Combination of Danazole With Berberine in the Treatment of ITP
Phase: PHASE2
Conditions: Corticosteroid-resistant or Relapsed ITP
Sponsor: Peking University People's Hospital

 
 
 
Official title: Combination of Danazole With Berberine in the 
Treatment of ITP 
NCT number: NCT03909763 
Document date: January 1, 2016 
 
 

Study Protocol and Statistical Analysis Plan 
Background:  
Immune thrombocytopenia (ITP) is an autoimmune bleeding disorder characterized by 
antibody-induced destruction of platelets and decreased production of platelets due to 
impaired thrombopoiesis. Berberine (BBR), an isoquinoline alkaloid derived from 
plants, is widely used as a nonprescription drug to treat diarrhea. Our previous data 
demonstrated that gut microbiota dysbiosis may contribute to the development of 
steroid-resistant ITP (Sci China Life Sci, 2020). BBR may correct steroid-resistance by 
modulating the gut microbiota structure, representing a novel potential second-line 
candidate to treat ITP. Danazol is an attenuated androgen that has successfully been 
used in the treatment of ITP. Considering the side effects of a regular dose of danazol 
and that BBR and danazol share disparate mechanisms in the treatment of ITP, we 
hypothesized that combination of these two agents might be a promising option to 
maximize efficacy, while minimizing adverse effects. 
 
Objectives:  
To evaluate the long-term efficacy and safety of berberine plus danazol in patients with 
corticosteroid-resistant or relapsed ITP. 
 
Design and methods: 
The trial is an open-label, single-arm, phase 2 trial. The trial will be performed on 
nonsplenectomized patients with steroid-resistant or relapsed ITP from the Peking 
University People’s Hospital and other 5 large medical hematological centers in China. 
Eligible patients are 18 years to 80 years with a platelet (PLT) count of <30×109/L on 
two occasions or a PLT of no less than 30×109/L combined with bleeding manifestation.  
Patients who are receiving other maintenance regimens (primarily corticosteroids, 
mycophenolate mofetil, cyclosporine, or intravenous immunoglobulin) are also eligible 
if the dose has been stable in the past month and the dose is expected to be stable after 
enrolment and remains unchanged at least for the first 4 weeks of the study until initial 
response is assessed, unless severe adverse events are suspected. Participants will be 
excluded if they have malignant diseases, hepatitis B or C, positive serology for HIV, 
other active infections, drug-associated thrombocytopenia, or are pregnant. Each 
patient will sign and date the written informed consent. Our primary outcome is a 6-
month sustained response rate defined as PLT counts maintained > 50×109/L without 
any additional ITP-modifying therapy at 6-month follow up. Secondary outcome 
measures include response at day 28 (partial response: PLT of 30×10⁹/L or more and at 
least a doubling of baseline platelet count; complete response: PLT of 100×10⁹/L or 
more and the absence of bleeding without rescue medication), duration of response 
(DOR), adverse events and cumulative rate of bleeding. Treatment consists of oral BBR 
(300 mg three times daily) plus oral danazol (200 mg twice daily). Treatment period 
will last for 16 weeks unless otherwise specifies. Patients will not be withdrawn from 
the study unless severe adverse events occur. Treatment will be interrupted if PLT count 
is more than 300*109 per L in two consecutive tests with a minimal interval of 2 weeks. 

The follow-up period will last until the required number of events have occurred or 2 
years after the last patient enrolment, whichever comes first. Complete blood count is 
assessed at baseline, weekly for 28 days, monthly until month 6, and three months a 
time after then. In addition, we will do clinical examination, and record bleeding score, 
liver enzyme and creatinine concentrations, concomitant medications given, and 
adverse events.  
 
Statistical analysis plan:  
Patient characteristics will be reported as numbers (%) or medians (IQR, expressed as: 
first; third quartiles). The 6-month sustained-response-rate estimates (95% confidence 
interval [CI]) will be reported. Analyses of secondary end points used point estimates. 
Treatment safety profiles and side effects were assessed according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The 
analysis was performed with SPSS software version 24.0.