Clinical Trials Register

Summary
EudraCT Number:	2018-001836-24
Sponsor's Protocol Code Number:	CCFZ533A2202
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-02-20
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - PEI

A.2

EudraCT number

2018-001836-24

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study of the safety and efficacy of the drug CFZ533 (Iscalimab) in subjects who have received a liver transplant

A.3.2

Name or abbreviated title of the trial where available

CONTRAIL I

A.4.1

Sponsor's protocol code number

CCFZ533A2202

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03781414

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma GmbH
B.5.2	Functional name of contact point	Medizinischer Infoservice (MCC)
B.5.3	Address:
B.5.3.1	Street Address	Roonstrasse 25
B.5.3.2	Town/ city	Nürnberg
B.5.3.3	Post code	90429
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 911 273-12100
B.5.5	Fax number	+49 911 27312160
B.5.6	E-mail	infoservice.novartis@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Iscalimab
D.3.2	Product code	CFZ533
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Iscalimab
D.3.9.2	Current sponsor code	CFZ533
D.3.9.3	Other descriptive name	CFZ533
D.3.9.4	EV Substance Code	SUB130512
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Iscalimab
D.3.2	Product code	CFZ533
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Iscalimab
D.3.9.2	Current sponsor code	CFZ533
D.3.9.3	Other descriptive name	CFZ533
D.3.9.4	EV Substance Code	SUB130512
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	150
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Liver transplantation

E.1.1.1

Medical condition in easily understood language

Adult patients that receive a liver from another person (donor)

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10024715
E.1.2	Term	Liver transplant rejection
E.1.2	System Organ Class	10021428 - Immune system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To evaluate the rate of composite efficacy failure (Biopsy Proven Acute Rejection (BPAR), graft loss or death) with CFZ533 regimens compared to TAC Control at Month 12 post-transplantation.

E.2.2

Secondary objectives of the trial

-To evaluate the renal function with CFZ533 regimens compared to TAC Control at Month 12 post-transplantation.
-To evaluate eGFR and change in eGFR to Month 12 and Month 24 post-transplantation.
-To evaluate whether CFZ533 regimens have lower incidence rates over 12 and 24 months post-transplantation compared to TAC control arm for the following events:
- BPAR
- tBPAR
- AR
- Antibody mediated (humoral) rejection
- Graft Loss
- Death
-To assess the safety and tolerability of CFZ533 regimens compared to TAC control at Month 12 and Month 24.
-To assess the pharmacokinetics of multiple doses of CFZ533 over the 12-month and 24-month treatment and explore the dose-exposure relationship.
-Additional secondary objectives as per protocol

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Screening period up to liver transplantation:
-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 (based on laboratory values, using the United Network for Organ Sharing (UNOS) MELD calculator: https://unos.org/resources/allocation-calculators/).
-Transplantation to occur within defined screening period following
informed consent signature.
At randomization:
-Recipients with no active HCV and HBV replicationIncluded are
recipients with HCV antibody positive with no detectable HCV-RNA.
Recipients with Hepatitis B infection should have no detectable HBV
DNA. Cases of spontaneous HCV clearance should be discussed with sponsor
-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.
-Recipients who have been initiated on an immunosuppressive regimen that contains TAC, mycophenolate mofetil (MMF) and corticosteroids (CS) as per protocol.

E.4

Principal exclusion criteria

Screening period up to liver transplantation:
-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.
-Recipients negative for Epstein Barr virus (EBV) test.
-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 is evidence of local recurrence or metastases.
-Hepatocellular carcinoma that does 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 donors HIV positive.
-Recipients with donors HBsAg positive.
-Recipients who are 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

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 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 (after anti-TB treatment, patients with history of latent TB may become eligible according to national guidelines).
-Recipients who are on renal replacement therapy at randomization.
-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 < 30 kg or > 180 kg.

E.5 End points

E.5.1

Primary end point(s)

Incidence of composite efficacy failure at Month 12, where BPAR is from biopsy data indicating a rejection activity index (RAI) ≥3

E.5.1.1

Timepoint(s) of evaluation of this end point

Month 12

E.5.2

Secondary end point(s)

1)Mean change in eGFR from randomization to Month 12.
2)To evaluate eGFR values and change from randomization to Month 24.
3)Free CFZ533 plasma concentrations over time (CFZ533-treated subjects only).
4) Proportion of subjects with:
- Adverse events
- Serious adverse events
- AEs related to study drug
5)Event rates over 12 months and 24 months posttransplantation.
Additional secondary end points as per protocol.

E.5.2.1

Timepoint(s) of evaluation of this end point

1) Month 12
2), 3), 4) and 5) month 12 and month 24

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

United States

Belgium

Czechia

France

Germany

Hungary

Italy

United Kingdom

Netherlands

Spain

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

103

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

100

F.4.2.2

In the whole clinical trial

128

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Participants who complete participation in this trial and continue to derive clinical benefit from the treatment based on the investigator's evaluation may receive post-trial drug access program or have the opportunity to enter a follow-up study. Details of the follow-up study will be described in a separate protocol which will require endorsement in participating countries and sites as per local laws and regulations.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-04-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-16

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-01-26

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