Lupus Nephritis
Conditions
Keywords
Lupus Nephritis, enteric-coated mycophenolate sodium, EC-MPS, Myfortic
Brief summary
The study will investigate the efficacy and safety of enteric-coated mycophenolate sodium in combination with two different corticosteroid (CS) regimes for the induction of remission of a lupus nephritis flare. Patients will be randomly allocated to standard CS regimen (group I) or to a reduced dose CS regimen (group II)
Interventions
Mycophenolate sodium as administered orally for 2 weeks at 1440mg daily and then increased to 2160mg daily for 22 weeks.
DRUGPrednisone
Oral prednisone or prednisone equivalent was started on Day 4 and subsequently tapered every 2 weeks according to the patient's weight.
DRUGMethylprednisolone
All patients received bolus therapy with 0.5 g of intravenous Methylprednisolone per day for 3 consecutive days.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients with systemic lupus erythematosus (SLE)(at least 4 classification criteria) * Aged ≥18 years, * Proliferative lupus nephritis classified as ISN/RPS class III or IV * Renal biopsy within the last 24-month preceding the study entry * Proteinuria defined as \>0.5 gram urine protein per gram urine creatinine at screening and baseline * Clinical activity defined by one or more of the following changes in renal function: Serum creatinine \>1.0 mg/dl (88.4 μmol/l) * Microscopic hematuria defined as \>5 red cells per high power field * Presence of cellular casts
Exclusion criteria
* Patients with calculated creatinine clearance \<30 ml/min (using the Cockcroft-Gault formula) * Patients having received an intravenous (i.v.) corticosteroid bolus during the last 3 months, * Patients having received oral or i.v. cyclophosphamide during the last 3 month * Patients having received mycophenolate mofetil (MMF) within the preceding 3 months * Use of any antibody therapy within the past 6 months * Pregnant or nursing (lactating) women or women of child-bearing potential who are planning to become pregnant, or are not willing to use effective means of contraception throughout the study and during one month after the end of the study. * Use of other investigational drugs within 1 month of enrollment (except for antibodies: within 6 months of enrollment * History of hypersensitivity to any of the study drugs or to drugs with similar chemical structures, * History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Complete Remission | 24 Weeks | Complete remission was defined as urine protein/urine creatinine ratio \< 0.5 gram urine protein per gram urine creatinine, urine sediment normalized (no cellular casts, \< 5 red cells per high power field), and serum creatinine within 10% of normal range according to local lab. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Partial Remission | Baseline to 12 and 24 weeks | Partial remission was defined as urine protein/creatinine ratio reduced by at least 50% from baseline and stable serum creatinine within 10% of baseline value) or improved. |
| Cumulative Dose of Prednisone Equivalent Corticosteroids (CS) | 12 Weeks and 24 Weeks | Corticosteroid use was measured as cumulative dose until 12 and 24 weeks of treatment as well as daily doses at baseline, 12 and 24 weeks. |
| Number of Patients With Moderate to Severe Flares | 12 and 24 weeks | A moderate to severe flare was defined as the occurrence of increased lupus activity after partial or complete remission, based on the presence of 1 BILAG A score or \>=3 BILAG B scores. British Isles Lupus Assessment Group (BILAG) index divides lupus activity in 8 organs/systems which are each given a score of A to E. A=disease sufficiently active to need disease modifying treatment; B=problems requiring symptomatic treatment; C=mild stable disease; D=previously affected but currently inactive system; E=the system or organ has never been involved. BILAG score: A=9, B=3, C=1, D/E=0; range(0-72) |
| Duration of Exposure to Study Medication | 24 weeks | The duration of exposure was calculated as the date of the last Mycophenolate sodium dose minus the date of the last Mycophenolate sodium dose +1. |
| Number of Patients With Complete Remission | 12 Weeks | Complete remission was defined as urine protein/urine creatinine ratio \< 0.5 gram urine protein per gram urine creatinine, urine sediment normalized (no cellular casts, \< 5 red cells per high power field), and serum creatinine within 10% of normal value. |
| Number of Patients With Treatment Failure | 12 Weeks and 24 Weeks | Treatment failure was defined as no therapeutic response (without complete or partial remission) or premature discontinuation during the first 24 weeks from study medication or the study for any reason except complete or partial remission. |
