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Clinical Trial Results:
A randomised, double-blind, placebo-controlled trial for establishing safety, tolerability, pharmacokinetics, pharmacodynamics and clinical efficacy of multiple subcutaneous doses of BI 655064 in healthy volunteers and in rheumatoid arthritis patients with prior inadequate response to methotrexate therapy.

Summary
EudraCT number	2012-004090-16
Trial protocol	DE ES CZ NL
Global end of trial date	27 Apr 2015

Results information
Results version number	v2(current)
This version publication date	24 Aug 2016
First version publication date	08 May 2016
Other versions	v1
Version creation reason	New data added to full data set New data is not added, but a note is deleted from the Limitation and Caveats sections stating that “the PK outcome measures will be adapted as soon as the final report is available”. The clinical trial report has been finalized now and no updates are required to the results which were posted earlier.

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

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Trial information

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Sponsor protocol code

1293.2

ISRCTN number

US NCT number

NCT01751776

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 800 243 0127, clintriage.rdg@boehringer-ingelheim.com

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

06 Jul 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

02 Mar 2015

Global end of trial reached?

Yes

Global end of trial date

27 Apr 2015

Was the trial ended prematurely?

Main objective of the trial

The trial objective was to evaluate safety and systemic and local tolerability of 4 weeks of repeated subcutaneous doses of 80, 120, 180 or 240 mg BI 655064 per week administered to healthy volunteers (HVs; Part 1, Phase Ib), and of 12 weeks of repeated doses of 120 mg BI 655064 per week in patients with rheumatoid arthritis (RA) who had prior inadequate response to methotrexate (MTX) therapy (Part 2, Phase IIa).

Protection of trial subjects

Prior to the initiation of any trial-related procedure, all patients were informed about the trial verbally and in writing by the investigator. Each patient signed and dated an informed consent form according to Good Clinical Practice (GCP) and local regulatory and legal requirements. Separate informed consent was obtained for pharmacogenomic testing. The trial had a multi-part design where the progression from one dose group to the higher one was contingent upon the favourable completion of the prior dose group. The accrued trial data were therefore evaluated by an independent Data Monitoring Committee (DMC), which in the absence of safety concerns, could recommend the initiation of the next higher dose group. Healthy volunteers were exposed to the risks of the trial procedures and trial medication, and did not receive a direct benefit from participation in this trial. However, they were under close medical supervision throughout the trial. Doses of 80 and 120 milligram (mg) BI 655064 were expected to be well tolerated by healthy volunteers. Advancement to the 2 higher doses (180 and 240 mg) was only to be allowed after safety review of the lower doses by the DMC, including preliminary PK assessment and projection of the anticipated exposure to the higher doses. All patients in Part 2 (Phase IIa) were to remain on background Methotrexate (MTX) for the 12 week period of BI 655064 treatment. Furthermore, therapy with systemic glucocorticoids (GCs) was permitted at up to a maximum dose of 10 mg prednisolone/day (or the equivalent) during the entire period of trial treatment. NSAIDs and analgesics were also permitted at the investigator’s discretion. The theoretical risks of thromboembolic events and uncontrolled cytokine release were to be mitigated by close clinical and laboratory monitoring.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Jan 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

New Zealand: 52

Country: Number of subjects enrolled

Czech Republic: 16

Country: Number of subjects enrolled

Germany: 15

Country: Number of subjects enrolled

Netherlands: 7

Country: Number of subjects enrolled

Poland: 46

Country: Number of subjects enrolled

Spain: 8

Worldwide total number of subjects

144

EEA total number of subjects

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)

126

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study included a part 1 (Phase Ib multiple rising dose) where 40 healthy volunteers were recruited, in 4 sequential groups of 10 subjects (8 of them received active drug,2 placebo) each. Thereafter a part 2 (Phase 2a) was conducted. 67 patients with RA and who had prior inadequate response to MTX treatment were randomised into 2 arms.

Screening details

All subjects were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial drug if any of the specific entry criteria was violated.

Period 1 title

Overall Study (overall period)

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

This study was a Randomised, placebo controlled and double blinded.

Are arms mutually exclusive

Yes

Part 1, Placebo BI 655064 80/120mg (HV)

Arm description

Part 1, Healthy volunteers (HV): Placebo matching BI 655064 80 or 120 milligram (mg) injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

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

Placebo matching BI 655064 80 or 120 milligram (mg) injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Part 1, Placebo BI 655064 180/240mg (HV)

Arm description

Part 1, Healthy volunteers (HV): Placebo matching BI 655064 180 or 240 mg injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks (180mg dosing group) or 8 weeks (240mg dosing group) follow-up period.

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

Placebo matching BI 655064 180 or 240 mg injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks (180mg dosing group) or 8 weeks (240mg dosing group) follow-up period.

Part 1, BI 655064 80mg (HV)

Arm description

Part 1, Healthy volunteers (HV): 80 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Arm type

Experimental

Investigational medicinal product name

BI 655064

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

80 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Part 1, BI 655064 120mg (HV)

Arm description

Part 1, Healthy volunteers (HV): 120 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Arm type

Experimental

Investigational medicinal product name

BI 655064

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

120 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Part 1, BI 655064 180mg (HV)

Arm description

Part 1, Healthy volunteers (HV): 180 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Arm type

Experimental

Investigational medicinal product name

BI 655064

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Part 1, BI 655064 240mg (HV)

Arm description

Part 1, Healthy volunteers (HV): 240mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 8 weeks follow-up period.

