Clinical Trials Register

Summary
EudraCT Number:	2010-021184-32
Sponsor's Protocol Code Number:	GP13-201
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-06-12
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2010-021184-32

A.3

Full title of the trial

A randomized, double-blind, controlled study to evaluate pharmacokinetics, pharmacodynamics, safety and efficacy of GP2013 and rituximab in patients with rheumatoid arthritis refractory or intolerant to standard DMARDs and
one or up to three anti-TNF therapies

A.3.1

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

GP2013 in the Treatment of RA Patients Refractory to or Intolerant of Standard Therapy

A.4.1

Sponsor's protocol code number

GP13-201

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT01274182

A.5.4

Other Identifiers

Name:

Novartis study code

Number:

GPN013A2301

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	Hexal AG
B.1.3.4	Country	Germany
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	HEXAL AG
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	HEXAL AG
B.5.2	Functional name of contact point	Tamas Shisha
B.5.3	Address:
B.5.3.1	Street Address	Industriestr 25
B.5.3.2	Town/ city	Holzkirchen
B.5.3.3	Post code	83607
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49 8024 476 4717
B.5.5	Fax number	+49 8024 476 2979
B.5.6	E-mail	tamas.shisha@sandoz.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	NA
D.3.2	Product code	GP2013
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.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	rituximab
D.3.9.2	Current sponsor code	GP2013
D.3.9.3	Other descriptive name	NA
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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	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	Rituxan (INN: Rituximab), brand name in the United States
D.2.1.1.2	Name of the Marketing Authorisation holder	Genentech, Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Rituxan
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.3.8 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.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1000
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	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

Refractory rheumatoid arthritis

E.1.1.1

Medical condition in easily understood language

Rheumatoid Arthritis

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	18.0
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 assess bioequivalence between GP2013 and MabThera®/Rituxan® in combination with MTX in patients with active Rheumatoid Arthritis who have not responded adequately, or have shown intolerance, to DMARDs, including MTX, and one or up to three anti-TNF therapies.

E.2.2

Secondary objectives of the trial

To evaluate:
• Additional pharmacokinetic (PK) parameters, pharmacodynamic (PD) and efficacy of GP2013 and MabThera®/Rituxan® in subjects with active RA [ Time Frame: 1.5 years ]
• Safety and tolerability of GP2013 and MabThera®/Rituxan® in patients with RA [ Time Frame: 1.5 years ]
For additional secondary objectives please see full protocol

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients eligible for inclusion in this study have to fulfill all of the following criteria:
1. Patients must give written informed consent before any study-related assessment is performed.
2. Patients must be ≥ 18 years of age.
3. Patients must have a diagnosis of Rheumatoid Arthritis, based on the ACR 1987 criteria.
At least 4 of the following 7 criteria must be fulfilled (and criteria a. through d. must have been present for at least 6 weeks) to confirm the diagnosis of RA:
a. joint morning stiffness of at least one hour
b. swelling of joints in at least three joint areas, diagnosed by a doctor, c. swelling of MCP and wrist joints, diagnosed by a doctor
d. bilateral, symmetric swelling of joints in the same joint areas, diagnosed by a doctor
e. rheumatoid nodule
f. rheumatoid factor seropositivity
g. positive findings in hand radiographs.
4. Patients must have had the diagnosis of RA for at least 6 months at Visit 2.
5. Patients must have active RA at baseline (Visit 2):
• ≥ 6 swollen joints (of 66 joints assessed)
• ≥ 6 tender joints (of 68 joints assessed)
• CRP ≥ 10 mg/L
OR ESR ≥ 28 mm/1st hour
Note: If one of the above criteria is not met at Visit 2, the patient is not eligible for randomization at this time point. A re-assessment (i.e., an additional Visit 2) can be done once within 14 days at the discretion of the investigator. A patient can repeat the whole screening phase (be re-screened) only once.
6. Patients must be seropositive for rheumatoid factor (RF) and/or have antibodies to cyclic citrullinated peptide (anti-CCP) at Visit 1.

For additional inclusion criteria, please refer to section 4.1 of the protocol.

E.4

Principal exclusion criteria

Patients eligible for inclusion in this study must not fulfill any of the following criteria:
1. RA patients with functional status class IV classified according to the ACR 1991 revised criteria.
2. Patients with levels of serum IgG, IgM and IgA below LLN at Visit 1 and/or Visit 2.
3. Patients with systemic manifestations of RA, with the exception of Sjögren’s syndrome.
4. Patients taking high potency opioid analgesics (e.g. methadone, hydromorphone, morphine).
5. Female patients nursing (lactating / breast-feeding), pregnant or planning of pregnancy within 12 months after the last infusion of study drug, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (cut-off as defined by the central laboratory).
6. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are using a highly effective method of birth control (i.e. one that results in a less than 1% per year failure rate when used consistently and correctly, such as implants, injectables, combined oral contraceptives, and intrauterine devices (IUDs)). Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) is not acceptable.
7. Patients who have had any therapy with intra-articular injections (e. g. corticoid) required by a flare up to 4 weeks before randomization.

For additional exclusion criteria, please refer to section 4.2 of the protocol.

E.5 End points

E.5.1

Primary end point(s)

The primary PK variable is
• AUC(0-∞), i.e. the PK profile will be derived over the entire 1st treatment course including both infusions, of GP2013 and MabThera®/Rituxan® concentrations determined in serum samples collected over
24 weeks.
The primary analysis will be based on the PAS population in part I of the study and on PAS+A population in part II of the study, with the PAS population used as part of the sensitivity analysis

E.5.1.1

Timepoint(s) of evaluation of this end point

Primary endpoint determined based on serum samples collected over
24 weeks.

E.5.2

Secondary end point(s)

PK parameters: In addition to AUC(0-∞) and Cmax of the 1st infusion the PK parameters
• AUC(0-14d), AUC(0-12w), AUC(0-24w), Cmax of the 2nd infusion, and tmax (for both infusions), of rituximab (MabThera®/Rituxan®) concentrations determined in serum samples collected over 24 weeks will be assessed.

PD parameter: • Area under the effect-time curve (AUEC(0-t)) from time 0 (before the 1st infusion) up to the
2nd infusion (AUEC(0-14d)) as a percent change from baseline value derived by the linear- trapezoidal rule.
• Percent peripheral B cell levels relative to baseline by visit.
•Number and % of patients with a B cell count below the limit of quantification by Day 1 (after first infusion), 4, 8, and 15 (before second infusion).

Please refer to the clinical study protocol for additional details.

E.5.2.1

Timepoint(s) of evaluation of this end point

Please refer to the clinical study protocol Section 6: Visit schedule and assessmentsfor additional details and Table 6-1: Assessment schedule

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

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)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

Yes

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)

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)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Rituxan

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

Austria

Belgium

Brazil

Bulgaria

Estonia

Germany

Hungary

India

Italy

Poland

Romania

Russian Federation

Spain

Turkey

United Kingdom

United States

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

A patient will be considered to have completed the study when all scheduled study assessments and procedures up to and including Visit 14 (week 52) or, in case of retreatment with another course of study medication, his/ her 26 weeks safety, efficacy and PD follow-up visit, whichever is later, have been concluded.

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:

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

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

124

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

2015-01-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-03-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2016-11-10

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials