E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated | |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 4.1 | E.1.2 | Level | Low | E.1.2 | Classification code | 10025140 | |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial | Primary Objective for Induction: To assess the efficacy of MMF compared to IVC for inducing response in subjects with lupus nephritis. Primary Objective for Maintenance: To assess the long term efficacy of MMF compared to azathioprine in maintaining remission and renal function in subjects with lupus nephritis | |
E.2.2 | Secondary objectives of the trial | To assess other safety and efficacy parameters of MMF vs cyclophosphamide during induction therapy To assess other safety and efficacy parameters of MMF vs azathioprine during maintenance therapy | |
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria | Induction Phase: 1. Provision of written informed consent by subject or guardian, (with written assent for underage subjects) 2. Subject of either sex, 12 to 75 years of age (inclusive) 3. Diagnosis of SLE according to the American College of Rheumatology criteria (1997) 4. Kidney biopsy within the 6 months prior to first randomization with a histologic diagnosis of lupus nephritis (ISN/RPS 2003 classification of lupus nephritis) classes III, IV-S or IV-G, (A) or (A/C), or class V, alone or in combination with class III or IV. For biopsies reported according to ISDKC/WHO 1982 criteria, see Protocol Appendix 4 5. Laboratory evidence of active nephritis at screening, defined as: Class IV-S or IV-G •proteinuria ≥1000 mg/24 h or •serum creatinine above 1.3 mg/dL (115 µmol/L) or •active urinary sediment: any of >5 WBC/hpf, >5 RBC/hpf, 2+ or more on dipstick, or red cell casts in the absence of infection or other causes Class III or V •proteinuria ≥ 2000 mg/24 h or •serum creatinine above 1.3 mg/dL (115 µmol/L) Maintenance Phase: 1. Response after 24 weeks of induction therapy (Visit 9) or complete (renal) remission. Response is defined as: • Decrease in proteinuria, definded as decrease in the urine protein/creatinine ratio to <3 in subjects with baseline nephritic range proteinuria (>/=3 urine protein/creatinine ratio) or decrease in the urine protein/creatinine ratio by >/= 50% subjects with sub-nephrotic proteinuria (<3 urine protein/creatinine ratio). This ratio is based on the 24 hour urine collection. • and stabilization of serum creatinine (i.e. a week 24 serum creatinine level +/- 25% of baseline), or improvement. Complete (renal) remission is defined as: • return to normal serum creatinine, proteinuria </= 500mg/24 hours, • and an inactive urinary sediment. | |
E.4 | Principal exclusion criteria | Induction Phase: 1.Inability or unwillingness to provide written informed consent (and assent by underage subjects) 2. Inability or unwillingness to comply with the requirements of the protocol as determined by the investigator 3. In the opinion of the investigator, does not require long-term immunosuppressive treatment (in addition to corticosteroids) 4. Known hypersensitivity or contraindication to MMF, mycophenolic acid (MPA), cyclophosphamide, azathioprine (including known inherited TPMT deficiency), corticosteroids or any components of these drug products (e.g., allergy to Tween-80) 5. Pregnancy, nursing (breastfeeding) or use of a non-reliable method of contraception 6. Continuous dialysis starting more than 2 weeks before randomization into the induction phase and/or continuous dialysis with an anticipated duration of more than 8 weeks 7. Previous kidney transplant or planned transplant 8. Presence or history of: •pancreatitis or GI hemorrhage within 6 months prior to first randomization •active unhealed peptic ulcer within 3 months prior to first randomization. If an ulcer has healed and the subject is on adequate therapy, the subject may be randomized •congenital or acquired immunodeficiency •clinically significant drug or alcohol abuse •malignancy within 5 years of first randomization, with the exception of basal cell carcinoma treated by complete excision •lymphoproliferative disease or previous total lymphoid irradiation •severe viral infection (CMV, HBV, HCV) within 3 months of first randomization; or known HIV infection 9. Other known clinically significant active medical conditions, such as: •severe cardiovascular disease including CHF •liver dysfunction [aspartate