This study is a multicentre, randomised, double-blind, simulant parallel-controlled clinical trial, with a total of 216 patients randomly assigned to the herbal treatment and control groups. The treatment group is divided into syndromes of Qi deficiency, stagnant and jamming dampness-heat, and spleen-kidney deficiency, and are administered Yi Aikang capsule, Tangcao tablet, and Jian Aikang concentrated pill according to the results of the symptom differentiation. Similarly, the control group is also divided on the same basis but are administered simulants of the above tablets according to the results of symptom differentiation. Patients’ symptoms will be identified during the follow-up period, and pharmaceutical preparations corresponding to the syndrome type will be administered each month according to the symptom differentiation results. The clinical efficacy of TCM in delaying the onset of HIV infection in patients will be evaluated using the time to endpoint events and incidence rate as the primary evaluation indicators and the immune function, viral load, symptoms, and TCM symptoms of HIV/AIDS patients as secondary effect indicators.
During the follow-up period, subjects may develop common community-acquired pneumonia. Therefore, the treatment group will be divided into a syndrome of phlegm-heat obstructing the lung and syndrome of phlegm-damp obstructing the lung according to TCM symptoms and treated with Qing Fei Pei Yuan Granules and Wen Fei Pei Yuan Granules, respectively. The control group will also be divided into the syndrome of phlegm-heat obstructing the lung and syndrome of phlegm-damp obstructing the lung according to TCM symptoms and treated with simulants of Qing Fei Pei Yuan Granules and Wen Fei Pei Yuan Granules, respectively. CAP will undergo directly observed treatment for 14 days. Clinical symptoms, TCM symptoms, inflammation indices, C-reactive protein (CRP), procalcitonin (PCT), IL-17, CD4+ IL-17+Th17, CD4+IL-4+Th2, IFN-γ, and CD4+IFN-γ+Th1 will be used as observation indices to study the effect of Qing Fei Pei Yuan micro-pellets on reducing the morbidity and endpoint events as well as immune-enhancing effects in patients with AIDS lung infections.
During the follow-up period, the subjects may develop common diarrhoea, and the treatment group is diagnosed as a syndrome of dampness-heat blocking collaterals according to the TCM symptom differentiation and treated with Xielikang Capsules. The control group will be diagnosed as a syndrome of dampness-heat blocking collaterals according to the TCM symptom differentiation and treated with simulant of Xielikang capsules. Diarrhoea will be observed and treated for 7 days. The number of diarrhoeas, TCM symptoms, and stool routine will be used as observation indices to study the effects of Xielikang capsules in reducing the incidence of diarrhoea and endpoint events in patients with diarrhoea in AIDS.
As the leading unit of research, the First Affiliated Hospital of the Henan University of TCM is responsible for training the standard operating procedures and monitoring the progress of all clinical trials. Other participating units and recruitment allocations: Shanghai Public Health Clinical Centre (30 patients), Beijing Ditan Hospital Capital Medical University (16 patients), Sichuan Academy of Chinese Medical Sciences (50 patients), Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine (50 patients), Kunming Municipal Hospital of Traditional Chinese Medicine (30 patients), and the First Affiliated Hospital of Henan University of Chinese Medicine (40 patients). The flow chart is shown in Figure 1. This study protocol is registered with the China Clinical Trial Registry, Trial registration number: ChiCTR1800018365.
