Clinical Trials Register

Summary
EudraCT Number:	2013-000114-38
Sponsor's Protocol Code Number:	986
National Competent Authority:	Bulgarian Drug Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-09-09
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

Bulgarian Drug Agency

A.2

EudraCT number

2013-000114-38

A.3

Full title of the trial

A 24-week phase IIb, randomized, double-blind, placebo-controlled, multicenter study to investigate the efficacy and safety of tregalizumab (BT061) in combination with methotrexate in the treatment of subjects with active rheumatoid arthritis who have had an inadequate response to methotrexate alone, followed by a 24-week extension phase:
T cell REgulating Arthritis Trial 2b (TREAT 2b)

A.3.1

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

A 24-week, placebo-controlled, multicenter study to investigate the efficacy and safety of tregalizumab (BT061) in combination with methotrexate in the treatment of subjects with active rheumatoid arthritis who have had an insufficient response to methotrexate alone, followed by a 24-week extension phase:
T cell REgulating Arthritis Trial 2b (TREAT 2b)

A.3.2

Name or abbreviated title of the trial where available

T cell REgulating Arthritis Trial 2b (TREAT 2b)

A.4.1

Sponsor's protocol code number

986

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	Biotest 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	Biotest 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	Biotest AG
B.5.2	Functional name of contact point	Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	Landsteinerstrasse 5
B.5.3.2	Town/ city	Dreieich
B.5.3.3	Post code	63303
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49(0)8011225
B.5.5	Fax number	+49(0)801180
B.5.6	E-mail	986@biotest.de

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	Tregalizumab
D.3.2	Product code	BT061
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	Tregalizumab
D.3.9.2	Current sponsor code	BT061
D.3.9.3	Other descriptive name	A
D.3.9.4	EV Substance Code	SUB33013
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	12.5
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tregalizumab
D.3.9.2	Current sponsor code	BT061
D.3.9.3	Other descriptive name	B
D.3.9.4	EV Substance Code	SUB33013
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	25
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tregalizumab
D.3.9.2	Current sponsor code	BT061
D.3.9.3	Other descriptive name	C
D.3.9.4	EV Substance Code	SUB33013
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	50
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tregalizumab
D.3.9.2	Current sponsor code	BT061
D.3.9.3	Other descriptive name	D
D.3.9.4	EV Substance Code	SUB33013
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	75
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tregalizumab
D.3.9.2	Current sponsor code	BT061
D.3.9.3	Other descriptive name	E
D.3.9.4	EV Substance Code	SUB33013
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	100
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	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
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

Subjects with active rheumatoid arthritis incompletely controlled on stable MTX doses

E.1.1.1

Medical condition in easily understood language

Subjects with active rheumatoid arthritis incompletely controlled on stable MTX doses

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	17.1
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 determine the efficacy and safety of three doses of tregalizumab administered
over 24 weeks, followed by a 24-week extension phase (active treatment only), in
combination with methotrexate (MTX), for the treatment of adult subjects with active
rheumatoid arthritis (RA) who have had an inadequate response to MTX alone
(MTX-IR).

E.2.2

Secondary objectives of the trial

Not applicable

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subject demonstrates active RA according to the 1987 American College of Rheumatology (ACR) or 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for RA with functional class I–III for ≥6 months.
2. Subject receives oral or parenteral MTX treatment for ≥12 weeks (overall), with
an unchanged mode of application and stable MTX dose of ≥15 mg per week (or ≥12.5 mg per week in case of MTX intolerance), but no more than the highest locally approved dose for RA, for ≥8 weeks prior to baseline. The dose of MTX is expected to remain stable throughout the study and may be adjusted only for
safety reasons. If applicable, the dose of folic acid must be unchanged for ≥8 weeks prior to baseline.
3. Subject meets the following two criteria at both screening and baseline:
− At least 6 swollen joints at 28-joint assessment.
− At least 6 tender joints at 28-joint assessment.
4. Subject has an erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) above the upper limit of normal (ULN) at screening. These tests may be repeated once during the screening period at the discretion of the investigator.
5. Subject is ≥18 and ≤75 years of age.
6. Subject has a body mass index ≥18 and ≤35 kg/m².
7. Subject receives treatment with corticosteroids ≤10 mg prednisone equivalent,
stable for at least 4 weeks prior to baseline and during the study, if applicable.
8. Subject receives treatment with non-steroidal anti-inflammatory drugs (NSAIDs), stable for at least 2 weeks prior to baseline and during the study, if applicable.
9. Female subjects of childbearing potential: has both a negative serum pregnancy test at screening and a negative urine pregnancy test at baseline.
10. Subject is judged to be in good general health as determined by the investigator
based upon the results of medical history, laboratory profile, physical examination, chest X-ray (within 3 months before screening date is acceptable), and 12−lead electrocardiogram (ECG).
11. Subject has a cluster of differentiation 4 (CD4) cell count of >400/µL at screening.
12. Subject is willing and able to provide written informed consent.
13. Subject is willing and able to self administer SC injections or has a qualified person available to administer SC injections.
From week 24 onwards:
14. Subject has completed the main phase of the study (Visit V10 at 24 weeks)
15. Subjects who experienced a SAE or a medically significant laboratory or ECG abnormality in the main phase of the study who have not been previously discontinued must have completely recovered prior to entering the extension phase.
16. Subject must have a CD4 cell count of 400/µL at Week 16.
17. Subjects must have achieved a reduction in TJC and SJC of ≥20% at Week 24

E.4

Principal exclusion criteria

1. Subject has previous exposure to any systemic biologic therapy (details in protocol), to Janus kinase (JAK) or spleen tyrosine kinase (SYK) inhibitors, or to tregalizumab. Previous treatment with an anti-TNF agent is allowed only, if all of the following criteria apply:
− treatment was stopped for reasons other than lack of efficacy or adverse events (AEs)
− treatment was stopped at least 12 weeks or five half-lives of the compound prior to baseline (whichever is longer), and − the treatment period did not exceed 6 weeks.
2. Subject received treatment with conventional disease-modifying anti-rheumatic drugs (DMARDs) apart from MTX in the 12 weeks prior to baseline, and for DMARD leflunomide in the 24 weeks prior to baseline (exeptions in protocol).
3. Subject has been treated with intra-articular or parenteral administration of corticosteroids in the 4 weeks prior to baseline. Inhaled corticosteroids for stable medical conditions are allowed.
4. Subject has undergone joint surgery in the 12 weeks prior to baseline (at joints to be assessed within the study) or has undergone major surgery in the 8 weeks prior to baseline.
5. Subject has a history of acute inflammatory joint disease of an origin other than RA or subject has any other rheumatic disease other than RA . However, subjects may have secondary Sjögren's syndrome.
6. Vaccination with live vaccines in the 12 weeks prior to baseline or vaccination with killed vaccines in the 4 weeks prior to baseline.
7. Subject has a history of an allergic reaction or significant sensitivity to constituents of study drugs or a history of severe allergic or anaphylactic reaction to proteins of human origin.
8. Subject has participated in another clinical study in the 90 days prior to baseline or within 5 half lives of the investigated compound—whichever is longer—or plans to do so during the study.
9. Subject has a poorly controlled medical condition - detailed list in the protocol.
10. Subject has a history of clinically significant hematologic, renal, or liver disease , or gastroenteric ulcer or has, at screening, clinically relevant deviations in laboratory tests - detailed list in the protocol.
11. Subject has a presence or history of malignancy within the previous 5 years (exeptions in protocol).
12. Subject has a presence or history of lymphoproliferative disease.
13. Subject has a positive diagnosis for acute or chronic infections (list in protocol).
14. Subject has a history or presence of active or latent tuberculosis.
15. Subject has an acute or clinically symptomatic Epstein Barr virus (EBV) or cytomegalovirus (CMV) infection.
16. Subject has a serious local or systemic infection or recurrent chronic infections in the 6 weeks prior to the screening visit (Visit V1) or during the screening period.
17. Subject has any infection requiring antibiotic or antiviral therapy by any route of administration in the 2 weeks prior to baseline.
18. Subject currently uses or plans to use anti retroviral therapy at any time during the study.
19. Subject received an alkylating agent in the 6 months prior to baseline.
20. Subject has a history of clinically significant drug or alcohol abuse within the last 12 months.
21.Subject is a pregnant or nursing woman or is considering becoming pregnant during the study or in the 3 months after the last dose of study drug.
22.Subject is a woman of childbearing potential (unless surgically sterile or post menopausal >52 weeks) who is not using two independent effective contraceptive methods during the study and for at least 3 months after the last administration of study drug OR
Subject is a man and is not vasectomized or is not using two independent effective contraceptive methods or who is planning sperm donation during the study and for at least 3 months after the last administration of study drug.
For both women and men sexual abstinence is an acceptable method of contraception.
23. Blood donation between 56 days prior to baseline and study end.
24. Subject is an employee of any involved study investigator or any involved institution including the sponsor.
25. Subject is not able or is lacking motivation to adhere to the study requirements and to comply with the study schedule.
From Week 24 onwards
26. Subject has had a change in his/her preexisting medical condition or the onset of a new medical condition
27. Subject has, at Week 16, clinically relevant deviations in laboratory tests - details in protocol.
28. Subject has an acute or clinically symptomatic EBV or CMV infection.
29. Subject has a serious local or systemic infection or recurrent chronic infection at Week 24.
30. Subject is a pregnant or nursing woman or considering becoming pregnant during the study or within 3 months after the last dose of study medication.

