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Clinical Trial Results:
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)

Summary
EudraCT number	2013-000114-38
Trial protocol	DE HU CZ EE LT SK BG
Global end of trial date	31 Jul 2015

Results information
Results version number	v1(current)
This version publication date	30 Oct 2021
First version publication date	30 Oct 2021
Other versions
Summary report(s)	Biotest-BT061

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

Study 986

ISRCTN number

US NCT number

NCT01999192

WHO universal trial number (UTN)

Sponsor organisation name

Biotest AG

Sponsor organisation address

Landsteiner Str. 5, Dreieich , Germany, 63303

Public contact

Clinical Trial Information, Biotest AG, +49 (0)8011225, 986@biotest.de

Scientific contact

Clinical Trial Information, Biotest AG, +49 (0)8011225, 986@biotest.de

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Jul 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

31 Jul 2015

Was the trial ended prematurely?

Yes

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).

Protection of trial subjects

1) Possibility of home administration after training at site to reduce visit burden 2) 'Rescue' pain/analgesic treatment on demand 3) Physical exam and test of laboratory safety parameters at each visit 4) Special withdrawal criteria: (a) CD4 cell count below 400/μL measured at two sequential assessments 2 weeks apart (b) Any opportunistic or systemic infection requiring parenteral anti-infectives or hospitalization (c) Active TB 5) Collection of AEs that occurred during the injection or since their last visit 6) Regular medical review of subject data

Background therapy

Methotrexate ≥15 mg (or ≥12.5 mg in case of MTX intolerance)

Evidence for comparator

Actual start date of recruitment

20 Sep 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy

Long term follow-up duration

6 Months

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Mexico: 32

Country: Number of subjects enrolled

United States: 11

Country: Number of subjects enrolled

Russian Federation: 53

Country: Number of subjects enrolled

Ukraine: 38

Country: Number of subjects enrolled

Canada: 2

Country: Number of subjects enrolled

Serbia: 9

Country: Number of subjects enrolled

Poland: 67

Country: Number of subjects enrolled

Slovakia: 7

Country: Number of subjects enrolled

Bulgaria: 30

Country: Number of subjects enrolled

Czech Republic: 30

Country: Number of subjects enrolled

Estonia: 5

Country: Number of subjects enrolled

Germany: 14

Country: Number of subjects enrolled

Hungary: 18

Country: Number of subjects enrolled

Lithuania: 5

Worldwide total number of subjects

321

EEA total number of subjects

176

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

281

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

In total, 321 subjects were randomized (83, 80, and 78 in the BT061 25 mg, 100 mg and 200 mg groups, respectively and 80 in the placebo group). A total of 321 subjects were included in the Safety set (SS), 313 were included in the Full analysis set (FAS), and 183 subjects were included in the Per-protocol set (PPS).

Screening details

screening period (28-OCT-2013 to 30-Sep-2014): 715 patients screened and 321 patients randmised; Main inclusion: subjects 18-75 yrs with active RA ≥6 months; stable MTX treatment for ≥12 weeks; ≥6 swollen/tender joints at 28-joint count; Exclusion: Anti-TNF failures; Previous exposure to systemic biologics.

Period 1 title

Main Phase 1

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

double dummy techniques; BT061 solution and the placebo formulation with identical volume and in identical containers. Systemic effects of BT061 on laboratory parameters : lymphocytes and CD3CD4 cell count and IL-6, TNF-α levels, and CRP were kept blinded during the study. Unblinding was only to be carried out if a medical emergency required the identification of the IMP for that particular subject. Any subject for whom the blind was broken was to be discontinued from the study.

Are arms mutually exclusive

Placebo

Arm description

Placebo SC, once weekly

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

1 ml SC once weekly

Tregalizumab 25 mg

Arm description

Active treatment : Tregalizumab 25 mg SC, once weekly

Arm type

Experimental

Investigational medicinal product name

Tregalizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

25 mg SC once weekly

Tregalizumab 100 mg

Arm description

Active treatment: Tregalizumab 100 mg SC, once weekly

Arm type

Experimental

Investigational medicinal product name

Tregalizumab 100 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

100 mg SC once weekly

Tregalizumab 200 mg

Arm description

Active treatment: Tregalizumab 200 mg SC, once weekly

Arm type

Experimental

Investigational medicinal product name

Tregalizumab 200 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

200 mg SC once weekly

Number of subjects in period 1	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Started	80	83	80	78
Qualify for FAS	79	80	78	76
Completed	72	72	70	70
Not completed	8	11	10	8
Adverse event, serious fatal	-	-	-	1
Consent withdrawn by subject	3	2	3	4
Adverse event, non-fatal	2	5	2	1
Failure to meet randomisation criteria	2	2	2	1
NK	1	-	1	1
Lost to follow-up	-	1	-	-
Lack of efficacy	-	1	2	-

Period 2 title

Main Phase 2

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Blinding implementation details

same as Main Phase 1

Are arms mutually exclusive

Placebo

Arm description

no active component

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

1 ml SC once weekly

Tregalizumab 25 mg

Arm description

Active treatment

Arm type

Experimental

Investigational medicinal product name

Tregalizumab 25mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

25 mg SC once weekly

Tregalizumab 100 mg

Arm description

Active treatment

Arm type

Experimental

Investigational medicinal product name

Tregalizumab 100 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

100 mg SC once weekly

Tregalizumab 200 mg

Arm description

Active treatment

Arm type

Experimental

Investigational medicinal product name

Tregalizumab 200 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

200 mg SC once weekly

Number of subjects in period 2	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Started	44	53	49	69
Completed	43	46	44	56
Not completed	1	7	5	13
Consent withdrawn by subject	-	2	1	3
Adverse event, non-fatal	1	2	-	5
Failure to meet randomisation criteria	-	1	3	3
NK	-	2	-	-
Lack of efficacy	-	-	1	2

Period 3 title

Extension Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Tregalizumab 25 mg

Arm description

Active treatment

Arm type

Experimental

Investigational medicinal product name

Tregalizumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

25 mg SC once weekly

Tregalizumab 100 mg

Arm description

Active treatment

Arm type

Experimental

Investigational medicinal product name

Tregalizumab 100 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

100 mg SC once weekly

Tregalizumab 200 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Tregalizumab 200 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

200 mg SC once weekly

Number of subjects in period 3	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Started	54	57	67
Completed	41	38	44
Not completed	13	19	23
Consent withdrawn by subject	4	3	4
Physician decision	1	-	2
Adverse event, non-fatal	-	1	2
Sponsor decision, early termination	5	8	9
NK	2	5	5
Lost to follow-up	-	1	1
Protocol deviation	1	-	-
Lack of efficacy	-	1	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Placebo SC, once weekly

Reporting group title

Tregalizumab 25 mg

Reporting group description

Active treatment : Tregalizumab 25 mg SC, once weekly

Reporting group title

Tregalizumab 100 mg

Reporting group description

Active treatment: Tregalizumab 100 mg SC, once weekly

Reporting group title

Tregalizumab 200 mg

Reporting group description

Active treatment: Tregalizumab 200 mg SC, once weekly

Notes
[1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
Justification: The statistical analysis are based on the FAS set, 8 subjects (1x Placebo, 3 x 25mg, 2x 100mg, 2x 200mg) did not fullfill the FAS requirements to receive at least one dose of study medication and have one post-baseline assessment. Therefore instead of 321 sujects randomised only 313 are included in the FAS.

