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

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

This study was 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.

Study Overview

• Status: Completed
• Conditions: Lupus Nephritis
• Intervention / Treatment: Drug: Placebo; Drug: CFZ533

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.

• Study Type: Interventional
• Enrollment (Actual): 57
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, X5016KEH
    • Novartis Investigative Site
  • Buenos Aires
    • Ciudad Autonoma de Bs As, Buenos Aires, Argentina, C1015ABO
      • Novartis Investigative Site
• China
  • Beijing, China, 100730
    • Novartis Investigative Site
  • Shanghai, China, 200127
    • Novartis Investigative Site
  • Guangdong
    • Guangzhou, Guangdong, China, 510000
      • Novartis Investigative Site
  • Hunan
    • Changsha, Hunan, China, 410008
      • Novartis Investigative Site
  • Xinjiang
    • Urumqi, Xinjiang, China, 830001
      • Novartis Investigative Site
• Germany
  • Mainz, Germany, 55131
    • Novartis Investigative Site
• Hong Kong
  • HongKong, Hong Kong
    • Novartis Investigative Site
• Hungary
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
  • Seocho Gu
    • Seoul, Seocho Gu, Korea, Republic of, 06591
      • Novartis Investigative Site
• Russian Federation
  • Rostov On Don, Russian Federation, 344022
    • Novartis Investigative Site
  • Saint Petersburg, Russian Federation, 197022
    • Novartis Investigative Site
  • St Petersburg, Russian Federation, 197110
    • Novartis Investigative Site
  • Yaroslavl, Russian Federation, 150062
    • Novartis Investigative Site
• Taiwan
  • Taichung, Taiwan, 40447
    • Novartis Investigative Site
  • Taichung, Taiwan, 40705
    • Novartis Investigative Site
  • Taipei, Taiwan, 10048
    • Novartis Investigative Site
• Tunisia
  • Tunis, Tunisia, 1008
    • Novartis Investigative Site
• Turkey
  • Kocaeli, Turkey, 41380
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CFZ533; Investigational drug CFZ533 will be administred as multiple doses	Drug: CFZ533; Multiple doses of 10 mg/kg CFZ533 intravenous (IV) infusion. CFZ533 was administered every 4 weeks (Q4W; from Day 1 to Day 141), plus an additional dose of 10 mg/kg IV at Day 15, resulting in a Q2W loading regimen up to the third dose on Day 29.
Placebo Comparator: Placebo; Investigational drug matching placebo will be administered as multiple doses	Drug: Placebo; multiple doses of placebo intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	Number of participants with treatment emergent AEs (any AE regardless of seriousness), AEs led to study treatment discontinuation, SAEs and SAEs led to study treatment discontinuation.	Adverse events were reported from first dose of study treatment until end of study treatment plus follow up period, up to a maximum duration of approximately 49 weeks.
Ratio to Baseline in Urinary Protein Creatinine Ratio (UPCR)	A urine protein creatinine ratio (UPCR) test is a urine test. It measures the levels of protein and creatinine in urine. UPCR was assessed using the first morning void if available at a visit otherwise using the clinic spot sample, and was expressed as protein/creatinine (mg/mmol). High UPCR values can be a sign of kidney disease. An UPCR ratio to baseline <1 indicates improvement from baseline.	Baseline, Day 169

