Study design

This will be a multicentre, randomised, double-blind, simulated, parallel-controlled clinical trial. Participants will be recruited from six centres: Shanghai Public Health Clinical Centre; Beijing Ditan Hospital, Capital Medical University; Sichuan Academy of Chinese Medical Sciences; Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine; Kunming Municipal Hospital of Traditional Chinese Medicine; and the First Affiliated Hospital of Henan University of Chinese Medicine. The study schema and estimated recruitment numbers are presented in Fig. 1. Eligible participants will be randomised to be assigned to the test group (TCM groups) or control groups (placebo) in a 1:1 ratio. Both groups will undergo a treatment period of 72 weeks and a follow-up period. Nineteen visits will be scheduled for each patient: baseline and each 4 weeks, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68 and 72.

Fig. 1

Flow of patients through the trial. TEE, time to endpoint events; EEIR, endpoint event incidence rate; CS, common symptom; VL, virological load; II, immunological indicator; IF, inflammatory factor; QOL, quality of life; PRO, patient-reported outcomes. Safety assessment: blood, urine, stool routine, liver and kidney function, electrocardiogram and chest X-ray. YAK, Yiaikang capsule; TCP, Tangcaopian tables; JAK, Jianaikang pill

Ethics and communication

The study received ethical approval from the Research Ethics Committee of the First Affiliated Hospital of Henan University of Chinese Medicine (Approval No. 2018HL-042). This trial adhered to the Declaration of Helsinki and has been registered at the Chinese Clinical Trials Registry (ChiCTR1800018365) on September 13, 2018. Patients willing to participate will sign a consent form prior to participating.

Setting and participants

Participants will be recruited from six large comprehensive hospitals in China: (1) Shanghai Public Health Clinical Centre; (2) Beijing Ditan Hospital, Capital Medical University; (3) Sichuan Academy of Chinese Medical Sciences; (4) Ruikang Hospital Affiliated to Guangxi University of Chinese Medicine: (5) Kunming Municipal Hospital of Traditional Chinese Medicine; and (6) the First Affiliated Hospital of Henan University of Chinese Medicine.

Inclusion criteria are as follows:

(1)

Patients who meet the criteria of HIV/AIDS diagnostic and chosen not to use ART

(2)

Number of CD4+ T cells ranges from 250 to 500/μL

(3)

Patients whose symptoms meet the Qi deficiency, damp heat and spleen and kidney deficiency according to the ‘Diagnostic criteria for HIV/AIDS (WS293-2008)’, ‘Clinic terminology of traditional Chinese medical diagnosis and treatment syndromes (2002)’ [11] and the ‘TCM diagnosis and treatment criteria for HIV/AIDS (2016)’ [12]

(4)

Patients aged 18–65 years and of either sex

(5)

Agree to sign the informed consent voluntarily

Exclusion criteria are as follows:

(1)

Patients who are participating in other clinical trials or have participated in other clinical trials within the last 3 months

(2)

Patients receiving highly active antiretroviral 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 the upper limit of normal values), patients with abnormal renal function (serum creatinine greater than 1.5 times the upper limit of the normal value), patients with active tuberculosis or patients undergoing antituberculosis treatment and patients with haematologic disorders

(4)

Patients with combined tumours

(5)

Patients with severe psychiatric or neurological disorders

(6)

Pregnant or lactating women or women preparing for pregnancy

(7)

Patients with allergies and patients who are allergic to the test substances

(8)

Patients with a history of alcoholism (drinking more than 150 mL of alcohol per day) or those with manifestations of alcohol dependence syndrome

Randomisation and blinding

Centralised randomisation was carried out by the Institute of Basic Research in Clinical Medicine, China Academy Of Chinese Medical Sciences, using the Clinical Research System (CRS), a remote electronic data capture. When an eligible participant is enrolled, the CRC has to register the detailed information of the participant on CRS. Then, after the confirmation of the investigator, the participant will be assigned to either the test or control groups in an allocation ratio of 1:1. The CRS will automatically generate the participant’s ID numbers and feedback to the investigator.

This trial is a double-blind trial in which the participants and investigators are blinded. The patients will receive a TCM drug or placebo.

Interventions

Eligible patients will be randomised into two groups: receiving a placebo or a TCM treatment. The TCM regimens include three kinds of TCM treatment corresponding to the three most common types of TCM syndromes in HIV/AIDS patients. As shown in Table 1, participants with indications of a syndrome type, including all clinical symptoms, tongue and pulse, and more than two systemic symptoms, will be diagnosed with the type by TCM physicians and received the matched drugs. Since participants’ symptoms are likely to change over time along with the treatment, the diagnosis of types will be redone before each cycle to determine which kind of CMP is the most tailored one.

