Clinical Trials Register

Summary
EudraCT Number:	2018-001392-21
Sponsor's Protocol Code Number:	P018.087
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-09-25
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

Netherlands - Competent Authority

A.2

EudraCT number

2018-001392-21

A.3

Full title of the trial

A randomized trial to investigate the reset of humoral autoimmunity by combining belimumab with rituximab in severe 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 – 2nd study

A.4.1

Sponsor's protocol code number

P018.087

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	Dr. Y.K.O. 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	2333ZA
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31715262148
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	Comparator
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	belimumab or benlysta
D.2.1.1.2	Name of the Marketing Authorisation holder	GlaxoSmithKline
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.3.4	Pharmaceutical form	Solution for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
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	Comparator
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	anti-CD20 B cell depletion with Truxima
D.2.1.1.2	Name of the Marketing Authorisation holder	Celltrion Healthcare Hungary Kft
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	truxima
D.3.4	Pharmaceutical form	Concentrate for emulsion for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	Yes
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

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	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10042947
E.1.2	Term	Systemic lupus erythematosus synd
E.1.2	System Organ Class	100000004859

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10029142
E.1.2	Term	Nephritis systemic lupus erythematosus
E.1.2	System Organ Class	100000004857

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10042948
E.1.2	Term	Systemic lupus erythematosus syndrome aggravated
E.1.2	System Organ Class	100000004859

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

In this study the primary objective is to assess long-term efficacy of the combination treatment of belimumab with rituximab (BLM+RTX) compared to standard of care with mycophenolate and steroids and the association with more effective and sustained B-cell depletion. The primary clinical efficacy parameter is treatment failure rate during the 2 year study period. The main functional and immunological parameter for autoreactive B-cells is the reduction of disease relevant autoantibodies, in particular anti-dsDNA autoantibodies, at 28 weeks after treatment.

E.2.2

Secondary objectives of the trial

The evaluation of long-term effects of BLM+RTX with respect to clinical response correlated to immunological parameters in comparison to standard of care with mycophenolate+steroids; a.the sustained reduction of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies at 28+104 weeks b.seroconversion of pathogenic autoantibodies, in particular anti-dsDNA autoantibodies at 28+104 weeks c.the reduction of memory B-cells at 28+104 weeks d.the regression of excessive NET formation at 28+104 weeks e.the feasibility of the combination treatment with tapering of concomitant immunosuppression f.the safety of the combination treatment according to the Common toxicity Criteria developed by the National Cancer Institute g.the clinical response other than treatment failure;reduction in SLEDAI scores and no worsening of PGA, in case of lupus nephritis:the number of partial and complete renal responders, the number of moderate or severe flares and renal flares, time to treatment failure

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects enrolled in the study must meet the following inclusion criteria:
1) Age 16 years,
2) Have a clinical diagnosis of SLE according to the SLICC criteria 2012 (see appendix 1)
3) Severe, active SLE disease (see also section 5.3.3.2.), defined as a situation in which 1 or more of the following criteria are met:
a. SLEDAI (SLE Disease Activity Index) with 12 or more points
b. New or worse SLE-related activity of major organs, i.e.: CNS-SLE (includes NPSLE), vasculitis, nephritis, pericarditis and/or myocarditis, myositis, thrombocytopenia < 60, hemolytic anemia < 4.4mmol/L (=7.0g/dL)
c. high disease activity that requires or warrants induction treatment by switching to or increasing dosage of oral mycophenolate
4) Persisting or progressive disease activity despite the use of conventional maintenance immunosuppressive treatment (e.g. mycophenolate or azathioprine)
5) Positive for relevant SLE-specific autoantibodies defined as a situation in which 1 or more of the
following criteria are met:
a. 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.
b. 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.
6) Female subjects are eligible to enter the study if she is:
- Not pregnant or nursing
- Of non-child-bearing potential (i.e. after hyseterectomy, postmenopausal, bilateral ovariectomy or
documented bilateral tubal ligation or other permanent female sterilization procedure)
- Use of effective contraception:
• Complete abstinence from intercourse from 2 weeks prior to administration of the 1st dose of
study agent until 16 weeks after the last dose of study agent (Sexual inactivity by abstinence
must be consistent with the preferred and usual lifestyle of the subject.
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and
withdrawal are not acceptable methods of contraception; OR
• Consistent and correct use of 1 of the following acceptable methods of birth control for 1 month
prior to the start of the study agent, during the study, and 16 weeks after the last dose of study
agent:
o Oral contraceptive, either combined or progestogen alone
o Injectable progestogen
o Implants of levonorgestrel or etonogestrel
o Estrogenic vaginal ring
o Percutaneous contraceptive patches
o Intrauterine device (IUD) or intrauterine system (IUS) with <1% failure rate as stated in the
product label
o Male partner sterilisation (vasectomy with documentation of azoospermia) prior to the female
subject's entry into the study, and this male is the sole partner for that subject. For this
definition, “documented” refers to the outcome of the investigator's/designee’s medical
examination of the subject or review of the subject's medical history for study eligibility, as
obtained via a verbal interview with the subject or from the subject’s medical records.
o Double barrier method: condom and occlusive cap (diaphragm or cervical/vault caps)
plus spermicidal agent (foam/gel/film/cream/suppository)
• These allowed methods of contraception are only effective when used consistently, correctly and in accordance with the product label. The investigator is responsible for ensuring subjects
understand how to properly use these methods of contraception.
• Female subjects using mycophenolate mofetil (MMF) should be made aware that MMF affects
the metabolism of oral contraceptives and may reduce their effectiveness. As such, women
receiving MMF who are using oral contraceptives for birth control should employ an additional
method (e.g., barrier method).

