Trial design
AYPB-MDD-Ⅲ is a multi-center, randomized, double-blinded, placebo-controlled, parallel groups phase Ⅲ clinical trial of Auyu Peibo Capsule to treat adults with MDD, sponsored by Su Zhou YiHua Biotechnology Co. LTD, conducted in Shanghai Mental Health Center and other 13 sites in China (Appendix 1).
Study objectives
The primary objective is to investigate the efficacy and safety of Anyu Peibo Capsule in comparison to placebo in adults with MDD. To identify potential predictive biomarkers for efficacy variables is the exploratory objective.
Participants and eligibility
Patients diagnosed with MDD at the time of screening will be enrolled in 14 sites in China. The trail period will be from July 2019 to December 2020. Inclusion, exclusion and withdraw criteria of AYPB-MDD-Ⅲ (Table 1) have been chosen to exclude patients at risk of suicide.
Any of the following medications and treatments will be prohibited:
- Other psychoactive drugs (except the drugs allowed to be used in protocol), at least including antipsychotics, antidepressants, mood stabilizers, anti-anxiety drugs, nootropics, etc.
- Traditional Chinese medicine (including Chinese patent medicine and traditional Chinese medicine decoction) which maybe have the effect of relieving depression.
- Modified electroconvulsive therapy (MECT), transcranial magnetic stimulation (TMS), vagus nerve stimulation (VNS), light therapy, laser therapy, acupuncture and other traditional Chinese medicine treatment, biofeedback therapy and other treatment methods.
- Systematic psychotherapy, such as psychoanalysis, cognitive behavior therapy, etc.
- Other medications and treatments that may significantly affect the efficacy and safety of antidepressants.
Some of the combination therapy will be allowed in the trial:
- For serious insomnia subjects, zolpidem, zopiclone, right zopiclone and zaleplon can be used before sleep, the dose does not exceed the upper limit specified in drug labels, the cumulative dose during the trial duration does not exceed 2 weeks.
- The medications used to treat physical diseases and try to keep the type and dosage of the drugs unchanged during the trial.
Randomisation
Patients enrolled in AYPB-MDD-Ⅲ trial treatment are allocated to treatment with Auyu Peibo Capsule or placebo in a ratio of 1:1, via the clinical trial electronic central stochastic system (DAS) for interactive web response system (IWRS).
Trial interventions
Auyu Peibo is a capsule containing 20mg of extracts (main ingredient: amide alkaloids), the placebo is an identically shaped capsule containing no effective materials. Study drug or placebo will be administered orally, with water, 30 minutes after breakfast and supper, 4 tablets once, twice per day for 8 weeks.
The participant flow was displayed in Fig. 1 according to Consolidated Standards of Reporting Trials (CONSORT) [12] diagram, and the SPRIT [13] scheme of study procedures is shown in Fig 2.
Blinding
AYPB-MDD-Ⅲ is double-blinded. Participant, care provider, investigator, outcomes assessor will not know the treatment allocation. The investigated drug is prepared by the central pharmacy, the ready-to-use drug or placebo, labelled with a random number and a patient number. Emergency unblinding can be done via DAS for IWRS.
Recruitment
The participants will be recruited from 14 sites (psychiatric hospitals) in China, research psychiatrists and clinical staff from each site will invite potential participants to the study.
Data management and quality assurance
Trained research psychiatrists from each site will record the collected data on source document and a web-based eCRF (DAS for EDC V6.0, in Chinese). Verification and cross-check of the eCRF will be conducted by the study monitor, who will be provided by the site clinical research organization as well as the sponsor. Omissions, errors, and values requiring further clarifications will be reviewed. Corrections should be made only by authorized personnel and be documented by audit trail.
Strategies to improve adherence to interventions
Reminder texts will send to the participants before each visit. Public transportation fee will be reimbursed for the participants’ attendance to visits.
Provisions for post-trial care
There will be no special post-trial care for the participants. They will continue their usual health care at their centers when the trial has been finished.
Data collection methods
Study instruments
Chinese version of Montgomery Asberg Depression Rating Scale (MADRS)
Chinese version of MADRS[14,15] is translated from the original English version, consists of 10 items rated on a 0–6 continuum (0=no abnormality, 6=severe) to assess core symptoms of depression. Inter-rater reliability on the Chinses MADRS with different pairs of raters has been reported to be 0.954, reliability, validity and sensitivity has been demonstrated to be good. [16]
17-items Hamilton Depression Scale (HAMD17) Chinese version
Chinese version of HAMD17 is translated from the original English version, consists of 17 items rated assessing symptoms of depression. Chinese HAMD17 Cronbach's alpha coefficients were calculated to be over 0.70, interior consistence and validity has been demonstrated to be good. [17]
Chinese version of the Sheehan Disability Scale (SDS)
The Chinese SDS measures the impairment in work/school, social life and family life responsibilities. The Chinses version of SDS has been reported with good validity and reliability. [18]
Primary outcome
The primary outcome is the changes in the MADRS score, comparing the baseline score and the last observed score after eight weeks of treatment.
Secondary outcomes
Secondary efficacy endpoints are evaluated as following:
- Clinical Remission Rate according to total score of MADRS at the end of study. Remission=at the end of study, total score of MADRS ≤10
- Clinical Remission Rate according to 1HAMD17 total score at the end of study. Remission=at the end of study, total score of HAMD17 ≤7
- Clinical Response Rate according to HAMD17 total score at the end of study. Response=at the end of study, decreased rate (from baseline) of MADRS total score or HAMD17 total score ≥50%
- The change of total score of MADRS by time
- The change of total score from baseline in HAMD17
- The change of total score from baseline in Hamilton Anxiety Scale (HAMA) [19]
- The change of score from baseline in Clinical Global Impression-Severity of Illness (CGI-S) [20]
- Clinical Global Impression of improvement (CGI-I) [21] score in different visits
- The change of total score from baseline in Discriminative Scale Space Tracker (DSST) [22]
- The change of total score from baseline in Trail Making Test (TMT) A&B [23]
- The change of total score from baseline in Sheehan Disability Scale (SDS) [24,25]
- Proportion of subjects who withdrew from clinical trial due to poor efficacy,investigator will assess subject's efficacy according to his/her clinical status with rating scales, including MADRS, HAMD17, HAMA and CGI, which already listed in outcome
- Proportion of subjects who combined medication to treat insomnia
Safety evaluation
Every patient enrolled in the trial will be assessed for occurrence of adverse events (AE), the incidence rate of AE will be measured as the main safety outcome. The following measures will be applied when evaluating the study drug safety:
- Breath Rate per minutes, Pulse Rate per minutes, Heartbeat Rate per minutes, Diastolic and Systolic blood pressure, Sitting position (mmHg)
- Electrocardiogram (ECG), the number of subjects with abnormal ECG report by 12-lead electrocardiogram
- Assessment of C-SSRS
- Assessment of Arizona Sexual Experience Scale (ASES)
- Number of Participants with AE result in early withdrawal from clinical trials
- Number of Participants with Serious Adverse Event (SAE) result in early withdrawal from clinical trials
- Number of Emerging AE during drug withdrawal period
Statistical Analysis
The statistical analysis software shall be SAS statistical analysis software version 9.4 or above. All statistical tests are double sided, P value less than or equal to 0.05 will be considered statistically significant. The statistical analysis shall be carried out according to the statistical analysis plan. Statistical description case of counting data Number (%); statistics of measurement data describes the number of use cases, mean, standard deviation, median, minimum and maximum.
Sample size determination
For the sample size estimation in the current phase III study, it is based on results of covariance (ANCOVA) comparing changes in the MADRS score from baseline to the last observed one during the 8 weeks of treatment between the study drug group and the placebo group. Referencing the results from trial PhaseⅡb, the decrease of the MADRS score in study drug group is 16.04 with 12.75 in placebo group. Considering a significance level of 5%, a power of 80%, and a dropout rate of 20%, the sample size should be 133 for each group.
Primary efficacy analysis
The treatment effect will be evaluated using analysis of ANCOVA with the study drug group, the site, depressive episode and baseline MADRS score as the explanatory variables. The 95% confidence interval, and the P-value will be presented. Missing data will be handled with Last Observation Carried Forward (LOCF).
Secondary efficacy analysis
Clinical remission rate of MADRS and HAMD17 at the end of study will be analyzed using ordinal logistic regression as the (proportional) odds ratio of Anyu Peibo versus placebo with a two-sided Wald 95% confidence interval. Treatment, baseline MADRS(total score under beyond or under 30) or HAMD17 (beyond or under Median), site, and depressive episode (single episode or relapse) will be included in the model.
The t-test with a two-sided alpha level of 0.05 will be used to analyze the following variables: total scores of MADRS, score of MADRS by time, CGI-I score in different visits, the change of total score from baseline in HAMD17, HAMA, CGI-S, DSST, TMT A&B and SDS. The mean difference in the scores and the 95% confidence interval under Anyu Peibo and placebo will be used as the treatment effect estimate.
The estimate of the difference in proportions of subjects who withdrew from clinical trial due to poor efficacy and in proportions of patients who combined medication to treat insomnia (Anyu Peibo versus Placebo), 95% confidence interval and Chi-square p value will be calculated. In the case of lower cell frequencies (< 5), the Fisher exact test will be used instead.
Trial management, monitoring and auditing
An independent Data and Safety Monitoring Board(DSMB)monitors the quality of the trial and has access to trial outcome and accumulated safety data, including serious adverse events (SAEs), suspected unexpected serious adverse reactions (SUSARs) and mortality. In addition, the DSMB will review the safety data from a clinical and safety point of view on an on-going basis.
The sponsor will perform monitoring visits as frequently as necessary. Representatives of the sponsor’s quality assurance department will visit the trial site at any time during the study to conduct an audit of the study in compliance with regulatory guidance.