Arm type

Experimental

Investigational medicinal product name

BI 655064

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

240 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 8 weeks follow-up period.

Part 2, Placebo BI 655064 120mg (RA)

Arm description

Part 2, patients with Rheumatoid arthritis (RA) who had prior inadequate response to Methotrexat (MTX) therapy: Placebo matching BI 655064 120 milligram (mg) injected subcutaneous on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (once weekly for 12 weeks) followed by 8 weeks follow-up period.

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

Placebo matching BI 655064 120 milligram (mg) injected subcutaneous on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (once weekly for 12 weeks) followed by 8 weeks follow-up period.

Part 2, BI 655064 120mg (RA)

Arm description

Part 2, patients with Rheumatoid arthritis (RA)who had prior inadequate response to MTX therapy: 120 milligram (mg) of BI 655064 injected subcutaneous on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (once weekly for 12 weeks) followed by 8 weeks follow-up period.

Arm type

Experimental

Investigational medicinal product name

BI 655064

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Part 2, patients with Rheumatoid arthritis (RA): 120 milligram (mg) of BI 655064 injected subcutaneous on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (once weekly for 12 weeks) followed by 8 weeks follow-up period.

Number of subjects in period 1 ^[1]	Part 1, Placebo BI 655064 80/120mg (HV)	Part 1, Placebo BI 655064 180/240mg (HV)	Part 1, BI 655064 80mg (HV)	Part 1, BI 655064 120mg (HV)	Part 1, BI 655064 180mg (HV)	Part 1, BI 655064 240mg (HV)	Part 2, Placebo BI 655064 120mg (RA)	Part 2, BI 655064 120mg (RA)
Started	4	4	8	8	8	8	23	44
Completed	4	4	8	8	8	8	19	40
Not completed	0	0	0	0	0	0	4	4
Adverse event, serious fatal	-	-	-	-	-	-	-	1
Consent withdrawn by subject	-	-	-	-	-	-	-	1
Adverse event, non-fatal	-	-	-	-	-	-	4	1
Other reason not specified above	-	-	-	-	-	-	-	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one of the trial medication.

Baseline characteristics

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Reporting group title

Part 1, Placebo BI 655064 80/120mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): Placebo matching BI 655064 80 or 120 milligram (mg) injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Reporting group title

Part 1, Placebo BI 655064 180/240mg (HV)

Reporting group description

Reporting group title

Part 1, BI 655064 80mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 80 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Reporting group title

Part 1, BI 655064 120mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 120 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Reporting group title

Part 1, BI 655064 180mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 180 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Reporting group title

Part 1, BI 655064 240mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 240mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 8 weeks follow-up period.

Reporting group title

Part 2, Placebo BI 655064 120mg (RA)

Reporting group description

Reporting group title

Part 2, BI 655064 120mg (RA)

Reporting group description

Reporting group values	Part 1, Placebo BI 655064 80/120mg (HV)	Part 1, Placebo BI 655064 180/240mg (HV)	Part 1, BI 655064 80mg (HV)	Part 1, BI 655064 120mg (HV)	Part 1, BI 655064 180mg (HV)	Part 1, BI 655064 240mg (HV)	Part 2, Placebo BI 655064 120mg (RA)	Part 2, BI 655064 120mg (RA)	Total
Number of subjects	4	4	8	8	8	8	23	44	107
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	21.5 ( 1.3 )	34 ( 15.4 )	25.9 ( 4.1 )	31.4 ( 13.3 )	37.3 ( 10.8 )	29.5 ( 10.6 )	55.1 ( 8.3 )	53.7 ( 13.3 )	-
Gender, Male/Female
Units: Participants
Female	0	2	2	0	2	1	18	37	62
Male	4	2	6	8	6	7	5	7	45

End points

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Reporting group title

Part 1, Placebo BI 655064 80/120mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): Placebo matching BI 655064 80 or 120 milligram (mg) injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Reporting group title

Part 1, Placebo BI 655064 180/240mg (HV)

Reporting group description

Reporting group title

Part 1, BI 655064 80mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 80 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Reporting group title

Part 1, BI 655064 120mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 120 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Reporting group title

Part 1, BI 655064 180mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 180 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 6 weeks follow-up period.

Reporting group title

Part 1, BI 655064 240mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 240mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly, for 4 weeks) followed by 8 weeks follow-up period.

Reporting group title

Part 2, Placebo BI 655064 120mg (RA)

Reporting group description

Reporting group title

Part 2, BI 655064 120mg (RA)

Reporting group description

Subject analysis set title

Part 1, Placebo BI 655064 (HV)

Subject analysis set type

Safety analysis

Subject analysis set description

Part 1, Healthy volunteers (HV): Placebo of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly) followed by a 6 weeks (120mg dosing group) or a 8 weeks (240mg dosing group) follow-up period. Within each dose group two subjects were to receive placebo.

Primary: Part 1: Cmax after the first and last dose

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End point title

Part 1: Cmax after the first and last dose ^[1]

End point description

Part 1: This outcome measure presents the maximum measured concentration of BI 655064 in plasma (Cmax) after the first and last (fourth) dose. More detailed time frame: Pharmacokinetic (PK) sample times: 0:30 hour (h) prior first administration of BI 655064 and 1 h, 8 h, 12 h, 24 h, 48 h, 72 h, 84 h, 96 h, 108 h, 120 h, 144 h, 167:30 h, 335:30 h, 503:30 h, 505 h, 516 h, 528 h, 552 h, 576 h, 600 h, 624 h, 648 h, 672 h, 696 h, 744 h, 816 h, 912 h, 1008 h, 1176 h, 1344 h, 1512 h, 1848 h thereafter; further administration times for BI 655064: 168 h, 336 h, and 504 h after first administration. All subjects were treated and provided data for at least 1 primary pharmacokinetic (PK) endpoint and therefore all subjects were also included in the PK set (PKS).

