A Study of Mycophenolate Mofetil (CellCept) in Management of Patients With Lupus Nephritis.
- Conditions
- Lupus Nephritis
- Interventions
- Registration Number
- NCT00377637
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This 2 arm study assessed the efficacy of Mycophenolate Mofetil (MMF; CellCept) compared to cyclophosphamide in inducing a response in patients with lupus nephritis, and the long term efficacy of MMF compared to azathioprine in maintaining remission and renal function. Patients were randomized to receive either MMF (1.5 g twice daily \[bid\]) or cyclophosphamide (0.5-1.0 g/m\^2 in monthly pulses) in the induction phase. Those patients meeting criteria for response were re-randomized for entry into the maintenance phase, to receive either MMF (1 g bid) or azathioprine (2 mg/kg/day).
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 370
- male or female patients, 12-75 years of age;
- diagnosis of systemic lupus erythematosus;
- kidney biopsy within 6 months of study, with histological diagnosis of lupus nephritis;
- laboratory evidence of active nephritis.
- continuous dialysis starting >2 weeks before randomization into induction phase, and/or with an anticipated duration of >8 weeks;
- previous or planned kidney transplant;
- other clinically significant active medical conditions.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Induction Phase: Mycophenolate mofetil Mycophenolate mofetil (MMF) Participants received oral mycophenolate mofetil (MMF) 1.5 g twice a day and concomitant corticosteroids for the 24 weeks of the Induction Phase. Induction Phase: Mycophenolate mofetil Corticosteroid Participants received oral mycophenolate mofetil (MMF) 1.5 g twice a day and concomitant corticosteroids for the 24 weeks of the Induction Phase. Induction Phase: Cyclophosphamide Corticosteroid Participants received monthly infusions of cyclophosphamide, 0.5 to 1.0 g per square meter of body surface area and concomitant treatment with corticosteroids for the 24 week Induction Phase. Maintenance Phase: Mycophenolate mofetil Mycophenolate mofetil (MMF) Participants received mycophenolate mofetil (MMF) 1.0 g orally twice a day, placebo to azathioprine orally once a day and corticosteroid for the 36 weeks Maintenance Phase. Maintenance Phase: Mycophenolate mofetil Placebo to Azathioprine Participants received mycophenolate mofetil (MMF) 1.0 g orally twice a day, placebo to azathioprine orally once a day and corticosteroid for the 36 weeks Maintenance Phase. Maintenance Phase: Mycophenolate mofetil Corticosteroid Participants received mycophenolate mofetil (MMF) 1.0 g orally twice a day, placebo to azathioprine orally once a day and corticosteroid for the 36 weeks Maintenance Phase. Maintenance Phase: Azathioprine Placebo to Mycophenolate mofetil Participants received azathioprine (AZA) 2 mg/kg/day orally once a day, placebo to mycophenolate mofetil orally twice a day and corticosteroid for the 36 weeks Maintenance Phase. Maintenance Phase: Azathioprine Corticosteroid Participants received azathioprine (AZA) 2 mg/kg/day orally once a day, placebo to mycophenolate mofetil orally twice a day and corticosteroid for the 36 weeks Maintenance Phase. Induction Phase: Cyclophosphamide Cyclophosphamide Participants received monthly infusions of cyclophosphamide, 0.5 to 1.0 g per square meter of body surface area and concomitant treatment with corticosteroids for the 24 week Induction Phase. Maintenance Phase: Azathioprine Azathioprine Participants received azathioprine (AZA) 2 mg/kg/day orally once a day, placebo to mycophenolate mofetil orally twice a day and corticosteroid for the 36 weeks Maintenance Phase.
- Primary Outcome Measures
Name Time Method Induction Phase: Number of Patients Showing Treatment Response 24 weeks Treatment response was adjudicated by a blinded clinical endpoints committee (CEC) and defined as: a) Decrease in proteinuria, defined as a decrease in the urine protein to creatinine ratio (UPCr) to \<3 in subjects with baseline proteinuria ≥3 UPCr or a decrease in the UPCr by ≥50% in subjects with proteinuria \<3 UPCr at Baseline, and b) Stabilization of serum creatinine or improvement. UPCr were derived from the 24 hour urine collection. Patients who did not show a treatment response at Week 24 or who withdrew earlier than Week 24 were considered non-responders.
Maintenance Phase: Kaplan-Meier Estimates of Percentage of Participants Treatment Failure Free, by Time Interval From the start of the Maintenance Phase to Month 36 Treatment Failure was adjudicated by a clinical endpoints committee and was defined as the time to the earliest occurrence of any one of the following: death, end stage renal disease, sustained doubling of serum creatinine, renal flare, or a requirement for rescue therapy for exacerbation or deterioration of Lupus nephritis. Kaplan-Meier survival curves were estimated from the observed time to treatment failure for each patient. The data presented are the percentage of participants who were treatment-failure free at each time interval as estimated by Kaplan-Meier.
