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Clinical Trial Results:
A 48-week, phase II, randomized, double-blind, placebo controlled, proof of concept and dose-finding study of three different dose regimens of BI 655066 administered subcutaneously in patients with ankylosing spondylitis

Summary
EudraCT number	2013-003666-13
Trial protocol	ES FI DE IT BE NL
Global end of trial date	26 Jul 2016

Results information
Results version number	v1(current)
This version publication date	06 Aug 2017
First version publication date	06 Aug 2017
Other versions

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

1311.8

ISRCTN number

US NCT number

NCT02047110

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 8002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, 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 Sep 2016

Is this the analysis of the primary completion data?

Yes

Primary completion date

05 Mar 2015

Global end of trial reached?

Yes

Global end of trial date

26 Jul 2016

Was the trial ended prematurely?

Main objective of the trial

This trial assessed the efficacy and safety of three subcutaneous doses of BI 655066 in adult patients with ankylosing spondylitis (AS) for clinical proof of concept and dose selection. The primary objective was to compare the efficacy of BI 655066 with placebo. The assessment of efficacy was based on the percentage of patients who achieved a clinical response according to the Assessment in SpondyloArthritis international Society 40 (ASAS 40) criteria at Week 12.

Protection of trial subjects

Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.

Background therapy

Evidence for comparator

Actual start date of recruitment

04 Mar 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 18

Country: Number of subjects enrolled

Finland: 20

Country: Number of subjects enrolled

France: 24

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

Hong Kong: 10

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Netherlands: 14

Country: Number of subjects enrolled

Korea, Republic of: 13

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

Taiwan: 55

Country: Number of subjects enrolled

United States: 20

Worldwide total number of subjects

219

EEA total number of subjects

121

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)

216

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The trial had a DB treatment period up to Week 24, an Escape treatment period up to Week 40, and an open-label-extension (OLE) treatment period that lasted 26 weeks after OLE entry. Each of the treatment periods was followed by a 24- week post-treatment follow-up period.

Screening details

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

Period 1 title

DB treatment period up to Week 24

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Blinding implementation details

Double-blind trial; The patients, investigators, site staff, and the study team were blinded to treatment allocation.

Are arms mutually exclusive

Yes

Placebo

Arm description

Subcutaneous injection of Placebo (solution for injection matching BI 655066, 1 mL pre-filled syringe) administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Arm type

Placebo

Investigational medicinal product name

matching Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BI 655066 18 mg

Arm description

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks

BI 655066 90 mg

Arm description

Subcutaneous injection of BI 655066 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection of BI 655066 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

BI 655066 180 mg

Arm description

Subcutaneous injection of BI 655066 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection of BI 655066 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Number of subjects in period 1 ^[1]	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Started	40	40	39	40
Completed	35	38	36	38
Not completed	5	2	3	2
Consent withdrawn by subject	1	-	-	1
Adverse event, non-fatal	1	-	-	-
Other than specified	1	2	3	1
Lost to follow-up	1	-	-	-
Protocol deviation	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.

Period 2 title

DB (Week 12 up to Week 24)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Blinding implementation details

Double-blind trial; The patients, investigators, site staff, and the study team were blinded to treatment allocation. As patients from the previous period continue in this period, hence non-mutually exclusive arms.

Are arms mutually exclusive

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

matching Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BI 655066 18 mg

Arm description

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks

BI 655066 90 mg

Arm description

Subcutaneous injection of BI 655066 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection of BI 655066 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

BI 655066 180 mg

Arm description

Subcutaneous injection of BI 655066 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injection of BI 655066 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Number of subjects in period 2	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Started	9	17	13	12
Completed	9	15	12	12
Not completed	0	2	1	0
Consent withdrawn by subject	-	1	-	-
Other than specified	-	1	1	-

Period 3 title

Escape treatment period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Blinding implementation details

Are arms mutually exclusive

Placebo

Arm description

Subcutaneous injection of Placebo (solution for injection matching BI 655066, 1 mL pre-filled syringe) administered every 8 week (At Day1 and at Week 8) up to 2 times during the regular treatment period. For escape period, the patients who did not achieve Assessment in SpondyloArthritis international Society 20 (ASAS 20) response at week 12 received up to 4 additional injections of 180 mg from week 16 (total of 6 injections)

Arm type

Placebo

Investigational medicinal product name

matching Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BI 655066 18 mg

Arm description

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo at week 8, up to 2 times during the regular treatment period. For escape period, the patients who did not achieve ASAS 20 at week 12 received up to 4 additional injections of 180 mg from week 16 (total of 6 injections)

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BI 655066 90 mg

Arm description

Subcutaneous injection of BI 655066 90 mg administered at Day 1 and Week 8, up to 2 times during the treatment period. For escape period, the patients who did not achieve ASAS 20 at week 12 received up to 4 additional injections of 180 mg from week 16 (total of 6 injections)

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BI 655066 180 mg

Arm description

Subcutaneous injection of BI 655066 180 mg administered at Day 1 and Week 8, up to 2 times during the treatment period. For escape period, the patients who did not achieve ASAS 20 at week 12 received up to 4 additional injections of 180 mg from week 16 (total of 6 injections)

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 3	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Started	26	21	23	26
Completed	23	15	20	24
Not completed	3	6	3	2
Consent withdrawn by subject	1	2	1	1
Adverse event, non-fatal	1	2	2	-
Other than specified	1	2	-	1