End point type

Primary

End point timeframe

after the first dose on day 1 and after the last dose on day 22

Notes
[1] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 1, BI 655064 80mg (HV)	Part 1, BI 655064 120mg (HV)	Part 1, BI 655064 180mg (HV)	Part 1, BI 655064 240mg (HV)
Number of subjects analysed	8 ^[2]	8 ^[3]	8 ^[4]	8 ^[5]
Units: microgram (µg)/ millilitre (mL)
geometric mean (geometric coefficient of variation)
after the first dose	1.59 ( 492 )	7.7 ( 29.5 )	9.87 ( 67.8 )	18 ( 46.3 )
after the last (fourth) dose	13.1 ( 59.1 )	28.7 ( 35.6 )	39.8 ( 37.4 )	68.4 ( 21.9 )

Notes
[2] - PKS
[3] - PKS
[4] - PKS
[5] - PKS

Cmax after the first dose of BI 655064, day 1

Statistical analysis description

Dose proportionality for Cmax was explored after the first adminstration of BI 65564 on Day 1.

Comparison groups

Part 1, BI 655064 120mg (HV) v Part 1, BI 655064 80mg (HV) v Part 1, BI 655064 180mg (HV) v Part 1, BI 655064 240mg (HV)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[6]

Method

Parameter type

Slope

Point estimate

2.0506

Confidence interval

level

95%

sides

2-sided

lower limit

1.1843

upper limit

2.9168

Variability estimate

Standard error of the mean

Dispersion value

0.4242

Notes
[6] - Measure type: Dose proportionality was explored using a regression model. Based on the estimate for the slope parameter, a two sided 95% confidence interval for the slope was computed. Perfect dose proportionality would correspond to a slope of 1. PK endpoints on the log-transformed scale.

Cmax after the last dose of BI 655064, day 22

Statistical analysis description

Dose proportionality for Cmax was explored after the last adminstration of BI 65564 on Day 22.

Comparison groups

Part 1, BI 655064 80mg (HV) v Part 1, BI 655064 120mg (HV) v Part 1, BI 655064 180mg (HV) v Part 1, BI 655064 240mg (HV)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[7]

Method

Parameter type

Slope

Point estimate

1.4227

Confidence interval

level

95%

sides

2-sided

lower limit

1.0869

upper limit

1.7584

Variability estimate

Standard error of the mean

Dispersion value

0.1644

Notes
[7] - Measure type: Dose proportionality was explored using a regression model. Based on the estimate for the slope parameter, a two sided 95% confidence interval for the slope was computed. Perfect dose proportionality would correspond to a slope of 1. PK endpoints on the log-transformed scale.

Primary: Part 1: AUC 0-infinity after the last dose

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End point title

Part 1: AUC 0-infinity after the last dose ^[8]

End point description

Primary PK endpoint (Part 1): Area under the concentration-time curve of BI 655064 in plasma over the time interval from 0 extrapolated to infinite (AUC 0-infinity).

End point type

Primary

End point timeframe

PK sample times: 1 h, 12 h, 24 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 192 h, 240 h, 312 h, 408 h, 504 h, 672 h, 840 h, 1008 h, 1344 h after the last administration of BI 655064 on day 22

Notes
[8] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 1, BI 655064 80mg (HV)	Part 1, BI 655064 120mg (HV)	Part 1, BI 655064 180mg (HV)	Part 1, BI 655064 240mg (HV)
Number of subjects analysed	8 ^[9]	8 ^[10]	8 ^[11]	8 ^[12]
Units: µg* hours (h)/mL
geometric mean (geometric coefficient of variation)	3940 ( 53.9 )	11000 ( 42.5 )	19200 ( 41.1 )	39300 ( 26.1 )

Notes
[9] - PKS
[10] - PKS
[11] - PKS
[12] - PKS

AUC 0-infinity after the last dose

Statistical analysis description

Dose proportionality for AUC 0-infinity was explored after the last adminstration of BI 65564 on Day 22.

Comparison groups

Part 1, BI 655064 80mg (HV) v Part 1, BI 655064 120mg (HV) v Part 1, BI 655064 180mg (HV) v Part 1, BI 655064 240mg (HV)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[13]

Method

Parameter type

Slope

Point estimate

2.0091

Confidence interval

level

95%

sides

2-sided

lower limit

1.6607

upper limit

2.3575

Variability estimate

Standard error of the mean

Dispersion value

0.1706

Notes
[13] - Dose proportionality was explored using a regression model. Based on the estimate for the slope parameter, a two sided 95% confidence interval for the slope was computed. Perfect dose proportionality would correspond to a slope of 1. PK endpoints on the log-transformed scale.

Primary: Part 1: AUCtau after the last dose

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End point title

Part 1: AUCtau after the last dose ^[14]

End point description

Area under the concentration-time curve of BI 655064 in plasma after the 4th dose over a uniform dosing interval t (AUC t,4) after the first and 4th dose. AUCtau is synonymus with AUC0-168.