Reporting group values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg	Total
Number of subjects	80	83	80	78
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Mean Age
Units: years
arithmetic mean (standard deviation)	53.9 ( 11.2 )	53.7 ( 9.85 )	48.9 ( 11.78 )	52.8 ( 11.2 )	-
Gender categorical
Units: Subjects
Female	66	71	68	58	263
Male	13	9	10	18	50
Unknown	1	3	2	2	8
Race
Units: Subjects
Caucasian	70	69	69	69	277
Black/African	0	2	0	1	3
American	0	0	0	0	0
Asian	0	0	0	0	0
Other	9	9	9	6	33
Unknown	1	3	2	2	8
Functional capacity class
Units: Subjects
Class I	10	10	9	4	33
Class II	57	56	60	56	229
Class III	12	14	9	16	51
Class IV	0	0	0	0	0
Unknown	1	3	2	2	8
Rheumatoid Factor
Units: Subjects
Positive	57	55	63	52	227
Negative	13	15	9	14	51
Unknown	10	13	8	12	43
BMI
Units: kg/m2
arithmetic mean (standard deviation)	27.59 ( 4.332 )	27.24 ( 4.616 )	25.91 ( 4.645 )	26.77 ( 4.395 )	-
Time since diagnosis of Rheumatoid Arthritis
Units: Years
arithmetic mean (standard deviation)	7.09 ( 7.847 )	7.08 ( 6.838 )	7.58 ( 7.779 )	7.78 ( 7.426 )	-
Duration of methotrexate treatment
Units: Years
arithmetic mean (standard deviation)	2.46 ( 4.254 )	2.22 ( 3.866 )	2.83 ( 4.181 )	2.45 ( 2.912 )	-
Methotrexate dose
Units: mg/day
arithmetic mean (standard deviation)	2.36 ( 0.462 )	2.37 ( 0.444 )	2.42 ( 0.990 )	2.43 ( 0.751 )	-

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

The FAS comprised all subjects randomized who received at least one dose of study medication and had at least one post-dose assessment. The FAS was used as the primary analysis set for reporting the analysis of efficacy endpoints.

Subject analysis set title

Safety Set (SS)

Subject analysis set type

Safety analysis

Subject analysis set description

The Safety set comprised all subjects who received at least one dose of study medication. The Safety set was used as the population for the reporting of safety endpoints.

Subject analysis set title

Pharmacokinetic Analysis Set (PKS)

Subject analysis set type

Sub-group analysis

Subject analysis set description

The Pharmacokinetic Analysis Set included all subjects in the SS who have at least one plasma concentration measurement of tregalizumab.

Subject analysis set title

Per-Protocol Set (PPS)

Subject analysis set type

Per protocol

Subject analysis set description

The PPS comprised all subjects in the FAS who finished the main phase of the study or terminated the study prematurely in line with the protocol and excluding those with major protocol deviations. Subjects who missed more than two doses of the study medication prior to the primary endpoint at Week 12 did not qualify for the PPS. Subjects must have received the last two study medication injections of Week 10 and Week 11 to qualify for the PPS.

Subject analysis sets values	Full Analysis Set (FAS)	Safety Set (SS)	Pharmacokinetic Analysis Set (PKS)	Per-Protocol Set (PPS)
Number of subjects	313	321	321	183
Age categorical
Units: Subjects
In utero
Preterm newborn infants (gestational age < 37 wks)
Newborns (0-27 days)
Infants and toddlers (28 days-23 months)
Children (2-11 years)
Adolescents (12-17 years)
Adults (18-64 years)
From 65-84 years
85 years and over
Age continuous
Mean Age
Units: years
arithmetic mean (standard deviation)	( )	( )	( )	( )
Gender categorical
Units: Subjects
Female	263
Male	50
Unknown
Race
Units: Subjects
Caucasian	277
Black/African	3
American	0
Asian	0
Other	33
Unknown	0
Functional capacity class
Units: Subjects
Class I	33
Class II	229
Class III	51
Class IV	0
Unknown	0
Rheumatoid Factor
Units: Subjects
Positive	227
Negative	51
Unknown	35
BMI
Units: kg/m2
arithmetic mean (standard deviation)	( )	( )	( )	( )
Time since diagnosis of Rheumatoid Arthritis
Units: Years
arithmetic mean (standard deviation)	7.38 ( 7.451 )	( )	( )	( )
Duration of methotrexate treatment
Units: Years
arithmetic mean (standard deviation)	( )	( )	( )	( )
Methotrexate dose
Units: mg/day
arithmetic mean (standard deviation)	( )	( )	( )	( )

End points

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Reporting group title

Placebo

Reporting group description

Placebo SC, once weekly

Reporting group title

Tregalizumab 25 mg

Reporting group description

Active treatment : Tregalizumab 25 mg SC, once weekly

Reporting group title

Tregalizumab 100 mg

Reporting group description

Active treatment: Tregalizumab 100 mg SC, once weekly

Reporting group title

Tregalizumab 200 mg

Reporting group description

Active treatment: Tregalizumab 200 mg SC, once weekly

Reporting group title

Placebo

Reporting group description

no active component

Reporting group title

Tregalizumab 25 mg

Reporting group description

Active treatment

Reporting group title

Tregalizumab 100 mg

Reporting group description

Active treatment

Reporting group title

Tregalizumab 200 mg

Reporting group description

Active treatment

Reporting group title

Tregalizumab 25 mg

Reporting group description

Active treatment

Reporting group title

Tregalizumab 100 mg

Reporting group description

Active treatment

Reporting group title

Tregalizumab 200 mg

Reporting group description

Subject analysis set title

Full Analysis Set (FAS)

Subject analysis set type

Full analysis

Subject analysis set description

Subject analysis set title

Safety Set (SS)

Subject analysis set type

Safety analysis

Subject analysis set description

The Safety set comprised all subjects who received at least one dose of study medication. The Safety set was used as the population for the reporting of safety endpoints.

