Clinical Trials Register

Summary
EudraCT Number:	2012-003230-17
Sponsor's Protocol Code Number:	MO28457
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-10-08
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

Germany - PEI

A.2

EudraCT number

2012-003230-17

A.3

Full title of the trial

A RANDOMIZED, OPEN-LABEL, MULTI-CENTRE STUDY TO EVALUATE PATIENT PREFERENCE WITH SUBCUTANEOUS ADMINISTRATION OF RITUXIMAB VERSUS INTRAVENOUS RITUXIMAB IN PREVIOUSLY UNTREATED PATIENTS WITH CD20+ DIFFUSE LARGE B-CELL LYMPHOMA OR CD20+ FOLLICULAR NON-HODGKIN’S LYMPHOMA GRADES 1, 2 OR 3A

A.3.1

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

A study to assess patient preference after subcutaneous injections of
Mabthera versus intravenous infusions Mabthera in previously-untreated patients with diffuse large B-cell lymphoma or follicular non-Hodgkin’s lymphoma.

A.4.1

Sponsor's protocol code number

MO28457

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	F. Hoffmann-La Roche Ltd.
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	F. Hoffmann-La Roche Ltd.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	F. Hoffmann-La Roche Ltd.
B.5.2	Functional name of contact point	Trial Information Support Line-TISL
B.5.3	Address:
B.5.3.1	Street Address	Grenzacherstrasse 124
B.5.3.2	Town/ city	Basel
B.5.3.3	Post code	4070
B.5.3.4	Country	Switzerland
B.5.6	E-mail	global.rochegenentechtrials@roche.com

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	No
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/ rHuPH20 SC
D.3.2	Product code	RO0452294/F04
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.3.8 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	RO0452294
D.3.9.4	EV Substance Code	SUB12570MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	120
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	Yes
D.3.11.13.1	Other medicinal product type	Recombinant humanized monoclonal antibody
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	MabThera
D.2.1.1.2	Name of the Marketing Authorisation holder	Roche Registration Limited
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	Concentrate and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 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	RO0452294
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	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	Yes
D.3.11.13.1	Other medicinal product type	recombinant humanized monoclonal antibody

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

The target population will consist of adults with previously untreated CD20+ DLBCL or CD20+ follicular NHL Grade 1, 2 or 3a, according to the WHO classification system.

E.1.1.1

Medical condition in easily understood language

previously untreated CD20-positive diffuse large B-cell lymphoma
(DLBCL)

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10012818
E.1.2	Term	Diffuse large B-cell lymphoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 evaluate the proportion of patients indicating an overall preference via a Patient Preference Questionnaire (PPQ) for either the SC or the IV route of rituximab administration.

E.2.2

Secondary objectives of the trial

•To evaluate the safety of rituximab SC
•To evaluate and compare the methods of rituximab administration (SC vs. IV) in terms of:
- Rituximab administration time defined as the time from start to end of the rituximab SC injection or from start to end of the rituximab IV infusion
- Patient-assessed satisfaction and convenience using the Cancer Therapy Satisfaction Questionnaire (CTSQ) and Rituximab Administration Satisfaction Questionnaire (RASQ)
•Immunogenicity (anti-rituximab and anti-rHuPH20 antibodies and the associated rituximab concentration level at each anti-rituximab sampling time point).
•To evaluate efficacy of rituximab SC in terms of:
- complete response rate (CR) including complete response unconfirmed (CRu), 4-8 weeks after the last dose of induction treatment
- EFS
- DFS
- PFS
- overall survival (OS).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age ≥ 18 and ≤ 80 years at time of randomization
2. Histologically confirmed, previously untreated CD20+ DLBCL or CD20+ follicular NHL Grade 1, 2 or 3a, according to the WHO classification system
3. An IPI score of 1-4 or IPI score of 0 with bulky disease, defined as one lesion ≥ 7.5 cm, or FLIPI (low, low-intermediate, high-intermediate, high)
4. At least one bi-dimensionally measurable lesion defined as ≥ 1.5 cm in its largest dimension on CT scan
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3.

