E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025140 |
E.1.2 | Term | Lupus nephritis |
E.1.2 | System Organ Class | 10038359 - Renal and urinary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the safety and tolerability of 24 weeks of treatment with CFZ533 as an add-on therapy to standard of care in moderately active lupus nephritis (LN) patients; To assess the effect of CFZ533 on renal proteinuria in moderately active lupus nephritis patients after 24 weeks of treatment as an add-on therapy to standard of care as compared to placebo |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of CFZ533 on relevant renal outcomes at different time points; To evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of CFZ533 in LN patients, after multiple 10 mg/kg IV doses; To evaluate the immunogenicity of CFZ533 in LN patients, after multiple 10 mg/kg IV doses |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Exploratory kidney biopsy substudy (2019-05-22, version 02): The substudy includes two optional kidney biopsy assessments. As part of the assessment, the activity- and chronicity indices will be collected. Protein and gene expression profiles may also be established using a variety of different techniques (e.g. immunohistochemistry, RNAseq). |
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E.3 | Principal inclusion criteria |
Population eligible for inclusion in this study must fulfill all of the following criteria: 1. Understand the study procedures and provide written informed consent before any study-related assessment is performed. 2. Men and women with systemic lupus erythematosus (see below), aged ≥18 years and ≤75 years at screening, fulfilling at least 4 out of 11 criteria for SLE as defined by the American College of Rheumatology (Tan et al 1982, revised by Hochberg 1997). 3. Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m2. (BMI = Body weight (kg) / [Height (m)]2) to participate in the study at Screening visit 4. Histological diagnosis of proliferative lupus nephritis World Health Organization (WHO) ISN/RPS (Weening et al 2004) Class III or IV within 5 years of screening 5. Presence of antinuclear autoantibody (ANA titer ≥1:80 at screening) 6. First morning void or spot urine UPCR ≥0.5 mg/mg (56.52 mg/mmol) at Screening visit and Baseline visit. 7. At least one of the following at Screening visit: a. low complement level (C3 < 0.8 g/L or C4 < 1.6 g/L), and/or b. elevated anti-dsDNA (≥30 IU/mL), and/or c. urine sediment consistent with active proliferative lupus nephritis such as presence of cellular (granular or red blood cell) casts or hematuria (>5 red blood cells per high power field) if other causes such as menstrual bleeding are excluded 8. Patient must have sufficient kidney function as estimated by eGFR >30 mL/min/1.73m2 at screening and baseline visits 9. Patients must have active disease as defined by proteinuria and additional symptoms as defined above (criterion 7) despite standard of care therapy for lupus nephritis as considered appropriate by the treating physician (e.g., corticosteroids and/or immunosuppressive or immunomodulatory treatments such as mycophenolate, azathioprine, methotrexate or hydroxychloroquine). For guidance, see published guidelines such as by Bertsias et al 2012 and Hahn et al 2012 10. If the patient is taking oral corticosteroid treatment at screening, the dose (max. 30 mg prednisone or equivalent per day) must be stable for at least 2 weeks prior to randomization 11. If the patient is taking immunosuppressive or immunomodulatory treatment such as mycophenolate, azathioprine, methotrexate or hydroxychloroquine, the dose must be stable for at least 4 weeks prior to randomization and for the duration of the study 12. If the patient is taking a medication potentially affecting renal function (such as ACE inhibitors, cholesterol-lowering agents) the dose must be stable for at least 4 weeks prior to randomization and for the duration of the study 13. Patients not requiring vaccination during the study and until at least 16 weeks after the last administration of the study drug. Any vaccinations, if deemed necessary, must be administered prior to randomization in the study. 14. Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) must use highly effective methods of contraception before entering the study, during dosing and until study completion.