Period 4 title

OLE treatment period

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

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

Blinding implementation details

Are arms mutually exclusive

Placebo

Arm description

Arm type

Placebo

Investigational medicinal product name

matching Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BI 655066 18 mg

Arm description

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks. For OLE treatment period, the patient received 4 additional 180 mg treatments

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BI 655066 90 mg

Arm description

Subcutaneous injection of BI 655066 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period. For OLE treatment period, the patient received 4 additional 180 mg treatments

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

BI 655066 180 mg

Arm description

Subcutaneous injection of BI 655066 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period. For OLE treatment period, the patient received 4 additional 180 mg treatments

Arm type

Experimental

Investigational medicinal product name

BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Injection

Routes of administration

Subcutaneous use

Dosage and administration details

Number of subjects in period 4	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Started	4	8	5	9
Completed	4	8	4	9
Not completed	0	0	1	0
Other than specified	-	-	1	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

BI 655066 18 mg

Reporting group description

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks

Reporting group title

BI 655066 90 mg

Reporting group description

Subcutaneous injection of BI 655066 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Reporting group title

BI 655066 180 mg

Reporting group description

Subcutaneous injection of BI 655066 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Reporting group values	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Total
Number of subjects	40	40	39	40	159
Age categorical
Units: Subjects
Age Continuous
Treated set (TS): All patients who received at least 1 dose of trial medication
Units: years
arithmetic mean (standard deviation)	37.6 ± 11	38 ± 11.1	39.5 ± 10.8	40.6 ± 11.9	-
Gender, Male/Female
Treated set (TS): All patients who received at least 1 dose of trial medication
Units: Subjects
Female	15	12	9	10	46
Male	25	28	30	30	113

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

BI 655066 18 mg

Reporting group description

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks

Reporting group title

BI 655066 90 mg

Reporting group description

Subcutaneous injection of BI 655066 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Reporting group title

BI 655066 180 mg

Reporting group description

Subcutaneous injection of BI 655066 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Reporting group title

Placebo

Reporting group description

Reporting group title

BI 655066 18 mg

Reporting group description

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks

Reporting group title

BI 655066 90 mg

Reporting group description

Subcutaneous injection of BI 655066 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Reporting group title

BI 655066 180 mg

Reporting group description

Subcutaneous injection of BI 655066 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Reporting group title

Placebo

Reporting group description

Reporting group title

BI 655066 18 mg

Reporting group description

Reporting group title

BI 655066 90 mg

Reporting group description

Reporting group title

BI 655066 180 mg

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

BI 655066 18 mg

Reporting group description

Reporting group title

BI 655066 90 mg

Reporting group description

Reporting group title

BI 655066 180 mg

Reporting group description

Primary: Percentage of patients who achieved Assessment of Spondyloarthritis International Society (ASAS) 40 improvement criteria at Week 12.

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End point title

Percentage of patients who achieved Assessment of Spondyloarthritis International Society (ASAS) 40 improvement criteria at Week 12.

End point description

ASAS 40 evaluations are based on the following 4 components (also called domains) that include patient' self-assessments on a numerical rating scale (NRS) from 0 to 10 with higher numbers representing a worse disease status: -Global AS disease activity -Inflammation based on the mean of Bath AS Disease Activity Index (BASDAI) questions addressing the level of morning stiffness and duration -Spinal pain based on the mean of 2 questions -Physical function based on the Bath AS Functional Index (BASFI) The ASAS 40 response is defined as an improvement in 3 of 4 components and no worsening in the remaining component; an improvement is defined as a reduction from baseline of ≥40% and an absolute reduction of ≥2 units in each of the 3 components. Full Analysis set (FAS) is the population set for this endpoint. FAS comprised of all randomised patients who received at least 1 dose of trial medication

End point type

Primary

End point timeframe

Week 12

End point values	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Number of subjects analysed	40 ^[1]	40 ^[2]	39 ^[3]	40 ^[4]
Units: Percentage of participants
number (not applicable)	17.5	25	20.5	15

Notes
[1] - FAS
[2] - FAS
[3] - FAS
[4] - FAS

Statistical analysis 1

Statistical analysis description

To control the type I error rate, the primary endpoint was tested in a hierarchical fixed sequence approach. The proportion of patients achieving ASAS 40 response at Week 12 was pairwise compared in the following sequence: BI 655066 180 mg vs. placebo (1.) and BI 655066 90 mg vs. placebo (2.). The significance level was 5% (1-sided). The comparison BI 655066 18 mg vs. placebo was not included in the formal testing sequence; an exploratory p-value was provided.

Comparison groups

Placebo v BI 655066 18 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.2652 ^[6]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

7.5

Confidence interval

level

90%

sides

2-sided

lower limit

-12.1

upper limit

26.6

Notes
[5] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper-Pearson method. Difference calculated as "BI 655066 18 mg minus Placebo".
[6] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the primary endpoint, ASAS 40 response at Week 12, between treatment groups.

Statistical analysis 2

Statistical analysis description

Comparison groups

Placebo v BI 655066 90 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.4129 ^[8]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-15.9

upper limit

20.8

Notes
[7] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 90 mg minus Placebo".
[8] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the primary endpoint, ASAS 40 response at Week 12, between treatment groups.

Statistical analysis 3

Statistical analysis description

Comparison groups

Placebo v BI 655066 180 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.4243 ^[10]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

-2.5

Confidence interval

level

90%

sides

2-sided

lower limit

-21.8

upper limit

Notes
[9] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 180 mg minus Placebo".
[10] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the primary endpoint, ASAS 40 response at Week 12, between treatment groups

Secondary: Change from baseline to Week 12 in disease activity assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS).

