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Comparison Between Tacrolimus (TAC) and Mycophenolate Mofetil (MMF) for Induction of Remission in Lupus Nephritis

Primary Purpose

Lupus Nephritis

Status
Completed
Phase
Not Applicable
Locations
Thailand
Study Type
Interventional
Intervention
Tacrolimus vs. Mycophenolate mofetil for Induction Therapy in Lupus Nephritis
Sponsored by
Ramathibodi Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lupus Nephritis focused on measuring Lupus nephritis, Tacrolimus, Mycophenolate mofetil, Complete remission

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • The patient who had biopsy-proven lupus nephritis class III, IV or V according to the International Society of Nephrology (ISN)/Renal Pathology Society (RPS) 2003 classification (ISN/RPS2003) within 16 weeks of randomization and had ANA or anti-dsDNA positive.
  • Laboratory tests documented the presence of active nephritis, defined as proteinuria (protein excretion >1 g/24 h or spot UPCR > 1 for at least two samples) or increased serum creatinine level (>0.3 mg/dL of baseline but less than 2.0 mg/dl) with active urinary sediment (any of >5 red blood cells/high-power field, >5 white blood cells/high-power field, or red blood cell casts in the absence of infection or other causes).
  • Willingness to participate in the study, and be able to read and provide informed consent.

Exclusion Criteria:

  • Severe extra-renal manifestations that may require high-dose steroids or other immunomodulating treatments. The definition of severe extra-renal diseases in this investigation are defined by

    • Active central nervous system deemed to be severe or progressive and/ or associated with significant cognitive impairment leading to inability to provide informed consent and/ or comply with the protocol.
    • Any condition, including clinical findings or the laboratory results, which the investigators consider the patients have high disease activity and need high dose steroid and immunosuppressive drugs or other therapy depending on investigator opinion.
    • Severe myocarditis with congestive heart failure or renal failure.
  • Previous therapy with calcineurin inhibitor or MMF or CYC within the previous 4 months before randomization.
  • Allergy with macrolide antibiotics.
  • Uncontrolled hypertension (systolic blood pressure ≥160mmHg or diastolic blood pressure ≥100mmHg) at screening day.
  • Severely deteriorated renal function or rapid progressive crescentic Glomerulonephritis.
  • Severe myocarditis or cardiomyopathy which may or may not be related to SLE
  • Patients who have thrombotic microangiopathy who require treatment with plasmapheresis or IVIG.
  • Severe infection or active TB.
  • Active hepatitis and evidence of chronic liver disease.
  • HIV infection.
  • Diabetes mellitus.
  • Women who were pregnant or unwilling to use contraception.
  • Patients who response to steroid (complete remission) during the run in period (4 weeks).
  • Known hypersensitivity or contraindication to MMF, mycophenolic acid (MPA), tacrolimus, corticosteroids or any components of these drug products.

Sites / Locations

  • Ramathibodi Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Mycophenolate Mofetil (MMF)

Tacrolimus (TAC)

Arm Description

MMF was initiated at a dose of 500 mg twice daily (for patients > 50 Kg and Estimated Glomerular Filtration rate (eGFR) > 60 ml/min) for 2 weeks, and advanced to 750 mg twice daily in LN patients weighing less than 50 kg or 1,000 mg twice daily in LN patients weighing 50 kg or more. .

TAC was started at a dosage of 0.1 mg/kg/day divided into 2 daily doses at 12-hour intervals, and the dosage was titrated to achieve trough blood concentrations of 6-10 ng/mL in the first and second month and then 4-8 ng/mL., thereafter

Outcomes

Primary Outcome Measures

Complete remission
Return of serum creatinine to previous baseline, plus a decline in the UPCR to <500 mg/g (<50 mg/mmol)

Secondary Outcome Measures

Partial remission
Stabilization (±25%), or improvement of serum creatinine, but not to normal, plus a ≥50% decrease in UPCR. If there was nephrotic-range proteinuria (UPCR ≥3000 mg/g [≥300 mg/mmol]), improvement requires a ≥50% reduction in UPCR, and a UPCR <3000 mg/g [<300 mg/mmol]
Urine protein to creatinine ratio (UPCR)
g/day
Serum creatinine
mg/dL
Glomerular filtration rate (GFR)
mL/min/1.73m2
Adverse events
Infection, leukopenia, gastrointestinal (GI) symptoms, new onset diabetes mellitus (DM)/hyperglycemia
Serious dverse events
Hospitalization, death
EQ5D
The Euro quality of life -5 Dimensions
SF36
The 36-Item Short Form Health Survey
SLEQOL
Systemic Lupus Erythematosus Quality of Life Questionnaire
SLEDAI-2K
Systemic Lupus Erythematosus Disease Activity Index 2000