Subject analysis set title

Pharmacokinetic Analysis Set (PKS)

Subject analysis set type

Sub-group analysis

Subject analysis set description

The Pharmacokinetic Analysis Set included all subjects in the SS who have at least one plasma concentration measurement of tregalizumab.

Subject analysis set title

Per-Protocol Set (PPS)

Subject analysis set type

Per protocol

Subject analysis set description

Primary: ACR 20 Response rate at Week 12

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End point title

ACR 20 Response rate at Week 12

End point description

Full Analysis Set for observed cases (OC) at Week 12

End point type

Primary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	71	66	70
Units: percentage of subject number	25	30	31	31

Attachments

ACR20/50/70 Response rate at Week 12 (FAS, OC)

Statistical Test

Statistical analysis description

using Chi square test ; If ≥25% of the cells that have expected counts less than 5, stratification will not be taken in to consideration (i.e. Chi-square analysis will be performed). The difference will be presented as a relative risk. There will be no adjustment for multiplicity, which is aligned with the sample size calculation. The analysis will be performed on Observed Cases (OC).

Comparison groups

Tregalizumab 25 mg v Placebo v Tregalizumab 100 mg v Tregalizumab 200 mg

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Chi-squared

Parameter type

Risk difference (RD)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: ACR 20 Response rate at Week 24

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End point title

ACR 20 Response rate at Week 24

End point description

Full analysis Set for observed cases analyses at Week 24, subjects who have moved from Placebo to active medication or to a higher active dose at Week 12 are presented with their Week 24 response against the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	56	55
Units: percentage of subject number	35	36	31	31

statistical test

Statistical analysis description

Comparison groups

Placebo v Tregalizumab 25 mg v Tregalizumab 100 mg v Tregalizumab 200 mg

Number of subjects included in analysis

237

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Chi-squared

Parameter type

Risk difference (RD)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: ACR 50 Response rate at Week 12

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End point title

ACR 50 Response rate at Week 12

End point description

Full Analysis Set for observed cases (OC) at Week 12

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	71	66	70
Units: percentage of subject number	7	9	6	9

Statistical Test

Statistical analysis description

Comparison groups

Placebo v Tregalizumab 25 mg v Tregalizumab 100 mg v Tregalizumab 200 mg

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Chi-squared

Parameter type

Risk difference (RD)

Confidence interval

level

95%

Secondary: ACR 50 Response rate at Week 24

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End point title

ACR 50 Response rate at Week 24

End point description

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	56	55
Units: percentage of subject number	13	13	11	11

Statistical analysis

Statistical analysis description

Comparison groups

Placebo v Tregalizumab 25 mg v Tregalizumab 100 mg v Tregalizumab 200 mg

Number of subjects included in analysis

237

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Chi-squared

Parameter type

Risk difference (RD)

Confidence interval

level

95%

Secondary: ACR 70 Response rate at Week 12

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End point title

ACR 70 Response rate at Week 12

End point description

Full Analysis Set for observed cases (OC) at Week 12

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	71	66	70
Units: percentage of subject number	1	2	1	3

Statistical test

Statistical analysis description

Comparison groups

Placebo v Tregalizumab 25 mg v Tregalizumab 100 mg v Tregalizumab 200 mg

Number of subjects included in analysis

278

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Chi-squared

Parameter type

Risk difference (RD)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: ACR 70 Response rate at Week 24

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End point title

ACR 70 Response rate at Week 24

End point description

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	56	55
Units: percentage of subject number	2	6	1	4

Statistical test

Statistical analysis description

Comparison groups

Placebo v Tregalizumab 25 mg v Tregalizumab 100 mg v Tregalizumab 200 mg

Number of subjects included in analysis

237

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Chi-squared

Parameter type

Risk difference (RD)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Secondary: Proportion of subjects with a DAS28 < 2.6 at Week 12

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End point title

Proportion of subjects with a DAS28 < 2.6 at Week 12

End point description

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	69	70	66	70
Units: subjects	2	0	0	2

No statistical analyses for this end point

Secondary: Proportion of subjects with a DAS28 <2.6 at Week 24

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End point title

Proportion of subjects with a DAS28 <2.6 at Week 24

End point description

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	44	53	48	48
Units: subjects	0	2	0	4

No statistical analyses for this end point

Secondary: Proportion of subjects with low disease activity at Week 12

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End point title

Proportion of subjects with low disease activity at Week 12

End point description

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	69	69	64	70
Units: subjects	3	2	0	4

No statistical analyses for this end point

Secondary: Proportion of Subjects with Low Disease Activity at Week 24

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End point title

Proportion of Subjects with Low Disease Activity at Week 24

End point description

Low disease activity was defined as DAS28 <3.2, SDAI ≤11, CDAI ≤10. Percentages are based upon the number of subjects in the full analysis set at Main Phase with a value at the relevant timepoint by treatment group (observed cases). Subjects are presented according to the treatment they were randomized to at Week 0. Full analysis Set for observed cases analyses at Week 24, subjects who have moved from Placebo to active medication or to a higher active dose at Week 12 are presented with their Week 24 response against the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	63	59	53	52
Units: subjects	3	7	1	6

No statistical analyses for this end point

Secondary: Proportion of Subjects in Remission According to the 2011 ACR/EULAR Criteria at Week 12

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End point title

Proportion of Subjects in Remission According to the 2011 ACR/EULAR Criteria at Week 12

End point description

Percentages are based upon the number of subjects in the full analysis set at Main Phase with a value at the relevant timepoint by treatment group (observed cases). Subjects are presented according to the treatment they were randomized to at Week 0. ACR/EULAR defined remission as tender joint count <=1, swollen joint count <=1, CRP <=1mg/dL and Patient Global Assessment <=1 (on a 0-10 scale).

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	69	70	65	70
Units: subjects	1	0	0	1

Superiority vs placebo

Statistical analysis description

Statistical Analysis was based on Fishers Exact Test as >=25% of cells had expected counts of less than 5.

