Clinical Trials Register

Summary
EudraCT Number:	2012-003314-13
Sponsor's Protocol Code Number:	P1200_11
National Competent Authority:	Sweden - MPA
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-02-27
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

Sweden - MPA

A.2

EudraCT number

2012-003314-13

A.3

Full title of the trial

RING – RItuximab for lupus Nephritis with remission
as a Goal, an investigator-initiated randomized international open multicentric study

A.3.1

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

RING – RItuximab for lupus Nephritis with remission
as a Goal, an investigator-initiated randomized international open multicentric study

A.3.2

Name or abbreviated title of the trial where available

RING

A.4.1

Sponsor's protocol code number

P1200_11

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	Cliniques Universitaires Saint Luc, Université catholique de Louvain
B.1.3.4	Country	Belgium
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	Cliniques Universitaires Saint Luc, Université catholique de Louvain
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Cliniques Universitaires Saint Luc, Université catholique de Louvain
B.5.2	Functional name of contact point	Pôle de pathologies rhumatismales
B.5.3	Address:
B.5.3.1	Street Address	avenue Hippocrate 10
B.5.3.2	Town/ city	Bruxelles
B.5.3.3	Post code	1200
B.5.3.4	Country	Belgium
B.5.4	Telephone number	+3227645395
B.5.5	Fax number	+3227645394
B.5.6	E-mail	genevieve.depresseux@uclouvain.be

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	Mabthera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Ltd.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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 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	RITUXIMAB
D.3.9.1	CAS number	174722-31-7
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	500
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

Lupus Nephritis

E.1.1.1

Medical condition in easily understood language

Lupus Nephritis

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	PT
E.1.2	Classification code	10025140
E.1.2	Term	Lupus nephritis
E.1.2	System Organ Class	10038359 - Renal and urinary 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

OBJECTIVE: To test whether RTX is efficacious to achieve complete renal response (CR) in LN patients with persistent proteinuria (≥1g/d) despite at least 6 months of standard of care (SOC).

E.2.2

Secondary objectives of the trial

1.Number of deaths ;2.Number of side-effects ;3.Number of SAEs ;4.Number of infections requiring antibiotics ;5.Number of discontinuations for toxicity ;6.Number of patients reaching ESRD ;7.Number of patients with sustained doubling of serum creatinine or sustained fall >25% in eGFR ;8.Number of renal flares, nephritic or proteinuric according to Moroni et al. (Kidney Int 1996; 50 : 2047) ;9.Time to CR ;10.Time to CR for patients achieving CR at w104 ;11.Number of patients achieving a proteinuria <0.2g/d ;12.Number of patients achieving the ACR response criteria for renal disease in SLE (Arthritis Rheum 2006; 54 : 421) ;13.Number of mild/moderate and severe flares according the to SELENA-SLEDAI flare index ;14.Number of patients with normalized serum complement levels (centrally measured on stored samples);15.Number of patients with decrease in serum anti-DNA Ab titers by 2 compared to baseline (centrally measured on stored samples);16.Grams equivalent prednisolone exposure.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria (at screening)
All the following inclusion criteria are to be met :
1. SLE, according to ACR and/or SLICC (Arthritis Rheum 2012; May 2; doi: 10.1002/art.34473) criteria ;
2. Age ≥15y (except if local ethics committee imposes ≥18y) ;
3. ISN/RPS 2003 Class III (A or A/C), IV (A or A/C ; S or G) or V lupus GN confirmed on renal biopsy performed within 24 months before screening ;
4. Having received one out of four following immunosuppressive regimens: i): Euro-Lupus (EL) intravenous (IV) cyclophosphamide (CY) (6x 500 mg q2w) followed by AZA/MMF for 3 months; ii): NIH IVCY for 6M (6 monthly pulses) followed by AZA/MMF for 3 months; iii): MMF for at least 6 months; iv): AZA for at least 6 months
All patients should be on AZA or MMF at screening. In all regimens, MMF can be replaced by enteric-coated mycophenolic acid (eMPA) ;
5. If on GC, being on maximum 10 mg equivalent prednisolone/d at screening (for at least 2 weeks) ;
6. uP/C ratio ≥1 (expressed in mg/mg) measured in a 24-h urine collection, confirmed at randomization (w-2) ;
7. Contraception (any type ; sexual abstinence is an alternative to
contraception in paediatric patients) ;
8. Signed informed consent (drafted according to local practice and approved by the local ethics committee).

E.4

Principal exclusion criteria

Exclusion criteria (at screening, except exclusion criteria 1 at randomization).
Any of the following :
1. Recent or ongoing renal flare defined as either i) : fall in estimated glomerular filtration rate (eGFR ; MDRD) ≥25% within 3 month prior to screening or between screening and randomization ; or ii) : increase in urine protein by ≥100% to >3.5g/d compared to previous assessment ;
2. 24-h proteinuria decline >50% over previous 6 months ;
3. Treatment with ≥10 mg equivalent prednisolone/d in the last 2 weeks before screening ;
4. Pregnancy or breast-feeding ;
5. Anticipated non-compliance with the protocol ;
6. History of malignancy (except non-melanoma skin and cervical intraepithelial cancer) ;
7. Previous treatment with RTX (whenever) and previous treatment with another biologic agent within the last 6 months ;
8. HIV infection ;
9. Active HBV/HCV/TB infection ;
10. Severe liver, cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, haematologic or psychiatric disturbances, that would contraindicate inclusion in the protocol, as judged by the clinician.

E.5 End points

E.5.1

Primary end point(s)

Primary endpoint
The primary endpoint is the percentage of patients achieving renal complete response (CR) at w104.
CR is defined as :
- uP/C ratio ≤0.5 (expressed in mg/mg) measured in a 24-h urine collection;
and
- eGFR >= 60ml/min or, if <60ml/min at screening, not fallen by >20% compared to screening;
and
- no increase of GC throughout the study (except for two limited courses as per protocol; vide infra);
and
- no introduction of another immunosuppressant.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week104

E.5.2

Secondary end point(s)

The secondary endpoints (evaluated at w104) are:
1. Number of deaths ;
2. Number of side-effects ;
3. Number of SAEs ;
4. Number of infections requiring antibiotics ;
5. Number of drops for toxicity ;
6. Number of patients reaching ESRD ;
7. Number of patients with sustained doubling of serum creatinine or sustained fall >25% in eGFR ;
8. Number of renal flares, nephritic or proteinuric according to Moroni et al. (Kidney Int 1996; 50 : 2047) ;
9. Time to CR ;
10. Time to CR for patients achieving CR at w104 ;
11. Number of patients achieving a proteinuria <0.2g/d ;
12. Number of patients achieving the ACR response criteria for renal disease
in SLE (Arthritis Rheum 2006; 54 : 421) ;
13. Number of mild/moderate and severe flares according the to SELENASLEDAI flare index ;
14. Number of patients with normalized serum complement levels (centrally
measured on stored samples);
15. Number of patients with decrease in serum anti-DNA Ab titers by 2
compared to baseline (centrally measured on stored samples);
16. Grams equivalent prednisolone exposure.
Analyses will be performed on the Intent-To-Treat (ITT) population and the

E.5.2.1

Timepoint(s) of evaluation of this end point

Week104

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

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Standard of care

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

Brazil

Colombia

European Union

Morocco

Russian Federation

Switzerland

Turkey

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

179

F.1.3

Elderly (>=65 years)

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

140

F.4.2.2

In the whole clinical trial

194

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)

According to physician's and patient's best judgments

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Lupus Nephritis Trial Network
G.4.3.4	Network Country	Belgium

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2013-09-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-12-18

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

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