A Study of Mycophenolate Mofetil (CellCept) in Management of Patients With Lupus Nephritis.

Study Overview
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Brief Summary
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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).

Official Title
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A Prospective, Randomized, Active Controlled, Parallel Group, Multi-center Trial to Assess the Efficacy and Safety of Mycophenolate Mofetil (MMF) in Inducing Response and Maintaining Remission in Subjects With Lupus Nephritis.

Conditions
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Lupus Nephritis

Intervention / Treatment
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* Drug: Mycophenolate mofetil (MMF)
* Drug: Cyclophosphamide
* Drug: Azathioprine
* Drug: Placebo to Azathioprine
* Drug: Placebo to Mycophenolate mofetil
* Drug: Corticosteroid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction Phase: Mycophenolate mofetil<br>Participants received oral mycophenolate mofetil (MMF) 1.5 g twice a day and concomitant corticosteroids for the 24 weeks of the Induction Phase. | Drug: Mycophenolate mofetil (MMF)<br>* Supplied as 500 mg tablets taken orally twice a day (BID). Dose specific for each arm. Dosing started at 500 mg BID for the first week, increasing by 500 mg in subsequent weeks until the final target dose was reached.<br>* Other names: CellCept;Drug: Corticosteroid<br>* Oral prednisolone (or equivalent) starting at a dose of 0.75-1.0 mg/kg/day (maximum 60 mg/day) tapered to 10 mg/day.<br>|
| Active Comparator: Induction Phase: Cyclophosphamide<br>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. | Drug: Cyclophosphamide<br>* Intravenous cyclophosphamide (IVC) was administered every four weeks (monthly) to a total of six infusions. Dosing was started at 0.75 g/m^2 of body surface area for the first month, with subsequent doses at 0.5-1.0 g/m^2. The target dose was 1.0 g/m^2, but doses were titrated by 0.25 g/m^2 increments to maintain nadir leukocyte count between 2500-4000/mm^3.<br>* Other names: Endoxan®;Drug: Corticosteroid<br>* Oral prednisolone (or equivalent) starting at a dose of 0.75-1.0 mg/kg/day (maximum 60 mg/day) tapered to 10 mg/day.<br>|
| Experimental: Maintenance Phase: Mycophenolate mofetil<br>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. | Drug: Mycophenolate mofetil (MMF)<br>* Supplied as 500 mg tablets taken orally twice a day (BID). Dose specific for each arm. Dosing started at 500 mg BID for the first week, increasing by 500 mg in subsequent weeks until the final target dose was reached.<br>* Other names: CellCept;Drug: Placebo to Azathioprine<br>* Placebo capsules matching Azathioprine taken orally once a day.<br>Drug: Corticosteroid<br>* Oral prednisolone (or equivalent) starting at a dose of 0.75-1.0 mg/kg/day (maximum 60 mg/day) tapered to 10 mg/day.<br>|
| Active Comparator: Maintenance Phase: Azathioprine<br>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. | Drug: Azathioprine<br>* 2 mg/kg/day orally, provided as 50 mg capsules to be taken after meals.<br>* Other names: Imuran®;Drug: Placebo to Mycophenolate mofetil<br>* Placebo tablets matching Mycophenolate mofetil taken orally twice daily.<br>Drug: Corticosteroid<br>* Oral prednisolone (or equivalent) starting at a dose of 0.75-1.0 mg/kg/day (maximum 60 mg/day) tapered to 10 mg/day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Phase: Number of Patients Showing Treatment Response | 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. | 24 weeks | 
| Maintenance Phase: Kaplan-Meier Estimates of Percentage of Participants Treatment Failure Free, by Time Interval | 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. | From the start of the Maintenance Phase to Month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Induction Phase: Number of Participants Achieving Complete Remission | 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. | 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 | 24-hour urine protein was measured at Baseline and Week 24. | Baseline, 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 | 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. | Baseline, 24 weeks | 
| Induction Phase: Change From Baseline in Short-Form Health Survey (SF-36) Domain and Component Scores | 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. | Baseline and 24 weeks | 
| Maintenance Phase: Events Contributing to the Primary Endpoint: Number of Deaths | 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). | From the start of the Maintenance Phase to Month 36 | 
| Maintenance Phase: Events Contributing to the Primary Endpoint: Number of Participants With End-stage Renal Disease (ESRD) | 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. | From the start of the Maintenance Phase to Month 36 | 
| Maintenance Phase: Events Contributing to the Primary Endpoint: Number of Participants With Sustained Doubling of Serum Creatinine | 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. | From the start of the Maintenance Phase to Month 36 | 
| Maintenance Phase: Events Contributing to the Primary Endpoint: Kaplan-Meier Estimates of Percentage of Participants Renal Flare Free, by Time Interval | 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. | From the start of the Maintenance Phase to Month 36 | 
| Maintenance Phase: Events Contributing to the Primary Endpoint: Kaplan-Meier Estimates of Percentage of Participants Not Receiving Rescue Therapy | 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. | From the start of the Maintenance Phase to Month 36 | 
| Maintenance Phase: Participants With Major Extra-renal Flare | 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. | From the start of the Maintenance Phase to Month 36 |