Study of Efficacy, Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) of an Anti-CD40 Monoclonal Antibody, CFZ533, in Kidney Transplant Recipients (CIRRUS I)

A Partially-blinded, Active-controlled, Multicenter, Randomized Study Evaluating Efficacy, Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) of an Anti-CD40 Monoclonal Antibody, CFZ533, in de Novo and Maintenance Kidney Transplant Recipients (CIRRUS I)

This study was to compare CFZ533 to tacrolimus (TAC) in prevention of organ rejection in kidney transplant.

Study Overview

• Status: Completed
• Conditions: Kidney Transplantation
• Intervention / Treatment: Biological: CFZ533 - Cohort 1/Cohort 2; Drug: Mycophenolate Mofetil (MMF); Drug: Corticosteroids (CS); Drug: Induction therapy: basiliximab; Drug: Induction therapy: rabbit anti-thymocyte globulin (rATG); Drug: Placebo 1 mL; Drug: Tacrolimus; Drug: Maintenance population: EC-MPS; Drug: Maintenance population: MMF

Detailed Description

The purpose of this study was to investigate the safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) of three CFZ533 dose regimens in kidney transplant recipients.

Study CCFZ533A2201 was a randomized, planned 60-month (5 year) study comprising of 12-months treatment for the primary analysis plus an additional 48-month treatment period. The study had 2 different cohorts: adult de novo kidney transplant recipients and maintenance kidney transplant population (6-24 months post-transplant).

The study was terminated after the interim analysis.

• Study Type: Interventional
• Enrollment (Actual): 418
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, W3400ABH
    • Novartis Investigative Site
  • Corrientes, Argentina, W3400
    • Novartis Investigative Site
  • Córdoba, Argentina, X5016KEH
    • Novartis Investigative Site
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Novartis Investigative Site
  • South Australia
    • Adelaide, South Australia, Australia, 5000
      • Novartis Investigative Site
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Novartis Investigative Site
• Belgium
  • Leuven, Belgium, 3000
    • Novartis Investigative Site
• Brazil
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90020-090
      • Novartis Investigative Site
  • São Paulo
    • São Paulo, São Paulo, Brazil, 05403 000
      • Novartis Investigative Site
    • São Paulo, São Paulo, Brazil, 04038-002
      • Novartis Investigative Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Novartis Investigative Site
• Czechia
  • Prague, Czechia, 146 24
    • Novartis Investigative Site
• France
  • Bordeaux, France, 33076
    • Novartis Investigative Site
  • Créteil, France, 94010
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • Lyon, France, 69003
    • Novartis Investigative Site
  • Nantes, France, 44093
    • Novartis Investigative Site
  • Paris, France, 75015
    • Novartis Investigative Site
  • Toulouse, France, 31054
    • Novartis Investigative Site
  • Tours, France, 37044
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Dresden, Germany, 01307
    • Novartis Investigative Site
  • Erlangen, Germany, 91054
    • Novartis Investigative Site
  • Essen, Germany, 45147
    • Novartis Investigative Site
  • Hamburg, Germany, 20246
    • Novartis Investigative Site
  • Heidelberg, Germany, 69120
    • Novartis Investigative Site
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Bavaria
    • Regensburg, Bavaria, Germany, 93053
      • Novartis Investigative Site
• Hungary
  • Budapest, Hungary, H-1083
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• Italy
  • MI
    • Milan, MI, Italy, 20132
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00133
      • Novartis Investigative Site
• Japan
  • Kumamoto, Japan, 861-8520
    • Novartis Investigative Site
  • Osaka, Japan, 545-8586
    • Novartis Investigative Site
  • Aichi-ken
    • Nagakute, Aichi-ken, Japan, 480-1195
      • Novartis Investigative Site
    • Nagoya, Aichi-ken, Japan, 466-8650
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo, Hokkaido, Japan, 060-8604
      • Novartis Investigative Site
    • Sapporo, Hokkaido, Japan, 060 8648
      • Novartis Investigative Site
  • Kanagawa
    • Yokohama, Kanagawa, Japan, 232 0024
      • Novartis Investigative Site
  • Okinawa
    • Tomigusuku, Okinawa, Japan, 9010224
      • Novartis Investigative Site
  • Osaka
    • Suita, Osaka, Japan, 565 0871
      • Novartis Investigative Site
• Latvia
  • Riga, Latvia, LV 1002
    • Novartis Investigative Site
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Utrecht, Netherlands, 3584CX
    • Novartis Investigative Site
  • South Holland
    • Rotterdam, South Holland, Netherlands, 3015 GD
      • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0424
    • Novartis Investigative Site
• South Korea
  • Seoul, South Korea, 03080
    • Novartis Investigative Site
• Spain
  • Zaragoza, Spain, 50009
    • Novartis Investigative Site
  • Balearic Islands
    • Palma de Mallorca, Balearic Islands, Spain, 07120
      • Novartis Investigative Site
  • Barcelona
    • L'Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Novartis Investigative Site
  • Catalonia
    • Barcelona, Catalonia, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalonia, Spain, 08036
      • Novartis Investigative Site
    • Barcelona, Catalonia, Spain, 08003
      • Novartis Investigative Site
• Sweden
  • Gothenburg, Sweden, 413 45
    • Novartis Investigative Site
  • Uppsala, Sweden, 751 85
    • Novartis Investigative Site
• Switzerland
  • Bern, Switzerland, 3010
    • Novartis Investigative Site
• United Kingdom
  • Glasgow, United Kingdom, G51 4TF
    • Novartis Investigative Site
  • London, United Kingdom, SW17 0QT
    • Novartis Investigative Site
  • Manchester, United Kingdom, M13 9WL
    • Novartis Investigative Site
• United States
  • California
    • Los Angeles, California, United States, 90033
      • Novartis Investigative Site
    • San Francisco, California, United States, 94143 0116
      • Novartis Investigative Site
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Novartis Investigative Site
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Novartis Investigative Site
    • Chicago, Illinois, United States, 60611
      • Novartis Investigative Site
  • Kansas
    • Kansas City, Kansas, United States, 66103
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Novartis Investigative Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Novartis Investigative Site
  • Michigan
    • Detroit, Michigan, United States, 48202 2689
      • Novartis Investigative Site
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Novartis Investigative Site
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Novartis Investigative Site
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • Novartis Investigative Site
    • Cincinnati, Ohio, United States, 45267-0585
      • Novartis Investigative Site
  • Texas
    • Dallas, Texas, United States, 75390
      • Novartis Investigative Site
  • Washington
    • Seattle, Washington, United States, 98195
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Key inclusion criteria for both cohorts

