Prospective, randomized, parallel-group controlled, open-label, international (Asian) multicenter, comparison of corticosteroids combined with tacrolimus and corticosteroids combined with mycophenolate mofetil.
There is accumulating evidence that tacrolimus (TAC) could serve as an effective medication for the treatment of lupus nephritis (LN). TAC is a calcineurin inhibitor, which is a key component in first-line combination immunosuppressive regimens after kidney transplantation, based on its proven efficacy in the prevention and treatment of allograft rejection and acceptable tolerability profile. Although it primarily targets T lymphocyte activation, its immunosuppressive actions encompass multiple immune response pathways due to the complex interactions between different cellular and soluble immune mediators. Moreover, the effect of calcineurin inhibitors on podocyte morphology and function, independent of their immunosuppressive effect, has translated into therapeutic efficacy in the treatment of proteinuric glomerular diseases such as membranous nephropathy and focal segmental glomerulosclerosis. Recent data from short-term studies showed that combination immunosuppressive regimens that included TAC and corticosteroids with or without mycophenolate mofetil (MMF) appeared at least as effective as other standard-of-care treatments for Class III/IV±V LN, and the inclusion of TAC might lead to more effective suppression of proteinuria. There is also preliminary data on its favorable tolerability when used as long-term maintenance treatment. This study aims to examine the role of TAC combined with corticosteroids, in comparison with the most commonly used standard-of-care treatment MMF plus corticosteroids, in the management of lupus nephritis.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
130
Dosage: start at 2mg twice a day, then titrated according to therapeutic drug level monitoring using 12-hour post-dose blood sampling
Dosage: start at 1g twice a day, then taper as per protocol
The University of Hong Kong
Hong Kong, Hong Kong
Efficacy of combined corticosteroids and TAC compared to combined corticosteroids and MMF in achieving sustained renal response (RR) in patients with active lupus nephritis [Class III/IV±V (LN)]
Sustained RR defined as satisfying all of the following criteria: 1. proteinuria improved by ≥50% compared with baseline 2. 24-hr urine protein \<1 g 3. serum creatinine not higher than 15% above baseline level or eGFR not less than 60 mL/min/1.73m2 4. no occurrence of disease flare AFTER achieving response to treatment. Disease flare is defined as the need for 'rescue' immunosuppressive therapy with any one of the following i. increase of prednisolone dose from ≤7.5 mg/D to ≥15 mg/D for 4 weeks or longer ii. change of originally assigned immunosuppressive agent iii. addition of immunosuppressive medications prohibited in protocol
Time frame: 96 weeks
Rate of complete renal remission
* proteinuria not higher than 0.5 g/D * serum creatinine not higher than 15% above baseline level or eGFR not less than 60 mL/min/1.73m2
Time frame: 96 weeks
Rate of partial renal remission
* proteinuria above 0.5 g/D and below 3 g/D and with ≥50% improvement compared with baseline level * serum creatinine not higher than 15% above baseline level or eGFR not less than 60 mL/min/1.73m2
Time frame: 96 weeks
Efficacy of combined corticosteroids and TAC compared to combined corticosteroids and MMF in achieving sustained renal response (RR) in patients with active lupus nephritis [Class III/IV±V (LN)]
Sustained RR defined as satisfying all of the following criteria: 1. proteinuria improved by ≥50% compared with baseline 2. 24-hr urine protein \<1 g 3. serum creatinine not higher than 15% above baseline level or eGFR not less than 60 mL/min/1.73m2 4. no occurrence of disease flare AFTER achieving response to treatment. Disease flare is defined as the need for 'rescue' immunosuppressive therapy with any one of the following i. increase of prednisolone dose from ≤7.5 mg/D to ≥15 mg/D for 4 weeks or longer ii. change of originally assigned immunosuppressive agent iii. addition of immunosuppressive medications prohibited in protocol
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Time frame: 48 weeks
Refractory disease