| Change From Baseline in Overall Disease Activity With Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) | From Baseline to week 4, week 12 and week 24 | SLEDAI stands for Systemic Lupus Erythematosus Disease Activity Index and was a well established global score index based on assessment of 24 items measuring a disease activity in the 10-day period prior to the assessment. SLEDAI item weights range from 1 for fever to 8 for seizures. A maximum theoretical score is 105. Total score range from 1 to 105. A flare has been defined as a SLEDAI score increase of 3 or more to a level of 8 or higher. During flares SLEDAI scores of 25 to 30 are common. |
| Change From Baseline in Overall Disease Activity With British Isles Lupus Assessment Group (BILAG) | From Baseline to week 4, week 12 and week 24 | BILAG (British Isles Lupus Assessment Group) index divides lupus activity into 8 organs/systems and was based on the principle of the physician's intention to treat, assessing activity in the previous one month. Each organ or system was given a score of A to E, where A = disease that is sufficiently active to require disease modifying treatment; a B = problems requiring symptomatic treatment; C = stable mild disease; D = previously affected but currently inactive system; and E = the system or organ has never been involved. \[A=9, B=3, C=1, D/E=0 the score range for each patient will be 0-72\]. |
| Number of Patients With Adverse Events and Infections | 24 weeks | Safety assessments included collecting all adverse events (AEs), serious adverse events (SAEs), with their severity and relationship to study drug. According to FDA 21CFR 314.80, a serious adverse event (SAE) is described as any adverse event that leads to death, is life threatening ( NIH criteria Grade 4), causes or prolongs hospitalization, results in a congenital anomaly, or any other important medical event not described above. |
Countries
Colombia, France, Germany, Greece, Hungary, Italy, Spain, Taiwan, United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Dose Mycophenolate sodium was administered orally in combination with a standard dose of corticosteroids (CS) administered as prednisone or prednisone equivalent (PRED). Mycophenolate sodium was administered in divided doses at a daily dose of 1440 mg during the first 2 weeks of the study and then at 2160 mg daily for the next 22 weeks. The dose of CS was started at 1 mg per kg body weight and subsequently tapered according to the patient's weight. The planned treatment duration was 24 weeks. | 42 |
| Low Dose Mycophenolate sodium was administered orally in combination with a reduced dose of corticosteroids (CS) administered as prednisone or prednisone equivalent (PRED). Mycophenolate sodium was administered in divided doses at a daily dose of 1440 mg during the first 2 weeks of the study and then at 2160 mg daily for the next 22 weeks. The dose of CS was started at 0.5 mg per kg body weight and subsequently tapered according to the patient's weight. The planned treatment duration was 24 weeks. | 39 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative problems | 0 | 1 |
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Death | 2 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 0 | 1 |
Baseline characteristics
| Characteristic | Standard Dose | Low Dose | Total |
|---|---|---|---|
| Age Continuous | 32.2 years STANDARD_DEVIATION 8.53 | 34.2 years STANDARD_DEVIATION 10.74 | 33.1 years STANDARD_DEVIATION 9.65 |
| Age, Customized 18-29 years | 20 participants | 18 participants | 38 participants |
| Age, Customized 30-39 years | 16 participants | 10 participants | 26 participants |
| Age, Customized 40-49 years | 4 participants | 6 participants | 10 participants |
| Age, Customized 50-59 years | 2 participants | 4 participants | 6 participants |
| Age, Customized >=60 years | 0 participants | 1 participants | 1 participants |
| Sex: Female, Male Female | 37 Participants | 29 Participants | 66 Participants |
| Sex: Female, Male Male | 5 Participants | 10 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 42 | 18 / 39 |
| serious Total, serious adverse events | 8 / 42 | 4 / 39 |
Outcome results
Primary
Number of Patients With Complete Remission
Complete remission was defined as urine protein/urine creatinine ratio \< 0.5 gram urine protein per gram urine creatinine, urine sediment normalized (no cellular casts, \< 5 red cells per high power field), and serum creatinine within 10% of normal range according to local lab.