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End point title

Change from baseline to Week 12 in disease activity assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS).

End point description

This is the key secondary endpoint. ASDAS score is calculated with a formula integrating C-reactive serum protein (CRP) level [milligram per Litre (mg/L)] in serum and 4 variables of patients' assessments based on NRS: back pain based on BASDAI question 2; duration of morning stiffness based on BASDAI question 6; global AS disease activity; peripheral joint pain/swelling based on BASDAI question 3.

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Number of subjects analysed	40 ^[11]	40 ^[12]	39 ^[13]	40 ^[14]
Units: Unit on scale
median (inter-quartile range (Q1-Q3))	-0.2 (-0.9 to 0.2)	-0.7 (-1.3 to -0.2)	-0.6 (-1 to 0.1)	-0.7 (-1.1 to -0.3)

Notes
[11] - FAS
[12] - FAS
[13] - FAS
[14] - FAS

Statistical analysis 1

Comparison groups

Placebo v BI 655066 18 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.0229 ^[16]

Method

Wilcoxon rank−sum test

Parameter type

Median estimate by Hodges−Lehmann method

Point estimate

-0.4

Confidence interval

level

90%

sides

2-sided

lower limit

-0.7

upper limit

-0.1

Notes
[15] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Moses method. Difference calculated as "BI 655066 18 mg minus Placebo".
[16] - One sided p-value from Wilcoxon rank−sum test

Statistical analysis 2

Comparison groups

Placebo v BI 655066 90 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.1038 ^[18]

Method

Wilcoxon rank−sum test

Parameter type

Median estimate by Hodges−Lehmann method

Point estimate

-0.3

Confidence interval

level

90%

sides

2-sided

lower limit

-0.6

upper limit

0.1

Notes
[17] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Moses method. Difference calculated as "BI 655066 90 mg minus Placebo".
[18] - One sided p-value from Wilcoxon rank−sum test

Statistical analysis 3

Comparison groups

Placebo v BI 655066 180 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.0101 ^[20]

Method

Wilcoxon rank−sum test

Parameter type

Median estimate by Hodges−Lehmann method

Point estimate

-0.5

Confidence interval

level

90%

sides

2-sided

lower limit

-0.7

upper limit

-0.1

Notes
[19] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Moses method. Difference calculated as "BI 655066 180 mg minus Placebo".
[20] - One sided p-value from Wilcoxon rank−sum test

Secondary: Percentage of patients who achieved ASAS 5/6 improvement criteria at Week 12

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End point title

Percentage of patients who achieved ASAS 5/6 improvement criteria at Week 12

End point description

The ASAS 5/6 evaluation is based on 6 components: -Global AS disease activity -Inflammation based on the mean of BASDAI questions addressing the level-of morning stiffness and duration -Spinal pain -Physical function based on the Bath AS Functional Index (BASFI) -Spinal mobility assessment (lateral lumbar flexion), corresponding to one out of 5 measurements of Bath Ankylosing Spondylitis Metrology Index (BASMI) -Serum CRP levels The ASAS 5/6 response is defined as an improvement in any 5 of the 6 components and no worsening in the remaining component. A reduction from baseline of ≥20% is defined as an improvement according to the ASAS criteria.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Number of subjects analysed	40 ^[21]	40 ^[22]	39 ^[23]	40 ^[24]
Units: Percentage of participants
number (not applicable)	5	20	23.1	17.5

Notes
[21] - FAS
[22] - FAS
[23] - FAS
[24] - FAS

Statistical analysis 1

Comparison groups

Placebo v BI 655066 18 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

= 0.0238 ^[26]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-4.6

upper limit

33.8

Notes
[25] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper-Pearson method. Difference calculated as "BI 655066 18 mg minus Placebo".
[26] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the endpoint at Week 12, between treatment groups.

Statistical analysis 2

Comparison groups

Placebo v BI 655066 90 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

= 0.012 ^[28]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

18.1

Confidence interval

level

90%

sides

2-sided

lower limit

-0.8

upper limit

35.3

Notes
[27] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 90 mg minus Placebo".
[28] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the endpoint at Week 12, between treatment groups.

Statistical analysis 3

Comparison groups

Placebo v BI 655066 180 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.0465 ^[30]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

12.5

Confidence interval

level

90%

sides

2-sided

lower limit

-7.1

upper limit

31.4

Notes
[29] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 180 mg minus Placebo".
[30] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the endpoint at Week 12, between treatment groups

Secondary: Percentage of patients who achieved partial remission according to the ASAS criteria at Week 12

Top of page

End point title

Percentage of patients who achieved partial remission according to the ASAS criteria at Week 12

End point description

Percentage of patients who achieved partial remission according to the ASAS criteria at Week 12 is presented

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Number of subjects analysed	40 ^[31]	40 ^[32]	39 ^[33]	40 ^[34]
Units: Percentage of participants
number (not applicable)	2.5	2.5	2.6	10

Notes
[31] - FAS
[32] - FAS
[33] - FAS
[34] - FAS

Statistical analysis 1

Statistical analysis description

p-values are not presented as they were not meaningful; 3 treatment groups had only a single patient with partial remission.

Comparison groups

Placebo v BI 655066 18 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

Method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

-19.4

upper limit

19.4

Notes
[35] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper-Pearson method. Difference calculated as "BI 655066 18 mg minus Placebo".

