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

• ClinicalTrials.gov Identifier: NCT03610516
• Recruitment Status: Active, not recruiting
• First Posted: August 1, 2018
• Last Update Posted: April 26, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: June 1, 2018
• First Posted Date: August 1, 2018
• Last Update Posted Date: April 26, 2023
• Actual Study Start Date: September 12, 2018
• Estimated Primary Completion Date: July 3, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (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: Same as current

Current Secondary Outcome Measures (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: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Safety, Pharmacokinetics and Preliminary Efficacy Study of CFZ533 in Patients With Lupus Nephritis.
• 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
• 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Lupus Nephritis

Intervention

• Drug: CFZ533
  multiple doses of CFZ533 intravenous infusion
• Drug: Placebo
  multiple doses of placebo intravenous infusion

Study Arms

• 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

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 29, 2022): 57
• Original Estimated Enrollment (submitted: July 31, 2018): 60
• Estimated Study Completion Date: July 3, 2023
• Estimated Primary Completion Date: July 3, 2023 (Final data collection date for primary outcome measure)

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:

  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

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, China, Germany, Hong Kong, Hungary, Korea, Republic of, Russian Federation, Taiwan, Tunisia, Turkey
• Removed Location Countries: United States

Administrative Information

• NCT Number: NCT03610516
• Other Study ID Numbers: 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: Not Provided
• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: April 2023