Tacrolimus Combined With Entecavir on HBV Associated Glomerulonephritis(HBV-GN)

Study Overview
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Brief Summary
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This study was to evaluate the efficacy and safety of Tacrolimus combined with entecavir antiviral therapy for HBV-associated glomerulonephritis in china. Tacrolimus combined with entecavir rapidly and effectively induced remission of HBV-GN in Chinese adults. Meanwhile, Tacrolimus may have a synergistic antiviral effect with entecavir. The study protocol was reviewed and approved by Guangdong General Hospital's Ethic Committee, and all participants provided written informed consents. The study will be a prospective, randomized,controlled,single-blind, multi-centre, withdrawal study conducted by Guangdong general hospital, Guangdong Academy of Medical Sciences.there will be two phases, phase 1, Screening and enrolling 112 HBV-GN patients about one year,and phase 2, ongoing follow-up for 24 weeks.The data of all patients will be recorded in the HBV-GN electronic database.Before the randomisation, All patients will receive entecavir routine antiviral therapy for two weeks.And then they will be randomized to two different group,the treatment group: Tacrolimus combined with entecavir antiviral therapy,the control group: The Tacrolimus placebo and entecavir antiviral therapy. The Tacrolimus target trough concentration was 5-10 ng/mL during the therapy. The primary outcome variables were the number of patients who reached complete or partial remission (CR or PR) after the 25 week-treatment. CR was deﬁned as <0.3 g/24 h proteinuria (UPCR<300mg/g.cr) or lower plus stable renal function (eGFR>50 ml/min/1.73 m2) and PR as proteinuria 0.3-3.0 g/24 h (UPCR 300-3000mg/g.cr) and 50% lower than baseline proteinuria plus stable renal function. Secondary outcome variables: 1) The number of patients who reached complete or partial remission (CR or PR) after the 13 week-treatment. 2) Serum creatinine (SCr) increased 2 times the baseline levels or 50% lower than the baseline eGFR(according to chronic kidney disease-EPI (CKD-EPI) )after the 25 week-treatment. 3)Serum HBV DNA was undetectable(HBV DNA<500copies/ml) at the end of 25 week-treatment. 4) The number of patients who present acute kidney injury at the end of 25 week-treatment.

Official Title
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The Therapy of Tacrolimus Combined With Entecavir on HBV Associated Glomerulonephritis : A Multicenter, Prospective, Randomized, Controlled, Single-blind Trial.

Conditions
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Hepatitis B Virus Associated Nephrotic Syndrome

Intervention / Treatment
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* Drug: Tacrolimus &entecavir
* Drug: placebo & entecavir


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged between 18 and 65 years with HBV-GN; All HBV-GN cases with biopsy-proven; Evidence of chronic HBV infection based on the presence of HBsAg, HBeAg or HBV DNA in the serum;(HBsAg, HBeAg was positive, HBV DNA ≥10*3 IU/ml). Chronic HBV infection lasted for six months, and all patients did not receive the antiviral therapy in the past six months; Proteinuria more than 3.0g/24h, UPCR>3000mg/g.cr, the result will be proofed by at least two tests; No glucocorticoid and immunosuppressive treatment within the previous 2 weeks. Exclusion Criteria: The diagnosis of idiopathic membranous nephropathy(MN), systemic lupus erythematosus, malignancy, diabetes mellitus, severe infections or any other systemic disease known to be associated with secondary MN; eGFR<30ml/min.1.73m*2; Renal pathology showed that Tubular atrophy or Interstitial fibrosis was more than 50%; The participant is allergy to tacrolimus, entecavir; History of diabetes mellitus; History of severe heart disease or cerebrovascular diseases; Other active infection such as cytomegalovirus (CMV),Tuberculosis,Hepatitis A virus (HAV),Hepatitis C virus (HCV),Hepatitis D virus (HDV); Innate or acquired immunodeficiency; liver cirrhosis, liver malignment tumor; Pregnant, trying to become pregnant or breast feeding;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus & entecavir<br>Tacrolimus capsule, 0.5mg/capsule,1.0mg/capsule, 0.05-0.1mg/kg.d by mouth , every 12 hours for a day.Entecavir 0.5mg tablet by mouth every night. | Drug: Tacrolimus &entecavir<br>* HBV-GN patients with nephrotic syndrome were randomly givenTacrolimus (0.05-0.1 mg/kg/day) combined with entecavir. Tacrolimus was divided into two daily doses at 12-hour intervals. Subsequent doses were adjusted to achieve a whole blood 12-hour trough level between 5 and 10 ng/ml.All patients will receive entecavir antiviral therapy(0.5mg/d), entecavir was taken once a day. All of HBV-GN patients were followed up to 25week.<br>* Other names: FK506,Prograf, baraclude;|
| Active Comparator: placebo & entecavir<br>Tacrolimus capsule, 0.5mg/capsule,1.0mg/capsule, 0.05-0.1mg/kg.d by mouth , every 12 hours for a day.Entecavir 0.5mg tablet by mouth every night. | Drug: placebo & entecavir<br>* HBV-GN patients with nephrotic syndrome were randomly givenTacrolimus placebo (0.05-0.1 mg/kg/day) combined with entecavir.Tacrolimus placebo was divided into two daily doses at 12-hour intervals. All patients will receive entecavir antiviral therapy(0.5mg/d), entecavir was taken once a day. All of HBV-GN patients were followed up to 25week.<br>* Other names: baraclude;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission rate of proteinuria | the number of patients who reached complete or partial remission (CR or PR) after the 25 week-treatment. CR was deﬁned as <0.3 g/24 h proteinuria (UPCR<300mg/g.cr) or lower plus stable renal function (eGFR>50 ml/min/1.73 m2) and PR as proteinuria 0.3-3.0 g/24 h (UPCR 300-3000mg/g.cr) and 50% lower than baseline proteinuria plus stable renal function. | 25 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission rate of proteinuria | The number of patients who reached complete or partial remission (CR or PR) after the 13 week-treatment. | 13 weeks | 
| The change of Scr | SCr increased 2 times the baseline levels or 50% lower than the baseline eGFR(according to CKD-EPI) | 25 weeks | 
| Serum HBV DNA | Serum HBV DNA was undetectable(HBV DNA<500copies/ml) at the end of 25 week-treatment. | 25 weeks | 
| The rate of acute kidney injury | The number of patients who present acute kidney injury at the end of 25 week-treatment. | 25 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis B virus, tacrolimus,membranous nephropathy