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Clinical Trial Results:
A 48 weeks study of three different dose regimens of BI 655066 administered subcutaneously in patients with moderate to severe chronic plaque psoriasis (randomised, dose-ranging, active-comparator-controlled (ustekinumab), double-blind within dose groups of BI 655066)

Summary
EudraCT number	2012-004384-48
Trial protocol	FI SE DE NO
Global end of trial date	31 Jul 2015

Results information
Results version number	v1(current)
This version publication date	14 Aug 2016
First version publication date	14 Aug 2016
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

1311.2

ISRCTN number

US NCT number

NCT02054481

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

15 Sep 2015

Is this the analysis of the primary completion data?

Yes

Primary completion date

25 Nov 2014

Global end of trial reached?

Yes

Global end of trial date

31 Jul 2015

Was the trial ended prematurely?

Main objective of the trial

The overall purpose of this trial is to assess clinical efficacy and safety of different subcutaneous doses of BI 655066 in adult patients with chronic plaque psoriasis in order to select doses for further clinical trials.

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. Rescue medication was allowed for all patients as required.

Background therapy

Evidence for comparator

Ustekinumab (Stelara®) administered by subcutaneous injection plus two saline injections at Week 0, Stelara® injection plus one saline injection at Weeks 4 and 16. Stelara® dose was 45 mg for patients with body weight ≤100 kg at randomisation or 90 mg for patients with body weight >100 kg at randomisation.

Actual start date of recruitment

26 Feb 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 37

Country: Number of subjects enrolled

Finland: 4

Country: Number of subjects enrolled

France: 30

Country: Number of subjects enrolled

Germany: 27

Country: Number of subjects enrolled

Norway: 7

Country: Number of subjects enrolled

Sweden: 6

Country: Number of subjects enrolled

United States: 120

Worldwide total number of subjects

231

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

210

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

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 strictly implemented 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

Treatment period (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Assessor, Subject

Blinding implementation details

The different dose groups of BI 655066 were double-blind. Patients, investigators, and efficacy assessors were blinded to treatment. Stelara® was open-label to investigators and blinded to patients and efficacy assessors.

Are arms mutually exclusive

Yes

BI 655066 18 mg

Arm description

18 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by two placebo matching BI 655066 injections each at Weeks 4 and 16.

Arm type

Experimental

Investigational medicinal product name

BI 655066 18 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

18 mg BI 655066 administered by subcutaneous injection at Week 0.

Investigational medicinal product name

Placebo matching BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Two placebo matching BI 655066 injections administered each at Weeks 0, 4 and 16.

BI 655066 90 mg

Arm description

90 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by 90 mg BI 655066 plus one placebo matching BI 655066 injection at Weeks 4 and 16.

Arm type

Experimental

Investigational medicinal product name

BI 655066 90 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

90 mg BI 655066 administered by subcutaneous injection at Weeks 0, 4 and 16.

Investigational medicinal product name

Placebo matching BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

2 placebo matching BI 655066 injections administered at Weeks 0 and 1 placebo matching BI 655066 injection at Weeks 4 and 16.

BI 655066 180 mg

Arm description

180 mg BI 655066 administered by subcutaneous injection as two injections plus a placebo matching BI 655066 injection at Week 0, followed by 180 mg BI 655066 administered as two injections at Weeks 4 and 16.

Arm type

Experimental

Investigational medicinal product name

BI 655066 180 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

180 mg BI 655066 administered by subcutaneous injection as two injections at Weeks 0, 4 and 16.

Investigational medicinal product name

Placebo matching BI 655066

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Placebo matching BI 655066 injection administered at Week 0.

Stelara®

Arm description

Stelara® administered by subcutaneous injection plus two saline injections at Week 0, Stelara® injection plus one saline injection at Weeks 4 and 16. Stelara® dose was 45 mg for patients with body weight ≤100 kg at randomisation or 90 mg for patients with body weight >100 kg at randomisation.

Arm type

Active comparator

Investigational medicinal product name

Stelara®

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Stelara® 45 mg or 90 mg was administered by subcutaneous injection at Weeks 0, 4 and 16.

Investigational medicinal product name

Saline injection

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Saline injection was done at Weeks 0, 4 and 16. 2 injections at Week 0 and 1 injection at Weeks 4 and 16.

