation.

The treatment drugs and their emulsifiers conform to the national standard Chinese medicine formula granules, which are basically consistent with the traditional Chinese medicine formula in terms to smell,color,shape and so on.

Randomization

The randomization of the trial will be completed by the independent data center named Interact Voice Responding System(IVRS).According to a random sequence table(generated by SARS8.2),participants who satisfied the inclusion criteria will be allocated randomly into one of the 2 groups with a ratio of 1:1.The identification code and random number which is unique for each participant,will be generated by the IVRS.

Blindness

The blinding method is adopted in this study.The placebo of TCM granules have the same appearance and packaging with TCM granules,so the researchers and patients can not know the kind of treatment and control group.

Sample size

The sample size is calculated based on the evidence from the previous study and the recommendation of clinical specialists [8]. It is assumed that the frequency of exacerbation of COPD is 1.0 in the treatment group,compared to 1.7 in the placebo group.The standard deviation is 1.0 in each group.To detect a significant difference between treatment and placebo group with a power of 90%and type I error of 5%,the number of each group should be 36.Considering a 10% drop-out rate, a total of 80 patients will be enrolled with 40 patients in each group.

Patients identification and enrollment

The inclusion criteria are as follows

(1)A confirmed diagnosis of mild/moderate COPD;

(2) The degree of disease of remission patients belong to grade I and grade II;

(3)Person aged between 40 and 80 years old;

(4)Not having participated in other interventional trials in the previous 2 months;

(5)Completed and submitted an informed consent form.

Exclusion criteria include

(1) Patients with an acute aggravating period of COPD;

(2) The degree of disease of remission patients belong to grade III and grade IV;

(3) Pregnancy, preparation of pregnancy and lactating women;

(4) Suffering from mental diseases or non-cooperation patients;

(5)Serious cardiac insufficiency and hemodynamic instability;

(6) Complication of neuromuscular disorders affecting respiration or of tumors;

(7) Complication of serious hepatic and renal diseases;

(8)A long period of bed rest;

(9)Using of oral or parenteral corticosteroids in the 1month before the first visit;

(10)Congenital or acquired immunodeficiency;

(11)Participating in other trials or being allergic to the used medicine.

Rejection criteria

(1) Could not take medicine according to the protocol;

(2) Data is incomplete: suspension criteria, poor compliance, serious adverse events, complications and special physiological changes, unblinded abnormally;

(3)Reluctance to continue this study;

(4)Taking medicine forbidding in this study;

(5)Withdraw for various reasons,such as failure to follow up for death.

(6)Incomplete information which will influence the study;

(7) Big mistake in the protocol or significant deviation in implement(such as the leak of blind);

(8)National laws,ministry of science and technology or other authorities decided to terminate the study.

Follow up

Intervention period:9 months,once a month for 9 months. After intervention: once a month after intervention,12 months.

Outcome measures

Primary outcome measure

Exacerbation:the frequency and duration of acute exacerbations of COPD(AECOPD)is the primary outcome measure.AECOPD is characterized by a change in patients,original conditions of dyspnea,cough,and(or)expectoration in the development of the disease,which is beyond daily routine variation and requires a change in regular medication.Frequency of exacerbation of COPD will be evaluated at every 3 months of the treatment phase and every 6 months of the follow-up phase.If the interval between two onsets of an acute exacerbation is within 5 days,it can be counted as one period of acute exacerbation.

The mitigation of pulmonary function:pulmonary function,namely forced vital capacity(FVC),FEV1,FEV1%will be evaluated prior to treatment.The third month,the sixth month and the ninth month of the treatment phase,as well as the sixth month and the twelfth month of the follow-up period.

Secondary outcome measure

The improvement of clinical symptoms and signs:recorded by every 3 months of the treatment period and every 6 months of the follow-up period.

Dyspnea:The Dyspnea Scale Questionnaire will be observed and recorded every 3 months of the treatment period and every 6 months of the follow-up period.

Quality of life:test CAT and short-form 36-item questionnaire(SF-36)will be recorded at every 3 months of the treatment period and every 6 months of the follow-up period.

Health economic indicators

The cost-effectiveness analysis is adopted to evaluate the economic of TCM intervention for COPD.Use cost-effectiveness ratio and increased cost-effectiveness ratio to analysis this results.

The costs:the study will calculate mainly the cost,which is used for disease diagnosis and treatment for patients with COPD,namely the direct costs,such as the cost of the examination,medication,treatment.

The effectiveness indicator is the frequency of exacerbation of COPD.

Adverse event monitoring

When an adverse event happens, the researchers should fill the adverse event report form according to the real circumstances, such as occurrence time,severity,duration,adopted the measure.At the same time, judgement of the relationship between the administration time and adverse reactions is very important.For example,judgment of the relationship between suspected and known adverse reactions of the investigational drug.

Security evaluation criterion

If no adverse drug reaction happens,the result is safe;if mild adverse drug reactions happen and do not need unnecessary treatment,it is proved relative safe;if adverse drug reactions happen and need necessary treatment, it is proved moderate adverse drug reactions and must stop to take investigational drugs.

Conclusion

The practical randomized controlled trial reveal that the COPD patients will be benefit from therapy with Traditional Chinese medicine treatment.

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