• Written informed consent obtained before any assessment.
• Male or female patient ≥ 18 years old.
• Up to date vaccination as per local immunization schedules.

Key inclusion criteria specific to Cohort 1:

• Recipients of a primary kidney transplant from a brain-dead donor, living unrelated or non-human leukocyte antigen (HLA) identical living related donors.
• Recipients of a kidney with a cold ischemia time < 24 hours.

Key inclusion criteria specific to Cohort 2:

• Recipients of a primary graft received 6 to 24 months prior enrollment, on a regimen containing TAC+MMF/ Enteric-coated mycophenolate sodium (EC-MPS)±corticosteroids (CS).
• Patients with an actual eGFR according to Modification of Diet in Renal Disease (MDRD-4) ≥ 45 mL/min/1.73m2.

Exclusion Criteria:

Key exclusion criteria for both cohorts

• Recipient who tests positive for anti-HIV, HBsAg or anti-HCV (without proof of sustained viral response (SVR12) after anti-HCV treatment) within 28 days prior to baseline visit.
• Recipient who tests negative for Epstein Barr virus (EBV) within 28 days prior to baseline visit.
• Evidence of advanced liver disease (Child-Pugh C), or any sign of liver decompensation.
• Patient with severe systemic infections, current or within the two weeks prior to randomization.
• History of malignancy of any organ system, treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases, with the exception of localized excised non-melanomatous skin lesions.
• Patients who weighed less than 30 kg or more than 180 kg.

Key exclusion criteria specific to Cohort 1:

• Multi-organ transplant recipients, including en bloc and dual kidney transplantation, or prior kidney transplant
• Recipients of an organ from a donor after cardiac death.
• Recipient of an organ from an HLA identical living related donor.
• ABO incompatible or complement-dependent lymphocytotoxic crossmatch positive transplant (isolated positive B cell crossmatches were not an exclusion criterion).
• Recipients of kidneys from donors who were older than >65 years.
• Recipients of kidneys from donors with terminal serum creatinine > 2 mg/dL.
• Patients at high immunological risk for rejection as determined for assessment of anti-donor reactivity:
• high panel reactive antibodies> 20% or
• Presence of pre-formed DSA. Results 12 weeks prior to enrollment were acceptable if no blood transfusion or abortion occurred during this period.
• Recipient of a kidney from a donor who tests positive for HIV, HBsAg or HCV.

