TerminatedNCT03781414CONTRAIL IUpdated May 16, 2025Results posted

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

A Phase 2 interventional study of CFZ533 and Tacrolimus - MMF - corticosteroids in Liver Transplant Rejection, sponsored by Novartis Pharmaceuticals. Terminated at 29 sites in 10 countries. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2025-05-16.

Sponsored by Novartis Pharmaceuticals · Phase 2, Interventional, and Treatment

Why this study was terminated

The study was terminated following less favorable efficacy by Iscalimab (CFZ533) in liver transplant patients compared to tacrolimus.

Phase: Phase 2
Study type: Interventional
Enrollment: 129
Allocation: Randomized
Ages: 18 Years to 70 Years
Sex: All

Study summary

This was a multicenter, open-label, active-controlled study to evaluate the efficacy, safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of two CFZ533 maintenance doses in de novo liver transplant recipients.

Read the detailed description

The study was designed as a randomized, 36-month clinical trial comprised of:

A screening period (up to 2 months) starting from informed consent, screening visit, and including successful liver transplantation (LTx).
A run-in treatment period following successful transplantation that ended on the day of randomization or randomization failure, at Day 8 (with visit window of +/- 2 days) post-LTx.
The primary treatment period (Treatment Period 1) starting at randomization Day 8 +/- 2 post-LTx up to Month 12 followed by a 12-month follow-up treatment period (Treatment Period 2) until Month 24.
The long-term extension period (Treatment Period 3) starting post Month 24 until the end of the study (EOS).
A minimum 12-week safety follow-up period for all patients after EOS.

The study was terminated following less favorable efficacy by Iscalimab (CFZ533) in liver transplant patients compared to tacrolimus.

Conditions studied

Liver Transplant Rejection

Keywords

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

In context

Lead sponsor

Novartis Pharmaceuticals is the lead sponsor of 2,673 studies on the registry; 228 are open to participants now.

Of its 576 completed or terminated interventional studies of FDA-regulated products, 431 (75%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years to 70 Years
Sexes eligible: All
Accepts healthy volunteers: No

Eligibility criteria

Key Inclusion Criteria:

Screening period up to liver transplantation:

Written informed consent obtained before any assessment.
Male or female patients 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.
Transplantation to occur within defined screening period following informed consent signature.

At randomization (Day 8 +/- 2):

Recipients with no active HCV and HBV replication.
Allograft is functioning at an acceptable level by the time of randomization as defined by AST, ALT and 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.
Recipients who have been initiated on an immunosuppressive regimen that contains TAC, mycophenolate mofetil (MMF) and corticosteroids (CS) as per protocol.

Key Exclusion Criteria:

Screening period up to liver transplantation:

Use of other investigational drugs at screening within 30 days or 5 half-lives of screening.
Recipients of multiple solid organ or islet cell transplants, or recipients that have previously received a tissue transplant, or a combined liver-kidney transplant.
Recipients of a liver from a donor after cardiac death (DCD), from a living donor, or of a split liver.
Recipient who tested negative for Epstein Barr virus (EBV) within 28 days prior to baseline visit.
Recipients receiving an ABO incompatible allograft.
History of malignancy of any organ system (except hepatocellular carcinoma (HCC) or localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there was evidence of local recurrence or metastases.
Hepatocellular carcinoma that did not fulfill Milan criteria (1 nodule ≤ 5 cm, 2-3 nodules all ≤ 3 cm, without evidence of metastatic disease or vascular invasion) at the time of transplantation.
Recipients transplanted for acute liver failure (does not apply to acute on chronic liver failure).
Any use of antibody induction therapy, or use of any immunosuppressive medications (or other medications prohibited by the protocol).
Patients who have received a live vaccine within four weeks prior to transplantation.
Recipients with HIV positive donor.
Recipients with donors HBsAg positive.
Recipients who were HCV antibody-positive without documented sustained viral response (SVR) at 12 weeks after finishing anti HCV treatment (e.g., direct-acting antivirals).
Recipients with HCV RNA-positive donors.
Recipients with donors with macrovesicular steatosis > 30%.
Pregnant or nursing (lactating) women.

At randomization (Day 8 +/- 2):

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. Absence of any graft vascular thrombosis or occlusion (by diagnostic method used at the site to assess vascular patency) must be confirmed by imaging prior to randomization.
Recipients with platelet count \< 50,000/mm3.
Recipients with 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.
Recipients who are in a critical care setting at the time of randomization requiring life support measures such as mechanical ventilation, dialysis, requirement of vasopressor agents.
Recipients who were on renal replacement therapy at randomization.
Any episode of acute rejection or suspected rejection prior to randomization.
HCC patients whose explanted liver graft pathology report shows (i) pathologic Tumor-Node-Metastasis (pTNM) stage beyond T2N0M0, (ii) presence of mixed carcinoma, (iii) microvascular invasion despite pTNM stage.
Patients with body weight \< 30 kg or > 180 kg.

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel assignment
Masking: None (open label)
Enrollment: 129 participants (actual)

Study arms

Active comparator
TAC Control
Tacrolimus (TAC) + Mycophenolate mofetil (MMF) + Corticosteroids (CS) up to End of Study (EOS). Initial TAC target trough were between 5-15 ng/mL during the run-in period. From randomization onwards, the TAC levels were adjusted as per local label.
Drug: Tacrolimus - MMF - corticosteroids
Experimental
CFZ533 600 mg regimen
Loading doses of 30 mg/kg IV on Day 8 (with +/- 2 days window), and 15 mg/kg IV on Day 15. The subcutaneous (SC) administration of 600 mg (2 injections of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.
Biological: CFZ533
Experimental
CFZ533 300 mg regimen
Single loading dose of 30 mg/kg IV on Day 8 (with +/- 2 days window). The SC administration of 300 mg (1 injection of 2 mL CFZ533 at 150 mg/mL) every 2 weeks started on Day 29, in combination with MMF and CS up to EOS.
Biological: CFZ533

Interventions

BiologicalCFZ533
Comparison with standard of care immunosuppression
DrugTacrolimus - MMF - corticosteroids
Standard of care immunosuppresive regimen

What researchers measure

Primary outcomes

Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months
The occurrence of biopsy proven acute rejection (BPAR) was evaluated based on central pathologist evaluation. Graft loss and death was evaluated as per local evaluation.
Time frame: Baseline to Month 12

Secondary outcomes

Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12
Renal function as measured by estimated Glomerular Filtration Rate (eGFR) was evaluated using the MDRD formula: eGFR = 175 x (serum concentration of creatinine (SCr))-1.154 x (age)-0.203 x 0.742 \[if female\] x 1.212 \[if Black\].
Time frame: Baseline to Month 12
Number of Participants With Treatment Emergent Adverse Events
The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs), Deaths due to AEs and TEAEs leading to discontinuation, through the monitoring of relevant clinical and laboratory safety parameters.
Time frame: Baseline up to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks.
Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment
The number and percentage of participants with dose changes (MMF and TAC), dose interruptions (only in cases of ascites drainage), and permanent discontinuation was summarized. In the CFZ533 arms, during the immediate peri and post-transplant period, TAC was given to provide immunological coverage but TAC needed to be completely weaned off by Day 22.
Time frame: Baseline to Month 24

Results

Posted Jul 3, 2024

Participant flow

The patients were enrolled at 3 sites in Argentina, 1 in Belgium, 1 in Czech Republic, 4 in France, 4 in Germany, 1 in Hungary, 1 in Italy, 1 in The Netherlands, 4 in Spain and 9 in United States.

Participant flow — Overall Study
Milestone	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF)	TAC Control (TAC + MMF)
Started	48	48	32
Safety set (saf)	48	47	32
Completed	0	0	0
Not completed	48	48	32
Withdrew: Study terminated by sponsor	39	34	25
Withdrew: Adverse event	3	6	3
Withdrew: Physician decision	2	0	1
Withdrew: Withdrawal by subject	2	3	3
Withdrew: Death	1	4	0
Withdrew: Lost to follow-up	1	1	0

Outcome measures

PrimaryPercentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months

The occurrence of biopsy proven acute rejection (BPAR) was evaluated based on central pathologist evaluation. Graft loss and death was evaluated as per local evaluation.

Time frame:: Baseline to Month 12
Reported as:: Count of participants · Participants

Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months
Participants	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF)	TAC Control (TAC + MMF)
Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months	8	12	3

Statistical analysis

CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) vs TAC Control (TAC + MMF) · Rate difference: 0.0759 · 95% CI -0.0729 to 0.2165
CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) vs TAC Control (TAC + MMF) · Rate difference: 0.1696 · 95% CI 0.0072 to 0.3276

SecondaryMean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12

Renal function as measured by estimated Glomerular Filtration Rate (eGFR) was evaluated using the MDRD formula: eGFR = 175 x (serum concentration of creatinine (SCr))-1.154 x (age)-0.203 x 0.742 \[if female\] x 1.212 \[if Black\].

