Setting and design:
This study is a multicentre, randomized, double-blinded, placebo-controlled, parallel-group 6-week treatment clinical trial. Eligible participants will be randomly assigned to an intervention group (Antianxiety Granule) or placebo group at a ratio of 2:1. The participants will be recruited from the following six hospitals: Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai Seventh People's Hospital, Shanghai Chinese and Western Medicine Hospital, The Fifth People's Hospital of Shanghai, Fudan University, Jingan District Hospital of Traditional Chinese Medicine, and Yangpu District Hospital of Traditional Chinese Medicine. The study consists of three periods: a 1- to 7-day screening period, a 6-week primary treatment period, and a 1-week follow-up period. Participants will be assessed at baseline, and at 2th, 4th and 6th weeks after the intervention begins. Follow-up assessments will be conducted 1 week after the last visit with face-to-face interviews or by telephone (Fig. 1). In this study, the clinical efficacy of Antianxiety Granule will be assessed for the treatment of GAD by examining changes in the Hamilton anxiety scale (HAMA) score, state-trait anxiety inventory (STAI) score and the TCM symptom scale in GAD patients who receive daily TCM treatment. The flowchart of the study progress can be seen in Figure 1, and the timing of the treatment visits and data collection can be seen in Table 1.
Participants
Inclusion criteria
The study inclusion criteria are as follows:
- The participant is a male or female outpatient aged 18-70 years
- The participant meets the diagnosis criteria of GAD (International Classification of Diseases, 10th Revision (ICD–10)) and meets the symptom criteria for at least 6 months
- The participant has never taken anxiolytics or has stopped anxiolytics for at least half a month
- The participant has a HAMA score > 14
- The participant has high adherence and will take the granule for 6 weeks and will participate in a follow-up 1 week later
- The participant was diagnosed with a TCM syndrome type according to the Diagnosis and Treatment Scheme for Anxiety Disorder of TCM, which is in line with the TCM Internal Medicine and the Mental Illness key specialties of the Shanghai Municipal Hospital of Traditional Chinese Medicine
- The participant participates voluntarily; signed informed consent is required
- Strict criteria: The participant has experienced poor psychosocial functioning and has feelings of unbearable pain and the inability to escape
Exclusion criteria
The exclusion criteria are as follows:
- The participant has organic psychosyndrome or an anxiety disorder caused by psychoactive substances and non-addictive substances
- The participant is currently pregnant or lactating or is of reproductive age and is not willing or unable to cease contraceptive use during treatment
- The participant has obvious heart, liver, kidney or other systemic symptoms
- The participant’s laboratory tests and electrocardiogram (ECG) show no clinically significant abnormalities, and the judgement method by the investigators can influence the evaluation of the granule or the participant's safety
- The participant’s aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels exceed 2.0 times the upper limit of normal
- The participant participated in other drug clinical trials within the previous 4 weeks
- The participant has a Hamilton depression scale (HAMD) score ≥18
Sample size
A sample size of 252 participants will be recruited on the basis of the pre-post trial. On the basis of previous results and considering an anticipated loss rate of 20%, with a significance level of 0.05, 252 patients will be needed. These 252 patients will be randomly divided into two groups (168 participants in the Antianxiety Granule group and 84 participants in the placebo group, with a ratio of 2:1).
Recruitment
The participants will be recruited via advertisement posters on bulletin boards in the hospital. If they are willing to participate, they can initially be screened by phone to determine if the basic criteria are met. Then, participants will be further assessed face-to-face by professional researchers. Once the participants are evaluated with the inclusion or exclusion criteria and volunteer to participate, the researchers will explain the study’s procedure in detail, and they will be asked to sign a written informed consent form before the intervention begins.
All participants can withdraw their consent at any time during the trial.
Randomization, allocation, and blinding
The random allocation schedule will be generated by Bingshun Wang, Ph.D.,Professor of Medical Statistics, Head, Department of Biostatistics, Shanghai Jiao Tong University School of Medicine (SJTU_SM). Randomization will be performed in SAS version 9.4 by computerized, permuted blocks and stratified by trial centre. The random allocation schedule (including the random numbers and block size) will be sealed in an opaque envelope to conceal group allocation, and allocation concealment will be maintained by the main study administrator/sponsor to avoid selection bias. The randomized allocation schedule and duplicated blinding codes will not be opened during the trial. Simultaneously, a corresponding emergency letter will be prepared for each participant, and the envelope containing the treatment mode will be marked with the participant number. The emergency letter will not be removed unless it is required to do.
The treatment is a double-dummy trial. Participants who meet the inclusion criteria will be randomly assigned to an intervention group (Antianxiety Granule) or placebo group at a ratio of 2:1. Both participants and attending study personnel will not be able to identify the intervention group or placebo group by appearance, packing, labelling or shape. All the researchers will receive training on the specifications of this study and will be asked to strictly adhere to those specifications.
