Safety, Pharmacokinetics and Preliminary Efficacy Study of CFZ533 in Patients With Lupus Nephritis.

Study Overview
=================
Brief Summary
-----------------
This study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary therapeutic efficacy of multiple doses of CFZ533 anti-CD40 monoclonal antibody in patients with moderately active lupus nephritis.

Detailed Description
-----------------
This was a randomized, subject and investigator blind, placebo controlled multicenter study with multiple doses of CFZ533 administered by 1-hour intravenous infusion over a 24 week treatment period, as compared to matched placebo infusion. The treatment period was followed by a 24-week safety follow-up period.The duration of the study (including the screening period) for each patient was approximately 53 weeks. The investigational drug or placebo was administered on top of standard of care therapy for lupus nephritis. Patients were screened within 29 days of the first study drug infusion. Eligibility was confirmed at the baseline visit within one week before the first dose. Eligible patients were assigned a randomization number and receive the intravenous infusion within 3 days of baseline visit.

Official Title
-----------------
A Randomized, Placebo-controlled, Patient and Investigator Blinded, Study Investigating the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Multiple Doses of CFZ533 in Patients With Moderately Active Proliferative Lupus Nephritis

Conditions
-----------------
Lupus Nephritis

Intervention / Treatment
-----------------
* Drug: CFZ533
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: Men and women with systemic lupus erythematosus (SLE) 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 at al 1982, revised by Hochberg 1997) Subjects must have a body mass index (BMI) within the range of 18 - 40 kg/m2 at screening visit 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 Presence of antinuclear autoantibody (ANA titer ≥ 1:80) at screening Morning UPCR ≥ 0.5 at screening visit and baseline visit At least one of the following: low complement level (C3 ˂ 0.9 g/L) or (C4 ˂ 0.1 g/L), and/or elevated anti-dsDNA (≥ 30 IU/mL), and/or urine sediment consistent with active proliferative LN 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 Patient must have sufficient kidney function as estimated by eGFR ˃ 30mL/min/1.73 m2 at screening and baseline visits (Levey et al 2009) Patient must have active disease as defined by proteinuria and additional symptoms as above despite standard of care therapy for LN 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 Bertsias et all 2012 and Hahn et al 2012. Women of childbearing potential (defined as all women physiologically capable of becoming pregnant) must use highly effective methods of contraception during dosing and until study completion. Key Exclusion Criteria: 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. Hypoalbuminemia (serum albumin of less than 2.0 g/dL) Patients who have received: oral or i.v. cyclophosphamide within 3 months prior to randomization i.v. corticosteroid bolus (dose ˃ 1 mg/kg) within 3 months prior to randomization rituximab or other B cell depleting agent within 12 months. for patients who received such treatment earlier, B cell count should be within normal ranges prior to randomization belimumab within 6 months prior to randomization any other biologic drug or an investigational drug within one months or five times the half-life, whichever is longer prior to randomization any calcineurin inhibitor (e.g., tacrolimus or cyclosporin A) within 3 months prior to randomization Patients who are at significant risk for the 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 Have had signs or symptoms of a clinically significant systemic viral, bacterial or fungal infection within 30 days prior to randomization Live vaccines within 4 weeks of the first study drug infusion Other protocol-defined inclusion/exclusion criteria may apply. -

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CFZ533<br>Investigational drug CFZ533 will be administred as multiple doses | Drug: CFZ533<br>* multiple doses of CFZ533 intravenous infusion<br>|
| Placebo Comparator: Placebo<br>Investigational drug matching placebo will be administered as multiple doses | Drug: Placebo<br>* multiple doses of placebo intravenous infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety as assessed by adverse events | Number and percentage of patients with adverse events | From baseline to week 49 | 
| Renal proteinuria | Ratio from baseline in urinary protein creatinine ratio (UPCR) to week 25 | From baseline to week 25 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine protein creatinine ratio (UPCR) and hematuria and cellular casts | Ratio from baseline for urine protein creatinine ratio (UPCR) and hematuria and cellular casts to evaluate the renal effect. | From baseline to week 49 | 
| Plasma pharmacokinetics (PK) of CFZ533: the area under plasma concentration-time curve calculated to the last quantifiable concentration point (AUClast). | The following PK parameter will be determined from the plasma concentration time profile of CFZ533: AUClast: AUClast is the area under plasma concentration-time curve calculated to the last quantifiable concentration point. | From baseline to week 49, pre dose and 1 hour post dose | 
| Complete renal remission | Proportion of patients who fulfill the criteria for complete renal remission according to ACR recommendation | From baseline to week 49 | 
| Plasma pharmacokinetics (PK) of CFZ533: The observed plasma concentration that is just prior to the beginning of, or at the end of a dosing interval (Cthrough) | Cthrough: The observed plasma concentration that is just prior to the beginning of, or at the end of a dosing interval | From baseline to week 49, pre dose and 1 hour post dose | 
| Plasma pharmacokinetics (PK) of CFZ533: The observed maximum plasma concentration following drug administration at steady state (Cmax,ss) | Cmax,ss: The observed maximum plasma (or serum or blood) concentration following drug administration at steady state [mass/volume] | From baseline to week 49, pre dose and 1 hour post dose | 
| Plasma pharmacokinetics (PK) of CFZ533 The lowest plasma concentration observed during a dosing interval at steady state (Cmin,ss) | Cmin,ss: The lowest plasma (or serum or blood) concentration observed during a dosing interval at steady state [mass/volume] | From baseline to week 49, pre dose and 1 hour post dose | 
| Total soluble CD40 concentrations | Total soluble CD40 concentrations in plasma | From baseline to week 49 | 
| Immunogenicity of CFZ533 | Incidence of ADA-positive patients | From baseline to week 49 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
anti-CD40, CFZ533, moderately active lupus nephritis