Childhood-onset systemic lupus erythematosus (cSLE) is a severe chronic autoimmune disease with a high burden of major-organ involvement. Lupus nephritis (LN) affects more than half of children with SLE, and proliferative LN-including class III, IV, III+V, and IV+V disease-is associated with acute kidney injury, progression to end-stage kidney disease, and poor long-term outcomes. Glucocorticoids remain a cornerstone of induction therapy for proliferative LN. However, the optimal initial dose in children is uncertain. Although recent adult SLE and LN guidelines increasingly recommend lower-dose glucocorticoid regimens with rapid tapering, pediatric guidelines still commonly recommend high initial prednisone doses of 1.5-2.0 mg/kg/day. Adult trials and comparative observational studies suggest that lower-dose glucocorticoid regimens may preserve efficacy while reducing treatment-related toxicity. Because cumulative glucocorticoid exposure in children may impair growth, development, psychosocial well-being, and medication adherence, this trial will compare low-dose versus high-dose initial glucocorticoid regimens for induction treatment of pediatric proliferative LN. The objective is to determine whether a lower-dose regimen is non-inferior in efficacy while reducing glucocorticoid-related adverse effects and improving quality of life.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
198
All participants will receive two courses of intravenous methylprednisolone pulse therapy (10-30 mg/kg/day for 3 consecutive days per course; maximum 500 mg/day). Participants will then be randomized in a 1:1 ratio to the two treatment groups. In the standard-dose (control) group, oral prednisone will be initiated at 1.4-1.6 mg/kg/day (maximum 60 mg/day), followed by gradual tapering according to the predefined schedule. For participants weighing \<40 kg, doses will be adjusted in proportion to body weight using the following formula: Individual dose = standard dose × body weight (kg) × 0.025. All participants will receive background therapy with oral hydroxychloroquine, mycophenolate mofetil, and intravenous belimumab at standard doses.
All participants will receive two courses of intravenous methylprednisolone pulse therapy (10-30 mg/kg/day for 3 consecutive days per course; maximum 500 mg/day). Participants will then be randomized in a 1:1 ratio to the two treatment groups. Participants in the intervention group will receive oral prednisone at an initial dose of 0.6-0.8 mg/kg/day, with a maximum dose of 30 mg/day, followed by gradual tapering according to the predefined schedule. For participants weighing \<40 kg, doses will be adjusted in proportion to body weight using the following formula: Individual dose = standard dose × body weight (kg) × 0.025. The estimated cumulative prednisone dose over 24 weeks will be approximately 50% of that in the control group. All participants will receive background therapy with oral hydroxychloroquine, mycophenolate mofetil, and intravenous belimumab at standard doses.
Peking Union Medical College Hospital, Chinese Academy of Medical Sciences
Beijing, Beijing Municipality, China
RECRUITINGBeijing Children's Hospital, Capital Medical University
Beijing, Beijing Municipality, China
RECRUITINGChidren's Hospital of Chongqing Medical University
Chongqing, Chongqing Municipality, China
NOT_YET_RECRUITINGShenzhen Children's Hospital
Shenzhen, Guangdong, China
NOT_YET_RECRUITINGThe Second Xiangya Hospital of Central South University
Changsha, Hunan, China
NOT_YET_RECRUITINGChildren's Hospital of Nanjing Medical University
Nanjing, Jiangsu, China
NOT_YET_RECRUITINGJilin University
Changchun, Jilin, China
NOT_YET_RECRUITINGChildren's Hospital of Fudan University
Shanghai, Shanghai Municipality, China
NOT_YET_RECRUITINGTotal Renal Response at Week 24
Total renal response (TRR) is defined as achievement of complete renal response (CRR), primary efficacy renal response (PERR), or partial renal response (PRR). Complete renal response (CRR) is defined as meeting both of the following criteria: 1. Proteinuria \<0.5 g/1.73 m², or 24-hour urinary protein excretion \<300 mg/m², or urine protein-to-creatinine ratio (UPCR) \<0.5 g/g; and 2. Estimated glomerular filtration rate (eGFR) within the normal range, or eGFR ≥85% of baseline, or a normal serum creatinine level with an increase of no more than 25% from baseline. Primary efficacy renal response (PERR) is defined as meeting both of the following criteria: 1. UPCR \<0.7 g/g; and 2. eGFR ≥80% of baseline or eGFR ≥60 mL/min/1.73 m². Partial renal response (PRR) is defined as meeting both of the following criteria: 1. A ≥50% reduction in proteinuria from baseline and UPCR \<3 g/g; and 2. eGFR ≥85% of baseline.
