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

This study has been completed.
Sponsor:
Collaborator:
Aspreva Pharmaceuticals
Information provided by (Responsible Party):
Hoffmann-La Roche
ClinicalTrials.gov Identifier:
NCT00377637
First received: September 15, 2006
Last updated: October 31, 2011
Last verified: October 2011
  Purpose

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).


Condition Intervention Phase
Lupus Nephritis
Drug: Mycophenolate mofetil (MMF)
Drug: Cyclophosphamide
Drug: Azathioprine
Drug: Placebo to Azathioprine
Drug: Placebo to Mycophenolate mofetil
Drug: Corticosteroid
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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.

Resource links provided by NLM:


Further study details as provided by Hoffmann-La Roche:

Primary Outcome Measures:
  • Induction Phase: Number of Patients Showing Treatment Response [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of the Maintenance Phase to Month 36 ] [ Designated as safety issue: No ]
    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:
  • Induction Phase: Number of Participants Achieving Complete Remission [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
  • Induction Phase: Change From Baseline to Week 24 in 24-hour Urine Protein [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
    24-hour urine protein was measured at Baseline and Week 24.

  • Induction Phase: Change From Baseline to Week 24 in Serum Albumin [ Time Frame: Baseline, Week 24 ] [ Designated as safety issue: No ]
  • Induction Phase: Change in Renal British Isles Lupus Assessment Group (BILAG) Score [ Time Frame: Baseline, 24 weeks ] [ Designated as safety issue: No ]

    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 [ Time Frame: Baseline and 24 weeks ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of the Maintenance Phase to Month 36 ] [ Designated as safety issue: No ]
    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) [ Time Frame: From the start of the Maintenance Phase to Month 36 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of the Maintenance Phase to Month 36 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of the Maintenance Phase to Month 36 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of the Maintenance Phase to Month 36 ] [ Designated as safety issue: No ]
    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 [ Time Frame: From the start of the Maintenance Phase to Month 36 ] [ Designated as safety issue: No ]
    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.


Enrollment: 370
Study Start Date: July 2005
Study Completion Date: March 2010
Primary Completion Date: March 2007 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Induction Phase: Mycophenolate mofetil
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)
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.
Other Name: CellCept
Drug: 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.
Active Comparator: Induction Phase: 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.
Drug: 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.

Other Name: Endoxan®
Drug: 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.
Experimental: Maintenance Phase: Mycophenolate mofetil
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)
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.
Other Name: CellCept
Drug: Placebo to Azathioprine
Placebo capsules matching Azathioprine taken orally once a day.
Drug: 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.
Active Comparator: Maintenance Phase: 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.
Drug: Azathioprine
2 mg/kg/day orally, provided as 50 mg capsules to be taken after meals.
Other Name: Imuran®
Drug: Placebo to Mycophenolate mofetil
Placebo tablets matching Mycophenolate mofetil taken orally twice daily.
Drug: 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.

  Eligibility

Ages Eligible for Study:   12 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00377637

  Show 108 Study Locations
Sponsors and Collaborators
Hoffmann-La Roche
Aspreva Pharmaceuticals
Investigators
Study Director: Clinical Trials Hoffmann-La Roche
  More Information

No publications provided by Hoffmann-La Roche

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT00377637     History of Changes
Obsolete Identifiers: NCT00121082
Other Study ID Numbers: WX17801
Study First Received: September 15, 2006
Results First Received: August 11, 2011
Last Updated: October 31, 2011
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lupus Nephritis
Nephritis
Glomerulonephritis
Kidney Diseases
Urologic Diseases
Lupus Erythematosus, Systemic
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Azathioprine
Cyclophosphamide
Mycophenolate mofetil
Mycophenolic Acid
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Enzyme Inhibitors

ClinicalTrials.gov processed this record on April 16, 2014