Clinical Trials Register

Summary
EudraCT Number:	2014-000488-42
Sponsor's Protocol Code Number:	Teng-001
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-05-09
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

Netherlands - Competent Authority

A.2

EudraCT number

2014-000488-42

A.3

Full title of the trial

The SYNBioSe Study
A proof-of-concept study involving synergetic B-cell imunnomodulation in patients with refractory systemic lupus erythematosus

A.3.1

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

Synergetic B-cell immunomodulation in SLE

A.3.2

Name or abbreviated title of the trial where available

SynBiose

A.4.1

Sponsor's protocol code number

Teng-001

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	Leiden University Medical Center
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Leiden University Medical Center
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Leiden University Medical Center
B.5.2	Functional name of contact point	Teng
B.5.3	Address:
B.5.3.1	Street Address	Albinusdreef 2
B.5.3.2	Town/ city	Leiden
B.5.3.3	Post code	2333 ZA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31715268157
B.5.6	E-mail	y.k.o.teng@lumc.nl

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	Yes
D.2.1.1.1	Trade name	rituximab
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Ltd
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Rituximab
D.3.4	Pharmaceutical form	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	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
D.3.9.2	Current sponsor code	Teng-001
D.3.9.4	EV Substance Code	SUB12570MIG
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	2000
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	Yes
D.2.1.1.1	Trade name	Benlysta
D.2.1.1.2	Name of the Marketing Authorisation holder	Glaxo Group Ltd
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Belimumab
D.3.4	Pharmaceutical form	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	BELIMUMAB
D.3.9.1	CAS number	356547-88-1
D.3.9.2	Current sponsor code	Teng-001
D.3.9.4	EV Substance Code	SUB25607
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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

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

E.1.1.1

Medical condition in easily understood language

systemic lupus erythematosus

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10025139
E.1.2	Term	Lupus erythematosus systemic
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

In this proof-of-concept study the primary objective is to assess whether a combination treatment ofrituximab (anti-CD20) and belimumab (anti-BAFF) will lead to a sustained reduction of pathogenic autoantibodies and thereby inhibition of NET formation, which portentially forms the basis of a new therapeutic approach in severe SLE.

E.2.2

Secondary objectives of the trial

Secondary goals are to evaluate clinical improvement, reduction of circulating immune complexes, safety and feasibility.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

4.1. Inclusion criteria
Subjects enrolled in the study must meet the following inclusion criteria:
1) age 18 years,
2) ACR diagnosis of SLE (1997 revised criteria, see appendix 1)
3) Severe SLE flare at screening (see also section 5.2.3.2.), defined as a situation in which 1 or more of the following criteria are met:
- Increase in SLEDAI (SLE Disease Activity Index) with 12 or more points
- New or worse SLE-related activity of major organs, i.e.: CNS-SLE (includes NPSLE), vasculitis, nephritis, pericarditis and/or myocarditis, myositis, trombocytopenia < 60, hemolytic anemia < 4.4mmol/L (=7.0g/dL).
4) Refractory disease, defined as persisting or progressive disease activity (SLEDAI > 6 points) despite conventional immunosuppressive treatment and 1 or more of the following criteria:
- failure of the initial induction treatment at six months, for which a switch to another induction therapy regime has already been carried out;
- intolerance or contraindication for cyclophosphamide and mycophenolate mofetil (MMF);
- exceeding a cumulative dose of 15 gram of cyclophosphamide;
- a second relapse within two years after start of the initial induction therapy
- a relative contraindication for high-dose oral or intravenous (iv) prednisone, such as avascular osteonecrosis, previous psychosis on corticosteroids, osteoporosis and/or severe obesity (BMI ≥35 kg/m2).
5) ANA seropositivity, as defined by a positive ANA-titer ≥ 1:80, before and at screening :
- Positive test results from 2 independent time points within the study screening period; OR
- One positive historical test result and 1 positive result during the screening period. Historical documentation of a positive test of ANA (eg, ANA by HEp-2 titer, ANA by ELISA) must include the date of the test.
6) Anti-DNA seropositivity, as defined by a positive anti-dsDNA serum antibody ≥ 30 IU/mL, before and at screening:
- Positive test results from 2 independent time points within the study screening period.
- One positive historical test result and 1 positive result during the screening period. Historical documentation of a positive test of anti-dsDNA (eg, anti-dsDNA by Farr assay or ELISA) must include the date of the test.
7) Immune-complex mediated complement usage, as defined by:
- a low C3 serum level ≤ 0.9 g/L; OR
- a low C4 serum level ≤ 95 mg/L; OR
- a reduced activation of the classical pathway < 75%
8) Use of effective contraception

E.4

Principal exclusion criteria

Subjects will be excluded from participation if they meet any of the following exclusion criteria:
1) Active pregnancy, as proven by a positive urine beta-HCG test or a positive serum beta-HCG
2) Significant B-cell depletion (peripheral B-cell counts < 60x10E6)
3) Significant hypogammaglobulinemia (IgG < 8.0 g/L)
4) Immunization with a live vaccine 1 month before screening
5) Active infection at time of screening, as follows:
- Hospitalization for treatment of infection within previous 2 months of day 0 of the study
- Use of parenteral (intravenous of intramuscular) antibiotics ( including anti-bacterials, anti-virals, anti-fungals or anti-parasitic agents) within previous 2 months of day 0 of the study

E.5 End points

E.5.1

Primary end point(s)

In this proof-of-concept study the primary objective is to assess whether a combination treatment of rituximab and belimumab will lead to a sustained reduction of pathogenic autoantibodies and thereby inhibition of NET formation. Therefore, the primary endpoints are:
- a sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies, at 24 weeks after treatment start
- an inhibition of the formation of NETs at 24 weeks after treatment start

E.5.1.1

Timepoint(s) of evaluation of this end point

at 24 weeks

E.5.2

Secondary end point(s)

The main secondary objective is to evaluate the effects of long-term B-cell depletion which will involve assessments of the clinical response correlated with immunological parameters. To this end, the relevant study parameters will be evaluated after 4 weeks (short term), 24 weeks (intermediate term) and 104 weeks (long-term). The secondary endpoints measured at these times are:
- the effects on the reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
- the inhibition of the formation of NETs
- seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies
- the normalization of complement usage, i.e. C3/C4 levels and C1Q-binding

Other secondary objectives are to evaluate:
- the safety and feasibility of the combination treatment according to the WHO toxicity criteria
- the clinical response of refractory SLE patients upon long-term B-cell depletion by:
* a reduction in SLEDAI scores, no new BILAG A involvement and the SLE responder index
* in case of lupus nephritis: the number of partial and complete renal responders
* the number of moderate or severe flares and renal flares

E.5.2.1

Timepoint(s) of evaluation of this end point

4 weeks (short term), 24 weeks (intermediate term) and 104 weeks (long-term).

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

E.6.4

Safety

Yes

E.6.5

Efficacy

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

The trial ends at the last visit of the last patient

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

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:

F.1.3

Elderly (>=65 years)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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)

At the end of the study, the treating physician of the patient will decide whether treatment with belimumab is continued, tapered or replaced by other immunosuppressive therapy

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

2014-05-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-05-12

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2018-10-31

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