End point type

Primary

End point timeframe

PK sample times: 1, 12, 24, 48, 72, 96, 120, 144, 168, 192, 240, 312, 408, 504, 672, 840, 1008, 1344 h after the last administration of trial drug on day 22

Notes
[14] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 1, BI 655064 80mg (HV)	Part 1, BI 655064 120mg (HV)	Part 1, BI 655064 180mg (HV)	Part 1, BI 655064 240mg (HV)
Number of subjects analysed	8	8	8	8
Units: µg*h/mL
geometric mean (geometric coefficient of variation)	1790 ( 56.4 )	4140 ( 35.4 )	5470 ( 37.4 )	9460 ( 22.4 )

AUCtau after the last dose

Statistical analysis description

Dose proportionality for AUCtau was explored after the last administration of BI 65564 on Day 22.

Comparison groups

Part 1, BI 655064 80mg (HV) v Part 1, BI 655064 120mg (HV) v Part 1, BI 655064 180mg (HV) v Part 1, BI 655064 240mg (HV)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other ^[15]

Method

Parameter type

Slope

Point estimate

1.4225

Confidence interval

level

95%

sides

2-sided

lower limit

1.0876

upper limit

1.7574

Variability estimate

Standard error of the mean

Dispersion value

0.164

Notes
[15] - Dose proportionality was explored using a regression model. Based on the estimate for the slope parameter, a two sided 95% confidence interval for the slope was computed. Perfect dose proportionality would correspond to a slope of 1. PK endpoints on the log-transformed scale.

Primary: Part 1: Percentage of subjects with drug related Adverse Events

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End point title

Part 1: Percentage of subjects with drug related Adverse Events ^[16] ^[17]

End point description

In Part 1 (Phase Ib): The primary safety endpoint was the percentage of subjects with AEs related to treatment with trial medication.

End point type

Primary

End point timeframe

from first administration of study medication (day 1) up to day 64 (dosing groups 80, 120, 180mg) or up to day 78 post-treatment (dosing group 240mg)

Notes
[16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
[17] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 1, BI 655064 80mg (HV)	Part 1, BI 655064 120mg (HV)	Part 1, BI 655064 180mg (HV)	Part 1, BI 655064 240mg (HV)	Part 1, Placebo BI 655064 (HV)
Number of subjects analysed	8 ^[18]	8 ^[19]	8 ^[20]	8 ^[21]	8 ^[22]
Units: Percentage of participants
number (not applicable)	25	12.5	50	0	50

Notes
[18] - Of the 40 subjects, all were treated and included in the treated set (TS).
[19] - TS
[20] - TS
[21] - TS
[22] - TS

No statistical analyses for this end point

Primary: Part 2: American College of Rheumatology (ACR) 20 response rate at week 12

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End point title

Part 2: American College of Rheumatology (ACR) 20 response rate at week 12 ^[23] ^[24]

End point description

ACR20 (week 12) relative to the patient’s status at baseline: that is, at least 20 percent (%) improvement (impr.) in swollen joint count, at least 20% impr. in tender joint count, and at least 20% impr. in ≥3 of the following 5 variables: 1) patient’s assessment of pain on visual analogue scale (VAS), rated on a scale of 1 to 10; 2) patient’s global assessment of disease on VAS, rated on a scale of 1 to 10; 3) investigator’s global assessment of disease on VAS; 4) patient’s assessment of disability on health assessment questionnaire (HAQ), rated on a scale of 1 to 3; and 5) concentrations of acute phase reactants. For all scales (1-4): smaller values better. ACR20 were evaluated descriptively. Data were analysed with a Bayesian approach using an informative prior for the placebo treatment group; predictive probability that treatment difference was larger than 0, 5, 10, 15, 20, 25, 30, 35, 40 or 45% was to be evaluated. “99999” entered instead of “not applicable” (system limitations)

End point type

Primary

End point timeframe

at week 12 (day 85) from the initiation of study treatment

Notes
[23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
[24] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2, Placebo BI 655064 120mg (RA)	Part 2, BI 655064 120mg (RA)
Number of subjects analysed	22 ^[25]	44 ^[26]
Units: Percentage of participants
number (not applicable)
Subjects with ACR20 response	45.5	68.2
Observed difference of ACR20 response (resp.)	99999	22.7
Posterior mean difference (diff.) of ACR20 resp.	99999	33
Probability that the diff. of ACR20 resp. is > 0%	99999	99.9
Probability that the diff. of ACR20 resp. is > 5%	99999	99.7
Probability that the diff. of ACR20 resp. is > 10%	99999	98.7
Probability that the diff. of ACR20 resp. is > 15%	99999	96
Probability that the diff. of ACR20 resp. is > 20%	99999	90
Probability that the diff. of ACR20 resp. is > 25%	99999	79
Probability that the diff. of ACR20 resp. is > 30%	99999	62.5
Probability that the diff. of ACR20 resp. is > 35%	99999	42.9

Notes
[25] - Full analysis set (FAS):randomised and treated patients; Non-completers assumed to be failures (NCF)
[26] - FAS (NCF)

No statistical analyses for this end point

Secondary: Part 2: ACR50 response rates at week 12

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End point title

Part 2: ACR50 response rates at week 12 ^[27]

End point description

ACR 50 criteria at week 12 relative to the patient’s status at baseline: that is, at least 50 % improvement in swollen joint count, at least 50% improvement in tender joint count, and at least 50% improvement in ≥3 of the following 5 variables: 1) patient’s assessment of pain on the visual analogue scale (VAS), rated on a scale of 1 to 10; 2) patient’s global assessment of disease on the VAS, rated on a scale of 1 to 10; 3) investigator’s global assessment of disease on the VAS; 4) patient’s assessment of disability on the health assessment questionnaire (HAQ), rated on a scale of 1 to 3; and 5) concentrations of acute phase reactants. For all scales (1-4): smaller values better. The percentage of subjects with ACR50 response is presented.

