A Series of N-of-1 Trials of Traditional Chinese Medicine Based on Bayesian Method

Phase 4

• Conditions: Sputum; Bronchiectasis; Quality of Life; Traditional Chinese Medicine; Individuality; Symptoms
• Interventions: Drug: Individualized Decoction; Drug: placebo; Drug: Tested drug minus heat-clearing herbs

• Registration Number: NCT04601792
• Lead Sponsor: Shanghai University of Traditional Chinese Medicine

Brief Summary

The guiding role of parallel randomized controlled trials in clinical practice is limited due to the insufficiency of individual information. Our previous studies showed that Single case randomized controlled trials (referred to as N-of-1 trials) could reflect the individualized characteristics of traditional Chinese medicine (TCM) syndrome differentiation with good feasibility, but the sensitivity was low.

This study aims to compare the efficacy of treatment based on syndrome differentiation with controlled decoctions (placebo, and the method of strengthening the body resistance and removing phlegm) among patients with stable bronchiectasis through a series of N-of-1 trials (single-patient, double-blind, randomized, multiple crossover design), with the 7 point-likert scale of the most concerned symptoms as the main outcome. Hierarchical Bayesian statistical methods and some parameters and variables will be introduced, such as TCM syndrome type, potential residue effect of TCM, etc. The sensitivity and applicability of various mathematical models (Hierarchical Bayesian, paired t-test and Meta-analysis) for N-of-1 trials of TCM will be tested, for the purpose of improving the sensitivity and applicability of N-of-1 trials of TCM both on individual and group levels.

Detailed Description

TCM has made great progress in the context of modern science and technology, but compared with the rapid development of modern medicine, the development of TCM has been relatively slow. The randomized controlled trial based on population is incompatible with the characteristics of TCM syndrome differentiation. The lack of reliable efficacy evaluation methods based on evidence-based medicine has hindered the internationalization and development of TCM.

The clinical trial (International clinicaltrials.gov Identifier: NCT03147443) the investigators just finished found that the improved mixed effects model can detect the residual effect of TCM in the N-of-1 trials and improve the sensitivity of group data statistics. However, the sensitivity of this study method is low at the individual statistical level due to the inherent nature of N-of-1 trials, and more cases need to be studied for further improvement. Now that hierarchical Bayesian statistical method has become one of the major statistical methods in a series of N-of-1 trials. Compared with the frequentist statistical methods, the advantages of Bayesian method are as follows: (1) the integration analysis of both individual and group data can be carried out at the same time; (2) it is easy to introduce confounding variables, such as the physique or gene type of different subjects, or different TCM syndrome types (which are helpful to distinguish different TCM syndrome types and the difference of the effects); (3) in addition, there is a special advantage: if a large number of patients have completed similar N-of-1 trials with the variance within an individual patient greater than that between the patients, through "borrowing from strength" , the results of other patients can be used to improve the accuracy of an individual result, that is, to improve the sensitivity of N-of-1 trials, without the need to increase the pairs of N-of-1 trials. At present, this statistic method is rarely used in N-of-1 trials of TCM, so it is worth using for reference in our future research.

The key hypothesis of this study is that: (1) the efficacy of syndrome differentiation will be better than placebo in patients with stable bronchiectasis through N-of-1 trials. (2) the efficacy of syndrome differentiation will be better than the same prescription minus heat-clearing Chinese herbs in patients with stable bronchiectasis through N-of-1 trials. However, at the individual level, with the severity of individual phlegm heat, the efficacy will be different, reflecting the effect of individual treatment based on syndrome differentiation of Chinese medicine. (3) Hierarchical Bayesian statistical model will improve the sensitivity and applicability of N-of-1 trials of TCM both on individual and group levels.