Time frame: Week 24
Complete Renal Response at Week 12 and 24
CRR is defined as meeting both of the following criteria: (1) Urine protein \<0.5 g/1.73 m², or 24-hour urine protein \<300 mg/m², or urine protein-to-creatinine ratio (UPCR) \<0.5 g/g; AND (2) Estimated glomerular filtration rate (eGFR) within the normal range; or eGFR at least 85% of baseline; or normal serum creatinine with an increase of no more than 25% from baseline.
Time frame: Week 12, 24
Primary Efficacy Renal Response at Week 12 and 24
PERR is defined as meeting both of the following criteria: (1) UPCR \<0.7 g/g; AND (2) eGFR at least 80% of baseline or eGFR ≥60 mL/min/1.73 m².
Time frame: Week 12, 24
Partial Renal Response at Week 12 and 24
PRR is defined as meeting both of the following criteria: (1) Urine protein reduced by ≥50% from baseline and UPCR \<3 g/g; AND (2) eGFR at least 85% of baseline.
Time frame: Week 12, 24
Time to TRR
Total renal response (TRR) is defined as achievement of complete renal response (CRR), primary efficacy renal response (PERR), or partial renal response (PRR). Complete renal response (CRR) is defined as meeting both of the following criteria: 1. Proteinuria \<0.5 g/1.73 m², or 24-hour urinary protein excretion \<300 mg/m², or urine protein-to-creatinine ratio (UPCR) \<0.5 g/g; and 2. Estimated glomerular filtration rate (eGFR) within the normal range, or eGFR ≥85% of baseline, or a normal serum creatinine level with an increase of no more than 25% from baseline. Primary efficacy renal response (PERR) is defined as meeting both of the following criteria: 1. UPCR \<0.7 g/g; and 2. eGFR ≥80% of baseline or eGFR ≥60 mL/min/1.73 m². Partial renal response (PRR) is defined as meeting both of the following criteria: 1. A ≥50% reduction in proteinuria from baseline and UPCR \<3 g/g; and 2. eGFR ≥85% of baseline.
Time frame: Week 0-24
Time to CRR
Complete renal response (CRR) is defined as meeting both of the following criteria: (1) Urine protein \<0.5 g/1.73 m², or 24-hour urine protein \<300 mg/m², or urine protein-to-creatinine ratio (UPCR) \<0.5 g/g; (2) Estimated glomerular filtration rate (eGFR) within the normal range; or eGFR at least 85% of baseline; or normal serum creatinine with an increase of no more than 25% from baseline.
Time frame: Week 0-24
Time to PERR
Primary efficacy renal response (PERR) is defined as meeting both of the following criteria: (1) UPCR \<0.7 g/g; (2) eGFR at least 80% of baseline or eGFR ≥60 mL/min/1.73 m².
Time frame: Week 0-24
Time to PRR
Partial renal response (PRR) is defined as meeting both of the following criteria: (1) Urine protein reduced by ≥50% from baseline and UPCR \<3 g/g; (2) eGFR at least 85% of baseline.
Time frame: Week 0-24
Change of C3 from baseline to Week 24
To assess the improvement of SLE serum activity
Time frame: Week 0, 24
Changes of C4 from baseline to Week 24
To assess the improvement of SLE serum activity
Time frame: Week 0, 24
Change of anti-dsDNA titer from baseline to Week 24
To assess the improvement of SLE disease activity
Time frame: Week 0, 24
Change of anti-dsDNA value from baseline to Week 24
To assess the improvement of SLE disease activity
Time frame: Week 0, 24
Change of SLEDAI-2K from baseline to Week 24
To assess the level of disease activity improvement by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score.
Time frame: Week 0, 24
Change of PGA from baseline to Week 24
Physician Global Assessment (PGA) is a clinical tool utilizing a 0 to 3 visual analogue scale to measure overall disease activity by experienced rheumatologists.
