Liver Transplant RejectionPhase 2CONTRAIL INCT03781414
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 study testing CFZ533 and Tacrolimus - MMF - corticosteroids in people with Liver Transplant Rejection, run by Novartis Pharmaceuticals at 29 sites in 10 countries.
Trial 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 more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Liver Transplant Rejection
- What is being tested?
- CFZ533 and Tacrolimus - MMF - corticosteroids
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 129 participants
- Where
- 29 sitesin 10 countries
- Study dates
- 7 Oct 2019to 20 Apr 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
Show all 28Show fewer
- 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.
Trial locations and contacts
29 sites in 10 countries.
29 sites in 10 countries
United States9 sites
University of Colorado Hospital - Aurora
Aurora, Colorado, 80045
Medical University of South Carolina MUSC
Charleston, South Carolina, 29425
Northwestern University
Chicago, Illinois, 60611
University Of Cincinnati
Cincinnati, Ohio, 45267
Henry Ford Hospital
Detroit, Michigan, 48202 2689
Duke Univ Medical Center
Durham, North Carolina, 27710
The Methodist Hospital
Houston, Texas, 77030
University of Southern California
Los Angeles, California, 90033
Wash U School of Medicine
St Louis, Missouri, 63110
France4 sites
Novartis Investigative Site
Chambray-lès-Tours, 37170
Novartis Investigative Site
Lille, 59037
Novartis Investigative Site
Montpellier, 34295
Novartis Investigative Site
Villejuif, 94805
Germany4 sites
Novartis Investigative Site
Berlin, 13353
Novartis Investigative Site
Hamburg, 20246
Novartis Investigative Site
Münster, 48149
Novartis Investigative Site
Regensburg, Bavaria, 93053
Spain4 sites
Novartis Investigative Site
Barcelona, Catalonia, 08036
Novartis Investigative Site
L'Hospitalet de Llobregat, Barcelona, 08907
Novartis Investigative Site
Madrid, 28009
Novartis Investigative Site
Seville, Andalusia, 41013
Argentina3 sites
Novartis Investigative Site
Caba, Buenos Aires, C1280AEB
Novartis Investigative Site
CABA, Buenos Aires, C1118AAT
Novartis Investigative Site
CABA, Buenos Aires, C1181ACH
Netherlands1 site
Novartis Investigative Site
Rotterdam, South Holland, 3015 GD
About this study
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 Additionalr Follow-up and a Long-term Extension (CONTRAIL I)
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
- Liver Transplant Rejection
- Being tested
- CFZ533, Tacrolimus - MMF - corticosteroids
- Keywords
- Liver transplantation, de novo recipients, deceased donor, CFZ533, CNI-free immunosuppression, Transplant rejection
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CFZ533Biological
Comparison with standard of care immunosuppression
Tacrolimus - MMF - corticosteroidsDrug
Standard of care immunosuppresive regimen
| Study group | Role | What they receive |
|---|---|---|
| TAC Control | Active comparator | 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. Receives: Drug: Tacrolimus - MMF - corticosteroids |
| CFZ533 600 mg regimen | Experimental | 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. Receives: Biological: CFZ533 |
| CFZ533 300 mg regimen | Experimental | 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. Receives: Biological: CFZ533 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to Month 12
Secondary outcomes (3)
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].
Measured: 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.
Measured: 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.
Measured: Baseline to Month 24
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Dec 2018
- Study start7 Oct 2019
- Primary completion20 Apr 2023
- Study completion20 Apr 2023
Why it stopped: The study was terminated following less favorable efficacy by Iscalimab (CFZ533) in liver transplant patients compared to tacrolimus.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Liver Transplant RejectionStudies of the same condition, open and under way.
- More trials run by Novartis PharmaceuticalsThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 129 participants (actual)
Sponsor and investigators
- Lead sponsor
- Novartis Pharmaceuticals
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Novartis Pharmaceuticals, Study director, Novartis Pharmaceuticals
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03781414
- Sponsor's protocol ID
- CCFZ533A2202
- Other IDs
- 2018-001836-24, 2018
- Acronym
- CONTRAIL I
- Status last verified
- May 2025
- First submitted
- 18 Dec 2018
- Last updated
- 16 May 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- 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
Study at a glance
From the registry record, last updated by the sponsor on 16 May 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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 Additionalr Follow-up and a Long-term Extension (CONTRAIL I)
- ClinicalTrials.gov ID
- NCT03781414
- Acronym / sponsor ID
- CONTRAIL I / CCFZ533A2202
- Conditions
- Liver Transplant Rejection
- Keywords
- Liver transplantation, de novo recipients, deceased donor, CFZ533, CNI-free immunosuppression, Transplant rejection
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: The study was terminated following less favorable efficacy by Iscalimab (CFZ533) in liver transplant patients compared to tacrolimus.
- Enrolment
- 129 participants (actual)
- Lead sponsor
- Novartis PharmaceuticalsIndustry (pharma, biotech, devices)
- Study start
- 7 Oct 2019 (actual)
- Primary completion
- 20 Apr 2023 (actual)
- Study completion
- 20 Apr 2023 (actual)
- First posted
- 19 Dec 2018 (actual)
- Results
- Posted 3 Jul 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| TAC Control | Active comparator | Drug: Tacrolimus - MMF - corticosteroidsTacrolimus (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. |
| CFZ533 600 mg regimen | Experimental | Biological: CFZ533Loading 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. |
| CFZ533 300 mg regimen | Experimental | Biological: CFZ533Single 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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- 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.
Key exclusion criteria (28 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CFZ533Comparison with standard of care immunosuppression | Biological | CFZ533 300 mg regimen, CFZ533 600 mg regimen |
| Tacrolimus - MMF - corticosteroidsStandard of care immunosuppresive regimen | Drug | TAC Control |
Primary outcome
Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months
Time frame: Baseline to Month 12
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.
3 secondary outcomes
Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12
Time frame: Baseline to Month 12
Number of Participants With Treatment Emergent Adverse Events
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
Time frame: Baseline to Month 24
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 16 May 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- A Plain Language Trial Summary is available on www.novctrd.comLink provided by the sponsor.
- Individual participant dataSharing planned: 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
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Novartis Pharmaceuticals study director
Novartis Pharmaceuticals
29 sites in 10 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing CFZ533 and Tacrolimus - MMF - corticosteroids in people with Liver Transplant Rejection, run by Novartis Pharmaceuticals at 29 sites in 10 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 16 May 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 29 sites in United States, France, Germany, Spain, Argentina and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 Jul 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months (time frame: Baseline to Month 12). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 16 May 2025.