End point type

Secondary

End point timeframe

at week 12 (day 85)

Notes
[27] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2, Placebo BI 655064 120mg (RA)	Part 2, BI 655064 120mg (RA)
Number of subjects analysed	22 ^[28]	44 ^[29]
Units: Percentage of participants
number (confidence interval 95%)
unadjusted	18.2 (5.2 to 40.3)	36.4 (22.4 to 52.2)
adjusted	15.6 (5.5 to 36.9)	35.6 (22.3 to 51.5)

Notes
[28] - FAS (NCF)
[29] - FAS (NCF)

Placebo vs. BI655064, unadjusted

Statistical analysis description

The exact 95% confidence interval was calculated by Clopper and Pearson.

Comparison groups

Part 2, BI 655064 120mg (RA) v Part 2, Placebo BI 655064 120mg (RA)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0754 ^[30]

Method

One-sided exact test (see description)

Parameter type

Risk difference, unadjusted

Point estimate

18.2

Confidence interval

level

95%

sides

2-sided

lower limit

-6.6

upper limit

38.6

Notes
[30] - one-sided exact test for superiority testing.

Placebo vs. BI655064, adjusted

Statistical analysis description

The 95 % confidence interval was determined by root method to determine the cumulative distribution function.

Comparison groups

Part 2, Placebo BI 655064 120mg (RA) v Part 2, BI 655064 120mg (RA)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

Method

Parameter type

Risk difference, adjusted

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4.6

upper limit

Notes
[31] - Adjusted for treatment, region and anti-Tumour Necrosis Factor (TNF).

Secondary: Part 2: ACR70 response rates at 12 weeks

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End point title

Part 2: ACR70 response rates at 12 weeks ^[32]

End point description

ACR70 criteria at week 12 relative to the patient’s status at baseline: that is, at least 70 % improvement in swollen joint count, at least 70% improvement in tender joint count, and at least 70% improvement in ≥3 of the following 5 variables: 1) patient’s assessment of pain on the visual analogue scale (VAS), rated on a scale of 1 to 10; 2) patient’s global assessment of disease on the VAS, rated on a scale of 1 to 10; 3) investigator’s global assessment of disease on the VAS; 4) patient’s assessment of disability on the health assessment questionnaire (HAQ), rated on a scale of 1 to 3; and 5) concentrations of acute phase reactants. For all scales (1-4): smaller values better). The percentage of subjects with ACR50 response is presented.

End point type

Secondary

End point timeframe

at week 12 (day 85)

Notes
[32] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2, Placebo BI 655064 120mg (RA)	Part 2, BI 655064 120mg (RA)
Number of subjects analysed	22 ^[33]	44 ^[34]
Units: Percentage of participants
number (confidence interval 95%)
unadjusted	13.6 (2.9 to 34.9)	18.2 (8.2 to 32.7)
adjusted	13 (4 to 34.6)	17 (8.3 to 31.6)

Notes
[33] - FAS (NCF)
[34] - FAS (NCF)

Placebo vs. BI 655064, unadjusted

Statistical analysis description

The exact 95% confidence interval was calculated by Clopper and Pearson.

Comparison groups

Part 2, Placebo BI 655064 120mg (RA) v Part 2, BI 655064 120mg (RA)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3938 ^[35]

Method

one-sided exact test (see description)

Parameter type

risk difference, unadjusted

Point estimate

4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-18.4

upper limit

22.3

Notes
[35] - one-sided exact test for superiority testing.

Placebo vs. BI 655064, adjusted

Statistical analysis description

The 95 % confidence interval was determined by root method to determine the cumulative distribution function.

Comparison groups

Part 2, Placebo BI 655064 120mg (RA) v Part 2, BI 655064 120mg (RA)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

Method

Parameter type

risk difference, adjusted

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-18.9

upper limit

21.1

Notes
[36] - Adjusted for treatment, region and anti-TNF history

Secondary: Part 2: EULAR DAS28-CRP at week 12

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End point title

Part 2: EULAR DAS28-CRP at week 12 ^[37]

End point description

Response as assessed by European League Against Rheumatism (EULAR) categorization as good, moderate, or nonresponders based on improvement from baseline using the disease activity score in 28 joints and C-reactive protein (DAS28-CRP) at week 12. In this outcome measure the frequency of EULAR response rates (change from the day of first dose to the day of visit 14 in week 12) are presented. Improvement (impr.) is abbreviated in the category names.

End point type

Secondary

End point timeframe

week 12 (day 85)

Notes
[37] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2, Placebo BI 655064 120mg (RA)	Part 2, BI 655064 120mg (RA)
Number of subjects analysed	20 ^[38]	39 ^[39]
Units: Percentage of participants
number (not applicable)
DAS28-CRP <=3.2, improvement (>0.6 and <=1.2)	5	2.6
DAS28-CRP <=3.2, improvement <=0.6	0	0
DAS28-CRP (>3.2 and <=5.1), improvement >1.2	25	35.9
DAS28-CRP (>3.2 and <=5.1), impr. (>0.6 and <=1.2)	5	7.7
DAS28-CRP (>3.2 and <=5.1), improvement <=0.6	10	2.6
DAS28-CRP >5.1, improvement >1.2	10	0
DAS28-CRP>5.1, improvement (>0.6 and <=1.2)	10	7.7
DAS28-CRP >5.1, improvement <=0.6	10	7.7
DAS28-CRP <=3.2, improvement >1.2	25	35.9

Notes
[38] - FAS (observed cases)
[39] - FAS (observed cases)

No statistical analyses for this end point

Secondary: Part 2: EULAR DAS28-ESR at week 12

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End point title

Part 2: EULAR DAS28-ESR at week 12 ^[40]

End point description

Response as assessed by European League Against Rheumatism (EULAR) using Disease activity score in 28 joints and the erythrocyte sedimentation rate (DAS28-ESR) at week 12. In this outcome measure the frequency of EULAR response rates (change from the day of first dose to the day of visit 14 in week 12) are presented. Improvement (impr.) is abbreviated in the category names.