Number of subjects in period 1 ^[1]	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®
Started	43	41	42	40
Completed	39	39	40	39
Not completed	4	2	2	1
Adverse event, non-fatal	1	1	-	1
Lost to follow-up	1	-	-	-
Other reasoon	2	1	2	-

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 dose of the trial medication.

Baseline characteristics

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Reporting group title

BI 655066 18 mg

Reporting group description

18 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by two placebo matching BI 655066 injections each at Weeks 4 and 16.

Reporting group title

BI 655066 90 mg

Reporting group description

Reporting group title

BI 655066 180 mg

Reporting group description

Reporting group title

Stelara®

Reporting group description

Reporting group values	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®	Total
Number of subjects	43	41	42	40	166
Age categorical
Units: Subjects
Age Continuous
Safety Set (SAF) which Included all randomised patients who received at least 1 dose of trial medication and was based on the first treatment received.
Units: Years
arithmetic mean (standard deviation)	44.1 ( 14.2 )	49.3 ( 13.3 )	44.9 ( 14 )	45.4 ( 12.1 )	-
Gender, Male/Female
Units: Participants
Female	20	11	13	13	57
Male	23	30	29	27	109

End points

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Reporting group title

BI 655066 18 mg

Reporting group description

18 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by two placebo matching BI 655066 injections each at Weeks 4 and 16.

Reporting group title

BI 655066 90 mg

Reporting group description

Reporting group title

BI 655066 180 mg

Reporting group description

Reporting group title

Stelara®

Reporting group description

Subject analysis set title

BI 655066 90+180 mg

Subject analysis set type

Full analysis

Subject analysis set description

90 mg BI 655066 or 180 mg BI 655066 administered by subcutaneous injection at Weeks 0, 4 and 16, plus matching placebos.

Primary: Achievement of ≥90% reduction from baseline PASI score (PASI90) at Week 12

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End point title

Achievement of ≥90% reduction from baseline PASI score (PASI90) at Week 12

End point description

Percentage of participants who achieved ≥90% reduction from baseline in Psoriasis Area and Severity Index score (PASI90) at Week 12. PASI score ranges from 0 (best) to 72 (worst). Full Analysis Set (FAS): Which included all randomised patients who received at least 1 dose of trial medication and was based on the randomised treatment.

End point type

Primary

End point timeframe

Baseline and Week 12

End point values	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®	BI 655066 90+180 mg
Number of subjects analysed	43 ^[1]	41 ^[2]	42 ^[3]	40 ^[4]	83 ^[5]
Units: Percentage of participants
number (confidence interval 95%)	32.6 (19.1 to 48.5)	73.2 (57.1 to 85.8)	81 (65.9 to 91.4)	40 (24.9 to 56.7)	77.1 (66.6 to 85.6)

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

Statistical Analysis 1

Statistical analysis description

The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more Tumour Necrosis Factor (TNF) antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.

Comparison groups

Stelara® v BI 655066 90+180 mg

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[6]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (net)

Point estimate

36.4

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

53.8

Notes
[6] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

Secondary: Achievement of ≥75% reduction from baseline in PASI score (PASI75) at Weeks 12 and 24

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End point title

Achievement of ≥75% reduction from baseline in PASI score (PASI75) at Weeks 12 and 24

End point description

Percentage of participants who achieved ≥75% reduction from baseline in Psoriasis Area and Severity Index score (PASI75) at Weeks 12 and 24. PASI score ranges from 0 (best) to 72 (worst).

End point type

Secondary

End point timeframe

Baseline, Week 12 and Week 24

End point values	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®	BI 655066 90+180 mg
Number of subjects analysed	43 ^[7]	41 ^[8]	42 ^[9]	40	83 ^[10]
Units: Percentage of participants
number (confidence interval 95%)
Week 12	67.4 (51.5 to 80.9)	97.6 (87.1 to 99.9)	90.5 (77.4 to 97.3)	77.5 (61.5 to 89.2)	94 (86.5 to 98)
Week 24	55.8 (39.9 to 70.9)	92.7 (80.1 to 98.5)	92.9 (80.5 to 98.5)	70 (53.5 to 83.4)	92.8 (84.9 to 97.3)

Notes
[7] - FAS
[8] - FAS
[9] - FAS
[10] - FAS

Statistical Analysis 1 (Week 12)

Statistical analysis description

The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.

