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)

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

This study will allow assessment of the ability of CFZ533 to replace Calcineurin inhibitors (CNIs) in terms of anti-rejection efficacy, while providing better renal function with a better safety and tolerability profile. Results of this study will be used to inform the CFZ533 dose and regimen selection for investigation in later phases of clinical development.

Study Overview

• Status: Completed
• Conditions: Kidney Transplant Rejection
• Intervention / Treatment: Biological: CFZ533 - MMF - CS; Drug: Tacrolimus - MMF - +/- corticosteroids

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

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, W3400ABH
    • Novartis Investigative Site
  • Cordoba, Argentina, X5016KEH
    • Novartis Investigative Site
  • Corrientes, Argentina, W3400
    • 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
  • RS
    • Porto Alegre, RS, Brazil, 90020-090
      • Novartis Investigative Site
  • SP
    • Sao Paulo, SP, Brazil, 05403 000
      • Novartis Investigative Site
    • São Paulo, SP, Brazil, 04038-002
      • Novartis Investigative Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Novartis Investigative Site
• Czechia
  • Prague 4, Czechia, 140 21
    • Novartis Investigative Site
• France
  • Bordeaux Cedex, France, 33067
    • Novartis Investigative Site
  • Creteil, France, 94010
    • Novartis Investigative Site
  • Grenoble, France, 38043
    • Novartis Investigative Site
  • Lyon, France, 69437
    • Novartis Investigative Site
  • Nantes Cedex 1, France, 44093
    • Novartis Investigative Site
  • Paris cedex 15, France, 75015
    • Novartis Investigative Site
  • Toulouse Cedex 4, 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, 1085
    • Novartis Investigative Site
  • Debrecen, Hungary, 4032
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20132
      • Novartis Investigative Site
  • RM
    • Roma, RM, Italy, 00133
      • Novartis Investigative Site
• Japan
  • Osaka, Japan, 545-8586
    • Novartis Investigative Site
  • Aichi
    • Nagakute-city, Aichi, Japan, 480-1195
      • Novartis Investigative Site
    • Nagoya-city, Aichi, Japan, 466-8650
      • Novartis Investigative Site
  • Hokkaido
    • Sapporo city, Hokkaido, Japan, 060 8648
      • Novartis Investigative Site
    • Sapporo-city, Hokkaido, Japan
      • Novartis Investigative Site
  • Kanagawa
    • Yokohama city, Kanagawa, Japan, 232 0024
      • Novartis Investigative Site
  • Kumamoto
    • Kumamoto-city, Kumamoto, Japan, 861-8520
      • Novartis Investigative Site
  • Okinawa
    • Tomigusuku, Okinawa, Japan, 901-0224
      • Novartis Investigative Site
  • Osaka
    • Suita city, Osaka, Japan, 565 0871
      • Novartis Investigative Site
• Korea, Republic of
  • Seoul, Korea, Republic of, 03080
    • Novartis Investigative Site
• Latvia
  • Riga, Latvia, LV 1002
    • Novartis Investigative Site
• Netherlands
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3000 CA
    • Novartis Investigative Site
  • The Netherlands
    • Utrecht, The Netherlands, Netherlands, 3508 GA
      • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0424
    • Novartis Investigative Site
• Spain
  • Zaragoza, Spain, 50009
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08035
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08036
      • Novartis Investigative Site
    • Barcelona, Catalunya, Spain, 08003
      • Novartis Investigative Site
  • Cataluña
    • L'Hospitalet de Llobregat, Cataluña, Spain, 08907
      • Novartis Investigative Site
  • Islas Baleares
    • Palma de Mallorca, Islas Baleares, Spain, 07014
      • Novartis Investigative Site
• Sweden
  • Göteborg, Sweden, SE-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
      • Novartis Investigative Site
  • Missouri
    • Saint 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: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Written informed consent obtained before any assessment.
• Male or female patient ≥ 18 years old.
• Up to date vaccination as per local immunization schedules.
• Recipients of a kidney transplant
• Recipients of a primary kidney transplant from a heart-beating deceased, living unrelated or non-HLA identical living related donors.

Exclusion Criteria:

• Multi-organ transplant recipients or prior kidney transplant.
• Recipients of an organ from a non-heart beating donor.
• Recipient of an organ from an HLA identical living related donor.
• ABO incompatible or complement-dependent lymphocytotoxic (CDC) crossmatch positive transplant
• Recipients of kidneys from donors who are older than 65 years.
• Recipients of kidneys from donors with terminal serum creatinine > 2 mg/dL.
• Patients at high immunological risk for rejection
• Patient who is anti-HIV positive, HBsAg-positive or anti-HCV positive (without proof of sustained viral response (SVR) after anti-HCV treatment).
• Recipient of a kidney from a donor who tests positive for HIV, HBsAg/HBc positive or HCV.
• A negative Epstein Barr virus (EBV) test.
• 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.

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 dose A+ MMF + Corticosteroids	Biological: CFZ533 - MMF - CS; Comparison with standard of care immunosuppression
Experimental: Arm 2/Cohort 1; CFZ533 dose B + MMF + Corticosteroids	Biological: CFZ533 - MMF - CS; Comparison with standard of care immunosuppression
Active Comparator: Arm 3/Cohort 1; Control/Standard of Care: TAC + MMF + Corticosteroids	Drug: Tacrolimus - MMF - +/- corticosteroids; Standard of care immunosupprevive regimen
Experimental: Arm 1/Cohort 2; CFZ533 dose C + MMF ± Corticosteroids	Biological: CFZ533 - MMF - CS; Comparison with standard of care immunosuppression
Active Comparator: Arm 2/Cohort 2; Tac + MMF ± Corticosteroids	Drug: Tacrolimus - MMF - +/- corticosteroids; Standard of care immunosupprevive regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with composite event (BPAR, Graft Loss or Death)	Cohorts 1 and 2-Proportion of patients with composite event (BPAR, Graft Loss or Death) over 12 months	Month 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cohorts 1 and 2-Mean eGFR over 12 months	Renal function at Month 12	Baseline to month 12
Cohorts 1 and 2-Cohorts 1 and 2-safety of CFZ533 regimens compared to a tacrolimus based regimen	Proportion of patients with AEs, SAEs, infections, malignancies, thromboembolic events, major adverse cardiovascular events, new onset diabetes mellitus (NODM).	Baseline to month 12
Cohorts 1 and 2-Cohorts 1 and 2 - tolerability of CFZ533 regimens compared to a tacrolimus based regimen	Tolerability assessment by rate of premature discontinuation from study, premature discontinuation of study drug, dose interruption and dose adjustment	Baseline to month 12
Cohorts 1 and 2-pharmacokinetics of CFZ533 during the 60 months treatment period and explore the dose-exposure relationship	Free CFZ533 plasma concentrations over time	Baseline to month 60
Cohorts 1 and 2-immunogenicity of CFZ533 during the 60 months treatment period	Semi-quantitative analysis of anti-CFZ533 antibodies in plasma	Baseline to month 60

Collaborators and Investigators

• Sponsor: 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): June 13, 2022
• Last Update Submitted That Met QC Criteria: June 8, 2022
• Last Verified: June 1, 2022

More Information

Terms related to this study

• Keywords: Renal transplantation, CFZ533, CNI-free immunosuppression, transplant rejection, allograft rejection.
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Calcineurin Inhibitors; Tacrolimus
• Other Study ID Numbers: CCFZ533A2201 (Other Identifier: Novartis); 2017-003607-22 (EudraCT Number); 03663335 (Other Identifier: Clinicaltrials.gov)

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