Childhood-onset Lupus Nephritis Initial Glucocorticoid-dose Harmonization Trial (LIGHT Trial)

Official title

Low- Versus High-Dose Initial Glucocorticoid Therapy for Childhood-Onset Proliferative Lupus Nephritis: a Multicenter Open-Label Noninferiority Randomized Controlled Trial

Overview

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

• Drug High-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
• Drug Low-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

Primary outcome measures

• Total Renal Response at Week 24 [Time frame: Week 24]

Secondary outcome measures (12)

• Complete Renal Response at Week 12 and 24 [Time frame: Week 12, 24]
• Primary Efficacy Renal Response at Week 12 and 24 [Time frame: Week 12, 24]
• Partial Renal Response at Week 12 and 24 [Time frame: Week 12, 24]
• Time to TRR [Time frame: Week 0-24]
• Time to CRR [Time frame: Week 0-24]
• Time to PERR [Time frame: Week 0-24]
• Time to PRR [Time frame: Week 0-24]
• Change of C3 from baseline to Week 24 [Time frame: Week 0, 24]
• Changes of C4 from baseline to Week 24 [Time frame: Week 0, 24]
• Change of anti-dsDNA titer from baseline to Week 24 [Time frame: Week 0, 24]
• Change of anti-dsDNA value from baseline to Week 24 [Time frame: Week 0, 24]
• Change of SLEDAI-2K from baseline to Week 24 [Time frame: Week 0, 24]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 8 centers

• Peking Union Medical College Hospital, Chinese Academy of Medical Sciences — Beijing
• Beijing Children's Hospital, Capital Medical University — Beijing
• Chidren's Hospital of Chongqing Medical University — Chongqing
• Shenzhen Children's Hospital — Shenzhen
• The Second Xiangya Hospital of Central South University — Changsha
• Children's Hospital of Nanjing Medical University — Nanjing
• Jilin University — Changchun
• Children's Hospital of Fudan University — Shanghai

Publications

• Wang Y, Li X, Jian S, Li J, Yan J, Sun S, Yang Z, Zheng W, Li Q, Zheng Q, Lu M, Wang M, Yang Q, Mao H, Han T, Lin Y, Zhang Q, Du Y, Tang Y, Cai Y, Sun L, Zhang J, Liu J, Rong Z, Jiang L, Bai H, Chen Y, Yang J, Wang L, Zhang W, Wei X, Zhu Y, Li X, Xie X, Zhou D, Li Y, Cao Y, Shen T, Liu Q, Song H, Wu X; Chinese Alliance of Pediatric Rheumatic and Immunologic Diseases. Mycophenolate Mofetil versus C PMID 40938672
• Gong Y, Liu S, Liu H, Shi Y, Li Y, Guan W, Zeng Q, Lv Q, Zhang X, Wei Q, Chen J, Shen Q, Xu H, Sun L. Efficacy of initial combination with belimumab in newly diagnosed childhood-onset lupus nephritis: a single-centre historical control study. Lupus Sci Med. 2024 Dec 15;11(2):e001350. doi: 10.1136/lupus-2024-001350. PMID 39675786
• Brogan P, Naden R, Ardoin SP, Cooper JC, De Benedetti F, Dicaire JF, Eleftheriou D, Feldman B, Goldin J, Karol SE, Price-Kuehne F, Skuse D, Stratakis CA, Webb N, Stone JH. The pediatric glucocorticoid toxicity index. Semin Arthritis Rheum. 2022 Oct;56:152068. doi: 10.1016/j.semarthrit.2022.152068. Epub 2022 Jul 14. PMID 35917759
• Brunner HI, Holland MJ, Beresford MW, Ardoin SP, Appenzeller S, Silva CA, Flores F, Goilav B, Avar Aydin PO, Wenderfer SE, Levy DM, Ravelli A, Khubchandani R, Avcin T, Klein-Gitelman MS, Ruperto N, Feldman BM, Ying J; Paediatric Rheumatology International Trial Organisation and Pediatric Rheumatology Collaborative Study Group. American College of Rheumatology Provisional Criteria for Clinically Re PMID 30680946
• Brunner HI, Abud-Mendoza C, Viola DO, Calvo Penades I, Levy D, Anton J, Calderon JE, Chasnyk VG, Ferrandiz MA, Keltsev V, Paz Gastanaga ME, Shishov M, Boteanu AL, Henrickson M, Bass D, Clark K, Hammer A, Ji BN, Nino A, Roth DA, Struemper H, Wang ML, Martini A, Lovell D, Ruperto N; Paediatric Rheumatology International Trials Organisation (PRINTO) and the Pediatric Rheumatology Collaborative Study PMID 32699034
• Brunner HI, Higgins GC, Wiers K, Lapidus SK, Olson JC, Onel K, Punaro M, Ying J, Klein-Gitelman MS, Giannini EH. Prospective validation of the provisional criteria for the evaluation of response to therapy in childhood-onset systemic lupus erythematosus. Arthritis Care Res (Hoboken). 2010 Mar;62(3):335-44. doi: 10.1002/acr.20103. PMID 20391479
• Varni JW, Seid M, Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med Care. 1999 Feb;37(2):126-39. doi: 10.1097/00005650-199902000-00003. PMID 10024117
• Filocamo G, Davi S, Pistorio A, Bertamino M, Ruperto N, Lattanzi B, Consolaro A, Magni-Manzoni S, Galasso R, Varnier GC, Martini A, Ravelli A. Evaluation of 21-numbered circle and 10-centimeter horizontal line visual analog scales for physician and parent subjective ratings in juvenile idiopathic arthritis. J Rheumatol. 2010 Jul;37(7):1534-41. doi: 10.3899/jrheum.091474. Epub 2010 Jun 15. PMID 20551105

Identifiers

NCT: NCT07719140 · K10405 · 2025-PUMCH-C-047

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