Time frame: 24 Weeks
Population: Intention to treat (ITT) population: All randomized patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Dose | Number of Patients With Complete Remission | Yes | 8 Participants |
| Standard Dose | Number of Patients With Complete Remission | No | 34 Participants |
| Low Dose | Number of Patients With Complete Remission | Yes | 8 Participants |
| Low Dose | Number of Patients With Complete Remission | No | 31 Participants |
Secondary
Change From Baseline in Overall Disease Activity With British Isles Lupus Assessment Group (BILAG)
BILAG (British Isles Lupus Assessment Group) index divides lupus activity into 8 organs/systems and was based on the principle of the physician's intention to treat, assessing activity in the previous one month. Each organ or system was given a score of A to E, where A = disease that is sufficiently active to require disease modifying treatment; a B = problems requiring symptomatic treatment; C = stable mild disease; D = previously affected but currently inactive system; and E = the system or organ has never been involved. \[A=9, B=3, C=1, D/E=0 the score range for each patient will be 0-72\].
Time frame: From Baseline to week 4, week 12 and week 24
Population: Intent-to-treat (ITT) populationincluded all randomized patients who received at least one dose of study drug. Only patients with assessments at both baseline and post-baseline visits are summarized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard Dose | Change From Baseline in Overall Disease Activity With British Isles Lupus Assessment Group (BILAG) | Change from baseline Week 4: (N= 40, 37) | -4.8 Units on a scale | Standard Deviation 5.34 |
| Standard Dose | Change From Baseline in Overall Disease Activity With British Isles Lupus Assessment Group (BILAG) | Change from baseline Week 12: (N= 41, 35) | -8.6 Units on a scale | Standard Deviation 6.76 |
| Standard Dose | Change From Baseline in Overall Disease Activity With British Isles Lupus Assessment Group (BILAG) | Change from baseline Week 24: (N= 40, 34) | -8.6 Units on a scale | Standard Deviation 5.79 |
| Low Dose | Change From Baseline in Overall Disease Activity With British Isles Lupus Assessment Group (BILAG) | Change from baseline Week 4: (N= 40, 37) | -5.5 Units on a scale | Standard Deviation 6.5 |
| Low Dose | Change From Baseline in Overall Disease Activity With British Isles Lupus Assessment Group (BILAG) | Change from baseline Week 12: (N= 41, 35) | -8.7 Units on a scale | Standard Deviation 6.19 |
| Low Dose | Change From Baseline in Overall Disease Activity With British Isles Lupus Assessment Group (BILAG) | Change from baseline Week 24: (N= 40, 34) | -9.4 Units on a scale | Standard Deviation 5.52 |
Secondary
Change From Baseline in Overall Disease Activity With Systematic Lupus Erythematosus Disease Activity Index (SLEDAI)
SLEDAI stands for Systemic Lupus Erythematosus Disease Activity Index and was a well established global score index based on assessment of 24 items measuring a disease activity in the 10-day period prior to the assessment. SLEDAI item weights range from 1 for fever to 8 for seizures. A maximum theoretical score is 105. Total score range from 1 to 105. A flare has been defined as a SLEDAI score increase of 3 or more to a level of 8 or higher. During flares SLEDAI scores of 25 to 30 are common.
Time frame: From Baseline to week 4, week 12 and week 24
Population: Intent-to-treat (ITT) population included all randomized patients who received at least one dose of study drug. Only patients with assessments at both baseline and post-baseline visits are summarized.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard Dose | Change From Baseline in Overall Disease Activity With Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) | Change from Baseline to Week 4: (N= 39, 37) | -7.4 Units on a scale | Standard Deviation 5.63 |
| Standard Dose | Change From Baseline in Overall Disease Activity With Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) | Change from Baseline to Week 12: (N= 41, 35) | -9.7 Units on a scale | Standard Deviation 7.08 |
| Standard Dose | Change From Baseline in Overall Disease Activity With Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) | Change from Baseline to Week 24: (N= 39, 34) | -10.3 Units on a scale | Standard Deviation 7.32 |
| Low Dose | Change From Baseline in Overall Disease Activity With Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) | Change from Baseline to Week 4: (N= 39, 37) | -7.7 Units on a scale | Standard Deviation 6.62 |
| Low Dose | Change From Baseline in Overall Disease Activity With Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) | Change from Baseline to Week 12: (N= 41, 35) | -10.3 Units on a scale | Standard Deviation 8.31 |
| Low Dose | Change From Baseline in Overall Disease Activity With Systematic Lupus Erythematosus Disease Activity Index (SLEDAI) | Change from Baseline to Week 24: (N= 39, 34) | -9.8 Units on a scale | Standard Deviation 8.35 |
Secondary
Cumulative Dose of Prednisone Equivalent Corticosteroids (CS)
Corticosteroid use was measured as cumulative dose until 12 and 24 weeks of treatment as well as daily doses at baseline, 12 and 24 weeks.
