Efficacy and Safety of Tacrolimus Versus Mycophenolate in Lupus Nephritis

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

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

Study Overview

• Status: Completed
• Conditions: Lupus Nephritis
• Intervention / Treatment: Drug: Mycophenolate mofetil; Drug: Tacrolimus

Detailed Description

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
• Enrollment (Actual): 130
• Phase: Phase 3

Contacts and Locations

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • The University of Hong Kong

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

Exclusion Criteria:

1. Renal disease unrelated to SLE (e.g. diabetes mellitus, other glomerular or tubulointerstitial disease, renovascular disease), or transplanted kidney.
2. 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.
3. Renal biopsy showing cellular or fibrocellular crescent in more than 25% of glomeruli.
4. CNS or other severe organ manifestation of lupus that necessitate aggressive immunosuppressive therapy on its own.
5. Co-morbidities that require corticosteroid therapy (e.g. asthma, inflammatory bowel disease).
6. Treatment with prednisolone (or prednisone, or equivalent) at ≥20 mg/D for over 4 weeks within the past 3 months.
7. Treatment with MMF at >1.5 g/D for over 4 weeks within the past 3 months.
8. Known hypersensitivity or intolerability to prednisolone (or prednisone, or equivalent), TAC, or MMF at a dose of 1.25 g or below per day.
9. 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.
10. 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).
11. Uncontrolled hypertension with systolic BP >160 mmHg or diastolic BP >95 mmHg.
12. Women who are pregnant or breastfeeding.
13. Women with childbearing potential or their male partners, who refuse to use an effective birth control method

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Tacrolimus; route: oral duration: 96 weeks	Drug: Tacrolimus; 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
Active Comparator: Mycophenolate Mofetil; route: oral duration: 96 weeks	Drug: Mycophenolate mofetil; Dosage: start at 1g twice a day, then taper as per protocol; Other Names: Cellcept

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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: 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	96 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Refractory disease	Never achieving partial renal remission since commencement of study	96 weeks
Changes in SELENA-SLEDAI scores	Changes in SELENA-SLEDAI scores from baseline to week 96	96 weeks
Changes in PGA scores	Changes in PGA scores from baseline to week 96	96 weeks
Changes in SFI scores	Changes in SFI scores from baseline to week 96	96 weeks
Changes in BILAG (2004) scores	Changes in BILAG (2004) scores from baseline to week 96	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	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	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: 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	48 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	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	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)	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	96 weeks
Rate of infection	Number of patients who had infection that required hospitalization and its causative agents	96 weeks
Rate of Hospitalization	Number of patients who had been hospitalized, the cause and duration of hospitalization	96 weeks
Incidence of hyperkalemia	Number of patients who had serum potassium level >5.6 mmol/L	96 weeks
Incidence of metabolic acidosis	Number of patients who had serum bicarbonate level <17 mmol/L	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)	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)	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	96 weeks
Rate of disease complication leading to premature study discontinuation	Number of patients who developed complication that led to premature study discontinuation	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	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.	96 weeks
Incidence of adverse events	Number and type of adverse events, irrespective of whether the event was treatment-related or not	96 weeks
Incidence of serious adverse events	Number and type of serious adverse events, irrespective of whether the event was treatment-related or not	96 weeks

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Investigators: Principal Investigator: Tak-Mao Daniel Chan, The University of Hong Kong

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2015
• Primary Completion (Actual): December 27, 2024
• Study Completion (Actual): December 27, 2024

Study Registration Dates

• First Submitted: December 5, 2015
• First Submitted That Met QC Criteria: December 14, 2015
• First Posted (Estimated): December 15, 2015

Study Record Updates

• Last Update Posted (Estimated): September 25, 2025
• Last Update Submitted That Met QC Criteria: September 21, 2025
• Last Verified: September 1, 2025

More Information

Terms related to this study

• Keywords: mycophenolate mofetil; tacrolimus; Lupus Nephritis
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Nephritis; Skin and Connective Tissue Diseases; Lupus Nephritis; Organic Chemicals; Fatty Acids; Lipids; Acids, Acyclic; Carboxylic Acids; Macrolides; Lactones; Caproates; Mycophenolic Acid; Tacrolimus
• Other Study ID Numbers: ALNN-IIS-17JUL15-1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No