Efficacy and Safety of Tacrolimus Versus Mycophenolate in Lupus Nephritis

Phase 4

Completed

• Conditions: Lupus Nephritis
• Interventions: Drug: Tacrolimus; Drug: Mycophenolate mofetil

• Registration Number: NCT02630628
• Lead Sponsor: The University of Hong Kong

Brief Summary

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

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 Timeline

• Study Start: 2015-12-05
• Study First Submitted: 2015-12-05
• Study First Submitted QC: 2015-12-14
• Study First Posted: 2015-12-15
• Primary Completion: 2024-12-27
• Study Completion: 2024-12-27
• Status Verified: 2025-03
• Last Update Submitted: 2025-03-17
• Last Update Posted: 2025-03-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 130

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.

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 for over 4 weeks within the past 12 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tacrolimus	Tacrolimus	route: oral duration: 96 weeks
Mycophenolate Mofetil	Mycophenolate mofetil	route: oral duration: 96 weeks

Primary Outcome Measures

Name	Time	Method
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)]	96 weeks	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, defined as receiving 'rescue' increase of immunosuppressive therapy with any one of the following - requiring increase of prednisolone (or prednisone, or equivalent) dose to above 15 mg/D for 4 weeks or longer, change of originally assigned immunosuppressive agent, or addition of immunosuppressive medications prohibited in protocol

Secondary Outcome Measures

Name	Time	Method
Changes in SFI scores	96 weeks	Changes in SFI scores from baseline to week 96
Changes in BILAG (2004) scores	96 weeks	Changes in BILAG (2004) scores from baseline to week 96
Rate of partial remission	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
Refractory disease	96 weeks	Never achieving partial renal remission since commencement of study
Rate of non-renal flare	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
Rate of complete remission	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
Safety and tolerability of study medications	96 weeks	Monitor the side effects of study medications; 1. Increase of serum creatinine level \>15% from baseline; 2. Episodes with TAC blood level above target range; 3. New onset hypertension; 4. Infections requiring hospitalization and the causative agents; 5. Duration and cause of hospitalization; 6. New onset diabetes mellitus; 7. New onset hypercholesterolemia; 8. Premature discontinuation from study due to treatment intolerance, disease complications, disease flare or other reasons; 9. Failure to adhere to protocol defined corticosteroid reduction regimen; 10. Other adverse clinical events or events considered clinically significant
Changes in SELENA-SLEDAI scores	96 weeks	Changes in SELENA-SLEDAI scores from baseline to week 96
Changes in PGA scores	96 weeks	Changes in PGA scores from baseline to week 96

Trial Locations

Locations (1)

The University of Hong Kong; 🇭🇰 Hong Kong, Hong Kong