Comparison groups

Tregalizumab 25 mg v Tregalizumab 100 mg v Tregalizumab 200 mg

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

≤ 0.05 ^[2]

Method

Fisher exact

Parameter type

Risk difference (RD)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[1] - p-value is for comparison of each group vs Placebo.
[2] - the default significant level was < or = 0.05 (5%)

Secondary: Proportion of Subjects in Remission According to the 2011 ACR/EULAR Criteria at Week 24

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End point title

Proportion of Subjects in Remission According to the 2011 ACR/EULAR Criteria at Week 24

End point description

Percentages are based upon the number of subjects in the full analysis set at Main Phase with a value at the relevant timepoint by treatment group (observed cases). Subjects are presented according to the treatment they were randomized to at Week 0. Full analysis Set for observed cases analyses at Week 24, subjects who have moved from Placebo to active medication or to a higher active dose at Week 12 are presented with their Week 24 response against the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg. ACR/EULAR defines remission as Tender joint count <=1, Swollen Joint count <=1, CRP <=1mg/dL and Patient Global Assessment <=1 (on a 0-10 scale).

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	63	59	53	53
Units: subjects	0	0	0	2

Fisher’s exact test

Statistical analysis description

Statistical Analysis was based on Fishers Exact Test as >=25% of cells have expected counts of less than 5.

Comparison groups

Placebo v Tregalizumab 25 mg v Tregalizumab 100 mg v Tregalizumab 200 mg

Number of subjects included in analysis

228

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05 ^[3]

Method

Fisher exact

Parameter type

Risk difference (RD)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Notes
[3] - The default significant level was < or = 0.05 (5%)

Secondary: Mean change in SDAI at Week 12

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End point title

Mean change in SDAI at Week 12

End point description

Change from baseline was analyzed using an analysis of covariance model with treatment in Main Phase 1 and CRP level (≤ULN, >ULN) as factors and baseline as a covariate. Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects are presented according to the treatment they were randomized to at Week 0. Change from baseline is defined as value at baseline minus value at post-baseline visit. A positive change/percentage change indicates an improvement.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	69	69	64	70
Units: scores
arithmetic mean (standard deviation)	14.54 ( 13.223 )	16.90 ( 13.121 )	13.25 ( 13.718 )	13.68 ( 11.188 )

No statistical analyses for this end point

Secondary: Mean change in SDAI at Week 24

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End point title

Mean change in SDAI at Week 24

End point description

Change from baseline was analyzed using an analysis of covariance model with treatment in Main Phase 1 and CRP level (≤ULN, >ULN) as factors and baseline as a covariate. Change from baseline is defined as value at baseline minus value at post-baseline visit. A positive change/percentage change indicates an improvement. Baseline was defined as the last non-missing value prior to first dose of study medication. Full analysis Set for observed cases analyses at Week 24, subjects who have moved from Placebo to active medication or to a higher active dose at Week 12 are presented with their Week 24 response against the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	63	59	53	52
Units: scores
arithmetic mean (standard deviation)	21.17 ( 12.395 )	22.78 ( 12.982 )	17.73 ( 15.847 )	20.03 ( 12.421 )

Fisher's Exact test

Comparison groups

Placebo v Tregalizumab 25 mg v Tregalizumab 100 mg v Tregalizumab 200 mg

Number of subjects included in analysis

227

Analysis specification

Pre-specified

Analysis type

superiority

P-value

≤ 0.05

Method

Fisher exact

Parameter type

Mean difference (final values)

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

Variability estimate

Standard deviation

Secondary: Mean Change in CDAI at Week 12

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End point title

Mean Change in CDAI at Week 12

End point description

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	70	65	70
Units: scores
arithmetic mean (standard deviation)	14.21 ( 13.284 )	16.75 ( 13.048 )	13.28 ( 13.375 )	14.26 ( 10.711 )

No statistical analyses for this end point

Secondary: Mean Change in CDAI at Week 24

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End point title

Mean Change in CDAI at Week 24

End point description

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	56	54
Units: scores
arithmetic mean (standard deviation)	21.46 ( 12.392 )	22.72 ( 12.344 )	17.95 ( 15.564 )	20.13 ( 12.035 )

No statistical analyses for this end point

Secondary: Mean Change in tender joint counts (68) at Week 12

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End point title

Mean Change in tender joint counts (68) at Week 12

End point description

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	72	71	66	70
Units: joints
arithmetic mean (standard deviation)	8.41 ( 10.983 )	11.65 ( 10.414 )	8.76 ( 10.804 )	8.40 ( 9.665 )

No statistical analyses for this end point

Secondary: Mean change in tender joint counts (68) at Week 24

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End point title

Mean change in tender joint counts (68) at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Change from baseline is defined as value at baseline minus value at post-baseline visit. A positive change indicates an improvement. The maximum tender joint counts was 68. Full analysis Set for observed cases analyses at Week 24, subjects who have moved from Placebo to active medication or to a higher active dose at Week 12 are presented with their Week 24 response against the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	66	61	57	55
Units: joints
arithmetic mean (standard deviation)	12.89 ( 10.123 )	14.72 ( 10.202 )	12.56 ( 12.463 )	11.98 ( 11.649 )

No statistical analyses for this end point

Secondary: Mean Change in swollen joint counts (66) at Week 12

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End point title

Mean Change in swollen joint counts (66) at Week 12

End point description

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	72	71	66	70
Units: joints
arithmetic mean (standard deviation)	6.00 ( 7.571 )	8.38 ( 8.171 )	7.55 ( 8.294 )	7.43 ( 7.789 )

No statistical analyses for this end point

Secondary: Mean Change in swollen joint counts (66) at Week 24

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End point title

Mean Change in swollen joint counts (66) at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Change from baseline is defined as value at baseline minus value at post-baseline visit. A positive change indicated an improvement. The maximum swollen joint counts was 66. Full analysis Set for observed cases analyses at Week 24, subjects who have moved from Placebo to active medication or to a higher active dose at Week 12 are presented with their Week 24 response against the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	66	61	57	55
Units: joints
arithmetic mean (standard deviation)	9.63 ( 6.673 )	10.68 ( 9.067 )	10.27 ( 9.928 )	8.96 ( 7.164 )

No statistical analyses for this end point

Secondary: Mean Change in CRP level at Week 12

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End point title

Mean Change in CRP level at Week 12

End point description

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	70	71	67	70
Units: mg/L
arithmetic mean (standard deviation)	0.5 ( 13.73 )	-2.4 ( 10.96 )	-0.9 ( 14.51 )	-5.7 ( 20.02 )

No statistical analyses for this end point

Secondary: Mean Change in CRP level at Week 24

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End point title

Mean Change in CRP level at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Where C-reactive protein (CRP)was reported as <1, i.e. below the lower limit of quantification, this was set equal to 1, the limit of quantification. Change from baseline was defined as value at baseline minus value at post-baseline visit. A positive change indicated an improvement. Subjects were presented according to the treatment they were randomized to at Week 0. Full analysis Set for observed cases analyses at Week 24, subjects who have moved from Placebo to active medication or to a higher active dose at Week 12 are presented with their Week 24 response against the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	64	59	54	53
Units: mg/L
arithmetic mean (standard deviation)	-1.2 ( 17.51 )	-1.2 ( 13.35 )	-0.4 ( 11.56 )	-0.5 ( 13.71 )