Comparison groups

Stelara® v BI 655066 90+180 mg

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0355 ^[11]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (net)

Point estimate

14.6

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

28.2

Notes
[11] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

Statistical analysis 2 (Week 24)

Statistical analysis description

The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.

Comparison groups

Stelara® v BI 655066 90+180 mg

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0062 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (net)

Point estimate

21.1

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

36.2

Notes
[12] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

Secondary: Achievement of 100% reduction from baseline in PASI score (PASI100) at Week 12

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End point title

Achievement of 100% reduction from baseline in PASI score (PASI100) at Week 12

End point description

Percentage of participants who achieved 100% reduction from baseline in Psoriasis Area and Severity Index score (PASI100) at Week 12. PASI score ranges from 0 (best) to 72 (worst).

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®	BI 655066 90+180 mg
Number of subjects analysed	43 ^[13]	41 ^[14]	42 ^[15]	40	83 ^[16]
Units: Percentage of participants
number (confidence interval 95%)	14 (5.3 to 27.9)	41.5 (26.3 to 57.9)	50 (34.2 to 65.8)	17.5 (7.3 to 32.8)	45.8 (34.8 to 57.1)

Notes
[13] - FAS
[14] - FAS
[15] - FAS
[16] - FAS

Statistical Analysis 1

Statistical analysis description

The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.

Comparison groups

Stelara® v BI 655066 90+180 mg

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008 ^[17]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (net)

Point estimate

27.1

Confidence interval

level

95%

sides

2-sided

lower limit

11.3

upper limit

42.9

Notes
[17] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

Secondary: Achievement of ≥50% reduction from baseline in PASI score (PASI50) at Week 12

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End point title

Achievement of ≥50% reduction from baseline in PASI score (PASI50) at Week 12

End point description

Percentage of participants who achieved ≥50% reduction from baseline in Psoriasis Area and Severity Index score (PASI50) at Week 12. PASI score ranges from 0 (best) to 72 (worst).

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®	BI 655066 90+180 mg
Number of subjects analysed	43 ^[18]	41 ^[19]	42 ^[20]	40	83 ^[21]
Units: Percentage of participants
number (confidence interval 95%)	93 (80.9 to 98.5)	100 (91.4 to 100)	95.2 (83.8 to 99.4)	87.5 (73.2 to 95.8)	97.6 (91.6 to 99.7)

Notes
[18] - FAS
[19] - FAS
[20] - FAS
[21] - FAS

Statistical Analysis 1

Statistical analysis description

The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.

Comparison groups

Stelara® v BI 655066 90+180 mg

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0706 ^[22]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (net)

Point estimate

10.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

21.1

Notes
[22] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

Secondary: Achievement of PASI90 at Week 24

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End point title

Achievement of PASI90 at Week 24

End point description

Percentage of participants who achieved PASI90 at Week 24. PASI score ranges from 0 (best) to 72 (worst).

End point type

Secondary

End point timeframe

Week 24

End point values	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®	BI 655066 90+180 mg
Number of subjects analysed	43 ^[23]	41 ^[24]	42 ^[25]	40 ^[26]	83 ^[27]
Units: Percentage of participants
number (confidence interval 95%)	30.2 (17.2 to 46.1)	65.9 (49.4 to 79.9)	85.7 (71.5 to 94.6)	55 (38.5 to 70.7)	75.9 (65.3 to 84.6)

Notes
[23] - FAS
[24] - FAS
[25] - FAS
[26] - FAS
[27] - FAS

Statistical Analysis 1

Statistical analysis description

The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.

Comparison groups

Stelara® v BI 655066 90+180 mg

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.03 ^[28]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (net)

Point estimate

19.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.9

upper limit

37.7

Notes
[28] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

Secondary: Percentage change in PASI score from baseline at Week 12

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End point title

Percentage change in PASI score from baseline at Week 12

End point description

Percentage change in Psoriasis Area and Severity Index (PASI) from baseline at Week 12. PASI score ranges from 0 (best) to 72 (worst).

