The protocol was developed following superiority trial design, to compare the efficacy and safety of tripterygium wilfordii multiglycosides over RAS inhibitors in IMN.
Study setting
The EAST -trial will be performed in Sichuan Provincial People’s Hospital. Patients are recruited at the nephrology clinic if they meet the criteria as defined below.
Design
This is an open-label randomized controlled clinical trial in a single tertiary center. 20 eligible patients with IMN will be randomly assigned to an intervention group and a control group at a rate of 1:1, with ten patients in each group. The intervention group will be receive tripterygium wilfordii multiglycosides tablets on the basis of RAS inhibitors, while the control group will continue with RAS inhibitors. The study duration will be six months, during which clinical data and samples will be collected according to a visit schedule at each follow-up. A flowchart of the trial design is shown in Figure 1.
Inclusive criteria
Patients diagnosed as IMN by renal biopsy will be included in this study. Inclusive criteria are: (1) has no evidence of secondary membranous nephropathy; (2) Age between 18 to 65 years old; (3) has 24-hour albuminuria between 1.0 and 6.0g after at least three month of standard dose of RAS inhibitor treatment; (4) estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m2 according to CKD-EPI formula using the latest serum creatinine value at screening;(5) has not participated in other clinical trials within the last three months; (5) has negative pregnancy test result for women of childbearing age; and (6) agrees to voluntarily participate in the study and signs an informed consent form.
Exclusive criteria
Patients with any one of the following criteria will be excluded: (1) has received glucocorticoids or other immunosuppressants in the past six months; (2) has any clinical evidence of secondary membranous nephropathy (tumors, drugs, other autoimmune diseases such as systemic lupus erythematosus, etc.); (3) has any of the following comorbidities including chronic liver disease, myocardial infarction, stroke, uncontrolled hypertension and diabetes, malignant tumor; (4) is known to allergic to tripterygium wilfordii multiglycosides or has contraindications for use; (5) female patients who are pregnant (or intend to be pregnant within half a year), breastfeeding or unwilling to take contraceptive measures; (6) has an expected life expectancy less than six months; (7) is currently participating or have participated in other clinical trials within 3 months; (8) refuses to sign an informed consent form or be unable or unwilling to comply with research protocol approved by the researcher; (9) has any other conditions which the researchers believe makes the subject unsuitable for this study.
Sample size
We identified a total of 87 IMN patients by screening renal biopsy data and clinical follow-up data from January 2010 to December 2017 in our center’s Renal Treatment System. The average amount of proteinuria per day in this population was 2.89 ±0.62 g at the time of diagnosis. According to the clinical data of our center, combined with the published data on proteinuria in patients with IMN, we expect the mean decrease of proteinuria in the intervention group being 2.0 g/day higher than that in the control group to be considered as effective. Therefore, we set a standard deviation (s) of 1.5 g/day, the necessary sample size in each group to provide a power of 80% to detect an effect size of 2 g/day, with type I error (α) = 0.05 (bilateral) and 1:1 randomization was calculated as follows:
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)
The total number increased to 20 cases considering a loss of follow-up rate of 10%. Therefore, 20 subjects will be included in this study.
Randomization
A random number list will be generated by SPSS version 24.0 (IBM Corporation, USA) using simple randomization. Eligible patients will be randomly assigned to the interventional group or the control group at a rate of 1:1 by the number inside a concealed envelope containing random codes according to the order of enrollment.
Interventions
All patients will have received ACEi/ARB treatment for at least three months before enrollment. After randomization, patients in the interventional group will receive tripterygium wilfordii multiglycosides tablets (1-1.5mg/kg body weight/day, per oral, divided to three time daily) in addition to their ACEi/ARB treatment , and patients in the control group will proceed with their ACEi/ARB treatment. The overall treatment will last for six months.
Withdraw criteria
Patients with any of the following conditions will be withdrawn from this study: (1) being found having any of the exclusive criteria after enrollment; (2) takes glucorsteroids or other immunosuppressants during the study; (3) has intolerable side effects of drugs; (4) has any serious adverse event that makes subjects unsuitable for continuation, such as severe infection, uncontrollable hyperglycemia and/or hypertension; (5) the patient asks to withdraw; (6) other situations which the researchers believe makes the patient not appropriate to continue.