Time frame: 12 Weeks and 24 Weeks
Population: Intention to treat (ITT) population: All randomized patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Standard Dose | Cumulative Dose of Prednisone Equivalent Corticosteroids (CS) | Week 12 | 106.1 mg/kg | Standard Deviation 13.55 |
| Standard Dose | Cumulative Dose of Prednisone Equivalent Corticosteroids (CS) | Week 24 | 114.2 mg/kg | Standard Deviation 15.01 |
| Low Dose | Cumulative Dose of Prednisone Equivalent Corticosteroids (CS) | Week 12 | 68.2 mg/kg | Standard Deviation 16.41 |
| Low Dose | Cumulative Dose of Prednisone Equivalent Corticosteroids (CS) | Week 24 | 73.0 mg/kg | Standard Deviation 17.76 |
Secondary
Duration of Exposure to Study Medication
The duration of exposure was calculated as the date of the last Mycophenolate sodium dose minus the date of the last Mycophenolate sodium dose +1.
Time frame: 24 weeks
Population: Safety population: All patients who received at least one dose of study drug and had at least one post-baseline safety assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Dose | Duration of Exposure to Study Medication | 164.5 days | Standard Deviation 24.87 |
| Low Dose | Duration of Exposure to Study Medication | 157.7 days | Standard Deviation 41.15 |
Secondary
Number of Patients With Adverse Events and Infections
Safety assessments included collecting all adverse events (AEs), serious adverse events (SAEs), with their severity and relationship to study drug. According to FDA 21CFR 314.80, a serious adverse event (SAE) is described as any adverse event that leads to death, is life threatening ( NIH criteria Grade 4), causes or prolongs hospitalization, results in a congenital anomaly, or any other important medical event not described above.
Time frame: 24 weeks
Population: Safety population: All patients who received at least one dose of study drug and had at least one post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Standard Dose | Number of Patients With Adverse Events and Infections | At least one adverse event | 35 participants | 5.63 |
| Standard Dose | Number of Patients With Adverse Events and Infections | Any severe adverse event | 7 participants | 7.08 |
| Standard Dose | Number of Patients With Adverse Events and Infections | Any drug related adverse event | 18 participants | 7.32 |
| Standard Dose | Number of Patients With Adverse Events and Infections | Any serious adverse event | 8 participants | — |
| Standard Dose | Number of Patients With Adverse Events and Infections | Any infection | 25 participants | — |
| Standard Dose | Number of Patients With Adverse Events and Infections | Any severe infection | 3 participants | — |
| Standard Dose | Number of Patients With Adverse Events and Infections | Any drug related infection | 10 participants | — |
| Standard Dose | Number of Patients With Adverse Events and Infections | Any serious infection | 4 participants | — |
| Low Dose | Number of Patients With Adverse Events and Infections | Any serious infection | 1 participants | — |
| Low Dose | Number of Patients With Adverse Events and Infections | At least one adverse event | 30 participants | 6.62 |
| Low Dose | Number of Patients With Adverse Events and Infections | Any infection | 17 participants | — |
| Low Dose | Number of Patients With Adverse Events and Infections | Any severe adverse event | 3 participants | 8.31 |
| Low Dose | Number of Patients With Adverse Events and Infections | Any drug related infection | 6 participants | — |
| Low Dose | Number of Patients With Adverse Events and Infections | Any drug related adverse event | 16 participants | 8.35 |
| Low Dose | Number of Patients With Adverse Events and Infections | Any severe infection | 1 participants | — |
| Low Dose | Number of Patients With Adverse Events and Infections | Any serious adverse event | 4 participants | — |
Secondary
Number of Patients With Complete Remission
Complete remission was defined as urine protein/urine creatinine ratio \< 0.5 gram urine protein per gram urine creatinine, urine sediment normalized (no cellular casts, \< 5 red cells per high power field), and serum creatinine within 10% of normal value.