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ratio to Baseline for Urine Protein Creatinine Ratio (UPCR)	A urine protein creatinine ratio (UPCR) test is a urine test. It measures the levels of protein and creatinine in urine. UPCR was assessed using the first morning void if available at a visit otherwise using the clinic spot sample, and was expressed as protein/creatinine (mg/mmol). High UPCR values can be a sign of kidney disease. An UPCR ratio to baseline <1 indicates improvement from baseline.	Day 197, Day 225, Day 253, Day 281, Day 309, Day 337 (End of Study)
Area Under Plasma Concentration-time Curve From Time Zero to the Last Measurable Concentration Sampling Time (AUClast) of CFZ533	Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. AUClast is the area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration (tlast) of free CFZ533.	Day 141: pre dose and 1 hour post dose
Pre-dose Trough Concentration (Ctrough) of CFZ533	Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. Ctrough is the observed plasma concentration that is just prior to the beginning of, or at the end of a dosing interval.	Pre-dose at: Day 1, Day 15, Day 29, Day 57, Day 85, Day 113 and Day 141
The Observed Maximum Plasma Concentration Following CFZ533 Administration at Steady State (Cmax,ss)	Pharmacokinetic parameters were directly derived from the PK concentration data using non-compartmental analysis. Cmax,ss is the observed maximum plasma concentration following CFZ533 administration at steady state [mass/volume].	Day 141: pre dose and 1 hour post dose
Total Soluble CD40 Plasma Concentrations	Total soluble CD40 concentrations in plasma. An increase in soluble CD40 concentrations is considered a marker for CFZ533 target engagement. This endpoint is only applicable to the CFZ533 arm.	Day 1, Day 15, Day 29, Day 57, Day 113, Day 169, Day 225, Day 281, Day 337 (End of Study)
Number of Participants With Anti-CFZ533 Antibodies	To evaluate the immunogenicity of CFZ533 via the quasi-quantitative analysis of anti-CFZ533 antibodies.	Day 1, Day 15, Day 29, Day 57, Day 113, Day 169, Day 225, Day 281, Day 337 (End of study)
Hematuria Casts- Urine White Blood Cell Casts	Urine was tested using a dipstick. If the dipstick result was positive for protein, nitrite, leucocytes and/or blood, a microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts was performed. Hematuria is the presence of blood in the urine. Hematuria casts were assessed by microscopic urinalysis and classified as granular casts and WBC casts. Only in the event of a positive result, these samples were submitted to reflex testing microscopic analysis for counting of casts which resulted in a numeric value related to the number of respective casts presented in the urine.	Baseline, Day 1 (Pre dose), and Day 309
Hematuria Casts- Casts Granular	Urine was tested using a dipstick. If the dipstick result was positive for protein, nitrite, leucocytes and/or blood, a microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts was performed. Hematuria is the presence of blood in the urine. Hematuria casts were assessed by microscopic urinalysis and classified as granular casts and WBC casts. Only in the event of a positive result, these samples were submitted to reflex testing microscopic analysis for counting of casts which resulted in a numeric value related to the number of respective casts presented in the urine.	Day 1 (Pre dose), Day 15 (Pre dose), Day 29 (Pre dose), Day 253, and Day 337 (end of study)
Change From Baseline in Urine Hyaline Casts	Urine was tested using a dipstick. If the dipstick result was positive for protein, nitrite, leucocytes and/or blood, a microscopic analysis of white blood cells (WBC), red blood cells (RBC) and casts was performed. Urine hyaline casts were assessed by microscopic urinalysis.	Baseline, Day 1 (Pre dose), Day 15 (Pre dose), Day 29 (Pre dose), Day 57 (Pre dose), Day 85 (Pre dose), Day 113 (Pre dose), Day 141 (Pre dose), Day 169, Day 197, Day 225, Day 253, Day 281, Day 309 and Day 337 (end of study)
Number of Participants Who Fulfil the Criteria for Complete Renal Remission (CRR)	The criteria for CRR were defined as: Urinary protein creatinine ratio (UPCR) ≤ 0.2 mg/mg; Estimated glomerular filtration rate (eGFR) ≤ 25% of Baseline; Normal urine sediment. If the UPCR from the first morning void sample was not available, then the UPCR from the corresponding spot sample taken at the investigator site was used in the derivation of complete renal remission.	Baseline, up to Day 169

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• A Plain Language Trial Summary is available on novctrd.com

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2018
• Primary Completion (Actual): June 29, 2023
• Study Completion (Actual): June 29, 2023

Study Registration Dates

• First Submitted: June 1, 2018
• First Submitted That Met QC Criteria: July 31, 2018
• First Posted (Actual): August 1, 2018

Study Record Updates

• Last Update Posted (Actual): October 9, 2024
• Last Update Submitted That Met QC Criteria: October 7, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Keywords: anti-CD40; CFZ533; moderately active lupus nephritis
• Additional Relevant MeSH Terms: Immune System Diseases; Autoimmune Diseases; Kidney Diseases; Urologic Diseases; Connective Tissue Diseases; Glomerulonephritis; Lupus Erythematosus, Systemic; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Nephritis; Lupus Nephritis
• Other Study ID Numbers: CCFZ533X2202

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No