Efficacy outcome measures
The primary outcome measure for efficacy is absolute decrease of proteinuria after six months.
The secondary outcome measures include:
- absolute decrease of urine albumin-to-creatinine ratio (ACR) after six months;
- the percentage of patients who have achieved complete response, defined as proteinuria less than 0.3g/day and serum albumin≥3.5g/dL;
- the percentage of patients who have achieved partial response, defined as a decrease of proteinuria≥50% compared with baseline level and proteinuria between 0.3 to 3.5 g/day.
Safety outcomes measures
Since the main adverse effects of tripterygium wilfordii multiglycosides is liver dysfunction and gonadal suppression [12,13], we will closely monitor manifestations of these two aspects in addition to routine practice on safety surveillance. Therefore, safety parameters in this study will include but not limited to the following:
- Clinical: blood pressure, edema, anemia, menstruation status in the females;
- Blood biological tests: CBC, creatine, albumin, alanine aminotransferase, aspartic aminotransferase, total bilirubin, direct bilirubin, indirect bilirubin, lactate dehydrogenase;
- Urine biological tests: red blood cells, white blood cells.
Assessment
All enrolled patients will have their first visit at the time of screening, the second visit at randomization and be followed up at the end of each month afterwards. In addition, there will be one follow up at two weeks after randomization (Visit 3), of which the main purpose is to closely monitor potential adverse effect of tripterygium wilfordii multiglycosides. The overall duration of treatment will be six months. At each follow-up as shown in Table 1, the medical history will be enquired, and blood and urine tests will be carried out in the central lab in Sichuan Provincial People’s Hospital with standardized methods.
Table 1 Visit arrangement.
Research program
|
Screening
|
Randomization
|
Clinic Visit
|
Visit number
|
1
|
2
|
3
|
4
|
5
|
6
|
7
|
8
|
9
|
Visit Day
|
-14(±7)
|
0
|
14 (±3)
|
30(±3)
|
60(±3)
|
90(±3)
|
120(±3)
|
150(±3)
|
180(±3)
|
Informed consent
|
√
|
|
|
|
|
|
|
|
|
Inclusion/Exclusive criteria
|
√
|
√
|
|
|
|
|
|
|
|
Random assignment
|
|
√
|
|
|
|
|
|
|
|
Demographics
|
√
|
|
|
|
|
|
|
|
|
Medical history
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
Physical examination
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
Vital signs
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
Blood lab tests*
|
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
Urine lab tests*
|
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
Collect blood and urine samples
|
|
√
|
|
|
√
|
|
√
|
|
√
|
Pregnancy test
|
√
|
√
|
|
|
|
|
|
|
|
Combined medication
|
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
Adverse events
|
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
√
|
Drug distribution
|
|
√
|
√
|
|
√
|
√
|
√
|
√
|
|
Drug compliance reminder
|
|
√
|
√
|
|
√
|
√
|
√
|
√
|
|
Data management
In this study, the paper version of CRF table will be used for data collection, RedCap online database will be used to manage data, double input comparison method will be used for data entry and verification, and corresponding data verification and cleaning will be carried out. During the study period, the principal researchers will check the trial data once a month to ensure internal consistency.
Data analysis
Continuous data will be described by mean ± standard deviation or median (interquartile range). Classified data will be described by the number and percentages. Chi-square test (Fisher’s Exact test, if the expected number < 5) for categorical variables and Student’s t-test or Wilcoxon Rank Sum test for continuous variables will be applied to detect the differences between the intervention and the control groups. A two-tailed p < 0.05 will be considered to be significant. Statistical analysis will be performed using SPSS version 24.0 (IBM Corporation, Armonk, NY) and RStudio for Windows, version 4.0.3 (RStudio, Inc.) and supervised by a skilled statistician.
Ethnic Consideration
The study received approval from the Ethics Committee of Sichuan Provincial people's Hospital (No. 2021.325-1). The study will be conducted following Ethical Principles of Helsinki Declaration and relevant local clinical research norms and regulations. Written informed consent will be acquired from every participant before study-related procedure. A verification of the consents will be carried out after each inclusion, followed by an auditing of the files at regular time intervals. The participants’ personal data will be kept confidential throughout the study and only available to the research team. Any change to the protocol should be approved by the Ethics Committee before it can be implemented and will be applied to the clinical registry for protocol changes.