End point type

Secondary

End point timeframe

week 12 (day 85)

Notes
[40] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2, Placebo BI 655064 120mg (RA)	Part 2, BI 655064 120mg (RA)
Number of subjects analysed	20 ^[41]	39 ^[42]
Units: Percentage of participants
number (not applicable)
DAS28-ESR <=3.2, improvement >1.2	10.5	20.5
DAS28-ESR <=3.2, improvement (>0.6 and <=1.2)	0	0
DAS28-ESR <=3.2, improvement <=0.6	0	0
DAS28-ESR (>3.2 and <=5.1), improvement >1.2	42.1	51.3
DAS28-ESR (>3.2 and <=5.1), impr. (>0.6 and <=1.2)	5.3	5.1
DAS28-ESR (>3.2 and <=5.1), improvement <=0.6	0	0
DAS28-ESR >5.1, improvement >1.2	21.1	10.3
DAS28-ESR >5.1, improvement (>0.6 and <=1.2)	5.3	7.7
DAS28-ESR >5.1, improvement <=0.6	15.8	5.1

Notes
[41] - FAS (observed cases)
[42] - FAS (observed cases)

No statistical analyses for this end point

Secondary: Part 2: Percentage of patients with a decrease in DAS28-CRP of >1.2 at week 12

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End point title

Part 2: Percentage of patients with a decrease in DAS28-CRP of >1.2 at week 12 ^[43]

End point description

Percentage of patients who had a decrease of >1.2 on the Disease activity score in 28 joints and C-reactive protein (DAS28-CRP) at week 12 (day 85) compared to baseline. The adjusted absolute risk difference was adjusted for treatment, region and anti-TNF history.

End point type

Secondary

End point timeframe

baseline (day 1) and week 12 (day 85)

Notes
[43] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2, Placebo BI 655064 120mg (RA)	Part 2, BI 655064 120mg (RA)
Number of subjects analysed	22 ^[44]	44 ^[45]
Units: Percentage of participants
number (confidence interval 95%)
Unadjusted	59.1 (36.4 to 79.3)	65.9 (50.1 to 79.5)
Adjusted	58.2 (36.7 to 77)	67.1 (51.6 to 79.6)

Notes
[44] - FAS (Last observation carried forward)
[45] - FAS (Last observation carried forward)

Placebo vs. BI 655064, unadjusted

Statistical analysis description

The exact 95% confidence interval was calculated by Clopper and Pearson.

Comparison groups

Part 2, BI 655064 120mg (RA) v Part 2, Placebo BI 655064 120mg (RA)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference, unadjusted

Point estimate

6.8

Confidence interval

level

95%

sides

2-sided

lower limit

-17.6

upper limit

32.7

Placebo vs. BI 655064, adjusted

Statistical analysis description

The 95 % confidence interval was determined by root method to determine the cumulative distribution function.

Comparison groups

Part 2, BI 655064 120mg (RA) v Part 2, Placebo BI 655064 120mg (RA)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference, adjusted

Point estimate

8.9

Confidence interval

level

95%

sides

2-sided

lower limit

-15.9

upper limit

34.2

Secondary: Part 2: Change in DAS28-CRP score at week 12

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End point title

Part 2: Change in DAS28-CRP score at week 12 ^[46]

End point description

Change at week 12 in the Disease activity score in 28 joints and C-reactive protein (DAS28-CRP) compared with the score at baseline. The mean was adjusted for region, anti-TNF history and baseline DAS28-CRP.

End point type

Secondary

End point timeframe

baseline (day 1) and week 12 (day 85)

Notes
[46] - 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.

End point values	Part 2, Placebo BI 655064 120mg (RA)	Part 2, BI 655064 120mg (RA)
Number of subjects analysed	22 ^[47]	44 ^[48]
Units: units on a scale
arithmetic mean (standard error)
Mean	-1.45 ( 0.238 )	-1.61 ( 0.14 )
Adjusted mean	-1.47 ( 0.215 )	-1.6 ( 0.151 )

Notes
[47] - FAS (last observation carried forward)
[48] - FAS (last observation carried forward)

Placebo vs. BI 655064

Statistical analysis description

difference calculated as BI 655064 120mg minus placebo. The ANCOVA model was used. In this model the mean was adjusted for region, anti-TNF history and baseline DAS28-CRP.

Comparison groups

Part 2, BI 655064 120mg (RA) v Part 2, Placebo BI 655064 120mg (RA)

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Adjusted mean

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

0.39

Variability estimate

Standard error of the mean

Dispersion value

0.266

Adverse events

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Timeframe for reporting adverse events

From first administration of study medication (day 1) up to day 64 (dosing groups 80, 120, 180mg) or up to day 78 post-treatment (dosing group 240mg) in part 1 and up to 141 days in part 2.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Part 1, Placebo (HV)

Reporting group description

Reporting group title

Part 1, BI 655064 80mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 80 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly) followed by 6 weeks follow-up period.