Time frame: Week 0, 24
Change of ParentGA from baseline to Week 24
Parental Global Assessment (ParentGA) is a parent-reported outcome measure used to quantify a caregiver's perception of their child's overall disease impact and well-being. ParentGA consists of a horizontal line containing 21 circles numbered from 0 to 10. The scale moves in 0.5 increments. The score of 0 indicates "very well" (best possible health status/disease activity) and 10 indicates "very poor" (worst possible health status/disease activity).
Time frame: Week 0, 24
Change of PedsQL from baseline to Week 24
The Pediatric Quality of Life Inventory (PedsQL) is a modular assessment tool used to measure health-related quality of life in children, evaluating physical, emotional, social, and school functioning to generate an overall health score.
Time frame: Week 0, 24
Change of serum creatinine from baseline to Week 24
To measure renal function levels
Time frame: Week 0, 24
Change of eGFR from baseline to Week 24
eGFR (estimated Glomerular Filtration Rate) is a calculated value used to assess kidney filtration function. Pediatric eGFR \[mL/(min·1.73m2)\] = K × 88.4 × Height (cm)/Serum Creatinine (μmol/L). When serum creatinine is measured using the Jaffe method, the K coefficient is proportional to an individual's muscle mass and varies with age. In adolescents, it varies according to sex: Children and adolescent females: K = 0.55; Adolescent males: K = 0.77. When creatinine is measured using an enzymatic assay: K = 0.413
Time frame: Week 0, 24
Change of 24-hour urine protein from baseline to Week 24
A 24-hour urine protein test measures kidney function by quantifying how much protein the body excretes in a full day.
Time frame: Week 0, 24
Changes of UPCR from baseline to Week 24
A UPCR (Urine Protein Creatinine Ratio) test measures the amount of protein relative to creatinine in a single urine sample. It is a highly accurate, convenient alternative to 24-hour urine test.
Time frame: Week 0, 24
Rate of LN treatment failure at Week 24
LN treatment failure is defined as the occurrence of any of the following: 1. Death; 2. New-onset end-stage renal disease (ESRD), or the need for dialysis or kidney transplantation; 3. Doubling of serum creatinine (compared with the baseline level); 4. Renal flare, defined by either (a) or (b): 1. Proteinuric flare: after excluding secondary causes such as infection, 24-hour urinary protein excretion or the urine protein-to-creatinine ratio (UPCR) increased to at least twice the baseline level; or 2. Nephritic flare: after excluding secondary causes such as infection, serum creatinine increased by 25% from baseline, together with any of the following: * 24-hour urinary protein increased to at least twice the baseline level and exceeded 2 g/24 h, or the equivalent UPCR; * New-onset hematuria graded as 2+ or more; * New-onset cellular casts.
Time frame: Week 24
Rate of renal flare at Week 24
Renal flare, defined by either (a) or (b): 1. Proteinuric flare: after excluding secondary causes such as infection, 24-hour urinary protein excretion or the urine protein-to-creatinine ratio (UPCR) increased to at least twice the baseline level; or 2. Nephritic flare: after excluding secondary causes such as infection, serum creatinine increased by 25% from baseline, together with any of the following: * 24-hour urinary protein increased to at least twice the baseline level and exceeded 2 g/24 h, or the equivalent UPCR; * New-onset hematuria graded as 2+ or more; * New-onset cellular casts.
Time frame: Week 24
Rate of SLE flare at Week 24
SLE flare is defined according to SELENA-SLEDAI definitions: 1. An increase in the SLEDAI score of ≥3 points compared with the previous assessment; 2. New-onset or worsening manifestations of lupus activity, including cutaneous lesions, oral or nasal ulcers, pleuritis, pericarditis, arthritis, fever, neuropsychiatric lupus, vasculitis, nephritis, myositis, platelet count \<60 × 10⁹/L, hemolytic anemia (hemoglobin \<70 g/L or a decrease of \>30 g/L), lupus myocarditis, or lupus pneumonitis; 3. Initiation or dose escalation of medications because of disease activity, including NSAIDs, glucocorticoids, cyclophosphamide, methotrexate, or azathioprine; 4. A Physician Global Assessment (PGA; range, 0-3) score of ≥1.
Time frame: Week 24
Rate of LLDAS at Week 24
LLDAS was defined as meeting all of the following criteria: 1. SLEDAI-2K score ≤4, with no activity in major organ systems (renal, neuropsychiatric, cardiopulmonary, vasculitic, or constitutional activity), no hemolytic anemia, and no gastrointestinal activity; 2. No new manifestations of SLE disease activity compared with baseline; 3. SELENA-SLEDAI Physician Global Assessment score (range, 0-3) ≤1; 4. Prednisone dose, or equivalent glucocorticoid dose, ≤7.5 mg/day.
