CONTRAIL I: 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

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT03781414

Collaborator

(none)

132

Enrollment

Locations

Arms

86.8

Anticipated Duration (Months)

4.6

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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

Actual Enrollment :

132 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.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 an 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 :

Oct 7, 2019

Anticipated Primary Completion Date :

Jul 1, 2022

Anticipated Study Completion Date :

Jan 1, 2027

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

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

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

Secondary Outcome Measures

Mean eGFR at 12 months post-transplantation [Baseline to month 12]
Renal function at Month 12
Proportion of patients with AEs and SAEs [Baseline to month 12 and month 24]
Proportion of patients with AEs, SAEs, AEs related to study drug, AEs of special interest
Proportion of patients with premature discontinuation from study and premature discontinuation of study drug [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

Criteria

Ages Eligible for Study:

18 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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, Total Bilirubin, and Alkaline Phosphatase levels ≤ 5 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Los Angeles	California	United States	90033
2	Novartis Investigative Site	Aurora	Colorado	United States	80045
3	Novartis Investigative Site	Chicago	Illinois	United States	60611
4	Novartis Investigative Site	Detroit	Michigan	United States	48202
5	Novartis Investigative Site	Saint Louis	Missouri	United States	63110
6	Novartis Investigative Site	Durham	North Carolina	United States	27710
7	Novartis Investigative Site	Cincinnati	Ohio	United States	45267
8	Novartis Investigative Site	Charleston	South Carolina	United States	29425
9	Novartis Investigative Site	Houston	Texas	United States	77030
10	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1118AAT
11	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1181ACH
12	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1280AEB
13	Novartis Investigative Site	Gent		Belgium	9000
14	Novartis Investigative Site	Praha 4	Czech Republic	Czechia	140 21
15	Novartis Investigative Site	Chambray les Tours		France	37044
16	Novartis Investigative Site	Lille Cedex		France	59 037
17	Novartis Investigative Site	Montpellier		France	34295
18	Novartis Investigative Site	Villejuif		France	94805
19	Novartis Investigative Site	Regensburg	Bavaria	Germany	93053
20	Novartis Investigative Site	Berlin		Germany	13353
21	Novartis Investigative Site	Hamburg		Germany	20246
22	Novartis Investigative Site	Muenster		Germany	48149
23	Novartis Investigative Site	Budapest		Hungary	1085
24	Novartis Investigative Site	Pisa	PI	Italy	56124
25	Novartis Investigative Site	Rotterdam		Netherlands	3015 CE
26	Novartis Investigative Site	Sevilla	Andalucia	Spain	41013
27	Novartis Investigative Site	L Hospitalet De Llobregat	Cataluna	Spain	08907
28	Novartis Investigative Site	Barcelona	Catalunya	Spain	08036
29	Novartis Investigative Site	Madrid		Spain	28009