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Completed

NCT Number: NCT02630628

Efficacy and Safety of Tacrolimus Versus Mycophenolate in Lupus Nephritis

Prospective, randomized, parallel-group controlled, open-label, international (Asian) multicenter, comparison of corticosteroids combined with tacrolimus and corticosteroids combined with mycophenolate mofetil.

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Key information

Conditions

Lupus Nephritis Autoimmune Diseases Connective Tissue Diseases Female Urogenital Diseases Female Urogenital Diseases and Pregnancy Complications Glomerulonephritis Immune System Diseases Kidney Diseases Lupus Erythematosus, Systemic Male Urogenital Diseases Nephritis Skin and Connective Tissue Diseases Urogenital Diseases Urologic Diseases

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

The University of Hong Kong

Hong Kong

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Biopsy-proven LN Class III/IV±V (ISN/RPS 2003), with biopsy performed within 12 weeks of randomization.
  • Positive anti-dsDNA.
  • Active LN with proteinuria (urine protein/creatinine ratio ≥1.0 or 24-hr urine protein ≥1.0 g at baseline), with or without hematuria.
  • Both 'incident' (i.e. new) patients and 'flare' patients can be included.
  • Males or females aged 18 to 75 years inclusive at the time of screening.

Exclusion criteria

  • Renal disease unrelated to SLE (e.g. diabetes mellitus, other glomerular or tubulointerstitial disease, renovascular disease), or transplanted kidney.
  • Estimated glomerular filtration rate (eGFR by MDRD) ≤20 mL/min per 1.73 m2 or serum creatinine ≥300 micromol/L (3.39 mg/dL) at screening.
  • Renal biopsy showing cellular or fibrocellular crescent in more than 25% of glomeruli.
  • CNS or other severe organ manifestation of lupus that necessitate aggressive immunosuppressive therapy on its own.
  • Co-morbidities that require corticosteroid therapy (e.g. asthma, inflammatory bowel disease).
  • Treatment with prednisolone (or prednisone, or equivalent) at ≥20 mg/D for over 4 weeks within the past 3 months.
  • Treatment with MMF at >1.5 g/D for over 4 weeks within the past 3 months.
  • Known hypersensitivity or intolerability to prednisolone (or prednisone, or equivalent), TAC, or MMF at a dose of 1.25 g or below per day.
  • Subjects who are already on treatment with TAC, cyclosporine or any other calcineurin inhibitor on the day of screening; or have received treatment with TAC, cyclosporine or other calcineurin inhibitor for over 4 weeks within the past 6 months.
  • Treatment with cyclophosphamide, leflunomide, or methotrexate for over 2 weeks, or use of biological agent(s) regardless of duration, within the past 6 months (Note: prior use of azathioprine, mizoribine, intravenous immunoglobulins and anti-malarials is allowed).
  • Uncontrolled hypertension with systolic BP >160 mmHg or diastolic BP >95 mmHg.
  • Women who are pregnant or breastfeeding.
  • Women with childbearing potential or their male partners, who refuse to use an effective birth control method

Treatment and study plan

Tacrolimus

Drug

Dosage: start at 2mg twice a day, then titrated according to therapeutic drug level monitoring using 12-hour post-dose blood sampling

Other names: Prograf

Mycophenolate mofetil

Drug

Dosage: start at 1g twice a day, then taper as per protocol

Other names: Cellcept

Primary outcomes

  1. 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)]

    Time frame: 96 weeks

    Sustained RR defined as satisfying all of the following criteria:

    • proteinuria improved by ≥50% compared with baseline
    • 24-hr urine protein <1 g
    • serum creatinine not higher than 15% above baseline level or eGFR not less than 60 mL/min/1.73m2
    • 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

Secondary outcomes

  1. Rate of complete renal remission

    Time frame: 96 weeks

    • 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

  2. Rate of partial renal remission

    Time frame: 96 weeks

    • 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

  3. 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)]

    Time frame: 48 weeks

    Sustained RR defined as satisfying all of the following criteria:

    • proteinuria improved by ≥50% compared with baseline
    • 24-hr urine protein <1 g
    • serum creatinine not higher than 15% above baseline level or eGFR not less than 60 mL/min/1.73m2
    • 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

  4. Refractory disease

    Time frame: 96 weeks

    Never achieving partial renal remission since commencement of study

  5. Rate of non-renal flare

    Time frame: 96 weeks

    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

  6. Incidence of acute kidney injury

    Time frame: 96 weeks

    Number of patients who had increase of serum creatinine level ≥15% from baseline and whether the increase was reversible or irreversible

  7. Incidence of TAC blood level above target range

    Time frame: 96 weeks

    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)

  8. Incidence of new onset hypertension or worsening hypertensive control

    Time frame: 96 weeks

    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

  9. Rate of infection

    Time frame: 96 weeks

    Number of patients who had infection that required hospitalization and its causative agents

  10. Rate of Hospitalization

    Time frame: 96 weeks

    Number of patients who had been hospitalized, the cause and duration of hospitalization

  11. Incidence of hyperkalemia

    Time frame: 96 weeks

    Number of patients who had serum potassium level >5.6 mmol/L

  12. Incidence of metabolic acidosis

    Time frame: 96 weeks

    Number of patients who had serum bicarbonate level <17 mmol/L

  13. Incidence of new onset diabetes mellitus

    Time frame: 96 weeks

    Number of patients who had fasting glucose > 6.0 mmol/L and/or required addition of blood glucose lowering drug(s)

  14. Incidence of new onset hypercholesterolemia

    Time frame: 96 weeks

    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)

  15. Rate of treatment intolerance leading to premature study discontinuation

    Time frame: 96 weeks

    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

  16. Rate of disease complication leading to premature study discontinuation

    Time frame: 96 weeks

    Number of patients who developed complication that led to premature study discontinuation

  17. Rate of disease flare leading to premature study discontinuation

    Time frame: 96 weeks

    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

  18. Number of patients who failed to adhere to protocol defined corticosteroid reduction regimen

    Time frame: 96 weeks

    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.

  19. Incidence of adverse events

    Time frame: 96 weeks

    Number and type of adverse events, irrespective of whether the event was treatment-related or not

  20. Incidence of serious adverse events

    Time frame: 96 weeks

    Number and type of serious adverse events, irrespective of whether the event was treatment-related or not

  21. Changes in SELENA-SLEDAI scores

    Time frame: 96 weeks

    Changes in SELENA-SLEDAI scores from baseline to week 96

  22. Changes in PGA scores

    Time frame: 96 weeks

    Changes in PGA scores from baseline to week 96

  23. Changes in SFI scores

    Time frame: 96 weeks

    Changes in SFI scores from baseline to week 96

  24. Changes in BILAG (2004) scores

    Time frame: 96 weeks

    Changes in BILAG (2004) scores from baseline to week 96

Sponsors and collaborators

Lead sponsor

The University of Hong Kong

Other

Registry information

Official study title

A Randomized Open-label Study to Evaluate the Efficacy and Safety of Tacrolimus and Corticosteroids in Comparison With Mycophenolate Mofetil and Corticosteroids in Subjects With Class III/IV±V Lupus Nephritis

Important dates

Study start
2015
Primary completion
2024
Study completion
2024
First posted
Dec 15, 2015
Registry last updated
Sep 25, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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