Traditional Chinese Medicine (Xiao Tan San Jie Granule) for Covid-19 Patients in Rehabilitation Stage: Study Protocol for a Randomized Controlled Trial

Background: The Corona Virus Disease 2019 (Covid-19) caused pandemic all over the world. As more and more patients gradually are recovering from Covid-19, they still have some symptoms like short of breath, cough, and phlegm. how to improve their quality of life and shorten the rehabilitation time is still no widely recognized clinical program. In this study, we designed Xiao Tan San Jie (XTSJ) Granule based on traditional Chinese medicine (TCM) theory and assess its e�ciency and safety during rehabilitation stage of Covid-19 patients. Method/Design: This study is a 12-week, randomized, double-blinded, controlled, clinical trial that will include 132 Covid-19 patients. Eligible participants will be randomly assigned to XTSJ granule group or placebo group. Participants will receive 28 days treatment. The primary outcome assessment is scores of lung CT scan at week 2 and week 4. The secondary outcome assessment includes pulmonary function test, scores of Visual Analogue Scale (VAS) of Covid-19 symptoms, Scores of Qi De�ciency and Phlegm Stasis syndrome scale, Scores of St. George's Respiratory Questionnaire (SGRQ) at week 2 and week 4. Discussion: In TCM theory XTSJ granule has a regulate effect on respiratory function, lung infection, cough and phlegm which has the potential treatment effect on COVID19 patients. This study will provide initial evidence regarding the e�cacy and safety of XTSJ granule for Covid-19 patients in rehabilitation stage.

The imaging shows multi-lateral or multi-lobe in ltration [2].After the outbreak occurred, China quickly responded to the pandemic, established sheltered hospitals, implement strict quarantine, and issue a diagnosis and treatment plan.The number of con rmed cases was gradually decreasing and new cases of each day was less than 10 since 17, March.The current outbreak has been clearly controlled.And the recovery rate is getting higher and higher [3,4].However, patients discharged from hospital still have different degrees of lung dysfunction or interstitial lung disease, and therefore certain degrees of respiratory impairment [5,6].The prognosis and recovery of patients has profound impact on quality of life and economic burden of individuals, which is worthy of same attention.With a deeper understanding of the disease and rich experience in diagnosis and treatment, we focus not only on the treatment of the Covid-19 but also how to help patients recover from the sequela of the disease.
Since the outbreak of Covid-19, traditional Chinese medicine (TCM) has been playing an important role in the prevention and treatment.Some studies showed it could effectively reduce the disease progress rate from mild to severe and alleviate even cure the typical symptoms [7,8].It has a long history to apply Chinese medicine in rehabilitation [9], which accumulated abundant experiences.Chinese medicine in rehabilitation includes a variety of treatments like Chinese Herbs, acupuncture, physical therapy et al [10,11].This study aims to evaluate the effectiveness and safety of XTSJ granule for patients ever infected by Covid-19 and currently are in the rehabilitation stage.This rigorous designed randomized controlled trial (RCT) will provide an evidence with high level certainty regarding the value of TCM for controlling the epidemic and managing sequelae from Covid-19.

Design
This study is designed as a randomized, double-blind, multi-center, placebo-controlled trial.All participants will be recruited and followed by three medical centers (ChiBi, DongHu, XiHu hosptical) from HuangGang, China.Informed consent should be obtained from eligible participants before randomizing them into either XTSJ granule or placebo group.Both groups will receive the same respiratory training as the basic treatment.Besides, patients who don't consent to randomization but are strongly eager to receive treatment will be included in a nonrandomized XTSJ granule group.The study's schedule and ow chart is shown below(Tables 1 and 2).

Ethics
This study has been approved by the Ethics Committee of Beijing University of Chinese Medicine (No: 2020BZHYLL0111) in accordance with the principles of the Declaration of Helsinki (2013 version).Each eligible patient must sign a written informed consent before they are enrolled in the study.Participants will be informed in details about the risks and bene ts of participating in this trial.

Sample size calculation
This is a pilot study.The parameters for further sample size calculation in future expanded scale studies will be derived from the results of this trial.Feasibility including acceptability, e ciency and safety for XTSJ granule will be explored.Based on the principle of precision and e ciency, the sample size of 55 per group was planned in this study [12].Assuming the possible loss to follow-up rate is 20%, the total sample size will be 132, i.e. 66 patients for each group.We prepared 75 packages (1 package for each person) of drugs for each group to guard against the possible wastage of drugs or packing.Randomization An independent clinical research institution-GCP ClinPlus Co., Ltd.(GCP for short) (Beijing) company will generate the random sequence using SAS 9.2 software (SAS Institute Inc., Cary, NC, USA).Block randomization will be used to maintain the balance between groups in each center.The random sequence will be preserved by GCP ClinPlus Co., Ltd.If an emergency event occurs during the trial, the blinding could be uncovered with the consent of principal investigator of this study.Formal unblinding will be performed by GCP company once the trial ended.

Non-randomization Group
For patients who don't consent to randomization but are strongly eager to receive treatment, as this situation could re ect the real clinical scenario in future, we recruit them into the nonrandomized XTSJ granule group.Blinding This study is a double-blind RCT.The number of group and treatment will be sealed in envelop separately in emergency letter.The treatment and group information also will be blinded to both participates and investigators until the entire study is completed.The placebo was made as same appearance as the XTSJ granule.Both active drug and placebo are provided by Guangdong Yifang Pharmaceutical.The Active drug and placebo use the same box and label.The drug administrator will receive standardized training so that he can instruct patient clearly about the way to take the medicine.The evaluation of clinical e cacy was done by independent research members without knowing of the allocation information.