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 hypogammaglobulinemia (IgG < 4.0 g/L) or an IgA deficiency (IgA < 0.1 g/L)
3) Immunization with a live vaccine 1 month before screening
4) Active infection at time of screening, as follows:
- Hospitalization for treatment of infection within previous 60 days 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 60 days of day 0 of the study
- Serological evidence of uncontrolled, active viral hepatitis defined as: patients positive for HbsAg
test or HBcAb or a positive hepatitis C antibody not treated with antiviral medication
5) Have a historically positive HIV test or test positive at screening for HIV
6) Have a history of a primary immunodeficiency
7) Have a neutrophil count of < 1.5x10E9/L
8) Have a significant infection history that in the opinion of the investigator would make the
candidate unsuitable for the study
9) Have a history of an anaphylactic reaction to parenteral administration of contrast agents, human or
murine proteins or monoclonal antibodies
10) Have any other clinically significant abnormal laboratory value in the opinion of the investigator
11) Have current drugs or alcohol abuse or dependence within 365 days prior to Day 0 of the study
12) Have an active malignant neoplasm or one in the history of the last 5 years, except basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the uterine cervix treated locally and with no evidence of metastatic disease for 3 years
13) Have evidence of serious suicide risk including any history of suicidal behavior in the last 6 months and/or any suicidal ideation in the last 2 months or who, in the investigator’s opinion, poses a significant suicide risk
14) Have any other clinically significant abnormal laboratory value, any intercurrent significant medical or psychiatric illness that in the opinion of the investigator would make the candidate unsuitable for the study

E.5 End points

E.5.1

Primary end point(s)

With the above-described detailed evaluations, in order to assess the study’s primary endpoint, we will compare the treatment failure rate during the 2 years study period between the two treatment arms.

E.5.1.1

Timepoint(s) of evaluation of this end point

week 104

E.5.2

Secondary end point(s)

In order to assess the study’s main secondary endpoints, the percentage reduction in absolute serum levels of anti-dsDNA autoantibodies per patient at week 28 compared to baseline values.
For other secondary endpointswe will:
Ad a. A sustained reduction of serum levels of anti-dsDNA autoantibodies will be defined as the absence of a doubling of serum level on at least 2 consecutive visits or a seroconversion to positive on at least 2 consecutive visits

Ad b. Seroconversion of anti-dsDNA autoantibodies will be defined by the immunofluorescence assay when changed from (strongly) positive to negative or to ‘weakly’ positive

Ad c. The reduction of memory B-cells will be assessed by flowcytometry and quantified as the percentage reduction in absolute CD19+CD27+ memory B-cell counts

Ad d. A sustained reduction of CD19+CD27+ memory B-cell will be defined as the absence of an increase in their absolute number on flowcytometry on at least 2 consecutive visits

Ad e. A regression in excessive NET formation will be quantified by an in-house established assay where ‘normal’ amount of NET formation is assessed by serum from normal human subjects. The regression in sera from SLE patients is calculated in relation to the negative control of normal human serum, as described by the assay.

Ad f. A sustained regression of excessive NET formation will be defined as the absence of a doubling of NET formation on at least 2 consecutive visits
Ad g & h. Feasibility and safety of combination treatment will be assessed by monitoring the occurrence of hypogammaglobulinemia, infectious events and allergic events

Ad i. Clinical responses will be evaluated.

E.5.2.1

Timepoint(s) of evaluation of this end point

Relevant study parameters will be evaluated after 28 weeks, 60 weeks and 104 weeks

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

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

Yes

E.6.13.1

Other scope of the trial description

Immunological secondairy endpoints to assess whether a combination treatment of belimumab with rituximab will lead to the improvement of pivotal, SLE-specific autoimmune phenomena compared SLE patients treated with conventional immunosuppression

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)

Yes

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

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

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

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

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)

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

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)

Treatment during the study is defined up to 100 weeks after which the treatment with belimumab can be continued or patients can be switched to another immunosuppressive regimen. This decision is left to the discretion of the treating physician. Patients will be followed up to 100 weeks after initiation of the study treatment regardless of the chosen follow-up treatment.

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

2018-09-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-09-06

P. End of Trial
P.	End of Trial Status	Ongoing

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