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

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ClinicalTrials.gov Identifier: NCT03610516
Recruitment Status : Recruiting
First Posted : August 1, 2018
Last Update Posted : April 13, 2021
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE June 1, 2018
First Posted Date  ICMJE August 1, 2018
Last Update Posted Date April 13, 2021
Actual Study Start Date  ICMJE September 12, 2018
Estimated Primary Completion Date September 22, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 31, 2018)
  • Safety as assessed by adverse events [ Time Frame: From baseline to week 49 ]
    Number and percentage of patients with adverse events
  • Renal proteinuria [ Time Frame: From baseline to week 25 ]
    Ratio from baseline in urinary protein creatinine ratio (UPCR) to week 25
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 31, 2018)
  • Urine protein creatinine ratio (UPCR) and hematuria and cellular casts [ Time Frame: From baseline to week 49 ]
    Ratio from baseline for urine protein creatinine ratio (UPCR) and hematuria and cellular casts to evaluate the renal effect.
  • Plasma pharmacokinetics (PK) of CFZ533: the area under plasma concentration-time curve calculated to the last quantifiable concentration point (AUClast). [ Time Frame: From baseline to week 49, pre dose and 1 hour post dose ]
    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.
  • Immunogenicity of CFZ533 [ Time Frame: From baseline to week 49 ]
    Presence of anti-CFZ533 antibodies in plasma
  • Complete renal remission [ Time Frame: From baseline to week 49 ]
    Proportion of patients who fulfill the criteria for complete renal remission according to ACR recommendation
  • Plasma pharmacokinetics (PK) of CFZ533: The observed maximum plasma concentration following drug administration (Cmax) [ Time Frame: From baseline to week 49, pre dose and 1 hour post dose ]
    Cmax: The observed maximum plasma concentration following drug administration
  • Plasma pharmacokinetics (PK) of CFZ533: The observed minimum plasma concentration following drug administration (Cmin) [ Time Frame: From baseline to week 49, pre dose and 1 hour post dose ]
    Cmin: The observed minimum plasma concentration following drug administration
  • 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) [ Time Frame: From baseline to week 49, pre dose and 1 hour post dose ]
    Cthrough: The observed plasma concentration that is just prior to the beginning of, or at the end of a dosing interval
  • Plasma pharmacokinetics (PK) of CFZ533: The observed maximum plasma concentration following drug administration at steady state (Cmax,ss) [ Time Frame: From baseline to week 49, pre dose and 1 hour post dose ]
    Cmax,ss: The observed maximum plasma (or serum or blood) concentration following drug administration at steady state [mass/volume]
  • Plasma pharmacokinetics (PK) of CFZ533 The lowest plasma concentration observed during a dosing interval at steady state (Cmin,ss) [ Time Frame: From baseline to week 49, pre dose and 1 hour post dose ]
    Cmin,ss: The lowest plasma (or serum or blood) concentration observed during a dosing interval at steady state [mass/volume]
  • Total soluble CD40 concentrations [ Time Frame: From baseline to week 49 ]
    Total soluble CD40 concentrations in plasma
  • Immunogenicity of CFZ533 [ Time Frame: From baseline to week 49 ]
    Incidence of ADA-positive patients
  • Pharmacodynamic response of CFZ533 as assessed by receptor occupancy [ Time Frame: From baseline to week 49 ]
    Total soluble CD40 concentrations in plasma: pre-dose, during treatment and follow up. Rate, extent and duration of target engagement
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety, Pharmacokinetics and Preliminary Efficacy Study of CFZ533 in Patients With Lupus Nephritis.
Official Title  ICMJE 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
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 is 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 will be followed by a 24-week safety follow-up period.The duration of the study (including the screening period) for each patient will be approximately 53 weeks. The investigational drug or placebo will be administered on top of standard of care therapy for lupus nephritis.

Patients will be screened within 29 days of the first study drug infusion. Eligibility will be confirmed at the baseline visit within one week before the first dose. Eligible patients will be assigned a randomization number and receive the intravenous infusion within 3 days of baseline visit.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Lupus Nephritis
Intervention  ICMJE
  • Drug: CFZ533
    multiple doses of CFZ533 intravenous infusion
  • Drug: Placebo
    multiple doses of placebo intravenous infusion
Study Arms  ICMJE
  • Experimental: CFZ533
    Investigational drug CFZ533 will be administred as multiple doses
    Intervention: Drug: CFZ533
  • Placebo Comparator: Placebo
    Investigational drug matching placebo will be administered as multiple doses
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 12, 2021)
75
Original Estimated Enrollment  ICMJE
 (submitted: July 31, 2018)
60
Estimated Study Completion Date  ICMJE September 22, 2022
Estimated Primary Completion Date September 22, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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:

    1. low complement level (C3 ˂ 0.9 g/L) or (C4 ˂ 0.1 g/L), and/or
    2. elevated anti-dsDNA (≥ 30 IU/mL), and/or
    3. 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:

    1. oral or i.v. cyclophosphamide within 3 months prior to randomization
    2. i.v. corticosteroid bolus (dose ˃ 1 mg/kg) within 3 months prior to randomization
    3. 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
    4. belimumab within 6 months prior to randomization
    5. any other biologic drug or an investigational drug within one months or five times the half-life, whichever is longer prior to randomization
    6. 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:

    1. history of either thrombosis or 3 or more spontaneous abortions
    2. 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.

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Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111
Listed Location Countries  ICMJE Argentina,   China,   Germany,   Hong Kong,   Hungary,   Korea, Republic of,   Russian Federation,   Taiwan,   Tunisia,   Turkey,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03610516
Other Study ID Numbers  ICMJE CCFZ533X2202
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP