Study design
This trial is a prospective, randomized, single-centered, parallel-controlled clinical study with double-blind design. The study design is detailed in Fig. 1.
Recruitment
A total of 96 patients will be recruited from outpatient department of Beijing Anding Hospital affiliated to the Capital Medical University of China. Clinicians will diagnose and screen the patients for eligibility according to the inclusion and exclusion criteria. Potentially eligible patients will be informed and explained the detailed procedures of the study. Only those willing to provide written informed consent will be included to ensure that participation is entirely voluntary. We started recruitment in December 2019 and will finish in December 2020.
Inclusion criteria
- Meet the criteria of schizophrenia in ICD-10
- antipsychotic medication naive patients
- Age ≥16 and ≤ 40 years
- Patient can understand the follow-up questionnaire survey
- Meet the criteria of traditional Chinese medicine syndrome of JQG, which usually manifests as hallucination, delusion, weird thinking, incoherence of thinking, allophasis, infantilism, irritability, dry mouth, constipation, reddened tongue, yellow fur, rapid pulse, stringy pulse or slippery pulse
- Patient or proxy has signed written informed consent
Exclusion criteria
- Have a history of psychoactive substance abuse
- Have severe suicidal tendencies
- Women during pregnancy, lactation or Intending to become pregnant
- With serious heart, liver, kidney, endocrine, blood and other medical conditions
- Intake of antipsychotic medications in the previous 4 weeks
- Unattended
- Participation in other clinical drug trials in prior 30 days
- Compared to baseline, the reduction of PANSS screening score is more than 25%
Randomization, allocation concealment, and blinding
All participants will be randomly allocated to study group or control group (48 cases each) in a 1:1 ratio. An independent administrator manage the random processes. He or she will produce a computer-generated random sequence using SAS software, and seal serially the group assignments in opaque envelopes before the research. Participants will be grouped according to recruitment order and grouping code in the corresponding envelope. All participants, principal researchers, outcome assessors and statistician experts will blind to treatment assignment. In case of adverse events , the blinding should be removed immediately and the reason and time should be recorded in the Case Report Form. The unblinded participant will be excluded from the study.
Interventions
Patients assigned to experimental group will receive JQG and aripiprazole orally after completion of the randomization. And control group will be given placebo and aripiprazole. Aripiprazole is 5mg/tablet and will be provided by Zhejiang Otsuka Pharmaceutical Co, Ltd. JQG and placebo prepared by Beijing Kangrentang Pharmaceutical Co, Ltd, Beijing, China. The placebo is the same in color, smell, taste, appearance, packaging, and tag as JQG, but made from 5% original medicine, dextrin, food colorants, bitters, and water.
Aripiprazole will be started at 2.5mg qd., with an increase of 5mg every 1-2 days to the maximum dose of 20-30mg qd.. JQG or placebo will be brought back by the patient or the patient's caregiver. They will dissolve granules into 100 ml of boiled water, then take it between 30°C and 36°C. Each time 1 bag of granules, half an hour after meals in the morning and evening. The course of treatment is 12 weeks.
During the trial, trihexyphenidyl 2-4mg/day may be approved for treat aripiprazole - induced extrapyramidal reactions. Zopiclone and zolpidem are allowed to treat insomnia, but cannot be used continuously for more than 1 week. Notably, applying other drugs ,like antipsychotics, sedatives, antidepressants, anxiolytics, mood stabilizers, and other treatment is prohibited.
An overall schedule of trial-related activities are shown in Fig. 2.
Outcome measures
Primary outcome
Positive and Negative Syndrome Scale (PANSS) , a widely recognized rating scale for assessing schizophrenia symptoms[12], will be used as a primary measure of efficacy. We set the decrease of PANSS score before and after treatment as primary outcome. PANSS will be measured by independent professionals at baseline and every 4 weeks during follow-up. We will record the score of each measurement, and compare baseline score with post-treatment score to calculate the reduction rate. The higher reduction indicats greater effectiveness.
Secondary outcomes
- Assessment of cognitive function: comparison of scores of self face test and MATRICS Consensus Cognitive Battery (MCCB) from baseline to every 4 weeks.
- Evaluation of biological indicators: measure TNFα, IL-6, IL-1β and BDNF at before and after 12-week of treatment. We will take 5mL venous blood samples from each participant and store them at a low temperature. Various indexes will be determined by a professional using enzyme-linked immunosorbent assay (ELISA).
- Estimated security: observe variation of vital signs, complete blood count, liver and kidney function tests, urinalysis, and electrocardiograph. Vital signs include blood pressure, heart rate, temperature and weight. Those indexes will be measured at screening time and the end of 12 weeks’ follow-up by a researcher using the same testing instruments and methods.
Safety-reporting
In this trial, we will ensure that the study meets the highest ethical standards and patient safety. Treatment Emergent Symptom Scale (TESS) will be used to check the adverse events (AEs) at every visit[13]. Any AEs arising in participants during the intervention will be recorded. Then reporting it to the principal researcher and ethics committee to decide whether the participant needs to be drop out of the trial. In case of serious AEs, the report will be completed by email or telephone within 24 hours.
Data collection
CRFs designed for this study are used for data acquisition. After completion, they will be archived and stored by the principal researchers. Before statistical analysis, paper data will double-entered in Epidata to ensure the accuracy. All original files should be kept for a prescribed time-limit.
Follow-up
After finishing the baseline, participants will begin treatment respectively. Follow-up will be carried out at the 4th, 8th and 12th week after treatment. During this period, all interviews and indicators will be recorded and retained.
Data management and quality assurance
Before this trial, an independent organization will be founded. It is responsible for the data management and monitoring to ensure the accuracy and reliability of the data. Firstly, all investigators were required to abidance by the protocol through onsite training before recruitment. Secondly, any changes to the protocol should be reported to the primary researcher and can only be implemented after recording and permission. Thirdly, members of this organization supervise the collection, entry and storage of data throughout the trial. Researchers will be notified promptly if there are any errors. Fourthly, all electronic and paper data related to this study will be safely kept in the Clinical Research Center of Beijing Anding Hospital.
Sample size
According to previous studies, the response rate of atypical antipsychotics in combination with traditional Chinese medicine in the treatment of schizophrenia was (p1) 95.6%, and atypical antipsychotics for first-episode schizophrenia was (p2)84.3%. Set α = 0.025, β = 0.2, Δ=0.3. Applying superiority test, based on the formula n1=n2=([(Z(1-α)+Z(1-β))]2[p1(1-p1)/k+p2(1-p2)])/[(p1-p2+Δ)]2, we used software to calculate the sample size of each group is 40. Meanwhile, considering a 20% dropout rate, we finally decided to collect 48 cases in each group.
Statistical analyses
All data statistics and analysis are conducted by statisticians who using SPSS software (20.0) for Windows (SPSS, Chicago, IL). They will use general descriptive statistics, repetitive measurement deviation analysis, chi-square or non-parametric test to analyze the data within each group and between groups.
In general statistical description, metrological data are described by mean±standard deviation and enumeration data are represented by constituent ratio. Repetitive measurement deviation analysis will be used to compare metrological data between groups and within groups and chi-square or non-parametric test for enumeration data. The chi-square is appropriate to equal variance and non-parametric test is applicable to unequal variance.