Statistical analysis 2

Statistical analysis description

p-values are not presented as they were not meaningful; 3 treatment groups had only a single patient with partial remission.

Comparison groups

Placebo v BI 655066 90 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

Method

Parameter type

Risk difference (RD)

Point estimate

0.1

Confidence interval

level

90%

sides

2-sided

lower limit

-18.3

upper limit

18.3

Notes
[36] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 90 mg minus Placebo".

Statistical analysis 3

Statistical analysis description

p-values are not presented as they were not meaningful; 3 treatment groups had only a single patient with partial remission.

Comparison groups

Placebo v BI 655066 180 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

Method

Parameter type

Risk difference (RD)

Point estimate

7.5

Confidence interval

level

90%

sides

2-sided

lower limit

-12.1

upper limit

26.6

Notes
[37] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 180 mg minus Placebo".

Secondary: Percentage of patients who achieved ASAS 20 improvement criteria at Week 12

Top of page

End point title

Percentage of patients who achieved ASAS 20 improvement criteria at Week 12

End point description

ASAS 20 evaluations are based on the following 4 components (also called domains) that include patient' self-assessments on a numerical rating scale (NRS) from 0 to 10 with higher numbers representing a worse disease status: -Global AS disease activity -Inflammation based on the mean of Bath AS Disease Activity Index (BASDAI) questions addressing the level of morning stiffness and duration -Spinal pain based on the mean of 2 questions -Physical function based on the Bath AS Functional Index (BASFI) The ASAS 20 response is defined as an improvement in 3 of 4 components and no worsening in the remaining component; an improvement is defined as a reduction from baseline of ≥20% and an absolute reduction of ≥1 units in each of the 3 components.

End point type

Secondary

End point timeframe

Week 12

End point values	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Number of subjects analysed	40 ^[38]	40 ^[39]	39 ^[40]	40 ^[41]
Units: Percentage of participants
number (not applicable)	20	45	33.3	32.5

Notes
[38] - FAS
[39] - FAS
[40] - FAS
[41] - FAS

Statistical analysis 1

Comparison groups

Placebo v BI 655066 18 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

P-value

= 0.0092 ^[43]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

90%

sides

2-sided

lower limit

5.5

upper limit

43.1

Notes
[42] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper-Pearson method. Difference calculated as "BI 655066 18 mg minus Placebo".
[43] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the endpoint at Week 12, between treatment groups.

Statistical analysis 2

Comparison groups

Placebo v BI 655066 90 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

P-value

= 0.1243 ^[45]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

13.3

Confidence interval

level

90%

sides

2-sided

lower limit

-5.9

upper limit

30.5

Notes
[44] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 90 mg minus Placebo".
[45] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the endpoint at Week 12, between treatment groups.

Statistical analysis 3

Comparison groups

Placebo v BI 655066 180 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

P-value

= 0.1198 ^[47]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

12.5

Confidence interval

level

90%

sides

2-sided

lower limit

-7.1

upper limit

31.4

Notes
[46] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 180 mg minus Placebo".
[47] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the endpoint at Week 12, between treatment groups

Secondary: Change from baseline to Week 12 in disease activity assessed by BASDAI

Top of page

End point title

Change from baseline to Week 12 in disease activity assessed by BASDAI

End point description

BASDAI assesses the AS disease activity of a patient within the last week based on 6 questions on a NRS (1 to 10) How would you describe the overall level of 1] fatigue/tiredness you have experienced? 2] AS neck, back or hip pain you have had? 3] pain/swelling in joints other than neck, back or hips you have had? 4] discomfort you have had from any areas tender to touch or pressure? 5] morning stiffness you have had from the time you wake up? How long does your 6] morning stiffness last from the time you wake up? A score of 10 means very severe disease activity for each of the BASDAI questions 1, 2, 3, 4 and 5. BASDAI question 6 addresses the stiffness duration. A NRS of 0 means 0 h; a NRS of 10 mean ≥2 h. The BASDAI was computed in the following way: the sum of the values of question 1 to 4 was calculated and the mean of questions 5 and 6 was added. This value was divided by 5.

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Number of subjects analysed	40 ^[48]	40 ^[49]	39 ^[50]	40 ^[51]
Units: Unit on scale
median (inter-quartile range (Q1-Q3))	-0.6 (-2.8 to -0.1)	-1.2 (-2.8 to -0.4)	-0.8 (-2.1 to 1)	-1 (-2 to -0.2)

Notes
[48] - FAS
[49] - FAS
[50] - FAS
[51] - FAS

Statistical analysis 1

Comparison groups

Placebo v BI 655066 18 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[52]

P-value

= 0.1241 ^[53]

Method

Wilcoxon rank−sum test

Parameter type

Median estimate by Hodges−Lehmann method

Point estimate

-0.4

Confidence interval

level

90%

sides

2-sided

lower limit

-1

upper limit

0.2

Notes
[52] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Moses method. Difference calculated as "BI 655066 18 mg minus Placebo".
[53] - One sided p-value from Wilcoxon rank−sum test

Statistical analysis 2

Comparison groups

Placebo v BI 655066 90 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

P-value

= 0.3033 ^[55]

Method

Wilcoxon rank−sum test

Parameter type

Median estimate by Hodges−Lehmann method

Point estimate

0.3

Confidence interval

level

90%

sides

2-sided

lower limit

-0.5

upper limit

Notes
[54] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Moses method. Difference calculated as "BI 655066 90 mg minus Placebo".
[55] - One sided p-value from Wilcoxon rank−sum test