E.5 End points

E.5.1

Primary end point(s)

The proportion of subjects who achieve an ACR20 at Week 12 following treatment with tregalizumab (25 mg, 100 mg or 200 mg) + MTX compared with subjects treated with placebo + MTX.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 12

E.5.2

Secondary end point(s)

Proportion of subjects with an ACR20 at Week 24,
Proportion of subjects with an ACR50 at Week 12,
Proportion of subjects with an ACR50 at Week 24
Proportion of subjects with an ACR70 at Week 12
Proportion of subjects with an ACR70 at Week 24
Proportion of subjects with a Disease Activity Score (DAS)28 ≤2.6 at Week 12
Proportion of subjects with a DAS28 ≤2.6 at Week 24
Proportion of subjects with low disease activity (DAS28 ≤3.2, Simplified Disease Activity Index [SDAI] ≤11, Clinical Disease Activity Index [CDAI] ≤10) at Week 12
Proportion of subjects with low disease activity (DAS28 ≤3.2, SDAI ≤11, CDAI ≤10) at Week 24
ACR score by visit
DAS28 by visit
EULAR response by visit
ACR and DAS28 score components by visit
-TJC (68 joint count, incl. 28 joint count)
- SJC (66 joint count, incl. 28 joint count)
-CRP
-ESR
- Patient's assessment of pain (Visual Analog Scale [VAS])
- Patient's Global Assessment of Disease Activity (VAS)
- Physician Global Assessment of Disease Activity (VAS)
- Health Assessment Questionnaire Disability Index (HAQ DI)
Morning stiffness by visit
SDAI by visit
CDAI by visit
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue by visit
Short Form (36)® Health Survey, Version 2.0 (SF 36) by visit
Work Productivity and Activity Impairment Questionnaire: Rheumatoid Arthritis WPAI RA by visit

E.5.2.1

Timepoint(s) of evaluation of this end point

Screening, Weeks 0, 1, 2, 4, 6, 8, 12, 16, 24, 28, 32, 40, 48 except FACIT-Fatigue, SF-36, WPAI-RA (Screening, Weeks 0, 2, 6, 12, 24, 32, 48)

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Immunogenicity

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)

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)

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

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

Bulgaria

Canada

Czech Republic

Estonia

Germany

Hungary

Lithuania

Mexico

Poland

Russian Federation

Serbia

Slovakia

Sweden

Ukraine

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

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

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:

243

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Illiterate people are allowed to participate

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

178

F.4.2.2

In the whole clinical trial

304

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)

Normal 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

2013-10-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-10-23

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2015-06-25

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