Reporting group title

Part 1, BI 655064 120mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 120 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly) followed by 6 weeks follow-up period.

Reporting group title

Part 1, BI 655064 180mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 180 mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly) followed by 6 weeks follow-up period.

Reporting group title

Part 1, BI 655064 240mg (HV)

Reporting group description

Part 1, Healthy volunteers (HV): 240mg of BI 655064 injected subcutaneous on days 1, 8, 15, and 22 (once weekly) followed by 8 weeks follow-up period.

Reporting group title

Part 2, Placebo (RA)

Reporting group description

Part 2, patients with Rheumatoid arthritis (RA): Placebo matching BI 655064 120mg injected subcutaneous on days 1, 8, 15, 22, 29, 36, 43, 50, 57, 64, 71, and 78 (once weekly for 12 weeks) followed by 8 weeks follow-up period.

Reporting group title

Part 2, BI 655064 120mg (RA)

Reporting group description

Serious adverse events	Part 1, Placebo (HV)	Part 1, BI 655064 80mg (HV)	Part 1, BI 655064 120mg (HV)	Part 1, BI 655064 180mg (HV)	Part 1, BI 655064 240mg (HV)	Part 2, Placebo (RA)	Part 2, BI 655064 120mg (RA)
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	2 / 44 (4.55%)
number of deaths (all causes)	0	0	0	0	0	0	1
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiopulmonary failure
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 44 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part 1, Placebo (HV)	Part 1, BI 655064 80mg (HV)	Part 1, BI 655064 120mg (HV)	Part 1, BI 655064 180mg (HV)	Part 1, BI 655064 240mg (HV)	Part 2, Placebo (RA)	Part 2, BI 655064 120mg (RA)
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 8 (87.50%)	7 / 8 (87.50%)	6 / 8 (75.00%)	6 / 8 (75.00%)	6 / 8 (75.00%)	17 / 23 (73.91%)	29 / 44 (65.91%)
General disorders and administration site conditions
Catheter site oedema
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Chest pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Injection site bruising
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences all number	0	1	0	0	0	0	1
Fatigue
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	2 / 23 (8.70%)	0 / 44 (0.00%)
occurrences all number	1	1	0	2	1	2	0
Injection site pain
subjects affected / exposed	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences all number	2	0	0	0	0	0	1
Injection site rash
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Malaise
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Pyrexia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences all number	1	0	0	0	0	0	2
Vessel puncture site bruise
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	0	0	0	1	0	0
Reproductive system and breast disorders
Dyspareunia
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	2 / 44 (4.55%)
occurrences all number	0	0	1	0	0	0	2
Oropharyngeal pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	1	1	1	0	0
Throat irritation
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Psychiatric disorders
Depression
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 44 (0.00%)
occurrences all number	0	0	1	0	0	1	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	3 / 8 (37.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	2 / 44 (4.55%)
occurrences all number	3	0	1	0	0	1	2
Head injury
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Laceration
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences all number	0	0	3	1	0	0	1
Skin abrasion
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Sunburn
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	0	3	0	0	0	0
Nervous system disorders
Headache
subjects affected / exposed	4 / 8 (50.00%)	3 / 8 (37.50%)	2 / 8 (25.00%)	3 / 8 (37.50%)	1 / 8 (12.50%)	3 / 23 (13.04%)	3 / 44 (6.82%)
occurrences all number	4	5	4	3	1	3	4
Lethargy
subjects affected / exposed	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	2	0	0	0	0	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Eye disorders
Eye pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Photophobia
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	3 / 44 (6.82%)
occurrences all number	0	0	0	0	0	0	3
Food poisoning
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Nausea
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 44 (2.27%)
occurrences all number	0	1	0	1	0	1	1
Toothache
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 44 (2.27%)
occurrences all number	0	0	0	1	0	1	1
Vomiting
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences all number	0	0	0	0	1	0	1
Hepatobiliary disorders
Liver disorder
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	2 / 44 (4.55%)
occurrences all number	0	0	0	0	0	4	2
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Dermatitis contact
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	0	2	0	0	0
Rash
subjects affected / exposed	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences all number	0	2	0	0	0	0	1
Rash erythematous
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Rash pruritic
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Rash macular
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Xeroderma
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 23 (8.70%)	2 / 44 (4.55%)
occurrences all number	0	0	0	0	0	2	2
Joint laxity
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	0	0	1	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Myalgia
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	0	0	1	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 44 (0.00%)
occurrences all number	0	1	0	1	0	1	0
Infections and infestations
Cellulitis
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Chlamydial infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Fungal infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	2 / 8 (25.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	1 / 44 (2.27%)
occurrences all number	0	0	0	2	0	1	1
Nasopharyngitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	5 / 23 (21.74%)	6 / 44 (13.64%)
occurrences all number	0	0	0	0	0	5	8
Pharyngitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences all number	0	0	0	1	0	0	1
Rhinitis
subjects affected / exposed	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 8 (12.50%)	2 / 8 (25.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	1 / 44 (2.27%)
occurrences all number	0	0	1	2	0	0	1
Upper respiratory tract infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	2 / 8 (25.00%)	2 / 8 (25.00%)	1 / 8 (12.50%)	1 / 23 (4.35%)	1 / 44 (2.27%)
occurrences all number	1	0	2	2	1	1	1
Viral infection
subjects affected / exposed	0 / 8 (0.00%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 23 (0.00%)	0 / 44 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	1 / 8 (12.50%)	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 44 (0.00%)
occurrences all number	2	1	0	0	0	1	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 8 (12.50%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	0 / 8 (0.00%)	1 / 23 (4.35%)	0 / 44 (0.00%)
occurrences all number	1	0	0	0	0	1	0