No statistical analyses for this end point

Secondary: Mean Change in Erythrocyte Sedimentation Rate (ESR) at Week 12

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End point title

Mean Change in Erythrocyte Sedimentation Rate (ESR) at Week 12

End point description

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	70	71	68	70
Units: mm/h
arithmetic mean (standard deviation)	12.1 ( 13.93 )	14.8 ( 46.03 )	10.2 ( 26.67 )	9.9 ( 24.25 )

No statistical analyses for this end point

Secondary: Mean Change in Erythrocyte Sedimentation Rate (ESR) at Week 24

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End point title

Mean Change in Erythrocyte Sedimentation Rate (ESR) at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Change from baseline is defined as value at baseline minus value at post-baseline visit. A positive change indicates an improvement. Full analysis Set for observed cases analyses at Week 24, subjects who have moved from Placebo to active medication or to a higher active dose at Week 12 are presented with their Week 24 response against the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	66	60	56	53
Units: mm/h
arithmetic mean (standard deviation)	12.3 ( 15.99 )	17.5 ( 50.79 )	10.7 ( 24.92 )	10.0 ( 18.66 )

No statistical analyses for this end point

Secondary: Change in subject’s global assessment of pain at Week 12

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End point title

Change in subject’s global assessment of pain at Week 12

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Change from baseline was defined as value at baseline minus value at post-baseline visit. A positive change indicated an improvement. Subjects were presented according to the treatment they were randomized to at Week 0. The subject was asked to assess his or her current level of pain in the past week by marking a vertical tick on a 100 mm horizontal VAS with the left end marked as “no pain” and the right end marked as “worst possible pain”, where the maximum possible value is 100 mm.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	72	69	70
Units: visual analog scales (VAS)
arithmetic mean (standard deviation)	13.5 ( 19.52 )	13.1 ( 26.80 )	10.4 ( 22.08 )	11.0 ( 25.34 )

No statistical analyses for this end point

Secondary: Change in subject’s global assessment of pain at Week 24

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End point title

Change in subject’s global assessment of pain at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Change from baseline is defined as value at baseline minus value at post-baseline visit. A positive change indicates an improvement. Full analysis Set for observed cases analyses at Week 24, subjects who have moved from Placebo to active medication or to a higher active dose at Week 12 are presented with their Week 24 response against the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg. The subject was asked to assess his or her current level of pain in the past week by marking a vertical tick on a 100 mm horizontal VAS with the left end marked as “no pain” and the right end marked as “worst possible pain”, where the maximum possible value is 100 mm.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	57	56
Units: visual analog scale (VAS)
arithmetic mean (standard deviation)	18.8 ( 22.95 )	16.8 ( 26.67 )	12.5 ( 24.49 )	15.9 ( 25.07 )

No statistical analyses for this end point

Secondary: Change in subject's global assessment of disease activity at Week 12

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End point title

Change in subject's global assessment of disease activity at Week 12

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. The subject’s overall assessment of his or her disease activity during the last 24 hours was recorded using the 100 mm horizontal VAS where the left end represents no disease activity (symptom free and no arthritis symptoms) and the right end represents maximum disease activity (maximum arthritis disease activity), where the maximum possible value is 100 mm. The subject was asked to give an overall assessment of how the arthritis is affecting them at present by marking a vertical tick on a VAS from “no arthritis activity” to “extremely active arthritis”. Change from baseline was defined as value at baseline minus value at post-baseline visit. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	72	69	70
Units: visual analog scale (VAS)
arithmetic mean (standard deviation)	15.0 ( 18.39 )	16.8 ( 25.04 )	9.3 ( 21.11 )	12.8 ( 26.19 )

No statistical analyses for this end point

Secondary: Change in subject's global assessment of disease activity at Week 24

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End point title

Change in subject's global assessment of disease activity at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg. The subject’s overall assessment of his or her disease activity during the last 24 h was recorded using the 100 mm horizontal VAS where the left end represents no disease activity (symptom free and no arthritis symptoms) and the right end represents maximum disease activity (maximum arthritis disease activity), where the maximum possible value is 100 mm. Change from baseline was defined as value at baseline minus value at post-baseline visit. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	46	42	42
Units: visual analoge scale (VAS)
arithmetic mean (standard deviation)	19.8 ( 23.11 )	20.3 ( 24.38 )	14.8 ( 25.78 )	16.7 ( 21.45 )

No statistical analyses for this end point

Secondary: Change in Physician's global assessment of disease activity at Week 12

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End point title

Change in Physician's global assessment of disease activity at Week 12

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. The physician’s assessment of a subject’s disease activity during the last 24 hours was recorded using the 100 mm horizontal VAS. Results will be expressed in millimeters measured between the left end of the scale and the crossing point of the vertical line of the tick, where the maximum possible value was 100 mm. Change from baseline was defined as value at baseline minus value at post-baseline visit. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	71	68	70
Units: mm (VAS)
arithmetic mean (standard deviation)	20.0 ( 19.11 )	22.7 ( 22.16 )	21.0 ( 16.94 )	20.0 ( 20.90 )

No statistical analyses for this end point

Secondary: Change in Physician's global assessment of disease activity at Week 24

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End point title

Change in Physician's global assessment of disease activity at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg. The physician’s assessment of a subject’s disease activity during the last 24 hours was recorded using the 100 mm horizontal VAS. Results will be expressed in millimeters measured between the left end of the scale and the crossing point of the vertical line of the tick, where the maximum possible value was 100 mm. Change from baseline was defined as value at baseline minus value at post-baseline visit. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	57	55
Units: mm (VAS)
arithmetic mean (standard deviation)	31.5 ( 20.71 )	32.0 ( 21.53 )	28.6 ( 23.17 )	33.9 ( 21.22 )

No statistical analyses for this end point

Secondary: Change in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12

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End point title

Change in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. The HAQ-DI is a questionnaire comprising of 20 items assessing each of 8 functional areas (dressing and grooming, arising, eating, walking, hygiene, reach, grip and activities). For each item, there is a four-level response set that is scored from 0 (no difficulty) to 3 (unable to perform activity) that measures the ability to perform (daily) activities over the previous week. Total score is between 0–3.0, in 0.125 increments. Increasing scores indicate worse functioning with 0 indicating no functional impairment and 3 indicating complete impairment. Change from baseline was defined as value at baseline minus value at post-baseline visit. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	72	69	70
Units: scores
arithmetic mean (standard deviation)	0.22 ( 0.424 )	0.26 ( 0.635 )	0.22 ( 0.423 )	0.15 ( 0.607 )