Statistical analysis 3

Comparison groups

Placebo v BI 655066 180 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

P-value

= 0.3203 ^[57]

Method

Wilcoxon rank−sum test

Parameter type

Median estimate by Hodges−Lehmann method

Point estimate

-0.2

Confidence interval

level

90%

sides

2-sided

lower limit

-0.8

upper limit

0.4

Notes
[56] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Moses method. Difference calculated as "BI 655066 180 mg minus Placebo".
[57] - One sided p-value from Wilcoxon rank−sum test

Secondary: Percentage of patients who achieved ASAS 40 improvement criteria at Week 24

Top of page

End point title

Percentage of patients who achieved ASAS 40 improvement criteria at Week 24

End point description

Percentage of patients who achieved ASAS 40 improvement criteria at Week 24 is presented

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg
Number of subjects analysed	40 ^[58]	40 ^[59]	39 ^[60]	40 ^[61]
Units: Percentage of participants
number (not applicable)	15	22.5	23.1	12.5

Notes
[58] - FAS
[59] - FAS
[60] - FAS
[61] - FAS

Statistical analysis 1

Comparison groups

Placebo v BI 655066 18 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[62]

P-value

= 0.2639 ^[63]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

7.5

Confidence interval

level

90%

sides

2-sided

lower limit

-12.1

upper limit

26.6

Notes
[62] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper-Pearson method. Difference calculated as "BI 655066 18 mg minus Placebo".
[63] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the endpoint at Week 24, between treatment groups.

Statistical analysis 2

Comparison groups

Placebo v BI 655066 90 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[64]

P-value

= 0.2691 ^[65]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

8.1

Confidence interval

level

90%

sides

2-sided

lower limit

-10.9

upper limit

25.7

Notes
[64] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 90 mg minus Placebo".
[65] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the endpoint at Week 24, between treatment groups.

Statistical analysis 3

Comparison groups

Placebo v BI 655066 180 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority ^[66]

P-value

= 0.4174 ^[67]

Method

Suissa-Shuster unconditional exact test

Parameter type

Risk difference (RD)

Point estimate

-2.5

Confidence interval

level

90%

sides

2-sided

lower limit

-21.8

upper limit

Notes
[66] - The confidence interval for the difference in proportion between the treatment groups was obtained by the Clopper- Pearson method. Difference calculated as "BI 655066 180 mg minus Placebo".
[67] - The Suissa-Shuster unconditional exact test was used to test the difference in the proportion of patients achieving the endpoint at Week 24, between treatment groups

Adverse events

Top of page

Timeframe for reporting adverse events

All adverse events reported during the DB, the Escape, and the OLE treatment period; up to 50 weeks

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.0

Reporting group title

Placebo

Reporting group description

Reporting group title

BI 655066 18 mg

Reporting group description

Subcutaneous injection of BI 655066 18 mg administered at Day 1 only, followed by placebo every 8 weeks (i.e. at Week 8, 16 and 24), up to a total duration of 24 weeks.

Reporting group title

BI 655066 90 mg

Reporting group description

Subcutaneous injection of BI 655066 90 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Reporting group title

BI 655066 180 mg

Reporting group description

Subcutaneous injection of BI 655066 180 mg administered every 8 weeks (At Day1 and at Weeks 8, 16, and 24) up to 4 times during the regular treatment period

Reporting group title

Escape Low

Reporting group description

Patients who received BI 655066 180 mg in the Escape treatment period and who were randomized to either Placebo or BI 655066 18 mg at Day 1 of the DB treatment period

Reporting group title

Escape High

Reporting group description

Patients who received BI 655066 180 mg in the Escape treatment period and who were randomized to either BI 655066 90 mg or BI 655066 180 mg at Day 1 of the DB treatment period

Reporting group title

Escape

Reporting group description

Patients who received escape treatments of BI 655066 180 mg regardless of the initial randomization group

Reporting group title

Open label Extension (OLE)

Reporting group description

Patients who received 180 mg BI 655066 (administered subcutaneously) every 8 weeks in OLE treatment period

Reporting group title

BI 655066 High

Reporting group description

Patients who received at least one BI 655066 90 mg or 180 mg treatment during the entire trial

Reporting group title

BI 655066 Total

Reporting group description

Patients who received at least one BI 655066 treatment at any dose level

Reporting group title

Total_all

Reporting group description

All randomised patients

Serious adverse events	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Escape Low	Escape High	Escape	Open label Extension (OLE)	BI 655066 High	BI 655066 Total	Total_all
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 40 (5.00%)	0 / 40 (0.00%)	2 / 39 (5.13%)	2 / 40 (5.00%)	1 / 47 (2.13%)	2 / 48 (4.17%)	3 / 95 (3.16%)	1 / 26 (3.85%)	9 / 138 (6.52%)	9 / 149 (6.04%)	10 / 159 (6.29%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0	0	0	0	0
Nervous system disorders
Sciatica
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	0 / 26 (0.00%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	1 / 39 (2.56%)	0 / 40 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	0 / 26 (0.00%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	0 / 26 (0.00%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Inguinal hernia
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	1 / 39 (2.56%)	0 / 40 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	0 / 26 (0.00%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	1 / 47 (2.13%)	0 / 48 (0.00%)	1 / 95 (1.05%)	0 / 26 (0.00%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Ankylosing spondylitis
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 47 (0.00%)	1 / 48 (2.08%)	1 / 95 (1.05%)	0 / 26 (0.00%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	1 / 40 (2.50%)	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	0 / 26 (0.00%)	0 / 138 (0.00%)	0 / 149 (0.00%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	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	0 / 0	0 / 0	0 / 0	0 / 0
Spondylitis
subjects affected / exposed	1 / 40 (2.50%)	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	0 / 26 (0.00%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	1 / 26 (3.85%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	0 / 39 (0.00%)	0 / 40 (0.00%)	0 / 47 (0.00%)	1 / 48 (2.08%)	1 / 95 (1.05%)	0 / 26 (0.00%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Incision site cellulitis
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	1 / 39 (2.56%)	0 / 40 (0.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	0 / 26 (0.00%)	1 / 138 (0.72%)	1 / 149 (0.67%)	1 / 159 (0.63%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	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	Placebo	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Escape Low	Escape High	Escape	Open label Extension (OLE)	BI 655066 High	BI 655066 Total	Total_all
Total subjects affected by non serious adverse events
subjects affected / exposed	21 / 40 (52.50%)	21 / 40 (52.50%)	22 / 39 (56.41%)	22 / 40 (55.00%)	10 / 47 (21.28%)	17 / 48 (35.42%)	27 / 95 (28.42%)	11 / 26 (42.31%)	85 / 138 (61.59%)	91 / 149 (61.07%)	99 / 159 (62.26%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	2 / 39 (5.13%)	0 / 40 (0.00%)	0 / 47 (0.00%)	1 / 48 (2.08%)	1 / 95 (1.05%)	0 / 26 (0.00%)	3 / 138 (2.17%)	3 / 149 (2.01%)	3 / 159 (1.89%)
occurrences all number	0	0	3	0	0	1	1	0	4	4	4
Blood creatine phosphokinase increased
subjects affected / exposed	3 / 40 (7.50%)	1 / 40 (2.50%)	2 / 39 (5.13%)	1 / 40 (2.50%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	0 / 26 (0.00%)	5 / 138 (3.62%)	5 / 149 (3.36%)	7 / 159 (4.40%)
occurrences all number	5	1	2	1	0	0	0	0	5	5	9
Injury, poisoning and procedural complications
Wound
subjects affected / exposed	0 / 40 (0.00%)	2 / 40 (5.00%)	0 / 39 (0.00%)	1 / 40 (2.50%)	0 / 47 (0.00%)	3 / 48 (6.25%)	3 / 95 (3.16%)	0 / 26 (0.00%)	5 / 138 (3.62%)	6 / 149 (4.03%)	6 / 159 (3.77%)
occurrences all number	0	2	0	1	0	3	3	0	5	6	6
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	2 / 39 (5.13%)	1 / 40 (2.50%)	0 / 47 (0.00%)	1 / 48 (2.08%)	1 / 95 (1.05%)	0 / 26 (0.00%)	4 / 138 (2.90%)	4 / 149 (2.68%)	4 / 159 (2.52%)
occurrences all number	0	0	2	1	0	1	1	0	4	4	4
Headache
subjects affected / exposed	3 / 40 (7.50%)	5 / 40 (12.50%)	3 / 39 (7.69%)	4 / 40 (10.00%)	2 / 47 (4.26%)	1 / 48 (2.08%)	3 / 95 (3.16%)	0 / 26 (0.00%)	14 / 138 (10.14%)	15 / 149 (10.07%)	17 / 159 (10.69%)
occurrences all number	3	5	3	4	2	1	3	0	14	15	17
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 40 (5.00%)	2 / 40 (5.00%)	1 / 39 (2.56%)	4 / 40 (10.00%)	1 / 47 (2.13%)	1 / 48 (2.08%)	2 / 95 (2.11%)	0 / 26 (0.00%)	9 / 138 (6.52%)	11 / 149 (7.38%)	11 / 159 (6.92%)
occurrences all number	2	2	1	4	1	1	2	0	9	11	11
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	2 / 39 (5.13%)	0 / 40 (0.00%)	0 / 47 (0.00%)	1 / 48 (2.08%)	1 / 95 (1.05%)	0 / 26 (0.00%)	3 / 138 (2.17%)	3 / 149 (2.01%)	3 / 159 (1.89%)
occurrences all number	0	0	2	0	0	1	1	0	3	3	3
Diarrhoea
subjects affected / exposed	0 / 40 (0.00%)	2 / 40 (5.00%)	1 / 39 (2.56%)	3 / 40 (7.50%)	1 / 47 (2.13%)	1 / 48 (2.08%)	2 / 95 (2.11%)	0 / 26 (0.00%)	8 / 138 (5.80%)	8 / 149 (5.37%)	8 / 159 (5.03%)
occurrences all number	0	2	1	3	1	1	2	0	8	8	8
Skin and subcutaneous tissue disorders
Eczema
subjects affected / exposed	1 / 40 (2.50%)	0 / 40 (0.00%)	2 / 39 (5.13%)	1 / 40 (2.50%)	0 / 47 (0.00%)	2 / 48 (4.17%)	2 / 95 (2.11%)	2 / 26 (7.69%)	7 / 138 (5.07%)	7 / 149 (4.70%)	7 / 159 (4.40%)
occurrences all number	1	0	2	1	0	2	2	2	7	7	7
Renal and urinary disorders
Renal colic
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	2 / 39 (5.13%)	0 / 40 (0.00%)	0 / 47 (0.00%)	1 / 48 (2.08%)	1 / 95 (1.05%)	0 / 26 (0.00%)	3 / 138 (2.17%)	3 / 149 (2.01%)	3 / 159 (1.89%)
occurrences all number	0	0	2	0	0	1	1	0	3	3	3
Musculoskeletal and connective tissue disorders
Ankylosing spondylitis
subjects affected / exposed	2 / 40 (5.00%)	1 / 40 (2.50%)	1 / 39 (2.56%)	1 / 40 (2.50%)	1 / 47 (2.13%)	5 / 48 (10.42%)	6 / 95 (6.32%)	1 / 26 (3.85%)	8 / 138 (5.80%)	9 / 149 (6.04%)	11 / 159 (6.92%)
occurrences all number	4	1	1	1	1	5	6	1	10	11	15
Arthralgia
subjects affected / exposed	4 / 40 (10.00%)	0 / 40 (0.00%)	2 / 39 (5.13%)	1 / 40 (2.50%)	0 / 47 (0.00%)	1 / 48 (2.08%)	1 / 95 (1.05%)	0 / 26 (0.00%)	6 / 138 (4.35%)	6 / 149 (4.03%)	8 / 159 (5.03%)
occurrences all number	4	0	3	1	0	1	1	0	7	7	9
Back pain
subjects affected / exposed	3 / 40 (7.50%)	3 / 40 (7.50%)	2 / 39 (5.13%)	2 / 40 (5.00%)	2 / 47 (4.26%)	1 / 48 (2.08%)	3 / 95 (3.16%)	0 / 26 (0.00%)	10 / 138 (7.25%)	12 / 149 (8.05%)	12 / 159 (7.55%)
occurrences all number	3	3	2	2	2	1	3	0	10	12	12
Plantar fasciitis
subjects affected / exposed	0 / 40 (0.00%)	1 / 40 (2.50%)	0 / 39 (0.00%)	0 / 40 (0.00%)	1 / 47 (2.13%)	0 / 48 (0.00%)	1 / 95 (1.05%)	2 / 26 (7.69%)	3 / 138 (2.17%)	3 / 149 (2.01%)	3 / 159 (1.89%)
occurrences all number	0	1	0	0	1	0	1	2	3	3	3
Infections and infestations
Bronchitis
subjects affected / exposed	1 / 40 (2.50%)	1 / 40 (2.50%)	1 / 39 (2.56%)	3 / 40 (7.50%)	1 / 47 (2.13%)	1 / 48 (2.08%)	2 / 95 (2.11%)	0 / 26 (0.00%)	8 / 138 (5.80%)	8 / 149 (5.37%)	8 / 159 (5.03%)
occurrences all number	1	2	1	3	2	1	3	0	10	10	10
Gastroenteritis
subjects affected / exposed	1 / 40 (2.50%)	1 / 40 (2.50%)	1 / 39 (2.56%)	0 / 40 (0.00%)	0 / 47 (0.00%)	1 / 48 (2.08%)	1 / 95 (1.05%)	2 / 26 (7.69%)	4 / 138 (2.90%)	5 / 149 (3.36%)	6 / 159 (3.77%)
occurrences all number	1	1	1	0	0	1	1	2	4	5	6
Influenza
subjects affected / exposed	1 / 40 (2.50%)	2 / 40 (5.00%)	2 / 39 (5.13%)	2 / 40 (5.00%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	2 / 26 (7.69%)	6 / 138 (4.35%)	7 / 149 (4.70%)	8 / 159 (5.03%)
occurrences all number	1	2	2	2	0	0	0	2	7	8	9
Nasopharyngitis
subjects affected / exposed	4 / 40 (10.00%)	7 / 40 (17.50%)	7 / 39 (17.95%)	5 / 40 (12.50%)	5 / 47 (10.64%)	5 / 48 (10.42%)	10 / 95 (10.53%)	2 / 26 (7.69%)	30 / 138 (21.74%)	32 / 149 (21.48%)	33 / 159 (20.75%)
occurrences all number	5	8	7	5	5	5	10	4	36	38	39
Sinusitis
subjects affected / exposed	1 / 40 (2.50%)	0 / 40 (0.00%)	3 / 39 (7.69%)	1 / 40 (2.50%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	0 / 26 (0.00%)	5 / 138 (3.62%)	5 / 149 (3.36%)	5 / 159 (3.14%)
occurrences all number	1	0	3	1	0	0	0	0	5	5	5
Upper respiratory tract infection
subjects affected / exposed	0 / 40 (0.00%)	2 / 40 (5.00%)	1 / 39 (2.56%)	2 / 40 (5.00%)	1 / 47 (2.13%)	1 / 48 (2.08%)	2 / 95 (2.11%)	2 / 26 (7.69%)	8 / 138 (5.80%)	8 / 149 (5.37%)	8 / 159 (5.03%)
occurrences all number	0	3	1	2	1	1	2	2	10	10	10
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	0 / 40 (0.00%)	0 / 40 (0.00%)	2 / 39 (5.13%)	1 / 40 (2.50%)	0 / 47 (0.00%)	0 / 48 (0.00%)	0 / 95 (0.00%)	1 / 26 (3.85%)	3 / 138 (2.17%)	3 / 149 (2.01%)	3 / 159 (1.89%)
occurrences all number	0	0	2	1	0	0	0	1	4	4	4

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Were there any global substantial amendments to the protocol? Yes

03 Jun 2014

3 exclusion criteria were clarified; Criterion No. 3 clarified that patients were to be excluded if they participated in trials that tested any biological immune-modulating agent; Criterion No. 10 confirmed that patients with a latent or active tuberculosis infection were to be excluded from the trial. It was specified under which conditions patients could be included if their infection had been adequately treated. Criterion No. 15 was changed to make clear that drug abuse was an exclusion criterion, however, a positive drug screening result due to consumption of prescribed drugs was not. Amendment included 4 changes to clarify the definition, the timing, and the purpose of MRI assessments. MRI assessments at Week 12 were performed only for patients who entered the Escape period. MRI assessments were also performed for patients who discontinued treatment prematurely and who were at least 8 weeks under treatment because for these patients the MRI assessments were performed as their final assessment. The time windows for MRI assessments were modified to increase operational flexibility.The blinding procedure was updated to harmonise it across the project.The evaluation of the safety parameter 'local tolerability' by the investigator was specified.The administration site of the s.c. injection was to be assessed with regard to 'swelling', 'induration', 'heat', 'redness', 'pain', or 'other findings'.The time window for the assignment of adverse events after the last treatment was changed from 16 to 15 weeks to align with the project standard.Adverse events that occurred 15 weeks after the last treatment were to be assigned to the on-treatment period.Section 4.1.5.1 describing blinding and unblinding procedures of the trial was clarified.The specification of the unconditional exact test was deleted to harmonise the statistical model for the binary endpoint on project level.TCM was replaced. Several editorial changes were made and typographical errors were corrected.

18 Jun 2014

The following inclusion criterion was deleted from the CTP: 'Serum level of CRP at screening >ULN according to the range of the central lab used in the trial’. This change was implemented, because of challenges in patient recruitment and a significant proportion of patients with a limited elevation of CRP levels.

08 Apr 2015

In this non-substantial amendment, few changes to the text were made to align the protocol with the terminology of the clinical trial protocol template, to harmonise it with the information presented in the flow charts, and to reconcile the terminology across the entire protocol.

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.

The hierarchical testing p-values are exploratory in nature, due to the study design, as the primary endpoint of study failed to meet the desired objective.

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Clinical trials

Clinical Trial Results:
A 48-week, phase II, randomized, double-blind, placebo controlled, proof of concept and dose-finding study of three different dose regimens of BI 655066 administered subcutaneously in patients with ankylosing spondylitis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of patients who achieved Assessment of Spondyloarthritis International Society (ASAS) 40 improvement criteria at Week 12.

Primary: Percentage of patients who achieved Assessment of Spondyloarthritis International Society (ASAS) 40 improvement criteria at Week 12.

Secondary: Change from baseline to Week 12 in disease activity assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS).

Secondary: Change from baseline to Week 12 in disease activity assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS).

Secondary: Percentage of patients who achieved ASAS 5/6 improvement criteria at Week 12

Secondary: Percentage of patients who achieved ASAS 5/6 improvement criteria at Week 12

Secondary: Percentage of patients who achieved partial remission according to the ASAS criteria at Week 12

Secondary: Percentage of patients who achieved partial remission according to the ASAS criteria at Week 12

Secondary: Percentage of patients who achieved ASAS 20 improvement criteria at Week 12

Secondary: Percentage of patients who achieved ASAS 20 improvement criteria at Week 12

Secondary: Change from baseline to Week 12 in disease activity assessed by BASDAI

Secondary: Change from baseline to Week 12 in disease activity assessed by BASDAI

Secondary: Percentage of patients who achieved ASAS 40 improvement criteria at Week 24

Secondary: Percentage of patients who achieved ASAS 40 improvement criteria at Week 24

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical trials

Clinical Trial Results: A 48-week, phase II, randomized, double-blind, placebo controlled, proof of concept and dose-finding study of three different dose regimens of BI 655066 administered subcutaneously in patients with ankylosing spondylitis

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of patients who achieved Assessment of Spondyloarthritis International Society (ASAS) 40 improvement criteria at Week 12.

Primary: Percentage of patients who achieved Assessment of Spondyloarthritis International Society (ASAS) 40 improvement criteria at Week 12.

Secondary: Change from baseline to Week 12 in disease activity assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS).

Secondary: Change from baseline to Week 12 in disease activity assessed by the Ankylosing Spondylitis Disease Activity Score (ASDAS).

Secondary: Percentage of patients who achieved ASAS 5/6 improvement criteria at Week 12

Secondary: Percentage of patients who achieved ASAS 5/6 improvement criteria at Week 12

Secondary: Percentage of patients who achieved partial remission according to the ASAS criteria at Week 12

Secondary: Percentage of patients who achieved partial remission according to the ASAS criteria at Week 12

Secondary: Percentage of patients who achieved ASAS 20 improvement criteria at Week 12

Secondary: Percentage of patients who achieved ASAS 20 improvement criteria at Week 12

Secondary: Change from baseline to Week 12 in disease activity assessed by BASDAI

Secondary: Change from baseline to Week 12 in disease activity assessed by BASDAI

Secondary: Percentage of patients who achieved ASAS 40 improvement criteria at Week 24

Secondary: Percentage of patients who achieved ASAS 40 improvement criteria at Week 24

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A 48-week, phase II, randomized, double-blind, placebo controlled, proof of concept and dose-finding study of three different dose regimens of BI 655066 administered subcutaneously in patients with ankylosing spondylitis