In this study, the investigators will conduct a single center N-of-1 trials in 71 patients with stable bronchiectasis without hemoptysis and respiratory failure. These N-of-1 trials will be randomized, double-blind, crossover comparisons of individualized herbal decoction with control decoction within individual patients. Each N-of-1 trial will have 3 pairs of treatment periods. The duration of each treatment period will be 4 weeks. The investigators will compare: (1) the efficacy of syndrome differentiation (individualized decoction) with placebo, (2) the efficacy of syndrome differentiation (individualized decoction) with the same prescription minus heat-clearing Chinese herbs, in patients with stable bronchiectasis through a series of N-of-1 trials. The primary outcome is patient self-reported symptoms (such as cough, expectoration, shortness of breath, chest pain, and fatigue) scores on a 7 point likert scale. Secondary outcomes are 24-hour sputum volume and the chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) scores. Hierarchical Bayesian statistical methods and some parameters and variables will be introduced, such as TCM syndrome type, potential residue effect of TCM, etc. The sensitivity and applicability of various mathematical models (Hierarchical Bayesian, paired t-test and Meta-analysis) for N-of-1 trials of TCM will be tested, for the purpose of improving the sensitivity and applicability of N-of-1 trials of TCM both on individual and group levels.

Study Timeline

• Study Start: 2019-12-01
• Study First Submitted: 2020-08-24
• Status Verified: 2020-09
• Study First Submitted QC: 2020-10-20
• Last Update Submitted: 2020-10-20
• Study First Posted: 2020-10-26
• Last Update Posted: 2020-10-26
• Primary Completion: 2021-12-31
• Study Completion: 2022-12-31

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 71

Inclusion Criteria

• according to the consensus of domestic experts, combined with the guidelines for the management of adult bronchiectasis published by the European Respiratory Society in 2017;
• male or female, aged 18-70 years;
• being in the stable stage, and no acute exacerbation of bronchiectasis within the past three weeks;
• frequency of acute exacerbation of bronchiectasis ≤3 times every year;
• signed informed consent for participation.