No statistical analyses for this end point

Secondary: Change in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24

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End point title

Change in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg. The HAQ-DI is a questionnaire comprising of 20 items assessing each of 8 functional areas (dressing and grooming, arising, eating, walking, hygiene, reach, grip and activities). For each item, there is a four-level response set that is scored from 0 (no difficulty) to 3 (unable to perform activity) that measures the ability to perform (daily) activities over the previous week. Total score is between 0–3.0, in 0.125 increments. Increasing scores indicate worse functioning with 0 indicating no functional impairment and 3 indicating complete impairment. Change from baseline was defined as value at baseline minus value

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	57	56
Units: scores
arithmetic mean (standard deviation)	0.29 ( 0.466 )	0.41 ( 0.653 )	0.24 ( 0.620 )	0.31 ( 0.534 )

No statistical analyses for this end point

Secondary: Change in duration of Morning Stiffness at Week 12

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End point title

Change in duration of Morning Stiffness at Week 12

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. Subjects were asked about duration of morning stiffness on the day prior to the study visit to capture actual symptoms. Change from baseline was defined as value at baseline minus value at post-baseline visit. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	72	69	70
Units: minute
arithmetic mean (standard deviation)	50.9 ( 79.73 )	34.8 ( 127.63 )	56.0 ( 166.32 )	42.7 ( 122.07 )

No statistical analyses for this end point

Secondary: Change in duration of Morning Stiffness at Week 24

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End point title

Change in duration of Morning Stiffness at Week 24

End point description

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	57	56
Units: minute
arithmetic mean (standard deviation)	48.1 ( 95.05 )	41.8 ( 174.42 )	73.7 ( 208.88 )	23.2 ( 208.70 )

No statistical analyses for this end point

Secondary: Change in functional assessment of chronic illness therapy-fatigue scale (FACIT-Fatigue) at Week 12

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End point title

Change in functional assessment of chronic illness therapy-fatigue scale (FACIT-Fatigue) at Week 12

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. FACIT-F is a self-assessment questionnaire measuring fatigue in subjects with RA. It consists of 13 questions rated on a 5-point scale (0=not at all, 1=a little bit, 2=somewhat, 3=quite a bit, 4=very much). Except for items “I have energy” and “I am able to do my usual activities”, the responses are reversed (i.e.4 becomes 0), to calculate the total score. The scores for the individual items are summed to provide a total FACIT- fatigue score. Score range 0-52. A score of less than 30 indicates severe fatigue. The higher the score, the better the quality of life. Change from baseline was defined as value at post-baseline visit minus value at baseline. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	72	69	70
Units: scores
arithmetic mean (standard deviation)	4.6 ( 9.22 )	4.8 ( 10.84 )	4.0 ( 7.50 )	4.5 ( 9.15 )

No statistical analyses for this end point

Secondary: Change in functional assessment of chronic illness therapy-fatigue scale (FACIT-Fatigue) at Week 24

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End point title

Change in functional assessment of chronic illness therapy-fatigue scale (FACIT-Fatigue) at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg. FACIT-F is a self-assessment questionnaire measuring fatigue in subjects with RA. Score range 0-52. A score of less than 30 indicates severe fatigue. The higher the score, the better the quality of life. Change from baseline was defined as value at post-baseline visit minus value at baseline. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	57	56
Units: scores
arithmetic mean (standard deviation)	6.3 ( 9.76 )	8.0 ( 10.98 )	5.5 ( 11.44 )	6.4 ( 9.95 )

No statistical analyses for this end point

Secondary: Change in SF-36 Physical Component Score at Week 12

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End point title

Change in SF-36 Physical Component Score at Week 12

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. The SF-36 is a short-form health survey consisting of 36 questions, yielding eight health-related quality of life domains: physical functioning, role-physical, bodily pain, general health, vitality, social function, role-emotional, mental health. A higher score represents better quality of life. Change from baseline was defined as value at post-baseline visit minus value at baseline. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	71	72	69	70
Units: scores
arithmetic mean (standard deviation)	4.12 ( 6.368 )	4.70 ( 7.906 )	2.83 ( 6.864 )	3.72 ( 8.326 )

No statistical analyses for this end point

Secondary: Change in SF-36 Physical Component Score at Week 24

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End point title

Change in SF-36 Physical Component Score at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg. The SF-36 is a short-form health survey consisting of 36 questions, yielding eight health-related quality of life domains: physical functioning, role-physical, bodily pain, general health, vitality, social function, role-emotional, mental health. A higher score represents better quality of life. Change from baseline was defined as value at post-baseline visit minus value at baseline. A positive change indicated an improvement.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	61	57	56
Units: scores
arithmetic mean (standard deviation)	6.05 ( 7.342 )	5.23 ( 9.558 )	3.81 ( 6.903 )	4.33 ( 7.655 )

No statistical analyses for this end point

Secondary: DAS28 EULAR response at Week12

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End point title

DAS28 EULAR response at Week12

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. Disease Activity Score 28 =DAS28 ;European League Against Rheumatism =EULAR DAS28 is measured on a continuous scale ranging from 0 to 9.4. The level of disease activity is interpreted as low (DAS28 <3.2), moderate (3.2 ≤ DAS28 ≤ 5.1), and high (DAS28 >5.1). A DAS28 <2.6 corresponds to being in remission. A Reduction from scores at baseline means improvement. Improvements in DAS 28 were categorized using the DAS28 EULAR response criteria as Good response or Moderate response or No response.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	69	70	66	70
Units: subjects
Good response	5	2	0	4
Moderate response	30	42	41	37

No statistical analyses for this end point

Secondary: DAS28 EULAR response at Week 24

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End point title

DAS28 EULAR response at Week 24

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg. Disease Activity Score 28 =DAS28 ;European League Against Rheumatism =EULAR DAS28 is measured on a continuous scale ranging from 0 to 9.4. The level of disease activity is interpreted as low (DAS28 <3.2), moderate (3.2 ≤ DAS28 ≤ 5.1), and high (DAS28 >5.1). A DAS28 <2.6 corresponds to being in remission. A Reduction from scores at baseline means improvement. Improvements in DAS 28 were categorized using the DAS28 EULAR response criteria as Good response or Moderate response or No response.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	60	53	53
Units: subjects
Good response	6	9	1	6
Moderate response	46	37	34	34

No statistical analyses for this end point

Secondary: BT061 Plasma levels at Week 12

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End point title

BT061 Plasma levels at Week 12 ^[4]

End point description

In order to study the BT061 PK profile, blood samples for the determination of BT061 plasma levels will be taken prior to the administration of study drug at specified visit. Subjects were presented according to the treatment they were randomized to at Week 0.