End point type

Secondary

End point timeframe

Baseline and Week 12

End point values	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®	BI 655066 90+180 mg
Number of subjects analysed	39 ^[29]	41 ^[30]	41 ^[31]	37 ^[32]	82 ^[33]
Units: Percentage of PASI score
arithmetic mean (standard deviation)	-79.7 ( 19.5 )	-93.4 ( 7.7 )	-90.7 ( 23.1 )	-82.1 ( 19.5 )	-92.1 ( 17.1 )

Notes
[29] - FAS
[30] - FAS
[31] - FAS
[32] - FAS
[33] - FAS

No statistical analyses for this end point

Secondary: Achievement of sPGA clear or almost clear at Week 12

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End point title

Achievement of sPGA clear or almost clear at Week 12

End point description

Percentage of participants who achieved static Physician Global Assessment (sPGA) clear or almost clear at Week 12. sPGA is assessed on a six-point scale from 0 (clear) to 5 (severe).

End point type

Secondary

End point timeframe

Week 12

End point values	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®	BI 655066 90+180 mg
Number of subjects analysed	43 ^[34]	41 ^[35]	42 ^[36]	40	83 ^[37]
Units: Percentage of participants
number (confidence interval 95%)	62.8 (46.7 to 77)	90.2 (76.9 to 97.3)	90.5 (77.4 to 97.3)	67.5 (50.9 to 81.4)	90.4 (81.9 to 95.7)

Notes
[34] - FAS
[35] - FAS
[36] - FAS
[37] - FAS

Statistical Analysis 1

Statistical analysis description

The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.

Comparison groups

Stelara® v BI 655066 90+180 mg

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0072 ^[38]

Method

Cochran-Mantel-Haenszel

Parameter type

Mean difference (net)

Point estimate

21.2

Confidence interval

level

95%

sides

2-sided

lower limit

5.7

upper limit

36.6

Notes
[38] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

Secondary: Time to loss of PASI50 response

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End point title

Time to loss of PASI50 response

End point description

Time to loss of PASI50 response. 99999: Summary statistics were not calculable due to low number of patients with events.

End point type

Secondary

End point timeframe

From first drug administration until end of follow-up period, up to 48 weeks.

End point values	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®	BI 655066 90+180 mg
Number of subjects analysed	43 ^[39]	41 ^[40]	42 ^[41]	40 ^[42]	83 ^[43]
Units: Days
median (confidence interval 95%)	253 (212 to 285)	99999 (99999 to 99999)	99999 (99999 to 99999)	338 (253 to 99999)	99999 (99999 to 99999)

Notes
[39] - FAS
[40] - FAS
[41] - FAS
[42] - FAS
[43] - FAS

Statistical Analysis 1

Statistical analysis description

BI 655066 treatment groups BI 90 mg + 180 mg were tested vs. Stelara® using a stratified Kaplan-Meier estimate and the log-rank test.

Comparison groups

Stelara® v BI 655066 90+180 mg

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[44]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.1844

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

0.4

Notes
[44] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

Adverse events

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Timeframe for reporting adverse events

From first drug administration until 15 weeks after the last drug administration, up to 231 days.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

18.1

Reporting group title

BI 655066 18 mg

Reporting group description

18 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by two placebo matching BI 655066 injections each at Weeks 4 and 16.

Reporting group title

BI 655066 90 mg

Reporting group description

90 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed 90 mg BI 655066 plus one placebo matching BI 655066 injection at Weeks 4 and 16.

Reporting group title

BI 655066 180 mg

Reporting group description

180 mg BI 655066 administered by subcutaneous injection as two injections plus a placebo matching BI 655066 injection at Week 0, followed 180 mg BI 655066 administered as two injections at Weeks 4 and 16.