Full Information

First Posted
April 17, 2012
Last Updated
September 10, 2018
Sponsor
Ramathibodi Hospital
Collaborators
King Chulalongkorn Memorial Hospital, Maharaj Nakorn Chiang Mai Hospital, Rajavithi Hospital, Srinagarind Hospital, Khon Kaen University, Siriraj Hospital, Songklanagarind Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT01580865
Brief Title
Comparison Between Tacrolimus (TAC) and Mycophenolate Mofetil (MMF) for Induction of Remission in Lupus Nephritis
Official Title
Comparison Between Tacrolimus and Mycophenolate Mofetil for Induction of Remission in Lupus Nephritis
Study Type
Interventional

2. Study Status

Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
May 2012 (undefined)
Primary Completion Date
March 2017 (Actual)
Study Completion Date
March 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Ramathibodi Hospital
Collaborators
King Chulalongkorn Memorial Hospital, Maharaj Nakorn Chiang Mai Hospital, Rajavithi Hospital, Srinagarind Hospital, Khon Kaen University, Siriraj Hospital, Songklanagarind Hospital

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Prospective, multi-center, randomized, controlled, trial to compare tacrolimus with mycophenolate mofetil (MMF) for induces complete remission in lupus nephritis patients. The study duration is one year. Research hypothesis The proportion of patients who have achieved complete remission between regimen of tacrolimus plus prednisolone is greater than MMF plus prednisolone as an induction therapy in lupus nephritis.
Detailed Description
The patients with a pathological diagnosis of active lupus nephritis whom are currently followed up or referred to outpatient department (OPD) of 7 participating medical centers in Thailand. Patients who come to attend will be selected according to the inclusion and exclusion criteria. Outcome measurements The patients will be follow-up for 1 year and will be evaluated for clinical manifestations and laboratory investigations of lupus nephritis and any adverse effects of therapy on each visit. Blood pressure and laboratory assessments, including complete blood cell count, urinalysis, urine protein creatinine ratio (UPCR), and kidney and liver function, will be performed at each visit for 24 weeks and at the end of study (48 weeks). Serum anti-double-stranded DNA antibodies and serum C3 will be measured every 8 weeks after treatment until 24 weeks and at the end of study (48 weeks). A fasting lipid profile will be also measured every 8 weeks until 24 weeks and at the end of study (48 weeks). Renal and extrarenal disease activity of SLE was measured using the SLEDAI2K. The SLEDAI2K will be evaluated at the time of entry into the study and every 8 weeks after treatment until 24 weeks and at the end of study (48 weeks). SLICC damage index, SF-36, EQ5D, and SLEQOL will be evaluated at the time of entry, at 24 weeks, and at the end of the study. Patients' serum and urine (blood 3ml and urine 50 ml) will be collected at baseline, 2nd week, 4th week, 12th week, and 48th week for further analysis of biomarkers in the future.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lupus Nephritis
Keywords
Lupus nephritis, Tacrolimus, Mycophenolate mofetil, Complete remission