More information

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Were there any global substantial amendments to the protocol? Yes

06 Mar 2013

In Amendment 1, at the request of the Spanish health authority, more specific wording was included in inclusion criterion 7 with regard to contraception for patients with Rheumatoid arthritis (RA). The stopping criteria for the trial were clarified at the request of the Paul Ehrlich Institute (PEI). Additional information was provided with respect to Quantiferon TB Gold testing and the laboratory assay for CD40 receptor occupancy. It was also specified that the tender joint count (TJC), swollen joint count (SJC), and disease activity score in 28 joints (DAS 28) scores would be calculated automatically in the eCRF in order to minimize the risk of investigator error. In addition, several typographical errors and inconsistencies in the CTP were corrected. In the original CTP, it was planned to treat an additional cohort of patients with RA at a dose of 180 mg BI 655064.

10 Jun 2013

In Amendment 2, this planned cohort was canceled due to concerns from the regulatory authority (PEI) and the trial team about projected too-high exposure to BI, and the total number of patients to be enrolled in the trial was adjusted as a result. The amendment also specified that the trial bioanalysts could have indirect unblinded access to PK, PD, and biomarker data. In addition, there were some changes in the collection of biomarker samples to facilitate evaluation of the effectiveness of BI 655064, clarification of PK and safety endpoints, and correction of additional typographical and language errors. The primary PK endpoints for Part 1 were also clarified in Amendment 2 (that is, that the primary endpoints were Cmax and AUCτ after the first and last dose, and AUC0-∞ after the last dose).

09 Dec 2013

In Amendment 3, the inclusion and exclusion criteria for Part 2 of the trial were changed in order to allow a larger patient population to be tested, without interfering with the scientific validity of the trial. These alterations included allowing patients with RA who had previously had no response to anti-TNF medications to participate in the trial and adjustment of the trial analysis to include anti-TNF history in the model; the cut-off CRP value for inclusion was lowered from 1.0 to 0.8 mg/dL and the option to be included based on ESR values was also added; patients with a history of RA of longer than 5 years were also to be allowed to participate; and exclusion with regard to malignancies was updated to align with BI standards. The CTP was also amended to allow testing of the 240 mg dose of BI 655064 in healthy subjects. Some clarifications were also made in the trial flowchart and the assessment of AEs was updated to include drug-induced liver injury. The change in DAS28-CRP at Week 12 compared with baseline was also added as a secondary endpoint.

07 May 2014

In Amendment 4, the TCM responsibilities were reassigned. In addition, in order to increase the pool of potential participants, the dosing requirements for patients with MTX intolerance were adapted and it was specified that patients who had anti-rheumatoid factor positivity could be enrolled in the trial. DAS28-ESR EULAR response was added as a secondary endpoint. AE reporting was updated, an interim PK analysis was added in Part 2, and the randomization process was clarified.

23 Jul 2014

In Amendment 5, it was clarified that the trial was a Phase Ib (healthy subjects)/Phase IIa (patients with RA) study, and that the statistical testing would be applied to both parts of the trial. The joint assessment form was also updated.

16 Oct 2014

In Amendment 6, an additional interim analysis was added to evaluate data for the primary endpoint from the first 36 patients who completed the Phase IIa part of the trial. DAS28-CRP AUC0-12week was added to the 'other efficacy endpoints'. IgG and IgM analyses were added to the safety laboratory tests. In addition, the statistical analyses were updated: a Bayesian efficacy analysis was added as the primary analysis of the primary endpoint and an exploratory analysis of steady state at Week 12 were added. It was specified that the informative prior for the Bayesian analysis was an expected response rate of 25% in the placebo group. The sample size computation was also adapted.

Were there any global interruptions to the trial? No

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: Part 1: Cmax after the first and last dose

Primary: Part 1: Cmax after the first and last dose

Primary: Part 1: AUC 0-infinity after the last dose

Primary: Part 1: AUC 0-infinity after the last dose

Primary: Part 1: AUCtau after the last dose

Primary: Part 1: AUCtau after the last dose

Primary: Part 1: Percentage of subjects with drug related Adverse Events

Primary: Part 1: Percentage of subjects with drug related Adverse Events

Primary: Part 2: American College of Rheumatology (ACR) 20 response rate at week 12

Primary: Part 2: American College of Rheumatology (ACR) 20 response rate at week 12

Secondary: Part 2: ACR50 response rates at week 12

Secondary: Part 2: ACR50 response rates at week 12

Secondary: Part 2: ACR70 response rates at 12 weeks

Secondary: Part 2: ACR70 response rates at 12 weeks

Secondary: Part 2: EULAR DAS28-CRP at week 12

Secondary: Part 2: EULAR DAS28-CRP at week 12

Secondary: Part 2: EULAR DAS28-ESR at week 12

Secondary: Part 2: EULAR DAS28-ESR at week 12

Secondary: Part 2: Percentage of patients with a decrease in DAS28-CRP of >1.2 at week 12

Secondary: Part 2: Percentage of patients with a decrease in DAS28-CRP of >1.2 at week 12

Secondary: Part 2: Change in DAS28-CRP score at week 12

Secondary: Part 2: Change in DAS28-CRP score at week 12

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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