Study of Efficacy, Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) of an Anti-CD40 Monoclonal Antibody, CFZ533, in Liver Transplant Recipients With Additional 12-month Follow-up and Long-term Extension (CONTRAIL I)

• ClinicalTrials.gov Identifier: NCT03781414
• Recruitment Status: Active, not recruiting
• First Posted: December 19, 2018
• Last Update Posted: January 18, 2023
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Liver Transplant Rejection	Biological: CFZ533; Drug: Tacrolimus - MMF - corticosteroids	Phase 2

Detailed Description:

This study will allow assessment of the ability of CFZ533 to replace Calcineurin inhibitors (CNIs) in terms of anti-rejection efficacy, while providing potentially better renal function with an expected similar 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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 131 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Study CCFZ533A2202 is a randomized, 12-month, active-controlled, multicenter, dose range finding study to evaluate the efficacy, safety, tolerability, PK and PD of CFZ533, as compared to standard of care comprised of tacrolimus, MMF and corticosteroids, with a 12-month additional follow up.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 12-month, Open-label, Multicenter, Randomized, Safety, Efficacy, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Two Regimens of Anti-CD40 Monoclonal Antibody, CFZ533 vs. Standard of Care Control, in Adult de Novo Liver Transplant Recipients With a 12-month Additional Follow-up and a Long-term Extension (CONTRAIL I)
• Actual Study Start Date: October 7, 2019
• Estimated Primary Completion Date: October 19, 2026
• Estimated Study Completion Date: October 19, 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Proportion of patients with composite event (BPAR, Graft Loss or Death) over 12 months [ Time Frame: Baseline to Month 12 ]
   Rate of composite efficacy failure

Secondary Outcome Measures :

1. To mean eGFR up to Month 24 post-transplantation [ Time Frame: Baseline to month 24 ]
   Renal function at Month 24 measured by Estimated Glomerular Filtration Rate (eGFR)
2. Proportion of patients with AEs and SAEs [ Time Frame: Baseline to month 12 and month 24 ]
   Proportion of patients with AEs, SAEs, AEs related to study drug
3. Proportion of patients with premature discontinuation from study and premature discontinuation of study drug [ Time Frame: Baseline to month 12 and month 24 ]
   Tolerability assessment by rate of premature discontinuation from study, premature discontinuation of study drug, dose interruption and dose adjustment

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

Screening period up to liver transplantation: -Written informed consent obtained before any assessment.

• Male or female subjects between 18 to 70 years of age.
• Recipients of a primary liver transplant from a deceased donor.
• Up to date vaccination as per local immunization schedules.
• Recipients tested negative for HIV.
• MELD score ≤30.

At randomization:

• Recipients with no active HCV and HBV replication (no detectable RNA/DNA by PCR).
• Allograft is functioning at an acceptable level by the time of randomization as defined by AST, ALT, Alkaline Phosphatase levels ≤ 5 times ULN and Total bilirubin ≤ 2 times ULN.
• Renal function (eGFR, MDRD-4 formula) ≥ 30 mL/min/1.73 m2 based on most recent post-transplant value prior to randomization.

Exclusion Criteria:

Screening period up to liver transplantation:

• Recipients of a liver from a donor after cardiac death (DCD), from a living donor, or of a split liver.
• A negative Epstein Barr virus (EBV) test.
• Recipients receiving an ABO incompatible allograft.
• History of malignancy of any organ system treated or untreated, within the past 5 years.
• Hepatocellular carcinoma that does not fulfill Milan criteria.
• Recipients transplanted for acute liver failure.
• Any use of antibody induction therapy, or use of any immunosuppressive medications
• Patients who have received a live vaccine within four weeks prior to transplantation.
• Recipients with donors HIV positive, HBsAg positive, HCV positive.
• Recipients with donors with hepatic steatosis > 30%.

At randomization:

• Any post-transplant history of thrombosis, occlusion or stent placement in any hepatic arteries, hepatic veins, portal vein or inferior vena cava at any time during the run-in period prior to randomization.
• Recipients with platelet count < 50,000/mm3, an absolute neutrophil count of < 1,000/mm³ or white blood cell count of < 2,000/mm³.
• Recipients with clinically significant systemic infection requiring use of intravenous (IV) antibiotics.
• Evidence of active tuberculosis (TB) infection.
• Any episode of acute rejection or suspected rejection prior to randomization.
• HCC participants whose explanted liver graft pathology report shows i) pTNM stage beyond T2N0M0, ii) presence of mixed carcinoma, iii) microvascular invasion despite pTNM stage.
• Participants with body weight &lt; 30 kg or &gt; 180 kg.

Contacts and Locations

Locations

United States, California

Novartis Investigative Site

Los Angeles, California, United States, 90033

United States, Colorado

Novartis Investigative Site

Aurora, Colorado, United States, 80045

United States, Illinois

Novartis Investigative Site

Chicago, Illinois, United States, 60611

United States, Michigan

Novartis Investigative Site

Detroit, Michigan, United States, 48202

United States, Missouri

Novartis Investigative Site

Saint Louis, Missouri, United States, 63110

United States, North Carolina

Novartis Investigative Site

Durham, North Carolina, United States, 27710

United States, Ohio

Novartis Investigative Site

Cincinnati, Ohio, United States, 45267

United States, South Carolina

Novartis Investigative Site

Charleston, South Carolina, United States, 29425

United States, Texas

Novartis Investigative Site

Houston, Texas, United States, 77030

Argentina

Novartis Investigative Site

Caba, Buenos Aires, Argentina, C1118AAT

Novartis Investigative Site

Caba, Buenos Aires, Argentina, C1181ACH

Novartis Investigative Site

Caba, Buenos Aires, Argentina, C1280AEB

Belgium

Novartis Investigative Site

Gent, Belgium, 9000

Czechia

Novartis Investigative Site

Praha 4, Czech Republic, Czechia, 140 21

France

Novartis Investigative Site

Chambray les Tours, France, 37044

Novartis Investigative Site

Lille Cedex, France, 59 037

Novartis Investigative Site

Montpellier, France, 34295

Novartis Investigative Site

Villejuif, France, 94805

Germany

Novartis Investigative Site

Regensburg, Bavaria, Germany, 93053

Novartis Investigative Site

Berlin, Germany, 13353

Novartis Investigative Site

Hamburg, Germany, 20246

Novartis Investigative Site

Muenster, Germany, 48149

Hungary

Novartis Investigative Site

Budapest, Hungary, 1085

Italy

Novartis Investigative Site

Pisa, PI, Italy, 56124

Netherlands

Novartis Investigative Site

Rotterdam, Netherlands, 3015 CE

Spain

Novartis Investigative Site

Sevilla, Andalucia, Spain, 41013

Novartis Investigative Site

L Hospitalet De Llobregat, Cataluna, Spain, 08907

Novartis Investigative Site

Barcelona, Catalunya, Spain, 08036

Novartis Investigative Site

Madrid, Spain, 28009

Sponsors and Collaborators

Novartis Pharmaceuticals

More Information

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03781414
• Other Study ID Numbers: CCFZ533A2202; 2018-001836-24 ( EudraCT Number ); CCFZ533A2202 ( Other Identifier: Novartis )
• First Posted: December 19, 2018
• Last Update Posted: January 18, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Plan Description

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect 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

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Liver transplantation; de novo recipients; deceased donor; CFZ533; CNI-free immunosuppression; Transplant rejection

Additional relevant MeSH terms:

Tacrolimus; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Calcineurin Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action