End point type

Secondary

End point timeframe

0-11 weeks

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: No values for Tregalizumab Plasma Levels are available for the placebo group as these did not receive active treatment.

End point values	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	53	48	47
Units: ng/mL
arithmetic mean (standard deviation)	12.61 ( 2.589 )	30.85 ( 53.542 )	3605.29 ( 8092.025 )

No statistical analyses for this end point

Secondary: BT061 Plasma levels at Week 24

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End point title

BT061 Plasma levels at Week 24

End point description

In order to study the BT061 PK profile, blood samples for the determination of BT061 plasma levels were taken prior to the administration of study drug at the specified times. Subjects were presented according to the treatment they were randomized to at Week 0. It should be noted that 28 of the 72 Placebo subjects were switched to BT061 at Week 12: 18 subjects increased dose from 25 mg to 100 mg and 19 subjects increased dose from 100 to 200 mg.

End point type

Secondary

End point timeframe

0-24 weeks

End point values	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	45	41	38
Units: ng/mL
arithmetic mean (standard deviation)	12.74 ( 3.287 )	76.32 ( 213.096 )	3876.53 ( 8604.606 )

No statistical analyses for this end point

Secondary: Percent Change in CD3CD4 Cell Counts at Week 12

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End point title

Percent Change in CD3CD4 Cell Counts at Week 12

End point description

Mean Percent Change from Baseline of CD3CD4 Cell Counts at Week 12. Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	65	69	63	62
Units: cells/microlitre
arithmetic mean (standard deviation)	7.350 ( 35.759 )	-2.882 ( 31.810 )	-6.732 ( 39.299 )	-22.502 ( 33.949 )

No statistical analyses for this end point

Secondary: Number of Subjects with CD4 Counts of Lymphocytes <400 cells/μL during Main Phase 1

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End point title

Number of Subjects with CD4 Counts of Lymphocytes <400 cells/μL during Main Phase 1

End point description

Baseline was defined as the last non-missing value prior to first dose of study medication. Subjects were presented according to the treatment they were randomized to at Week 0. Number of Subjects with CD4 Counts of Lymphocytes <400 cells/μL at Least Once or at Least Twice during the Main Phase 1.

End point type

Secondary

End point timeframe

0-11 weeks

End point values	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Number of subjects analysed	80	83	80	78
Units: subjects
<400 at Least Once	5	9	13	14
<400 at Least Twice	0	1	4	6

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

0-48 weeks

Adverse event reporting additional description

Adverse events (AEs) were coded using MedDRA central coding dictionary, Version 17.1. Treatment emergent AEs (TEAEs) are defined as AEs that started or worsened in severity on or after the first dose of study medication until the date of the subject’s last study visit.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Placebo

Reporting group description

Placebo Safety population

Reporting group title

Tregalizumab 25 mg

Reporting group description

Active treatment

Reporting group title

Tregalizumab 100 mg

Reporting group description

Active treatment

Reporting group title

Tregalizumab 200 mg

Reporting group description

Active treatment

Serious adverse events	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 80 (1.25%)	2 / 105 (1.90%)	1 / 117 (0.85%)	7 / 122 (5.74%)
number of deaths (all causes)	0	1	1	1
number of deaths resulting from adverse events	0	1	1	1
Investigations
Flavivirus test positive
subjects affected / exposed	1 / 80 (1.25%)	0 / 105 (0.00%)	0 / 117 (0.00%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Road traffic accident
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	1 / 117 (0.85%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Multiple injuries
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	1 / 117 (0.85%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Frostbite
Additional description: occurred in Extension Phase
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	0 / 117 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Shock hemorrhagic
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	1 / 117 (0.85%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 80 (0.00%)	1 / 105 (0.95%)	0 / 117 (0.00%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Nervous system disorders
Multiple sclerosis
subjects affected / exposed	1 / 80 (1.25%)	0 / 105 (0.00%)	0 / 117 (0.00%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalized tonic-clonic seizure
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	0 / 117 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral hemorrhage
Additional description: occurred in Extension Phase
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	0 / 117 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Death unknown cause
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	0 / 117 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Gastrointestinal disorders
Colitis
alternative assessment type: Non-systematic
subjects affected / exposed	0 / 80 (0.00%)	1 / 105 (0.95%)	0 / 117 (0.00%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	0 / 117 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Lichen planus
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	0 / 117 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	0 / 117 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis (exacerbation)
Additional description: occured in Extension Phase
subjects affected / exposed	0 / 80 (0.00%)	1 / 105 (0.95%)	0 / 117 (0.00%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Peritonitis
subjects affected / exposed	0 / 80 (0.00%)	1 / 105 (0.95%)	0 / 117 (0.00%)	0 / 122 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gangrene
Additional description: occurred in Extension Phase
subjects affected / exposed	0 / 80 (0.00%)	0 / 105 (0.00%)	0 / 117 (0.00%)	1 / 122 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	Tregalizumab 25 mg	Tregalizumab 100 mg	Tregalizumab 200 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	9 / 80 (11.25%)	15 / 105 (14.29%)	18 / 117 (15.38%)	18 / 122 (14.75%)
Nervous system disorders
Headache
subjects affected / exposed	3 / 80 (3.75%)	3 / 105 (2.86%)	6 / 117 (5.13%)	6 / 122 (4.92%)
occurrences all number	3	4	9	6
Musculoskeletal and connective tissue disorders
Rheumatoid arthritis
subjects affected / exposed	2 / 80 (2.50%)	5 / 105 (4.76%)	6 / 117 (5.13%)	5 / 122 (4.10%)
occurrences all number	3	5	6	5
Infections and infestations
Nasopharyngitis
subjects affected / exposed	4 / 80 (5.00%)	7 / 105 (6.67%)	6 / 117 (5.13%)	7 / 122 (5.74%)
occurrences all number	4	9	6	10

More information

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Were there any global substantial amendments to the protocol? Yes

22 Oct 2013

Global, version 3.0: 1. In response to the FDA and German regulatory (Paul-Ehrlich-Institut) recommendations an additional step was added to discontinue patients who do not have 20% improvement from baseline in TJC and SJC at Week 24. 2. The auto-injection device will no longer be used in the study, therefore all reference has been deleted. 3. It was clarified that an additional 12 mL of blood will be taken for the predictive bioassay at selected sites only. 4. It was clarified that a DAS28 less than 2.6 corresponds to being in remission, not less than or equal to. 5. It was clarified that samples will be stored for up to 15 years. 6. Minor corrections, clarifications and administrative changes including staff changes in the study management. 7. Incorporation of the non-substantial amendment 1.