aminotransferase (AST), alanine aminotransferase (ALT), or bilirubin greater than 2.5 times the upper limit of normal] measured on at least 2 separate occasions •COPD, or asthma requiring oral steroids •bone marrow insufficiency unrelated to active SLE (according to investigator judgment) with white blood cell count (WBC) <2500/mm3; absolute neutrophil count (ANC) <1.3 x 103/μL; thrombocytopenia (platelet count) <50,000/mm3 •active bleeding disorders •current infection requiring IV antibiotics 10. Any overlapping autoimmune condition for which the condition or treatment of the condition may affect the study assessments or outcomes (e.g., scleroderma with significant pulmonary hypertension; any condition for which additional immunosuppression is indicated). Overlapping conditions for which the condition or treatment is not expected to affect assessments or outcomes (e.g., Sjogren’s syndrome) are not excluded. 11. Other major physical or psychiatric illness or major traumatic injury within 6 months prior to first randomization 12. Other medical condition which, in the investigator’s judgment, may be associated with increased risk to the subject or may interfere with study assessments or outcomes 13.Participation in another clinical trial and/or receipt of investigational drugs within 4 weeks prior to screening visit 14. Use of medications prohibited prior to first randomization Maintenance Phase: 1. Does not meet maintenance phase inclusion criteria. | |
E.5 End points |
E.5.1 | Primary end point(s) | Induction phase: The primary efficacy parameter for the induction phase is the number and percentage of subjects showing treatment response at 24 weeks, as adjudicated by the Clinical Endpoints Committee (CEC). Treatment response is defined as: (a) Decrease in proteinuria, defined as decrease in the urine protein/creatinine ratio to <3 mg/mg in subjects with baseline nephrotic range proteinuria (≥3 mg/mg urine protein/creatinine ratio) or decrease in the urine protein/creatinine ratio by ≥50% in subjects with sub-nephrotic proteinuria (<3 mg/mg urine protein/creatinine ratio) and (b) Stabilization of serum creatinine (i.e., a week 24 serum creatinine level ±25% of baseline), or improvement Maintenance phase: The primary efficacy parameter is the time to treatment failure, as adjudicated by the CEC. A subject will be considered a treatment failure if he or she meets any of the following criteria: 1. Death 2. End Stage Renal Disease (ESRD) 3. Sustained doubling of serum creatinine concentration defined as the first serum creatinine value that is twice the mean of the lowest two values from screening to end of induction, as confirmed by a second serum creatinine value obtained at least 4 weeks after the initial doubling [modeled on Brenner et al., 2001] 4. Renal flare, defined as: (a) proteinuric •doubling of the urinary protein:creatinine ratio, and •proteinuria ≥ 1 g/24 h in subjects with urinary protein ≤ 0.5 g/24 h at the end of the induction phase, or proteinuria ≥ 2 g/24 h in subjects with urinary protein > 0.5 g/24 h at the end of the induction phase OR (b) nephritic: •25% increase in serum creatinine over the best value achieved from screening to end of induction. Increase in creatinine must be accompanied by one or more of: •simultaneous doubling of proteinuria reaching a minimum of 2 g/24 h (or ratio equivalent) •new/increased hematuria (blood 2+ or more on dipstick) •appearance of cellular casts. All suspected renal flares in (a) or (b) should be confirmed by a second measurement 2 weeks later, in the absence of any change in ACE/ARB medication, use of NSAIDs/COX2 inhibitors, or intercurrent infection. 5. Requirement for rescue corticosteroid therapy, PPE, IVIG, or non-protocol immunosuppressive therapy, to treat deterioration or exacerbation of lupus nephritis. | |
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description | 2-phase study: induction phase is open lable; maintenance phase is double blind | |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 | The trial involves single site in the Member State concerned | No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned | |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 | Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial | Until the last subject has been followed for 36 months. | |
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 5 |