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

Lupus Nephritis Clinical Trial

Official title:

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00377637
• Other study ID #: WX17801
• Status: Completed
• Phase: Phase 3
• First received: September 15, 2006
• Last updated: October 31, 2011
• Start date: July 2005
• Est. completion date: March 2010

Study information

• Verified date: October 2011
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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).

Other known NCT identifiers

• NCT00121082

Recruitment information / eligibility

• Status: Completed
• Enrollment: 370
• Est. completion date: March 2010
• Est. primary completion date: March 2007
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years to 75 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lupus Nephritis
• Nephritis

Intervention

Drug:
• Mycophenolate mofetil (MMF)
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.
• Cyclophosphamide
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.
• Azathioprine
2 mg/kg/day orally, provided as 50 mg capsules to be taken after meals.
• Placebo to Azathioprine
Placebo capsules matching Azathioprine taken orally once a day.
• Placebo to Mycophenolate mofetil
Placebo tablets matching Mycophenolate mofetil taken orally twice daily.
• Corticosteroid
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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Hoffmann-La Roche	Aspreva Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Belgium,  Brazil,  Canada,  China,  Czech Republic,  France,  Germany,  Greece,  Hungary,  Italy,  Mexico,  Portugal,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Primary	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	No
Secondary	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	No
Secondary	Induction Phase: Change From Baseline to Week 24 in Serum Creatinine		Baseline, Week 24	No
Secondary	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	No
Secondary	Induction Phase: Change From Baseline to Week 24 in Serum Albumin		Baseline, Week 24	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No