Reporting group title

Stelara®

Reporting group description

Serious adverse events	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 43 (11.63%)	6 / 41 (14.63%)	0 / 42 (0.00%)	3 / 40 (7.50%)
number of deaths (all causes)	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	1 / 43 (2.33%)	1 / 41 (2.44%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Salivary gland neoplasm
subjects affected / exposed	0 / 43 (0.00%)	1 / 41 (2.44%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Pelvic fracture
subjects affected / exposed	1 / 43 (2.33%)	0 / 41 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 43 (2.33%)	0 / 41 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 43 (0.00%)	1 / 41 (2.44%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	0 / 43 (0.00%)	1 / 41 (2.44%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Abortion induced
subjects affected / exposed	1 / 43 (2.33%)	0 / 41 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 43 (0.00%)	1 / 41 (2.44%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	1 / 43 (2.33%)	0 / 41 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	1 / 43 (2.33%)	0 / 41 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Iron deficiency anaemia
subjects affected / exposed	0 / 43 (0.00%)	1 / 41 (2.44%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Allergy to arthropod bite
subjects affected / exposed	1 / 43 (2.33%)	0 / 41 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 43 (0.00%)	1 / 41 (2.44%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Erythema multiforme
subjects affected / exposed	1 / 43 (2.33%)	0 / 41 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 43 (0.00%)	0 / 41 (0.00%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 43 (0.00%)	0 / 41 (0.00%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perineal abscess
subjects affected / exposed	1 / 43 (2.33%)	0 / 41 (0.00%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 43 (0.00%)	0 / 41 (0.00%)	0 / 42 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	BI 655066 18 mg	BI 655066 90 mg	BI 655066 180 mg	Stelara®
Total subjects affected by non serious adverse events
subjects affected / exposed	33 / 43 (76.74%)	32 / 41 (78.05%)	29 / 42 (69.05%)	29 / 40 (72.50%)
Nervous system disorders
Headache
subjects affected / exposed	5 / 43 (11.63%)	2 / 41 (4.88%)	3 / 42 (7.14%)	4 / 40 (10.00%)
occurrences all number	6	2	3	5
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	1 / 43 (2.33%)	1 / 41 (2.44%)	3 / 42 (7.14%)	1 / 40 (2.50%)
occurrences all number	1	1	3	1
Psoriasis
subjects affected / exposed	3 / 43 (6.98%)	1 / 41 (2.44%)	0 / 42 (0.00%)	3 / 40 (7.50%)
occurrences all number	3	1	0	3
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 43 (2.33%)	2 / 41 (4.88%)	3 / 42 (7.14%)	2 / 40 (5.00%)
occurrences all number	2	2	3	2
Back pain
subjects affected / exposed	2 / 43 (4.65%)	4 / 41 (9.76%)	1 / 42 (2.38%)	1 / 40 (2.50%)
occurrences all number	2	4	1	1
Myalgia
subjects affected / exposed	0 / 43 (0.00%)	1 / 41 (2.44%)	3 / 42 (7.14%)	3 / 40 (7.50%)
occurrences all number	0	1	3	3
Infections and infestations
Folliculitis
subjects affected / exposed	3 / 43 (6.98%)	1 / 41 (2.44%)	1 / 42 (2.38%)	0 / 40 (0.00%)
occurrences all number	3	1	1	0
Gastroenteritis
subjects affected / exposed	1 / 43 (2.33%)	4 / 41 (9.76%)	0 / 42 (0.00%)	0 / 40 (0.00%)
occurrences all number	1	4	0	0
Nasopharyngitis
subjects affected / exposed	15 / 43 (34.88%)	14 / 41 (34.15%)	11 / 42 (26.19%)	5 / 40 (12.50%)
occurrences all number	19	20	17	6
Rhinitis
subjects affected / exposed	0 / 43 (0.00%)	3 / 41 (7.32%)	1 / 42 (2.38%)	1 / 40 (2.50%)
occurrences all number	0	4	1	1
Sinusitis
subjects affected / exposed	1 / 43 (2.33%)	0 / 41 (0.00%)	1 / 42 (2.38%)	4 / 40 (10.00%)
occurrences all number	1	0	1	4
Upper respiratory tract infection
subjects affected / exposed	0 / 43 (0.00%)	3 / 41 (7.32%)	1 / 42 (2.38%)	1 / 40 (2.50%)
occurrences all number	0	3	1	1

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Were there any global substantial amendments to the protocol? Yes

31 Mar 2014

Global protocol amendment 1 introduced the following key changes: 1. The inclusion criterion 8 was modified to add having vasectomized sexual partner(s) as an acceptable option of contraception for female patients. 2. Rules for blinding/unblinding of the trial team, investigators, efficacy assessors, and patients were specified. Unblinding of the trial bioanalyst and bioanalytical laboratory to support PK/ADA sample bioanalysis was introduced and blinded data reviews of PK/ADA results by the trial team were specified. 3. A restriction on the use of moisturizers/emollients containing retinoids and the use of tanning beds was introduced. Their use was not allowed as it could ameliorate psoriasis disease activity. 4. It was specified that body temperature could be measured orally or tympanically. The same BP recording instrument was to be used if possible. 5. Procedures for re-screening of patients in exceptional cases were introduced. 6. Further details on the procedure of obtaining skin biopsies were added.