Key exclusion criteria to Cohort 2

• Recipients of a kidney re-transplant.
• Recipient of a multi-organ transplant, including en bloc and dual kidney transplantation.
• DSA within 12 weeks prior enrollment.
• eGFR decline ≥10.0 mL/min within 12 weeks prior enrollment.
• Ongoing rejection or rejection that required treatment within 12 weeks prior enrollment.
• Severe humoral and/or cellular rejection (BANFF ≥ IIb) within 12 weeks before enrollment.
• Proteinuria > 1 g/day or UPCR >1.2 mg/mg at time of enrollment

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1/Cohort 1: CFZ533 600 mg + Mycophenolate Mofetil (MMF) + Corticosteroids; Eligible patients were randomized to CFZ533 600 mg sc bi-weekly (Q2W) + Mycophenolate Mofetil (MMF) + Corticosteroids. Patients randomized to CFZ533 arms were administered the first dose of CFZ533 at 30 mg/kg IV pre- or intra-operatively (Day 1) with completion of the infusion within one hour of unclamping and prior graft revascularization, in combination with MMF and corticosteroids. MMF and corticosteroids might be initiated prior to surgery according to local practice. A second IV dose of CFZ533 at 15 mg/kg was infused at Day 5 post-transplant. Subsequent doses starting at Day 15: 600 mg sc (2 injections of 2 mL CFZ533 at 150 mg/mL) Q2W, up to a planned Month 59.5 visit.	Biological: CFZ533 - Cohort 1/Cohort 2; CFZ533 was administered either by intravenous infusion or subcutaneous injection; Drug: Mycophenolate Mofetil (MMF); Per local practice, 250 mg or 500 mg taken orally or 500 mg taken intravenously.; Drug: Corticosteroids (CS); Taken either orally or intravenously.; Drug: Induction therapy: basiliximab; Lyophilized solution taken intravenously; Drug: Induction therapy: rabbit anti-thymocyte globulin (rATG); Lyophilized vial taken intravenously.; Other Names: Lyophilized solution
Experimental: Arm 2/Cohort 1: CFZ533 300 mg + Mycophenolate Mofetil (MMF) + Corticosteroids; Eligible patients were randomized to CFZ533 300 mg sc bi-weekly (Q2W) + Mycophenolate Mofetil (MMF) + Corticosteroids. Patients randomized to CFZ533 arms were administered the first dose of CFZ533 at 30 mg/kg IV pre- or intra-operatively (Day 1) with completion of the infusion within one hour of unclamping and prior graft revascularization, in combination with MMF and corticosteroids. MMF and corticosteroids might be initiated prior to surgery according to local practice. A second IV dose of CFZ533 at 15 mg/kg was infused at Day 5 post-transplant. Subsequent doses starting at Day 15: 300 mg sc (1 injection of 2 mL CFZ533 at 150 mg/mL, and 1 injection of 2 mL of the generic placebo) sc, Q2W, up to a planned Month 59.5 visit.	Biological: CFZ533 - Cohort 1/Cohort 2; CFZ533 was administered either by intravenous infusion or subcutaneous injection; Drug: Mycophenolate Mofetil (MMF); Per local practice, 250 mg or 500 mg taken orally or 500 mg taken intravenously.; Drug: Corticosteroids (CS); Taken either orally or intravenously.; Drug: Induction therapy: basiliximab; Lyophilized solution taken intravenously; Drug: Induction therapy: rabbit anti-thymocyte globulin (rATG); Lyophilized vial taken intravenously.; Other Names: Lyophilized solution; Drug: Placebo 1 mL; Solution taken subcutaneously and was used for blinding of the CFZ533 doses.
Active Comparator: Arm 3/Cohort 1: Control/Standard of Care: Tacrolimus (TAC) + MMF + Corticosteroids; Patients randomized to the TAC control arm were initiated on a TAC-based regimen with MMF and corticosteroids.	Drug: Mycophenolate Mofetil (MMF); Per local practice, 250 mg or 500 mg taken orally or 500 mg taken intravenously.; Drug: Corticosteroids (CS); Taken either orally or intravenously.; Drug: Induction therapy: basiliximab; Lyophilized solution taken intravenously; Drug: Induction therapy: rabbit anti-thymocyte globulin (rATG); Lyophilized vial taken intravenously.; Other Names: Lyophilized solution; Drug: Tacrolimus; Standard of care immunosuppressive regimen
Experimental: Arm 1/Cohort 2: CFZ533 450 mg + MMF ± Corticosteroids; Eligible patients who were 6 to 24 months post renal transplantation and were on a stable regimen containing TAC+MMF/Enteric-coated mycophenolate sodium (EC-MPS)±CS were randomized to CFZ533 450 mg sc Q2W. On Day 1, patients randomized to Arm 1 were administered the 1st dose of CFZ533 at 30 mg/kg IV, concomitantly with MMF/EC-MPS and 50% of the current TAC dose. At Day 15, CFZ533 were administered sc at 450 mg (1 injection of 2 mL & 1 injection of 1 mL CFZ533 at 150 mg/mL) concomitantly with MMF/EC-MPS, and TAC reduced by a further 50%. By Day 29, patients were fully tapered off their TAC. Subsequent doses of 450 mg sc Q2W, were administered in combination with MMF/EC-MPS with or without corticosteroids, up to Month 59.5 visit.	Biological: CFZ533 - Cohort 1/Cohort 2; CFZ533 was administered either by intravenous infusion or subcutaneous injection; Drug: Corticosteroids (CS); Taken either orally or intravenously.; Drug: Maintenance population: EC-MPS; Tablet that is taken orally; Drug: Maintenance population: MMF; Tablet that is taken orally
