Childhood-onset Systemic Lupus Erythematosus, Lupus Nephritis (LN)
Conditions
Keywords
Children, Systemic lupus erythematosus, Lupus nephritis, Glucocorticoid, Therapy
Brief summary
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.
Interventions
DRUGHigh-dose prednisone
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.
DRUGLow-dose prednisone
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.
Sponsors
Peking Union Medical College Hospital
Children's Hospital of Chongqing Medical University
Beijing Children's Hospital
Second Xiangya Hospital of Central South University
Shenzhen Children's Hospital
Nanjing Children's Hospital
Jilin University
Children's Hospital of Fudan University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥6 years and \<18 years, with body weight ≥20 kg * Meets the 2019 European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification criteria for Systemic Lupus Erythematosus (SLE) * Renal biopsy confirming Lupus Nephritis class III, IV, III+V, or IV+V according to the International Society of Nephrology / Renal Pathology Society (ISN/RPS) classification * At screening: 24-hour urinary protein ≥1.0 g (or ≥25 mg/kg), or urine protein-to-creatinine ratio (UPCR) ≥1.0 g/g * White blood cell count ≥3.0 × 10⁹/L and lymphocyte count ≥1.0 × 10⁹/L * No prior intravenous methylprednisolone pulse therapy before enrollment, and glucocorticoid exposure ≤2 weeks before enrollment, with a maximum prednisone-equivalent dose ≤30 mg/day (or ≤1 mg/kg/day) * Written informed consent obtained and good treatment compliance expected
Exclusion criteria
* Uncertain diagnosis of SLE, genetically confirmed monogenic lupus, or a history of immunodeficiency * Severe infection, including hepatitis C, active hepatitis B, HIV infection, tuberculosis infection, severe fungal infection, etc. * Severe neuropsychiatric lupus * Peripheral blood hemoglobin \<60 g/L, platelet count \<10 × 10⁹/L, or concomitant aplastic anemia * Severe cardiac insufficiency (NYHA functional class ≥ II) * Severe pulmonary involvement, including pulmonary hemorrhage, respiratory failure, pulmonary embolism, or other conditions requiring respiratory support * Estimated glomerular filtration rate (eGFR) \<60 mL/min/1.73 m² * Severe gastrointestinal bleeding, pancreatitis, or hepatic lesions * Patients deemed by the investigator to be unsuitable for participation in this trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Renal Response at Week 24 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Renal Response at Week 12 and 24 | Week 12, 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. |
| Primary Efficacy Renal Response at Week 12 and 24 | Week 12, 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. |
| Partial Renal Response at Week 12 and 24 | Week 12, 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 to TRR | Week 0-24 | 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 to CRR | Week 0-24 | 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 to PERR | Week 0-24 | 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 to PRR | Week 0-24 | 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. |
| Change of C3 from baseline to Week 24 | Week 0, 24 | To assess the improvement of SLE serum activity |
| Changes of C4 from baseline to Week 24 | Week 0, 24 | To assess the improvement of SLE serum activity |
| Change of anti-dsDNA titer from baseline to Week 24 | Week 0, 24 | To assess the improvement of SLE disease activity |
| Change of anti-dsDNA value from baseline to Week 24 | Week 0, 24 | To assess the improvement of SLE disease activity |
| Change of SLEDAI-2K from baseline to Week 24 | Week 0, 24 | To assess the level of disease activity improvement by Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score. |
| Change of PGA from baseline to Week 24 | Week 0, 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. |
| Change of ParentGA from baseline to Week 24 | Week 0, 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). |
| Change of PedsQL from baseline to Week 24 | Week 0, 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. |
| Change of serum creatinine from baseline to Week 24 | Week 0, 24 | To measure renal function levels |
| Change of eGFR from baseline to Week 24 | Week 0, 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 |
| Change of 24-hour urine protein from baseline to Week 24 | Week 0, 24 | A 24-hour urine protein test measures kidney function by quantifying how much protein the body excretes in a full day. |
| Changes of UPCR from baseline to Week 24 | Week 0, 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. |
| Rate of LN treatment failure at Week 24 | 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. |
| Rate of renal flare at Week 24 | 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. |
| Rate of SLE flare at Week 24 | 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. |
| Rate of LLDAS at Week 24 | 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. |
| Rate of DORIS remission at Week 24 | 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. |
| PRINTO/ACR cSLE response rate at Week 24 | 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). |
| Changes of Childhood Lupus Improvement Index (CHILI) from baseline to Week 24 | Week 0, 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) |
| Rate of clinical, minor, moderate and major improvement in cSLE at Week 24 | Week 0, 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. |
| Scores and changes of pGTI from baseline to Week 12 and 24 | Week 0, 12, 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) |
| SLICC/ACR Damage Index at Week 24 | 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) |
| Category, incidence and severity of adverse events | Week 0-24 | 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. |
| Change of blood pressure from baseline to Week 24 | Week 0, 24 | To measure improvement of kidney function, and monitor the side effect by glucocorticoids. |
| Change of fasting blood glucose from baseline to Week 24 | Week 0, 24 | To evaluate adverse events of glucocorticoids |
| Changes of serum triglycerides from baseline to Week 24 | Week 0, 24 | To monitor adverse effects of glucocorticoids |
| Changes of height from baseline to Week 24 | Week 0, 24 | To measure the growth velocity of children, and monitor the adverse events of glucocorticoids |
| Changes of bone marrow density from baseline to Week 24 | Week 0, 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. |
Countries
China
Contacts
CONTACTSihao Gao, MD, PhD
PRINCIPAL_INVESTIGATORHongmei Song, MD, PhD
Peking Union Medical College
Outcome results
None listed