Clinical Trials Register

Summary
EudraCT Number:	2021-000006-16
Sponsor's Protocol Code Number:	APHP201098
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-11-15
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

2021-000006-16

A.3

Full title of the trial

A phase 3 randomized and double-blind controlled trial comparing the efficacy and safety of subcutaneous belimumab or placebo in addition to rituximab in adult patients with persistent or chronic immune thrombocytopenia (ITP)
(RITUX-PLUS 2)

A.3.1

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

A.3.2

Name or abbreviated title of the trial where available

RITUX-PLUS 2

A.4.1

Sponsor's protocol code number

APHP201098

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	ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
B.1.3.4	Country	France
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	Laboratoire GSK France
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS
B.5.2	Functional name of contact point	DRCI Hôpital St Louis
B.5.3	Address:
B.5.3.1	Street Address	1, Avenue Claude VELLEFAUX
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	01 44 84 17 15
B.5.5	Fax number	01 44 84 17 01
B.5.6	E-mail	akim.souag@aphp.fr

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	BENLYSTA
D.2.1.1.2	Name of the Marketing Authorisation holder	GlaxoSmithKline (Ireland) Limited
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Bélimumab
D.3.4	Pharmaceutical form	Solution for injection in pre-filled syringe
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	Belimumab
D.3.9.1	CAS number	356547-88-1
D.3.9.2	Current sponsor code	GSK1550188
D.3.9.3	Other descriptive name	BENLYSTA
D.3.9.4	EV Substance Code	SUB25607
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	200
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	Yes
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	Yes
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 in pre-filled syringe
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

Adults with a definite diagnosis of primary chronic immune thrombocytopeniaaccording to the standard definition. Patients with antinuclear antibodies with no definite criteria for systemic lupus will be eligible.

E.1.1.1

Medical condition in easily understood language

adult patients with persistent or chronic immune thrombocytopenia (ITP)

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	23.0
E.1.2	Level	PT
E.1.2	Classification code	10083842
E.1.2	Term	Immune thrombocytopenia
E.1.2	System Organ Class	10005329 - Blood and lymphatic system 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

To assess the superiority at W52 of combination subcutaneous belimumab weekly over a 24 weeks period (Arm A) or subcutaneous placebo weekly during 24 weeks period (Arm B) with rituximab (Mabthera© or biosimilar) (at a fixed dose of 1,000 mg on Day 7 and Days 21).

E.2.2

Secondary objectives of the trial

- To analyze the overall response (complete response + response) of patients throughout the study until W104
- To assess the incidence of secondary severe hypogammaglobulinemia (<4 g/dl) in both arms at W12, W24, W36, W52, W88, W104
- To assess levels of gammaglobulin isotypes and subclasses over the course of the study period
- To compare in both arms the number of severe infections (requiring hospitalization), over the study period
- To assess bleeding events occurring throughout the study
- To compare the rate and type anti-platelets antibodies in both arms at baseline and at W24, W52, W104

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Age ≥ 18 years
2) Primary ITP defined according to the standard definition criteria (Rodeghiero, Blood 2008)
3) Previous response to corticosteroids and/or IgIV defined by a rise of platelet levels > 30 x 109/L with at least a twofold increase from baseline levels followed by a relapse.
4) Platelet count ≤ 30 x 109/L /L at inclusion or <50 x 109/L x 109/L if presence of haemorrhagic events or other reason left up to investigator discretion.
5) ITP duration of more than 3 months but less than 5 years from diagnosis.
6) Normal bone marrow smear for patients above 60 years of age
• 7) Negative pregnancy test results and effective contraception for women of childbearing age Female subjects of childbearing potential must not become pregnant and so must be sexually inactive by abstinence or use contraceptive methods with a failure rate of < 1%.
Therefore, these women must have a negative serum pregnancy test at screening, and confirmed monthly while in study, out to at least 4 months (5 half-lives) post last dose and agree to 1 of the following:
• 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 sterilization (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.

8) Gammaglobulin level > 7 g/L
9) Informed consent

E.4

Principal exclusion criteria

1) Splenectomy
2) Previous treatment with rituximab or any B-cell targeted therapy
3) Common variable immunodeficiency
4) Previous treatment with cyclophosphamide or ciclosporin
5) Inclusion in another clinical trial less than 1 month before inclusion
6) Previous anaphylactic shock to previous biologic therapy
7) Chronic or ongoing severe infection requiring treatment or hospitalization in the 60 days preceding inclusion.
8) Use of parenteral antibiotics within 60 days, current use of suppressive therapy for chronic infection such as tuberculosis, pneumocystis, cytomegalovirus, HSZ, herpes zoster, and atypical mycobacteria
9) 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 judgment, pose a significant suicide risk.
10) Psychiatric Illness impairing judgement.
11) Neutrophils count < 1,000/mm3 at inclusion
12) Positive HIV test and/or hepatitis virus C infection and/or positive hepatitis B virus surface antigen or core antibody (HbsAg or HBcAb)
13) Impaired renal function as indicated by a serum creatinine level > 2 mg/dl
14) Liver function: AST (SGOT) and ALT (SGPT) ≥5xULN Total bilirubin ≥3 x ULN
15) New York Heart Classification III or IV heart disease
16) Previous history of malignancy in the last 5 years other than cutaneous carcinoma
17) Previous history of Progressive multifocal leukoencephalopathy18) Previous history of major organ transplant or hematopoietic stem cell/marrow transplant or renal transplant.
19) Alcohol or drug abuse or dependence, either current or within 1year
20) Pregnant or breast-feeding woman
21) Live, attenuated vaccinations must be administered at least 30 days before inclusion in study
22) History of significant medical illness or clinically significant laboratory abnormality (or planned surgical procedure) which in the opinion of the investigator would interfere with the study procedures and / or assessments or compromise subject safety
22) Body mass index > 35
23) Patients under legal protection or unable to consent

E.5 End points

E.5.1

Primary end point(s)

Overall response rate (CR + R) in both arms at W52

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 52

semaine 52

E.5.2

Secondary end point(s)

- Number and proportion of patients developing a severe hypogammaglobulinemia (gammaglobulin level < 4 g/dl) in both arms at W12, W24, W36, W52, W88, W104
- Duration of severe hypogammaglobulinemia in patients with such complication
- Variation in gammaglobulin classes and subclass levels throughout the study (W0, W12, W24, W36, W52, W88, W104)
- Number and proportion of severe infections requiring hospitalization during the study
- Platelet levels at W6, W12, W24, W36, W52, W88, W104
- Total number and proportion of responders (responders + complete responses) at W6, W12, W 24, W36, W52, W88, W104.
- Number and proportion of haemorrhagic events evaluated by the Khellaf Score at W6, W12, W24, W36, W52, W88, W104.
- Change from baseline of each B-cell subpopulation, T Follicular helper population and levels of cytokines (including BAFF) at W12, W24, W36, W52, W88, W104 (ancillary study)

E.5.2.1

Timepoint(s) of evaluation of this end point

W6, W12, W24, W36, W52, W88, W104.

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

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)

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

non applicable

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 months

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

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

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

132

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)

None

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

2022-01-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-12-07

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

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