E.4

Principal exclusion criteria

1. Transformed lymphoma or FL IIIB
2. Primary CNS lymphoma, blastic variant of mantle-cell lymphoma, histologic evidence of transformation to a Burkitt lymphoma, primary mediastinal DLBCL, primary effusion lymphoma, primary cutaneous DLBCL or primary DLBCL of the testis
3. History of other malignancy that could affect compliance with the protocol or interpretation of results. This includes a malignancy that has been treated but not with curative intent, unless the malignancy has been in remission without treatment for ≥ 5 years prior to enrolment. Note: Patients with a history of curatively treated basal or squamous cell carcinoma or melanoma of the skin or in situ carcinoma of the cervix are eligible for the study.
4.Prior therapy for DLBCL or follicular NHL, with the exception of nodal biopsy or local irradiation
5.Prior treatment with cytotoxic drugs (with the exclusion of methotrexate for CNS prophylaxis in DLBCL) or rituximab for another condition (e.g., rheumatoid arthritis) or prior use of an anti-CD20 antibody
6.Prior use of any monoclonal antibody within 3 months prior to randomization

E.5 End points

E.5.1

Primary end point(s)

The proportion of patients who prefer Rituximab SC over Rituximab IV and the corresponding 95% confidence interval will be estimated

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary analysis of patient preference will take place when all patients have completed induction treatment.

E.5.2

Secondary end point(s)

Safety will be assessed by AEs, AEs of grade ≥ 3, serious adverse events (SAEs), premature withdrawal from the study and from study medication, laboratory parameters, vital signs and ECOG performance status. Adverse events will be coded in MedDRA. The incidence of AEs and SAEs will be summarized by primary system organ class and preferred term. Laboratory parameters will be presented in shift tables of NCI-CTC grade at baseline against worst grade recorded during each treatment period and overall. Other safety variables will be summarized.
The time required for rituximab administration defined as start of rituximab SC injection to end of the injection and start of rituximab IV infusion to the end of the infusion will be summarized.
Patient-assessed satisfaction and convenience using RASQ and CTSQ will be summarized and presented by treatment group.
Efficacy endpoints: The Complete Response (CR/CRu) rate measured 4-8 weeks after the end of treatment will be summarized. The time-to-event endpoints EFS, DFS, PFS and OS from randomization will be summarized overall and by the two treatment sequence groups using the Kaplan Meier approach.
Immunogenicity (anti-rituximab and anti-rHuPH20 antibodies) will be summarized.

E.5.2.1

Timepoint(s) of evaluation of this end point

Safety monitoring of data will be performed periodically by the IDMC.
The final analysis for the efficacy endpoints (CR/CRu, EFS, DFS, PFS and OS) will be provided when the last patient has completed at least 24 months of follow-up, had disease recurrence, withdrawn from the study, been lost to follow up or died, whichever occurs first

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

Yes

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

143

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

Australia

Brazil

Canada

Chile

Colombia

Croatia

Dominican Republic

Egypt

El Salvador

France

Germany

Guatemala

Hong Kong

Hungary

Indonesia

Ireland

Italy

Korea, Republic of

Malaysia

Netherlands

New Zealand

Panama

Peru

Philippines

Portugal

Romania

Sweden

Switzerland

Taiwan

Thailand

Turkey

Vietnam

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

The end of study, defined as last patient last visit (LPLV) will occur 2 years after the last rituximab administration.

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

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:

700

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

200

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

250

F.4.2

For a multinational trial

F.4.2.1

In the EEA

468

F.4.2.2

In the whole clinical trial

900

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)

The Sponsor does not intend to provide rituximab IV or rituximab SC to patients after conclusion of the study or to patients withdrawing before completion of the study.

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

2013-01-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-02-14

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-12-20

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