Other protocol defined inclusion criteria may apply. |
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E.4 | Principal exclusion criteria |
Eligible Population fulfilling any of the following criteria are not eligible for inclusion in this study: 1. Any glomerulonephritis other than WHO Class III or IV lupus nephritis. Patients with proliferative nephritis (Class III or IV) who, in addition, have overlapping histological signs for other glomerulonephritis, e.g. Class V are eligible at the investigator`s discretion 2. Hypoalbuminemia (serum albumin of less than 2.0 g/dL) 3. Patients who have received a) oral or IV cyclophosphamide within 3 months prior to randomization. b) IV corticosteroid bolus (dose higher than 1 mg/kg) within 3 months prior to randomization. c) rituximab or other B cell depleting agent received prior to randomization within: less than or equal to 6 months, no inclusion; >6 months but less than or equal to 12 months , B cell count must be within normal range, > 12 months prior to randomization, no special requirement. d) belimumab within 6 months prior to randomization. e) any other biologic drug or an investigational drug within one (1) month or five times the half-life, whichever is longer prior to randomization. f) calcineurin inhibitor (e.g., tacrolimus, cyclosporin A) within 3 months prior to randomization. 4. Patients who are at significant risk for thromboembolic events based on the following: - History of either thrombosis or 3 or more spontaneous abortions - Presence of lupus anticoagulant or prolonged activated partial thromboplastin time (aPTT) and no prophylactic treatment with aspirin or anticoagulants as per local standard of care 5. History or presence of any medically significant cardiac condition which according to the investigator may jeopardize the patient in case of participation in the study including ischemic heart disease, congestive heart failure or cardiomyopathy, myocardial infarction or stroke 6. History of malignancy with the exception of basal cell or squamous cell carcinoma of the skin or in situ carcinoma of the cervix within the last 3 years 7. Have had signs or symptoms of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to randomization 8. Evidence of active or latent tuberculosis as assessed by Quantiferon (or T-SPOT® or other types of ELISpot assays based on interferon-gamma release) testing at screening, see also Section 8.6.8.1. 9. Positive serology for HIV antibodies, hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (anti-HBc), except if HBV DNA is negative and hepatitis B monitoring (HBsAg and HBV DNA tested every 4 weeks until the end of study) is implemented; and hepatitis C antibodies confirmed by an appropriate licensed test at screening. 10. Any other current, active or latent infection susceptible to reactivation 11. Any significant concurrent medical condition such as pulmonary or liver disease that, in the opinion of the principal Investigator, could affect the patient's ability to tolerate or complete the study 12. Any of the following abnormal laboratory values at screening or baseline visits: a) total white blood cell count (WBC) outside the range of 1,500-15,000/mm3 (1.5-15.0 x 109/L) b) platelets <100,000/mm3 (<100 x 109/L) c) Hemoglobin (Hgb) <8.0 g/dL (<5mmol/L) d) lymphocyte count <500/mm3 (<0.5 X 109/L) e) neutrophil count <1500/mm3 (<1.5 X 109/L) f) Clinical evidence of liver disease or liver injury or any of the following hepatic conditions: - known history of alcohol abuse, chronic liver or biliary disease - conjugated bilirubin greater than the ULN - alkaline phosphatase (AP) greater than 3 x ULN - AST (SGOT), ALT (SGPT) greater than 3 x ULN - γ-glutamyl-transferase (GGT) greater than 3 x ULN 13. Live vaccines within 8 weeks of study drug infusion 14. Have donated blood or experienced a loss of blood >500mL within 4 weeks of screening 15. Known allergy to human therapeutic antibodies or hypersensitivity to any constituent of the product. No additional exclusions may be applied by the investigator, in order to ensure that the study population will be representative of all eligible patients. Other protocol defined exclusion criteria may apply; |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Safety: - AEs/SAEs - Vital signs - ECG evaluation - Standard hematology and chemistry evaluations
2. Ratio from baseline in urinary protein creatinine ratio (UPCR) at Week 25 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. All visits from baseline to Week 49 2. UPCR: visits Day 1 and Day 169 |
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E.5.2 | Secondary end point(s) |
- Ratio from baseline in the following parameters: -- UPCR -- hematuria and cellular casts - Proportion of patients who fulfill the criteria for complete renal remission (CRR) according to ACR recommendation (Wofsy et al 2012) - PK: Free CFZ533 concentrations in plasma. - Parameters (free CFZ533): Ctrough,ss or Cmin,ss, Cmax,ss, and AUClast (after last dose) - PD: Total soluble CD40 concentrations in plasma: pre-dose, during treatment and follow up. Rate, extent and duration of target engagement. - Anti-CFZ533 antibodies in plasma: baseline, during treatment and followup, incidence of ADA-positive patients |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline visit, and all visits from Day 1 to Day 337. |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 | No |
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 |
Argentina |
China |
Hong Kong |
Korea, Republic of |
Taiwan |
Tunisia |
United States |
Germany |
Hungary |
Russian Federation |
Turkey |
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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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 10 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |