Trial Outcomes & Findings for Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Clinical Effects of Multiple Rising Subcutaneous Doses of BI 655064 in Healthy Volunteers and in Rheumatoid Arthritis Patients With Prior Inadequate Response to Methotrexate Therapy (NCT NCT01751776)

Last Updated: 2024-03-21

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

107 participants

Primary outcome timeframe

From first day of drug administration till end of trial, up to 77 days. Detailed PK can be found in the endpoint description.

Results posted on

2024-03-21

Participant Flow

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

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.

Participant milestones

Participant milestones
Measure	Part 1, Placebo BI 655064 80/120mg (HV) 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.	Part 1, Placebo BI 655064 180/240mg (HV) 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.	Part 1, BI 655064 80mg (HV) 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.	Part 1, BI 655064 120mg (HV) 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.	Part 1, BI 655064 180mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.	Part 2, Placebo BI 655064 120mg (RA) 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.	Part 2, BI 655064 120mg (RA) Part 2, patients with 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.
Overall Study STARTED	4	4	8	8	8	8	23	44
Overall Study COMPLETED	4	4	8	8	8	8	19	40
Overall Study NOT COMPLETED	0	0	0	0	0	0	4	4

Reasons for withdrawal

Reasons for withdrawal
Measure	Part 2, Placebo BI 655064 120mg (RA) 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.	Part 2, BI 655064 120mg (RA) Part 2, patients with 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.
Overall Study Adverse Event	4	2
Overall Study Consent withdrawn	0	1
Overall Study Other reason not specified above	0	1

Baseline Characteristics

As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Part 1, Placebo BI 655064 80/120mg (HV) n=4 Participants 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.	Part 1, Placebo BI 655064 180/240mg (HV) n=4 Participants 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.	Part 1, BI 655064 80mg (HV) n=8 Participants 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.	Part 1, BI 655064 120mg (HV) n=8 Participants 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.	Part 1, BI 655064 180mg (HV) n=8 Participants 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.	Part 1, BI 655064 240mg (HV) n=8 Participants 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.	Part 2, Placebo BI 655064 120mg (RA) n=23 Participants 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.	Part 2, BI 655064 120mg (RA) n=44 Participants Part 2, patients with 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.	Total n=107 Participants Total of all reporting groups
Age, Continuous Part 1	21.5 years STANDARD_DEVIATION 1.3 • n=4 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.	34.0 years STANDARD_DEVIATION 15.4 • n=4 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.	25.9 years STANDARD_DEVIATION 4.1 • n=8 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.	31.4 years STANDARD_DEVIATION 13.3 • n=8 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.	37.3 years STANDARD_DEVIATION 10.8 • n=8 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.	29.5 years STANDARD_DEVIATION 10.6 • n=8 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.	—	—	30.4 years STANDARD_DEVIATION 10.8 • n=40 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.
Age, Continuous Part 2	—	—	—	—	—	—	55.1 years STANDARD_DEVIATION 8.3 • n=23 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.	53.7 years STANDARD_DEVIATION 13.3 • n=44 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.	54.2 years STANDARD_DEVIATION 11.8 • n=67 Participants • As pre-specified in the protocol, subjects in part 1 and part 2 were analyzed separately.
Sex: Female, Male Female	0 Participants n=4 Participants	2 Participants n=4 Participants	2 Participants n=8 Participants	0 Participants n=8 Participants	2 Participants n=8 Participants	1 Participants n=8 Participants	18 Participants n=23 Participants	37 Participants n=44 Participants	62 Participants n=107 Participants
Sex: Female, Male Male	4 Participants n=4 Participants	2 Participants n=4 Participants	6 Participants n=8 Participants	8 Participants n=8 Participants	6 Participants n=8 Participants	7 Participants n=8 Participants	5 Participants n=23 Participants	7 Participants n=44 Participants	45 Participants n=107 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=4 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=23 Participants	0 Participants n=44 Participants	0 Participants n=107 Participants
Race (NIH/OMB) Asian	1 Participants n=4 Participants	0 Participants n=4 Participants	2 Participants n=8 Participants	1 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=23 Participants	1 Participants n=44 Participants	5 Participants n=107 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=4 Participants	2 Participants n=4 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	3 Participants n=8 Participants	2 Participants n=8 Participants	0 Participants n=23 Participants	0 Participants n=44 Participants	7 Participants n=107 Participants
Race (NIH/OMB) Black or African American	0 Participants n=4 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=23 Participants	0 Participants n=44 Participants	0 Participants n=107 Participants
Race (NIH/OMB) White	3 Participants n=4 Participants	2 Participants n=4 Participants	6 Participants n=8 Participants	7 Participants n=8 Participants	5 Participants n=8 Participants	6 Participants n=8 Participants	23 Participants n=23 Participants	43 Participants n=44 Participants	95 Participants n=107 Participants
Race (NIH/OMB) More than one race	0 Participants n=4 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=23 Participants	0 Participants n=44 Participants	0 Participants n=107 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=4 Participants	0 Participants n=4 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=8 Participants	0 Participants n=23 Participants	0 Participants n=44 Participants	0 Participants n=107 Participants

PRIMARY outcome

Timeframe: From first day of drug administration till end of trial, up to 77 days. Detailed PK can be found in the endpoint description.

Population: All subjects were treated and and provided data for at least 1 primary pharmacokinetic (PK) endpoint and therefore all subjects were also included in the PK set (PKS).

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=8 Participants 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.	Part 1, BI 655064 120mg (HV) n=8 Participants 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.	Part 1, BI 655064 180mg (HV) n=8 Participants 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.	Part 1, BI 655064 240mg (HV) n=8 Participants 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.	Part 1, BI 655064 240mg (HV) 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.
Part 1: Cmax After the First and Last Dose after the first dose	1.59 microgram (µg)/ millilitre (mL) Geometric Coefficient of Variation 492	7.70 microgram (µg)/ millilitre (mL) Geometric Coefficient of Variation 29.5	9.87 microgram (µg)/ millilitre (mL) Geometric Coefficient of Variation 67.8	18.0 microgram (µg)/ millilitre (mL) Geometric Coefficient of Variation 46.3	—
Part 1: Cmax After the First and Last Dose after the last (fourth) dose	13.1 microgram (µg)/ millilitre (mL) Geometric Coefficient of Variation 59.1	28.7 microgram (µg)/ millilitre (mL) Geometric Coefficient of Variation 35.6	39.8 microgram (µg)/ millilitre (mL) Geometric Coefficient of Variation 37.4	68.4 microgram (µg)/ millilitre (mL) Geometric Coefficient of Variation 21.9	—

PRIMARY outcome

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

Population: PKS

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).

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=8 Participants 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.	Part 1, BI 655064 120mg (HV) n=8 Participants 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.	Part 1, BI 655064 180mg (HV) n=8 Participants 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.	Part 1, BI 655064 240mg (HV) n=8 Participants 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.	Part 1, BI 655064 240mg (HV) 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.
Part 1: AUC 0-infinity After the Last Dose	3940 µg* hours (h)/mL Geometric Coefficient of Variation 53.9	11000 µg* hours (h)/mL Geometric Coefficient of Variation 42.5	19200 µg* hours (h)/mL Geometric Coefficient of Variation 41.1	39300 µg* hours (h)/mL Geometric Coefficient of Variation 26.1	—

PRIMARY outcome

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 trial drug on day 22

Population: PKS

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 synonymous with AUC0-168.

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=8 Participants 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.	Part 1, BI 655064 120mg (HV) n=8 Participants 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.	Part 1, BI 655064 180mg (HV) n=8 Participants 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.	Part 1, BI 655064 240mg (HV) n=8 Participants 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.	Part 1, BI 655064 240mg (HV) 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.
Part 1: AUCtau After the Last Dose	1790 µg*h/mL Geometric Coefficient of Variation 56.4	4140 µg*h/mL Geometric Coefficient of Variation 35.4	5470 µg*h/mL Geometric Coefficient of Variation 37.4	9460 µg*h/mL Geometric Coefficient of Variation 22.4	—

PRIMARY outcome

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)

Population: TS

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

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=8 Participants 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.	Part 1, BI 655064 120mg (HV) n=8 Participants 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.	Part 1, BI 655064 180mg (HV) n=8 Participants 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.	Part 1, BI 655064 240mg (HV) n=8 Participants 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.	Part 1, BI 655064 240mg (HV) n=8 Participants 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.
Part 1: Percentage of Subjects With Drug Related Adverse Events	50.0 Percentage of participants	25.0 Percentage of participants	12.5 Percentage of participants	50.0 Percentage of participants	0.0 Percentage of participants

PRIMARY outcome

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

Population: The full analysis set (FAS) included 66 of 67 randomised and treated patients; 1 patient (placebo group) was excluded due to insufficient efficacy data (excluded due to important protocol violations). Noncompleters were assumed to be failures (NCF).

ACR 20 criteria at week 12 relative to the patient's status at baseline: that is, at least 20 percent (%) improvement in swollen joint count, at least 20% improvement in tender joint count, and at least 20% 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 ACR20 were evaluated descriptively. The data were analysed with a Bayesian approach using an informative prior for the placebo treatment group; predictive probability that the treatment difference was larger than 0%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40% or 45% was to be evaluated.

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=22 Participants 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.	Part 1, BI 655064 120mg (HV) n=44 Participants 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.	Part 1, BI 655064 180mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.
Part 2: American College of Rheumatology (ACR)20 Response Rate at Week 12	45.5 Percentage of participants	68.2 Percentage of participants	—	—	—

SECONDARY outcome

Timeframe: at week 12 (day 85)

Population: FAS (NCF)

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.

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=22 Participants 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.	Part 1, BI 655064 120mg (HV) n=44 Participants 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.	Part 1, BI 655064 180mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.
Part 2: ACR50 Response Rates at Week 12 unadjusted	18.2 Percentage of participants Interval 5.2 to 40.3	36.4 Percentage of participants Interval 22.4 to 52.2	—	—	—
Part 2: ACR50 Response Rates at Week 12 adjusted	15.6 Percentage of participants Interval 5.5 to 36.9	35.6 Percentage of participants Interval 22.3 to 51.5	—	—	—

SECONDARY outcome

Timeframe: at week 12 (day 85)

Population: FAS (NCF)

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.

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=22 Participants 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.	Part 1, BI 655064 120mg (HV) n=44 Participants 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.	Part 1, BI 655064 180mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.
Part 2: ACR70 Response Rates at Week 12 unadjusted	13.6 Percentage of participants Interval 2.9 to 34.9	18.2 Percentage of participants Interval 8.2 to 32.7	—	—	—
Part 2: ACR70 Response Rates at Week 12 adjusted	13.0 Percentage of participants Interval 4.0 to 34.6	17.0 Percentage of participants Interval 8.3 to 31.6	—	—	—

SECONDARY outcome

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

Population: FAS (observed cases)

Assessed by European League Against Rheumatism (EULAR) categorization as good, moderate, or nonresponders based on improvement from baseline using the 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. DAS28-CRP is calculated as 0.56\*√(TJC) + 0.28\*√(SJC) + 0.36\*Ln(CRP+1) + 0.014\*VAS + 0.96. The total score ranges from 1.0 to 9.4, where a higher score indicates a better outcome. EULAR response states were classified as follows: good responders were patients with an improvement of \>1.2 and a present score of ⩽3.2; moderate responders were patients with an improvement of \>0.6 to ⩽1.2 and a present score of ⩽5.1, or an improvement of \>1.2 and a present score of \>3.2; non-responders were any patients with an improvement of ⩽0.6, or patients with an improvement of \>0.6 to ⩽1.2 and a present score of \>5.1. Improvement (impr.) is abbreviated in the category names.

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=20 Participants 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.	Part 1, BI 655064 120mg (HV) n=39 Participants 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.	Part 1, BI 655064 180mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 DAS28-CRP <=3.2, improvement (>0.6 and <=1.2)	5.0 Percentage of participants	2.6 Percentage of participants	—	—	—
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 DAS28-CRP <=3.2, improvement <=0.6	0.0 Percentage of participants	0.0 Percentage of participants	—	—	—
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 DAS28-CRP (>3.2 and <=5.1), improvement >1.2	25.0 Percentage of participants	35.9 Percentage of participants	—	—	—
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 DAS28-CRP (>3.2 and <=5.1), impr. (>0.6 and <=1.2)	5.0 Percentage of participants	7.7 Percentage of participants	—	—	—
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 DAS28-CRP (>3.2 and <=5.1), improvement <=0.6	10.0 Percentage of participants	2.6 Percentage of participants	—	—	—
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 DAS28-CRP >5.1, improvement >1.2	10.0 Percentage of participants	0.0 Percentage of participants	—	—	—
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 DAS28-CRP>5.1, improvement (>0.6 and <=1.2)	10.0 Percentage of participants	7.7 Percentage of participants	—	—	—
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 DAS28-CRP >5.1, improvement <=0.6	10.0 Percentage of participants	7.7 Percentage of participants	—	—	—
Part 2: EULAR Disease Activity Score in 28 Joints and C-reactive Protein (DAS28-CRP) at Week 12 DAS28-CRP <=3.2, improvement >1.2	25.0 Percentage of participants	35.9 Percentage of participants	—	—	—

SECONDARY outcome

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

Population: FAS (observed cases)

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. DAS28-ESR is calculated as 0.56\*√(TJC) + 0.28\*√(SJC) + 0.70 \*Ln(ESR) + 0.014\*VAS. The total score ranges from 0 to 9.4, where a higher score indicates a better outcome. EULAR response states were classified as follows: good responders were patients with an improvement of \>1.2 and a present score of ⩽3.2; moderate responders were patients with an improvement of \>0.6 to ⩽1.2 and a present score of ⩽5.1, or an improvement of \>1.2 and a present score of \>3.2; non-responders were any patients with an improvement of ⩽0.6, or patients with an improvement of \>0.6 to ⩽1.2 and a present score of \>5.1. Improvement (impr.) is abbreviated in the category names.

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=20 Participants 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.	Part 1, BI 655064 120mg (HV) n=39 Participants 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.	Part 1, BI 655064 180mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.
Part 2: EULAR DAS28-ESR at Week 12 DAS28-ESR <=3.2, improvement >1.2	10.5 Percentage of participants	20.5 Percentage of participants	—	—	—
Part 2: EULAR DAS28-ESR at Week 12 DAS28-ESR <=3.2, improvement (>0.6 and <=1.2)	0.0 Percentage of participants	0.0 Percentage of participants	—	—	—
Part 2: EULAR DAS28-ESR at Week 12 DAS28-ESR <=3.2, improvement <=0.6	0.0 Percentage of participants	0.0 Percentage of participants	—	—	—
Part 2: EULAR DAS28-ESR at Week 12 DAS28-ESR (>3.2 and <=5.1), improvement >1.2	42.1 Percentage of participants	51.3 Percentage of participants	—	—	—
Part 2: EULAR DAS28-ESR at Week 12 DAS28-ESR (>3.2 and <=5.1), impr. (>0.6 and <=1.2)	5.3 Percentage of participants	5.1 Percentage of participants	—	—	—
Part 2: EULAR DAS28-ESR at Week 12 DAS28-ESR (>3.2 and <=5.1), improvement <=0.6	0.0 Percentage of participants	0.0 Percentage of participants	—	—	—
Part 2: EULAR DAS28-ESR at Week 12 DAS28-ESR >5.1, improvement >1.2	21.1 Percentage of participants	10.3 Percentage of participants	—	—	—
Part 2: EULAR DAS28-ESR at Week 12 DAS28-ESR >5.1, improvement (>0.6 and <=1.2)	5.3 Percentage of participants	7.7 Percentage of participants	—	—	—
Part 2: EULAR DAS28-ESR at Week 12 DAS28-ESR >5.1, improvement <=0.6	15.8 Percentage of participants	5.1 Percentage of participants	—	—	—

SECONDARY outcome

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

Population: FAS (Last observation carried forward)

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. DAS28-CRP is calculated using Tender Joint Count 28 (TJC28), Swollen Joint Count 28 (SJC28), C-reactive protein (CRP) (in mg/L), Patient's Global Assessment of Arthritis Disease Activity (PtGA) (visual analogue scale with values from 0=best to 100=worst), where the total score is calculated as follows: 0.56\*√(TJC) + 0.28\*√(SJC) + 0.36\*Ln(CRP+1) + 0.014\*VAS + 0.96. The total score ranges from 1.0 to 9.4, where a higher score indicates a better outcome.

Outcome measures

Outcome measures
Measure	Part 1, BI 655064 80mg (HV) n=22 Participants 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.	Part 1, BI 655064 120mg (HV) n=44 Participants 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.	Part 1, BI 655064 180mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.	Part 1, BI 655064 240mg (HV) 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.
Part 2: Percentage of Patients With a Decrease in DAS28-CRP of >1.2 at Week 12 Unadjusted	59.1 Percentage of participants Interval 36.4 to 79.3	65.9 Percentage of participants Interval 50.1 to 79.5	—	—	—
Part 2: Percentage of Patients With a Decrease in DAS28-CRP of >1.2 at Week 12 Adjusted	58.2 Percentage of participants Interval 36.7 to 77.0	67.1 Percentage of participants Interval 51.6 to 79.6	—	—	—

SECONDARY outcome

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

Population: FAS (last observation carried forward)

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. DAS28-CRP is calculated using Tender Joint Count 28 (TJC28), Swollen Joint Count 28 (SJC28), C-reactive protein (CRP) (in mg/L), Patient's Global Assessment of Arthritis Disease Activity (PtGA) (visual analogue scale with values from 0=best to 100=worst), where the total score is calculated as follows: 0.56\*√(TJC) + 0.28\*√(SJC) + 0.36\*Ln(CRP+1) + 0.014\*VAS + 0.96. The total score ranges from 1.0 to 9.4, where a higher score indicates a better outcome.