Time frame:: Baseline to Month 12
Reported as:: Mean · mL/min/1.73 m^2

Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12
mL/min/1.73 m^2	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF)	TAC Control (TAC + MMF)
Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12	2.05 (-60.4 to 71.5)	-9.31 (-55.8 to 28.7)	-14.74 (-104.0 to 20.6)

SecondaryNumber of Participants With Treatment Emergent Adverse Events

The distribution of adverse events was done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs), Deaths due to AEs and TEAEs leading to discontinuation, through the monitoring of relevant clinical and laboratory safety parameters.

Time frame:: Baseline up to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks.
Reported as:: Count of participants · Participants

Number of Participants With Treatment Emergent Adverse Events
Participants	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF)	TAC Control (TAC + MMF)
TEAEs	48	44	32
TESAEs	30	29	20
Fatal TESAEs	1	4	0
TEAEs leading to discontinuation	14	17	8

SecondaryPercentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment

The number and percentage of participants with dose changes (MMF and TAC), dose interruptions (only in cases of ascites drainage), and permanent discontinuation was summarized. In the CFZ533 arms, during the immediate peri and post-transplant period, TAC was given to provide immunological coverage but TAC needed to be completely weaned off by Day 22.

Time frame:: Baseline to Month 24
Reported as:: Count of participants · Participants

Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment
Participants	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF)	TAC Control (TAC + MMF)
CFZ533: Subjects with dose interrupted	8	5	—
CFZ533: Subjects with permanent discontinuation of study treatment	2	3	—
TAC: Subjects with dose interrupted	3	3	6
TAC: Subjects with permanent discontinuation of study treatment	4	8	4
MMF: Subjects with dose interrupted	18	23	15
MMF: Subjects with permanent discontinuation of study treatment	9	5	1

Post-hocAll Collected Deaths

On-treatment deaths were reported from first dose of study treatment to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks. Post-treatment deaths were collected in the post treatment period from 15 weeks after last dose of study medication (CFZ533 participants, Arms 2 \& 3) and from 13 weeks for TAC participants (Arm 1), up to approx. 184 weeks. These are not considered Adverse Events.

Time frame:: On-treatment deaths: Up to approximately 184 weeks. Post-treatment deaths: Up to approximately 184 weeks.
Reported as:: Count of participants · Participants

All Collected Deaths
Participants	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF)
On-treatment deaths	1	3
Post-treatment deaths	0	1
All deaths	1	4

Adverse events

Collected over On-treatment adverse events and deaths were reported from first dose of study treatment to 14 weeks after last dose of study medication (CFZ533 participants) and until 12 weeks for TAC participants, up to approx. 184 weeks. Post-treatment deaths were collected in the post treatment period from 15 weeks after last dose of study medication (CFZ533 participants) and from 13 weeks for TAC participants, up to approx. 184 weeks. These are not considered Adverse Events.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) (On-Treatment)	1/48 (2.1%)	30/48 (62.5%)	45/48 (93.8%)
CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) (On-Treatment)	3/47 (6.4%)	29/47 (61.7%)	42/47 (89.4%)
TAC Control (TAC + MMF) (On-Treatment)	0/32 (0%)	20/32 (62.5%)	30/32 (93.8%)
CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) (Post-Treatment)	0/47 (0%)	—	—
CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) (Post-Treatment)	1/44 (2.3%)	—	—
TAC Control (TAC + MMF) (Post-Treatment)	0/32 (0%)	—	—

Most frequent serious events

Showing 10 of 135

Most frequent serious events
Event	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) (On-Treatment)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) (On-Treatment)	TAC Control (TAC + MMF) (On-Treatment)	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) (Post-Treatment)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) (Post-Treatment)	TAC Control (TAC + MMF) (Post-Treatment)
PyrexiaGeneral disorders	5/48	5/47	0/32	—	—	—
Transplant rejectionImmune system disorders	4/48	2/47	2/32	—	—	—
COVID-19Infections and infestations	4/48	2/47	2/32	—	—	—
Hepatic enzyme increasedInvestigations	0/48	3/47	1/32	—	—	—
AscitesGastrointestinal disorders	2/48	0/47	2/32	—	—	—
Cytomegalovirus infectionInfections and infestations	3/48	0/47	0/32	—	—	—
Incisional herniaInjury, poisoning and procedural complications	1/48	1/47	2/32	—	—	—
Hepatic artery stenosisHepatobiliary disorders	0/48	2/47	0/32	—	—	—
Graft versus host diseaseImmune system disorders	0/48	2/47	0/32	—	—	—
Cytomegalovirus viraemiaInfections and infestations	0/48	2/47	1/32	—	—	—

