Rationale:
Lupus nephritis (LN) is a very common complication of systemic lupus erythematosus (SLE). Currently available all guidelines suggest an induction phase with glucocorticoids along with another immunosuppressive agent. However, the basis of using high dose of glucocorticoids are mostly empirical. There is no published data comparing low and high dose glucocorticoids in the treatment of LN. Use of high dose of glucocorticoids may increase morbidity like osteopenia, osteonecrosis of neck of femur, Cushing syndrome etc. Moreover, rate of infectious disease is very high in the investigator's country. Patient treated with high dose glucocorticoids may prone to develop serious infectious conditions. Researchers are currently trying to develop new regimen, which can replace the use of long-term glucocorticoids to treat LN. Unless the alternative regimen developed, well-controlled study is necessary to establish a lowest possible dose of glucocorticoid to treat this condition.
Research question:
Is lower dose prednisolone similar efficacious as the higher dose regimen in achieving complete remission of proliferative lupus nephritis?
Null hypothesis:
Lower dose prednisolone regimen is inferior to the higher dose regimen by more than - Δ in achieving the complete remission of proliferative lupus nephritis.
H0: P1-P2 ≤ - Δ P1 = Test drug (Prednisolone 0.5 mg/kg/day) P2 = Control drug (Prednisolone 1 mg/kg/day) Δ = Non-inferiority margin
Alternative hypothesis:
Lower dose prednisolone regimen is inferior to the higher dose regimen by less than - Δ in achieving the complete remission of proliferative lupus nephritis.
H1: P1-P2 \> - Δ
General objective:
To assess efficacy of prednisolone 0.5 mg/kg/day in achieving remission of proliferative LN compared to 1 mg/kg/day
Specific objectives:
To compare:
* Changes of UTP level from the baseline to 24 weeks
* Changes of active urinary sediments level from the baseline to 24 weeks
* Changes of serum creatinine level from the baseline to 24 weeks
* Changes of quality of life from the baseline to 24 weeks
* Adverse effects during study period
Primary endpoint: (Time frame: at the end of 24th week)
• Complete renal remission
Secondary endpoints: (Time frame: at the end of 24th week)
* Renal remission (complete/partial) at 24 weeks
* Changes of UTP level from the baseline at 24 weeks
* Proportion of subjects with active urinary sediment at 24 weeks
* Changes of serum creatinine level from the baseline at 24 weeks
* Changes of eGFR from the baseline at 24 weeks
* Changes of anti-dsDNA level from the baseline at 24 weeks
* Changes of complements (C3 and C4) level from the baseline at 24 weeks
* Changes of SELENA-SLEDAI score from the baseline at 24 weeks
* Changes of SF-12 score from the baseline at 24 weeks
Study procedure:
This open labeled randomized controlled clinical trial was conducted in the outpatient and the inpatient department of Rheumatology, BSMMU from July 2018 to September 2019. Patients of SLE were interviewed after taking verbal consent. They were screened with history, physical examination, urine RME, 24hours UTP reports. Patients fulfilling the inclusion and exclusion criteria were enrolled in the study after taking informed written consent. Total 32 patients of SLE with proliferative LN were enrolled in the study. After the enrollment study subjects were randomized into experimental group (low dose group) and control group (high dose group) by lottery. Baseline laboratory tests were urine R/M/E, 24 hours UTP, serum creatinine, anti-dsDNA, C3, C4, CBC with ESR, SGPT. Baseline quality of life was assessed by Bengali version SF-12 questionnaire.
Both groups received pulse I/V methylprednisolone 500 mg/day daily for 3 doses. Then, patients of the low dose group received oral prednisolone 0.5 mg/kg/day (maximum 30 mg/day) and high dose group received oral prednisolone 1 mg/kg/day (maximum 60 mg/day) for initial 4 weeks. In the low dose group, prednisolone was tapered by 5 mg/day in every two weeks until 10 mg/day was reached, then after two weeks the dose was tapered by 2.5 mg/day to a maintenance dose of 7.5 mg/day. In the high dose group, prednisolone was tapered by 10 mg/day in every two weeks until 40 mg, then 5 mg/day in every two weeks until 10 mg/day is reached, after two weeks it was tapered by 2.5 mg/day to a maintenance dose of 7.5 mg/day.
Patients of both groups were treated with monthly CYC infusion, first dose 750 mg/m2 body surface area, subsequent doses were adjusted based on leukocyte nadir (≥ 4000 cells/mm3, doses were increased by 25%, to a maximum of 1 gm/m2 body surface area, the dose were reduced by 25% for leukocyte counts \<4000 cells/mm3). Both groups of patients received hydroxychloroquine (HCQ), angiotensin receptor blocker (ARB) and other relevant medications. Patient education, vaccinations against influenza and pneumococcus were given to all the enrolled subjects. All patients were given Pneumocystis jirovecii prophylaxes.
Primary endpoint (complete remission) was assessed at the end of 24th week. Urine R/M/E, CBC with ESR, SGPT and serum creatinine were done in every 4 weeks. Twenty-four hours UTP were done at the end of 12 weeks and 24 weeks. Anti-dsDNA, C3 and C4 were done at the end of 24 weeks. Data were collected from a set of written questionnaires which was supplied to the patients and from physical examination and investigation findings. Quality of life was assessed by Bengali version of SF-12 questionnaire.