Exclusion Criteria

• failing to meet the above criteria for diagnosis and inclusion;
• having developed respiratory failure with estimated survival time less than one year;
• having hemoptysis as a comorbidity;
• having complications by active tuberculosis;
• being pregnant or with severe heart, liver, or kidney dysfunctions;
• participating in other pharmacological clinical trials within the past 3 months.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Individualized Decoction	Individualized Decoction	It is the highly individualized treatment of TCM, the modification of Bronchiectasis Stabilization Decoction (Rhizoma Fagopyri Cymosi 30g, Radix Lithospermi 15g, Radix Ophiopogonis 15g, Poria cocos 15g, Radix Astragali 20g, Rhizoma Bletillae 10g, Platycodon grandiflorum 10g, Semen Coicis 30g) based on syndrome differentiation. For subjects with lung and spleen qi deficiency syndrome, the investigators added Radix Codonopsis Pilosulae, Pericarpium Citri Reticulatae, and Atractylodes Macrocephala Koidz. The investigators can adjust the individualized decoction in accordance with the change in the patient's condition throughout the whole study duration. The Chinese herbal decoction is taken by one decoction a day and divided into 2 doses, for 3 weeks in each observation period.
Individualized Decoction	placebo	It is the highly individualized treatment of TCM, the modification of Bronchiectasis Stabilization Decoction (Rhizoma Fagopyri Cymosi 30g, Radix Lithospermi 15g, Radix Ophiopogonis 15g, Poria cocos 15g, Radix Astragali 20g, Rhizoma Bletillae 10g, Platycodon grandiflorum 10g, Semen Coicis 30g) based on syndrome differentiation. For subjects with lung and spleen qi deficiency syndrome, the investigators added Radix Codonopsis Pilosulae, Pericarpium Citri Reticulatae, and Atractylodes Macrocephala Koidz. The investigators can adjust the individualized decoction in accordance with the change in the patient's condition throughout the whole study duration. The Chinese herbal decoction is taken by one decoction a day and divided into 2 doses, for 3 weeks in each observation period.
Individualized Decoction	Tested drug minus heat-clearing herbs	It is the highly individualized treatment of TCM, the modification of Bronchiectasis Stabilization Decoction (Rhizoma Fagopyri Cymosi 30g, Radix Lithospermi 15g, Radix Ophiopogonis 15g, Poria cocos 15g, Radix Astragali 20g, Rhizoma Bletillae 10g, Platycodon grandiflorum 10g, Semen Coicis 30g) based on syndrome differentiation. For subjects with lung and spleen qi deficiency syndrome, the investigators added Radix Codonopsis Pilosulae, Pericarpium Citri Reticulatae, and Atractylodes Macrocephala Koidz. The investigators can adjust the individualized decoction in accordance with the change in the patient's condition throughout the whole study duration. The Chinese herbal decoction is taken by one decoction a day and divided into 2 doses, for 3 weeks in each observation period.
placebo	Individualized Decoction	Placebo is made by dextrin, bitter agent, edible pigment etc. and added 5% test drug. The placebo and test drug have no differences in dosage form, appearance, color, specification, label, and so forth. The placebo is taken by one decoction a day and divided into 2 doses, for 3 weeks in each observation period.
placebo	placebo	Placebo is made by dextrin, bitter agent, edible pigment etc. and added 5% test drug. The placebo and test drug have no differences in dosage form, appearance, color, specification, label, and so forth. The placebo is taken by one decoction a day and divided into 2 doses, for 3 weeks in each observation period.
Tested drug minus heat-clearing herbs	Individualized Decoction	It is the decoction of the Individualized Syndrome Differentiation Decoction (tested drug) minus heat-clearing herbs. For example, heat-clearing herbs such as Scutellaria Baicalensis, Rhizoma Coptidisor Herba Violae will be removed from the Syndrome Differentiation Decoction. This control Chinese herbal decoction is taken by one decoction a day and divided into 2 doses, for 3 weeks in each observation period.
Tested drug minus heat-clearing herbs	Tested drug minus heat-clearing herbs	It is the decoction of the Individualized Syndrome Differentiation Decoction (tested drug) minus heat-clearing herbs. For example, heat-clearing herbs such as Scutellaria Baicalensis, Rhizoma Coptidisor Herba Violae will be removed from the Syndrome Differentiation Decoction. This control Chinese herbal decoction is taken by one decoction a day and divided into 2 doses, for 3 weeks in each observation period.

Primary Outcome Measures

Name	Time	Method
Patient Self-Rated Symptom Score (likert scale)	4 weeks	Patients rated the severity of the symptoms (such as cough, expectoration, shortness of breath and chest pain) on a 7 point likert scale. Optimize the number of questions to ensure that the most important aspects of the patient's problem are detected (usually four to eight items). Every day each patient scored the severity of these problems on the 7 point Likert scales supplemented by Visual Analogue Scales (VAS). The higher the score, the more severe the symptom.; The investigators consider an improvement of 0.5 points per question corresponds to a noticeable improvement in the patient's well-being. If there are seven questions, a total change of 3.5 or more points is considered clinically significant. Thus the mean difference of 0.5 points was defined as the "Minimal Clinically Important Difference (MCID)" for the 7 point scales.

Secondary Outcome Measures

Name	Time	Method
24 hours sputum volume	4 weeks	The investigators measured the 24h sputum volume at the beginning and the end of each treatment period of the trial. To ensure the accuracy of the measurement, the investigators asked the patients to spit sputum into a collector with scales from 8:00 am to the next 8:00 am. The investigators used the mean value of the sputum volume for 3 consecutive days as the outcome.
COPD Assessment Test (CAT)	4 weeks	The CAT had been proven to be effective and reliable in patients with bronchiectasis. CAT questionnaire is composed of 8 items. Each item has a score ranging from 0 to 5, thereby making the total score range from 0 to 40. Score of 0 represents the best quality of life and 40 does the worst. The MCID for the CAT has not been established officially, but it was estimated to be around 2 points.

Trial Locations

Locations (1)

Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine; 🇨🇳 Shanghai, China