Patients with HIV/AIDS who chose not to use ART and patients with Qi deficiency, damp-heat, sleep, and kidney will be enrolled in this study. Referring to the “Diagnostic criteria for HIV/AIDS (WS293-2008),” "Clinic terminology of traditional Chinese medical diagnosis and treatment-Syndromes (2002)" "TCM diagnosis and treatment criteria for HIV/AIDS (2016)" as follows: (1) Syndrome of Qi deficiency or unidentifiable syndrome; the primary symptoms are fatigue, weakness, and disinclination to talk. Secondary symptoms are dizziness, dim-complexioned, palpitations, and spontaneous perspiration. The tongue is slightly pale or normal, and the pulse is either deficient or normal or there are no obvious clinical symptoms and TCM signs and symptoms, with normal signs of pulse and tongue colour. (2) Syndrome of stagnant and jamming dampness-heat; the primary symptoms are dizziness and sleepiness. The secondary symptoms are chest tightness, abdominal fullness, mucous mouth dullness, loose stools, and sticky and foul-smelling vaginal discharge in females. The tongue appears red, with a thick, greasy, or yellowish and greasy coating, or both yellowish and whitish. The pulse is soft or slippery. (3) Deficiency of the spleen and kidney; the primary symptoms are fatigue, soreness, and weakness of the waist and knees or lumbago. The secondary symptoms include abdominal fullness, loss of appetite, intolerance of cold, pale face, loose stools, frequent urination, and tinnitus. The tongue is pale or swollen, with a thin white or white smooth coating and a deep and faint pulse.
CAP in this study refers to the “Guidelines for the diagnosis and treatment of CAP in Chinese adults (2016)” and “TCM diagnosis and treatment of AIDS cough (CAP).” TCM differentiation criteria for community-acquired pneumonia are as follows: (1) Syndrome of phlegm-heat obstructing the lung; the primary symptoms are cough, fever, shortness of breath, and yellow and thick or white sticky sputum. Secondary symptoms include dry mouth, bitterness, dysphoria, constipation, short and red urine, persistent coughing and vomiting, or bloody sputum, as well as distension and fullness in the chest. The tongue is red with a yellow and greasy coating, and the pulse is slippery. (2) Syndrome of phlegm-dampness retention of the lung; the main symptom is a heavy, muddy cough with excessive phlegm, which is sticky and greasy or thickened into lumps. The secondary symptoms are chest tightness, abdominal fullness, vomiting, poor appetite, and fatigue. The tongue is pale, with white and greasy coating, and the pulse is soft and slow or slippery.
Diarrhoea is referred to “TCM diagnosis and treatment plan for AIDS (adult).” TCM differentiation criteria for diarrhoea; syndrome of dampness-heat blocking collaterals; the main symptoms are diarrhoea and abdominal pain, persistent diarrhoea, yellowish-brown faeces, foul odour, and driving discharge. The secondary symptoms are burning sensation in the anus, irritability and thirst, and short yellowish urine. In addition, the tongue is red with a yellowish and greasy coating, and the pulse is soft or slippery.
Patients must meet all the following criteria: (1) HIV/AIDS diagnostic criteria; (2) the number of CD4+ T cells ranges from 250 to 500/μl; (3) comply with the criteria for TCM syndrome criteria; (4) age of 18-65years old, sex is not limited; (5) provision of signed, informed consent.
Patients meeting the following criteria are excluded from the study: (1) patients who are participating in other clinical trials or have participated in other clinical trials within the past 3 months; (2) patients receiving HAART(Highly Active Antiroviral Therapy); (3) patients with a combination of severe organic heart disease and severe arrhythmia, patients with abnormal liver function (alanine transaminase or aspartate transaminase greater than two times of the upper limit of normal value), patients with abnormal renal function (serum creatinine greater than 1.5 times the upper limit of normal value), patients with active tuberculosis or patients undergoing anti-tuberculosis treatment, patients with haematologic disorders; (4) patients with combined tumours; (5) patients with severe psychiatric and neurological disorders; (6) pregnant or lactating women, or women preparing for pregnancy; (7) patients with allergies and patients who are allergic to the test article; (8) patients with a history of alcoholism (drinking more than 150 mL of alcohol per day) or those with manifestations of alcohol dependence syndrome.
According to our pre-experiment, the incidence of endpoint events in the control group was 35%; meanwhile, the incidence of endpoint events was 8% in the TCM group. Therefore, the required sample size was 33 cases in the control group and 66 cases in the treatment group. According to the situation of the existing subjects and the 10% shedding rate, the final sample size for the whole experiment is 216 cases.