- Secondary Outcome Measures
Name Time Method Induction Phase: Number of Participants Achieving Complete Remission 24 weeks Number of participants achieving complete remission as defined by return to normal serum creatinine, proteinuria ≤500 mg/24 hours and an inactive urinary sediment (absence of red blood cells, white blood cells or cellular or granular casts) after 24 weeks.
Induction Phase: Change From Baseline to Week 24 in Serum Creatinine Baseline, Week 24 Induction Phase: Change From Baseline to Week 24 in 24-hour Urine Protein Baseline, Week 24 24-hour urine protein was measured at Baseline and Week 24.
Induction Phase: Change From Baseline to Week 24 in Serum Albumin Baseline, Week 24 Induction Phase: Change in Renal British Isles Lupus Assessment Group (BILAG) Score Baseline, 24 weeks BILAG indices provide a scoring system for the assessment of lupus disease activity in terms of the need for steroid treatment in 8 organs/systems. Eighty-six items were scored resulting in a classification of A (severe activity), B (moderate activity), C (mild activity), D (no current activity) and E (no activity ever observed) for each organ system. The BILAG individual system summaries were calculated by a program supplied by ADS-Limathon (Sheffield, UK).
The score at baseline was compared to the score at the 24 week endpoint for each treatment group, reported here for the renal system.Induction Phase: Change From Baseline in Short-Form Health Survey (SF-36) Domain and Component Scores Baseline and 24 weeks The SF-36 is a 36 item quality of life questionnaire. The short-form version has eleven questions that permit the participant to rate how they feel that particular day. The SF-36 consists of eight scaled scores and two component scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 score with the higher scores indicating better quality of life.
Maintenance Phase: Events Contributing to the Primary Endpoint: Number of Deaths From the start of the Maintenance Phase to Month 36 Treatment Failure was adjudicated by a clinical endpoints committee (CEC) and was defined as the time to the earliest occurrence of any one of the following: death, end stage renal disease, sustained doubling of serum creatinine, renal flare, or a requirement for rescue therapy for exacerbation or deterioration of Lupus nephritis (LN).
Maintenance Phase: Events Contributing to the Primary Endpoint: Number of Participants With End-stage Renal Disease (ESRD) From the start of the Maintenance Phase to Month 36 Time to treatment failure, adjudicated by the Clinical Endpoints Committee (CEC), was defined as any 1 the following: death, ESRD, sustained doubling of serum creatinine, renal flare (proteinuric or nephritic), or requirement for rescue therapy to treat deterioration or exacerbation of Lupus nephritis. ESRD is defined as progression to chronic hemodialysis or renal transplant.
Maintenance Phase: Events Contributing to the Primary Endpoint: Number of Participants With Sustained Doubling of Serum Creatinine From the start of the Maintenance Phase to Month 36 Sustained doubling of serum creatinine concentration is defined as the first serum creatinine value that is twice the mean of the lowest 2 values from screening to end of induction, as confirmed by a second serum creatinine value obtained at least 4 weeks after the initial doubling.
Maintenance Phase: Events Contributing to the Primary Endpoint: Kaplan-Meier Estimates of Percentage of Participants Renal Flare Free, by Time Interval From the start of the Maintenance Phase to Month 36 A proteinuric flare is defined as a doubling of the urine protein:creatinine ratio, and proteinuria ≥1 g/24 h in patients with urine protein ≤0.5 g/24 h at the end of the induction phase, or proteinuria ≥2 g/24 h if urine protein was \>0.5 g/24 h at the end of the induction phase. A nephritic flare is defined as a 25% increase in serum creatinine accompanied by 1 or more of the following: (a) simultaneous doubling of the proteinuria reaching a minimum of 2 g/24 h (b) new/increased hematuria or (c) the appearance of cellular casts. All flares were adjudicated by a clinical endpoints committee.
Maintenance Phase: Events Contributing to the Primary Endpoint: Kaplan-Meier Estimates of Percentage of Participants Not Receiving Rescue Therapy From the start of the Maintenance Phase to Month 36 The primary efficacy parameter was the time to treatment failure, adjudicated by the Clinical Endpoints Committee (CEC), defined as any of the following: death, end stage renal disease, sustained doubling of serum creatinine, renal flare, or requirement for rescue therapy to treat deterioration or exacerbation of Lupus nephritis. Kaplan-Meier survival curves were estimated from the observed time to rescue treatment for each patient. The data presented are the percentage of participants who were rescue treatment free at each time interval as estimated by Kaplan-Meier.
Maintenance Phase: Participants With Major Extra-renal Flare From the start of the Maintenance Phase to Month 36 A major extra-renal flare is defined as a British Isles Lupus Assessment Group (BILAG) Score category A in one extrarenal organ or three organs with concurrent category B scores. BILAG indices provide a scoring system for the assessment of lupus disease activity in terms of the need for steroid treatment in 8 organs/systems. Eighty-six items were scored resulting in a classification of A (severe activity), B (moderate activity), C (mild activity), D (no current activity) and E (no activity ever observed) for each organ system.