03 Dec 2014

Final Protocol (version 4/4.1; 03 Dec 2014) 1. Removal of baseline check for exclusion criterion 15: Subject has an acute or clinically symptomatic Epstein-Barr virus (EBV) or cytomegalovirus (CMV) infection, as the baseline laboratory results will not be available at the time of randomization. 2. Clarification that HBV, HCV, HIV, EBV and CMV blood samples taken at Visit 2 are retention samples only. 3. Clarification of EBV serology assessment in case of positive PCR result only. 4. Clarification of CMV serology assessment in case of positive PCR result only. 5. Addition to clarify that unused pharmacokinetic backup plasma samples may be used to measure soluble CD4 (sCD4), as an additional optional analytical variable. 6. Clarification that laboratory samples for EBV and CMV at FU Visit/EoT will be taken as retention samples only. 7. Clarification of tregalizumab storage conditions. 8. Correction of the typographical error for the definition of DAS28 low disease activity to DAS28 <3.2 and not DAS28 ≤3.2. 9. Correction of information relating to temperature measurement i.e., removal of requirement to record region used in the eCRF and removal of reference to tympanic measurements. 10. Correction of information relating to the visit schedule Week 6/Visit 6 as no drug will be dispensed at this visit as correctly indicated in the flowchart. 11. Correction of information relating to the visit schedule as the subject diary will only be dispensed once in this study at Week 2/Visit 4. 12. Replacement of the Medical Manager Thorsten Holzkämper with Andrea Wartenberg-Demand and Xuefei Zhou, and replacement of the Statistician Dermot Whyms with Vanessa Steele.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
31 Jul 2015	The Extension Phase of the study was terminated early on the 31 July 2015 due to lack of clinical efficacy.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: ACR 20 Response rate at Week 12

Primary: ACR 20 Response rate at Week 12

Secondary: ACR 20 Response rate at Week 24

Secondary: ACR 20 Response rate at Week 24

Secondary: ACR 50 Response rate at Week 12

Secondary: ACR 50 Response rate at Week 12

Secondary: ACR 50 Response rate at Week 24

Secondary: ACR 50 Response rate at Week 24

Secondary: ACR 70 Response rate at Week 12

Secondary: ACR 70 Response rate at Week 12

Secondary: ACR 70 Response rate at Week 24

Secondary: ACR 70 Response rate at Week 24

Secondary: Proportion of subjects with a DAS28 < 2.6 at Week 12

Secondary: Proportion of subjects with a DAS28 < 2.6 at Week 12

Secondary: Proportion of subjects with a DAS28 <2.6 at Week 24

Secondary: Proportion of subjects with a DAS28 <2.6 at Week 24

Secondary: Proportion of subjects with low disease activity at Week 12

Secondary: Proportion of subjects with low disease activity at Week 12

Secondary: Proportion of Subjects with Low Disease Activity at Week 24

Secondary: Proportion of Subjects with Low Disease Activity at Week 24

Secondary: Proportion of Subjects in Remission According to the 2011 ACR/EULAR Criteria at Week 12

Secondary: Proportion of Subjects in Remission According to the 2011 ACR/EULAR Criteria at Week 12

Secondary: Proportion of Subjects in Remission According to the 2011 ACR/EULAR Criteria at Week 24

Secondary: Proportion of Subjects in Remission According to the 2011 ACR/EULAR Criteria at Week 24

Secondary: Mean change in SDAI at Week 12

Secondary: Mean change in SDAI at Week 12

Secondary: Mean change in SDAI at Week 24

Secondary: Mean change in SDAI at Week 24

Secondary: Mean Change in CDAI at Week 12

Secondary: Mean Change in CDAI at Week 12

Secondary: Mean Change in CDAI at Week 24

Secondary: Mean Change in CDAI at Week 24

Secondary: Mean Change in tender joint counts (68) at Week 12

Secondary: Mean Change in tender joint counts (68) at Week 12

Secondary: Mean change in tender joint counts (68) at Week 24

Secondary: Mean change in tender joint counts (68) at Week 24

Secondary: Mean Change in swollen joint counts (66) at Week 12

Secondary: Mean Change in swollen joint counts (66) at Week 12

Secondary: Mean Change in swollen joint counts (66) at Week 24

Secondary: Mean Change in swollen joint counts (66) at Week 24

Secondary: Mean Change in CRP level at Week 12

Secondary: Mean Change in CRP level at Week 12

Secondary: Mean Change in CRP level at Week 24

Secondary: Mean Change in CRP level at Week 24

Secondary: Mean Change in Erythrocyte Sedimentation Rate (ESR) at Week 12

Secondary: Mean Change in Erythrocyte Sedimentation Rate (ESR) at Week 12

Secondary: Mean Change in Erythrocyte Sedimentation Rate (ESR) at Week 24

Secondary: Mean Change in Erythrocyte Sedimentation Rate (ESR) at Week 24

Secondary: Change in subject’s global assessment of pain at Week 12

Secondary: Change in subject’s global assessment of pain at Week 12

Secondary: Change in subject’s global assessment of pain at Week 24

Secondary: Change in subject’s global assessment of pain at Week 24

Secondary: Change in subject's global assessment of disease activity at Week 12

Secondary: Change in subject's global assessment of disease activity at Week 12

Secondary: Change in subject's global assessment of disease activity at Week 24

Secondary: Change in subject's global assessment of disease activity at Week 24

Secondary: Change in Physician's global assessment of disease activity at Week 12

Secondary: Change in Physician's global assessment of disease activity at Week 12

Secondary: Change in Physician's global assessment of disease activity at Week 24

Secondary: Change in Physician's global assessment of disease activity at Week 24

Secondary: Change in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12

Secondary: Change in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 12

Secondary: Change in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24

Secondary: Change in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24

Secondary: Change in duration of Morning Stiffness at Week 12

Secondary: Change in duration of Morning Stiffness at Week 12

Secondary: Change in duration of Morning Stiffness at Week 24

Secondary: Change in duration of Morning Stiffness at Week 24

Secondary: Change in functional assessment of chronic illness therapy-fatigue scale (FACIT-Fatigue) at Week 12

Secondary: Change in functional assessment of chronic illness therapy-fatigue scale (FACIT-Fatigue) at Week 12

Secondary: Change in functional assessment of chronic illness therapy-fatigue scale (FACIT-Fatigue) at Week 24