25 Jun 2014

Global protocol amendment 2 allowed for a pre-randomisation call to the IRT for logistical reasons.

03 Jul 2014

Global protocol amendment 3 introduced the following key changes: 1. Rules for roll-over to the open-label extension study 1311.13 were specified 2. Exclusion criterion 4 was specified with regards to latent and active tuberculosis. Patients with latent or active TB were to continue to be excluded from the trial, but in case of a positive QuantiFERON test and documentation of adequately treated infection with no signs and symptoms of currently ongoing active or latent TB infection, the patients could have been included. 3. Exclusion criterion 11, concerning prior participation in another trial, was modified to be consistent with the restricted medication rules.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results:
A 48 weeks study of three different dose regimens of BI 655066 administered subcutaneously in patients with moderate to severe chronic plaque psoriasis (randomised, dose-ranging, active-comparator-controlled (ustekinumab), double-blind within dose groups of BI 655066)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Achievement of ≥90% reduction from baseline PASI score (PASI90) at Week 12

Primary: Achievement of ≥90% reduction from baseline PASI score (PASI90) at Week 12

Secondary: Achievement of ≥75% reduction from baseline in PASI score (PASI75) at Weeks 12 and 24

Secondary: Achievement of ≥75% reduction from baseline in PASI score (PASI75) at Weeks 12 and 24

Secondary: Achievement of 100% reduction from baseline in PASI score (PASI100) at Week 12

Secondary: Achievement of 100% reduction from baseline in PASI score (PASI100) at Week 12

Secondary: Achievement of ≥50% reduction from baseline in PASI score (PASI50) at Week 12

Secondary: Achievement of ≥50% reduction from baseline in PASI score (PASI50) at Week 12

Secondary: Achievement of PASI90 at Week 24

Secondary: Achievement of PASI90 at Week 24

Secondary: Percentage change in PASI score from baseline at Week 12

Secondary: Percentage change in PASI score from baseline at Week 12

Secondary: Achievement of sPGA clear or almost clear at Week 12

Secondary: Achievement of sPGA clear or almost clear at Week 12

Secondary: Time to loss of PASI50 response

Secondary: Time to loss of PASI50 response

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 weeks study of three different dose regimens of BI 655066 administered subcutaneously in patients with moderate to severe chronic plaque psoriasis (randomised, dose-ranging, active-comparator-controlled (ustekinumab), double-blind within dose groups of BI 655066)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Achievement of ≥90% reduction from baseline PASI score (PASI90) at Week 12

Primary: Achievement of ≥90% reduction from baseline PASI score (PASI90) at Week 12

Secondary: Achievement of ≥75% reduction from baseline in PASI score (PASI75) at Weeks 12 and 24

Secondary: Achievement of ≥75% reduction from baseline in PASI score (PASI75) at Weeks 12 and 24

Secondary: Achievement of 100% reduction from baseline in PASI score (PASI100) at Week 12

Secondary: Achievement of 100% reduction from baseline in PASI score (PASI100) at Week 12

Secondary: Achievement of ≥50% reduction from baseline in PASI score (PASI50) at Week 12

Secondary: Achievement of ≥50% reduction from baseline in PASI score (PASI50) at Week 12

Secondary: Achievement of PASI90 at Week 24

Secondary: Achievement of PASI90 at Week 24

Secondary: Percentage change in PASI score from baseline at Week 12

Secondary: Percentage change in PASI score from baseline at Week 12

Secondary: Achievement of sPGA clear or almost clear at Week 12

Secondary: Achievement of sPGA clear or almost clear at Week 12

Secondary: Time to loss of PASI50 response

Secondary: Time to loss of PASI50 response

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A 48 weeks study of three different dose regimens of BI 655066 administered subcutaneously in patients with moderate to severe chronic plaque psoriasis (randomised, dose-ranging, active-comparator-controlled (ustekinumab), double-blind within dose groups of BI 655066)