Clinical Trials Register

Summary
EudraCT Number:	2018-001508-12
Sponsor's Protocol Code Number:	CVAY736X2208
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Temporarily Halted
Date on which this record was first entered in the EudraCT database:	2018-08-28
Trial 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

2018-001508-12

A.3

Full title of the trial

A placebo-controlled, patient and investigator blinded, randomized parallel
cohort study to assess pharmacodynamics, pharmacokinetics, safety,
tolerability and preliminary clinical efficacy of VAY736 and CFZ533 in
patients with systemic lupus erythematosus (SLE)

A.3.1

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

Study the efficacy and safety of VAY736 and CFZ533 in patients with systemic lupus erythematosus (SLE)

A.4.1

Sponsor's protocol code number

CVAY736X2208

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03656562

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.3.2	Product code	VAY736
D.3.4	Pharmaceutical form	Powder for solution for injection/infusion
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	ianalumab
D.3.9.2	Current sponsor code	VAY736
D.3.9.3	Other descriptive name	VAY736
D.3.9.4	EV Substance Code	SUB31641
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
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.3.2	Product code	CFZ533
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous 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.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for injection/infusion
D.8.4	Route of administration of the placebo	Subcutaneous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Concentrate for solution for injection/infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Systemic lupus erythematosus (SLE)

E.1.1.1

Medical condition in easily understood language

Systemic lupus erythematosus (SLE)

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10042945
E.1.2	Term	Systemic lupus erythematosus
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue 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

The primary objective of this study is to determine the effect of VAY736 and of CFZ533 versus their respective placebo on disease activity in SLE patients using the SRI-4 index.

E.2.2

Secondary objectives of the trial

- To assess safety and tolerability in patients with SLE by recording all adverse events
- To determine the change from baseline in the Physicians’ Global Assessment (PhGA) at Week 29 by using a visual analogue scale (VAS)
- To determine the change from baseline in the Patient's Global Assessment (PGA) at Week 29 by using a patients VAS
- To determine the pharmacokinetics (PK) of multiple doses of VAY736
(s.c.) and CFZ533 (i.v.) in SLE patients by analyzing PK concentrations in blood
- To assess the effect of VAY736 and of CFZ533 versus their respective
placebo to prevent disease flares in SLE patient’s using BILAG-2004
- To evaluate the immunogenicity of multiple doses of VAY736 (s.c.) or
CFZ533 (i.v.) in SLE patients by analyzing anti-drug antibodies in blood
- To evaluate the pharmacodynamics (PD; rate, extent and duration of
target engagement) of multiple doses of CFZ533 in SLE patients by analyzing total soluble CD40 in plasma

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Written informed consent must be obtained before any assessment is performed
- Male and female patients 18 to 75 years of age
- Fulfill ≥4 of the 11 American College of Rheumatology 1997 classification criteria for SLE
- Patient diagnosed with SLE for at least 6 months prior to screening
- Elevated serum titers at screening of ANA (≥1:80) of a pattern consistent with an SLE diagnosis, including at a minimum either anti-double stranded DNA (anti-ds DNA) or anti-Ro (SSA), anti-La (SSB), anti-nuclear ribonucleoprotein (anti-RNP) or anti-Smith (anti-Sm)
- Currently receiving corticosteroids and/or antimalarials and/or thalidomide treatment and/or another DMARD on a stable dose according to protocol requirements
-SLEDAI-2K score of ≥6 at screening
BILAG-2004 score at screening of:
-- at least one "A" in either the mucocutaneous domain or in the musculoskeletal domain,
OR
-- one "B" in either the mucocutaneous or musculoskeletal domain AND at least one "A" or "B" in a second domain
- Weigh at least 40 kg at screening
- Other protocol-defined inclusion criteria may apply

E.4

Principal exclusion criteria

Cohort 2 (CFZ533/Placebo) only:
- Patients who are at significant risk for thromboembolic events based on the following:
-- History of either thrombosis or 3 or more spontaneous abortions
-- Presence of lupus anticoagulant or significantly prolonged activated partial thromboplastin time (aPTT) consistent with co-existent anti-phospholipid syndrome and without concurrent prophylactic treatment with aspirin or anticoagulants as per local standard of care