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
84 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Mycophenolate Mofetil (MMF)
Arm Type
Active Comparator
Arm Description
MMF was initiated at a dose of 500 mg twice daily (for patients > 50 Kg and Estimated Glomerular Filtration rate (eGFR) > 60 ml/min) for 2 weeks, and advanced to 750 mg twice daily in LN patients weighing less than 50 kg or 1,000 mg twice daily in LN patients weighing 50 kg or more. .
Arm Title
Tacrolimus (TAC)
Arm Type
Experimental
Arm Description
TAC was started at a dosage of 0.1 mg/kg/day divided into 2 daily doses at 12-hour intervals, and the dosage was titrated to achieve trough blood concentrations of 6-10 ng/mL in the first and second month and then 4-8 ng/mL., thereafter
Intervention Type
Drug
Intervention Name(s)
Tacrolimus vs. Mycophenolate mofetil for Induction Therapy in Lupus Nephritis
Intervention Description
Patients were randomly assigned to receive regimen I or II: TAC plus prednisolone (TAC group) or MMF plus prednisolone (MMF group). TAC was started at a dosage of 0.1 mg/kg/day divided into 2 daily doses at 12-hour intervals, and the dosage was titrated to achieve trough blood concentrations of 6-10 ng/mL in the first and second month and then 4-8 ng/mL., thereafter. MMF was initiated at a dose of 500 mg twice daily (for patients > 50 Kg and Estimated Glomerular Filtration rate (eGFR) > 60 ml/min) for 2 weeks, and advanced to 750 mg twice daily in LN patients weighing less than 50 kg or 1,000 mg twice daily in LN patients weighing 50 kg or more. Patients received concomitant prednisone at a dose of 0.5-0.7 mg/kg/d (maximum 60 mg/day), with tapering by 5-10 mg/day every 2 weeks until a dose of 5 mg/d has been achieved, and this dosage was maintained until the end of 24 weeks.
Primary Outcome Measure Information:
Title
Complete remission
Description
Return of serum creatinine to previous baseline, plus a decline in the UPCR to <500 mg/g (<50 mg/mmol)
Time Frame
1 year
Secondary Outcome Measure Information:
Title
Partial remission
Description
Stabilization (±25%), or improvement of serum creatinine, but not to normal, plus a ≥50% decrease in UPCR. If there was nephrotic-range proteinuria (UPCR ≥3000 mg/g [≥300 mg/mmol]), improvement requires a ≥50% reduction in UPCR, and a UPCR <3000 mg/g [<300 mg/mmol]
Time Frame
1 year
Title
Urine protein to creatinine ratio (UPCR)
Description
g/day
Time Frame
1 year
Title
Serum creatinine
Description
mg/dL
Time Frame
1 year
Title
Glomerular filtration rate (GFR)
Description
mL/min/1.73m2
Time Frame
1 year
Title
Adverse events
Description
Infection, leukopenia, gastrointestinal (GI) symptoms, new onset diabetes mellitus (DM)/hyperglycemia
Time Frame
1 year
Title
Serious dverse events
Description
Hospitalization, death
Time Frame
1 year
Title
EQ5D
Description
The Euro quality of life -5 Dimensions
Time Frame
1 year
Title
SF36
Description
The 36-Item Short Form Health Survey
Time Frame
1 year
Title
SLEQOL
Description
Systemic Lupus Erythematosus Quality of Life Questionnaire
Time Frame
1 year
Title
SLEDAI-2K
Description
Systemic Lupus Erythematosus Disease Activity Index 2000
Time Frame
1 year

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: The patient who had biopsy-proven lupus nephritis class III, IV or V according to the International Society of Nephrology (ISN)/Renal Pathology Society (RPS) 2003 classification (ISN/RPS2003) within 16 weeks of randomization and had ANA or anti-dsDNA positive. Laboratory tests documented the presence of active nephritis, defined as proteinuria (protein excretion >1 g/24 h or spot UPCR > 1 for at least two samples) or increased serum creatinine level (>0.3 mg/dL of baseline but less than 2.0 mg/dl) with active urinary sediment (any of >5 red blood cells/high-power field, >5 white blood cells/high-power field, or red blood cell casts in the absence of infection or other causes). Willingness to participate in the study, and be able to read and provide informed consent. Exclusion Criteria: Severe extra-renal manifestations that may require high-dose steroids or other immunomodulating treatments. The definition of severe extra-renal diseases in this investigation are defined by Active central nervous system deemed to be severe or progressive and/ or associated with significant cognitive impairment leading to inability to provide informed consent and/ or comply with the protocol. Any condition, including clinical findings or the laboratory results, which the investigators consider the patients have high disease activity and need high dose steroid and immunosuppressive drugs or other therapy depending on investigator opinion. Severe myocarditis with congestive heart failure or renal failure. Previous therapy with calcineurin inhibitor or MMF or CYC within the previous 4 months before randomization. Allergy with macrolide antibiotics. Uncontrolled hypertension (systolic blood pressure ≥160mmHg or diastolic blood pressure ≥100mmHg) at screening day. Severely deteriorated renal function or rapid progressive crescentic Glomerulonephritis. Severe myocarditis or cardiomyopathy which may or may not be related to SLE Patients who have thrombotic microangiopathy who require treatment with plasmapheresis or IVIG. Severe infection or active TB. Active hepatitis and evidence of chronic liver disease. HIV infection. Diabetes mellitus. Women who were pregnant or unwilling to use contraception. Patients who response to steroid (complete remission) during the run in period (4 weeks). Known hypersensitivity or contraindication to MMF, mycophenolic acid (MPA), tacrolimus, corticosteroids or any components of these drug products.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Vasant Sumethkul, Prof.
Organizational Affiliation
Ramathibodi Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Ramathibodi Hospital
City
Rahathevi
State/Province
Bangkok
ZIP/Postal Code
10400
Country
Thailand

12. IPD Sharing Statement

Learn more about this trial

Comparison Between Tacrolimus (TAC) and Mycophenolate Mofetil (MMF) for Induction of Remission in Lupus Nephritis

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