The statistical unit uses the central stratified block randomisation method for a randomised assignment using a central randomisation system. First, the investigators will obtain the randomisation numbers of the patients from the data management unit, the Institute of Basic Research in Clinical Medicine, China Academy Of Chinese Medical Sciences, via the internet. The seed number is set to any 6-digit number, and the length of the block is 6. Then, the subjects are randomised into treatment and control groups at a 1:1 ratio. Finally, the treatment code is generated and used by each clinical centre according to the assigned drug number and in the order of case enrolment.
Volunteers meeting the inclusion criteria will receive an information form and be required to provide written consent to participate in the trial. Physical screening tests will then be performed to determine if other comorbidities might affect the trial. After the successful screening, they will participate in the test and obtain the identification number for the test. Allocation to a group according to the random sequence number, baseline measurements will be performed for each participant, including clinical symptoms scores and TCM syndrome scores, CD4+, CD8+T, CD4+/CD8+, HIV viral load, blood, urine, stool routine, etc. The research scheme flow path is shown in Table 1. All outcome measures will be managed by experienced medical workers, but the group classification of the participating groups is blinded to them.
The treatment group received three different TCM drugs (YAK capsule, TCP tablets, JPYQF pills) according to different syndrome differentiation. The control group received three different TCM placebo drugs (YAK capsule placebo, TCP tablet placebo, JPYQ pill placebo) according to different syndrome differentiation. According to the monthly follow-up of TCM syndrome differentiation, the treatment group and the control group were given corresponding TCM drugs and placebo drugs. The total study period was 18 months.
If the subjects were infected with CPA during the trial, based on antibiotic treatment, the treatment group would receive different TCM drugs (QFPY capsule, WFPY capsule) according to different syndrome differentiation. The control group would receive different TCM placebo drugs (QFPY capsule placebo, WFPY capsule placebo) according to different syndrome differentiation. The trial cycle continued for 14 days. The research scheme flow path is shown in Table 2.
If the subjects were infected with diarrhoea during the trial, based on antibiotic treatment, the treatment group would receive TCM drugs (XLK capsule) according to syndrome differentiation. According to different syndrome differentiation, the control group would receive TCM placebo drugs (XLK capsule placebo); the trial cycle continued for 7 days. The research scheme flow path is shown in Table 3.
TCP tablets have been approved by CFDA (z20050291) and produced by Shanghai Hundreds Ace Herbal Pharmaceutical co., Ltd. However, the composition of the drug (YAK capsule, TCP tablets, JPYQF pills, QFPY capsule, WFPY capsule, XLK capsule, produced by the affiliated hospital of Henan Academy of Chinese Medicine) cannot be disclosed because the formula is patented.
Placebo drugs consist of 1/10 of the original drug and starch produced by the same manufacturer. Placebo matches the appearance and taste of the drugs and is consistent with directions in the treatment group.
The major therapeutic index. In this trial, the time and incidence of endpoint events and clinical symptoms score as mentioned in Table 4 were used as the main evaluation indexes. In addition, a comparison of the difference between the treatment group and the control group and the incidence of observation indices were used as the basis for efficacy evaluation.
Endpoint event criteria refer to the “Chinese guidelines for the diagnosis and treatment of AIDS (2018).” Anyone with the following criteria can be diagnosed as AIDS: (1) unexplained per2sistent irregular fever of 38°C or higher, >1 month; (2) diarrhoea (stool more than three times/day), >1 month; (3) weight loss of 10% or more within 6 months; (4) recurrent oral fungal infections; (5) recurrent herpes simplex virus infections or herpes zoster virus infections; (6) pneumocystis pneumonia (PCP); (7) recurrent bacterial pneumonia; (8) active tuberculosis or nontuberculous mycobacteriosis; (9) deep fungal infections; (10) space-occupying lesions of the central nervous system; (11) dementia in the middle-aged and young adults; (12) active cytomegalovirus infection; (13) toxoplasma encephalopathy; (14) Talaromyces marneffei infection; (15) recurrent sepsis; (16) Kaposi's sarcoma, lymphoma of the skin mucosa or viscera.
