Study design and participants
This multicenter, randomized, parallel-group controlled trial recruited patients with GAD from eight hospitals (5 sites from Shanghai, Beijing, Guangdong province, Henan province) between January 2012 and September 2018.
The inclusion criteria were as follows: (1) inpatients or outpatients; (2) DSM-IV criteria for GAD; (3) aged 18–65 years; (4) Hamilton Anxiety Scale (HAMA) score of screening and baseline of ≥17; and (5) administration of SSRI, SNRI, and NASSA agreeing to discontinue and elute for 2 weeks.
The exclusion criteria were as follows: (1) severe suicidal tendencies; (2) score of item 6 in HAMA≥3; (3) Hamilton Depression Scale (HAMD) score ≥21 at screening; (4) baseline HAMA score reduction rate ≥25% compared with screening; (5) anxiety disorder secondary to other mental or physical diseases; (6) lactation, pregnancy, or possibility of becoming pregnant during the trial; (7) severe or unstable heart, liver, kidney, endocrine, blood, respiratory, and other medical diseases, or history of abnormal blood thyroid-stimulating hormone level; (8) history of epilepsy, except for childhood febrile convulsions; or (9) currently using benzodiazepines to treat anxiety.
This study was approved and supervised by the ethics committee of Tongji Hospital of Tongji University [Approval No. (Tong) Lun Shen No. (117)]. Written informed consent was signed by all patients. The trial registration no. was NCT01614041, the date of registration was June 7, 2012.
Randomization and intervention
Patients were randomized 1:1 into 60 mg/day and 30 mg/day groups using the stratified block randomization (the stratification factor was central).
Patients with GAD were given tandospirone 20 mg three times per day (60 mg/day group) or 10 mg three times per day (30 mg/day group) for six consecutive weeks and were followed up at weeks 0, 1, 2, 4, and 6.
The primary endpoint was the overall response rate at week 6. The secondary endpoints included significant response rate and recovery rate at week 6 and the change in HAMD-17, HAMA total score, and HAMA subscale score (somatic anxiety factor, psychic anxiety factor, fear symptom factor, insomnia symptom factor, memory symptom factor, cardiovascular symptom factor, and gastrointestinal symptom factor) from baseline till week 6.
The overall response rate was defined as the percentage of patients with a decrease in HAMA total score ≥50% relative to baseline. The significant response rate was defined as the percentage of patients with a decrease in HAMA total score ≥75% relative to baseline. The recovery was defined as a HAMA score of ≤7.
Adverse reaction reports were used for safety evaluation. The frequency and number of adverse reactions and adverse reactions leading to withdrawal were counted. The incidence of adverse reactions was calculated.
Calculation of sample size
Two-sided tests were used to calculate effectiveness, with α = 0.05 and β = 0.2 (power = 80%). According to the literature , the overall response rate of tandospirone in the low-dose group was estimated to be 67% after 6 weeks of treatment. It was estimated that the high-dose group would be 15% better than the low-dose group in the present study. Based on the ratio of 1:1, the sample size of each group was calculated as 133 patents. Given loss to follow-up, 150 patients were enrolled in each group from a total of 300 patients.
SAS 9.4 (SAS Institute Inc., NC, USA) and SPSS 20.0 software (IBM Corp., NY, USA) were used for statistical analysis. Continuous data were tested with the Kolmogorov–Smirnov test for normal distribution. Normally distributed continuous data were expressed as means ± standard deviation. Categorical data were expressed as n (%). Normally distributed continuous data were tested using the Student t test. Categorical data were analyzed using the chi-square test or Fisher’s exact test. All statistical tests were performed using two-sided tests, with P<0.05 considered statistically significant.
Full analytical set (FAS) includes qualified patients and those lost to follow-up but does not include excluded patients. When the primary efficacy indicators were missing, the previous results were carried forward according to an intention-to-treat analysis.
Per-protocol analysis (PPS) refers to the set of patients that met the inclusion criteria, did not meet the exclusion criteria, and completed the treatment plan, that is, patients that met the trial plan with good compliance and completed the case report form requirements.
Safety set (SS) refers to the actual data of patients who received at least one treatment with safety index records. The missing values of safety were not carried forward.
The endpoints were analyzed using FAS and PPS. Adverse events were analyzed using SS.