The Efficacy and Safety of Prednisone Combined With Huaiqihuang Granule for Primary Nephrotic Syndrome in Children

Study Overview
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Brief Summary
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This non-inferiority study aims to compare the efficacy of Prednisone combined with Huaiqihuang Granule against Prednisone combined with Levamisole in the treatment of primary nephrotic syndrome (PNS) in children.

Detailed Description
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Nephrotic syndrome (NS) is the most frequent glomerular disease in children, with an incidence of 1.15-16.9 per 100,000 children. Children present with the disease at a median age of 2-3 years, and it is twice as common in boys. More than 90% of children who present with NS respond to corticosteroid treatment, and current practice is to treat most patients empirically with prednisone. However, after initial successful treatment, around 80% of children with steroid sensitive NS have disease relapses requiring further courses of prednisone. About 50% of patients develop frequent relapsing or steroid dependent. Further, the long-term use of corticosteroids is associated with numerous side effects, like obesity, diabetes and hypertension. Traditional Chinese medicine plays a unique role in the enhancement of immune function and kidney function. Huaiqihuang granule is composed of Trametes robiniophila Murr, Fructus Lycii, and Polygonatum sibiricum. It has been used for the treatment of primary nephrotic syndrome (PNS) in China. Previous studies showed Huaiqihuang granule combined with corticosteroids could significantly decrease relapse and infection rates of PNS and were well tolerated by children. This non-inferiority study aims to compare the efficacy of Prednisone combined with Huaiqihuang Granule against Prednisone combined with Levamisole in the treatment of PNS in children. In this study, about 20 research centers will participate. A total of 402 participants will be divided into two groups (the intervention group and control group) at a ratio of 1:1. The intervention group will receive Prednisone, Huaiqihuang granule and Levamisole placebo, and the control group will receive Prednisone, Levamisole and Huaiqihuang granule placebo. The planned length of patient recruitment enrolment will be 2 years and the total length of visits be 6 months. After enrollment, participants will be followed up until the end of the study (6 months), second relapse, develop as steroid-resistant, lost to follow-up, withdrawal from the study for any reason, or die, whichever occurs first.

Official Title
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Compare the Efficacy and Safety of Prednisone Combined With Huaiqihuang Granule Versus Combined With Levamisole for Primary Nephrotic Syndrome in Children: A Prospective, Multi-center, Randomized, Double-blind, Non-inferiority Study

Conditions
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Nephrotic Syndrome in Children

Intervention / Treatment
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* Drug: Huaiqihuang granule
* Drug: Prednisone
* Drug: Levamisole placebo
* Drug: Levamisole
* Drug: Huaiqihuang Granule placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age from 1.5 to 18 years; According to the Evidence-based Guideline for Diagnosis and Treatment of Hormone-sensitive, Relapsed/dependent Nephrotic Syndrome in Children (2016), children diagnosed with PNS; At enrollment, estimated glomerular filtration rate (eGFR)≥90ml/min/1.73m2； At enrollment, serum albumin level below 30g/L, and morning urine protein is 4+ or urinary albumin/creatinine ratio (ACR)≥2.0g/g; Volunteered to participate in this study and signed informed consent. For children less than 8 years, legal guardians need to sign the informed consent. Exclusion Criteria: Children who were diagnosed as steroid-resistant NS; Patients who received Prednisone, other corticosteroids (like Prednisolone, Methylprednisolone), or immunosuppressants (Tacrolimus, Mycophenolate Mofetil, Cyclosporine A, Rituximab, Cyclophosphamide) within 3 months before enrollment; Secondary NS caused by lupus nephritis, hepatitis B associated nephritis, purpura nephritis, and EB virus, cytomegalovirus (CMV), etc; With combined diseases of autoimmune disorder or primary immunodeficiency or malignancy; With combined diseases of the cardiovascular, liver, hematopoietic system, mental disorders, and other serious diseases; With serious infectious diseases (like tuberculosis) in the past or at present; With combined diseases of Human immunodeficiency virus (HIV), hepatitis B and /or C virus (HBV, HCV), and other active virus infections; History of diabetes; Abnormal liver function: alanine aminotransferase and aspartate aminotransferase levels exceed twice the upper limit of the normal range; Participation in other ongoing clinical trials; Other reasons that the researcher considers unsuitable to participate in this study.