TCM syndrome score
TCM syndrome refers to the “Guiding principles for clinical research of new drugs of TCM (Trial) (2002)”, “TCM diagnosis and treatment criteria for HIV/AIDS (2016).” We conducted a comprehensive evaluation on fatigue, mental fatigue, dizziness, palpitation, etc. The evaluation criteria of the TCM syndrome score are shown in Table 5. Efficacy index (n) = [(pre-intervention scores - post-intervention scores)/pre-intervention scores] × 100%.
Clinical recovery: TCM clinical symptoms and signs approximately disappeared; TCM syndrome scores decreased by ≥90%.
Markedly effective: TCM clinical symptoms and signs are significantly improved; TCM syndrome scores reduced by ≥70%.
Effective: TCM clinical symptoms and signs are improved; TCM syndrome scores reduced by ≥30%.
Invalid: TCM clinical symptoms or signs are not improved and even aggravated; TCM syndrome scores reduced by <30%.
Effective: HIV load decreased >1 log/ml;
Invalid: HIV load increased >1 log/ml;
Steady: HIV load decreased or rose <1 log/ml;
Effective: CD4 cell count increased 50 cells/mm3 or >30%.
Invalid: CD4 cell count decreased 50 cells/mm3 or >30%.
Steady: CD4 cell count increased or decreased not up to 50 cells/mm3 or 30%.
From baseline to the end of the study, routine blood, urine, stool, liver and kidney functions, electrocardiogram and chest X-ray were performed every 4 weeks. Any adverse events during the trial will be recorded in detail.
The Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) figure of enrolment, interventions, and assessments is shown in Fig. 2. The SPIRIT checklist is provided as Additional file 1.
Quality control and data management
At the pre-clinical trial coordination meeting, the medical workers who participate in clic data acquisition system, and upload it to the central database. To maintain thenical research of each sub-centre shall be trained before the clinical trial. The team leader unit of the subproject shall control the quality of each sub-centre to ensure the authenticity and specification of data. The case form and electronic case collection management system were used together. During the clinical follow-up, the visiting doctors fill in the case report form, then double input it in the clinical research electroni objectivity of the data, we will ensure that observers and statisticians are blinded to the data. The whole process will be supervised by an independent quality inspector. Guangzhou Boji Pharmaceutical Biotechnology Co. Ltd is responsible for data management.
Serious adverse event reporting and monitoring
Any serious adverse events deemed to be related to the intervention or due to study participation will be reported to the chief investigator within 24 hours. The First Affiliated Hospital of Henan University of Chinese Medicine will be responsible for serious adverse events.
Drug compliance was determined at each visit. Compliance evaluation index: 80-120% of the prescribed dosage is the standard of good compliance, otherwise it is poor compliance. The compliance was calculated as follows: medication compliance = the total amount of drugs actually taken / the amount of drugs that should be taken × 100%.
It means that during the trial period (including the screening period and the treatment period), the same or similar efficacy of traditional Chinese medicine can not be used at the same time. If patients have common complications during the trial, anti-symptomatic measures were only scheduled. In case of community-acquired pneumonia and diarrhea specified in the plan, traditional Chinese medicine preparation specified in the plan will be given on the basis of conventional western medicine treatment. All drugs used during the trial should be recorded in the case report form.
All statistical analyses will be performed using SAS 9.0. All statistical tests were performed using a two-sided test, and a p-value less than 0.05 will be considered statistically significant. Baseline information, such as mean, standard deviation, minimum, and maximum values, will be calculated to describe quantitative indicators. Categorical indicators will be described by frequency. For the analysis of efficacy and safety indicators, Cox survival analysis will be used to compare the time to endpoint events between the two groups, and Chinese medicine symptoms will be analysed using the chi-square test or rank-sum test.
Patient and public involvement
Patients and their families did not participate in the study design. However, the results of the study will be widely distributed to scientific reports and academic conferences for the benefit of policymakers, clinicians, and patients.
Ethics and communication
All volunteers will sign an informed consent form, and the study will follow the tenets of the Helsinki Declaration. This trial will follow the Chinese clinical trial research regulations and norms. Biological samples will be treated following the national guidelines for biological waste management and disposal. The results will be published in international peer-reviewed journals and academic conferences. The results will also be fed back to volunteers to ask about the patient's health during the follow-up period.