The treatment for MDR-PTB is a complex and long-term undertaking, the content of the present study involves the following aspects.
Sputum will be collected and the M.tb strain will be determined using GeneXpert testing and culture with BD960 system, DST of M.tb stain will performed using the BD960 system. For each patient, M.tb strain identification and DST will be conducted once a week during weeks 0–12, then once per month during months 4–11 (Table 2).
Each patient will undergo chest computed tomography (CT), it will evaluate lesion absorption and cavity closure (Table 2).
The basic demographic information of each subject will be collected using a structured questionnaire, to include age, gender, height, weight, place of birth, residence, level of education, religion, level of income, basic disease characteristics. In addition, the structured questionnaire will be used to collect details of patient lifestyle, such as level of smoking, drinking, history of silicosis, pneumoconiosis, lung infection, contact history with MDR-PTB patients, and so on (Table 2).
Clinical manifestations of each patient will be recorded, including coughing, expectoration, hemoptysis, fever (low fever), fatigue, night sweats, tightness of the chest, chest pain, dyspnea, insomnia, emaciation, loss of appetite, or other symptoms (Table 2).
The short course chemotherapy regimen for MDR-PTB treatment will be consisted of a 6-month intensive treatment period (6MfxAmPtoCsZE) and a 5-month onsolidation phase (5MfxPtoZE). These chemotherapeutic drugs prescribed for each subject for the entire trial. In addition, the MDR-PTB cases with Qi-yin deficiency will be allocated to the treatment or control group at a ratio of 2:1 (treatment group:control group) using a randomization process. The treatment groups will receive chemotherapeutic drugs plus Chinese herbs granules (1 + 3 granules), whereas the control group will receive chemotherapeutic drugs plus Chinese herbs placebo (1 + 3 placebo granules). Meanwhile, MDR-PTB patients with Yin deficiency lung heat syndrome will be allocated randomly to the a treatment or control group at a ratio of 2:1 (treatment group: control group). The treatment group will be treated with chemotherapeutic drugs plus Chinese herbs granules (2 + 4 granules), and the control group will be treated with chemotherapeutic drugs plus Chinese herbs placebo (2 + 4 placebo granules, Table 3).
A drug administrator at each center will have the responsibility for the storage, distribution, recovery, record keeping, and retrieval of the experimental drugs. The chemotherapeutic drugs + Chinese herbs or chemotherapeutic drugs + Chinese herbs placebo will be provided to each subject by enrollment sequence. The grouping allocation of patients will remain unchanged throughout the trial. Drugs will be distributed at each follow-up examination during this study, while any unused drugs will be recovered during subsequent drug allocation.
All supplies of the chemical synthetic drugs and Chinese herbs will be stored at room temperature and protected from light, in a room with limited access, or within a locked cabinet in appropriate environmental conditions. Access to the study medication will be restricted to designated trial personnel. All medication will remain in the original packaging as delivered by the drug suppliers. The storage conditions and expiry date will be supplied with the investigational materials. A monitor will periodically check all supplies of study medication held by each investigator for accountability, and to ensure appropriate conditions of storage of the medication are utilized. At the end of the trial, all unused study medication will be collected by the monitor and returned to the sponsor, unless other arrangements are agreed.
As shown in Table 4, the primary efficacy endpoint is the cure rate, and the secondary efficacy endpoints are time to sputum culture conversion, lesion absorption rate, cavity closure rate and the effect rate of TCM syndrome between treatment group provide with chemotherapeutic drugs + Chinese herbs and control group treated with chemotherapeutic drugs + Chinese herbs placebo in Qi-yin deficiency patients, or in Yin deficiency lung heat syndrome.
Safety will be separately evaluated in terms of AEs (Table 4), clinical laboratory tests, ECG, physical examinations, and vital signs (Additional file 1: Appendix 1) for each trial period (screening stage, therapy process, and follow-up period).
AE is any inappropriate medical occurrence in a patient administered a pharmaceutical product that is not necessarily causally associated with the treatment. An AE can represent any unfavorable or unintended manifestation (including abnormal laboratory finding), symptoms, or disease temporally associated with the use of an investigational medicinal product, whether or not it is related to its administration. All AEs will be followed until they have abated, or until a stable situation has been reached. Depending on the event, follow-up may require additional tests or medical procedures, and/or referral to a general physician or a medical specialist.
Serious adverse event (SAE) is any unfavorable medical occurrence that shows in Table 4. SAEs need to be reported by the end of the study in China, as defined in the protocol.
Serious adverse reaction (SAR) is judged by either the reporting investigator or the sponsor as having a reasonable causal relationship. The expression “reasonable causal relationship” in general is used to indicate that there is evidence or an argument to suggest a causal relationship. Factors to consider when assessing causality of SARs are: (i) the nature of the reaction, (ii) timing of the reaction, and (iii) its relationship to the dose (Additional file 1: Appendix 1).
Discontinuation of study intervention
Participation in the clinical trial will be voluntary, all subjects having the right to suspend their consent from the trial prematurely, at any time and without stating a reason, and without disadvantaging any potential future medical treatment. In rare instances, it may be necessary for a participant to permanently discontinue study intervention (definitive discontinuation or withdrawal). Reasons for definitive discontinuation of the study intervention may include participant request, investigator request, pregnancy, protocol deviation (no longer satisfying all inclusion criteria, or fulfilling one or more of the exclusion criteria).
Note that discontinuation of study intervention does not represent a withdrawal from the study. If trial intervention is definitively discontinued, the participant will remain in the study and be evaluated for safety, immunogenicity, and potential efficacy. Follow-up for any evaluation required at the time of discontinuation will be conducted.
Discontinuation of study intervention, it must be documented on the appropriate CRF and in the medical records, including the participant has discontinued from further administration of study intervention alone, or also from the study procedures, post-treatment study follow-up, and/or future collection of additional information.
Participant withdrawal from the study
A participant may withdraw from this trial at any time at his/her own request. Reasons for discontinuation from the study may include the following: (1) Refusal to attend additional follow-up examinations. (2) Lost to follow-up. (3) Death. (4) Advice to withdraw because of poor compliance, comorbidities, or serious adverse events. (5) Participant request. (6) Investigator request. (7) Protocol deviation. (8) Patients who withdraw on their own due to poor curative effect, adverse reactions, or other reasons. (9) After allocation to…