Time frame: 12 Weeks
Population: Intention to treat (ITT) population: All randomized patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Dose | Number of Patients With Complete Remission | Yes | 9 participants |
| Standard Dose | Number of Patients With Complete Remission | No | 33 participants |
| Low Dose | Number of Patients With Complete Remission | Yes | 5 participants |
| Low Dose | Number of Patients With Complete Remission | No | 34 participants |
Secondary
Number of Patients With Moderate to Severe Flares
A moderate to severe flare was defined as the occurrence of increased lupus activity after partial or complete remission, based on the presence of 1 BILAG A score or \>=3 BILAG B scores. British Isles Lupus Assessment Group (BILAG) index divides lupus activity in 8 organs/systems which are each given a score of A to E. A=disease sufficiently active to need disease modifying treatment; B=problems requiring symptomatic treatment; C=mild stable disease; D=previously affected but currently inactive system; E=the system or organ has never been involved. BILAG score: A=9, B=3, C=1, D/E=0; range(0-72)
Time frame: 12 and 24 weeks
Population: Intention to treat (ITT) population: All randomized patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Dose | Number of Patients With Moderate to Severe Flares | At week 12 - Yes | 0 participants |
| Standard Dose | Number of Patients With Moderate to Severe Flares | At week 12 - No | 42 participants |
| Standard Dose | Number of Patients With Moderate to Severe Flares | At week 24 - Yes | 1 participants |
| Standard Dose | Number of Patients With Moderate to Severe Flares | At week 24 - No | 41 participants |
| Low Dose | Number of Patients With Moderate to Severe Flares | At week 24 - No | 39 participants |
| Low Dose | Number of Patients With Moderate to Severe Flares | At week 12 - Yes | 0 participants |
| Low Dose | Number of Patients With Moderate to Severe Flares | At week 24 - Yes | 0 participants |
| Low Dose | Number of Patients With Moderate to Severe Flares | At week 12 - No | 39 participants |
Secondary
Number of Patients With Partial Remission
Partial remission was defined as urine protein/creatinine ratio reduced by at least 50% from baseline and stable serum creatinine within 10% of baseline value) or improved.
Time frame: Baseline to 12 and 24 weeks
Population: Intention to treat (ITT) population: All randomized patients who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Dose | Number of Patients With Partial Remission | At 12 weeks - Yes | 16 Participants |
| Standard Dose | Number of Patients With Partial Remission | At 12 weeks - No | 26 Participants |
| Standard Dose | Number of Patients With Partial Remission | At 24 weeks - Yes | 20 Participants |
| Standard Dose | Number of Patients With Partial Remission | At 24 weeks - No | 22 Participants |
| Low Dose | Number of Patients With Partial Remission | At 24 weeks - No | 25 Participants |
| Low Dose | Number of Patients With Partial Remission | At 12 weeks - Yes | 11 Participants |
| Low Dose | Number of Patients With Partial Remission | At 24 weeks - Yes | 14 Participants |
| Low Dose | Number of Patients With Partial Remission | At 12 weeks - No | 28 Participants |
Secondary
Number of Patients With Treatment Failure
Treatment failure was defined as no therapeutic response (without complete or partial remission) or premature discontinuation during the first 24 weeks from study medication or the study for any reason except complete or partial remission.
Time frame: 12 Weeks and 24 Weeks
Population: Safety Population: All patients who received at least one dose of study drug and had at least one post-baseline safety assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Standard Dose | Number of Patients With Treatment Failure | At 12 weeks - Yes | 23 participants |
| Standard Dose | Number of Patients With Treatment Failure | At 12 weeks - No | 19 participants |
| Standard Dose | Number of Patients With Treatment Failure | At 24 weeks - Yes | 21 participants |
| Standard Dose | Number of Patients With Treatment Failure | At 24 weeks - No | 21 participants |
| Low Dose | Number of Patients With Treatment Failure | At 24 weeks - No | 17 participants |
| Low Dose | Number of Patients With Treatment Failure | At 12 weeks - Yes | 25 participants |
| Low Dose | Number of Patients With Treatment Failure | At 24 weeks - Yes | 22 participants |
| Low Dose | Number of Patients With Treatment Failure | At 12 weeks - No | 14 participants |