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prednisone, Huaiqihuang granule, and Levamisole placebo<br>In this group, patients will take Prednisone, Huaiqihuang granule, and Levamisole placebo. | Drug: Huaiqihuang granule<br>* Huaiqihuang Granule, oral administration, recommended daily dose: for body weight <10 kg, 5g, twice a day; for 10 kg ≤ body weight <20 kg, 10g, twice a day; for 20 kg≤body weight <30 kg, 15g, twice a day; for 30 kg≤body weight <50 kg, 20g, twice a day; for body weight>50 kg, 30g, twice a day. Continuous medication until the end of the study (6 months), second relapse, development as steroid-resistant, lost to follow-up, withdrawal from the study for any reason, or death, whichever occurs first.<br>Drug: Prednisone<br>* Prednisone, oral administration, recommended dose: 2mg/kg/d (maximum 60 mg/d) for 4 weeks followed by 2 mg/kg (maximum 60mg) on alternate days for the other 4 weeks. If patients have relapsed during reducing dosage or withdrawal, the patients will receive Prednisone for 8 weeks again [2mg/kg/d (maximum 60 mg/d) for 4 weeks followed by 2 mg/kg (maximum 60mg) on alternate days for the other 4 weeks]. If a second relapse is observed, patients will receive immunosuppressants and then withdraw from the trial.<br>Drug: Levamisole placebo<br>* Levamisole placebo, 1.25 mg/kg. once daily. Continuous medication until the end of the study (6 months), second relapse, development as steroid-resistant, lost to follow-up, withdrawal from the study for any reason, or death, whichever occurs first.<br>|
| Placebo Comparator: Prednisone, Levamisole, and Huaiqihuang granule placebo<br>In this group, patients will take Prednisone, Levamisole, and Huaiqihuang granule placebo. | Drug: Prednisone<br>* Prednisone, oral administration, recommended dose: 2mg/kg/d (maximum 60 mg/d) for 4 weeks followed by 2 mg/kg (maximum 60mg) on alternate days for the other 4 weeks. If patients have relapsed during reducing dosage or withdrawal, the patients will receive Prednisone for 8 weeks again [2mg/kg/d (maximum 60 mg/d) for 4 weeks followed by 2 mg/kg (maximum 60mg) on alternate days for the other 4 weeks]. If a second relapse is observed, patients will receive immunosuppressants and then withdraw from the trial.<br>Drug: Levamisole<br>* Levamisole, 1.25 mg/kg. once daily. Continuous medication until the end of the study (6 months), second relapse, development as steroid-resistant, lost to follow-up, withdrawal from the study for any reason, or death, whichever occurs first.<br>Drug: Huaiqihuang Granule placebo<br>* Huaiqihuang Granule placebo, oral administration, recommended daily dose: for body weight <10 kg, 5g, twice a day; for 10 kg ≤ body weight <20 kg, 10g, twice a day; for 20 kg≤body weight <30 kg, 15g, twice a day; for 30 kg≤body weight <50 kg, 20g, twice a day; for body weight>50 kg, 30g, twice a day. Continuous medication until the end of the study (6 months), second relapse, development as steroid-resistant, lost to follow-up, withdrawal from the study for any reason, or death, whichever occurs first.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maintaining remission rate | At the end of the study, the proportion of patients who maintained urine protein negative without relapse (removed the patients who developed steroid resistance at the first 4 weeks of treatment of Prednisone). | Start of randomization until 6-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of frequently relapse | Among patients who get remission after treatment, proportion of patients with more than two times of relapses within 6-month follow-up | Start of randomization until 6-month follow-up | 
| Infection rate | Proportion of patients experiencing infection during the treatment. Infections include respiratory tract infections, urinary tract infections, skin infections, gastrointestinal infections, and others. | Start of medication until 6-month follow-up | 
| Cumulative corticosteroids dosage adjusted by body weight | Total amount of per patient per kilogram cumulative corticosteroids dosage | Start of receiving corticosteroids until 6-month follow-up | 
| Change in serum creatinine and estimated glomerular filtration rate (eGFR) before and after treatment | The level change of serum creatinine, eGFR between baseline and the last testing result during follow-up | Start of randomization until 6-month follow-up | 
| Change in serum albumin before and after treatment | The level change of serum albumin between baseline and the last testing result during follow-up | Start of randomization until 6-month follow-up | 
| Change in urinary albumin/creatinine ratio (ACR) before and after treatment | The level change of urinary albumin/creatinine ratio (ACR) between baseline and the last testing result during follow-up | Start of randomization until 6-month follow-up | 
| Change in 24h urinary protein (applying to more than 3 years patients) before and after treatment | The level change of 24h urinary protein (applying to more than 3 years patients) between baseline and the last testing result during follow-up | Start of randomization until 6-month follow-up | 
| Incidence and severity of adverse events (AE) and serious adverse events (SAE) |  | Start of randomization until 6-month follow-up | 
| Incidence and severity of adverse reactions (ADR), serious adverse reactions (SADR), suspicious and unexpected serious adverse reactions (SUSAR) |  | Start of randomization until 6-month follow-up | 
| Remission time to first relapse | Among patients who get remission after treatment, time from the onset of remission to the first relapse | Start of onset of remission after treatment until first relapse, assessed up to 6-month | 
| Number of relapses | Among patients who get remission after treatment, number of relapse per patient | Start of randomization until 6-month follow-up | 
| Relapse rate | Among patients who get remission after treatment, proportion of patients with relapse | Start of randomization until 6-month follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Huaiqihuang granule, Children, Nephrotic syndrome