Table 1 Indication of TCM and placebo

For the TCM group, patients will be given TCM interventions based on the TCM syndrome patterns, respectively, which are TCP tablets for stagnant and congested damp heat syndrome, YAK capsules for Qi deficiency and JAK pills for spleen-kidney deficiency syndrome. The TCM interventions are also recognised as a whole comprehensive intervention. The TCM group is component preparations of Chinese herbs, and its main components are shown in Table 2. YAK capsules (0.5 g per softgel) will give five softgel each time, TCP tablets (0.5 g per tablet) will give eight tablets each time and JAK pills (5 g per bag) will give one bag each time. All types of drugs will be given orally, thrice a day for 72 weeks. TCP tablets and placebo are produced by Shanghai Hundreds Ace Herbal Pharmaceutical Co., Ltd., Shanghai, China. YAK capsules, JAK pills and each placebo are made by the Affiliated Hospital of Henan Academy of Chinese Medicine, Zhengzhou, China.

Table 2 Main components of traditional Chinese medicine treatment

While those in the control group will take placebo granules composed of 90% and Herba pogostemonis (10%) in order to achieve the same colour, smell, taste and texture, and the participants are required to return the drug boxes and labels to the clinical research coordinator (CRC) as evidence of timely medication.

Data collection

To maintain the quality of the research, researchers in each centre will be trained before the clinical trial. We will collect basic data from each patient including their characteristics and past history of HIV/AIDS, outcomes and safety assessment data at baseline and follow them up until the end of the trial (Table 3). After review by clinical inspectors, completed CRFs, data entry and management are completed by two individual data administrators to ensure the accuracy of the data.

Table 3 Schedule of data collectionAssessmentPrimary outcome measure

The primary outcome is the time to endpoint events (TEE) and endpoint event incidence (EEI) as the primary evaluation indicator. Endpoint event criteria will be defined by referring to the ‘Chinese guidelines for the diagnosis and treatment of AIDS (2018)’ [13].

Secondary outcomes

The secondary outcomes are as follows:

Common symptom and TCM syndrome score: The effectiveness of TCM is evaluated using the common symptom sore method (Table 4) and the TCM syndrome sore method (Table 5). According to Guiding principles for clinical research of new drugs of TCM (Trial) (2002) [14], a reduction in TCM syndrome score by ≥ 30% indicates that the clinical symptoms improved or disappeared and the treatment is considered clinically effective. The TCM syndrome score is calculated as follows: [(scores before treatment − scores after treatment)÷scores before treatment] × 100%.

Virological load: HIV virological load (VL) will be done at baseline and week 72 during the follow-up. According to and TCM diagnosis and treatment criteria for HIV/AIDS [15], ratings are effective, invalid and steady.

Immunological indicators and inflammatory factors: CD4+ cell count, CD8+ cell count and CD4/CD4 will be done at baseline and weeks 12, 24, 48, 60 and 72 during the treatment period. According to and TCM diagnosis and treatment criteria for HIV/AIDS [15], ratings are effective, invalid and steady. Changes in inflammatory factors (IF) include interleukin(IL)-17, IL-4, tumour necrosis factor (TNF)-a, interferon-γ (INF-γ) and immunological indicator(II) including natural killer cell (NK), CD4+CD45RA+T lymphocytes, and CD4+CD45RO+T lymphocytes will be done at weeks 0 and 72 of the follow-up phase.

Quality of life (QOL) and patient-reported outcomes (PRO): Assessment of the quality of life of PHIV by using the WHOQOL-HIV-brief [16]  and Patient Peport Outcomes Assessment Scale (PLWHA-PRO) [17]. They will be observed and recorded prior to treatment, at baseline and weeks 24, 48 and 72 of the follow-up phase.

Table 4 Evaluation criteria of common symptomsTable 5 Evaluation criteria of TCM syndrome scoreSafety assessments

The participants’ blood, urine, stool routine, liver and kidney function, electrocardiogram and chest X-ray will be monitored at baseline and weeks 24, 48 and 72 during the treatment period.

Adverse event and oversight

Investigators will ask every subject at each visit whether they have experienced any adverse events (AEs) during the study period. If they have any AEs, the investigator will provide appropriate treatment to the subject immediately and record the AEs. In the case of serious adverse events (SAEs), the investigator will offer appropriate treatment to the subject immediately and report the event to the First Affiliated Hospital of Henan University of Chinese Medicine within 24 h from the time of recognition. If necessary, blinding will be broken by adequate procedure, and the documented procedure will be kept in the investigator’s study file. Any adverse events during the trial will be recorded in detail.

The oversight is in charge of Guangzhou Boji Contract Research Organization (CRO), through quarterly independently monitoring by clinical research associates (CRA) in terms of safety, quality and progress of the study.

Sample size

A pilot experiment we performed showed that the incidence of endpoint events in the control group was 35%, and the incidence of endpoint events in the TCM group was 8%. Therefore, the required sample size is 33 cases in the control group and 66 cases in the treatment group. According to the preliminary project research and considering the typical 10% dropout rate of patients who participate in therapy, the final required sample size for the trial is 216 cases.

Statistical analysis

All statistical analyses will be performed using SAS 9.0. All statistical tests will be two-sided, and P < 0.05 will be considered statistically significant. Baseline information, such as mean, standard deviation and minimum and maximum values, will be calculated to describe the 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 TCM symptoms will be analysed using the chi-square test or rank-sum test.