Active Comparator: Arm 2/Cohort 2: TAC + MMF ± Corticosteroids; Patients received TAC-based regimen throughout the study.	Drug: Corticosteroids (CS); Taken either orally or intravenously.; Drug: Tacrolimus; Standard of care immunosuppressive regimen; Drug: Maintenance population: EC-MPS; Tablet that is taken orally; Drug: Maintenance population: MMF; Tablet that is taken orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Composite Efficacy Failure Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months Post-transplantation (Cohort 1)	The composite efficacy failure event is defined as any of the following: (1) biopsy-proven acute rejection (BPAR) or (2) graft loss or (3) death. BPAR (BANFF ≥ 1A) is based on the central and adjudicated assessments. Graft loss is defined as when the allograft was presumed lost on the day the participant started dialysis and was not able to subsequently be removed from dialysis or re-transplanted. If the participant underwent allograft nephrectomy prior to start of permanent dialysis, the day of the nephrectomy was day of graft loss.	12 Months
Percentage of Participants With Composite Efficacy Failure Event (BPAR, Graft Loss or Death) Over 12 Months Post-conversion (Cohort 2)	The composite efficacy failure event is defined as any of the following: (1) biopsy-proven acute rejection (BPAR) or (2) graft loss or (3) death. BPAR (BANFF ≥ 1A) is based on the central and adjudicated assessments. Graft loss is defined as when the allograft was presumed lost on the day the participant started dialysis and was not able to subsequently be removed from dialysis or re-transplanted. If the participant underwent allograft nephrectomy prior to start of permanent dialysis, the day of the nephrectomy was day of graft loss.	12 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohort 1: Mean Estimated Glomerular Filtration Rate (eGFR) ((MDRD4) at 12 Months Post-transplantation	In the de novo population (Cohort 1), the mean eGFR at Month 12 post-transplantation was the endpoint of interest. Estimated GFR using central laboratory serum creatinine values was calculated using the MDRD4 formula.	12 months
Cohort 2: Mean Change in Estimated Glomerular Filtration Rate (eGFR) ((MDRD4) at 12 Months Post-conversion	In the maintenance population (Cohort 2), a baseline kidney function and the mean change from baseline at Month 12 post-conversion of eGFR was the endpoint of interest. Estimated GFR using central laboratory serum creatinine values was calculated using the MDRD4 formula.	12 months
Free CFZ533 Plasma Concentrations Over Time (Cohort 1)	Pharmacokinetics were determined for free CFZ533 plasma concentrations during the treatment period.	Day 1-Pre-Dose to Month 30-Pre-Dose
Free CFZ533 Plasma Concentrations Over Time (Cohort 2)	Pharmacokinetics were determined for free CFZ533 plasma concentrations during the treatment period.	Day 1-Pre-Dose to Month 30-Pre-Dose
Semi-quantiative Analysis of Anti-CFZ533 Antibodes in Plasma (CFZ533 Treated Patients Only) (Cohort 1)	The presence of anti-CFZ533 antibodies was assessed using screening and confirmatory assays.	24 Months
Semi-quantiative Analysis of Anti-CFZ533 Antibodes in Plasma (CFZ533 Treated Patients Only) (Cohort 2)	The presence of anti-CFZ533 antibodies was assessed using screening and confirmatory assays.	24 Months

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): November 28, 2018
• Primary Completion (Actual): October 29, 2021
• Study Completion (Actual): October 29, 2021

Study Registration Dates

• First Submitted: June 4, 2018
• First Submitted That Met QC Criteria: September 6, 2018
• First Posted (Actual): September 10, 2018

Study Record Updates

• Last Update Posted (Actual): March 23, 2026
• Last Update Submitted That Met QC Criteria: March 2, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Renal transplantation; allograft rejection; transplant rejection; CFZ533; Kidney Transplant Rejection; CNI-free immunosuppression
• Additional Relevant MeSH Terms: Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Organic Chemicals; Fatty Acids; Lipids; Acids, Acyclic; Carboxylic Acids; Macrolides; Lactones; Caproates; Mycophenolic Acid; Tacrolimus; Adrenal Cortex Hormones
• Other Study ID Numbers: CCFZ533A2201 (Novartis); 2017-003607-22 (EudraCT Number)

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