Interventions
Eligible participants will receive an Antianxiety Granule or placebo treatment twice daily for 6 weeks according to the random assignment. The Antianxiety Granule is composed of Cyperi Rhizoma, Amomum aurantiacum, Cinnamomi Cortex, Curcumae Radix, Radix Salviae, Gardeniae Fructus, Licorice, Polygala tenuifolia, Albizzia bark, Polygoni Multiflori Caulis, and Daylily. The herbs will be mixed into brown, bitter, herbal extract granules, and the placebo will consist of one-tenth of the Antianxiety Granule. Both the Antianxiety Granule and placebo will have an identical appearance, colour, and smell. All granules will be packaged in sealed, opaque single-dose sachets with similar labelling. Participants will receive two packaged dose bags (14 doses per bag) every 2 weeks, three times in total, and they will be requested to return the unused granules to the research teams. The use and returning of the granules will be noted on the case report forms (CRF) by the researchers. All participants will receive some transportation allowances at the end of the trial.
Outcomes
Primary outcome
The primary outcome measure will be a change in the HAMA score[15]. The HAMA scale is the most widely used assessment tool for anxiety disorders in psychiatric clinical and scientific research. The HAMA scale is a fourteen-item observer-rating questionnaire that can be categorized into two orthogonal groups, ‘psychic’ and ‘somatic’ anxiety. The outcome will be assessed by the difference in the HAMA score from the baseline.
Secondary outcomes
Secondary outcomes include the STAI score and TCM symptom scale.
The STAI is used extensively in research and provides a reliable self-reported scale for measuring emotional state (S-Anxiety) and personality traits (T-Anxiety)[16]. The STAI consists of two 20-item scales (state anxiety inventory (S-AI) and trait anxiety inventory (T-AI)). The S-AI is used to assess the intensity of anxiety as a transitory emotional state, and the T-AI is used to measure anxiety as a relatively stable personality trait. Each item has a 1-4 score rating. The higher the total score is, the more severe the anxiety is[17].
The TCM symptom scale will be used to assess the improvement of symptoms but symptom improvement will not be scored. The improvement of symptoms is defined as a reduction in the number of symptoms from enrolment to the end of the study. Each patient is required to record any change in symptoms on the CRF. The researcher will assess the change in symptoms at each visit.
Safety assessment and adverse events
Safety will be monitored throughout the trial. Routine laboratory safety tests (including routine blood tests, urine tests, liver function tests (ALT, AST), and kidney function tests (blood urea nitrogen (BUN) and creatinine (Cr)) will be performed at the screening visit and visit 5. Safety will also be assessed via adverse events (AEs) and vital sign monitoring throughout the 6 weeks of treatment. AEs are defined as unexpected symptoms, signs, or diseases that occur during treatment, and all of the participants will be instructed to report any abnormal event. If AEs happen, the investigators will evaluate the relationship between the AE and the intervention. All AEs will be reported in detail on the CRF. The schedule of enrolment, interventions, assessments and data collection is presented in Table 1.
Quality control
To guarantee the rigour and quality of the study, it will be conducted at five hospitals. The investigators will be required to be trained to ensure the quality of the trial. All of the trial data will be fully integrated in the CRFs and monitored by the Clinical Research Centre of Drugs of the Shanghai Municipal Hospital of Traditional Chinese Medicine. Moreover, if any inconsistent data are identified, the primary data will be individually checked by the research monitor and the inconsistency will be reported. The database will be locked after it is reviewed and confirmed by the administrator and the inspector. The source data will be saved properly to assess the success of blinding, and patient-reported treatment guesses will be obtained to determine the success. Fisher’s exact tests will be used to analyse the data.
Statistical analyses
The main analysis will follow the intention-to-treat (ITT) principle and will be done as follows: the full analysis set (FAS) will include the randomized participants who received any treatment and completed at least one follow-up. The per protocol set (PPS) will include patients who complied with the protocol. Only when the minimum compliance rate of participants who received the investigational drug is 80% will we use the PPS. Participants who have at least one randomized treatment will be included in the ITT and safety set (SS). To estimate missing primary outcome variables, data from the last study will be used as the final result following the last observation carried forward (LOCF) principle. Data analyses will be performed by the statistical software SAS version 9.4 or SPSS 20.0.
Sociodemographic variables will be tested by t-tests for continuous variables. Matched data will be compared with the Wilcoxon test, and chi-squared tests will be performed for categorical variables. A repeated measures analysis of variance will be applied to assess the change across time of the primary and secondary outcomes. ANOVA for randomized block design will be utilized if the variance and covariance matrix meets the sphericity assumption. ANOVA for repeated measurement data may have two errors: errors among subjects are the errors corresponding to treatment, and errors within subjects are the errors corresponding to time and the interaction between treatment and time. Significance is considered when a two-sided alpha level of 0.05 is reached.
Clinical trial registration
The trial was registered under the registration number ChiCTR1800016039 (http://www.chictr.org.cn/showproj.aspx?proj=27210) on 8 May 2018. The study was approved by the Ethics Committee of the Shanghai Municipal Hospital of Traditional Chinese Medicine (2017SHL-KY-14).