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

Sponsor

Jianhua Zhou (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05772871

Collaborator

LinkDoc Technology (Beijing) Co. Ltd. (Industry)

402

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Nephrotic Syndrome in Children	Drug: Huaiqihuang granule Drug: Prednisone Drug: Levamisole placebo Drug: Levamisole Drug: Huaiqihuang Granule placebo	Phase 4

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

402 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Anticipated Study Start Date :

Mar 30, 2023

Anticipated Primary Completion Date :

Sep 15, 2025

Anticipated Study Completion Date :

Oct 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prednisone, Huaiqihuang granule, and Levamisole placebo In this group, patients will take Prednisone, Huaiqihuang granule, and Levamisole placebo.	Drug: Huaiqihuang granule 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. Drug: Prednisone 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. Drug: Levamisole placebo 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.
Placebo Comparator: Prednisone, Levamisole, and Huaiqihuang granule placebo In this group, patients will take Prednisone, Levamisole, and Huaiqihuang granule placebo.	Drug: Prednisone 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. Drug: Levamisole 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. Drug: Huaiqihuang Granule placebo 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.

Arm

Intervention/Treatment

Experimental: Prednisone, Huaiqihuang granule, and Levamisole placebo

In this group, patients will take Prednisone, Huaiqihuang granule, and Levamisole placebo.

Drug: Huaiqihuang granule

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.

Drug: Prednisone

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.

Drug: Levamisole placebo

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.

Placebo Comparator: Prednisone, Levamisole, and Huaiqihuang granule placebo

In this group, patients will take Prednisone, Levamisole, and Huaiqihuang granule placebo.

Drug: Prednisone

Drug: Levamisole

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.

Drug: Huaiqihuang Granule placebo

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.

Outcome Measures

Primary Outcome Measures

Maintaining remission rate [Start of randomization until 6-month follow-up]
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).

Secondary Outcome Measures

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

Other Outcome Measures

Change in blood pressure before and after treatment [Start of randomization until 6-month follow-up]
The level change of blood pressure before and after treatment
Change in height before and after treatment [Start of randomization until 6-month follow-up]
The level change of height before and after treatment
Change in body weight before and after treatment [Start of randomization until 6-month follow-up]
The level change of body weight before and after treatment
Change in BMI before and after treatment [Start of randomization until 6-month follow-up]
The level change of BMI before and after treatment
Change in serum cholesterol before and after treatment [Start of randomization until 6-month follow-up]
The level change of serum cholesterol before and after treatment
Change in serum triglycerides before and after treatment [Start of randomization until 6-month follow-up]
The level change of serum triglycerides before and after treatment
Change in serum immunoglobulin before and after treatment [Start of randomization until 6-month follow-up]
The level change of serum immunoglobulin before and after treatment
Change in cortisolv (collecting at 8 am) before and after treatment [Start of randomization until 6-month follow-up]
The level change of cortisolv (collecting at 8 am) before and after treatment
Change in serum 25-hydroxyvitamin D before and after treatment [Start of randomization until 6-month follow-up]
The level change of serum 25-hydroxyvitamin D before and after treatment
Change in T cell subtypes before and after treatment [Start of randomization until 6-month follow-up]
The level change of T cell subtypes before and after treatment

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Months to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.