Time frame: Week 24
Rate of DORIS remission at Week 24
DORIS remission is defined as meeting all of the following criteria: 1. Clinical SLEDAI score = 0; 2. Physician Global Assessment score (range, 0-3) \<0.5, irrespective of serological activity; 3. Treatment with antimalarial agents was permitted, as was prednisone at a dose of ≤5 mg/day (or an equivalent glucocorticoid dose) and/or stable immunosuppressive therapy, including biologic agents.
Time frame: Week 24
PRINTO/ACR cSLE response rate at Week 24
Response was defined as improvement of at least 50% from baseline in any two of the five core outcome measures, with no more than one of the remaining measures worsening by more than 30%. The five core outcome measures were Physician Global Assessment of overall disease activity (PGA), Parent Global Assessment of disease activity (ParentGA), proteinuria, the SLE Disease Activity Index 2000 (SLEDAI-2K), and the physical functioning domain of the Pediatric Quality of Life Inventory (PedsQL).
Time frame: Week 24
Changes of Childhood Lupus Improvement Index (CHILI) from baseline to Week 24
The Childhood Lupus Improvement Index (CHILI) is a validated measure of treatment response in childhood-onset SLE that primarily captures clinically meaningful improvement. The score is calculated using five core outcome measures: Physician Global Assessment of overall disease activity (PGA), Parent Global Assessment of disease activity (ParentGA), proteinuria assessed by the urine protein-to-creatinine ratio (UPCR) or 24-hour urinary protein excretion, the SLE Disease Activity Index 2000 (SLEDAI-2K), and the physical functioning domain of the Pediatric Quality of Life Inventory (PedsQL). (PMID: 30680946)
Time frame: Week 0, 24
Rate of clinical, minor, moderate and major improvement in cSLE at Week 24
Using the CHILI absolute-change definition, clinical improvement is defined as a CHILI score ≥54; minor improvement as CHILI ≥15; moderate improvement as CHILI ≥68; and major improvement as CHILI ≥92.
Time frame: Week 0, 24
Scores and changes of pGTI from baseline to Week 12 and 24
The pediatric glucocorticoid toxicity index (pGTI) is a composite index including 10 glucocorticoid toxicity domains: body mass index, growth and development, glucose tolerance, lipid metabolism, systolic blood pressure, bone mineral density, glucocorticoid-induced myopathy, skin toxicity, neuropsychiatric effects, and infection. (PMID: 35917759)
Time frame: Week 0, 12, 24
SLICC/ACR Damage Index at Week 24
The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR Damage Index, SDI) is designed to assess cumulative, irreversible organ damage occurring since the onset of SLE. It encompasses 39 types of chronic, irreversible damage across 12 organ systems, irrespective of ongoing inflammatory disease activity. (PMID: 8607884)
Time frame: Week 24
Category, incidence and severity of adverse events
Adverse events should be assessed at each study visit, including the event name, timing, management, severity, and outcome. Adverse event grading: Grade 1 (mild): Asymptomatic or mild symptoms; clinical or diagnostic findings only; no treatment required. Grade 2 (moderate): Requires minor or local treatment and limits instrumental activities of daily living. Grade 3 (severe): Medically significant but not immediately life-threatening; hospitalization may be required; limits self-care activities of daily living. Grade 4 (life-threatening): Requires urgent intervention. Grade 5 (death): Death related to the adverse event.
Time frame: Week 0-24
Change of blood pressure from baseline to Week 24
To measure improvement of kidney function, and monitor the side effect by glucocorticoids.
Time frame: Week 0, 24
Change of fasting blood glucose from baseline to Week 24
To evaluate adverse events of glucocorticoids
Time frame: Week 0, 24
Changes of serum triglycerides from baseline to Week 24
To monitor adverse effects of glucocorticoids
Time frame: Week 0, 24
Changes of height from baseline to Week 24
To measure the growth velocity of children, and monitor the adverse events of glucocorticoids
Time frame: Week 0, 24
Changes of bone marrow density from baseline to Week 24
To monitor the side effects of glucocorticoids, bone mineral density (BMD) is measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine.
Time frame: Week 0, 24
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