Clinical trial NCT03781414: 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
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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Liver Transplant Rejection
Keywords: Liver transplantation
de novo recipients
deceased donor
CFZ533
CNI-free immunosuppression
Transplant rejection
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2018-12-19
Enrollment: 129
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

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.

Primary outcomes:
measure: Percentage of Patients With Composite Event (Biopsy Proven Acute Rejection (BPAR), Graft Loss or Death) Over 12 Months
timeFrame: Baseline to Month 12
Secondary outcomes:
measure: Mean Change in Estimated Glomerular Filtration Rate (eGFR) From Randomization to Month 12
timeFrame: Baseline to Month 12
measure: Number of Participants With Treatment Emergent Adverse Events
timeFrame: 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.
measure: Percentage of Patients With Dose Interruptions and Permanent Discontinuation of Study Treatment
timeFrame: Baseline to Month 24
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital - Aurora
state: Colorado
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Saint Louis
country: United States
facility: Wash U School of Medicine
state: Missouri
city: Durham
country: United States
facility: Duke Univ Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: University Of Cincinnati
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina MUSC
state: South Carolina
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Caba
country: Argentina
facility: Novartis Investigative Site
state: Buenos Aires
city: Gent
country: Belgium
facility: Novartis Investigative Site
city: Prague 4
country: Czechia
facility: Novartis Investigative Site
city: Chambray les Tours
country: France
facility: Novartis Investigative Site
city: Lille
country: France
facility: Novartis Investigative Site
city: Montpellier
country: France
facility: Novartis Investigative Site
city: Villejuif
country: France
facility: Novartis Investigative Site
city: Regensburg
country: Germany
facility: Novartis Investigative Site
state: Bavaria
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Muenster
country: Germany
facility: Novartis Investigative Site
city: Budapest
country: Hungary
facility: Novartis Investigative Site
city: Pisa
country: Italy
facility: Novartis Investigative Site
state: PI
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
state: Zuid Holland
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Hospitalet de Llobregat
country: Spain
facility: Novartis Investigative Site
state: Barcelona
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: