Clinical Trials Register

Summary
EudraCT Number:	2018-004476-35
Sponsor's Protocol Code Number:	CCFZ533B2201
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2019-06-20
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

France - ANSM

A.2

EudraCT number

2018-004476-35

A.3

Full title of the trial

A 48-week, 6-arm, randomized, double-blind, placebo-controlled multicenter trial to assess the safety and efficacy of multiple CFZ533 doses administered subcutaneously in two distinct populations of patients with Sjögren’s Syndrome (TWINSS)

Etude multicentrique de 48 semaines, menée en double-aveugle sur 6 groupes, randomisée et contrôlée par placebo, destinée à évaluer la sécurité d’emploi et l’efficacité de plusieurs doses de CFZ533 par voie sous-cutanée, dans deux populations distinctes de patients atteints du syndrome de Sjögren (TWINSS)

A.3.1

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

Study of safety and efficacy of multiple doses of CFZ533 in two distinct populations of patients with Sjögren’s Syndrome

A.3.2

Name or abbreviated title of the trial where available

TWINSS

A.4.1

Sponsor's protocol code number

CCFZ533B2201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03905525

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 S.A.S
B.5.2	Functional name of contact point	Information&Communication Médicales
B.5.3	Address:
B.5.3.1	Street Address	2 et 4 rue Lionel Terray
B.5.3.2	Town/ city	Rueil-Malmaison
B.5.3.3	Post code	92500
B.5.3.4	Country	France
B.5.4	Telephone number	+33 1 5547 6600
B.5.5	Fax number	+33 1 5547 6100
B.5.6	E-mail	icm.phfr@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 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	iscalimab
D.3.9.2	Current sponsor code	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	Solution for injection/infusion
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Sjögren syndrome

E.1.1.1

Medical condition in easily understood language

Autoimmune condition of unknown cause where the body's own selfdefenses attack glands that secrete fluids resulting in inflammation of the glands. The inflammatory process can involve other organs.

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	10040767
E.1.2	Term	Sjogren's syndrome
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

Cohort 1
To demonstrate a dose-response of CFZ533 (iscalimab) based on change in ESSDAI from baseline at Week 24.

Cohort 2
To estimate the effect of CFZ533 (iscalimab) on the change in ESSPRI at Week 24.

E.2.2

Secondary objectives of the trial

Cohort 1
To demonstrate a dose response of iscalimab based on change in ESSPRI from baseline at Week 24

Cohort 2
To estimate the effects of iscalimab based on changes in ESSDAI from baseline at Week 24
To evaluate the efficacy of iscalimab in improving the dry eye symptoms measured by IDEEL at Week 24

Cohort 1 & 2
To estimate the effects of iscalimab based on:
- change in FACIT-F from baseline at Week 24
- change in physician's global assessment (PhGA) from baseline at Week 24
To assess:
- the effect of iscalimab in the serum Free Light Chains (FLC) levels over time
- the changes in IgG and IgM levels over time after iscalimab treatment
- the effect of iscalimab on plasma CXCL-13 over time
To assess:
- safety and tolerability of iscalimab
- immunogenicity of iscalimab
- the pharmacokinetics and dose-exposure relationship of iscalimab
To measure soluble CD40 in plasma

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

i) Salivary gland biopsy (2019-02-20, Version 00)
Biopsies will be performed for the purpose of exploring the effects of iscalimab on histopathology features of salivary gland biopsies (optional).
ii) Digital assessments: wearable sensor, cognitive and mood assessments (2019-02-20, Version 00).
Digital assessments will be performed to assess the efficacy of iscalimab in improving fatigue, cognitive and mood status digitally measured with wearable device or smartphone/tablet applications (optional assessments conducted at selected sites)
iii) Pharmacogenetics: blood samples for DNA and RNA analyses (2019-02-20, Version 00):
- The use of DNA to search for biomarkers of disease and drug action.
- The activity (the expression) of genes will be examined using RNA (or other nucleic acid) analytical technologies to examine the effect of iscalimab on transient RNA expression in blood and may support the identification of pathways/markers that characterize the disease or response of treatment with iscalimab.
The genetic research is optional.

E.3

Principal inclusion criteria

•Signed informed consent
•Male or female patient ≥ 18 years of age
•Classification of Sjögren's Syndrome according to ACR/EULAR 2016 criteria (Shiboski et al 2017)
•Seropositive for anti-Ro/SSA antibodies
•Stimulated whole salivary flow rate of ≥ 0.1 mL/min

Inclusion criteria specific for Cohort 1:
•ESSDAI ≥ 5 within the 8 predefined organ domains
•ESSPRI score of ≥5

Inclusion criteria specific for Cohort 2:
•ESSDAI < 5 within 8 domains scored for inclusion criterion for Cohort 1
•ESSPRI fatigue subscore ≥ 5 or ESSPRI dryness subscore ≥ 5

Other protocol-defined inclusion criteria may apply.

E.4

Principal exclusion criteria

•Sjögren's Syndrome overlap syndromes where another autoimmune rheumatic disease constitutes the principle illness
•Use of other investigational drugs
•Prior use of B cell depleting therapies, abatacept or any other immunosuppressants unless specifically allowe be the protocol.
•Use of steroids at dose >10 mg/day.
•Uncontrolled ocular rosacea (affecting the eye adnexa), posterior blepharitis or Meibomian gland disease (this criterion applies only to patients considered for Cohort 2)
•Active viral, bacterial or other infections requiring systemic treatment
•Receipt of live/attenuated vaccine within a 2-month period prior to randomization.
•Chronic infection with hepatitis B (HBV) or hepatitis C (HCV).
•Evidence of active tuberculosis (TB) infection.

Other protocol-defined exclusion criteria may apply.

E.5 End points

E.5.1

Primary end point(s)

1) Change in EULAR Sjögren Syndrome Disease Activity Index (ESSDAI) score from baseline at 24 weeks as compared to placebo [ Time Frame: 24 weeks ]
Cohort 1 - Efficacy

2) Change in EULAR Sjögren Syndrome Patient Reported Index (ESSPRI) score from baseline at 24 weeks as compared to placebo. [ Time Frame: 24 weeks ]
Cohort 2 - Efficacy

E.5.1.1

Timepoint(s) of evaluation of this end point

1) at Baseline and at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 40, 48, 52, 56, 60
2) at Baseline and at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 40, 48

E.5.2

Secondary end point(s)

1) Change from baseline in ESSPRI at Week 24 [ Time Frame: 24 weeks ]
Cohort 1 - Efficacy (Patient Reported Outcomes)

2) Change from baseline in score of Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F) questionnaire at Week 24 [ Time Frame: 24 weeks ]
Cohort 1&2 - Efficacy (Patient Reported Outcomes)

3) Change from baseline in Physician Global Assessment (PhGA) at Week 24 [ Time Frame: 24 weeks ]
Cohort 1&2 - Efficacy (Clinical Outcome Measures)

4) Change from baseline in ESSDAI at Week 24 [ Time Frame: 24 weeks ]
Cohort 2 - Efficacy (Clinical Outcome Measures)

5) Proportion of subjects with at least 12 points improvement measured by score of Impact of Dry Eye on Everyday Life (IDEEL) questionnaire symptom bother module at Week 24. [ Time Frame: 24 weeks ]
Cohort 2 - Efficacy (Patient Reported Outcomes)

6) Incidence of adverse events (AEs), serious adverse events (SAEs) from baseline to Week 24 and from week 24 to the end of study [ Time Frame: 60 weeks ]
Cohort 1&2 - Safety

7) Serum Free Light Chain (FLC) levels at analysis visit up to end of study [ Time Frame: 60 weeks ]
Cohort 1&2 - Biomarkers (1)

8) Immunoglobulin IgG and IgM levels at analysis visits up to end of study [ Time Frame: 60 weeks ]
Cohort 1&2 - Biomarkers (2)

9) Percent change from baseline in plasma CXCL-13 levels at analysis visits up to end of study [ Time Frame: 60 weeks ]
Cohort 1&2 - Biomarkers (3)

E.5.2.1

Timepoint(s) of evaluation of this end point

1), 2), 3), 4) at Baseline and at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 40, 48
5), 8), 9) at Baseline and at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 40, 48, 52, 56, 60
6) at baseline and repeatedly until study completion
7) at Baseline and at Weeks 4, 12, 24, 32, 48, 56, 60

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

Australia

Austria

Brazil

Canada

Chile

Colombia

France

Germany

Greece

Hungary

Israel

Italy

Japan

Korea, Republic of

Netherlands

Portugal

Romania

Russian Federation

Slovenia

Sweden

Turkey

United Kingdom

United States

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 (last visit of the last subject)

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:

221

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

131

F.4.2.2

In the whole clinical trial

260

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)

Continuing care should be provided by investigator and/or referring physician based on patient availability for follow-up. This care may include enrollment in an extension study, if any.

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

2019-08-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-07-03

P. End of Trial
P.	End of Trial Status	Completed

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