All Cohorts:
- History of receiving prior to screening:
-- Within 12 weeks: i.v. corticosteroids, calcineurin inhibitors or other oral DMARD
-- Within 24 weeks: cyclophosphamide or biologics such as intravenous Ig, plasmapheresis, anti-TNF-a mAb, CTLA4-Fc Ig (abatacept) or BAFF targeting agents (e.g., belimumab)
-Any B-cell depleting therapies (e.g., anti-CD20 mAb, anti-CD22 mAb, anti-CD52 mAb) or TACI-Ig (atacicept) administered within 52 weeks prior to screening, and a B-cell count <50 cells/μ at the time of screening
- Evidence of past exposure to tuberculosis as assessed by Quantiferon testing at screening
- Presence of human immunodeficiency virus (HIV) infection at screening
- Severe organ dysfunction or life threatening disease;
-Presence of severe lupus kidney disease as defined by proteinuria above 6 g/day or equivalent using spot urine protein creatinine ratio, or serum creatinine greater than 2.5 mg/dL (221.05 μmol/L), or requiring immune suppressive induction or maintenance treatment exceeding protocol defined limits
- Active viral, bacterial or other infections at the time of screening or enrollment
- Receipt of live/attenuated vaccine within a 2month period before first dosing
- Uncontrolled, co-existing serious disease, e.g., uncontrolled hypertension, heart failure, type I diabetes, thyroid disease within 3 months prior to first dosing, or significant, unresolved illness within 2
weeks prior to first dosing
- History of hypersensitivity to drugs of similar chemical class
-Chronic infection with hepatitis B (HBV) or hepatitis C (HCV). Subjects who are HBsAg negative and HBcAb positive are excluded unless negative for HBV DNA. Once past screening and enrolled into study, requirements for monitoring and antiviral treatment are enacted. Subjects with a positive HCV antibody test should have HCV RNA levels measured. Subjects with positive (detectable) HCV RNA should be excluded.

- Other protocol-defined exclusion criteria may apply

E.5 End points

E.5.1

Primary end point(s)

SRI-4 response status at Week 29 with reduced steroid dose maintained between Weeks 17 and 29

E.5.1.1

Timepoint(s) of evaluation of this end point

29 Weeks

E.5.2

Secondary end point(s)

- Changes between baseline and Week 29 in the PhGA visual analog scale (VAS) assessing patient’s overall disease activity
- Changes between baseline and Week 29 in the PGA visual analog scale (VAS) assessing patient’s global disease activity
- Flare rate and time to first flare, with flare defined as one new ‘A’ score or two or more ‘B’ score using BILAG-2004
- Time to first flare, with flare defined as one new ‘A’ score or two or more ‘B’ score using BILAG -2004
- PK Cohort 1 (VAY736): free VAY736 serum concentration (Cmax at steady state)
- PK Cohort 1 (VAY736): free VAY736 serum concentration (Ctrough at steady state)
- PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Cmax at steady state).
- PK Cohort 2 (CFZ533): free CFZ533 concentration in plasma (Ctrough at steady state).
- PD Cohort 2 (CFZ533): total soluble CD40 in plasma.

E.5.2.1

Timepoint(s) of evaluation of this end point

29 Weeks
29 Weeks
18 months
18 months
End of Study
End of Study
18 months
18 months
18 months

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

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

Yes

E.6.11

Pharmacogenomic

Yes

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity
Tolerability

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

Taiwan

Australia

China

Israel

Japan

Korea, Republic of

Russian Federation

Thailand

United States

Czechia

France

Germany

Hungary

Poland

Spain

E.8.7

Trial has a data monitoring committee

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:

115

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

F.4.2.2

In the whole clinical trial

135

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)

Each patient will be required to complete the study in its entirety and thereafter no further study treatment will be made available to them, unless required by local 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

2018-11-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-12-05

P. End of Trial
P.	End of Trial Status	Temporarily Halted

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