Diagnostic criteria
Discharge Criteria of Covid-19 pneumonia is based on Covid-19 Pneumonia Diagnosis and Treatment Program (Trial Version 7) [2].The patients who meet the below criteria can be discharged.
(1) body temperature returned to normal for more than 3 days.
(3) lung imaging showed signi cant improvement of acute exudative lesions.
(4) Nucleic acid was tested negative from sputum, Nasopharyngeal swabs or other respiratory tract specimens at least two consecutive times (sampling time at least 24 hours apart).Diagnostic criteria for TCM syndrome differentiation Qi de ciency and phlegm stasis syndrome: Qi de ciency and phlegm stasis syndrome of Covid-19 pneumonia refers to "Guiding Principles of Clinical Research on Traditional Chinese Medicine and New Drugs" and relevant literatures.Diagnose is made meeting at least three main symptoms and three secondary symptoms below, combining with tongue and pulse.
(3) Tongue and pulse: Pale or dark red tongue or with ecchymosis, greasy tongue fur, deep-feeble pulse, or small-uneven pulse.
(3) Meet the criteria of Qi de ciency and phlegm stasis syndrome in TCM.
(5) Lung CT scan shows the lesion is not absorbed within 14 days, scores ≧ 2.
(6) Can understand and sign informed consent.Exclusion criteria (1) Patients with severe primary and / or secondary cardiovascular, cerebrovascular, urogenital, endocrine, digestive, neurological and hematological diseases, tumors, or tuberculosis.
(2) Patients with pulmonary hypertension, congestive heart failure, deep vein thrombosis, unstable fractures, or other diseases.
(3) Those who have participated or are participating in other clinical trials within one month.
(4) Patients with mental disorders who cannot express their feelings.
(6) Other situations that cannot be included in this study.

Termination criteria
Participants have the right to discontinue to be investigated anytime even without any reason.subject withdrew from the study might due to dissatisfaction of treatment, intolerance of treatment, personal reasons, or economy issues et al.Intervention The participates in both experimental group and control group are administrated respiratory training as basic rehabilitation treatment following Covid-19 Pneumonia Rehabilitation Program for Discharged Patients (Trial) [13].The medicine intervention will last for 28 days.Investigators will distribute medicine to patients every two weeks.The investigator should record the amount of distributed, taken and returned medicine.Medication rate (actual dose/predicted dose) < 80% or > 120% is considered as poor compliance.The investigator should timely record all required information on the case report form.
(2) Placebo granule: 5% XTSJ, lactose, maltodextrin and food coloring.It is basically as the same as the XTSJ granule in terms of traits, color, and smell.It will be dissolved in warm water and be taken two times per day for 28 days.
(3) Primary outcome will also be evaluated by following categories: a. High improvement: CT score decreased by ≥ 70% ((CT scores before treatment-CT scores after treatment)/CT scores before treatment X100%).
c.No improvement: CT score decreased by less than 30%.
The observation is made before the intervention and on the fourth weekend of the intervention.

Diarrhea
Observation is made before the intervention and on the second and fourth weekend of the intervention.
(3) Improvement of TCM symptoms: Scores of Qi De ciency and Phlegm Stasis syndrome scale (Table 4).
Observation is made before the intervention and on the second and fourth weekend of the intervention.
Observation is made before the intervention and on the second and fourth weekend of the intervention.

Safety outcomes
The Safety outcomes will be performed before intervention as baseline, and on the second and fourth weekend of the intervention.

( 1 )
) Respiratory training in Covid-19 Pneumonia Rehabilitation Program for Discharged Patients (Trial):a.ACBT[14]: ACBT is a cycle of breathing control (BC), thoracic expansion exercises (TEE, bigger deep breaths), and forced expiration technique (FET, hu ng).BC is relaxed normal breathing using the lower chest.This helps to relax the airways for the next stage of deep breathing.TEE are three-to-four deep, full breaths where your lungs are slowly lled to full expansion.Hold your breath for 1-2 seconds, then exhale passively and easily.The FET is a combination of breathing control and one or two forced expirations (FET that should be performed by opening your mouth, keeping the back of your throat open and breath out sputum).Pay attention to cover up mouse using mask.b.Breathing pattern training: It Includes adjusting breathing rhythm (aspiration: exhalation = 1: 2), abdominal breathing training, and lip contraction breathing training, etc. c.Respiratory rehabilitation exercises: It includes neck exion and extension, chest expansion, turning, waist rotation, side body, squatting, leg raising, leg opening, ankle pump and other series of exercises according to the physical condition of the patient.(4).Combination therapy.a.If the participant has other diseases at the same time, and there is not necessary to terminate the previous medicine or treatment.b.Participants are not allowed to take other Chinese and Western medicines which is special for the recovery stage of Covid-19, or Chinese and Western medicines that might have interaction effects on the e cacy of XTSJ granule.c.The participants should report detailed information about the concomitant medication to investigators during the trial.The investigators should record and explain it in the case report, including the disease name, medicine, dose, usage, time of use, etc. Outcome assessment Primary Outcome Scores of lung CT scan Two senior radiologists read and analyze the CT performance and score it independently without aware of the allocation information.When the conclusions are not consistent, they should reach an agreement through consultation and review by the cardiothoracic doctor with the professional title.
the location and density of the lesion: Record the location of the lesion according to the lung lobes (left upper lobe, left lower lobe, right upper lobe, right middle lobe, right lower lobe), and record whether there is any lesion away from pleural.The Density of lesion is recorded as ground glass density or partially consolidated ground glass density.

Table 1
Schedule of Recruitment, Intervention, and Assessment.

Table 3
Lung CT Scan.

Table 4
Scores of Qi De ciency and Phlegm Stasis Syndrome Scale.Observation start before the intervention and on the fourth weekend of the intervention.