Never achieving partial renal remission since commencement of study
Time frame: 96 weeks
Rate of non-renal flare
Disease flare defined by the need for 'rescue' immunosuppressive therapy with any one of the following i. increase of prednisolone dose from ≤7.5 mg/D to ≥15 mg/D for 4 weeks or longer ii. change of originally assigned immunosuppressive agent iii. addition of immunosuppressive medications prohibited in protocol
Time frame: 96 weeks
Incidence of acute kidney injury
Number of patients who had increase of serum creatinine level ≥15% from baseline and whether the increase was reversible or irreversible
Time frame: 96 weeks
Incidence of TAC blood level above target range
Number of patients who had 12-hour post dose TAC blood level above i. 8 ng/mL (from baseline to end of week 24) ii. 7 ng/mL (from start of week 25 to end of week 48, and from start of week 49 to end of week 96 for patients who had serum creatinine level \<150 micromol/L) iii. 6 ng/mL (from start of week 49 to end of week 96 for patients who had serum creatinine level ≥150 micromol/L)
Time frame: 96 weeks
Incidence of new onset hypertension or worsening hypertensive control
Number of patients who had new onset hypertension (blood pressure \>140/90 mmHg) or worsening hypertensive control that required increase of number or dose of anti-hypertensive medications
Time frame: 96 weeks
Rate of infection
Number of patients who had infection that required hospitalization and its causative agents
Time frame: 96 weeks
Rate of Hospitalization
Number of patients who had been hospitalized, the cause and duration of hospitalization
Time frame: 96 weeks
Incidence of hyperkalemia
Number of patients who had serum potassium level \>5.6 mmol/L
Time frame: 96 weeks
Incidence of metabolic acidosis
Number of patients who had serum bicarbonate level \<17 mmol/L
Time frame: 96 weeks
Incidence of new onset diabetes mellitus
Number of patients who had fasting glucose \> 6.0 mmol/L and/or required addition of blood glucose lowering drug(s)
Time frame: 96 weeks
Incidence of new onset hypercholesterolemia
Number of patients who had total cholesterol\> 5.0 mmol/L and low density lipoprotein \>3.4 mmol/L presented at 6 months or beyond from baseline and/or required addition of lipid-lowering drug(s)
Time frame: 96 weeks
Rate of treatment intolerance leading to premature study discontinuation
Definition of treatment intolerance i. severe gastrointestinal disturbance or marrow suppression (white blood cell count \<2×10\^9/L OR platelet count \<50×10\^9/L OR hemoglobin \<8 g/dL) judged due to MMF and persisted despite reduction of MMF dosage to \< 1.25 g per day ii. significant hand-tremor or neurotoxicity related to TAC
Time frame: 96 weeks
Rate of disease complication leading to premature study discontinuation
Number of patients who developed complication that led to premature study discontinuation
Time frame: 96 weeks
Rate of disease flare leading to premature study discontinuation
Disease flare is defined as the need for 'rescue' immunosuppressive therapy with any one of the following i. increase of prednisolone dose from ≤7.5 mg/D to ≥15 mg/D for 4 weeks or longer ii. change of originally assigned immunosuppressive agent iii. addition of immunosuppressive medications prohibited in protocol
Time frame: 96 weeks
Number of patients who failed to adhere to protocol defined corticosteroid reduction regimen
Failure to adhere to corticosteroid reduction regimen was defined as deviation from protocol-defined corticosteroid dose by \>5mg/D for \>3 weeks due to unsatisfactory treatment response or new-onset disease activity.
Time frame: 96 weeks
Incidence of adverse events
Number and type of adverse events, irrespective of whether the event was treatment-related or not
Time frame: 96 weeks
Incidence of serious adverse events
Number and type of serious adverse events, irrespective of whether the event was treatment-related or not
Time frame: 96 weeks
Changes in SELENA-SLEDAI scores
Changes in SELENA-SLEDAI scores from baseline to week 96
Time frame: 96 weeks
Changes in PGA scores
Changes in PGA scores from baseline to week 96
Time frame: 96 weeks
Changes in SFI scores
Changes in SFI scores from baseline to week 96
Time frame: 96 weeks
Changes in BILAG (2004) scores
Changes in BILAG (2004) scores from baseline to week 96
Time frame: 96 weeks