Most frequent other events

Showing 10 of 81

Most frequent other events
Event	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) (On-Treatment)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) (On-Treatment)	TAC Control (TAC + MMF) (On-Treatment)	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF) (Post-Treatment)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF) (Post-Treatment)	TAC Control (TAC + MMF) (Post-Treatment)
LeukopeniaBlood and lymphatic system disorders	17/48	16/47	9/32	—	—	—
COVID-19Infections and infestations	15/48	15/47	8/32	—	—	—
NeutropeniaBlood and lymphatic system disorders	14/48	10/47	4/32	—	—	—
DiarrhoeaGastrointestinal disorders	12/48	8/47	9/32	—	—	—
Abdominal painGastrointestinal disorders	5/48	7/47	8/32	—	—	—
Oedema peripheralGeneral disorders	12/48	6/47	4/32	—	—	—
Urinary tract infectionInfections and infestations	4/48	4/47	7/32	—	—	—
HeadacheNervous system disorders	5/48	10/47	7/32	—	—	—
TremorNervous system disorders	5/48	6/47	7/32	—	—	—
ArthralgiaMusculoskeletal and connective tissue disorders	9/48	6/47	2/32	—	—	—

Baseline characteristics

Age, Continuous
Age, Continuous(Years)	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF)	TAC Control (TAC + MMF)	Total
Mean	56.7 ± 9.94	56.2 ± 6.98	54.0 ± 9.90	55.8 ± 8.92

Sex: Female, Male
Sex: Female, Male(Participants)	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF)	TAC Control (TAC + MMF)	Total
Female	11	15	8	34
Male	37	33	24	94

Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)	CFZ533 300 mg Regimen (CFZ533 300 mg + MMF)	CFZ533 600 mg Regimen (CFZ533 600 mg + MMF)	TAC Control (TAC + MMF)	Total
White	45	46	29	120
Black or African American	3	2	2	7
Unknown	0	0	1	1

Study locations

29 sites

University of Southern California
Los Angeles, California 90033, United States
University of Colorado Hospital - Aurora
Aurora, Colorado 80045, United States
Northwestern University
Chicago, Illinois 60611, United States
Henry Ford Hospital
Detroit, Michigan 48202 2689, United States
Wash U School of Medicine
Saint Louis, Missouri 63110, United States
Duke Univ Medical Center
Durham, North Carolina 27710, United States
University Of Cincinnati
Cincinnati, Ohio 45267, United States
Medical University of South Carolina MUSC
Charleston, South Carolina 29425, United States
The Methodist Hospital
Houston, Texas 77030, United States
Novartis Investigative Site
Caba, Buenos Aires C1118AAT, Argentina
Novartis Investigative Site
Caba, Buenos Aires C1181ACH, Argentina
Novartis Investigative Site
Caba, Buenos Aires C1280AEB, Argentina
Novartis Investigative Site
Gent, 9000, Belgium
Novartis Investigative Site
Prague 4, 146 24, Czechia
Novartis Investigative Site
Chambray les Tours, 37170, France
Novartis Investigative Site
Lille, 59037, France
Novartis Investigative Site
Montpellier, 34295, France
Novartis Investigative Site
Villejuif, 94805, France
Novartis Investigative Site
Regensburg, Bavaria 93053, Germany
Novartis Investigative Site
Berlin, 13353, Germany
Novartis Investigative Site
Hamburg, 20246, Germany
Novartis Investigative Site
Muenster, 48149, Germany
Novartis Investigative Site
Budapest, H-1083, Hungary
Novartis Investigative Site
Pisa, PI 56124, Italy
Novartis Investigative Site
Rotterdam, Zuid Holland 3015 GD, Netherlands
Novartis Investigative Site
Sevilla, Andalucia 41013, Spain
Novartis Investigative Site
Hospitalet de Llobregat, Barcelona 08907, Spain
Novartis Investigative Site
Barcelona, Catalunya 08036, Spain
Novartis Investigative Site
Madrid, 28009, Spain

References and documents

Study documents

Study protocol · Mar 5, 2021
Statistical analysis plan · Nov 24, 2023

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: Yes — 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

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on May 16, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT03781414
Lead sponsor: Novartis Pharmaceuticals
Responsible party: Sponsor
First posted: Dec 19, 2018
Start date: Oct 7, 2019
Primary completion: Apr 20, 2023
Completion: Apr 20, 2023
Results posted: Jul 3, 2024
Last update: May 16, 2025

Study contacts

Novartis Pharmaceuticals

study director · Novartis Pharmaceuticals

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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