Clinical Trials Register

Summary
EudraCT Number:	2020-002507-19
Sponsor's Protocol Code Number:	RTX-SC
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:	2020-09-03
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

2020-002507-19

A.3

Full title of the trial

Comparison of subcutaneous and intravenous continued treatment with ultra-low dose Rituximab in rheumatoid arthritis: a randomised open-label non-inferiority trial

Vergelijking tussen subcutane en intraveneuze toediening van ultra-lage doseringen rituximab bij reumatoïde artritis: een gerandomiseerde open-label non-inferiority trial

A.3.1

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

Research into administration of lower dosed rituximab with an injection

Onderzoek naar het toedienen van lagere doseringen rituximab via een injectie

A.3.2

Name or abbreviated title of the trial where available

RTX-SC

A.4.1

Sponsor's protocol code number

RTX-SC

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	Sint Maartenskliniek
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	Sint Maartenskliniek
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	Sint Maartenskliniek
B.5.2	Functional name of contact point	Principal investigator
B.5.3	Address:
B.5.3.1	Street Address	Hengstdal 3
B.5.3.2	Town/ city	Ubbergen
B.5.3.3	Post code	6574 NA
B.5.3.4	Country	Netherlands
B.5.6	E-mail	a.denbroeder@maartenskliniek.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	MabThera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration GmbH
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	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	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.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	Rixathon
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz GmbH
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	Concentrate for solution 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	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

rheumatoid arthritis

reumatoïde artritis

E.1.1.1

Medical condition in easily understood language

rheumatic disease

reuma

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.0
E.1.2	Level	PT
E.1.2	Classification code	10039073
E.1.2	Term	Rheumatoid arthritis
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

To investigate non-inferiority of rituximab SC 336 mg to rituximab IV 200 mg, with the lower boundary of the 95% confidence interval of AUC0-6mnd,SC : AUC0-6mnd,IV exceeding the non-inferiority margin of 0.8.

E.2.2

Secondary objectives of the trial

1. To describe the relevant pharmacokinetic parameters of rituximab 336 mg SC compared to 200 mg IV: peak level, trough level, Cavg;
2. To evaluate the between group difference in changes in disease activity (DAS28-CRP) after 6 months, compared to a NI margin of 0.6;
3. To evaluate the between group differences on on B-cell counts;
4. To assess the differences in incidence of anti-drug antibodies (ADAs);
5. To assess the incidence of AEs in both groups;
6. To assess patient preferences for either SC or IV formulation.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Rheumatoid arthritis: either 2010 EULAR/ACR RA and/or 1987 ACR RA criteria and/or clinical diagnosis of the treating rheumatologist;
2. Patients using rituximab in ultra-low dose: either 200 mg or 500 mg as previous dose, given every 6 months, with or without concomitant methotrexate;
3. Having sufficient response to rituximab treatment, operationalized as a DAS28-CRP < 2.9 3-6 months after the last infusion and/or judgment of low disease activity by the treating rheumatologist;
4. ≥16 years old and mentally competent;
5. Ability to read and communicate well in Dutch.

E.4

Principal exclusion criteria

1. Previous non-response to ultra-low dose rituximab (DAS28-CRP > 2.9);
2. Objection or contraindication to either of the treatment options;

E.5 End points

E.5.1

Primary end point(s)

The main study endpoint is non-inferiority of rituximab 336 mg SC to rituximab 200 mg IV, based on AUC0-6 months. The AUC will be calculated using the four samples with the trapezoid method.

E.5.1.1

Timepoint(s) of evaluation of this end point

Blood samples will be drawn pre-dose, post-dose (for IV directly after infusion, for SC 2-4 days after injection), at 3 months, and at 6 months.

E.5.2

Secondary end point(s)

Additional PK parameters
In addition to the AUC0-6months, the peak level, the trough level and the average concentration (Cavg) are considered relevant PK parameters to compare both formulas. Those parameters will be calculated using (some of) the four RTX samples drawn, analysed by the RTX assay of Sanquin.

Efficacy
Disease activity will be measured at baseline, at three months and at six months, using the DAS28-CRP score. Therefore, we collect the following parameters:
- Physical examination: swollen joint count, tender joint count;
- Patient Global Assessment of disease activity (VAS);
- Acute phase reactants: CRP.

B-cell count
B-cell count will be performed at baseline, at three months and at six months. For this analysis, blood will be drawn in a 3 ml EDTA tube. B-cell count will be performed at the Radboudumc immunology laboratory. The percentages and absolute number of B-cells will be determined within 24 hours after blood collection by using a combination of fluorochrome-labelled monoclonal antibodies, CD45, CD3, CD19 and CD16/56 (Tetra 2 combi from Beckman Coulter). With the use of a fully standardized volumetric counting flow cytometer, the Aquios (Beckman Coulter), samples will be incubated with MoAbs, erythrocytes will be lysed and subsequently the analysis will be automatically performed. Samples will be calibrated using standardized fixed cells samples (Aquios Immuno-Trol cells, Beckman Coulter). Quality control assessment is performed by participating in the regular program of the UK Neqas (Sheffield), the Alternative Immunomonitoring Program (12 samples per year).

Anti-drug antibodies
Presence of anti-drug antibodies against rituximab will be measured in the proportion of patients with undetectable rituximab levels. This means that in patients with rituximab levels < 0.1 mg/L anti-drug antibodies will be measured in serum. Samples will then be analysed using a validated ADA radio-immune assay at the bioanalytical laboratory of Sanquin.

Adverse Events
The occurrence of adverse events during the study period will be registered using the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.21 AEs that can occur using rituximab IV or SC are an increased risk for infections and (skin) malignancies. AEs will be monitored throughout the study.

Patient preferences
In the intervention group, patient preference for IV or SC RTX therapy will be assessed on the last visit in a small questionnaire, using a 7-point Likert-scale, with one end representing SC therapy and the other end IV therapy.

E.5.2.1

Timepoint(s) of evaluation of this end point

- PK parameters: Blood samples will be drawn pre-dose, post-dose (for IV directly after infusion, for SC 2-4 days after injection), at 3 months, and at 6 months.
- Efficacy: at baseline, at 3 months and at 6 months
- B-cell count: at baseline, at 3 months and at 6 months
- Anti-drug antibodies: antibodies will be determined for low RTX serum levels. Blood samples will be drawn pre-dose, post-dose (for IV directly after infusion, for SC 2-4 days after injection), at 3 months, and at 6 months.
- Adverse Events: throughout the study
- Patient preferences: for the SC group, at 6 months

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

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

Yes

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)

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

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

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

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)

Patients will receive the next dose of rituximab as 200 mg rituximab IV (standard care).

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

2020-09-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-09-07

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2024-09-13

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